rifampin and Chemical-and-Drug-Induced-Liver-Injury

Latent tuberculosis infection (LTBI) can progress to active tuberculosis disease, causing morbidity and mortality.. To review the evidence on benefits and harms of screening for and treatment of LTBI in adults to inform the US Preventive Services Task Force (USPSTF).. PubMed/MEDLINE, Cochrane Library, and trial registries through December 3, 2021; references; experts; literature surveillance through January 20, 2023.. English-language studies of LTBI screening, LTBI treatment, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of LTBI screening and treatment for public health surveillance or disease management were excluded.. Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when a sufficient number of similar studies were available.. Screening test accuracy; development of active tuberculosis disease, transmission, quality of life, mortality, and harms.. A total of 113 publications were included (112 studies; N = 69 009). No studies directly evaluated the benefits and harms of screening. Pooled estimates for sensitivity of the TST were 0.80 (95% CI, 0.74-0.87) at the 5-mm induration threshold, 0.81 (95% CI, 0.76-0.87) at the 10-mm threshold, and 0.60 (95% CI, 0.46-0.74) at the 15-mm threshold. Pooled estimates for sensitivity of IGRA tests ranged from 0.81 (95% CI, 0.79-0.84) to 0.90 (95% CI, 0.87-0.92). Pooled estimates for specificity of screening tests ranged from 0.95 to 0.99. For treatment of LTBI, a large (n = 27 830), good-quality randomized clinical trial found a relative risk (RR) for progression to active tuberculosis at 5 years of 0.35 (95% CI, 0.24-0.52) for 24 weeks of isoniazid compared with placebo (number needed to treat, 112) and an increase in hepatotoxicity (RR, 4.59 [95% CI, 2.03-10.39]; number needed to harm, 279). A previously published meta-analysis reported that multiple regimens were efficacious compared with placebo or no treatment. Meta-analysis found greater risk for hepatotoxicity with isoniazid than with rifampin (pooled RR, 4.22 [95% CI, 2.21-8.06]; n = 7339).. No studies directly evaluated the benefits and harms of screening for LTBI compared with no screening. TST and IGRAs were moderately sensitive and highly specific. Treatment of LTBI with recommended regimens reduced the risk of progression to active tuberculosis. Isoniazid was associated with higher rates of hepatotoxicity than placebo or rifampin.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Latent Tuberculosis; Mass Screening; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Rifampin; United States

Tuberculosis (TB) remains a major global health burden. Antitubercular drugs (ATDs) such as isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol are used as first-line therapy in TB patients. Drug-induced liver injury is one of the common side effects that leads to the discontinuation of ATDs in TB patients. Therefore, this review discusses the molecular pathogenesis of ATDs induced liver injury. The biotransformation of INH, RIF, and PZA in the liver liberates several reactive intermediates, leading to peroxidation of the hepatocellular membrane and oxidative stress. INH + RIF administration decreased the expression of bile acid transporters such as the bile salt export pump and multidrug resistance-associated protein 2 and induced liver injury by sirtuin 1 and farnesoid X receptor pathway. INH inhibits the nuclear translocation of Nrf2 by interfering with its nuclear importer, karyopherin β1, thereby inducing apoptosis. INF + RIF treatments alter Bcl-2 and Bax homeostasis, mitochondrial membrane potential, and cytochrome c release, thereby triggering apoptosis. RIF administration enhances the expression of genes involved in fatty acid synthesis and hepatocyte fatty acid uptake (CD36). RIF induces the expression of peroxisome proliferator-activated receptor -γ and its downstream proteins and perilipin-2 by activating the pregnane X receptor in the liver to increase fatty infiltration into the liver. ATDs administration induces oxidative stress, inflammation, apoptosis, cholestasis, and lipid accumulation in the liver. However, ATDs toxic potentials are not elaborately studied at the molecular level in clinical samples. Therefore, future studies are warranted to explore ATDs induced liver injuries at the molecular level in clinical samples whenever possible.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Humans; Isoniazid; Pyrazinamide; Rifampin

Tuberculous meningitis (TBM) is one of the most serious types of extrapulmonary tuberculosis and has caused distress to human. Effective treatment is particularly important. The aim of this meta-analysis is to compare the efficacy of high-dose and standard-dose rifampicin.. Databases including PubMed, Web of Science, Embase, Scopus and the Cochrane Library databases were electronically searched to identify randomized controlled trials that reported high-dose rifampicin in treatment of patients with TBM. The retrieval time is limited from inception to June 2021. Two reviewers independently screened literature, extracted data and assessed risk bias of included studies. Meta-analysis was performed by using STATA 12.0 software.. A total of 12 studies involving 1596 patients were included. The meta-analysis results showed no significant differences in 6-month mortality, 9-month mortality, Grade I-II AE, Grade III-V AE, hepatotoxicity, hepatotoxicity Grade I-II and cardiologic events between high-dose rifampicin (or high-dose rifampicin plus moxifloxacin or levofloxacin) and standard-dose groups. The log(C. High-dose rifampicin was not a protective factor for 6-month mortality, despite increased plasma C

Topics: Chemical and Drug Induced Liver Injury; Humans; Levofloxacin; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Meningeal

The mainstay therapy for latent tuberculosis infection is a 9-month regimen of daily isoniazid (9H) and a 3-month regimen of 12 once-weekly doses of isoniazid and rifapentine (3HP). We performed this updated meta-analysis to compare hepatotoxicity, efficacy and completion rate between these two regimens.. We searched all literature in the major medical databases using the subject search terms "isoniazid" and "rifapentine", and performed a systemic review and meta-analysis.. A total of 14 studies were eligible for the meta-analysis, which included 5600 (49%) patients who received the 3HP regimen and 5919 (51%) patients who received the 9H regimen. A total of 202 (2%) patients had a drug-induced liver injury (DILI) and 11 317 (98%) did not. The pooled odds ratio (OR) of DILI in the 3HP regimen was 0.18 (95% confidence interval [CI], 0.12-0.26; p < 0.0001), compared with the 9H regimen. This result remained consistent in subgroup analyses of ethnicity and study design. The 3HP regimen was superior to the 9H regimen in the prevention of active tuberculosis (OR, 0.38, 95% CI, 0.18-0.80, p = 0.01). Furthermore, the 3HP regimen was associated with a better completion rate than the 9H regimen (OR: 2.30, 95% CI, 2.10-2.53, p < 0.0001).. The 3HP regimen is superior to the 9H regimen, with less hepatotoxicity, and better efficacy and completion rate in treating latent tuberculosis infection.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Latent Tuberculosis; Medication Adherence; Middle Aged; Rifampin; Young Adult

Can therapy with clindamycin and rifampicin be safely continued long term beyond the recommended 10-week course?. Clindamycin and rifampicin are used in combination to treat hidradenitis suppurativa (HS). There is no data on the efficacy and safety of clindamycin/rifampicin combination therapy for HS beyond 10 weeks.. We identified the following major concerns that still lack a proper evidenced-based analysis: for rifampicin, drug-induced liver injury, interstitial nephritis, drug interaction and hepatic p450 3A4 enzyme induction; for clindamycin, the concern was community-acquired Clostridium difficile infection (CA-CDI); and experience with long-term treatment. Data sources were used as appropriate to answer the question. Systematic searches were used to assess the risk of CA-CDI and experience with long-term treatment with clindamycin.. The risk for rifampicin-induced liver injury is highest in the first 6 weeks of treatment, whereas interstitial nephritis is primarily observed during intermittent treatment. Enzyme induction due to rifampicin is usually complete after about 2 weeks of treatment and reduces clindamycin blood levels by about 90%. Three meta-analyses identified antibiotic use as a risk factor for CA-CDI. Two of them assigned the highest risk to clindamycin. None of them stratified by length of treatment. There is extensive experience with rifampicin, primarily for the treatment of tuberculosis. Long-term experience with clindamycin is limited.. The analysed risks associated with a combination of clindamycin and rifampicin for hidradenitis suppurative cluster within the first 10 weeks. Treatment can be continued beyond 10 weeks, if clinically necessary.

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clindamycin; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Drug Therapy, Combination; Enterocolitis, Pseudomembranous; Hidradenitis Suppurativa; Humans; Meta-Analysis as Topic; Nephritis, Interstitial; Rifampin; Risk Assessment; Systematic Reviews as Topic; Time Factors

Tuberculosis (TB) remains a common cause of death globally. A regimen of 12 doses of isoniazid (INH) and rifapentine given once weekly (INH/RPT-3) has recently been recommended by the World Health Organization for the treatment of latent TB infection (LTBI). We aimed to determine whether the INH/RPT-3 regimen had similar or lesser rates of adverse events compared to other LTBI regimens, namely INH for 9 months, INH for 6 months, rifampin for 3 to 4 months, and rifampin plus INH for 3 to 4 months.. We searched MEDLINE, Embase, CENTRAL, PubMed, ICTRP, clinicaltrials.gov, and Canadian Agency for Drugs and Technologies in Health's Gray Matters Light for randomized, postmarketing, and comparative nonrandomized studies of patients with confirmed LTBI that reported the frequency of at least 1 adverse event of relevance for a regimen of interest. The search included studies published until March 2017. The frequencies of adverse events were extracted and are presented descriptively.. Data from 23 randomized and 55 nonrandomized studies were included. Although inconsistent event reporting and high heterogeneity limited comparisons, the adverse event profile of INH/RPT-3 appeared generally favorable. Flu-like reactions were reported with an increased frequency and hepatotoxicity with a lower frequency than standard treatment.. While INH/RPT-3 had an overall low frequency of adverse events compared to INH monotherapy, reporting of adverse events for many regimens was limited meaning results should be interpreted cautiously. Future studies of LTBI treatment would benefit from more complete collection and reporting of adverse events and more consistent definitions of hepatotoxicity.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Humans; Incidence; Isoniazid; Latent Tuberculosis; Respiratory Tract Diseases; Rifampin

Efavirenz (EFV) and rifampicin-isoniazid (RH) are cornerstone drugs in human immunodeficiency virus (HIV)-tuberculosis (TB) coinfection treatment but with complex drug interactions, efficacy and safety challenges. We reviewed recent data on EFV and RH interaction in TB/HIV high-burden countries.. We conducted a systematic review of studies conducted in the high TB/HIV-burden countries between 1990 and 2016 on EFV pharmacokinetics during RH coadministration in coinfected patients. Two reviewers conducted article screening and data collection.. Anti-TB drug coadministration minimally affect the EFV exposure, efficacy and safety among TB-HIV coinfected African and Asian patients. This supports the current 600 mg EFV dosing when coadministered with anti-TB drugs.

Topics: Africa; Anti-HIV Agents; Antitubercular Agents; Asia; Body Weight; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Coinfection; Cost of Illness; Cytochrome P-450 CYP2B6; Drug Interactions; Female; HIV Infections; Humans; Isoniazid; Latin America; Male; Polymorphism, Single Nucleotide; Rifampin; Sex Factors; Treatment Outcome; Tuberculosis

Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.. To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.. PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.. Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).. 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.. The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.. Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.. Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.. U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Drug Combinations; Humans; Isoniazid; Latent Tuberculosis; Network Meta-Analysis; Pyrazinamide; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Effective treatment of latent tuberculosis infection (LTBI) is an important component of TB elimination programs. Promising new regimens that may be more effective are being introduced. Because few regimens can be directly compared, network meta-analyses, which allow indirect comparisons to be made, strengthen conclusions.. To determine the most efficacious regimen for preventing active TB with the lowest likelihood of adverse events to inform LTBI treatment policies.. PubMed, EMBASE, and Web of Science up to 29 January 2014; clinical trial registries; and conference abstracts.. Randomized, controlled trials that evaluated LTBI treatment in humans and recorded at least 1 of 2 prespecified end points (preventing active TB or hepatotoxicity), without language or date restrictions.. Data from eligible studies were independently extracted by 2 investigators according to a standard protocol.. Of the 1516 articles identified, 53 studies met the inclusion criteria. Data on 15 regimens were available; of 105 possible comparisons, 42 (40%) were compared directly. Compared with placebo, isoniazid for 6 months (odds ratio [OR], 0.64 [95% credible interval {CrI}, 0.48 to 0.83]) or 12 months or longer (OR, 0.52 [CrI, 0.41 to 0.66]), rifampicin for 3 to 4 months (OR, 0.41 [CrI, 0.18 to 0.86]), and rifampicin-isoniazid regimens for 3 to 4 months (OR, 0.52 [CrI, 0.34 to 0.79]) were efficacious within the network.. The risk of bias was unclear for many studies across various domains. Evidence was sparse for some comparisons, particularly hepatotoxicity.. Comparison of different LTBI treatment regimens showed that various therapies containing rifamycins for 3 months or more were efficacious at preventing active TB, potentially more so than isoniazid alone. Regimens containing rifamycins may be effective alternatives to isoniazid monotherapy.. None.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Pyrazinamide; Rifampin

Much remains unknown about latent infection with Mycobacterium tuberculosis. Existing immunodiagnostic tools for this condition have various limitations, most importantly in their ability to predict disease. Randomised controlled trials have established protective efficacy of isoniazid therapy for 6-12 months among non-HIV-infected and HIV-infected subjects. While efficacy may reach 90%, acceptance and adherence to prolonged therapy are less than desired. Rifampicin plus pyrazinamide for 2 months, though efficacious, has been associated with excess hepatotoxicity in non-HIV-infected persons. Isoniazid plus rifampicin for 3 months has proven efficacy, but adverse effects may be more frequent than isoniazid or rifampicin monotherapy. Rifampicin monotherapy for 3-4 months is well tolerated, but efficacy data are currently limited, and concerns remain over possible selection of rifampicin-resistant mutants. For contacts of patients with multidrug-resistant tuberculosis, expert opinions differ on whether to treat with at least two drugs or just a fluoroquinolone, and for how long. With the existing diagnostic and treatment tools, efficacy of preventive therapy does not necessarily translate into field effectiveness. A targeted approach is required to maximise cost-effectiveness. Each geographic region needs to set its own priority after taking into account available scientific data and local circumstances.

Topics: Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Communicable Disease Control; Drug Design; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Mycobacterium tuberculosis; Patient Compliance; Pyrazinamide; Rifampin; Treatment Outcome

To determine the age-related risk of hepatotoxicity under currently recommended treatment regimens for latent tuberculosis (TB) infection (LTBI).. A systematic review of the MEDLINE and EMBASE databases (from database inception to 2008) was performed to determine the risk of isoniazid (INH) and/or rifampicin hepatotoxicity in LTBI treatment stratified by patient age. Study selection, study quality assessment and data extraction were performed using piloted proformas. Rate data were meta-analysed to generate summary rates with 95%CI within age-related subgroups using a random effects model.. Seven relevant studies (18,610 participants, including 115 cases of hepatotoxicity) met the selection criteria. The median rate of hepatotoxicity was 1.8% (range 0.07-11.9). On average, rates were higher among those aged ≥ 35 years (1.7%, 95%CI 1.4-2.2) than those aged <35 years (0.2%, 95%CI 0.1-0.3).. The rates of hepatotoxicity were low. Summary estimates of risks generated in this review can be used for counselling individuals for whom chemoprophylaxis is recommended. The use of INH for the treatment of LTBI is safe in older patients with clinical or biochemical monitoring.

Topics: Age Factors; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Risk Factors

The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug-induced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Incidence; Isoniazid; Liver Diseases; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

To study the incidences of adverse reactions induced by anti-tuberculosis drugs in China.. Articles about adverse drug reactions (ADR) induced by anti-tuberculosis drugs published in 1996 - 2005 in China were searched. The incidences, possible risk factors, and prognoses of these ADR were analyzed.. According to our searching strategy and including criteria, 117 studies were included. The overall incidence of anti-tuberculosis drug induced ADR of these studies was 12.62%, and the overall incidence of hepatic injury was 11.9%, which was the highest among all kinds of ADR induced by anti-tuberculosis therapy. For different types of study, different diagnostic standards of hepatic injury, and different study institutions, the reported incidences of hepatic injury varied. Retrospective cohort studies showed that HBV(+) tuberculosis patients had a significantly higher risk of hepatic injury than HBV(-) patients. The prognosis of hepatic injury was good; 85.84% patients were cured of hepatic injury according to the articles which reported outcomes. The whole study was finished by 2006.. The incidence of adverse reactions induced by anti-tuberculosis drugs is high in China. Prevention and treatment of ADR are very important for improving the adherence of patients.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; China; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Isoniazid; Liver Diseases; Rifampin; Tuberculosis

Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunogenetics; Isoniazid; Liver; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Costs and Cost Analysis; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Emigration and Immigration; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Patient Compliance; Rifampin; Time Factors; Tuberculosis; United States

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Costs; Drug Therapy, Combination; HIV Infections; Humans; Liver Function Tests; Patient Compliance; Patient Selection; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Risk Factors; Safety; Tuberculin Test; Tuberculosis

One third of the world population has been infected with Mycobacterium tuberculosis, and the number of tuberculosis will increase worldwide without more effective programs of tuberculosis control. Despite of the presence of very potent anti-tuberculosis drugs the global tuberculosis situation is still very serious, and such gloomy feature are caused, at least partly, by the failures in the treatment of tuberculosis. The most important factor for the failure in chemotherapy is incompliance of the patients to the regimens. History of the chemotherapy of tuberculosis can be said as the history of the efforts to reduce such defaulters. Modern chemotherapy of tuberculosis has started from the discovery of streptomycin. Streptomycin monotherapy could improve temporally symptoms and bacteriological status, but could not cure the patients with moderately advanced pulmonary tuberculosis because of the emerge of drug-resistant tuberculosis. This problem was overcome by combining use of para-aminosalicylate and/or isoniazid developed later on. About 97% of patients with pulmonary tuberculosis became bacteriologically quiescent by the 12 months of streptomycin, para-aminosalicylate and isoniazid. Since 1950s through 1970s three drug combination of streptomycin, para-aminosalicylate and isoniazid had been the standard regimen for the treatment of tuberculosis. By the introduction of rifampicin, the duration of chemotherapy could be shortened to 9 months. Subsequent to the successful animal experiments carried out by Grosset which demonstrated that the addition of pyrazinamide for initial 2 months to the standard two-drug combination (isoniazid and rifampicin) could remarkably shorten the duration of chemotherapy, many clinical trials have been done all over the world to compare the efficacy and safety of pyrazinamide-containing intensified short-course regimen with those of standard regimen without pyrazinamide. Sputum negative conversion rates after 2 months of treatment with PZA-regimen was 70-95%, and the relapse rates after the completion of the treatment course were less than 4%. The incidence of adverse events was less than 4%. The pyrazinamide-containing 6 months short-course regimens has been established as a new standard regimen for the initial treatment of pulmonary tuberculosis worldwide. But, in Japan, this regimen had not been adapted as the standard until April 1996 because of undue fear for high incidence of liver toxicity induced by pyrazinamide. Howev

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Risk Factors; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Biliary Tract Diseases; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Pyrazinamide; Rifampin

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Rifampin; Tuberculosis

The etiology and the pathogenesis of different forms of hepatotoxicity are discussed; case reports are included to illustrate the importance of history-taking and examination of liver tissue in establishing a specific diagnosis. The role of alcohol as a hepatotoxin as well as an enzyme-inducing agent is stressed. Genetic factors have been identified that may determine susceptibility to alcoholism and the hepatotoxic effects of alcohol and other compounds. Some cases of drug-induced cholestasis may be explained by disturbances in the known pathways of bile acid uptake, transport, and excretion. The importance of small duct destruction in patients with progressive drug-induced cholestasis is discussed. Finally, the potential hepatic complications of some nonprescription remedies used by adherents of "alternative medicine" are described, emphasizing the relevance of thorough etiological inquiry in all patients presenting with hepatic dysfunction.

Topics: Acetaminophen; Acetylcysteine; Adenoma, Liver Cell; Adult; Amoxicillin; Anabolic Agents; Beverages; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Contraceptives, Oral; Female; Humans; Isoniazid; Liver Diseases; Liver Diseases, Alcoholic; Liver Neoplasms; Male; Nonprescription Drugs; Propylthiouracil; Rifampin

Two patients with liver failure secondary to isoniazid hepatotoxicity were successfully treated with orthotopic liver transplantation. A 49-year-old man received isoniazid prophylaxis for a positive tuberculin test, and a 60-year-old woman was treated for active pulmonary tuberculosis with isoniazid, rifampin, and pyrazinamide. Both patients developed hepatic failure 4 and 1.5 months after initiation of antituberculous drug therapy, respectively. Liver transplantation was performed for progressive hepatic failure and was successful in both patients. The patient with active pulmonary tuberculosis was successfully treated with a modified antituberculous drug regimen while taking standard doses of immunosuppressive drugs after transplantation. In conclusion, liver transplantation is feasible and effective therapy for patients with isoniazid-induced hepatic failure, and active pulmonary tuberculosis may represent a relative rather than absolute contraindication to transplantation.

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Hepatic Encephalopathy; Humans; Isoniazid; Liver Failure; Liver Transplantation; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Meta-Analysis as Topic; Rifampin; Tuberculosis

Tuberculosis, once considered a problem solved, is now dramatically on the rise. New approaches to chemotherapy will hopefully help to control this again serious problem. This article reviews the current status of tuberculosis chemotherapy, including the management of drug-resistant cases.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Hearing Loss, Bilateral; Humans; Immune Complex Diseases; Isoniazid; Neuritis; Rifampin; Streptomycin

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Chloramphenicol; Erythromycin Estolate; Humans; Isoniazid; Rifampin; Tetracyclines; Troleandomycin

Topics: Acetyltransferases; Adult; Aged; Autoimmune Diseases; Biotransformation; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enzyme Induction; Female; Humans; Isoniazid; Liver; Middle Aged; Pregnancy; Rifampin

In the United States, an increasing proportion of all forms of reactivation tuberculosis occurs in patients over the age of 60 years. Atypical presentations and presence of chronic illness obscure the diagnosis of tuberculosis in the elderly. Prompt diagnosis requires a high index of suspicion and aggressive procedures for diagnostic microbiology. Short-course (9 months) chemotherapy with isoniazid and rifampin is the treatment of choice for elderly patients with uncomplicated pulmonary tuberculosis. Isoniazid chemoprophylaxis is recommended for selected elderly patients.

Topics: Aged; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Pyridoxine; Rifampin; Streptomycin; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Urogenital; United States

Topics: Aminosalicylic Acid; Antitubercular Agents; Blood-Brain Barrier; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Injections, Spinal; Isoniazid; Optic Neuritis; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Butyrophenones; Chemical and Drug Induced Liver Injury; Cholestasis; Contraceptives, Oral, Hormonal; Humans; Novobiocin; Prognosis; Rifampin; Salicylates; Steroids

Pyrazinamide, an antituberculous drug discovered in 1952, was first considered as a toxic drug. As it appeared as a bactericidal drug for the organisms inside macrophages, its usefulness has been re-appraised. In combination with other bactericidal drugs, it contributes to speed up the sterilization of tuberculous lesions. A review of the more recent clinical trials allows to assess the real toxicity of Pyrazinamide. Prescribed at a daily dosage of 30 to 35 mg/kg (1,5 to 2 g daily), it gives no major side effects.

Topics: Chemical and Drug Induced Liver Injury; Diarrhea; Drug Eruptions; Gout; Humans; Isoniazid; Nausea; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

Topics: Alcohol Drinking; Carrier State; Chemical and Drug Induced Liver Injury; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis, Pulmonary

Topics: Acetaminophen; Anabolic Agents; Androgens; Animals; Chemical and Drug Induced Liver Injury; Cysteamine; Cysteine; Erythromycin; Estrogens; Halothane; Humans; Isoniazid; Liver; Nitrofurantoin; Rifampin

Topics: Anti-Bacterial Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Enzyme Induction; Griseofulvin; Humans; Liver; Novobiocin; Rifampin

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Topics: Acetylation; Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver Function Tests; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Ampicillin; Antitubercular Agents; Asparaginase; Chemical and Drug Induced Liver Injury; Chloramphenicol; Chlortetracycline; Erythromycin; Griseofulvin; Humans; Liver Diseases; Methicillin; Oleandomycin; Oxytetracycline; Penicillins; Rifampin; Tetracycline

Topics: Adenosine Triphosphate; Age Factors; Animals; Bilirubin; Biotransformation; Carbon Isotopes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chlordiazepoxide; Chlorpromazine; Cholestasis; Dogs; Humans; Infant, Newborn; Liver; Liver Diseases; Mice; Microsomes, Liver; Phenylbutazone; Rats; Rifampin; RNA

Topics: Chemical and Drug Induced Liver Injury; Costs and Cost Analysis; Drug Eruptions; Drug Resistance, Microbial; Ethambutol; Humans; Liver; Optic Neuritis; Rifampin; Thioacetazone; Tuberculosis

Topics: Animals; Antibiotics, Antineoplastic; Antitubercular Agents; Antiviral Agents; Bacteria; Bacterial Infections; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Humans; Leprosy; Microbial Sensitivity Tests; Rifampin; Tuberculosis

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cycloserine; Drug Resistance, Microbial; Drug Synergism; Drug Tolerance; Hemorrhagic Disorders; Humans; Isoniazid; Kanamycin; Phenylthiourea; Purpura, Thrombocytopenic; Pyrazines; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Abnormalities, Drug-Induced; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Resistance, Microbial; Endocarditis, Bacterial; Gonorrhea; Humans; Intestinal Absorption; Leprosy; Meningococcal Infections; Mycobacterium; Respiratory Tract Infections; Rifampin; Thrombocytosis; Tuberculosis; Tuberculosis, Pulmonary; Urologic Diseases; Viruses

Pyrazinamide (PZA) -including regimen had not been fully recommended for late elderly patients with tuberculosis (TB) by Japanese Society for Tuberculosis until 2018. Studies on the safety of adding PZA to other first-line TB drugs for late elderly patients are limited. In this prospective randomized open-label study, we aimed to assess the safety of regimen including PZA for patients aged 80 or older. Patients in their eighties with smear-positive pulmonary TB without any liver diseases were randomly assigned to HRE (isoniazid, rifampicin, ethambutol) group or HREZ (HRE and PZA) group. The primary endpoint was discontinuation or interruption rate of treatment due to liver injury. Other endpoint included overall rate of liver injury, time to culture conversion, and overall mortality. Eighty-nine patients were assigned to either HRE group (n = 45) or HREZ group (n = 44). Clinical background was not different in two groups including age, smear grade, body weight, serum albumin, and activity degree. Discontinuation of treatment due to liver injury occurred in 15.6% of HRE group and 9.1% of HREZ group, which showed no statistical difference. Incidence of liver injury was also comparable between two groups. Overall mortality was statistically higher in HREZ group (3 in HRE vs. 10 in HREZ), although all deaths seemed to be irrelevant to PZA use. Time to culture conversion was significantly shorter in HREZ group (43.6 days vs. 30.2 days). In conclusion, regimen including PZA seems to be safe for late elderly patients with pulmonary TB.

Topics: Age Factors; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Incidence; Isoniazid; Male; Mycobacterium tuberculosis; Prospective Studies; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Anti-tuberculosis drug-induced liver injury (ATLI) is common during the treatment of tuberculosis (TB). As an important enzyme in the metabolism of many drugs, UGT2B7 (uridine diphosphate glucuronyl transferase 2B7) was associated with drug-induced liver disorder. This study investigated the association between the polymorphisms of UGT2B7 and ATLI in Chinese Han. Totally, 280 newly diagnosed TB patients had been followed up for 3 months after the prescription of anti-TB therapy. Tag-single-nucleotide polymorphism (tag-SNPs) (rs10028494 and rs7668282) were genotyped with the MassARRAY platform. The associations between tag-SNPs and ATLI risk were analyzed by logistic regression analysis adjusting for confounding factors. In this prospective study, 33 patients were lost to follow-up, and 24 patients were diagnosed with ATLI and considered as the case group. The remaining 223 subjects without ATLI were considered as the control group. No significant association was observed in allele and genotype frequencies of UGT2B7 between the two groups. This study is the first attempt to investigate the association of genetic polymorphisms of UGT2B7 with ATLI in Chinese Han. There is no significant association between UGT2B7 polymorphisms and ATLI in Chinese Han.

Topics: Adult; Antitubercular Agents; Asian People; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Genetic Predisposition to Disease; Glucuronosyltransferase; Humans; Isoniazid; Male; Middle Aged; Polymorphism, Single Nucleotide; Pyrazinamide; Rifampin; Risk; Tuberculosis, Pulmonary; Young Adult

High-dose intravenous (i.v.) rifampicin improved the outcome of tuberculous meningitis (TBM) in a previous study. Unfortunately, i.v. rifampicin is not available in many high-endemic settings. This study examined exposures to and safety of higher oral rifampicin doses compared with i.v. rifampicin. Thirty adult Indonesian TBM patients were randomised to rifampicin 750 mg (ca. 17 mg/kg) orally, 900 mg (ca. 20 mg/kg) orally or 600 mg (ca. 13 mg/kg, as used previously) i.v. over 1.5 h for 14 days, combined with other TB drugs. The pharmacokinetics of rifampicin was assessed in the critical phase of TBM treatment (≤3 days after treatment initiation) and at ≥9 days. In the first days of treatment, the geometric mean (range) plasma AUC0-24 values following rifampicin 750 mg orally, 900 mg orally and 600 mg i.v. were 131.4 (38.1-275.1), 164.8 (66.9-291.2) and 145.7 (77.7-430.2) mg⋅h/L, respectively; Cmax values were 14.3 (6.1-22.2), 16.2 (5.7-28.3) and 24.7 (13.9-37.8) mg/L. CSF concentrations correlated with plasma exposures. After ≥9 days, AUC0-24 values had decreased to 100.1, 101.2 and 94.9 mg⋅h/L. Transient grade 3 ALT increases (8/30 patients) and one grade 4 ALT increase occurred, not related to rifampicin exposure. Higher oral rifampicin doses resulted in approximately similar plasma AUC0-24 but lower plasma Cmax values compared with 600 mg i.v. over 1.5 h. Exposures to rifampicin varied substantially and decreased due to autoinduction. Liver function disturbances occurred in this severely ill population. Future studies should examine even higher rifampicin doses in TBM treatment.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Female; Humans; Indonesia; Male; Middle Aged; Plasma; Random Allocation; Rifampin; Time Factors; Tuberculosis, Meningeal; Young Adult

Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear.. To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity.. Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV.. Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors.. The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

Topics: Adult; Antitubercular Agents; Aspartate Aminotransferases; Brazil; Canada; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis C; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Multivariate Analysis; Rifampin; Risk Factors; Spain; United States

The incidence of isoniazid (INH)- and rifampicin (RIF)-induced abnormal liver enzyme activity is 27% but only 19% with INH alone. Cytochrome P450 2E1 (CYP2E1) is thought to contribute to the synergistic effects of RIF and INH. Pharmaceutical excipients are inactive ingredients that are added to a pharmaceutical compound. The purpose of this study was to screen excipients for CYP2E1 inhibition and identify whether the screened excipients prevented INH/RIF-induced hepatotoxicity.. Fifty-five known pharmaceutical excipients were screened for CYP2E1 inhibition. The hepatotoxic doses of INH and RIF were 50 and 100 mg/kg/day, respectively. Hepatotoxicity was assessed by the galactose single point (GSP) method (a US Food and Drug Administration (FDA) recommended quantitative liver function test), liver histopathology, malondialdehyde (MDA) assay, and measurement of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. We chose the CYP2E1-specific substrate chlorzoxazone to assess CYP2E1 activity in animal and human.. Mannitol inhibited CYP2E1 activity by 54% in mice with INH/RIF-induced hepatotoxicity (p < 0.005). Serum AST, ALT and GSP levels were significantly increased 3.8- to 7.8-fold in these mice (p < 0.005), and these levels could be lowered by mannitol. Mannitol significantly alleviated the depletion of hepatic glutathione (GSH) and partially reversed the increase in MDA formation in mice treated with INH/RIF (p < 0.005). Mannitol also decreased CYP2E1 activity by 58% in humans (p < 0.005). Furthermore, an antituberculosis (TB) efficacy assay revealed that mannitol did not affect the anti-TB effects of INH/RIF.. Mannitol, an FDA-approved excipient, was found to be a CYP2E1 inhibitor. Mannitol may be a useful adjuvant for drugs that induce hepatotoxicity through CYP2E1, such as INH and RIF.

Topics: Adult; Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1 Inhibitors; Drug Combinations; Excipients; Female; Humans; Isoniazid; Male; Mannitol; Mice; Mice, Inbred Strains; Microsomes, Liver; Middle Aged; Mycobacterium tuberculosis; Rats; Rats, Sprague-Dawley; Rifampin; Young Adult

To evaluate the rate of and risk factors for hepatotoxicity in tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) co-infected patients while receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and a rifampicin (RMP)-containing anti-TB regimen. We analyzed data from the N2R study which was an open label, randomized, comparative trial comparing treatment outcomes between 71 TB/HIV-1 co-infected patients receiving efavirenz (EFV)-based and nevirapine (NVP)-based ART; all of whom were receiving RMP-containing anti-TB treatment. Demographic data, liver function test, CD4 cell count, plasma HIV-1 RNA, hepatitis B surface antigen and anti-hepatitis C virus antibody were collected before initiating ART (week 0). Liver enzymes and total bilirubin levels were monitored at 6 weeks, 12 weeks and 24 weeks after ART initiation. All patients were followed until TB therapy was completed. Of 142 patients, 8 patients were excluded. Among the remaining 134 patients, the mean+/-SD age was 36.8+/-8.6 years and 67.2% were male. Severe hepatotoxicity (grade 3 or 4) developed in 4 patients (2.9%); 3 patients (4.6%) in the NVP group and 1 patient (1.4%) in the EFV group. Severe hyperbilirubinemia (grade 3 or 4) occurred in 7 patients (5.2%); 5 patients (7.7%) in the NVP group and 2 patients (2.9%) in the EFV group. Grade 1 or 2 hepatotoxicity occurred in 34 patients (31.4%). Hepatitis C virus co-infection (adjusted OR 3.03; 95%CI 1.26-7.29) was an independent risk factor associated with grade 1-4 hepatotoxicity (p=0.013). Monitoring of hepatotoxicity should be considered in TB/HIV-1 co-infected patients who are infected with HCV and receiving NVP.

Topics: Adult; Alkynes; Antibiotics, Antitubercular; Benzoxazines; Chemical and Drug Induced Liver Injury; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Hyperbilirubinemia; Liver Function Tests; Logistic Models; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Risk Factors; Thailand; Tuberculosis; Young Adult

Drug-induced hepatotoxicity (DIH) is the most common adverse drug reaction leading to interruption of antituberculosis treatment. Worldwide, different reintroduction regimens have been advocated, but no consensus guidelines are available. Reintroduction of antituberculosis drugs in patients with DIH has never been studied systematically. We aimed to compare the safety of 3 different reintroduction regimens of antituberculosis drugs in patients with antituberculosis DIH.. A total of 175 patients with a diagnosis of antituberculosis DIH were randomized to receive 1 of 3 different predefined reintroduction regimens of antituberculosis drugs and were evaluated prospectively. Patients in arm I were given isoniazid, rifampicin, and pyrazinamide simultaneously at full dosage from day 1. In arm II, drugs were administered in a manner similar to that recommended in the American Thoracic Society guidelines for reintroduction. In arm III, drugs were administered in accordance with British Thoracic Society guidelines.. Nineteen patients (10.9%) had recurrence of DIH during follow-up. Eight, 6, and 5 patients had recurrence of hepatitis in arms I, II, and III, respectively (P = .69). Of all the clinical and laboratory parameters, pretreatment serum albumin level was the only statistically significant predictor of future recurrence of DIH on reintroduction of antituberculosis drugs (P < .01).. The recurrence rate of hepatotoxicity was not significantly different between the 3 groups. According to the findings of the present study, all 3 of the potentially hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide) can be reintroduced simultaneously at full dosage safely from day 1, especially for patients with bilateral extensive pulmonary tuberculosis, to halt disease transmission or to treat patients with life-threatening tuberculosis.. ClinicalTrials.gov identifier number: NCT00405301.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

Isoniazid, rifampicin, and pyrazinamide, the first-line antituberculosis (anti-TB) drugs, are associated with hepatotoxicity.. To study the hepatoprotective effect of N-acetylcysteine (NAC) on liver injury induced by anti-TB drugs.. A randomized clinical trial was conducted on 60 new TB patients who were aged 60 years or more. Patients were randomized into two groups. In group I (n=32), drug regimen included daily doses of isoniazid, rifampicin, pyrazinamide, and ethambutol. Patients in group II (n=28) were treated with the same regimen and NAC. The patients were followed up for 2 weeks. Liver enzymes and bilirubins were measured at baseline, after 1 and 2 weeks of treatment, and whenever the patients presented with clinical symptoms of hepatotoxicity.. The mean+/-SD values of aspartate aminotransferase and alanine aminotransferase were significantly higher in group I than in group II after 1 and 2 weeks of treatment. Hepatotoxicity occurred in 12 patients with (37.5%) group I and none in group II. The mean duration of treatment before the onset of hepatotoxicity was 4.67+/-4.58 days.. NAC protects against anti-TB drug-induced hepatotoxicity.

Topics: Acetylcysteine; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Therapy, Combination; Ethambutol; Female; Free Radical Scavengers; Humans; Isoniazid; Liver; Male; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

The present study evaluated the possible protective role of Livina (a polyherbal preparation) against anti-tubercular therapy (ATT)-induced liver dysfunction in patients of pulmonary tuberculosis. Patients were given intensive phase treatment with 4-drugs (rifampicin, INH, pyrazinamide and ethambutol) used for anti-tubercular therapy for 2 months, followed by a 4-month continuous phase treatment with 2 drugs (rifampicin and INH) under clinical advice and supervision. Both qualitative and quantitative measures of liver function were assessed, at different time intervals, before and after ATT. Analysis of data showed that the incidence of qualitative manifestations of liver dysfunction were greater in the placebo treated group as compared to the test drug group. None of the patients of either group showed clinical jaundice. Most signific changes ant were observed in the SGOT and SGPT levels in the placebo group, wherein the levels of both enzymes were higher at 4 and 8 weeks post-ATT, as compared to the respective baseline (0 week) values. When Livina (2 capsules twice daily) was given with ATT drugs, incidence of qualitative manifestation of liver dysfunction was insignificant and SGOT and SGPT levels were also significantly lower than the placebo+AITT drugs treated group. These results indicate that the test drug (Livina) was efficacious, against ATT-induced hepatic dysfunction in patients of pulmonary tuberculosis.

Topics: Adolescent; Adult; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Combinations; Ethambutol; Follow-Up Studies; Humans; Liver Diseases; Liver Function Tests; Middle Aged; Phytotherapy; Plant Preparations; Plants, Medicinal; Prospective Studies; Pyrazinamide; Rifampin; Single-Blind Method; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Pharmacokinetic interactions between rifampicin and nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs) pose challenges in the treatment of TB/HIV coinfection. We describe NNRTI plasma concentrations (PC) and treatment outcomes in TB/HIV coinfected patients receiving rifampicin and NNRTIs concomitantly. Single center prospective data were collected on all TB/HIV-coinfected patients who received concomitant NNRTI and rifampicin between 2001 and 2005. Of 103 TB/HIV coinfected patients, 26 received concomitant rifampicin with efavirenz (EFV) and 17 with nevirapine (NVP). NNRTIs were commenced after rifampicin in 18/26 (69%) and 7/17 (41%) subjects treated with EFV and NVP, respectively. Of these 88% completed antituberculosis therapy. There were two (5%) deaths, both due to lymphoproliferative malignancy. Three (7%) patients transferred care or discontinued therapy. Of subjects 83% had normal liver function tests (LFTs) and 11% had Grade 1-2 and 6% Grade 3-4 LFT abnormalities during concomitant therapy. PCs were measured in 31 patients. The first PCs were within the therapeutic range in 5/7 on NVP 200 mg bd, 2/4 on NVP 300 mg bd, 3/7 EFV 600 mg od, and 7/13 on EFV 800 mg od. PCs were subtherapeutic in 4/11 (36%) and 3/20 (20%) subjects on NVP and EFV, respectively. No virological rebounds were observed. Of subjects receiving concomitant NVP or EFV with rifampicin, 64% and 80%, respectively, had therapeutic NNRTI PCs. Subtherapeutic PCs were not associated with virological failure. Good clinical outcomes and a low incidence of hepatotoxicity were observed.

Topics: Adult; Alkynes; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Benzoxazines; Chemical and Drug Induced Liver Injury; Cyclopropanes; Drug Administration Schedule; Drug Monitoring; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Prospective Studies; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis

To evaluate the ability of Curcuma longa (CL) and Tinospora cordifolia (TC) formulation to prevent anti-tuberculosis (TB) treatment (ATT) induced hepatotoxicity.. Patients with active TB diagnosis were randomized to a drug control group and a trial group on drugs plus an herbal formulation. Isoniazid, rifampicin, pyrazinamide and ethambutol for first 2 mo followed by continuation phase therapy excluding Pyrazinamide for 4 mo comprised the anti-tuberculous treatment. Curcumin enriched (25%) CL and a hydro-ethanolic extract enriched (50%) TC 1 g each divided in two doses comprised the herbal adjuvant. Hemogram, bilirubin and liver enzymes were tested initially and monthly till the end of study to evaluate the result.. Incidence and severity of hepatotoxicity was significantly lower in trial group (incidence: 27/192 vs 2/316, P<0.0001). Mean aspartate transaminase (AST) (195.93+/-108.74 vs 85+/-4.24, P<0.0001), alanine transaminase (ALT) (75.74+/-26.54 vs 41+/-1.41, P<0.0001) and serum bilirubin (5.4+/-3.38 vs 1.5+/-0.42, P<0.0001). A lesser sputum positivity ratio at the end of 4 wk (10/67 vs 4/137, P=0.0068) and decreased incidence of poorly resolved parenchymal lesion at the end of the treatment (9/152 vs 2/278, P=0.0037) was observed. Improved patient compliance was indicated by nil drop-out in trial vs 10/192 in control group (P<0.0001).. The herbal formulation prevented hepatotoxicity significantly and improved the disease outcome as well as patient compliance without any toxicity or side effects.

Topics: Adult; Antitubercular Agents; Blood Sedimentation; Body Weight; Chemical and Drug Induced Liver Injury; Curcuma; Drug Therapy, Combination; Ethambutol; Female; Hemoglobins; Humans; Isoniazid; Liver Diseases; Male; Middle Aged; Patient Compliance; Plant Preparations; Pyrazinamide; Rifampin; Tinospora; Treatment Outcome; Tuberculosis

Treatment of latent tuberculosis infection with isoniazid for 9 months is complicated by poor patient adherence and the need for close follow-up of side effects, especially hepatotoxicity. Shorter and safer regimens are needed.. To compare the frequency of adverse events and treatment completion in 2 treatment regimens for latent tuberculosis infection.. Multicenter, randomized, open-label trial.. Tuberculosis clinics located in university hospitals in Canada, Brazil, and Saudi Arabia.. 847 patients without a contraindication for rifampin and requiring treatment for latent tuberculosis infection.. Four months of daily rifampin therapy or 9 months of daily isoniazid therapy.. Grade 3 to 4 drug-related adverse events resulting in drug discontinuation (primary outcome), and on-time treatment completion, grade 1 to 2 drug-related adverse events, and changes in liver enzymes and hematologic variables (secondary outcomes).. Seventeen of 422 participants who started isoniazid therapy developed grade 3 to 4 adverse events compared with 7 of 418 who started rifampin therapy (risk difference [rifampin minus isoniazid], -2.3% [95% CI, -5% to -0.1%]; P = 0.040). Grade 3 or 4 hepatitis occurred in 16 of 422 isoniazid recipients compared with 3 of 418 rifampin recipients (risk difference, -3.1% [CI, -5% to -1%]; P = 0.003). Grade 1 or 2 adverse events attributed to study drugs occurred with similar frequency. Asymptomatic reduction in platelet and leukocyte counts were more frequent in rifampin recipients. More patients completed rifampin treatment (78%) than isoniazid treatment (60%) (difference, 18% [CI, 12% to 24%]; P < 0.001]).. The study did not measure efficacy, and the open-label design may increase the chance of bias in ascertainment of adverse events.. Treatment of latent tuberculosis with 4 months of rifampin leads to fewer serious adverse events and better adherence than 9 months of isoniazid. These findings justify a large-scale trial to compare the efficacy of rifampin with that of isoniazid.

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Humans; Isoniazid; Liver; Male; Patient Compliance; Patient Dropouts; Prospective Studies; Rifampin; Transaminases; Tuberculosis; Young Adult

The aim of this study was to assess the frequency of gastrointestinal side effects (GSE) and hepatotoxicity in patients treated with rifampicin for an osteoarticular infection and to determine if there is an association between rifampicin plasma concentrations and side effects. Rifampicin plasma concentrations were prospectively measured before (trough concentration, C(0)) and 2 +/- 0.5 h (peak concentration, C(2)) after drug intake. The presence of GSE, the alanine transferase (ALT) value, and concomitantly administered medications were recorded on the day rifampicin concentrations were measured. C(0) and C(2) were compared for differences regarding the presence or absence of side effects. Multivariate analysis was performed, with associated medications being taken into account. Seventy C(0) and 57 C(2) values were measured in 46 adults after a median treatment of 8 days (range, 1-179). Wide inter-individual variability was observed for C(0) and C(2). Thirteen (28%) patients reported GSE at least once. When GSE occurred, C(0) (median, 1 mg L(-1); range, 0.1-9.9 mg L(-1)) and C(2) (median, 10.3 mg L(-1); range, 1.8-40.3 mg L(-1)) were similar to C(0) (median, 0.6 mg L(-1); range, 0.1-10.3 mg L(-1)) and C(2) (median, 10.9 mg L(-1); range, 2.9-29.0 mg L(-1)) without GSE. The ALT value was more than normal in only three patients (6.5%) after rifampicin treatment began. The patients received no different associated medications whether or not GSE were present. Multivariate analysis showed no association between rifampicin plasma concentrations and GSE. GSE occur frequently in patients receiving rifampicin for osteoarticular infection but without an association with rifampicin plasma concentrations. Thus, therapeutic drug monitoring of rifampicin is irrelevant in the management of GSE.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Diarrhea; Digestive System; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nausea; Osteomyelitis; Pilot Projects; Prospective Studies; Rifampin; Vomiting

Rifampin and pyrazinamide are recommended for treatment of latent tuberculosis infection in adults without HIV infection, but reports of severe hepatotoxicity have raised concerns about its safety. Clinical trials have not compared this treatment with isoniazid in adults without HIV infection.. To compare the safety and tolerance of a 2-month regimen of rifampin and pyrazinamide with that of a 6-month regimen of isoniazid for treatment of latent tuberculosis infection.. Multicenter, prospective, open-label trial.. Three urban public health tuberculosis clinics in the United States.. 589 adults with latent tuberculosis infection who met U.S. criteria for treatment.. Patients were assigned in alternate weeks to receive rifampin and pyrazinamide daily for 2 months (n = 307) or isoniazid daily for 6 months (n = 282).. Primary end points were hepatotoxicity, other adverse events, and percentage of patients who completed treatment.. Sixteen of 207 (7.7%) patients assigned to rifampin and pyrazinamide developed grade 3 or 4 hepatotoxicity compared with 2 of 204 (1%) patients assigned to isoniazid (odds ratio, 8.46 [95% CI, 1.9 to 76.5]; P = 0.001). The rifampin plus pyrazinamide regimen was more likely than the isoniazid regimen to be discontinued because of hepatotoxicity (odds ratio, 5.19; P = 0.033). The overall percentage of nonhepatotoxic adverse events was 20% in the rifampin-pyrazinamide group and 16% in the isoniazid group. The proportion of patients who completed the study treatment was 61% and 57%, respectively.. A 2-month regimen of rifampin and pyrazinamide was associated with an increased risk for grade 3 or 4 hepatotoxicity compared with a 6-month regimen of isoniazid. Liver enzymes should be measured routinely during treatment to screen for liver injury and prevent progression to severe toxicity.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Liver Function Tests; Male; Prospective Studies; Pyrazinamide; Rifampin

Standard chemotherapy for tuberculosis (TB) in children uses hepatotoxic drugs. Published data and guidelines on monitoring of liver function during TB treatment are often contradictory and not directly relevant to the pediatric population. We carefully monitored 43 children (age 6.6 years, 0.7-15.1 [median, range]; 49% male; 72% Caucasian) being treated for TB infection (n = 8) or disease (n = 35) with triple therapy, using pyrazinamide, rifampicin, and isoniazid in standard recommended doses. Children on other hepatotoxic drugs were excluded. Measurements of liver function tests (LFT) included aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin, and they were checked before and a median of 5 times (1-23) during treatment. Only one child had mildly abnormal LFTs pretreatment. Thirteen children (n = 13, [30%]; age 7.6 years, 1.8-10.9; 54% male; 77% Caucasian) developed abnormal LFTs (> mean + 2 SD) and of these 10 had TB disease. Eight of the 13 had mildly elevated enzymes (< twice upper limit of normal) while in five, all with disease, the enzymes were more markedly raised. In the group with normal LFTs (n = 30, [70%]; age 6.6 years 0.7-15.1; 47% male; 70% Caucasian) 25 had disease (83%). Liver enzyme elevation occurred early (1.65 weeks, 0.6-16.6). Only two children had symptoms (one jaundice, one pruritus) with treatment being stopped temporarily only in the jaundiced child. Otherwise, LFTs normalized without interrupting treatment. We conclude that elevated liver enzymes are not uncommon in children receiving triple therapy for TB, generally occurring early in treatment. Symptoms are rare. Current British Thoracic Society and American Thoracic Society guidelines (that if LFTs are normal prior to treatment then further monitoring should only be performed if clinically indicated) seem adequate for children.

Topics: Adolescent; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Liver; Liver Function Tests; Male; Monitoring, Physiologic; Prognosis; Pyrazinamide; Rifampin; Tuberculosis

Antituberculosis drug-induced hepatotoxicity is quite common. However, factors predicting its development are still controversial. The objective of the present study was to evaluate the role of certain factors (age and sex of the patient, alcoholism, chronic liver disease, hepatitis B virus carrier status, acetylator status, nutritional status and antituberculosis treatment (ATT) regimen) in predicting the development of ATT-induced hepatitis. In a case-control study, 60 consecutive patients with evidence of ATT-induced hepatitis were studied to assess the possible association of the above-mentioned factors with ATT-induced hepatitis. Body mass index was found to be significantly lower in ATT-induced hepatitis patients (17.2 +/- 2.7) than in controls (19.5 +/- 3.3) (p < 0.05). Pyrazinamide was used in addition to isoniazid and rifampicin in a significantly higher percentage of patients in the ATT-induced hepatitis group (70%) as compared with those in the control group (42%). No significant differences were observed between the two groups with regard to the rest of the parameters.

Topics: Adolescent; Adult; Antitubercular Agents; Body Mass Index; Case-Control Studies; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Male; Middle Aged; Nutrition Disorders; Pyrazinamide; Rifampin

In order to assess the potential additive liver toxicity of isoniazid to that of a thioamide-containing treatment, a prospective, randomized, double-blind trial of 24 weeks' duration involving 772 adult patients was conducted in four leprosy centers--two in India, one in Madagascar, and one in the Ivory Coast. Patients with multibacillary leprosy were given daily 100 mg dapsone (DDS) and 350 mg prothionamide (PTH) plus monthly 600 mg rifampin (RMP) in combination either with 350 mg isoniazid (INH) or with a placebo. After clinical and laboratory (including HBs-Ag testing) examinations on admission, the side effects (especially gastrointestinal disturbances and liver toxicity) were assessed at regular intervals during treatment by laboratory testing (aminotransferases, bilirubin, alkaline phosphatase) and by recording spontaneous complaints. Analysis of the frequency and seriousness of the side effects was made before breaking the code (with or without INH). Although 10% of the patients had liver toxicity leading to stopping treatment, no significant difference in the occurrence of side effects was observed between patients treated with or without INH. Most (75%) of the observed side effects occurred during the first 4 weeks of treatment, and the time of their onset was not related to INH. Body weight and age were factors related to the frequency of side effects [the higher the body weight, the lesser the rate of side effects (p = 0.03)] and the rate of serious side effects increased with age (p = 0.02). But, again, the frequency of the side effects was not related to INH administration. Therefore, from the present study it can be concluded that INH does not increase the toxicity of the thioamide-containing treatment.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Dapsone; Double-Blind Method; Drug Combinations; Female; Humans; Incidence; Isoniazid; Leprostatic Agents; Leprosy, Lepromatous; Liver Function Tests; Male; Middle Aged; Prospective Studies; Prothionamide; Rifampin

A controlled comparison of 3 short-course regimens was undertaken in patients with newly diagnosed, sputum-positive, pulmonary tuberculosis in South India. The regimens were: R3: rifampin plus streptomycin plus isoniazid plus pyrazinamide daily for 3 months; 5: the same as regimen R3 followed by streptomycin plus isoniazid plus pyrazinamide twice weekly for 2 months; Z5: the same as regimen R5 but without rifampin. The distributions of various pretreatment characteristics were similar in the 3 series. At the end of treatment, 6 patients (3 R3, 3 Z5) of 694 (228 R3, 230 R5, 236 Z5) with drug-sensitive organisms initially were classified as having an unfavorable response. By 24 months (21 months of follow-up for the R3 regimen and 19 months for the R5 and Z5 regimens), a bacteriologic relapse requiring treatment occurred in 20% of 200 R3, 4% of 187 R5, and 13% of 199 Z5 patients, the difference between the R3 and R5 series being highly significant (p = 0.00001). Considering patients with cultures initially resistant to isoniazid, 4 of 57 in the R3 and R5 series combined had an unfavorable response to treatment compared with 13 of 26 in the Z5 series (p less than 0.0001). Of the 4 patients with an unfavorable response in the R3 and R5 series combined, resistance to rifampin emerged in 2. Complaints of arthralgia were made by 45% of the R3 and R5 patients combined and 70% of the Z5 patients (p less than 0.00001). However, chemotherapy was modified in only 5 and 12%, respectively. Jaundice occurred in 7% of the R3 and R5 patients and 1% of the Z5 patients (p less than 0.00001).

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dizziness; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; India; Isoniazid; Joint Diseases; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

190 patients with positive cultures for M. tuberculosis were treated in the initial phase as inpatients for 2-3 months at random with either pyrazinamide (Z) or ethambutol (E) in combination with isoniazid (H) and rifampicin (R). In the continuation phase as out-patients they were treated by their family doctor for a further seven months with a new randomization using either R or E combined with H. Regular controls of drug intake using urine test strips were 97% positive. The patients treated with Z showed a tendency to more rapid conversion to negative cultures despite the significantly shorter duration of initial-phase treatment. During the average observation period of 33 months after commencing therapy there were five relapses (without development of drug resistance). The distribution over the four patient groups did not allow statistical conclusions to be drawn. All of the relapses occurred during the first year after the treatment ended. All relapsing patients showed an unusually long delay (108 days) before the tuberculosis cultures proved negative, in comparison with only 48 days in all patients. The relapse rate of 3.6% equals comparable controlled studies in the literature of the last four years, in which patients were initially hospitalized for two months or received medication under direct supervision as out-patients. The family doctors treated their patients on average for ten months instead of the nine months recommended in the treatment scheme ("doctor's compliance"). This seems to be a direct consequence of the earlier recommendations in favour of a longer duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Prospective Studies; Pyrazinamide; Random Allocation; Rifampin; Tuberculosis, Pulmonary

During treatment of multibacillary leprosy with the combination rifampin (RMP) 600 mg, ethionamide (ETH) 500 mg, and either dapsone (DDS) or clofazimine (CLO) 100 mg, hepatotoxicity was observed in 4.5% of 596 patients. Hepatitis appeared after 5-186 days, with a mean of 93 days and a median of 76 days. Mortality was 26%. ETH and DDS or CLO were administered daily in all regimens in which hepatitis occurred. RMP was given either daily or daily during the first two weeks or eight weeks, followed by a once-weekly dose. It is concluded that the combination RMP + ETH is the toxic component. In some patient groups there was a high correlation of toxicity with age. A regimen in which RMP was administered only twice a week during three months was not accompanied by hepatotoxicity. Future studies should show if reduction of the daily dose of ETH or reduction of the duration of the administration of RMP + ETH might reduce the incidence of hepatotoxicity while conserving the efficacy.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Female; Humans; Leprosy; Male; Middle Aged; Prospective Studies; Rifampin

In a multicenter trial of 2 regimens for treatment of pulmonary tuberculosis, all patients received 300 mg of isoniazid (INH) and 600 mg of rifampin (RIF) daily for 6 months (the Initial Phase). During the next 9 months (the Maintenance Phase) patients received either daily INH (300 mg) and ethambutol (EMB) (15 mg per kg body weight) or matching placebos. Of the 672 patients who met the admission criteria, only 309 (46%) completed the Initial and Maintenance Phases. Approximately 20% of the patients failed to keep their appointments. Adverse drug reaction, most commonly hepatotoxicity, accounted for the withdrawal of 37 patients (5.5%). No visual toxicity caused by EMB was observed. During the Maintenance Phase, 3 patients who were taking INH and EMB, and 16 who were taking placebos, developed relapses, i.e., 2 or more positive cultures. The significant difference in relapse rate between regimens (Fisher's exact test, p less than 0.001) demonstrates the inadequacy of INH-RIF given alone for only 6 months.

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Random Allocation; Rifampin; Tuberculosis, Pulmonary; United States

Recent experience suggests that the duration of chemotherapy of tuberculosis can be shortened to 6-9 months, without an increase in the relapse rate, if the treatment if started with 3 or 4 drugs including isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA). In a controlled study of culture-positive advanced pulmonary tuberculosis we have compared treatment regimens with PZA in a dosage of less than 2 g and with ethambutol (EMB). 113 patients were given, in random order for 2-3 months, either PZA (25 mg/kg body weight) or EMB (25 mg/kg) together with RMP (450 or 600 mg) and INH (5 mg/kg). The last two drugs were given for a total of 9 months. Patients treated with PZA showed a (not significantly) earlier conversion to negative cultures after an average of 7 weeks. After 18 months follow-up there have been no relapses on these regimens. 2 patients, both treated with EMB, did not respond to therapy. Drug-induced hepatitis was seen in 5 patients with PZA and in 2 patients with EMB. The hepatitis was always observed during the first month of therapy and was fully reversible. Three of the 4 patients with clinically apparent hepatitis were over 70 years of age. Three patients with elevated uric acid levels had arthralgia which led in one of them to termination of therapy. The preliminary results of our study show that the treatment regimen with PZA does not lead to a higher rate of side effects if used with particular moderation in older patients.

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Arkansas; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

An analysis is presented of the side effects which occurred in 530 patients treated with 6 months chemotherapy for newly detected pulmonary tuberculosis. Five treatment regimens were used. The initial phase of treatment consisted of daily isoniazid, rifampicin and ethambutol (HRE) or isoniazid, rifampicin, streptomycin and pyrazinamide (HRSZ) given for 2 months. The second phase of treatment consisted of isoniazid and rifampicin given twice weekly (H2R2) or isoniazid, rifampicin and ethambutol given daily (4HRE) or intermittently (H1R1E1 or H2R2E2) for 4 months. Side effects were detected in 66 (12.4%) patients. Hepatotoxic reactions occurred in 48 (9%) patients, mainly of amild and transient nature and the majority were attributable to isoniazid. The 'flu like' syndrome occurred in only 2 patients both during the daily phase of treatment, and it was not encountered in patients taking rifampicin intermittently (dose 600 mg). Inclusion of pyrazinamide in the initial phase of 1 regimen did not result in an increase of frequency of side effects. In 56% of patients on pyrazinamide the serum uric acid concentration was elevated but there was no arthralgia. Drug toxicity leading to alteration or withdrawal of treatment occurred in only 10 (1.8%) patients. This study shows that with these 6 month regimens the overall risk of drug toxicity was low, and less than that associated with more conventional treatment regimens.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

A history of alcoholism is often regarded as a relative contraindication to the use of isoniazid and rifampin in patients with tuberculosis. To test the validity of this assumption the outcome of 6 months of rifampin-isoniazid therapy was analyzed for the first 531 eligible patients enrolled in a U.S. Public Health Service Cooperative Trial of Short-Course Chemotherapy of Pulmonary Tuberculosis. In this study, data were available to classify a patient as an alcoholic in the following 2 ways: (1) patient's statement that he was a moderate, heavy, or excessive user of alcohol, or (2) patient's score of 6 or more on a Brief Michigan Alcoholism Screening Test (MAST). Based on their statements, 58% of the patients were classified as alcoholic, whereas only 17.9% were thus classified by their MAST scores. Although alcoholics had more abnormal concentrations of aspartate aminotransferase (AST) before and during therapy, there was no significant difference between the alcoholics and non-alcoholics in the incidence of adverse reactions, including hepatotoxic reactions, including hepatotoxic reactions, attributed to the drugs. We concluded that in the absence of clinically significant and persistent pretreatment abnormalities of hepatic function tests, rifampin and isoniazid are not contraindicated in patients categorized as alcoholic by our 2 commonly used methods.

Topics: Alcoholism; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver; Rifampin; Tuberculosis, Pulmonary

A total of 822 patients with newly diagnosed pulmonary tuberculosis were assigned randomly to one of 3 daily rifampin-isoniazid (RIF-INH) regimens: 450, 600, or 750 mg of RIF in combination with 300 mg of INH. After an initial 20 weeks of therapy with RIF-INH, patients recieved 300 mg of INH and 15 mg of ethambutol (EMB) per kg of body weight for either 12 or 18 months after their sputum cultures became negative. The rate of bacteriologic conversion of sputum among the 3 RIF-INH regimens was compared for 552 patients who completed the 20 weeks of RIF-INH therapy. Apporximately 60 per cent of these patients also completed their assigned INH-EMB therapy and were examined for relapse for at least one year after therapy was stopped. There was no significant difference in the rate of sputum conversion or rate of relapse between the group of patients who received 600 mg of RIF and those who received 750 mg of RIF. However, the 450-mg RIF regimen was significantly less effective than the other 2 regimens, as manifested by a lower rate of sputum conversion and a higher rate of treatment failures. Further analysis showed that RIF dosages of less than 9 mg per kg of body weight per day may be inadequate for treatment of pulmonary tuberculosis. The acceptability of these regimens was high, and the incidence of adverse reactions requiring discontinuation of RIF-INH therapy was quite low (3.3 per cent). A large proportion of patients (44 per cent) developed increased concentrations of transaminase during therapy with RIF-INH. These abnormalities were usually transient and, in most cases, of no clinical significance. In the relapse analysis, 12 months of chemotherapy after sputum conversion was shown to be as effective as 18 months of therapy after conversion of these RIF-containing regimens.

Topics: Adolescent; Adult; Aged; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Evaluation; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Recurrence; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary; United States; United States Public Health Service

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Topics: Acetylation; Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver Function Tests; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Alanine Transaminase; Alcoholism; Alkaline Phosphatase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Gastrointestinal Diseases; Humans; Isoniazid; Mycobacterium tuberculosis; Phenylthiourea; Pyridoxine; Recurrence; Rifampin; Streptomycin; Thrombocytopenia; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Radiography; Rifampin; Skin Diseases; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary; United Kingdom

This paper reports the nature, incidence, and severity of adverse reactions to regimens of rifampicin and ethambutol given once weekly, twice weekly, or daily and to a standard reserve regimen in a total of 330 Chinese failure patients who completed at least six months' chemotherapy in a therapeutic comparison in Hong Kong.The adverse reactions which occurred on the regimens of intermittent rifampicin were termed cutaneous, abdominal, "flu", and respiratory; in addition, purpura and abnormal liver function tests were encountered. There was an association of adverse reactions with the interval between doses and with the dose size of rifampicin, the highest incidence occurring with once-weekly rifampicin in high dosage. A procedure was developed for managing adverse reactions to intermittent rifampicin. Of 202 patients treated with intermittent rifampicin 60 developed adverse reactions, but in only 7 (3%) was it necessary to terminate the drug, though a further 10 (5%) were changed to daily rifampicin. On daily rifampicin, generalized hypersensitivity, cutaneous reactions, (one with purpura), and impaired liver function were encountered. Adverse reactions on the standard ethionamide, pyrazinamide, and cycloserine regimen were frequent and some were serious.

Topics: Alanine Transaminase; Antitubercular Agents; Bone Diseases; Chemical and Drug Induced Liver Injury; Colic; Drug Eruptions; Dyspnea; Ethambutol; Fever; Hong Kong; Humans; Jaundice; Purpura; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Aged; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Female; Finland; Hearing Disorders; Humans; Kidney Diseases; Male; Middle Aged; Pneumothorax; Rifampin; Tuberculosis, Pulmonary; Vision Disorders

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Ethambutol; Exanthema; Humans; Norway; Rifampin; Vestibule, Labyrinth; Vision Disorders

Topics: Adult; Aged; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Eosinophilia; Ethambutol; Female; Gastrointestinal Diseases; Humans; Kidney Diseases; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary; Uric Acid; Vision Disorders

Observational study indicated that folic acid (FA) supplementation may protect against tuberculosis-drug-induced liver injury (TBLI). The aim is to investigate the effect and mechanism of FA on TBLI in rats. Liver injury was induced by a daily gavage of isoniazid (INH) and rifampicin (RIF) in the model and FA groups. Rats in the FA group were also treated with 2.5 mg/kg body weight FA. Rats in the control group were not treated. Eight rats were used in each group. The severity of liver injury was measured by the serum levels of hepatic enzymes and histological score. The metabolites in serum and liver tissues were analyzed by HPLC-Q-TOF-MS/MS. FA treatment significantly reduced alanine aminotransferase and liver necrosis. Seventy-nine differential metabolites in the serum and liver tissues were identified among the three groups. N-acylethanolamines, INH and RIF metabolites, phosphatidylcholines, lysophosphatidylcholines, monoglycerides, diglycerides and bile acids were regulated by FA treatment, involving key metabolic pathways, such as N-acylethanolamine metabolism, INH and RIF metabolism, liver regeneration, inflammation alleviation and bile acid metabolism. RT-PCR and western blotting results confirmed the altered N-acylethanolamine metabolism and improved drug metabolism by FA. In conclusion, FA was protective against TBLI, which may be related to the regulation of N-acylethanolamine metabolism and drug detoxification by FA.

Topics: Animals; Chemical and Drug Induced Liver Injury; Liver; Metabolomics; Rats; Rats, Wistar; Rifampin; Tandem Mass Spectrometry; Tuberculosis

Rhus chinensis Mill. is a species of the genus Rhus belonging to the family Anacardiaceae. Its fruits used to treat/prevent liver related diseases (e.g., jaundice and hepatitis) in folk medicine. Otherwise, the effects and underlying mechanisms of the fruits on the prevention of isoniazid and rifampicin-caused liver injury have not been investigated.. To study the preventive effects and mechanisms of the Rhus chinensis Mill. fruits on isoniazid and rifampicin-caused liver injury.. This experiment was based on rifampicin (75 mg/kg/day) and isoniazid (75 mg/kg/day)-induced liver damage model to explain the pharmacological effects of Rhus chinensis Mill. fruits. The prevention of the extract from Rhus chinensis Mill. fruits on isoniazid and rifampicin-caused liver injury were evaluated using biochemical parameters, histopathological analysis, and immunofluorescence technique. Apart from that, the potential molecular mechanisms were elucidated by analyzing the expression of such crucial proteins participated in oxidative stress, apoptosis, and bile acid transport.. The extract from Rhus chinensis Mill. fruits significantly reduced the levels of ALT, AST, TBIL, ALP and MDA. Besides, the extract, especially 800 mg/kg b.w., was remarkably decreased the content of TNF-α,IL-6 and IL-1β, restored the levels of GSH and SOD. The results of Western blot also presented that the extract could activate the Nrf2 protein pathway and inhibit the expression of CYP2E1 to reduce oxidative stress. Meanwhile, the extract significantly up-regulated the expressions of BSEP and Mrp2 to regulate the transport of bile acid, and alleviated the cellular apoptosis via adjusting the expression of Bax and Bcl-2 proteins.. Rhus chinensis Mill. fruits can prevent the liver injury induced by isoniazid and rifampicin in mice through adjusting the expressions of multiple proteins in oxidative stress, apoptosis, and bile acid transport pathways. This paper may provide scientific basis for the fruits as a Chinese medicine to prevent/cure liver injury.

Topics: Animals; Apoptosis; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Fruit; Isoniazid; Liver; Mice; Oxidative Stress; Rhus; Rifampin

In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)- and isoniazid (INH)-induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen-activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4-desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH-induced liver injury.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Inflammation; Isoniazid; Liver; Mice; Mitogen-Activated Protein Kinases; Rifampin

Bergenin (BER), a natural component of polyphenols, has a variety of pharmacological activities, especially in improving drug metabolism, reducing cholestasis, anti-oxidative stress and inhibiting inflammatory responses. The aim of this study was to investigate the effects of BER on liver injury induced by isonicotinic acid hydrazide (INH) and rifampicin (RIF) in mice. The mice model of liver injury was established with INH (100 mg/kg)+RIF (100 mg/kg), and then different doses of BER were used to intervene. The pathological morphology and biochemical indicators of mice were detected. Meanwhile, RNA sequencing was performed to screen the differentially expressed genes and signaling pathways. Finally, critical differentially expressed genes were verified by qRT-PCR and Western blot. RNA sequencing results showed that 707 genes were significantly changed in the INH+RIF group compared with the Control group, and 496 genes were significantly changed after the BER intervention. These differentially expressed genes were mainly enriched in the drug metabolism, bile acid metabolism, Nrf2 pathway and TLR4 pathway. The validation results of qRT-PCR and Western blot were consistent with the RNA sequencing. Therefore, BER alleviated INH+RIF-induced liver injury in mice. The mechanism of BER improving INH+RIF-induced liver injury was related to regulating drug metabolism enzymes, bile acid metabolism, Nrf2 pathway and TLR4 pathway.

Topics: Animals; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Isoniazid; Liver; Mice; NF-E2-Related Factor 2; Rifampin; Toll-Like Receptor 4

Rifampicin-induced hepatotoxicity is a primary cause of drug-induced liver injury (DILI), posing a significant challenge to its continued clinical application. Moreover, the mechanism underlying rifampicin-induced hepatotoxicity remains unclear.. Human hepatocyte line-17 (HHL-17) cells were treated with an increasing dose of rifampicin for 24 h, and male Wistar rats were given rifampicin [150 mg/kg body weight (bw)] orally for 28 days. Viability assay, protein expression, and cell death assays were analyzed in vitro. Moreover, liver serum markers, body/organ weight, H&E staining, protein expression, etc., were assayed in vivo.. Rifampicin induced a dose-dependent hepatotoxicity in HHL-17 cells (IC. Rifampicin-induced hepatotoxicity involves ER stress-driven paraptosis as a novel mechanism of its toxicity that may be targeted to protect liver cells from rifampicin toxicity.

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum Stress; Humans; Male; Rats; Rats, Wistar; Reactive Oxygen Species; Rifampin

Anti-tuberculosis drugs are reported to cause hepatotoxicity, which varies from asymptomatic rise of the hepatic enzymes. Hepatoprotective plants plays important role to protect liver. This study investigated the hepatoprotective potential of the Solanum lycopersicum in rats intoxicated with Isoniazid and Rifampicin (INH+RIF) to induce hepatotoxicity. Thirty wistar albino rats were divided into five groups of six animals each. Group 1 rats were kept control while groups II, III, IV and V were administered with INH+RIF (75+150 mg/kg) orally, for seven consecutive days. For treatment, rats in group III received silymarin while animals in group IV and V were provided with 40 mg/kg and 80 mg/kg of Solanum lycopersicum extract, respectively. On day 0 and 8th blood samples were collected for the analysis of hepatic biomarkers. The data were subjected to one-way ANOVA and Bonferroni's post hoc test for statistical analysis. Hepatotoxicity induced by INH+RIF resulted in significant elevation of serum hepatic enzymes including Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and total bilirubin while decreased the albumin level. The Solanum lycopersicum at dose of 80 mg/kg significantly reduced the hepatic enzymes AST, ALT, ALP and bilirubin while the albumin level was significantly increased. The treatment had non-significant effect on body and liver weight. Drug induced hepatotoxicity can be effectively treated with Solanum lycopersicum at 80 mg/kg dose.

Topics: Animals; Chemical and Drug Induced Liver Injury; Isoniazid; Plant Extracts; Rats; Rats, Wistar; Rifampin; Solanum lycopersicum

Hepatotoxicity is a well-known adverse effect of many substances, with toxicity often resulting from interactions of drugs with other drug-like substances. With the increased availability of complementary and alternative medicines, including herbal medicines, the likelihood of adverse interactions between drugs and drug-like substances in herbs increases. However, the impact of potential herb-herb interactions is little understood. To assess the potential of two cytochrome P450 enzyme modulating phytochemicals common to many herbal medicines, atractylenolide I (ATR-I) and astragaloside IV (AST-IV), to interact with coumarin, another phytochemical common in many foods, a hepatocyte function model with a liver carcinoma cell line, HepG2, was exposed to these agents. To determine the effects of cytochrome P450 modulation by these phytochemicals certain cells were induced with rifampicin to induce cytochrome P450. Increasing concentrations of ATR-I combined with a fixed, nontoxic concentration of coumarin (200 µM), demonstrated significant additive interactions. 300 µM ATR-I produced a 31% reduction in cell viability (

Topics: Chemical and Drug Induced Liver Injury; Coumarins; Cytochrome P-450 Enzyme System; Herb-Drug Interactions; Humans; Lactones; Phytochemicals; Polypharmacy; Rifampin; Saponins; Sesquiterpenes; Triterpenes

Anti-tuberculosis drugs-induced liver injury may be associated with the hepatic farnesoid X receptor (FXR). However, the relationship between isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) coadministration-induced liver injury and FXR has not been clarified. The purpose of this study was to clarify the role of FXR in HRZE-induced liver injury. To measure indices of liver injury, blood samples were collected from clinical tuberculosis patients who had taken HRZE for approximately two months; in these patients serum total bile acids were increased, while other hepatic biochemical indexes showed no significant changes. When Wistar rats were orally administered isoniazid (30 or 60 mg/kg) + rifampicin (45 or 90 mg/kg) + pyrazinamide (150 or 300 mg/kg) + ethambutol (75 or 150 mg/kg) in combination for 15 days, the expression and function of FXR was up-regulated, and hepatic bile acids were decreased. However, following 30 days of HRZE treatment the expression and function of FXR was down-regulated and bile acids accumulated in the liver, suggestive of hepatotoxicity. Treatment of HepaRG cells with HRZE lead to time- and dose- dependent cytotoxicity, with the expression of FXR up-regulated in early stage, but down-regulated with prolonged HRZE treatment, consistent with the results of animal experiments. In summary, HRZE may upregulate FXR with short-term administration, but more prolonged treatment appears to suppress FXR function, resulting in hepatic bile acid accumulation.

Topics: Animals; Antitubercular Agents; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Ethambutol; Isoniazid; Liver; Pyrazinamide; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Rifampin

Increasing doses of an ethanolic leaf extract of. The results showed that administration of. The plant extract loweres the liver biomarker enzymes (ALT, ALP, AST) and preserves the histomorphology of the hepatocytes which is suggestive that the plant possess hepatoprotective properties.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Humans; Liver; Plant Extracts; Rats; Rats, Wistar; Rifampin

The protective effect of phloridzin (PHL) and its potential mechanism were examined in mice with liver injury induced by isoniazid (INH) and rifampicin (RFP). The mice were randomly divided into normal control group, model group, low (80 mg/kg), medium (160 mg/kg) and high (320 mg/kg) phloridzin-treated groups. After 28 d treatment, blood and liver tissue were collected and analysed. The results revealed that PHL regulated liver function related indicators and reduced the pathological tissue damage, indicating that PHL significantly alleviated the liver injury. Furthermore, the level of CYP450 enzyme, the expression of CYP3A4, CYP2E1, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein were inhibited by PHL. These results indicated that PHL exerts a protecting effect against liver injury induced by combination of RFP and INH. The potential mechanisms may be concerned with the activation of Nrf2/HO-1 signaling pathway containing its key antioxidant enzymes and regulation of CYP3A4 and CYP2E1.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Heme Oxygenase-1; Isoniazid; Liver; Mice; NF-E2-Related Factor 2; Oxidative Stress; Phlorhizin; Rifampin

The hepatotoxic mechanism resulting from coadministration of isoniazid (INH) and rifampicin (RIF) are complex and studies remain inconclusive. To systematically explore the underlying mechanisms, an integrated mass-based untargeted metabolomics and label-free quantitative proteomics approach was used to clarify the mechanism of INH/RIF-induced liver injury. Thirty male mice were randomly divided into three groups: control (receiving orally administered vehicle solution), INH (150 mg/kg) + RIF (300 mg/kg) orally administered for either 7 or 14 days, respectively. Serum was collected for the analysis of biochemical parameters and liver samples were obtained for mass spectrum-based proteomics, metabolomics, and lipidomics analysis. Overall, 511 proteins, 31 metabolites, and 23 lipids were dysregulated and identified, and disordered biological pathways were identified. The network of integrated multiomics showed that glucose, lipid, and amino acid metabolism as well as energy metabolism were mainly dysregulated and led to oxidative stress, inflammation, liver steatosis, and cell death induced by INH and RIF. Coadministration of INH and RIF can induce liver injury by oxidative stress, inflammation, liver steatosis, and cell death, and the reduction in glutathione levels may play a critical role in these systematic changes and warrants further study.

Topics: Animals; Chemical and Drug Induced Liver Injury; Fatty Liver; Inflammation; Isoniazid; Liver; Male; Mice; Proteomics; Rifampin

Rifampicin is the most common pathogenic factor in anti-tuberculosis drug-induced liver injury (AT-DILI), the mechanisms that it promotes hepatocyte damage in AT-DILI are not yet to be thoroughly elucidated. In this study, we investigated the potential molecular mechanisms for ferroptosis involving rifampicin hepatotoxicity.. Animal and cell injury models of rifampicin were constructed, and the toxicity of rifampicin was assessed by physicochemical staining and cell viability assay. Next, flow cytometry was employed to detect changes in ferroptosis-related markers, and Western blotting was used to detect protein expression. Then, the important role of autophagy and ferroptosis was verified with small molecule compound intervention.. We found that ferritinophagy-induced ferroptosis participates in the toxicity of rifampicin, and the mechanism is that rifampicin precisely activates high-throughput autophagy, which leads to the massive degradation of ferritin and the increase of free iron. Moreover, rifampicin exhibited conspicuous inhibition of Human 71 kDa heat shock cognate protein (HSPA8) that is intimately associated with Microtubule-associated protein light chain 3 isoform B (LC3B) expression, in turn, HSPA8 inducer attenuated intracellular autophagy flux. Of note, inducing HSPA8 or inhibition of autophagy and ferroptosis considerably relieved the hepatotoxicity of rifampicin in mouse model.. The present study highlights the crucial roles of the HSPA8 and autophagy in ferroptotic cell death driving by rifampicin, particularly illumines multiple promising regulatory nodes for therapeutic interventions in diseases involving AT-DILI.

Topics: Animals; Autophagy; Chemical and Drug Induced Liver Injury; Ferritins; Ferroptosis; HSC70 Heat-Shock Proteins; Humans; Mice; Microtubule-Associated Proteins; Rifampin

To analyse the incidence and risk factors of hepatotoxicity induced by antituberculosis (anti-TB) drugs in Renmin Hospital of Wuhan University, and to provide evidence for clinical prevention and treatment of anti-TB drug damage.. A retrospective analysis of patients who received first-line anti-TB drugs from January 2016 to December 2018 in Renmin Hospital of Wuhan University was conducted. Univariate analysis and binary logistic regression analysis with the forward stepwise method were used to assess the risk factors associated with hepatotoxicity induced by anti-TB drugs.. Of the 1603 patients treated with anti-TB drugs, only 1115 patients met the inclusion criteria and 42 subjects developed anti-TB drug-induced hepatotoxicity (ATDH). Significant differences (p<0.05) were seen in age (p=0.042), hypertension (p=0.021), treatment duration (p=0.000) and therapeutic regimen (p=0.001) between the non-ATDH and ATDH groups. Regression analysis further indicated that treatment duration (OR 1.053, 95% CI 1.031 to 1.076, p=0.000) and therapeutic regimens such as isoniazid (H), rifampicin (R), pyrazinamide (Z) and streptomycin (S) (HRZS) (OR 5.751, 95% CI 2.318 to 14.267, p=0.000), HRZ (OR 3.546, 95% CI 1.449 to 8.676, p=0.006) and RZ (OR 12.243, 95% CI 1.181 to 126.862, p=0.036) were risk factors for ATDH.. The incidence of ATDH in this study was 3.77%, which was lower than that of other hospital-based studies. Treatment duration and therapeutic regimen might be potential risk factors for ATDH during anti-TB therapy in hospital. Among these therapeutic combination regimens, HRZS, HRZ and RZ could significantly increase the occurrence of ATDH when used as anti-TB therapy, while isoniazid, rifampicin and ethambutol (HRE) might be safer.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Incidence; Isoniazid; Retrospective Studies; Rifampin; Risk Factors

Maintenance dialysis patients are at an increased risk for active tuberculosis (TB). In 2012, British Columbia, Canada, began systematically screening maintenance dialysis patients for latent TB infection (LTBI) and treating people with evidence of LTBI when appropriate. We examined LTBI treatment outcomes and compared treatment outcomes before and after rollout of the systematic screening program.. Retrospective cohort study.. The study comprised 365 people in British Columbia, Canada, initiating at least 90 days of dialysis from January 1, 2001, to May 31, 2017, and starting LTBI therapy: 290 (79.5%) people in the recent cohort and 75 (20.5%) in the historical cohort. People starting LTBI therapy from January 1, 2012, onward were classified as the recent cohort, whereas people starting LTBI therapy before January 1, 2012, were classified as the historical cohort.. Systematic LTBI screening and therapy.. Proportion of people who experience grade 3 to 5 adverse events (AEs) or any grade rash and end-of-treatment outcomes.. Outcomes were reported using descriptive statistics. 2-sample test of proportions using χ. 298 (81.6%) people successfully completed LTBI therapy. The proportion of people experiencing a grade 3 to 4 AE or any grade rash was 21.1%. Most AEs were related to gastrointestinal events, general malaise, or pruritus that resulted in regimen changes. 2 (0.5%) people were hospitalized for AEs related to LTBI therapy. No significant difference was found between the recent and historical cohorts in all outcomes of interest. No grade 5 AEs (deaths) were attributed to LTBI therapy.. Retrospective data and generalizability outside low-TB-burden settings.. Our findings suggest that a high proportion of people receiving maintenance dialysis can complete LTBI therapy. The rate of grade 3 to 4 AEs was high and associated with frequent medication changes during therapy. LTBI therapy in maintenance dialysis may be safe but requires close monitoring.

Topics: Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cohort Studies; Exanthema; Female; Gastrointestinal Diseases; Humans; Isoniazid; Kidney Failure, Chronic; Latent Tuberculosis; Male; Mass Screening; Middle Aged; Pruritus; Renal Dialysis; Retrospective Studies; Rifabutin; Rifampin; Treatment Outcome; Vitamin B 6

Adhatoda vasica Nees is widely used herb of indigenous system to treat various ailments especially upper respiratory tract infections. Not only, anti-tubercular efficacy of crude extract and phytoconstituents of A. vasica has been documented but its hepatoprotective role against various drugs mediated hepatic alterations in different animal models has also been observed.. Isoniazid, rifampicin and pyrazinamide (H-R-Z) are anti-tubercular drugs normally prescribed by health professionals for the treatment of tuberculosis, however along with their medical effectiveness these drugs also exhibit hepatotoxicity among TB patients. Unexpectedly, substantial toxicological data on the metabolism of anti-TB drugs are available but the mystery behind these xenobiotics is too complex and partly implicit. In this study, we further explored the hepatotoxic effects of these xeno-metabolic products and their amelioration by Adhatoda vasica Nees by elucidating its mechanistic action.. We generated a hepatotoxic rodent model by oral administration of H, R and Z (30.85, 61.7 and 132.65 mg/kg body weight) drugs for 25 days in Wistar rats. Additionally, to achieve hepatoprotection two different doses of Adhatoda vasica Nees ethanolic leaf extract (200 and 300 mg/kg body weight) were used along with H-R-Z dosage, orally and once daily for 25 days and tried to ascertain their mechanistic action. For this, initially phytoconstituents of the extract were evaluated followed by extract standardization using RP-HPLC and FTIR methods. Furthermore, antioxidant activity of the extract was analyzed by DPPH assay. Finally, different treated groups were analyzed for hepatic oxidative stress markers, antioxidant markers, histopathological changes and gene expression study including CYP2E1, CYP7A1, NAT, NR1I2 and UGT1A1 genes involved in phase I and phase II xeno-metabolism.. Estimated content of vasicine in RP-HPLC method and free-radical scavenging activity in DPPH assay was found to be 134.519 ± 0.00269μg/10mg of leaf extract and 47.81 μg/mL respectively. In H-R-Z treated group, a significant increase in the levels of thiobarbituric acid, significant reduction in the levels of GSH, and enzymatic markers and marked changes in hepatic histological architecture were observed. In addition, there was significance up-regulation of CYP7A and NAT genes, down-regulation of CYP2E1 gene and insignificant expression levels of NR1I2 and UGT1A1 genes were observed in H-R-Z group. Conversely, high dose of A. vasica extract effectively diminished these alterations by declining oxidative stress and boosting of antioxidant levels. In addition, it acted as bi-functional inducer of both phase I (CYP2E1) and phase II (NAT and UGT1A1) enzyme systems.. Hence, we concluded that anti-TB drugs exposure has potential to generate reactive metabolites that eventually cause hepatotoxicity by altering oxidant-antioxidant levels and their own metabolism. This study not only emphasized on xeno-metabolism mediated hepatic alterations but also explore the benefit of A. vasica on these toxic insults.

Topics: Alkaloids; Animals; Antitubercular Agents; Arylamine N-Acetyltransferase; Chemical and Drug Induced Liver Injury; Cholesterol 7-alpha-Hydroxylase; Cytochrome P-450 CYP2E1; Disease Models, Animal; Female; Free Radical Scavengers; Gene Expression Regulation; Glucuronosyltransferase; Isoniazid; Justicia; Oxidative Stress; Plant Extracts; Plant Leaves; Pregnane X Receptor; Pyrazinamide; Quinazolines; Rats, Wistar; Rifampin

Topics: Animals; Catalase; Chemical and Drug Induced Liver Injury; Interferon-gamma; Isoniazid; Liver; Male; NF-E2-Related Factor 2; NF-kappa B; Quercetin; Rats; Rats, Wistar; Rifampin; Toll-Like Receptor 4

Anti-TB drugs-isoniazid and rifampicin induced hepatotoxicity present a significant clinical problem. We aimed to evaluate the beneficial effect of gallic acid in anti-TB drug-induced liver injury in vivo and for the mechanism of action, we explored the influence of gallic acid on Nrf2 and NF-κB pathways.. We assessed serum liver function tests and histopathological analysis for the preventive effect of gallic acid on liver injury. For exploring the beneficial mechanism, we studied Nrf2 and NF-κB signalling pathways using molecular assays. Subsequently, we conducted in vitro cytotoxicity assays with Nrf2(ML385) and NF-κB(BAY 11-7085) antagonists.. Gallic acid co-administration attenuated the elevation of liver function enzymes, hepatic necrosis and inflammation compared to the anti-TB drug treatment alone. Mechanistic investigations reveal that gallic acid increased Nrf2 activation and induction of its downstream targets, preventing cytotoxicity by isoniazid and rifampicin. The protective effect of gallic acid diminished in the presence of Nrf2 antagonists in vitro. Furthermore, we found that gallic acid treatment inhibited NF-κB/TLR-4 axis upregulated by the anti-TB drugs.. Gallic acid is effective in preventing isoniazid and rifampicin induced hepatotoxicity in vivo by improving the redox homeostasis by activating Nrf2 and inhibiting NF-κB signalling pathways.

Topics: Animals; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Gallic Acid; Isoniazid; Liver Function Tests; NF-E2-Related Factor 2; NF-kappa B; Oxidation-Reduction; Protective Agents; Rats; Rats, Wistar; Rifampin; Signal Transduction; Toll-Like Receptor 4

The present study investigated the ameliorative effect of melittin, a major polypeptide in the venom of honeybee (Apis mellifera), on isoniazid-(INH) and rifampicin-(RIF) induced hepatotoxicity in male albino rats.. Thirty rats (140-200 g) were divided into five groups (n = 6): normal control (NC) received normal saline orally (NaCl, 0.9%; toxic (T) group received INH + RIF (each rat received 100 mg/kg, p.o.); melittin (Mel15, Mel30) groups (each rat received 15 or 30 μg/kg s.c); and normal recovery (NR) group received INH + RIF (each rat received 100 mg/kg, p.o.). Blood and liver samples were collected for biochemical, hematological and histopathological studies respectively.. The administration of melittin was found to prevent the antitubercular drug-induced alterations in the diagnostic markers; reduced glutathione (GSH), direct bilirubin (DB), total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and total serum protein (TSP). Besides, hematological alterations were significantly high in Mel groups when compared to the toxic group. The NR group exhibited lower levels of DB, TB, ALP, LDH and TSP. In addition, treatment with melittin offered protection in the NR group with respect to MDA levels.. Evidence from this study suggests that melittin is beneficial for the prevention of acute hepatic failure in antitubercular drug-induced hepatoxicity and could be used as a potential therapeutic agent.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Blood Proteins; Chemical and Drug Induced Liver Injury; Glutathione; Isoniazid; Liver; Male; Malondialdehyde; Melitten; Protective Agents; Rats; Rifampin

Six-month combination regimens could lead to serious hepatotoxicity, which may limit the clinical use of antituberculosis drugs. ABCC transporters are critical to the influx and efflux of compounds into and out of cells. The aim of this study was to explore whether the genetic variants in ABCC genes were related to the development of antituberculosis drug-induced hepatotoxicity. Here, we screened and genotyped 39 single-nucleotide polymorphisms of 13 ABCC genes in 746 eligible patients treated by first-line antituberculosis drugs in Western China Hospital. Genomic DNA was extracted from a peripheral blood sample of each patient, and clinical symptoms and laboratory results were recorded regularly. We found that the incidence rate of hepatotoxicity was 15.8% in the western Chinese Han population. As a result, the ABCC2 rs3740065 genotype, sex, and the baseline level of alanine aminotransferase are independent risk factors of antituberculosis drug-induced hepatotoxicity, with P values of .008, .014, and <.001, respectively. Our findings revealed a fraction of the underlying mechanism of hepatotoxicity, and larger validation studies on different populations are warranted to confirm these findings.

Topics: Adult; Alanine Transaminase; Antitubercular Agents; Asian People; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; China; Drug Therapy, Combination; Ethambutol; Female; Genetic Predisposition to Disease; Genotype; Humans; Isoniazid; Male; Middle Aged; Multidrug Resistance-Associated Protein 2; Polymorphism, Single Nucleotide; Pyrazinamide; Rifampin; Risk Factors; Sex Factors; Tuberculosis; Young Adult

Although rifampicin could have a hepatic toxic effect, it has also been shown that this chemical acts as a cellular protectant against oxidative stress. Therefore, we wondered whether rifampicin has a beneficial effect such as an anti-oxidant in the liver, because the efficacy of some drugs sometimes relates with their toxicity as well as protective effects. The present study aimed to investigate the antioxidant effect of rifampicin against arachidonic acid (AA) plus iron (AA + iron) cotreatment and against acetaminophen (APAP, 500 mg/kg)-induced oxidative stress, in vitro and in vivo, respectively. In vivo, oral administration of rifampicin (100 or 200 mg/kg) attenuated elevation of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), serum liver injury markers, against APAP treatment and, histologically, ameliorated tissue damage. Under in vitro examination, MTT assays were used to assess the cell death inhibitory effect of rifampicin against AA + iron-induced oxidative stress. In addition, DCFH-DA and Rh 123 staining showed that rifampicin treatment reduced reactive oxygen species (ROS) production and mitochondrial membrane damage, which had been induced by AA + iron treatment. Further, we explored whether rifampicin treatment enhanced phosphorylation of AMP-activated protein kinase (AMPK) by activation of liver kinase B1 (LKB1), the upstream kinase of AMPKα. Activated AMPKα induced activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), which are proteins functioning in redox balance. Moreover, we confirmed a reversed cell protective effect of rifampicin under compound C (an AMPK inhibitor) treatment. Overall, our data demonstrate that rifampicin effectively protects the liver against cellular oxidative stress through AMPKα and Nrf2 pathway.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Heme Oxygenase-1; Hep G2 Cells; Humans; Liver; Male; Mice; Mice, Inbred ICR; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Rifampin; Signal Transduction

Isoniazid (INH) and rifampicin (RIF) continue to be first line anti‑tuberculosis (TB) drugs. However, the use of these drugs is associated with hepatotoxicity. Nuclear factor‑κB (NF‑κB) plays a crucial role in regulating immunity and inflammation. It has been reported that pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF‑κB, exerts a hepatoprotective effect on acute and chronic liver damage. The aim of the present study was to explore the INH/RIF‑induced protective effects and mechanisms of PDTC on liver injury. Rats were intragastrically administered INH (50 mg/kg/day) and RIF (50 mg/kg/day) daily for 28 days. PDTC (50 mg/kg/day) was intraperitoneally injected 2 h after the co‑administration of INH and RIF to compare liver biochemical indicators in the serum, histopathological damage, NF‑κB activity, oxidative stress, hepatic mRNA expression of tumor necrosis factor (TNF)‑α, bile salt export pump (BSEP), and protein expression of BSEP. It was found that the inhibition of NF‑κB activation by PDTC treatment markedly alleviated liver biochemical and histological injury, decreased oxidative stress and mRNA levels of TNF‑α, and prevented decreases in BSEP mRNA and protein expression induced by the co‑administration of INH and RIF. Collectively, the present data suggested that INH/RIF‑induced liver injury is dependent on the activation of NF‑κB. PDTC exerted a therapeutic effect on INH/RIF‑induced liver injury by increasing BSEP expression, and exhibiting antioxidant and anti‑inflammatory activities.

Topics: Animals; Antioxidants; ATP Binding Cassette Transporter, Subfamily B, Member 11; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Humans; Isoniazid; Liver; NF-kappa B; Oxidative Stress; Pyrrolidines; Rats; Rifampin; Thiocarbamates; Tumor Necrosis Factor-alpha

Clinical trials suggest less hepatotoxicity and better adherence with 4 months rifampin (4R)

Topics: Antitubercular Agents; Canada; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Humans; Isoniazid; Latent Tuberculosis; Quebec; Retrospective Studies; Rifampin

Drug-induced liver injury (DILI) is a life-threatening, adverse reaction to certain drugs. The onset and extent of DILI can vary drastically in different patients using identical drugs. Association studies suggested that subtle differences in DNA methylation may help explain the individual differences in DILI. However, there are very few experimental methods to confirm such associations. In this study, we established a novel DNA methylation functional detection system in human hepatocytes, using CRISPR/dCas9 for targeted modification of DNA methylation, and set four parameters to indicate the liver injury by cell model. Using this system, we validated the association of hypermethylation of CYP2D6 and CYP2E1 with rifampin-induced DILI. Our results revealed that, following treatment of HepaRG cells with rifampin, the methylation levels of CYP2D6 and CYP2E1 were inversely proportional to cell viability and glutathione content, and directly proportional to caspase 3/7 activity. We expect that our methylation detection system will serve as a useful tool in validating correlations between DNA methylation and DILI in other in vitro systems. Our results establish a foundation for future investigations to better understand the mechanisms underlying DILI and may aid in advancing personalized DILI medicine.

Topics: Cell Line; Chemical and Drug Induced Liver Injury; CRISPR-Cas Systems; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2E1; DNA Methylation; Gene Editing; Hepatocytes; Humans; Pharmacogenetics; Pharmacogenomic Variants; Rifampin

BACKGROUND The aim of this study was to investigate the clinical characteristics and the risk factors associated with anti-tuberculosis (anti-TB) drug-induced liver injury (DILI). MATERIAL AND METHODS This retrospective study enrolled 140 hospitalized patients diagnosed with anti-TB DILI during January 2009 to December 2015. We assessed the baseline characteristics and performed regular follow-up up to the 24th week to assess the possible risk factors associated with the condition. RESULTS The study population was 58.6% male and 41.4% female patients; 20.7% were diagnosed with grades 4-5 DILI and 79.3% with grades 1-3 DILI. Female patients were significantly more likely to be diagnosed with grades 4-5 DILI than with grades 1-3 DILI (58.6% vs. 36.9%, p=0.036). Patients treated with a multidrug anti-TB regimen were more commonly affected with grades 4-5 DILI (86.2% vs. 68.5%, p=0.045). A significant number of patients who reinitiated anti-TB therapy suffered severe liver injury in comparison to patients with grades 1-3 DILI (41.4% vs. 10.8%, P<.001). Laboratory examinations revealed significantly higher values for total bilirubin (TBL), International normalized ratio (INR), and Hy's law (P<.001) in the grades 4-5 group compare to the grades 1-3 group. CONCLUSIONS Female gender, combination therapy for antitubercular drugs (isoniazid, rifampicin and pyrazinamide), re-challenge were the risk factors associated with the severity of anti-TB DILI.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis; Young Adult

Antituberculosis drug-induced liver injury (ATLI) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Rifampin (RIF) has been reported to cause haemolysis due to the production of drug-dependent antibodies, and haemolysis results in an increased level of free haem, which affects the function of hepatocytes. Blood group determinants can act as specific receptor sites for drug-antibody complexes, causing erythrocyte destruction in the presence of RIF. RIF-induced immune haemolysis may be a potential mechanism for ATLI. Thus, the study aimed to explore the role of ABO blood group systems in Chinese ATLI patients.. A 1:4 matched case-control study was conducted among 146 ATLI cases and 584 controls. Multivariable conditional logistic regression and Cox proportional regression were used to estimate the association between ABO blood group and risk of ATLI by odds ratio (OR), hazards ratio (HR) and 95% confidence intervals (CIs), and liver disease history and taking hepatoprotectant were used as covariates.. Patients in the A, B, AB and non-O blood groups had a significantly higher risk of ATLI than those in the O blood group (OR = 1.832, 95% CI: 1.126-2.983, P = .015; OR = 1.751, 95% CI: 1.044-2.937, P = .034; OR = 2.059, 95% CI: 1.077-3.938, P = .029; OR = 1.822, 95% CI: 1.173-2.831, P = .007, respectively). After considering the time of ALTI occurrence, similar results were found in the A, B, AB and non-O blood groups (HR = 1.676, 95% CI: 1.072-2.620, P = .024; HR = 1.620, 95% CI: 1.016-2.584, P = .043; HR = 2.010, 95% CI: 1.130-3.576, P = .018; HR = 1.701, 95% CI: 1.138-2.542, P = .010, respectively). Furthermore, subgroup analysis also detected a significant association between ABO blood group and ATLI in patients taking RIF (P < .05). However, no significant difference was observed in patients not taking RIF (P > .05).. The present study is the first to evaluate the role of ABO blood group systems in Chinese ATLI cases. Based on the present matched case-control study, the ABO blood group may be associated with susceptibility to ATLI in the Chinese antituberculosis population, especially in patients with blood groups A, B and AB who are taking RIF.

Topics: ABO Blood-Group System; Antitubercular Agents; Asian People; Case-Control Studies; Chemical and Drug Induced Liver Injury; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis

Rifampin (RIF), isoniazid (INH) and pyrazinamide (PZA) are essential components of the short-term first-line anti-tuberculosis (anti-TB) chemotherapy regimen and can cause hepatotoxicity. However, the mechanism of anti-TB drug-induced hepatotoxicity (ATDH) is currently unclear. We investigate the relevant contributions to liver injury and the pathway of the above-mentioned drugs administered alone or in combination.. UPLC-Q-TOF/MS-based metabolomics, bile acids (BAs) analysis and FXR/SHP detection were used to evaluate the toxicity of these drugs and clarify the underlying metabolism-related pathway.. In C57BL/6 mice administered the corrected clinical doses, RIF, INH and PZA could induced hepatotoxicity; with less toxicity in the combination therapy than RIF. The pathological biochemistry, BAs concentration and metabolically regulated FXR/SHP gene expression analyzes in mice were consistent with the metabolomics results. FXR played a role in the hepatotoxicity of anti-tuberculosis drugs in the obeticholic acid treated and FXR. ATDH was involved in bile acids and lipid and purine metabolism. The BAs metabolic pathway involvement in mice was validated in TB patients. The noninvasive metabolomics approach is more systemic than routine toxicity evaluation and can be used to assess compound toxicity and the underlying mechanism.

Topics: Animals; Antitubercular Agents; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Isoniazid; Lipid Metabolism; Male; Mass Spectrometry; Metabolomics; Mice; Mice, Inbred C57BL; Mice, Knockout; Purines; Pyrazinamide; Receptors, Cytoplasmic and Nuclear; Rifampin

Tuberculosis is a global health threat that affects millions of people every year, and treatment-limiting toxicity remains a considerable source of treatment failure. Recent reports have characterized the nature of

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Heme; Homocysteine; Iron-Sulfur Proteins; Isoniazid; Liver; Mice; Mice, Inbred C57BL; Niacinamide; Oxidative Stress; Proteome; Rifampin; Vitamin B 6

Rosa brunonii L., a less investigated plant contains flavonoid glycosides and is used to treat stomach ailments, heart problems, and diabetes in folk. The crude extract of the plant possesses antioxidant activity. The current work was aimed to investigate the presence of phytochemicals, antioxidative stress and protective potential of chloroform extract of the Rosa brunonii L. fruits (RBFCE) against liver and kidney toxicity induced by anti-tuberculosis drugs, rifampicin/isoniazid (Rif/INH) in Wistar albino rats. Animals were divided into six groups, each comprising 6 rats and fed with a standard pelleted diet. Normal control group was given only a standard pelleted diet. The vehicle control group received 0.5% carboxymethylcellulose (CMC) aqueous solution (vehicle). Negative and positive control groups were given Rif/INH (50+50 mg/kg, p.o) and silymarin (SILM) (200 mg/kg, p.o) in 0.5% vehicle for 30 days, respectively. Extract treated groups received low and high doses of RBFCE (500 mg/kg, p.o and 1000 mg/kg, p.o respectively) in 0.5% vehicle for 30 days. At a higher dose, animals showed significantly reduced Rif/INH induced toxicity in liver and kidney tissues as indicated by the normalized serum biochemical markers and histopathological investigations. The present exploration reveals the presence of strong antioxidant phytochemical constituents, antioxidative stress and protective potential of RBFCE against Rif/INH induced hepatic and renal damage.

Topics: Alanine Transaminase; Animals; Antioxidants; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Female; Fruit; Isoniazid; Kidney; Liver; Male; Plant Extracts; Protective Agents; Rats; Rats, Wistar; Rifampin; Rosa; Silymarin

Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a common adverse reaction of anti-tuberculosis drug treatment. Studies have shown that isoniazid (INH) and rifampicin (RFP) are mainly metabolized in the liver and a large amount of intracellular glutathione is used up during the metabolism of these drugs, resulting in lipid peroxidation and hepatocyte death. Ferroptosis is a novel form of programmed cell death caused by iron-ion-dependent lipid peroxidation. In this study, we explored lipid peroxidation and ferroptosis during ATB-DILI. Morphology of ferroptosis was discovered in ATB-DILI mouse livers by transmission electron microscopy. Flow cytometry was used to assess the molecular markers of lipid peroxidation and ferroptosis including reactive oxygen species, lipid peroxidation, and cellular iron content. Glutathione peroxidase 4 (GPX4) was depleted, while acyl-CoA synthetase long chain family member 4 (ACSL4) was overexpressed in the ATB-DILI tissues. And glutathione supplementation significantly reduced the level of lipid peroxidation and the risk of liver damage. Retrospective study of tuberculosis patients who underwent INH and RFP treatment also revealed an association between the intake of glutathione and a negative ATB-DILI rate. In addition, iron supplementation enhanced the degree of lipid peroxidation and liver injury induced by INH and RFP in vivo and clinical retrospective study. Taken together, these results indicate that lipid peroxidation and evidence suggestive of ferroptosis occurs during ATB-DILI, and glutathione replenishment prevents this process while iron supplementation augmenting this effect.

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Therapy, Combination; Ferroptosis; Glutathione; Humans; Iron; Isoniazid; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Reactive Oxygen Species; Rifampin

Tuberculosis (TB) is one of the deadliest infectious diseases in humankind history. Although, drug sensible TB is slowly decreasing, at present the rise of TB cases produced by multidrug-resistant (MDR) and extensively drug-resistant strains is a big challenge. Thus, looking for new therapeutic options against these MDR strains is mandatory. In the present work, we studied, in BALB/c mice infected with MDR strain, the therapeutic effect of supra-pharmacological doses of the conventional primary antibiotics rifampicin and isoniazid (administrated by gavage or intratracheal routes), in combination with recombinant human hepatocyte growth factor (HGF). This high dose of antibiotics administered for 3 months, overcome the resistant threshold of the MDR strain producing a significant reduction of pulmonary bacillary loads but induced liver damage, which was totally prevented by the administration of HGF. To address the long-term efficiency of this combined treatment, groups of animals after 1 month of treatment termination were immunosuppressed by glucocorticoid administration and, after 1 month, mice were euthanized, and the bacillary load was determined in lungs. In comparison with animals treated only with a high dose of antibiotics, animals that received the combined treatment showed significantly lower bacterial burdens. Thus, treatment of MDR-TB with very high doses of primary antibiotics particularly administrated by aerial route can produce a very good therapeutic effect, and its hepatic toxicity can be prevented by the administration of HGF, becoming in a new treatment modality for MDR-TB.

Topics: Animals; Antibiotics, Antitubercular; Antioxidants; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Hepatocyte Growth Factor; Humans; Isoniazid; Liver; Male; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant

To compare the incidence of anti tuberculosis drug-induced hepatotoxicity (ATDH) with those on old vs. revised WHO doses in human immunodeficiency virus (HIV) negative children. The secondary objective was to determine the overall incidence of hepatitis in children on Anti tubercular treatment (ATT) and isoniazid prophylactic therapy (IPT).. Children attending pediatric outpatient / admitted in wards, on ATT/ IPT between January 2007 and December 2017 (11 y) were included. Children were divided into Group 1 (treated based on old doses, from January 2007 to December 2011) and Group 2 (treated based on revised doses from January 2012 to December 2017). Children with multi drug resistant tuberculosis (MDRTB) and pre-existing liver disease were excluded.. A total of 515 children were enrolled. Twelve children developed ATDH with an overall incidence of 2.3%. Five out of 260 (1.9%) developed hepatitis with old doses vs. 7 of the 255 (2.7%) with revised doses; this difference was not statistically significant. When calculated only for active TB (excluding children on IPT), overall incidence of hepatitis was 2.7%. Comparison between group 1 (2.04%) and group 2 (3.5%) was again not statistically significant. Ten out of 12 children who developed hepatitis were restarted on ATT without recurrence. No child on IPT developed hepatitis. There was no mortality.. Revised WHO dosing does not increase incidence of hepatitis compared to old dosing in HIV negative children. Overall incidence was 2.3%. Hepatitis did not occur with IPT.

Topics: Adolescent; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Coinfection; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis; HIV; HIV Infections; Humans; Incidence; India; Infant; Isoniazid; Liver; Liver Function Tests; Male; Prospective Studies; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

Drug-induced liver injury complicates antituberculosis drug treatment and is a leading cause of death worldwide. The aim of this study is to establish the ethnomedicinal claim of hepatoprotective effects of fruit pulp extract of Telfairia occidentalis against rifampicin (RIF) and isoniazid (INH)-induced oxidative stress in rats.. T. occidentalis pulp extract (TOPE) (125-500 mg/kg) and silymarin (50 mg/kg) were evaluated in an induced hepatotoxicity model of oxidative stress in Wistar rats by intoxication with RIF and INH (100 mg/kg each) orally for 60 d. Markers indicating oxidative stress and hepatic damage such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed. Biomarkers of antioxidant status, including catalase, glutathione reductase, glutathione peroxidase and superoxide dismutase, and marker of lipid peroxidation, malondialdehyde (MDA), were assayed using standard procedures. The hematological profile, lipid profile, serum markers for kidney function and histopathological examination were also assessed.. Intoxication with RIF and INH markedly reduced the hematological indices and elevated the biochemical enzyme markers (AST, ALT and ALP, P < 0.001) and lipid profile (P < 0.001), while antioxidant biomarkers were significantly (P < 0.01) depressed and MDA was elevated. However, pretreatment with TOPE significantly (P < 0.001) alleviated this alteration and sustained the antioxidant potentials. The histopathological morphology supports the biochemical evidence of hepatoprotection.. Current study is indicative of potential antioxidant activity, hepatoprotective effects and plausible therapeutic alleviation of RIF-INH-induced hepatotoxicity of TOPE in laboratory animals.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Catalase; Chemical and Drug Induced Liver Injury; Cucurbitaceae; Humans; Isoniazid; Male; Malondialdehyde; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar; Rifampin; Superoxide Dismutase

Tuberculosis (TB) is one of the most prevalent infections. However, anti-TB drugs induce adverse liver injury in up to 40% of patients. Studies on candidate genes have suggested that single-nucleotide polymorphisms account for only a small contribution to the occurrence of anti-TB drug-induced liver injury (ATLI). In this study, whole-genome DNA methylation analysis was performed to systematically screen the ATLI-associated factors in a 49 vs. 51 case-control population. Next, 34 identified candidate probes were validated using MassARRAY in 296 cases and 288 controls. Our results indicated that 12 CpG sites on seven probes were positively associated with ATLI risk. Furthermore, we applied a CRISPR/Cas9-mediated methylation modifiable cell model and demonstrated that four CpGs in or near the gene region of AK2, SLC8A2, and PSTPIP2 affected the cellular response to rifampicin treatment. This study provides new biomarkers associated with ATLI occurrence.

Topics: Adaptor Proteins, Signal Transducing; Adenylate Kinase; Adult; Aged; Antitubercular Agents; Asian People; Chemical and Drug Induced Liver Injury; China; Cytoskeletal Proteins; DNA Methylation; Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Rifampin; Sodium-Calcium Exchanger

Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis. In the present study, we used chimeric mice with humanized liver as a model to study drug-induced cholestasis. Administration of a single dose of ketoconazole or rifampicin, known to potentially cause cholestasis by inhibiting BSEP, did not result in elevated levels of alkaline phosphatase (ALP), which are known hepatic biomarkers. The concentration of taurodeoxycholic acid increased in the liver after ketoconazole administration, whereas rifampicin resulted in increased tauromuricholic acid and taurocholic acid (TCA) levels in the liver and plasma. Furthermore, rifampicin resulted in an increase in the uniform distribution of a compound with m/z 514.3, presumed as TCA through imaging mass spectrometry. The mRNA levels of bile acid-related genes were also altered after treatment with ketoconazole or rifampicin. We believe these observations to be a part of a feedback mechanism to decrease bile acid concentrations. The changes in bile acid concentrations results may reflect the initial responses of the human body to cholestasis. Furthermore, these findings may contribute to the screening of drug candidates, thereby avoiding drug-induced cholestasis during clinical trials and drug development.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Ketoconazole; Liver; Male; Mice; Rifampin

The liver is an important organ that plays a vital role in homeostasis maintenance and regulation. Any liver damage or injury caused by drugs or chemicals is called hepatotoxicity. Isoniazid and rifampin are drugs used separately to treat tuberculosis but have unique side effects and potential hepatotoxicity. The metabolism of isoniazid (INH) and rifampin (RIF) takes place in liver hence hepatotoxicity is the main cause of their continuous use. Bacoside was obtained from the plant

Topics: Animals; Antioxidants; Bacopa; Body Weight; Chemical and Drug Induced Liver Injury; Female; Isoniazid; Liver; Protective Agents; Rats; Rats, Wistar; Rifampin; Saponins; Silymarin; Triterpenes

The Tamarix gallica leaves extract (TGLE) was investigated for hepatoprotective potential against rifampicin (RIF) plus isoniazid (INH)-induced liver injury in Sprague Dawley (SD) rats. All the rats of groups III and IV received 100 and 200 mg/kg body wt, respectively, of the suspension of TGLE while group V received silymarin 100 mg/kg body wt orally. After 10 min, they, along with group II, received INH plus RIF each day (50 mg/kg body wt, by mouth (PO) each) for 28 days. Group I received 10 ml/kg body wt, PO of vehicle, i.e., 1% aqueous carboxymethyl cellulose (1% CMC) throughout the study. At the end of the experiment, blood was obtained through the retro-orbital plexus under light anesthesia and the serum was separated from the sacrificed animals. A small portion of isolated liver tissue was fixed in 10% formaldehyde for histopathological examinations. The levels of elevated serum bilirubin (p > .05-p < .05), alanine transaminase (p > .05-p < .01), aspartate transaminase (p > .05-p < .01), alkaline phosphatase (p < .05-p < .01), lactate dehydrogenase (p < .05-p < .01), and cholesterol (p > .05-p < .01) decreased while the levels of decreased total protein (p > .05-p < .05) and albumin (p < .05-p < .05) increased in TGLE-treated groups III and IV as compared to group II, and the serum marker enzyme levels were toward normal, indicating protection against liver injury. It was well supported with histopathological results. Thus, Tamarix gallica leaves extract possesses promising hepatoprotective activity against RIF plus INH-induced liver injury in experimental rats.

Topics: Alanine Transaminase; Animals; Anti-Bacterial Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Isoniazid; Liver; Liver Function Tests; Male; Phytotherapy; Plant Extracts; Plant Leaves; Protective Agents; Rats; Rats, Sprague-Dawley; Rifampin; Tamaricaceae

Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform. The tricarboxylic acid circulation, arginine and proline metabolism and purine metabolic pathways were found to be affected by anti-TB drugs. The levels of pyroglutamate, isocitrate, citrate, and xanthine were significantly decreased after the administration of HRZE. The above mentioned pathways were also different between drug-induced liver injury (DILI) and non-DILI patients. Urate and cis-4-octenedioic acid levels in the DILI group were significantly increased compared to those in the non-DILI group, while the cis-aconitate and hypoxanthine levels were significantly decreased. These results highlight that superoxide generation can aggravate the hepatotoxic effects of the HRZE regimen. In addition, our metabolomic approach had the ability to predict hepatotoxicity for clinical applications.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Ethambutol; Female; Humans; Isoniazid; Liver; Male; Mass Spectrometry; Metabolic Networks and Pathways; Metabolomics; Middle Aged; Purines; Pyrazinamide; Rifampin; Tuberculosis; Young Adult

Isoniazid monotherapy for six or nine months and the combination of isoniazid and rifampicin for three or four months are the most used regimens for treating latent tuberculosis. The main aim of this retrospective study is to evaluate the safety of latent tuberculosis treatment by analysing side effects in both regimens.. Children with latent tuberculosis and treated with isoniazid or isoniazid and rifampicin were included. Periodic evaluations with clinical assessment and blood exams were carried out to detect any adverse reaction, including elevated serum transaminases.. 441 children were included, 14.5% treated with isoniazid and 85.5% with isoniazid and rifampicin. Five patients under combined treatment developed hepatotoxicity within the first month. None of the patients under isoniazid monotherapy presented hepatotoxicity. A slight increase of transaminases level was found in both groups (18.7% in isoniazid and 10.3% in isoniazid/rifampicin groups, respectively) without causing discontinuation of treatment, with values normalization at the subsequent checks.. Both regimens resulted safe. Hepatotoxicity occurred rarely and within the first month. For this reason, it may be appropriate to perform liver function tests after about one month from the beginning of therapy to avoid diagnostic delays.

Topics: Adolescent; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Latent Tuberculosis; Liver Function Tests; Male; Retrospective Studies; Rifampin; Time Factors; Transaminases

Topics: Chemical and Drug Induced Liver Injury; Cholestasis; Cohort Studies; Humans; Pruritus; Rifampin

The aim of this study is to evaluate the hepatoprotective effect of Lasianthera africana (Icacinaceae) against isoniazid (INH) and rifampicin (RIF)-induced liver damage in rats.. The hepatoprotective effects of hot aqueous L. africana (HALA) leaf extract (0.1-1 g/kg) and silymarin (50 mg/kg) were assessed in a model of oxidative liver damage induced by RIF and INH (100 mg/kg each) in Wistar rats for 28 days. Biochemical markers of hepatic damage such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed. The antioxidant statuses of plasma glutathione peroxidase (GSPx), glutathione reductase (GSH), catalase (CAT) and superoxide dismutase (SOD) and lipid peroxidation were evaluated.. The pretreatment of INH and RIF decreased hematological indices and the antioxidant levels (P < 0.001) and increased the levels of liver marker enzymes (P < 0.001). However, pretreatment with HALA extract and silymarin provoked significant elevation of hematological indices. The levels of AST, ALT, and ALP were depressed (P < 0.001). Total triglycerides, total cholesterol, total bilirubin and low-density lipoprotein were decreased (P < 0.001). However, high-density lipoprotein, bicarbonate, and electrolytes like chloride and potassium were elevated (P < 0.001), but sodium was depressed (P < 0.05). Additionally, GSH, GSPx, SOD and CAT were elevated (P < 0.01) and malondialdehyde was depressed (P < 0.001) when compared to the RIF-INH-treated rats. Histopathological evaluations support hepatoprotective activity.. This study demonstrated that HALA leaf extract attenuated RIF-INH-induced hepatotoxicity. L. africana could be exploited in management of RIF-INH-induced hepatitis.

Topics: Alanine Transaminase; Animals; Antibiotics, Antitubercular; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cholesterol; Female; Glutathione; Humans; Isoniazid; Liver; Magnoliopsida; Male; Malondialdehyde; Plant Extracts; Plant Leaves; Rats, Wistar; Rifampin; Superoxide Dismutase

The Drug-induced liver injury is one of the common unfavourable impacts, which seriously affects any drug therapy. This study documented the hepatoprotective efficacy of lawsone, the major bioactive naphthoquinone present in Lawsonia inermis L. (Lythraceae) using in vitro and in vivo models. Lawsone was isolated from the leaves of L. inermis and its structure was confirmed using spectroscopic data. In-vitro antioxidant effect of lawsone was evaluated using ABTS assay. Hepatoprotective effect of lawsone was determined with RIF-INH treated HepG2 cells and Wistar rats. Administration of RIF-INH reduced the viability of the HepG2 cells and the treatment with lawsone significantly restored the viability of the cells even at lower concentration (7.5 μM). The other parameters such as the leakage of transaminases and MDA levels were also significantly reduced by the treatment with lawsone. Oral administration of lawsone to the animals did not show any toxicity up to 2 g/kg b.w. concentration. Treatment with lawsone to the RIF-INH administered animals significantly lowered the serum transaminases levels. The ratio of albumin to globulin was improved and the level of bilirubin was lowered. This study indicated the hepatoprotective effect of lawsone; detailed investigations will give deeper understanding of the application of lawsone for hepatoprotection.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Cell Survival; Chemical and Drug Induced Liver Injury; Hep G2 Cells; Humans; Isoniazid; L-Lactate Dehydrogenase; Liver; Male; Naphthoquinones; Protective Agents; Rats, Wistar; Rifampin; Serum Albumin; Serum Globulins

Background Development of drug-induced hepatic damage (DIHD) during chemotherapy is the most common reason for interruption in chemotherapy. This study evaluated the hepatoprotective activity of the ethanolic extract of Tamarindus indica stem bark (EETI) against the induced DIHD in Sprague Dawley rats. Methods The rats were divided into five groups (n=5). Group I, group III, group IV, and group V rats received 1 mL 1% carboxymethyl cellulose, EETI 100 mg/kg body weight (b.wt), EETI 200 mg/kg b.wt, and silymarin 100 mg/kg b.wt, respectively, orally once every day for 28 days. After 1 h-group II, group III, group IV, and group V rats were administered with isoniazid (INH) and rifampicin (RIF) 50 mg/kg b.wt each orally once every day for 28 days. Then, 24 h after the last dosing, blood was withdrawn from the rats and analyzed for liver specific enzymes and biochemical markers. They were examined for histopathology. Results Co-administration of INH and RIF in group II significantly increased alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase, serum bilirubin, and cholesterol levels while reduced the total protein and albumin levels compared to that of group I. EETI in group III and group IV rats significantly restored the liver specific enzymes and biochemical markers altered due to co-administration of INH and RIF to normal in a dose-dependent manner. EETI 200 mg/kg b.wt showed better protection to liver than EETI 100 mg/kg b.wt and was comparable to silymarin 100 mg/kg b.wt. It was well supported with histopathology of liver tissues. Conclusions EETI possesses hepatoprotective activity against DIHD in rats. It may have a substantial impact on developing clinical strategies to treat patients with hepatic damage.

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Isoniazid; Plant Bark; Plant Extracts; Plant Stems; Rats; Rats, Sprague-Dawley; Rifampin; Tamarindus

The Sagittaria sagittifolia L. polysaccharide (SSP) is a purified form of a homogeneous polysaccharide isolated from the root tubers of S. sagittifolia, which has been used as a protectant against hepatotoxicity induced by coadministration of isoniazid and rifampicin. However, the protective effect of SSP against isoniazid- and rifampicin-induced liver injury has never been studied.. In this study, the hepatoprotective effect of SSP and its underlying mechanism were investigated in mice with isoniazid- and rifampicin-induced liver injury.. Liver injury was induced in mice by intragastric administration of isoniazid and rifampicin, and the mice were divided into the following six groups: standard control (administration of saline by gavage), model (intragastric administration of isoniazid and rifampicin at 100 mg/kg/day each), positive control (100 mg/kg/day silymarin by gavage 4 h after isoniazid and rifampicin administration), and SSP-treated (200, 400, or 800 mg/kg/day SSP by gavage after isoniazid and rifampicin administration). Subsequently, blood and liver samples were collected from all the animals and were assessed.. SSP significantly alleviated the liver injury, as evidenced by decreased activities of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in the serum and a decreased level of malondialdehyde in the liver, as well as by an increased level of glutathione and increased activities of superoxide dismutase and catalase in the liver. SSP also effectively reduced the pathological tissue damage. The gene and protein expression of cytochrome P450 (CYP) 2E1 and CYP3A4 was inhibited by SSP. The gene and protein expression of nuclear factor erythroid 2-related factor 2 (NRF2), glutamate-cysteine ligase, and heme oxygenase-1 were induced by SSP, whereas that of Kelch-like ECH-associated protein 1 was inhibited.. SSP exerts a protective effect against isoniazid- and rifampicin-induced liver injury in mice. The underlying mechanisms may involve activation of NRF2 and its target antioxidant enzymes and inhibition of the expression of CYPs.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Isoniazid; Male; Mice, Inbred BALB C; NF-E2-Related Factor 2; Polysaccharides; Protective Agents; Rifampin; Sagittaria; Signal Transduction

Methimazole (MMI) is a widely used drug for hyperthyroidism. However, its clinical use is associated with hepatotoxicity. Though the precise mechanism of hepatic damage is still far from clear, role of metabolic activation and reactive metabolites have been implicated. The present study was designed to investigate the role of enzyme induction in bioactivation based hepatotoxicity of methimazole in mice. Thirty male mice were randomly divided into five groups. Hepatotoxicity was induced by single intraperitoneal injection of methimazole (1000mg/kg). Pretreatment with rifampicin which is a potent enzyme inducer was carried out for 6 days prior to administration of methimazole. The extent of hepatic damage was determined by measuring serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) along with histopathological grading of liver samples. The elevated levels of biochemical markers by methimazole were potentiated by pretreatment with rifampicin. This potentiation of hepatic injury was also observed in liver histopathological examination. These findings suggest induction of microsomal enzymes as a potentiating factor of methimazole induced hepatotoxicity.

Topics: Alanine Transaminase; Animals; Antibiotics, Antitubercular; Antithyroid Agents; Aspartate Aminotransferases; Biomarkers; Chemical and Drug Induced Liver Injury; Drug Synergism; Liver; Male; Methimazole; Mice, Inbred BALB C; Rifampin

Topics: Animals; Chemical and Drug Induced Liver Injury; Isoniazid; Metabolome; Metabolomics; Mice; Mice, Inbred BALB C; Polysaccharides; Rifampin; Sagittaria

One approach that could increase the efficacy and reduce the duration of antituberculosis therapy is pharmacokinetics/pharmacodynamics-based optimization of doses. However, this could increase toxicity.. We mimicked the concentration-time profiles achieved by human equivalent doses of moxifloxacin 800 mg/day, rifampin 1800 mg/day, and pyrazinamide 4000 mg/day (high-dose regimen) vs isoniazid 300 mg/day, rifampin 600 mg/day, and pyrazinamide 2000 mg/day (standard therapy) in bactericidal and sterilizing effect studies in the hollow fiber system model of tuberculosis (HFS-TB). In an intracellular Mycobacterium tuberculosis (Mtb) HFS-TB experiment, we added a 3-dimensional human organotypic liver to determine potential hepatotoxicity of the high-dose regimen, based on lactate dehydrogenase (LDH). Treatment lasted 28 days and Mtb bacterial burden was based on colony counts. We calculated the time to extinction (TTE) of the Mtb population in the HFS-TB and used morphism-based transformation and Latin hypercube sampling to identify the minimum therapy duration in patients.. The kill rate of standard therapy in the bactericidal effect and sterilizing effect experiments were 0.97 (95% confidence interval [CI], .91-.99) log10 colony-forming units (CFU)/mL/day, and 0.56 (95% CI, .49-.59) log10 CFU/mL/day, respectively. The high-dose regimen's bactericidal and sterilizing effect kill rates were 0.99 (95% CI, .96-.99) log10 CFU/mL/day and 0.72 (95% CI, .56-.79) log10 CFU/mL/day, respectively. The upper confidence bound for TTE in patients was 4.5-5 months for standard therapy vs 3.7 months on the high-dose regimen. There were no differences in LDH concentrations between the 2 regimens at any time point (P > .05).. The high-dose regimen may moderately shorten therapy without increased hepatotoxicity compared to standard therapy.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Humans; Liver; Models, Biological; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

Antituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individual's susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients.. CYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis.. A total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P=0.039, OR=0.097, 95% CI: 0.011-0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P=0.020, OR=0.522, 95% CI: 0.301-0.903).. This study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result.

Topics: Adult; Alleles; Antitubercular Agents; Asian People; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2B6; Ethambutol; Female; Gene Expression; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Animals; Antibiotics, Antitubercular; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Computational Biology; Disease Models, Animal; Gene Ontology; Lethal Dose 50; Liver; Male; Mice; Proteome; Proteomics; Rifampin

The present study was undertaken to investigate the hepatoprotective effect of. Antituberculosis treated group showed significantly increase levels of TNF-a, the percentage of NK cells and the number of Th17 cells compared with the control group (. It was concluded that administration of

Topics: Aloe; Animals; Antibiotics, Antitubercular; Antitubercular Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Isoniazid; Killer Cells, Natural; Plant Extracts; Rats; Rifampin; Th17 Cells; Tumor Necrosis Factor-alpha

Renal transplant candidates (RTC) with latent tuberculosis infection (LTBI) are at significant risk for tuberculosis reactivation. Twelve-week rifapentine (RPT)/isoniazid (INH) is effective for LTBI but clinical experience in RTC is scarce.. We conducted a retrospective study of RTC with LTBI treated with either 12-week RPT/INH or 9-month INH from March 1, 2012, through February 28, 2014. We evaluated both groups for differences in rates of treatment completion, monthly follow-up visit compliance, transaminase elevations, and adverse reactions leading to discontinuation of LTBI treatment. The utility of weekly reminders was also evaluated in the 12-week regimen. Direct observed therapy was not performed in our study.. Of 153 patients, 43 (28%) and 110 (72%) were started on 12-week RPT/INH and 9-month INH, respectively. The treatment completion and monthly follow-up visit compliance rates were higher in the 12-week RPT/INH group (40 [93%] vs 52 [47%], P < 0.001) and (11/40 [28%] vs 13/104 [13%], P = 0.03), respectively. Transaminase elevations were not observed in the RPT/INH group, but occurred in 6 (5%) of the INH group. There were no differences in adverse reactions leading to discontinuation of LTBI treatment.. Twelve-week RPT/INH appears to be an excellent choice for LTBI in RTC. It has a higher treatment completion rate and causes less transaminase elevations, and weekly reminders may be an alternative when direct observed therapy is not feasible.

Topics: Adult; Aged; Antitubercular Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Choice Behavior; Drug Therapy, Combination; Female; Humans; Isoniazid; Kidney Diseases; Kidney Transplantation; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Reminder Systems; Retrospective Studies; Rifampin; Time Factors; Transaminases; Treatment Outcome; Treatment Refusal; Up-Regulation; Waiting Lists

Toxicities due to anti-TB treatment frequently occur among TB/HIV-coinfected patients.. To determine the association between anti-TB drug concentrations and the occurrence of hepatotoxicity and peripheral neuropathy among TB/HIV-coinfected patients.. TB/HIV-coinfected patients were started on standard dose anti-TB treatment according to WHO guidelines. Anti-TB drug concentrations were measured using HPLC 1, 2 and 4 h after drug intake at 2, 8 and 24 weeks following initiation of TB treatment. Participants were assessed for hepatotoxicity using Division of AIDS toxicity tables and for peripheral neuropathy using clinical assessment of tendon reflexes, vibration sensation or symptoms. Cox regression was used to determine the association between toxicities and drug concentrations.. Of the 268 patients enrolled, 58% were male with a median age of 34 years. Participants with no hepatotoxicity or mild, moderate and severe hepatotoxicity had a median C max of 6.57 (IQR 4.83-9.41) μg/mL, 7.39 (IQR 5.10-10.20) μg/mL, 7.00 (IQR 6.05-10.95) μg/mL and 3.86 (IQR 2.81-14.24) μg/mL, respectively. There was no difference in the median C max of rifampicin among those who had hepatotoxicity and those who did not ( P  =   0.322). There was no difference in the isoniazid median C max among those who had peripheral neuropathy 2.34 (1.52-3.23) μg/mL and those who did not 2.21 (1.45-3.11) μg/mL ( P  =   0.49).. There was no association between rifampicin concentrations and hepatotoxicity or isoniazid concentrations and peripheral neuropathy among TB/HIV-coinfected patients.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Coinfection; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Peripheral Nervous System Diseases; Prospective Studies; Regression Analysis; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

Combination of isoniazid (INH) and rifampicin (RFP) causes liver injury frequently among tuberculosis patients. However, mechanisms of the hepatotoxicity are not entirely understood. Protoporphyrin IX (PPIX) accumulation, as an endogenous hepatotoxin, resulting from isoniazid and rifampicin co-therapy (INH/RFP) has been reported in PXR-humanized mice. Aminolevulinic acid synthase1 (ALAS1), ferrochelatase (FECH) and breast cancer resistance protein (BCRP) play crucial roles in PPIX synthesis, metabolism and transport, respectively. Herein, this study focused on the role of INH/RFP in these processes. We observed PPIX accumulation in human hepatocytes (L-02) and mouse livers. FECH expression was initially found downregulated both in L-02 cells and mouse livers and expression levels of ALAS1 and BCRP were elevated in L-02 cells after INH/RFP treatment, indicating FECH inhibition and ALAS1 induction might confer a synergistic effect on PPIX accumulation. Additionally, our results revealed that curcumin alleviated INH/RFP-induced liver injury, declined PPIX levels and induced FECH expression in both L-02 cells and mice. In conclusion, our data provide a novel insight in the mechanism of INH/RFP-induced PPIX accumulation and evidence for understanding pathogenesis of INH/RFP-induced liver injury, and suggest that amelioration of PPIX accumulation might be involved in the protective effect of curcumin on INH/RFP-induced liver injury.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Curcumin; Isoniazid; Liver; Mice; Photosensitizing Agents; Protoporphyrins; Rifampin; Tuberculosis

To investigate the outcome of rifam- picin (RFP) monotherapy for latent tuberculosis infection (LTBI) and the incidence of RFP-induced liver toxicity. [Method] We conducted a retrospective chart review of patients who received RFP monotherapy as LTBI treatment at the Daiichi Dispensary Clinic. [Result] Of 61 patients who received RFP monotherapy, the treatment completion rate was 88.5%, self-termination rate was 3.3%, abandonment rate due to adverse drug effects was 8.2% (5 cases: 3 cases of skin eruption and 2 cases of liver dysfunction). Among the 2 cases of liver dysfunction, I was not associated with abnormal alkaline phosphatase (ALP) or gamma-glutamyl transferase (y GTP) levels. Among patients with liver dysfunction who did not discontinue RFP mono- therapy, no cases-of severely abnormal ALP and/or y GTP levels were reported. [Conclusion] The incidence of liver toxicity due to RFP is lower than that observed with isoniazid, and liver dysfunction due to RFP was not always associated with abnormal of ALP and/or yGTP levels.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Latent Tuberculosis; Male; Middle Aged; Retrospective Studies; Rifampin; Young Adult

The study aimed to evaluate the hepatoprotective potential of aqueous extract of Tamarindus indica fruit against combination of two antitubercular drugs viz. Isoniazid and Rifampicin induced hepatotoxicity in rats. In vitro antioxidant activity of aqueous extract of T. indica by DPPH-HPLC method was found to be 81.48%. Treatment with aqueous extract of T. indica significantly reduced the elevated levels of biochemical markers such as SGOT, SGPT, ALP, bilirubin, TBARS and increased the albumin level as well antioxidant activities of SOD, CAT and GSH in intoxicated rats. The biochemical changes were supported by histological observations. Results of this study clearly demonstrate that aqueous extract of T. indica fruit protects against anti tuberculosis induced oxidative liver damage in rats and thus possess significant hepatoprotective activity. Further, it could be suggested that supplementation with this food extract might prove beneficial in the individuals on anti-TB drugs.

Topics: Animals; Antioxidants; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Fruit; Isoniazid; Liver; Male; Plant Extracts; Rats; Rats, Wistar; Rifampin; Tamarindus

Engineering the liver in vitro is promising to provide functional replacement for patients with liver failure, or tissue models for drug metabolism and toxicity analysis. In this study, we describe a microfluidics-based biomimetic approach for the fabrication of an in vitro 3D liver lobule-like microtissue composed of a radially patterned hepatic cord-like network and an intrinsic hepatic sinusoid-like network. The hepatic enzyme assay showed that the 3D biomimetic microtissue maintained high basal CYP-1A1/2 and UGT activities, responded dynamically to enzyme induction/inhibition, and preserved great hepatic capacity of drug metabolism. Using the established biomimetic microtissue, the potential adverse drug reactions that induced liver injury were successfully analyzed via drug-drug interactions of clinical pharmaceuticals. The results showed that predosed pharmaceuticals which agitated CYP-1A1/2 and/or UGT activities would alter the toxic effect of the subsequently administrated drug. All the results validated the utility of the established biomimetic microtissue in toxicological studies in vitro. Also, we anticipate the microfluidics-based bioengineering strategy would benefit liver tissue engineering and liver physiology/pathophysiology studies, as well as in vitro assessment of drug-induced hepatotoxicity.

Topics: Acetaminophen; Biomimetic Materials; Chemical and Drug Induced Liver Injury; Drug Evaluation, Preclinical; Hep G2 Cells; Hepatocytes; Humans; Isoniazid; Microfluidic Analytical Techniques; Rifampin; Tissue Engineering

In vitro studies have suggested that 4-phenylbutyrate (PBA) may rescue missense mutated proteins that underlie some forms of progressive familial intrahepatic cholestasis. Encouraging preliminary responses to 4-PBA have been reported in liver disease secondary to mutations in ABCB11 and ATP8B1. A 4-year-old boy with Byler disease was treated with 4-PBA in the forms of sodium PBA (5 months) and then glycerol PBA (7 months) as part of expanded access single patient protocols. During this therapy serum total bilirubin fell and his general well-being was reported to be improved, although total serum bile acids were not reduced. Discontinuation of rifampin therapy, which had been used to treat pruritus, resulted in reversible severe acute liver injury that was potentially the result of phenylacetate toxicity. Interactions between 4-PBA and cytochrome P450 enzymes should be considered in the use of this agent with special attention to potential phenylacetate toxicity.

Topics: Antineoplastic Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Child, Preschool; Cholestasis, Intrahepatic; Humans; Infant; Liver; Liver Function Tests; Male; Phenylacetates; Phenylbutyrates; Pruritus; Rifampin

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Emergency Service, Hospital; Ethambutol; Female; Humans; Isoniazid; Mycobacterium tuberculosis; Parents; Pyrazinamide; Recurrence; Rifampin; Risk Assessment; Risk Factors; Siblings; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Drug-induced liver injury (DILI) is associated with altering expression of hepatobiliary membrane transporters. Monoammonium glycyrrhizin (MAG) is commonly used for hepatic protection and may have a correlation with the inhibition effect of multidrug resistance-associated protein 2 (Mrp2).. This study evaluates the dynamic protective effect of MAG on rifampicin (RIF)- and isoniazid (INH)-induced hepatotoxicity in rats.. Male Wistar rats were randomly divided into four groups of 15 rats. Liver injury was induced by co-treatment with RIF (60 mg/kg) and INH (60 mg/kg) by gavage administration; MAG was orally pretreated at the doses of 45 or 90 mg/kg 3 h before RIF and INH. Rats in each group were sacrificed at 7, 14, and 21 d time points after drug administration.. Liver function, histopathological analysis, and oxidative stress factors were significantly altered in each group. The expression of Mrp2 was significantly increased 230, 760, and 990% at 7, 14, and 21 time points, respectively, in RIF- and INH-treated rats. Compared with the RIF and INH groups, Mrp2 was reduced and Ntcp was significantly elevated by 180, 140, and 160% in the MAG high-dose group at the three time points, respectively. The immunoreaction intensity of Oatp1a4 was increased 170, 190, and 370% in the MAG low-dose group and 160, 290, and 420% in the MAG high-dose group at the three time points, respectively, compared with the RIF and INH groups.. These results indicated that MAG has a protective effects against RIF- and INH-induced hepatotoxicity. The underlying mechanism may have correlation with its effect on regulating the expression of hepatobiliary membrane transporters.

Topics: Administration, Oral; Animals; Antitubercular Agents; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Synergism; Gene Expression Regulation; Glycyrrhizic Acid; Isoniazid; Male; Organic Anion Transporters; Organic Anion Transporters, Sodium-Dependent; Rats, Wistar; Rifampin; Symporters

Drug-induced liver injury is a major challenge in treating tuberculosis with isoniazid (INH) and rifampicin (RIF). This study was aimed at evaluating the protective effects of Bacopamonnieri (Brahmi) against INH and RIF-induced hepatotoxicity in a rat model and also to study the patterns of interaction between pregnane X receptor (PXR) and chosen active compounds of B. monnieri. Hepatotoxicity was induced in the experimental animals by the oral administration of INH and RIF (50 mg/kg b.w. each/day) for 28 days. The effects of co-administration of B. monnieri (500 mg/kg b.w./day) in INH- and RIF-induced rats were studied by the estimation of biochemical analyses. The standard hepatoprotective drug silymarin (25 mg/kg b.w./day) was used for the purpose of comparison. In silico docking experiments were carried out using the PatchDock server and the results were analysed on the PyMol molecular viewer. There was significant reduction in the antioxidant status of INH and RIF-induced rats. Also, there was significant elevation in the levels of serum liver function markers in the INH- and RIF-induced rats. B. monnieri was able to normalise the tested parameters. In silico studies reveal significant interaction between PXR and bacopaside I. B. monnieri exerts significant protective effects against INH and RIF-induced hepatotoxicity in rats.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antitubercular Agents; Aspartate Aminotransferases; Bacopa; Catalase; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Glutathione Peroxidase; Glutathione Transferase; Interleukin-10; Isoniazid; Liver; Molecular Docking Simulation; Plant Extracts; Protective Agents; Rats, Wistar; Rifampin; Superoxide Dismutase

Topics: Alanine Transaminase; Animals; Antitubercular Agents; Aspartate Aminotransferases; ATP Binding Cassette Transporter, Subfamily B; Bilirubin; Chemical and Drug Induced Liver Injury; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hesperidin; Isoniazid; Liver; Male; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Rifampin; Up-Regulation

To investigate the clinical characteristics, adverse drug reactions, and outcomes of the oldest old patients (aged ≥80 years) with tuberculosis (TB) treated with rifampicin, isoniazid, and pyrazinamide (RIP)-containing regimens.. A retrospective chart review study.. A 1,200-bed tertiary teaching hospital in southwest Taiwan.. We conducted a retrospective observational study between January 1, 2005 and December 31, 2011. Seven hundred adult patients (aged ≥18 years) with TB treated with RIP-containing anti-TB regimens were reviewed, including 161 oldest old patients.. Clinical outcomes included clinical responsiveness and microbiological eradication. Adverse outcomes included drug-induced hepatitis, and other symptoms included gastrointestinal upset (eg, abdominal pain, vomiting, diarrhea, or dyspepsia), skin rash, joint pain, and hyperuricemia.. Compared with the non-oldest old adult patients, the oldest old patients more frequently had hepatitis (P=0.014), gastrointestinal upset (P=0.029), and unfavorable outcomes (P<0.001). In a multivariate analysis, hepatitis during treatment (adjusted odds ratio: 3.482, 95% confidence interval: 1.537-7.885; P<0.003) and oldest old age (adjusted odds ratio: 5.161, 95% confidence interval: 2.294-11.613; P<0.010) were independent risk factors for unfavorable outcomes. In the oldest old patients with hepatitis, rifampicin use was more common in the favorable outcome group than in the unfavorable outcome group (100% vs 37.5%; P=0.001).. The oldest old age and hepatitis during RIP treatment were associated with unfavorable outcomes. For the oldest old patients with TB having hepatitis during treatment, rifampicin rechallenge and use might benefit the treatment outcome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Comorbidity; Drug Therapy, Combination; Female; Hepatitis; Hospitals, Teaching; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Taiwan; Treatment Outcome; Tuberculosis; Young Adult

Traditional remedies employ herbal drugs for the treatment of liver ailments and hepatoprotection. Thus, the present study was designed to evaluate the hepatoprotective effect of "extract of Anacyclus pyrethrum Linn" (APE) against antitubercular drug-induced hepatotoxicity in rats.. Group I rats (normal control) received vehicle (1 % CMC), while group II rats (hepatotoxic control) isoniazid (INH) plus rifampicin (RIF) each 50 mg/kg/day po, for 28 days. Group III, IV and V rats were administered with APE 200, APE 400 and silymarin 100 mg/kg/day po, respectively, for 28 days. Concurrently, hepatotoxicity was tried to induce by coadministration of INH and RIF each 50 mg/kg/day po for 28 days in group III, IV and V rats. After 24 h of the last dosing, blood was obtained under light anesthesia and the rats were killed. Hepatoprotective effect was assessed by liver weight, relative liver weight and biochemical parameters such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), serum bilirubin, cholesterol, total protein and albumin levels.. Group IV rats showed significant (p<0.01) decrease in SGPT, SGOT, ALP, LDH, cholesterol, serum bilirubin, liver weight and relative liver weight Levels, while significant (p<0.01) increase in final body weight (b. wt.), total protein and albumin levels as compared to group II rats. Hepatoprotective effect of APE 400 mg/kg/day was comparable to that of silymarin 100 mg/kg/day and the hepatic marker levels were also restored. Hepatoprotective effect of APE was well supported by the histopathological results.. Hydroalcoholic APE root possesses hepatoprotective activity as it exhibited the protective effect against INH plus RIF-induced hepatotoxicity in rats.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antitubercular Agents; Aspartate Aminotransferases; Asteraceae; Bilirubin; Blood Proteins; Chemical and Drug Induced Liver Injury; Cholesterol; Isoniazid; L-Lactate Dehydrogenase; Liver; Male; Organ Size; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Rifampin

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse reaction to anti-tuberculosis (TB) treatment. Thioredoxin reductase 1 (TXNRD1), encoded by the TXNRD1 gene, is an important enzyme involved in oxidant challenge. TXNRD1 plays a key role in regulating cell growth and transformation, and protects cells against oxidative damage. We investigated the association between TXNRD1 polymorphisms and ATDH susceptibility. In this prospective study, 280 newly diagnosed TB patients were followed-up for 3 months after beginning anti-TB therapy. Tag single-nucleotide polymorphisms (tag-SNPs) of TXNRD1 were selected using Haploview 4.2 based on the HapMap database of the Chinese Han in Beijing (CHB) panel. Genotyping was performed using the MassARRAY platform. Of the 280 patients enrolled in this study, 33 were lost to follow-up, 24 had ATDH, and 223 were free from ATDH. After adjusting for sex, age, smoking status, and body mass index, there were no significant differences in the allele and genotype frequency distributions of TXNRD1 SNPs between the ATDH and non-ATDH groups (all P > 0.05). The haplotype analysis showed that haplotype TCAGCC was associated with an increased risk of ATDH susceptibility [P = 0.024, OR (95%CI) = 6.273 (1.023-38.485)]. Further stratified analyses showed that the haplotype TCAGCC was associated with ATDH susceptibility in female subjects [P = 0.036, OR (95%CI) = 5.711 (0.917-35.560)] and non-smokers [P = 0.029, OR (95%CI) = 6.008 (0.971-37.158)]. Our results suggest that TXNRD1 variants may favor ATDH susceptibility in females and non-smokers. Further studies are required to verify this association.

Topics: Adult; Age Factors; Alleles; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethambutol; Female; Gene Expression; Gene Frequency; Haplotypes; Humans; Isoniazid; Liver; Lung; Male; Middle Aged; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Prospective Studies; Pyrazinamide; Rifampin; Risk Factors; Sex Factors; Thioredoxin Reductase 1; Tuberculosis, Pulmonary

Drug-induced hepatitis is known to occur in a proportion of patients on treatment for active tuberculosis (TB).. We prospectively examined the incidence of drug-induced hepatitis in 2070 patients treated for TB with the standard regimen based on 6 months of rifampicin (R, RMP) and isoniazid (H, INH), with 2 months of initial pyrazinamide (Z, PZA) and ethambutol (E, EMB), over a 30-year period from 1981 to 2010, in Blackburn, UK.. Of the 1031 (49.8%) males and 1039 (50.2%) females studied, 451 (21.8%) were White and 1585 (76.6%) were of South Asian origin. Only 34 (1.6%) were of African or other origins. Of the total number of patients treated, 63 (3.0%) had drug-related hepatitis, 26 (5.8%) of whom were White, 37 (2.33%) Asians and 0 other. Incidence was significantly higher in Whites than Asians (OR 2.13, P = 0.008). Incidence increased with increasing age (OR 1.16, P = 0.02). The presumed causative drug was PZA 57%, RMP 32%, INH 11%, EMB 0%. There was no trend of increased hepatitis rates over time.. Rates of drug-induced hepatitis where change of treatment is required are low in patients treated with standard RHZE-based therapy (3%). Caucasians and older patients were more likely to develop hepatitis than their counterparts.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Ethambutol; Female; Follow-Up Studies; Hepatitis; Humans; Incidence; Infant; Infant, Newborn; Isoniazid; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis; Young Adult

In our days, tuberculosis, whet ever its localization, became a curable disease. The cornerstone is a 6 month course of isoniazid, rifampicine and pyrazinamide. All of the three first line antituberculosis drugs may induce hepatic damage which may have negative consequences for treatment outcome. Several risk factors were associated with the development of antituberculosis- drug-induced hepatotoxicity (ATDH). A retrospective study was conducted from July 2014 to March 2015 regarding all therapeutic drug-monitoring requests sent to the Laboratory of Poison Control and Pharmacovigilance Centre of Morocco. 142 patients diagnosed with active tuberculosis were included in study. Plasma peak levels of isoniazid, rifampicin and pyrazinamide were analyzed in plasma samples after 2 to 3 hours of administration of anti-tuberculosis treatment. Logistic regression was used to identify the ATDH risk factors. The incidence of ATDH was found 24.6% (35 patients out of 142). Intergroup differences in the plasma levels were statistically significant for isoniazid (p=0.036). ATDH was found to be associated with combined form of anti-TB drugs (p=0.002, COR=13.1, AOR= 13.5) and plasma concentration of INH superior to 2mg/l (p=0.045, COR=1.3, AOR= 1.4).age, gender, alcohol intake and smoking status were not significantly associated with ATDH. The finding of 24.6% incidence of hepatotoxicity is extremely high. Many factors can be associated with the development of ATDH such as genetic factors, combined forms of treatment and plasma peak levels.

Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Monitoring; Female; Humans; Incidence; Isoniazid; Logistic Models; Male; Middle Aged; Morocco; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis

Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro.. Thirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 μmol/L).. Serum bilirubin of patients with PHSF ranged from 264 to 755 μmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 μmol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTβ.. Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OSTβ could contribute to the anticholestatic effect of rifampicin in PHSF.

Topics: Adenosine Triphosphatases; Adolescent; Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Female; Genetic Predisposition to Disease; Glucuronosyltransferase; Hep G2 Cells; HT29 Cells; Humans; Liver; Liver Failure; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mutation; Pregnane X Receptor; Receptors, Steroid; Rifampin; Risk Factors; Severity of Illness Index; Treatment Outcome; Up-Regulation; Young Adult

The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Ethambutol; Female; Humans; Isoniazid; Liver; Liver Function Tests; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Tuberculosis, Pulmonary; Young Adult

Rifampicin (RIF) was encapsulated into solid lipid nanoparticles (SLNs) to overcome its poor and unreliable oral bioavailability. Novel microemulsification method with high drug loading (50%) and entrapment efficiency (∼67%) was developed (Indian Patent Application 3356/DEL/2013). RIF-SLNs were characterized using TEM, AFM, DSC and XRD. Near neutral SLNs (zeta -3.5 ± 0.8), with average particle size of 130.0 ± 22.6 nm showed 70.12% release in phosphate buffer pH 6.8 in 9 days. Single oral dose (50mg/kg) pharmacokinetic studies in Wistar rats indicated 8.14 times higher (in comparison to free RIF) plasma bioavailability with sustained levels for 5 days. Pharmacodynamic parameters viz. TMIC (120 h; time for which plasma levels were above MIC of 0.2 μg/ml), AUC0-∞/MIC (1868.9h) and Cmax/MIC (75.6) for RIF-SLNs were greater than free RIF by 2.5, 8.2 and 6.6 times, respectively. Similar LD50 (1570 mg/kg) and absence (or reversal in satellite group) of adverse events in repeat dose (three doses; highest dose was up to 50 times the human therapeutic dose) toxicity studies confirmed safety of RIF-SLNs. Improved pharmacokinetic profile of RIF-SLNs can be translated to a reduced dose and dosage frequency of RIF, thus resulting in lower or no hepatotoxicity commonly associated with its use.

Topics: Administration, Oral; Animals; Antibiotics, Antitubercular; Area Under Curve; Biological Availability; Calorimetry, Differential Scanning; Chemical and Drug Induced Liver Injury; Chemistry, Pharmaceutical; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Carriers; Emulsions; Lethal Dose 50; Lipids; Metabolic Clearance Rate; Microscopy, Atomic Force; Microscopy, Electron, Transmission; Nanomedicine; Nanoparticles; Particle Size; Powder Diffraction; Rats, Wistar; Rifampin; Solubility; Technology, Pharmaceutical

Treating latent tuberculosis infection is a strategy for eliminating tuberculosis, and isoniazid is recommended as preventive therapy. However, concerns have been raised regarding the application of isoniazid due to its toxicity, particularly hepatotoxicity; however, biochemical monitoring is not routinely performed during treatment. We herein present a case of fatal isoniazid-induced acute liver failure. The patient's liver function was not periodically examined and isoniazid therapy was continued for 10 days despite the onset of symptoms associated with hepatitis. The patient died four months after hospitalization. It is essential to consider the potential toxicities of isoniazid and establish strategies to prevent acute liver failure.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Hospitalization; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin

Co-treatment of isoniazid (INH) and rifampicin (RFP) is well known for clinically apparent liver injury. However, the mechanism of INH/RFP-induced liver injury is controversial. Emerging evidence shows links between inhibition of bile acids transporters and drug-induced liver injury (DILI). The present study investigates whether sodium taurocholate cotransporting polypeptide (NTCP/Ntcp; SLC10A1) and bile salt export pump (BSEP/Bsep; ABCB11) are involved in the anti-tuberculosis medicines induced liver injury. ICR female mice were intragastrically treated with INH (50 or 100 mg/kg), RFP (100 or 200 mg/kg), or the combination of INH/RFP (50 + 100 mg/kg or 100 + 200 mg/kg) for 14 consecutive days. Liver histopathological examination, serum biochemical and liver malondialdehyde tests were evaluated. Apparent histopathological alterations and hepatic oxidative stress showed in INH (100 mg/kg), RFP (200 mg/kg) and their combination group. The hepatoxic effect was also indicated by increased serum biomarkers, such as aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (DBil), total bilirubin (TBil) and total bile acids (TBA). Both doses of INH/RFP administration significantly down-regulated the expression of Ntcp and Bsep in liver. Furthermore, the combination of INH and RFP displayed stronger effect on the expression of Ntcp compared with the corresponding dose of INH or RFP alone. In conclusion, down-regulated expression of hepatic Ntcp and Bsep might play an important role in the development of INH and RFP induced liver injury.

Topics: Animals; Antitubercular Agents; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Female; Isoniazid; Liver; Liver Function Tests; Mice, Inbred ICR; Organic Anion Transporters, Sodium-Dependent; Rifampin; Symporters

Present study deals with the hepatoprotective activity of polyherbal formulation Hepatoplus (HP) as an oral supplement to the INH and RIF induced hepatitis in experimental rats. Rats treated with INH and RIF show abnormal liver function with significant increase in serum transaminases, bilirubin and clotting time (CT) and significant decrease in total protein and Albumin, which is brings to near normal levels by HP and LIV 52 treatments. Rats treated with INH and RIF suffer from oxidative stress in the hepatocytes, due to the decrease in Glutathione (GSH), Glutathione peroxidase (GPX), Catalase (CAT), Super oxide dismutase (SOD) and significant increase in Lipid Per oxidation (LPO). HP decreases the oxidative stress and protects the liver cells membrane from LPO. 85% of DNA damage (comet tail) seen with RIF and INH treatment is reduced to 34.1% on HP application. A decrease of hepatocytes mitochondrial dehydrogenase activity is observed in INH and RIF treatment is restored by HP supplementation. Hepatic apoptotic and CYP2E1 gene expressions were also studied, BAX, p53, Caspase 3 and CYP2E1 were significantly up regulated and Bcl2 was down- regulated in INH and RIF treated rats. Concomitant application of HP prevents the modulation of these gene expressions. It is concluded that high dose of HP (100mg/kg) supplemented along with INH and RIF effectively prevents the toxicity induced by INH and RIF, as effective as 100mg/kg of LIV52.

Topics: Animals; bcl-2-Associated X Protein; Caspase 3; Chemical and Drug Induced Liver Injury; Curcuma; Cycas; Cytochrome P-450 CYP2E1; Eclipta; Gene Expression; Genes, p53; Isoniazid; Liver; Medicine, Ayurvedic; Orchidaceae; Phyllanthus; Picrorhiza; Pinus; Pistacia; Plant Preparations; Protective Agents; Rats; Rifampin; Tephrosia; Withania

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin

Isoniazid (INH) and rifampicin (RIF), the most common anti-tubercular therapy, causes hepatotoxicity through a multi-step mechanism in certain individuals. The present study was an attempt to evaluate the hepatoprotective effect of coenzyme Q10 against INH + RIF-induced hepatotoxicity in Wistar albino rats.. Hepatotoxicity was induced by the oral administration of INH + RIF (50 mg/kg b.w. each/day) in normal saline water for 28 days. The hepatoprotective effect of coenzyme Q10 (10 mg/kg b.w./day) was compared with that of the standard drug silymarin (25 mg/kg b.w./day). Animals were sacrificed at the end of the study period, and blood and liver were collected for biochemical, immunological and histological analyses.. Evaluation of biochemical parameters showed that coenzyme Q10 treatment caused significant (P < 0.05) reduction in the elevated levels of serum liver function markers and restored normal levels of total protein, albumin and lipids in INH + RIF-treated rats. Also, it was observed that coenzyme Q10 was able to restore normal levels of enzymic antioxidants, reduced glutathione and lipid peroxidation in the INH + RIF-treated rats. Coenzyme Q10 was found to effectively reduce the extent of liver damage caused due to INH + RIF. In addition, the levels of IL-10 and IL-6 were significantly elevated in the INH + RIF-induced rats treated with CoQ10.. Our study indicates the protective role of coenzyme Q10 in attenuating the hepatotoxic effects of INH + RIF in a rat model and that it could be used as a food supplement during anti-tubercular therapy.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Dietary Supplements; Female; Interleukin-10; Isoniazid; Liver; Rats; Rats, Wistar; Rifampin; Silymarin; Ubiquinone; Vitamins

In our searching for novel antioxidants from natural sources, N-trans-Caffeoyldopamine which was from natural product was found to be a potential compound for its remarkable antioxidant activity. Isoniazid (INH) and Rifampicin (RFP) is widely used for the treatment of Tuberculosis (TB) as the first line drugs, have been known to be potentially hepatotoxic and may lead to drug-induced liver injury. Oxidative stress has been regarded as the major mechanism of the hepatotoxicity. Therefore, in this study, the possible protective effects of N-trans-Caffeoyldopamine was investigated in the hepatotoxicity caused by INH and RFP in rats. Results showed that serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and hepatic malondialdehyde (MDA) content were reduced dramatically, and hepatic superoxide dismutase (SOD) activity and glutathione (GSH) content were restored remarkably by N-trans-Caffeoyldopamine co-administration, as compared to the INH-RFP treated rats (p<0.01). Moreover, the histopathological damage of liver and the number of apoptotic hepatocytes were also significantly ameliorated by the treatment. It is therefore suggested that N-trans-Caffeoyldopamine can provide a definite protective effect against acute hepatic injury caused by INH and RFP in rats, which may mainly be associated with its antioxidative effect. Mechanisms studies indicated that it inhibited the lipid peroxidation through the cytochrome P450 2E1 (CYP2E1) downregulation.

Topics: Animals; Biological Products; Caffeic Acids; Chemical and Drug Induced Liver Injury; Dopamine; Isoniazid; Liver; Molecular Structure; Rats; Rifampin

The aim of this study was to examine hepatoprotective effect of ethanolic extract of propolis (KPEt) from Kashmir Himalaya against isoniazid and rifampicin (INH-RIF) induced liver damage in rats. Hepatic cellular injury was initiated by administration of INH-RIF combination (100 mg/kg) intraperitoneal (i.p.) injection for 14 days. We report the protective effects of KPEt against INH-RIF induced liver oxidative stress, inflammation, and enzymatic and nonenzymatic antioxidants. Oral administration of KPEt at both doses (200 and 400 mg/kg body weight) distinctly restricted all modulating oxidative liver injury markers and resulted in the attenuation of INH-RIF arbitrated damage. The free radical scavenging activity of KPEt was evaluated by DPPH, nitric oxide, and superoxide radical scavenging assay. The components present in KPEt identified by ultra high performance liquid chromatography diode array detector time of flight-mass spectroscopy (UHPLC-DAD-QToF-MS) were found to be flavonoids and phenolic acids. The protective efficacy of KPEt is possibly because of free radical scavenging and antioxidant property resulting from the presence of flavonoids and phenolic acids.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Lipid Peroxidation; Liver; Male; Oxidative Stress; Propolis; Rats; Rifampin

Socially anxious cannabis users are influenced by cannabis expectancies and normative perceptions. The present study examines the influence of psychosocial factors on cannabis use vulnerability factors as the result of interactions between norms perceptions, social anxiety, and expectancies.. Participants were 149 (36.2% female) current cannabis users aged 18-36 (. Among cannabis users with perceptions of greater injunctive norms, social anxiety was associated with greater cannabis craving when tension reduction expectancies were greater. However, social anxiety was unrelated to cannabis craving when expectances were low. This suggests that cannabis craving among socially anxious adults was greatest when cannabis use was viewed as acceptable and expected to reduce tension, and highlights the importance of considering norms, expectancies, and social anxiety in understanding cannabis-related behaviors.. The A876P-substitution bridges in vitro and in vivo studies using J6/JFH1-based recombinants. We provide the first in vivo evidence that HVR1 protects cross-genotype conserved HCV neutralisation epitopes, which advocates the possibility of using HVR1-deleted viruses as vaccine antigens to boost broadly reactive protective nAb responses.. We conclude that the photo-processing of eVSGs leads to the production of PAHs with attached aliphatic sidegroups that are revealed by the 3.4. De 4,331 publicaciones encontradas, 16 estudios cumplieron con los criterios de inclusión. El 50 % (8/16) de los estudios revisados fueron realizados en países de Sur América, Centro América y del Caribe. El diseño de casos y controles fue el más frecuente. El anterior sistema de clasificación de casos (OMS-1997) fue utilizado en todos los estudios incluidos en esta revisión.. El estrés oxidativo-nitrosativo se encuentra presente en el curso de la infección por virus dengue, demostrado por los cambios en las concentraciones plasmáticas de óxido nítrico, antioxidantes y marcadores de lipoperoxidación y de oxidación de proteínas. Por último, parece existir una asociación entre la elevación de los niveles plasmáticos de los carbonilos proteicos y malondialdehído con la severidad del dengue.

Topics: Acid-Base Imbalance; Acidosis, Renal Tubular; Aged; Air Pollution, Indoor; Amino Acid Substitution; Animals; Animals, Newborn; Anti-Bacterial Agents; Antibodies, Neutralizing; Apoptosis; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Bone Marrow Transplantation; Carbonic Anhydrase Inhibitors; Castleman Disease; Cat Diseases; Cats; Cell Proliferation; Cell- and Tissue-Based Therapy; Chemical and Drug Induced Liver Injury; Chemotaxis, Leukocyte; Clinical Trials as Topic; Coated Materials, Biocompatible; Diagnosis, Differential; Disease Models, Animal; Environmental Monitoring; Female; Gas Chromatography-Mass Spectrometry; Genotype; Granuloma, Foreign-Body; Heart Failure; Hepacivirus; Hepatitis C; Horse Diseases; Horses; Housing; Humans; Hypercalcemia; Hypokalemia; Immunophenotyping; In Vitro Techniques; Liver; Liver Function Tests; Lymphocytes; Macrophages; Male; Medicine, Chinese Traditional; Metabolomics; Mice; Mice, Inbred C57BL; Middle Aged; Models, Animal; Mutation; Myocardial Ischemia; Neovascularization, Physiologic; Neutrophil Infiltration; Ocular Hypertension; Ophthalmic Solutions; Parathyroid Hormone; Particulate Matter; Polyethylene Terephthalates; Prednisolone; Prospective Studies; Prosthesis Design; Prosthesis-Related Infections; Rats; Rats, Wistar; Reactive Oxygen Species; Rifampin; Saponins; Sepsis; Skin; Stem Cells; Stroke Volume; Sulfonamides; Texas; Thiophenes; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Viral Hepatitis Vaccines; Viral Nonstructural Proteins; Viral Proteins; Vitamin D; Wound Healing

Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.. These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; Humans; Male; Mitochondria, Liver; Rats; Rats, Sprague-Dawley; Severity of Illness Index

Short-course directly observed isoniazid plus rifapentine (INH/RPT) combination could have potential advantages over a standard 9-month INH regimen for the treatment of latent tuberculosis infection in solid-organ transplant (SOT) candidates.. We prospectively assessed the safety and tolerability of 12 weeks of INH/RPT given directly observed therapy in 17 consecutive SOT candidates with latent tuberculosis infection.. The median age was 57 years and 82% were men. Of the 17 patients, 13 (76%) successfully completed therapy and 4 (24%) eventually underwent SOT. Treatment was prematurely discontinued in four patients. One of these patients underwent a kidney transplant. The overall dose compliance was 83% (169/204 scheduled doses), and 12 (71%) of 17 patients received 100% of scheduled doses. No patient developed transaminase elevations greater than twice baseline or greater than four times the upper limit of normal or clinical hepatotoxicity. No cases of TB developed during 20.4 months after transplant among INH/RPT-treated recipients.. For carefully selected SOT candidates, combination INH/RPT weekly given as directly observed therapy seems to be reasonably well tolerated and is associated with a relatively high completion rate. Future larger prospective studies to confirm the safety and high completion rates reported here and to identify the most appropriate SOT candidates for this regimen are warranted.

Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Organ Transplantation; Prospective Studies; Rifampin

Isoniazid (INH) can cause serious idiosyncratic liver injury. An animal model would greatly facilitate mechanistic studies, but it is essential that the mechanism in the model be similar to the liver injury that can occur in humans. We attempted to replicate a previous study in which Wistar rats treated with INH and rifampicin (RMP) developed liver injury, which was promising because of its delayed onset similar to the liver injury that can occur in humans. Wistar rats were treated with either a high dose of INH (150 mg/kg/day) or a combination of INH and RMP (75 mg/kg/day and 50 mg/kg/day, respectively) for up to 4 weeks. However, we did not observe any liver injury or evidence of an inflammatory infiltrate as had been reported; rather, we observed an increase in CTLA4-positive cells in the cervical lymph nodes as well as a decrease in serum CXCL1 and MCP-1. In short, we were unable to reproduce a previously reported model of delayed onset INH-induced liver injury in Wistar rats.

Topics: Alanine Transaminase; Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; CTLA-4 Antigen; Cytokines; Drug Therapy, Combination; Glutamate Dehydrogenase; Interleukin-2 Receptor alpha Subunit; Isoniazid; Lymph Nodes; Male; Neck; Rats; Rats, Wistar; Rifampin; Succinate Dehydrogenase

Yulangsan polysaccharide (YLSPS) is often used in popular folk medicine in the Guangxi Zhuang Autonomous Region of China as a chief ingredient of Millettia pulchra, which is used as an hepatic protection, anti-aging and memory improving agent. In this study, the hepatoprotective effects of YLSPS against isoniazid (INH) or rifampicin and isoniazid (RFP+INH)-induced liver injury were investigated in mice.. The liver injury was induced by intragastric administration of INH or RFP+INH daily for 10 days. During the experiment, the model group received INH or RFP+INH only, and the normal control group received an equal volume of saline. Treatment groups received not only INH or RFP+INH but also the corresponding drugs, DDB (200mg/kg/day) or YLSPS (100, 200, and 400mg/kg/day) 2h after the administration of INH or RFP+INH.. Analysis experiments showed that YLSPS significantly alleviated liver injury as indicated by the decreased levels of ALT and AST and the increased levels of SOD, GSH and GSH-Px. Moreover, YLSPS could effectively reduce the pathological tissue damage. The research on the mechanisms underlying the hepatoprotective effect showed that YLSPS was able to reduce lipid peroxidation and activate the anti-oxidative defense system.. Our results show that YLSPS is effective in attenuating hepatic injury in the INH or RFP+INH-induced mouse model, and could be developed as a new drug for treatment of liver injury.

Topics: Animals; Antioxidants; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Isoniazid; Lipid Peroxidation; Male; Mice; Millettia; Polysaccharides; Rifampin

To compare the free and total plasma drug concentrations of rifampicin (RMP), isoniazid and pyrazinamide in subjects with or without anti-tuberculosis drug-induced hepatotoxicity (DIH).. A total of 110 tuberculosis (TB) patients were administered daily anti-tuberculosis treatment and were prospectively followed for the development of DIH. Plasma drug levels were measured at 0, 1, 2 and 4 h on days 1, 7 and 14 of treatment. Plasma drug levels in 15 patients who developed DIH (cases) were compared with 95 patients who did not (controls).. Female sex, body mass index < 17 kg/m(2) and baseline serum albumin < 4 g/dl predicted risk of DIH on univariate analyses. Free and total plasma RMP levels (Cmax and AUC0-4) on days 1, 7 and 14 were significantly higher in cases compared to controls and predicted development of DIH. Day 7 total RMP Cmax and AUC0-4 were higher in cases (mean 26.73, standard deviation [SD] 5.72 and 47.58, SD 33.10) than in controls (7.87, SD 10.95 and 14.01, SD 10.69, respectively).. Plasma RMP levels were higher in cases than in controls and independently predicted subsequent development of DIH. The Cmax of Day 7 total RMP level (cut-off 12.50 mg/l) predicted subsequent development of DIH in 93.3% of the patients.

Topics: Adult; Antitubercular Agents; Area Under Curve; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Metabolic Clearance Rate; Prospective Studies; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury.. In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays.. 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes.. In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury.

Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Chemical and Drug Induced Liver Injury; China; Cross-Sectional Studies; Cytochrome P-450 CYP2E1; Drug Therapy, Combination; Ethambutol; Female; Gene Frequency; Genetic Association Studies; Glutathione Transferase; Humans; Incidence; Isoniazid; Male; Middle Aged; Polymorphism, Single Nucleotide; Prevalence; Pyrazinamide; Rifampin; Sex Distribution; Tuberculosis, Pulmonary; Young Adult

Tarvada [Cassia auriculata Linn. (Caesalpiniaceae)] is used against liver ailments in Indian folk medicine, but there is a lack of scientific evidence for this traditional claim.. The present study investigated the protective effect of methanol extract of tarvada (MECA) roots on ethanol and antitubercular drug induced hepatotoxicity in rats.. In the therapeutic model, ethanol (40%, 4 g/kg b.w., p.o.) was administered to rats for 21 days and the intoxicated rats were treated with MECA (300 and 600 mg/kg, b.w.) and silymarin (100 mg/kg, b.w.) for next 7 days. In the prophylactic model, MECA and silymarin were administered simultaneously along with a combination of isoniazid (27 mg/kg, b.w.), rifampicin (54 mg/kg, b.w.) and pyrazinamide (135 mg/kg, b.w.) for 30 days. After the study duration, serum levels of AST, ALT, ALP, total bilirubin, total cholesterol, total protein, albumin were estimated along with hepatic catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and liver histopathology in each group.. Administration of tarvada root extract significantly (p < 0.01 and p < 0.05) lowered the elevated levels of serum AST, ALT, ALP, total bilirubin, total cholesterol, total protein and restored the abnormal levels of enzymatic antioxidants and MDA in liver due to toxicant administration in a dose-dependent manner. These results were confirmed by histopathological analysis.. Results suggest that tarvada root extract possess potent hepatoprotective activity against ethanol and antitubercular drug-induced hepatotoxicity in rats, which could be due to an inhibition of hepatic metabolizing enzymes and antioxidant activity.

Topics: Animals; Antioxidants; Antitubercular Agents; Cassia; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Female; India; Isoniazid; Male; Medicine, Traditional; Plant Extracts; Plant Roots; Pyrazinamide; Rats; Rats, Wistar; Rifampin; Silymarin

In preclinical hepatotoxicity testing cell based assays are frequently employed. However, prediction of clinical drug induced liver injury (DILI) remains a major challenge. Here we examined the usefulness of frequently employed markers of hepatocellular injury in cultures of primary human hepatocytes (PHH) in response to treatment with either paracetamol, rifampicin, petadolex and/or amiodarone. The changes in the metabolic competency (urea and albumin) and cellular injury (AST, ALT, ALP, LDH, γGT and succinate dehydrogenase) were determined at therapeutic and above drug concentrations as to evaluate the utility of these markers in in vitro systems. Initially, treatment of PHH with any of the drugs caused a statistically significant reduction in enzyme activities to suggest a switch from basic amino acid metabolism towards induced detoxification. However, treatment for prolonged periods of time caused cytolysis, as evidenced by the significant rise in extracellular LDH and the concomitant increase in ALT and AST activity. Notably, amongst the various endpoints studied, urea was best to demonstrate dose dependent metabolic stress, while other markers of hepatocellular injury were highly variable. Taken collectively, urea measurement proofed to be robust in predicting hepatocellular stress; therefore it should be included in preclinical testing strategies for an improved prediction of DILI.

Topics: Acetaminophen; Alanine Transaminase; Albumins; Alkaline Phosphatase; Amiodarone; Aspartate Aminotransferases; Biological Assay; Chemical and Drug Induced Liver Injury; gamma-Glutamyltransferase; Hep G2 Cells; Hepatocytes; Humans; L-Lactate Dehydrogenase; Liver Function Tests; Petasites; Plant Extracts; Rifampin; Urea

Therapy using Isoniazid (INH) and Rifampicin (RIF) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment. In this study, we assessed the effect of Spirulina fusiformis on INH and RIF induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin. Induction of hepatotoxicity was measured by changes in the liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase). The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, and lipid peroxidation levels. We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor (PXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of Spirulina fusiformis by in silico methods. The administration of INH and RIF resulted in significant (p < 0.05) decrease in the antioxidant levels and total protein levels. There was also a significant (p < 0.05) increase in the levels of liver marker enzymes. Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with INH and RIF in a dose-dependent manner. This was corroborated by histological examination of the liver. The results of the in silico analyses further support the wet lab results.

Topics: Animals; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Isoniazid; Ligands; Lipid Peroxidation; Liver; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Organ Size; Oxidoreductases; Pregnane X Receptor; Probiotics; Protective Agents; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Rifampin; Silymarin; Spirulina

Acute liver injury was induced in male BALB/c mice by coadministering isoniazid and rifampicin. In this work, the effects of resveratrol (1) were investigated in the hepatotoxicity caused by isoniazid-rifampicin in mice. Compound 1 was administered 30 min prior to isoniazid-rifampicin. Serum biochemical tests, liver histopathological examination, oxidative stress, myeloperoxidase activity, cytokine production (TNF-α, IL-12p70, and IL-10), and mRNA expression of SIRT1-7 and PPAR-γ/PGC1-α were evaluated. The administration of 1 significantly decreased aspartate transaminase and alanine aminotransferase levels, myeloperoxidase activity, and cytokine levels. Furthermore, 1 reverted the decrease of catalase and glutathione activities and ameliorated the histopathological alterations associated with antituberculosis drugs. Modulation of SIRT1 and PPAR-γ/PGC1-α expression is likely involved in the protective effects of 1. The results presented herein show that 1 was able to largely prevent the hepatotoxicity induced by isoniazid and rifampicin in mice, mainly by modulating SIRT1 mRNA expression.

Topics: Alanine Transaminase; Animals; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Glutathione; Interleukin-10; Isoniazid; Liver; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Oxidation-Reduction; Oxidative Stress; Peroxidase; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Resveratrol; Rifampin; Sirtuin 1; Stilbenes; Transcription Factors; Tumor Necrosis Factor-alpha

The purpose of this report is to present a case of hepatotoxicity secondary to off-label rifampin therapy for the treatment of chronic central serous choroidopathy.. Case report.. A patient with chronic central serous chorioretinopathy was treated with oral rifampin. Three weeks after the initiation of therapy, fatigue, nausea, and malaise associated with elevated liver enzyme elevations were noted. Symptoms resolved and liver enzymes normalized after discontinuing rifampin.. Rifampin-induced hepatic injury can occur during therapy for chronic central serous chorioretinopathy. Potential hepatotoxicity must be considered and followed closely during off-label rifampin treatment.

Topics: Aged; Central Serous Chorioretinopathy; Chemical and Drug Induced Liver Injury; Chronic Disease; Humans; Male; Nucleic Acid Synthesis Inhibitors; Rifampin

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Co-therapy with rifampicin (RIF) and isoniazid (INH) used to treat tuberculosis in humans frequently causes liver injury. Here, using a pregnane X receptor (PXR)-humanized mouse model, we found that co-treatment with RIF and INH causes accumulation of the endogenous hepatotoxin protoporphyrin IX in the liver through PXR-mediated alteration of the heme biosynthesis pathway. These results provide insight into the mechanism of liver injury induced by co-treatment with these compounds and may lead to their safer use in the clinic.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Heme; Humans; Isoniazid; Liver; Male; Mice; Mice, Transgenic; Pregnane X Receptor; Protoporphyrins; Receptors, Steroid; Rifampin

To assess the cost-effectiveness ratio of rifampin for 4 months and isoniazid for 6 months in contacts with latent tuberculosis infection.. The cost was the sum of the cost of treatment with isoniazid for 6 months or with rifampin for 4 months of all contacts plus the cost of treatment of cases of tuberculosis not avoided. The effectiveness was the number of cases of tuberculosis avoided with isoniazid for 6 months or with rifampin for 4 months. When the cost with one schedule was found to be cheaper than the other and a greater number of tuberculosis cases were avoided, this schedule was considered dominant. The efficacy adopted was 90% for rifampin for 4 months and 69% for isoniazid for 6 months. A sensitivity analysis was made for efficacies of rifampin for 4 months of 80%, 69%, 60% and 50%.. Of the 1002 patients studied, 863 were treated with isoniazid for 6 months and 139 with rifampin for 4 months The cost-effectiveness ratio with isoniazid for 6 month was € 19759.48/avoided case of tuberculosis and € 8736.86/avoided case of tuberculosis with rifampin for 4 months. Rifampin for 4 months was dominant. In the sensitivity analysis, rifampin for 4 months was dominant for efficacies from 60%.. Rifampin for 4 months was more cost-effective than isoniazid for 6 months.

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Drug Administration Schedule; Drug Costs; Female; Health Care Costs; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin; Sensitivity and Specificity; Spain; Treatment Outcome; Tuberculin Test; Young Adult

The worldwide increment of multidrug- and extensively drug-resistant tuberculosis has emphasized the importance of looking for new options in therapeutics. Long-time usage or higher doses of isoniazid and rifampicin have been considered for the treatment of multidrug-resistant tuberculosis; however, the risk of liver failure is proportionally increased. Hepatocyte growth factor (HGF) is a multitask growth factor that stimulates both antiapoptotic and antioxidant responses that counteract the toxic effects of drug metabolism in the liver. The present work was focused to address the antioxidant and antiapoptotic effects of HGF on isoniazid- and rifampicin-induced hepatotoxicity. BALB/c mice were subjected to rifampicin (150mg/kg, intragavage [ig]) plus isoniazid (75mg/kg, ig) for 7 days. Increments in alanine aminotransferase activity, steatosis, apoptosis, and oxidative stress markers were found in animals. Recombinant HGF (iv) prevented all the harmful effects by increasing the activation of Erk1/2 and PKCδ signaling pathways and glutathione (GSH) synthesis. Furthermore, inhibition of endogenous HGF with anti-HGF antibody (iv) enhanced the isoniazid- and rifampicin-induced oxidative stress damage and decreased the GSH content, aggravating liver damage. In conclusion, HGF demonstrated to be a good protective factor against antituberculosis drug-induced hepatotoxicity and could be considered a good adjuvant factor for the use of high doses of or the reintroduction of these antituberculosis drugs.

Topics: Alanine Transaminase; Animals; Antitubercular Agents; Apoptosis; Chemical and Drug Induced Liver Injury; Hepatocyte Growth Factor; Isoniazid; Liver; Mice; Mice, Inbred BALB C; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Rifampin

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Male; Receptors, Steroid; Rifampin

Hepatotoxicity is the most serious adverse effect related to tuberculosis treatment which interrupts the successful completion of tuberculosis treatment. The purpose of this study was to assess therapeutic effect of thymoquinone (TQ) against anti-tuberculosis drugs (ATD) induced liver damage. Rats were treated with ATD for 8 weeks (3 days/week) as given for the treatment of TB. This was followed by therapy of TQ for 8 weeks (3 days/week). Administration of combined ATD induced hepatotoxicity was evident from a significant elevation in the AST, ALT, ALP, bilirubin, albumin, cholesterol, urea, uric acid, creatinine, LPO and decreased activities of enzymes. These altered variables were significantly reversed toward control after treatment with TQ. Histological studies also supported biochemical findings. Results of this study strongly indicated protective effect of TQ and thus, can be expected as promising protective agent in maintenance of normal hepatic function during treatment with ATD.

Topics: Analysis of Variance; Animals; Antitubercular Agents; Benzoquinones; Blood Chemical Analysis; Chemical and Drug Induced Liver Injury; Ethambutol; Female; Isoniazid; Kidney; Lipid Peroxidation; Lipids; Liver; Liver Function Tests; Pyrazinamide; Rats; Rats, Sprague-Dawley; Rifampin; Superoxide Dismutase

Liver injury is the most common and clinically significant adverse reaction to anti-tuberculosis drugs, sometimes resulting in a fatal outcome. It has been reported that liver injury induced by isoniazid and pyrazinamide, which has the potential to cause hepatocellular injury, has a risk of becoming severe; while an injury induced by rifampicin, which has the potential to cause cholestatic injury, rarely becomes severe. However, mixed liver injury has not been studied thoroughly.. Of 321 tuberculosis patients who were admitted and treated in our hospital over the past 5 years, 7 patients (2.1 %) who developed mixed liver injury due to the use of antituberculosis drugs were clinically investigated through their medical records.. There were 4 male patients and 3 female patients, with a mean age of 66.7 (59-85) years. The mean duration from the start of oral anti-tuberculosis drugs to the onset of mixed liver injury was 28.5 days. In 2 of the patients, the event occurred within 2 weeks. Two of them had a total bilirubin level of > 5 mg/dl at the time of diagnosis. In 6 of the 7 patients, the liver injury improved on discontinuation of the anti-tuberculosis drugs. In the remaining 1 patient, the liver injury progressed even after discontinuation of the oral treatment, leading to death.. Since mixed liver injury sometimes results in a fatal outcome, it is necessary to take adequate precautions.

Topics: Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Insecta; Rats; Risk Factors

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

To assess the hepatoprotective effect of Solanum xanthocarpum (S. xanthocarpum) fruit extract against antitubercular drug-induced liver toxicity in experimental animals.. Ethanolic (50%) fruit extract of S. xanthocarpum (100, 200 and 400 mg/kg bw) was administered daily for 35 days in experimental animals. Liver toxicity was induced by combination of three antitubercular drugs [isoniazid (I) 7.5 mg/kg, rifampicin (R) 10 mg/kg and pyrazinamide (P) 35 mg/kg] given orally as suspension for 35 days in rats. The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatise (ALP), total bilirubin (TBL), albumin (ALB), total protein (TP), lactate dehydroginase (LDH), and serum cholesterol (CHL). Meanwhile, in vivo antioxidant activities as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured in rat liver homogenate. The biochemical observations were supplemented by histopathological examination.. The results demonstrated that treatment with S. xanthocarpum significantly (P<0.05-P<0.001) and dose-dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, S. xanthocarpum significantly (up to P<0.001) reduced the LPO in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels. Histopathology of the liver tissue showed that S. xanthocarpum attenuated the hepatocellular necrosis and led to reduction in inflammatory cells infiltration.. The results of this study strongly indicate the protective effect of S. xanthocarpum against liver injury which may be attributed to its hepatoprotective activity, and thereby scientifically support its traditional use.

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; Fruit; Gastrointestinal Agents; Histocytochemistry; Isoniazid; Liver; Liver Function Tests; Male; Mice; Plant Extracts; Plasma; Pyrazinamide; Rats, Wistar; Rifampin; Solanum

The outlook of inflammatory joint diseases has changed significantly with the advent of TNF blockers. However, these advances come with a trade off-risk of infections, especially tuberculosis. The Irish society of rheumatology has proposed guidelines to investigate and treat latent TB infection (LTBI), which is in accordance with majority of international recommendations. This protocol requires that every patient with LTBI should have chemoprophylaxis. INH and different anti-rheumatic drugs are known to cause hepatic and gastrointestinal complications. We sought to investigate the toxicity of adding prophylactic anti-TB medications to different DMARDs and anti-TNF agents. We prospectively documented the course of all patients who were prescribed chemoprophylaxis for LTBI, from August 2007 to August 2008. Arrangements were made for central re-issuing of prescription of INH or rifampicin, after reviewing monthly liver function tests and following telephone interview seeking presence of adverse events. Out of 132 patients who were commenced on different TNF blockers, only 23 patients (17%) were diagnosed with LTBI and were given prophylaxis as per recommended guidelines. Thirty-nine percent (9 out of 23) of patients discontinued INH because of adverse events. Primary reason for discontinuation in these 9 patients was as follows: 3 patients got marked transaminitis (transaminases >5 times the normal limit), 5 patients had non-resolving gastrointestinal intolerance (mainly nausea), and one patient developed non-resolving rash. We have found a significant number of our patients (39%) who could not continue anti-TB prophylaxis due to either gastrointestinal intolerance or hypertransaminesemia.

Topics: Adult; Aged; Antirheumatic Agents; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chemoprevention; Female; Gastrointestinal Diseases; Humans; Incidence; Isoniazid; Latent Tuberculosis; Liver Function Tests; Male; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Retrospective Studies; Rheumatic Diseases; Rifampin; Risk Factors; Tumor Necrosis Factor-alpha

Topics: 5-Aminolevulinate Synthetase; alpha-Thalassemia; Anemia, Sideroblastic; Antitubercular Agents; Aza Compounds; Bone Marrow; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; Hemolysis; Humans; Isoniazid; Middle Aged; Moxifloxacin; Peritonitis, Tuberculous; Pyrazinamide; Pyridoxine; Quinolines; Rifampin

Tuberculosis (TB) treatment can cause serious sequelae including adverse effects such as anti-TB drug-induced hepatotoxicity (ATDH). We performed a candidate gene-based association study between single nucleotide polymorphisms (SNPs) in 10 genes in the antioxidant pathway and ATDH susceptibility. The subjects comprised 100 Japanese patients with pulmonary TB who received a treatment regimen including isoniazid and rifampicin. Out of them, 18 patients had ATDH. Thirty-four tag SNPs in 10 genes were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing. The frequencies of alleles and genotypes between patients with and without ATDH were compared in three different genetic models. Statistical analyses revealed that a C/C genotype at rs11080344 in NOS2A, a C/C genotype at rs2070401 in BACH1, and a G/A or A/A genotype at rs4720833 in MAFK independently conferred ATDH susceptibility. Remarkably, the association of the latter two tag SNPs with ATDH susceptibility was highly statistically significant (P = 0.0006) with an odds ratio of 9.730. This study is the first report to demonstrate that NOS2A, BACH1, and MAFK appear to be genetic determinants of ATDH in Japanese patients with TB. Furthermore, a combination of BACH1 and MAFK polymorphisms may be useful as new biomarkers to identify high-risk Japanese TB patients for ATDH.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Basic-Leucine Zipper Transcription Factors; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Fanconi Anemia Complementation Group Proteins; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Isoniazid; MafK Transcription Factor; Male; Middle Aged; Nitric Oxide Synthase Type II; Oxidation-Reduction; Polymorphism, Single Nucleotide; Rifampin; Risk Factors; Tuberculosis, Pulmonary; Young Adult

Our observational study was conducted to assess if the case--crossover design could be applied to detect the risk of hepatoxic drugs on liver injury in the automated databases.. The study was conducted on approximately 22 million people enrolled in Taiwan's National Health Insurance database from 1997 to 2004. We applied case--crossover and case--control designs to assess the estimated risks of liver injury related to well-known hepatoxic drugs, including isoniazid, rifampicin, erythromycin, and diclofenac. Using case--crossover and case--control designs, we analyzed to explore the association between hospitalization and our target drugs through a conditional logistic regression model.. The adjusted odds ratios (ORs) of isoniazid, rifampicin, erythromycin, and diclofenac showed 24.4 (confidence interval [CI] =10.7-55.5), 30.8 (CI=14.1-67.1), 2.1 (CI=1.4-3.1), and 2.9 (CI=2.4-3.5) among 4,413 hospitalized liver injury patients during the 30-day exposure window by the case--crossover designs. Most adjusted ORs by case--crossover design were more conservative than ORs by case--control design.. In addition to a case--control design, the case--crossover design is a suitable method, for detecting the potential hepatotoxicity of drugs.

Topics: Adult; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Chemical and Drug Induced Liver Injury; Comorbidity; Cross-Over Studies; Databases as Topic; Diclofenac; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Female; Hospitalization; Humans; Isoniazid; Logistic Models; Male; Middle Aged; Odds Ratio; Pregnancy; Research Design; Rifampin; Risk Assessment; Taiwan; Time Factors; Young Adult

To evaluate the hepatoprotective potential of ethanolic (50%) extract of Ziziphus oenoplia (L.) Mill (Z. oenoplia) root against isoniazid (INH) and rifampicin (RIF) induced liver damage in animal models.. Five groups of six rats each were selected for the study. Ethanolic extract at a dose of 150 and 300 mg/kg as well as silymarin (100 mg/kg) were administered orally once daily for 21 d in INH + RIF treated groups. The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), and bilirubin were estimated along with activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione peroxidase, and hepatic melondialdehyde formation. Histopathological analysis was carried out to assess injury to the liver.. The considerably elevated serum enzymatic activities of glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, alkaline phosphatase and bilirubin due to INH + RIF treatment were restored towards normal in a dose dependent manner after the treatment with ethanolic extract of Z. oenoplia roots. Meanwhile, the decreased activities of superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase were also restored towards normal dose dependently. In addition, ethanolic extract also significantly prevented the elevation of hepatic melondialdehyde formation in the liver of INH + RIF intoxicated rats in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections.. The results of this study strongly indicate that ethanolic extract of Z. oenoplia has a potent hepatoprotective action against INH + RIF induced hepatic damage in rats.

Topics: Animals; Antioxidants; Antitubercular Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Enzymes; Ethanol; Hepatocytes; Isoniazid; Male; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Rifampin; Ziziphus

To investigate the cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on cultured QSG-7701 cells lines.. Isoniazid, rifampicin, mixture of rifampicin and isoniazid, acetylhydrazine, hydrazine were added in cultural media of QSG-7701 cells and cultured for 48 hours. The survival rate of cells was determined by MTT method. The cultural media and cells were collected and the activity of lactate dehydrogenase was detected by chromatometry.. Compared with control group, the survival rate decreased significantly and the lactate dehydrogenase released from cell increased significantly in cells treated with isoniazid, rifampicin, acetylhydrazine, hydrazine. Hydrazine, the metabolite of isoniazid produced significant damage on hepatocytes in low concentration.. Rifampicin together with rifampicin and metabolites of isoniazid produce cellular toxic effects and hydrazine may be the most toxiferous metabolite.

Topics: Analysis of Variance; Antitubercular Agents; Case-Control Studies; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Drug Combinations; Hepatocytes; Humans; Isoniazid; L-Lactate Dehydrogenase; Rifampin

The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n = 118) and without (non-DILI) (n = 155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 *1a, *1b, *5 and *15, with their respective frequencies being 23.44, 66.30, 0.73 and 9.52% in a total of 273 individuals. The logistic regression analysis indicated that the *15 haplotype was associated with susceptibility to DILI (p = 0.03, OR = 2.04, 95% CI 1.05-3.96). The frequency of the *15 haplotype in DILI patients was significantly higher than that in non-DILI patients (p = 0.03). In the subgroup analysis, the *15 haplotype was associated with susceptibility to cholestatic/mixed injury (p = 0.03, OR = 2.31, 95% CI 1.06-5.02). Functional assessment of the OATP1B1 *15 haplotype revealed that the activity of bile acid uptake was markedly reduced compared to the three other haplotypes. In the inhibition study, the inhibition by rifampin in the *15 haplotype was greater compared to that in the other haplotypes. These results suggest that the OATP1B1 *15 haplotype is an important predisposing factor for rifampin-induced liver injury.

Topics: Adult; Antibiotics, Antitubercular; Case-Control Studies; Chemical and Drug Induced Liver Injury; Female; Gene Expression; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; HEK293 Cells; Humans; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Organic Anion Transporters; Polymorphism, Single Nucleotide; Rifampin; Young Adult

Hepatotoxicity is one of the most frequent adverse events occurring during tuberculosis treatment that may negatively affect treatment compliance, clinical outcome. This study was designed to evaluate management, risk factors related to hepatotoxicity during tuberculosis treatment.. Hospitalized patients for tuberculosis treatment at Sureyyapasa Chest Diseases, and Chest Surgery Training and Research Hospital were included, between January 2004 and December 2007. Prevalence of hepatotoxicity, risk factors were evaluated among tuberculosis patients under anti-tuberculosis treatment according to World Health Organization (WHO) guideline. Hepatotoxicity was defined any elevated liver function tests with accompanying symptoms. Age, gender, past history of anti-tuberculosis treatment, extensity of radiological findings, co-morbid disorders and drug resistance were the risk factors evaluated in terms of development and recurrence of hepatotoxicity.. Of 1443 patients (38.37 ± 16.74 years; 64.5% were males), 106 (7.3%) was identified to develop hepatotoxicity on an average of 20 days after beginning treatment and lasting an average of 14 days. Hepatotoxicity for once in 78.3% (n= 83) of patients and more than once in 21.7% (n= 23) patients. All anti-tuberculosis drugs was continued at full dosage after the normalization of liver enzyme in 76.4% (n= 81). In recurrence a step-by-step treatment was re-started by exclusion of responsible drug/s. Treatment was administered without modification of WHO regimes in 79.2%. Pyrazinamide was omitted in 15 cases while rifampicin only in one patient. Triple drug regimen with isoniazid, ethambutol and streptomycin was used in six cases. Quinolon was added to treatment only in one patient. Presence of a co-morbidity was determined to be significant predictor of hepatotoxicity development OR= 3.093 (CI= 1.95-4.89; p= 0.000) past history of anti-tuberculosis treatment was significantly associated with recurrence (p= 0.027). There was no hepatotoxicity dependent mortality.. Hepatotoxicity can be successfully management of hepatotoxicity without second line tuberculosis drugs in ongoing treatment regime.

Topics: Adult; Age Factors; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Comorbidity; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver Function Tests; Male; Pyrazinamide; Recurrence; Rifampin; Risk Factors; Sex Factors; Treatment Outcome; Tuberculosis, Pulmonary

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

A 54-year-old woman was admitted for pleural tuberculosis diagnosed by right chest pain and cough. She received combination antituberculosis therapy consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide. However, liver damage was observed 15 days after initiation of therapy (aspartate aminotransferase (AST) 248 IU/l, alanine transaminase (ALT), 132 IU/l). The patient was given glycyrrhizinate intravenously, but liver damage gradually increased (AST 628 IU/l, ALT 467 IU/l) and all tuberculosis drugs were ceased. We diagnosed drug-induced liver damage due to isoniazid according to results of the drug lymphocyte stimulation test. We successfully reintroduced rifampicin and streptomycin, and carried out desensitization therapy for isoniazid without liver injury recurrence. Reintroduction of a drug suspected to cause drug-induced liver injury is generally not recommended; however, our experience suggests that isoniazid, a first-line antituberculosis drug, may be reintroduced after desensitization.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Desensitization, Immunologic; Ethambutol; Female; Humans; Isoniazid; Lymphocyte Activation; Middle Aged; Pyrazinamide; Radiography; Retreatment; Rifampin; Tuberculosis, Pleural

Guidelines recommend treatment of latent tuberculosis in patients at increased risk for active tuberculosis. Studies investigating the association of therapy with serious adverse events have not included the entire treated population nor accounted for comorbidities or occurrence of similar events in the untreated general population. Our objective was to estimate the risk of adverse events requiring hospital admission that were associated with therapy for latent tuberculosis infection in the general population.. Using administrative health data from the province of Quebec, we created a historical cohort of all residents dispensed therapy for latent tuberculosis between 1998 and 2003. Each patient was matched on age, sex and postal region with two untreated residents. The observation period was 18 months (from 6 months before to 12 months after initiation of therapy). The primary outcome was hospital admission for therapy-associated adverse events.. During the period of observation, therapy for latent tuberculosis was dispensed to 9145 residents, of whom 95% started isoniazid and 5% started rifampin. Pretreatment comorbid illness was significantly more common among patients receiving such therapy compared with the matched untreated cohort. Of all patients dispensed therapy, 45 (0.5%) were admitted to hospital for a hepatic event compared with 15 (0.1%) of the untreated patients. For people over age 65 years, the odds of hospital admission for a hepatic event among patients treated for latent tuberculosis infection was significantly greater than among matched untreated people after adjustment for comorbidities (odds ratio [OR] 6.4, 95% CI 2.2-18.3). Excluding patients with comorbid illness, there were two excess admissions to hospital for hepatic events per 100 patients initiating therapy compared with the rate among untreated people over 65 years (95% CI 0.1-3.87).. The risk of adverse events requiring hospital admission increased significantly among patients over 65 years receiving treatment for latent tuberculosis infection. The decision to treat latent tuberculosis infection in elderly patients should be made after careful consideration of risks and benefits.

Topics: Adult; Age Distribution; Aged; Antitubercular Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Comorbidity; Female; Humans; Isoniazid; Latent Tuberculosis; Logistic Models; Male; Middle Aged; Patient Admission; Quebec; Retrospective Studies; Rifampin; Risk Assessment

Antitubercular drugs have been known to be potentially hepatotoxic and may lead to drug-induced liver injury. In this study, we aimed to investigate the protective effects of ursodeoxycholic acid (UDCA) on liver injury caused by co-administration with isoniazid and rifampicin, two famous antitubercular drugs. Liver injury was induced by co-treatment with isoniazid (75mg/kg) and rifampicin (150mg/kg) for one week. Mice were orally administered with UDCA (15, 50 and 150mg/kg) 30min before isoniazid and rifampicin. We show that serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were significantly increased in mice treated with isoniazid plus rifampicin. An obvious fatty accumulation, accompanied by mild necrosis and inflammation, was observed in liver of mice treated with rifampicin plus isoniazid. In addition, isoniazid plus rifampicin resulted in hepatic apoptosis, as determined by terminal dUTP nick-end labeling (TUNEL) staining and caspase-3 activation. Additional experiment showed that isoniazid plus rifampicin significantly increased the level of hepatic malondialdehyde (MDA) and caused glutathione (GSH) depletion and 3-nitrotyrosine (3-NT) residues in liver. UDCA pretreatment significantly attenuated isoniazid plus rifampicin induced oxidative stress in liver. Importantly, UDCA pretreatment significantly alleviated isoniazid plus rifampicin induced hepatic apoptosis. Moreover, UDCA-mediated anti-apoptotic effect seemed to be associated with its regulation of Bcl-2 and Bax gene expression in liver. These findings suggest that UDCA might protect against isoniazid and rifampicin induced liver injury through its anti-oxidative and anti-apoptotic effects.

Topics: Animals; Antioxidants; Antitubercular Agents; Apoptosis; Chemical and Drug Induced Liver Injury; Cytoprotection; Drug Interactions; Female; Isoniazid; Liver; Mice; Oxidative Stress; Rifampin; Ursodeoxycholic Acid

Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis.. Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined.. The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression.. The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.

Topics: Animals; Apoptosis; Bile Acids and Salts; Carrier Proteins; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cholestasis; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation; Glycochenodeoxycholic Acid; Hepatectomy; Hepatocytes; Humans; Male; Membrane Glycoproteins; Middle Aged; Polymerase Chain Reaction; Rats; Rats, Wistar; Rifampin; RNA, Messenger

To compare rates of treatment interruption because of side effects and completion rates between subjects treated for latent tuberculosis infection (LTBI) by isoniazid (INH) for 6 months and subjects treated with rifampicin (RIF) for 4 months.. Retrospective analysis of all patients treated for LTBI by INH (1993-2002) or RIF (2004-2007) based on a database including age, gender, prior liver diseases, alcohol consumption, completion rates, time and cause of interruption and monthly analysis of ASAT and ALAT.. 624 subjects were included, 426 treated by INH and 198 by RIF. Gender, origin, history of prior hepatic disease and alcohol excess did not differ between groups. Treatment interruption because of hepatotoxicity was significantly higher in the INH group than in the RIF group (6.1% vs 2.0%; p = 0.03). Completion of treatment was significantly higher in the RIF group compared to the INH group (83% vs 74%; p = 0.02).. A 4-month RIF treatment was associated with significantly less interruption of treatment because of hepatotoxicity and higher completion rates compared to a 6-month INH regimen. These results support the RIF regimen as an alternative to the presently recommended 9 months of INH in clinical practice.

Topics: Adult; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Retrospective Studies; Rifampin; Young Adult

To analyse slow-acetylation N-acetyltransferase 2 (NAT2) polymorphisms for their association with the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH).. A case-control study including Caucasian patients with tuberculosis (TB) treated with isoniazid, rifampicin and pyrazinamide. NAT2 genotype results were compared between ATDH cases and controls and with a healthy Spanish control population of Caucasian origin.. Fifty cases and 67 controls were included in the study. Slow, intermediate and rapid NAT2 genotypes were found in respectively 72%, 18% and 10% of cases compared with 65.7%, 25.4% and 9% of controls (P> 0.05). On comparing NAT2 genotypes among cases with those among healthy controls (n = 1312), we found more slow NAT2 genotypes and fewer intermediate genotypes among cases (respectively 72% and 18% in cases vs. 54.8% and 38.1% in controls; OR 2.07, 95%CI 1.12-2.79, P = 0.016 and OR 0.37, 95%CI 0.18-0.75, P = 0.003).. We could not demonstrate an increased risk of ATDH related to the presence of slow NAT2 polymorphisms among this Caucasian TB cohort. However, we found a significantly greater frequency of slow and a significantly lower frequency of intermediate NAT2 genotypes among the ATDH cases compared with the healthy control population.

Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Case-Control Studies; Chemical and Drug Induced Liver Injury; Chi-Square Distribution; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Isoniazid; Logistic Models; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Genetic; Pyrazinamide; Rifampin; Risk Assessment; Risk Factors; Tuberculosis; White People

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Structure-Activity Relationship; Tetracyclines; Thiophenes

The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Assay; Biological Transport; Cell Line; Cell Membrane; Chemical and Drug Induced Liver Injury; Cytoplasmic Vesicles; Drug Evaluation, Preclinical; Humans; Liver; Rats; Reproducibility of Results; Spodoptera; Transfection; Xenobiotics

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

Topics: Bayes Theorem; Chemical and Drug Induced Liver Injury; Humans; Ligands

Thyolo District Hospital, rural Malawi.. To report on 1) clinical, immunological and virological outcomes and 2) safety among human immunodeficiency virus (HIV) infected patients with tuberculosis (TB) who received concurrent nevirapine (NVP) and rifampicin (RMP) based treatment.. Retrospective cohort study.. Analysis of programme data, June-December 2007.. Of a total of 156 HIV-infected TB patients who started NVP-based antiretroviral treatment, 136 (87%) completed TB treatment successfully, 16 (10%) died and 5 (4%) were transferred out. Mean body weight and CD4 gain (adults) were respectively 4.4 kg (95%CI 3.3-5.4) and 140 cells/mm(3) (95%CI 117-162). Seventy-four per cent of patients who completed TB treatment and had a viral load performed (n = 74) had undetectable levels (<50 copies/ml), while 17 (22%) had a viral load of 50-1000 copies/ml. Hepatotoxicity was present in 2 (1.3%) patients at baseline. Two patients developed Grade 2 and one developed Grade 3 alanine transaminase enzyme elevations during TB treatment (incidence rate per 10 years of follow-up 4.2, 95%CI 1.4-13.1). There were no reported deaths linked to hepatotoxicity.. In a rural district in Malawi, concomitant NVP and RMP treatment is associated with good TB treatment outcomes and appears safe. Further follow-up of patients would be useful to ascertain the longer-term effects of this concurrent treatment.

Topics: Adolescent; Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Follow-Up Studies; HIV Infections; Humans; Malawi; Male; Nevirapine; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Viral Load; Young Adult

Tumor necrosis factor (TNF) blockers increase the risk of tuberculosis infection. National recommendations in France for prevention of latent tuberculosis recommend treatment by rifampicin (RIF) 600 mg/day and isoniazid (INH) 300 mg/day for 3 months. However, its toxicity is unknown in this context and is a subject of debate.. To assess (a) frequency of prescription, (b) reasons for prescription, (c) tolerance of INH/RIF for prevention of tuberculosis.. Systematic retrospective study of medical records of one tertiary rheumatology unit, from 2002 to 2007, of all patients who were prescribed INH/RIF before receiving TNF blockers.. patients'demographic characteristics, reasons of prescription, tolerance and levels of aminotransferase before and during INH/RIF treatment.. Descriptive and determination of risk factors of hepatotoxicity by multivariate logistic regression.. Of 1028 patients treated by TNF blockers between 2002 and 2007, 216 (21.1%) received INH/RIF treatment. Of 93 patients with complete data, 17 (18.2%) presented hepatotoxicity of which only one above 10 times the upper limit of the norm. Fourteen (15.0%) had other side effects. Ten (10.7%) patients had to interrupt INH/RIF for intolerance. Factors predicting intolerance were male sex, aminotransferases before treatment, a higher body mass index and leflunomide comedication.. This systematic case review indicates a high rate of necessity for preventive treatment by INH/RIF, and in particular for positive skin tests. This association had a high rate of hepatotoxicity without severe consequences. A better screening of patients before preventive therapy is needed.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Female; Humans; Immunocompromised Host; Isoniazid; Logistic Models; Male; Middle Aged; Multivariate Analysis; Practice Guidelines as Topic; Retrospective Studies; Rheumatic Diseases; Rifampin; Risk Factors; Severity of Illness Index; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

Despite the great efficacy of isoniazid (INH) and rifampicin (RIF) combination, in the treatment of tuberculosis, hepatotoxicity is the most common serious complication. The potential protective effect of alpha-lipoic acid and aminoguanidine; against combination-induced hepatotoxicity was investigated in the present study. Administration of INH-RIF combination (50 mg/kg each for 14 days) resulted in an elevation of serum hepatic marker enzymes and a significant increase in lipid profile parameters. Combinations treatment increased lipid peroxidation products, decreased glutathione content, superoxide dismutase, catalase and myeloperoxidase activities. Furthermore, liver total nitrite level was significantly increased in INH-RIF treated rats. Co-administration of either alpha-lipoic acid or aminoguanidine significantly ameliorate combination-induced alterations in hepatic marker enzymes. These effects were directly linked to a greater decrease in the combination-induced elevation in lipid peroxidation products and total nitrite levels. Furthermore, co-administration of alpha-lipoic acid and aminoguanidine restore superoxide dismutase, catalase and myeloperoxidase activities and maintained the imbalance in the glutathione level. Additionally, such beneficial effect of alpha-lipoic acid was linked to a marked lipid-lowering effect. Histopathological examination revealed preservation of liver integrity of the protected groups compared to combination-treated rats alone.

Topics: Animals; Antioxidants; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Glutathione; Guanidines; Isoniazid; Lipid Peroxidation; Liver; Liver Function Tests; Male; Nitric Oxide; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Rifampin; Thioctic Acid

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

To investigate the effect of metallothionein (MT) on rifampicin (RFP)-induced hepatotoxicity and the possible mechanisms.. Male MT- I / II null (MT-/-) and wild type (MT+/+) mice were randomly divided into 4 groups, respectively, and were orally administered RFP (50, 100 or 200 mg/kg) or equal volumes of solvent daily for 15 consecutive days. Levels of plasma alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DB) were determined. Liver indexes were calculated and liver histopathologic changes were examined by hematoxylin and eosin (HE) staining. The content of glutathione (GSH) as well as the activities of glutathione peroxydase (GPx) and glutathione reductases (GR) were measured in the liver homogenates.. RFP treatment induced significant increases in plasma ALT, AST and DB, as well as liver index. Significant histopathologic changes which were charactered as fatty degeneration in liver were noteced. Moreover, augmentations of GSH content and GR activity and attenuation of GPx activity were observed. More severe hepatic injuries in MT-/- mice were observed as compared to MT+/+ mice, which were evidenced by higher liver/body weight ratio and GR activity, lower GSH content and GPx activity, and more serious fatty degeneration.. RFP-induced hepatotoxicity was associated with cholestasis and oxidative damage. MT -/- mice were more susceptible than MT +/+ mice to RFP-induced hepatotoxicity and the enhanced hepatotoxicity involves increased oxidative stress.

Topics: Animals; Chemical and Drug Induced Liver Injury; Gene Knockout Techniques; Liver; Male; Metallothionein; Mice; Mice, Inbred C57BL; Oxidative Stress; Rifampin

The standard antitubercular treatment (ATT), which consists of isoniazid (INH), rifampicin (RIF), ethambutol, and pyrazinamide (PZA), is the best available treatment for tuberculosis (TB). However, the hepatotoxicity of INH and PZA can be severe, and even after drug withdrawal, patients may require liver transplantation (LT). In these cases, the strategy for the treatment of TB is poorly defined. Between 1986 and 2008, 14 patients presented at our department with severe hepatitis secondary to INH and PZA treatment. Four of these patients were immunosuppressed: 2 after renal transplantation and 2 because of human immunodeficiency virus infection. In seven of the 14 patients an alternative ATT was begun on admission, which was well tolerated. Hepatitis improved spontaneously in 5 patients, and alternative ATT was continued for 9.3 ± 4.2 months; 1 patient deteriorated and underwent LT, and 1 patient died. ATT was stopped definitively in 2 patients. Six patients required urgent LT, and alternative ATT was started after transplantation and was successful. Five patients receiving RIF had an episode of acute rejection. In conclusion, hepatitis secondary to ATT can be successfully treated with alternative anti-TB regimens. The use of RIF in LT patients may lead to acute rejection. RIF should therefore be avoided in these patients.

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Disease Progression; Drug Therapy, Combination; Female; France; Graft Rejection; Humans; Isoniazid; Liver Failure, Acute; Liver Transplantation; Male; Middle Aged; Remission, Spontaneous; Rifampin; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Tuberculosis; Young Adult

This study evaluates the hepatoprotective effect of carotenoids against isoniazid (INH) and rifampicin (RIF). Thirty-six adult rats were divided into the following 4 groups: (1) control group treated with normal saline; (2) INH + RIF group treated with 50 mg·(kg body mass)-1·day-1 of INH and RIF each; (3) INH + RIF+ carotenoids group treated with 50 mg·(kg body mass)-1·day-1 of INH and RIF each and 10 mg·(kg body mass)-1·day-1 of carotenoids; and (4) carotenoids group treated with 10 mg·(kg body mass)-1·day-1 of carotenoids for 28 days intragastrically. Oxidative stress and antioxidant levels in liver and blood, liver histology and change in transaminases were measured in all the above-mentioned groups. There was an increase in lipid peroxidation with a reduction in thiols, catalase, and superoxide dismutase (SOD) in the liver and blood of rats accompanied by an increase in transaminases, bilirubin, and alkaline phosphatase. Treatment with carotenoids along with INH + RIF partially reversed lipid peroxidation, thiols, catalase, and SOD in the liver and blood of rats. Elevated levels of the enzymes in serum were also reversed partially by this treatment. The degree of necrosis, portal triaditis, and inflammation were also lowered in the carotenoids group. In conclusion, carotenoids supplementation in INH + RIF treated rats showed partial protection.

Topics: Alkaline Phosphatase; Animals; Antioxidants; Carotenoids; Catalase; Cells, Cultured; Chemical and Drug Induced Liver Injury; Glutathione; Isoniazid; Lipid Peroxidation; Liver; Oxidative Stress; Rats; Rats, Wistar; Rifampin; Superoxide Dismutase

Hepatoprotective activity of hydroalcoholic extract of Luffa acutangula (HAELA) against carbon tetrachloride (CCl4) and rifampicin-induced hepatotoxicity in rats was evaluated and probable mechanism(s) of action has been suggested. Administration of standard drug- silymarin and HAELA showed significant hepatoprotection against CCl4 and rifampicin induced hepatotoxicity in rats. Hepatoprotective activity of HAELA was due to the decreased levels of serum marker enzymes viz., (AST, ALT, ALP and LDH) and increased total protein including the improvement in histoarchitecture of liver cells of the treated groups as compared to the control group. HAELA also showed significant decrease in malondialdehyde (MDA) formation, increased activity of non-enzymatic intracellular antioxidant, glutathione and enzymatic antioxidants, catalase and superoxide dismutase. Results of this study demonstrated that endogenous antioxidants and inhibition of lipid peroxidation of membrane contribute to hepatoprotective activity of HAELA.

Topics: Administration, Oral; Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Female; Lipid Peroxidation; Luffa; Male; Malondialdehyde; Nucleic Acid Synthesis Inhibitors; Plant Extracts; Rats; Rats, Wistar; Rifampin

To determine the occurrence of hepatotoxicity associated with rifampin treatment of latent tuberculosis infection in patients from a public health tuberculosis clinic.. Evaluation of rifampin hepatotoxicity in adults aged >or=18 years from a database maintained from June 2001 to May 2007 in a public health department clinic. Rifampin 600 mg daily for 4 months was prescribed. Hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels more than 3 times the upper limit of normal (ULN) with symptoms or more than 5 times the ULN without symptoms.. Rifampin therapy was initiated in 348 patients. Among 205 patients with evaluable data, 4 (1.95%, 95% confidence interval: 0%-4.33%) had AST or ALT levels >5 times the ULN (2 patients at 1 month and 2 patients at 3 months). Three of these patients had elevated AST/ALT at baseline; 1 had hepatitis C and 1 had an unconfirmed history of hepatitis. Adherence to clinic visits and prescribed treatment was poor.. Rifampin hepatotoxicity associated with treatment of latent tuberculosis infection is rare. Our report suggests that hepatotoxicity is more likely in patients with baseline hepatic dysfunction and the need for increased vigilance in monitoring transaminases in these patients.

Topics: Adult; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Humans; Liver; Male; Middle Aged; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAP-induced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadministration of rifampicin and APAP, compared with APAP administration alone. In contrast, hPXR mice, wild-type mice, and Pxr-null mice exhibited significantly lower ALT/AST levels compared with TgCYP3A4/hPXR mice after APAP administration. Toxicity was coincident with depletion of hepatic glutathione and increased production of hydrogen peroxide, suggesting increased oxidative stress upon hPXR activation. Moreover, mRNA analysis demonstrated that CYP3A4 and other PXR target genes were significantly induced by rifampicin treatment. Urinary metabolomic analysis indicated that cysteine-APAP and its metabolite S-(5-acetylamino-2-hydroxyphenyl)mercaptopyruvic acid were the major contributors to the toxic phenotype. Quantification of plasma APAP metabolites indicated that the APAP dimer formed coincident with increased oxidative stress. In addition, serum metabolomics revealed reduction of lysophosphatidylcholine in the APAP-treated groups. These findings demonstrated that human PXR is involved in regulation of APAP-induced toxicity through CYP3A4-mediated hepatic metabolism of APAP in the presence of PXR ligands.

Topics: Acetaminophen; Alanine Transaminase; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Aspartate Aminotransferases; Biomarkers; Biotransformation; Chemical and Drug Induced Liver Injury; Cysteine; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Glutathione; Humans; Hydrogen Peroxide; Liver; Liver Diseases; Lysophosphatidylcholines; Male; Metabolomics; Mice; Mice, Knockout; Mice, Transgenic; Necrosis; Oxidative Stress; Pregnane X Receptor; Principal Component Analysis; Receptors, Steroid; Rifampin; RNA, Messenger; Time Factors

Rifampicin-induced hepatotoxicity has been well recognized in animals and patients. However, it is undetectable in cultured hepatocyte monolayers in vitro at the equivalent toxic concentration in vivo. This study investigated the rifampicin-induced toxicity on rat hepatocytes in gel entrapment vs. in monolayer culture. Thiazolyl tetrazolium reduction and albumin secretion were routinely detected to identify the toxic responses of rat hepatocytes to rifampicin, while reactive oxygen species (ROS) accumulation and intracellular glutathione (GSH) content were assayed as biomarkers of oxidative stress. In addition, Nile red staining and malondialdehyde (MDA) generation were, respectively, used as endpoints for lipid accumulation and peroxidation. After treatment of hepatocytes for 96 h at a serum rifampicin concentration (12 microM), gel-entrapped rat hepatocytes showed significant cellular damage indicated by alternations of all parameters indicated above, while hepatocyte monolayers did not show severe responses. In contrast to a lack of protections by cytochrome P 450 inhibitors, the ROS scavenger (glycyrrhizic acid) and thiol compounds (N-acetylcysteine and GSH) significantly reduced rifampicin toxicity in gel-entrapped hepatocytes. It appears that gel-entrapped rat hepatocytes reflected significant hepatotoxicity of rifampicin in vivo, and this toxicity was most possibly associated with oxidative stress and lipid accumulation.

Topics: Acetylcysteine; Albumins; Animals; Antitubercular Agents; Cell Culture Techniques; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Drug Antagonism; Enzyme Inhibitors; Glutathione; Glycyrrhizic Acid; Hepatocytes; Lipid Metabolism; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Rifampin; Tetrazolium Salts; Thiazoles

The protective effects of Ginkgoselect Phytosome (GBP) on Rifampicin (RMP) induced hepatotoxicity and the probable mechanism(s) involved in this protection were investigated in rats. Liver damage was induced in Wistar rats by administering rifampicin (500 mg/kg, p.o.) daily for 30 days. Simultaneously, GBP at 25 mg/kg and 50 mg/kg, and the reference drug silymarin (100 mg/kg) were administered orally for 30 days/daily to RMP treated rats. Levels of marker enzymes (SGOT, SGPT and SALP), albaumin (Alb) and total proteins (TP) were assessed in serum. The effects of GBP on lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) were assayed in liver homogenates to evaluate antioxidant activity. GBP (25 and 50 mg/kg) and silymarin elicited a significant hepatoprotective activity by lowering the levels of serum marker enzymes and lipid peroxidation and elevated the levels of GSH, SOD, CAT, GPX, GR, Alb and TP in a dose dependant manner. The present findings suggest that the hepatoprotective effect of GBP in RMP induced oxidative damage may be related to its antioxidant and free radical scavenging activity.

Topics: Animals; Antibiotics, Antitubercular; Antioxidants; Chemical and Drug Induced Liver Injury; Enzymes; Female; Free Radicals; Ginkgo biloba; Lipid Peroxidation; Liver; Liver Diseases; Male; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Rifampin; Silymarin

Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Drug Interactions; HIV Protease Inhibitors; Humans; Research Design; Rifampin; Tuberculosis

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Humans; Isoniazid; Patient Compliance; Rifampin; Tuberculosis

Isoniazid, rifampicin and pyrazinamide during short-course chemotherapy for tuberculosis can result in liver injury. The coexistence of tuberculosis and diabetes is common in patients who receive inadequate treatment. The risk of hepatotoxicity from many toxicants is increased in diabetic rats. Silymarin provides protection against liver injury caused by many hepatotoxicants, including antitubercular drugs (ATDs). In the wake of increased severity of ATD-induced hepatotoxicity in diabetes we report here the results of a study on the influence of diabetes on silymarin hepatoprotection in rats. Rats with diabetes induced via intraperitoneally injected streptozotocin (50 mg/kg), nondiabetic rats and insulin-treated diabetic rats received isoniazid (7.5 mg/kg/day), rifampicin (10 mg/kg/day) and pyrazinamide (35 mg/kg/day) orally (p.o.) with or without silymarin (100 mg/kg/day p.o.) treatment for 45 days. Compared to nondiabetic rats, liver function tests and histological changes of liver revealed exaggerated liver injury in diabetic rats caused by ATDs which was evident by 5- to 8-fold increases in serum levels of marker enzymes (aspartate and alanine aminotransferase, alkaline phosphatase and gamma-glutamyltranspeptidase) and 1- to 2-fold increases in bilirubin accompanied by a 2-fold decrease in total serum proteins, intense fatty and inflammatory infiltrations, necrosis and fibrosis. Coadministration of silymarin provided protection against ATD hepatotoxicity in all animals. However, insulin-treated diabetic animals showed greater silymarin-induced hepatoprotection against ATD-induced liver injury, which was characterized by near normal levels of marker enzymes, an increase in total proteins and normal hepatic structure. These results thus indicate that diabetes exaggerates ATD-induced liver injury and attenuates silymarin-induced hepatoprotection. However, insulin treatment for diabetes offers greater silymarin-induced hepatoprotection against ATD-induced liver injury.

Topics: Animals; Antitubercular Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Female; Isoniazid; Liver; Liver Diseases; Liver Function Tests; Male; Protective Agents; Pyrazinamide; Rats; Rats, Wistar; Rifampin; Silymarin; Streptozocin

To investigate retrospectively the incidence of drug-induced hepatitis (DIH) caused by antituberculosis drugs including isoniazid (INH), rifampicin (RFP), with and without pyrazinamide (PZA), and to evaluate risk factors for DIH in tuberculosis patients complicated with chronic hepatitis (CH).. One hundred and seven tuberculosis patients with CH (M/F= 96/11, mean age +/- SE, 60.8 +/- 1.4 yr) admitted to our hospital during 1998-2006, whose laboratory data had been followed before and at least 2 months after starting antituberculosis chemotherapy, were enrolled in this study. Of these, 58 were being treated with anti-tuberculosis chemotherapy consisting of INH, RFP and PZA (HRZ group) and the remaining 49 with INH and RFP (HR group). For a case-control study, patients admitted to the hospital during the same period and without CH were selected to each CH patient (n=107) of the same gender, the same treatment regimens, and the same age. Clinical diagnosis of CH was based on laboratory data and in some cases pathological findings; etiology of CH was C-CH (CH caused by hepatitis C virus) in 68 patients, B-CH (CH caused by hepatitis B virus) in 23, and alcoholic CH in 16.. DIH was defined by elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at 1 or 2 months after starting anti-tuberculosis chemotherapy. For patients with serum levels of AST or ALT already abnormally high before starting chemotherapy, an increase of > 1.5 times from the initial serum level was defined to indicate DIH, whereas for patients with AST and ALT within the normal range, and increase of > 3X the normal upper limit was defined to indicate DIH. The incidence of DIH was calculated separately in the groups HRZ and HR for patients with and patients without CH (control). In the HRZ group, the severity of DIH was defined by the maximum serum levels of AST and ALT, and their mean values were compared between CH patients and the control. Risk factors for DIH were examined by comparing patients with and without CH. The clinical course after development of DIH was also followed. [Results] The incidence of DIH in the HRZ group was 13/ 58 (22.4%) for CH patients and 10/36 (27.8%), 2/13 (15.4%) and 1/9 (11.1%) for C-CH, B-CH and alcoholic hepatitis patients, respectively, which was significantly (p < 0.05) higher than that in the control [4/58 (6.9%)]. Confining to the C-CH patients, the incidence of DIH was 10/36 (27.8%) compared with the control 2/36 (5.6%) (p < 0.05). In contrast, the incidence of DIH in the HR group was not significantly different between CH patients and the control, [2/49 (4.1%) vs 2/49 (4.1%)], respectively. The severity of DIH in the HRZ group estimated by the maximum level of serum AST and ALT was not significantly different in CH patients and the control (176.6 +/- 28.1 vs. 311.0 +/- 154.5 IU/L for AST and 187.8 +/- 19.1 vs. 277.8 +/- 72.4 IU/L for ALT). Of the 13 CH patients suffering from DIH caused by antituberculosis chemotherapy containing INH, RFP and PZA, 3 were continued treatment without altering the regimen, and 9 were continued treatment after changing the regimen to INH and RFP, omitting PZA. The one remaining patient was re-treated using INH, RFP and ethambutol (EB), but this again resulted in development of DIH, and he was ultimately treated with INH, EB and levofloxacin, with a successful outcome. Thus, at least 12 out of the 13 CH patients who developed DIH in the HRZ group could be treated by an anti-tuberculosis chemotherapy regimen containing INH and RFP excluding PZA. In C-CH patients who were treated with INH, RFP and PZA, the incidence of DIH was significantly higher when the dail. In CH patients, anti-tuberculosis chemotherapy containing INH and RFP without PZA can be used safely. The inclusion of PZA in the regimen does substantially increase the incidence of DIH but nonetheless it can be used with caution, especially bearing in mind that daily alcohol intake of >20 g is a significant risk factor for C-CH patients.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Hepatitis, Chronic; Humans; Isoniazid; Liver; Male; Middle Aged; Retrospective Studies; Rifampin; Tuberculosis

Antituberculosis drug-induced hepatotoxicity (ATDH) complicates the treatment of 5-10% of patients treated for active tuberculosis (TB). Knowledge regarding the mechanism of toxicity is still incomplete. Metabolism and the formation of toxic metabolites of the TB drugs may play an important role in the development of ATDH. We studied hepatotoxicity and interactions between isoniazid (INH), its toxic metabolite hydrazine (HYD), rifampicin (RIF) and pyrazinamide (PZA) in human hepatoma cells (HepG2). After 24h pre-treatment with a non-toxic concentration of one of the four compounds, cells were exposed to increasing concentrations of INH, HYD, RIF or PZA. To determine whether pre-treatment increased toxicity, changes in the concentration at which 50% of cell growth was inhibited (IC50) were quantified using the WST-1 cytotoxicity assay. Pre-treatment with INH, HYD or RIF decreased the INH IC50 by 24%, 26% and 15%, respectively, meaning that INH toxicity was increased. INH and HYD pre-treatment decreased the PZA IC50 by 30% and 38%, respectively. HYD and RIF toxicity were not affected by the pre-treatments. The present study is the first to demonstrate that pre-treatment with INH or its toxic metabolite HYD increases the in vitro toxicity of PZA. In addition, pre-treatment with INH, HYD or RIF increases the in vitro toxicity of INH. These results give us greater insight into the development of ATDH.

Topics: Antitubercular Agents; Cell Line, Tumor; Cell Survival; Chemical and Drug Induced Liver Injury; Humans; Hydrazines; Isoniazid; Liver; Pyrazinamide; Rifampin

Relatively little is known about the hepatotoxicity of pyrazinamide.. We compared continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampin with those containing isoniazid and rifampin to evaluate the hepatotoxicity of pyrazinamide.. Cohort and nested case-control analyses were conducted on a cohort of 3,007 patients with active tuberculosis (TB) managed at government chest clinics under a TB control program with treatment started from January 1 through June 30, 2001. Cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when serum alanine transaminase exceeded three times the upper limit of normal. Each case was matched by sex and age with three control subjects selected randomly from the rest of the cohort. Treatment regimens of cases within 4 weeks preceding hepatotoxicity were compared with those of matched control subjects in comparable periods relative to the date of commencing treatment.. Hepatotoxicity occurred in 150 (5.0%) patients at any time including 48 (1.6%) cases. From 12 or more weeks after starting treatment, the estimated risk of hepatotoxicity was 2.6% for regimens incorporating pyrazinamide, isoniazid, and/or rifampin, and 0.8% for standard regimens containing isoniazid and rifampin. Multivariable conditional logistic analysis showed a significant association between hepatotoxicity and, respectively, hepatitis B, previous hepatotoxicity, and treatment regimens. The adjusted odds ratio (95% confidence interval) of hepatotoxicity for regimens incorporating pyrazinamide, isoniazid, and/or rifampin relative to standard regimens was 2.8 (1.4-5.9).. Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.

Topics: Adult; Aged; Antitubercular Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Logistic Models; Male; Matched-Pair Analysis; Middle Aged; Multivariate Analysis; Pyrazinamide; Rifampin; Tuberculosis

This study investigated the hepatoprotective effect of two Indian medicinal plants Tinospora cordifolia (Tc), Phyllanthus emblica (Pe), and their combination, in a rat model of isoniazid, rifampicin and pyrazinamide induced hepatic damage. Hepatic damage was assessed using a composite score assigned to histopathological findings of degeneration, necrosis and fibrosis. The antituberculosis treatment (ATT), when given for 90 days, induced significant degeneration and necrosis (score: 7.5; p < 0.01 vs vehicle) associated with morphological changes. However, no change was found in the serum bilirubin and liver enzymes. Co-administration of silymarin (positive control, 50 mg/kg) with ATT protected against necrosis (score: 1.5; p < 0.001 vs ATT). Tc (100 mg/kg) showed a reduction in liver damage (score: 6.5), which was not statistically significant. On the other hand, Pe (300 mg/kg) prevented the necrotic changes to a significant extent (grade 1.0; p < 0.05; score [corrected] 5.5). Combination of Tc and Pe in their therapeutic doses (1:3) significantly prevented the necrosis (score: 3.5; p < 0.001 vs ATT). Similar effects were seen even when the doses were halved and were comparable to the silymarin group. Thus, this study proves the synergistic protective effects exerted by the combination of Tc and Pe when co-administered with ATT.

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Isoniazid; Liver Cirrhosis; Liver Diseases; Male; Necrosis; Phyllanthus emblica; Phytotherapy; Plant Extracts; Pyrazinamide; Rats; Rats, Wistar; Rifampin; Tinospora

Genetic variations in enzymes of isoniazid metabolism confer an increased risk for antituberculosis drug-induced hepatotoxicity in Asian populations. The present study was aimed at investigating the possible association of antituberculosis drug-induced hepatotoxicity with polymorphisms at the glutathione S-transferase (GST) gene in a Caucasian population.. A prospective case-control study was nested in a cohort of patients with active tuberculosis who were treated with a combination of isoniazid, rifampicin and pyrazinamide. Cases constituted patients with antituberculosis drug-induced hepatotoxicity (n=35), and controls constituted patients without any evidence of this complication (n=60). Homozygous null polymorphisms at GST loci M1 and T1 were analysed from genomic DNA from all participants.. The GSTT1 homozygous null polymorphism was significantly associated with antituberculosis drug-induced hepatotoxicity [odds ratio (OR) 2.60, 95% confidence interval (CI) 1.08-6.24, P=0.03]. No significant association was observed between the GSTM1 homozygous null polymorphism and antituberculosis drug-induced hepatotoxicity (OR 0.73, 95% CI 0.31-1.73, P=0.48).. The GSTT1 homozygous null polymorphism may be a risk factor of antituberculosis drug-induced hepatotoxicity in Caucasians.

Topics: Adult; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Glutathione Transferase; Homozygote; Humans; Isoniazid; Male; Middle Aged; Mutation; Polymorphism, Genetic; Prospective Studies; Pyrazinamide; Rifampin; White People

Tuberculosis is a dangerous disease and its death toll is increasing year by year. Intake of isoniazid and rifampicin, the most common antitubercular drugs, lead to fatal hepatotoxic condition. We have studied the protective effect of chitosan supplementation against the hepatotoxicity induced by antitubercular drugs with respect to the changes in the levels of protein, albumin-globulin ratio, urea and bilirubin in the serum and diagnostic marker enzymes (alanine amino transferase, aspartate amino transferase, acid phosphatase and alkaline phosphatase), protein, glycoprotein conjugates (hexose, hexosamine and sialic acid), lipid peroxidation and reduced glutathione in the liver tissue of normal and experimental groups of rats. Co-administration of chitosan was found to significantly prevent the antitubercular drugs-induced alterations in the levels of diagnostic marker enzymes, bilirubin and albumin/globulin ratio in experimental groups of rats. Isoniazid and rifampicin-induced lipid peroxidation was also found to be prevented by the administration of chitosan. Further, chitosan administration increased the levels of urea and protein (in serum and liver) in experimental groups compared to hepatotoxicity-induced group of rats. Levels of glycoconjugates were also maintained to near normal level by chitosan co-administration. From the results obtained, it can be concluded that chitosan is beneficial against antitubercualr drugs-induced hepatoxicity.

Topics: Analysis of Variance; Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chitosan; Isoniazid; Lipid Peroxidation; Liver; Liver Function Tests; Male; Protective Agents; Rats; Rats, Wistar; Rifampin

Topics: Adult; Antitubercular Agents; Biopsy; Chemical and Drug Induced Liver Injury; Cholangiopancreatography, Endoscopic Retrograde; Ethambutol; Female; Follow-Up Studies; Humans; Pancreatitis; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculosis

Antitubercular drug induced hepatotoxicity is a major hurdle for an effective treatment of tuberculosis. The present study was undertaken to assess the hepatoprotective potential of tocopherol (50 mg/kg and 100 mg/kg, ip) and to compare it with cimetidine (120 mg/kg, ip). Hepatotoxicity was produced by giving isoniazid (INH, 50 mg/kg, po) and rifampicin (RMP, 100 mg/kg, po) combination to albino rabbits for 7 days. Assessment of liver injury was done by estimating levels of alanine transaminase (ALT) and argininosuccinic acid lyase (ASAL) in serum and by histopathological examination of liver. Results revealed that pretreatment with high dose of tocopherol (100 mg/kg) prevented both biochemical as well as histopathological evidence of hepatic damage induced by INH and RMP combination. Moreover, tocopherol (100 mg/kg) was found to be a more effective hepatoprotective agent as compared to cimetidine.

Topics: Animals; Antioxidants; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cimetidine; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Isoniazid; Liver Diseases; Rabbits; Rifampin; Tocopherols

We have studied the protective effect of chitosan on isoniazid- and rifampicin-induced hepatotoxicity with respect to the changes in the levels of diagnostic marker enzymes (in serum), lipid components and lipid peroxidation (in serum and liver). The oral administration of antitubercular drugs caused a significant elevation in the levels of diagnostic marker enzymes and cholesterol, triglycerides, free fatty acids and lipid peroxidation in serum and liver of experimental rats. There was a slight decline in the level of phospholipids in liver tissue also observed. Co-administration of chitosan significantly prevented the antitubercular drugs-induced elevation in the levels of serum diagnostic marker enzymes (alanine amino transferase, aspartate amino transferase, lactate dehydrogenase, acid phosphatase and alkaline phosphatase) in experimental groups of rats. It exerted a significant antilipidemic effect against isoniazid- and rifampicin-induced hepatitis by maintaining the levels cholesterol, triglycerides, free fatty acids and phospholipids in serum and liver at near normalcy. A tendency to prevent the isoniazid- and rifampicin-induced lipid peroxidation was also observed. The results of the present study indicated that the hepatoprotective effect of chitosan might be ascribable to its antilipidemic effect and/or antioxidant property.

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chitosan; Cholesterol; Fatty Acids, Nonesterified; Isoniazid; Lipid Peroxidation; Lipid Peroxides; Liver; Liver Function Tests; Male; Rats; Rats, Wistar; Rifampin; Triglycerides

Severe liver injuries were attributed to the rifampin and pyrazinamide (RZ) regimen after it was recommended for treating latent tuberculosis infection. Implicating RZ as the likeliest cause required excluding alternative causes.. US health departments reported data on patients who died or were hospitalized for liver disease within 1 month after taking RZ for latent tuberculosis infection from October 1998 through March 2004. The circumstances were investigated on site for each case. Illness characteristics, reasons for RZ treatment, doses and frequency of administration of pyrazinamide, monitoring during treatment, and causes of liver injury were determined.. Liver injury was attributable to RZ use for all 50 patients reported, 12 of whom died. For 47 patients, RZ was the likeliest cause of liver injury. The median patient age was 44 years (range, 17-73 years). Thirty-two patients (64%) were male. Seven (16%) of 43 patients tested had hepatitis C virus antibodies, 1 (2%) of 45 had chronic hepatitis B, 3 (14%) of 22 had positive results of HIV serologic tests, 34 (71%) of 48 had alcohol use noted, and 33 (66%) of 50 were taking additional hepatotoxic medications. Six patients, 2 of whom died, had no predictors for liver disease. Patients who died were older (median age, 52 vs. 42 years; P=.08) and took a greater number of other medications (median number of medications, 4 vs. 2; P=.05) than did those who recovered, but these 2 factors were correlated (P<.01). Thirty-one patients (62%) were monitored according to guidelines, 9 of whom died.. RZ was the likeliest cause of most of these liver injuries, some of which were fatal in spite of monitoring. Fatality was predicted by age or use of other medications, but none of the cofactors showed promise as a reliable clinical predictor of severe liver injury.

Topics: Adolescent; Adult; Aged; Alcohol Drinking; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Risk Factors; Substance-Related Disorders; Tuberculosis; United States

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Hospitalization; Humans; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis

Terminalia chebula Gertn. (Combetraceae) is an important herbal drug in Ayurvedic pharmacopea. In the present study, a 95% ethanolic extract of T. chebula (fruit) (TC extract), which was chemically characterized on the basis of chebuloside II as a marker, was investigated for hepatoprotective activity against anti-tuberculosis (anti-TB) drug-induced toxicity. TC extract was found to prevent the hepatotoxicity caused by the administration of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) (in combination) in a sub-chronic mode (12 weeks). The hepatoprotective effect of TC extract could be attributed to its prominent anti-oxidative and membrane stabilizing activities. The changes in biochemical observations were supported by histological profile.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Drug Combinations; Fruit; Hepatocytes; Isoniazid; Lipid Peroxidation; Oxidative Stress; Pyrazinamide; Rats; Rifampin; Terminalia

Nine months of isoniazid therapy is the recommended regimen for treatment of latent tuberculosis infection, but low completion rates are a serious problem. The search for shorter regimens, compared with the standard isoniazid regimen, is of vital importance. We describe our experience using short-course regimens for the treatment of latent tuberculosis infection.. We conducted a nonrandomized, observational study of 459 patients in a county health department from June 2000 to January 2006. Short-course therapy was defined as pyrazinamide and rifampin taken daily or twice weekly for 2 months or rifampin taken daily for 4-6 months. Conventional therapy consisted of a 9-month regimen of isoniazid. Liver function testing was performed for both groups in accordance with clinical guidelines. Treatment completion and hepatotoxicity (according to the World Health Organization classification) were determined for the short-course and conventional therapy groups.. Treatment was completed by 241 (77.7%) of 310 patients in the short-course group and by 98 (65.8%) of 149 patients in the isoniazid group (P = .009). Moderate to severe hepatotoxicity (grades 3 and 4) occurred in 6.1% of patients receiving short-course therapy and in 2.0% of patients receiving isoniazid (P=.09). The hepatotoxicity observed in the short-course group was confined to patients receiving pyrazinamide and rifampin daily and was self limited in all cases after the medications were discontinued.. The rate of treatment completion was significantly higher with short-course regimens, compared with the isoniazid regimen. Although the overall risk of hepatotoxicity in patients receiving pyrazinamide and rifampin daily for the treatment of latent tuberculosis infection was higher, liver functions returned to normal after the medications were discontinued.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Patient Compliance; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

To assess the incidence of anti-tuberculosis (TB) drug induced hepatitis (AIH) in Sri Lankan patients, determine risk factors of AIH, and to address management options in AIH.. A prospective study.. Chest Hospital, Welisara, Sri Lanka, from April 2001 to April 2002.. Seven hundred and eighty three patients with a confirmed diagnosis of TB and resident in the Colombo and Gampaha districts who presented to Chest Hospital, Welisara, Sri Lanka.. WHO recommended treatment was commenced in all cases. AIH was diagnosed when patients complained of decreased appetite with nausea or vomiting and elevated serum bilirubin (SB; >1.1 mg/dL) or elevated serum alanine transferase (ALT; > 3 times upper limit of normal).. Of 783 enrolled patients, 74 (9.5%) developed AIH, the majority (58%) developing AIH within the first 2 weeks of the intensive phase of treatment. AIH was more common among patients over 60 years (p = 0.018), who developed pulmonary TB (p = 0.028), and in patients weighing 33-55 kg (p = 0.004). Age, weight and rifampicin overdosage were significant predictors of AIH. Of the 74 AIH patients, standard treatment was restarted in 60, treatment modified in six, two defaulted and six died.. The incidence of AIH in Sri Lanka is 9.5% in treated patients. AIH was associated with age, low body weight and rifampicin overdosage.

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Incidence; Isoniazid; Male; Middle Aged; Prospective Studies; Rifampin; Risk Assessment; Risk Factors; Sri Lanka; Streptomycin; Tuberculosis

Topics: Addison Disease; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Miliary

The case of a 30-y-old male with latent tuberculosis who developed chemical hepatitis requiring hospitalization after 50 d of treatment with rifampin and pyrazinamide is reported. This case justifies the CDC guidelines that were updated on 31 August 2003 advising against the use of this brief regimen for patients with latent tuberculosis due to its risk for hepatotoxicity.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Humans; Male; Pyrazinamide; Rifampin; Tuberculosis

Recently, a short-course treatment using 60 daily doses of rifampin and pyrazinamide was recommended for latent tuberculosis (TB) infection (LTBI).. To determine the acceptability, tolerability, and completion of treatment.. Observational cohort study.. Five county jails and TB outreach clinics for homeless populations in three cities.. Study staff enrolled 1,211 patients (844 inmates and 367 homeless persons).. Sites used 60 daily doses of rifampin and pyrazinamide, an approved treatment regimen for LTBI.. Types and frequency of drug-related adverse events and outcomes of treatment.. Prior to treatment, 25 of 1,178 patients (2.1%) had a serum aminotransferase measurement at least 2.5 times the upper limit of normal. Patients who reported excess alcohol use in the past 12 months were more likely than other patients to have an elevated pretreatment serum aminotransferase level (odds ratio, 2.1; 95% confidence interval, 1.1 to 6.1; p = 0.03). Treatment was stopped in 66 of 162 patients (13.4%) who had a drug-related adverse event. Among 715 patients who had serum aminotransferase measured during treatment, 43 patients (6.0%) had an elevation > 5 times the upper limits of normal, including one patient who died of liver failure attributed to treatment. In multivariate analyses, increasing age, an abnormal baseline aspartate aminotransferase level, and unemployment within the past 24 months were independent risk factors for hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%).. This study detected the first treatment-associated fatality with the rifampin and pyrazinamide regimen, prompting surveillance that detected unacceptable levels of hepatotoxicity and retraction of recommendations for its routine use. Completion rates for LTBI treatment using a short-course regimen exceeds historical rates using isoniazid. Efforts to identify an effective short-course treatment for LTBI should be given a high priority.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Humans; Ill-Housed Persons; Male; Middle Aged; Patient Compliance; Prisoners; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

To determine whether inactive hepatitis B surface antigen (HBsAg) carriers are at a higher risk of drug-induced hepatotoxicity than control subjects during antituberculosis treatment with standard short-course regimens of isoniazid, rifampin, ethambutol, and/or pyrazinamide.. Retrospective case-control study.. Tertiary university medical center.. One hundred ten inactive HBsAg carriers with newly diagnosed active tuberculosis who had been treated with isoniazid, rifampin, ethambutol, and/or pyrazinamide were included in the study population. Inactive HBsAg carriers were defined as follows: (1) positive for HbsAg; (2) negative for hepatitis B e antigen (HBeAg), positive for antibody to HBeAg; (3) < 10(5) copies per mL of serum hepatitis B virus DNA; and (4) normal pretreatment aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels. Ninety-seven HBsAg-negative patients who received standard antituberculosis medication were selected as control subjects.. The baseline characteristics of the 110 inactive HBsAg carriers were similar to those of the 97 noncarriers. A total of 85% of persons in both groups had received an initial treatment regimen that included pyrazinamide. Thirty-eight inactive HBsAg carriers (35%) and 19 control subjects (20%) exhibited elevated liver enzyme levels during antituberculosis treatment (p = 0.016). Drug-induced hepatotoxicity, which was defined as a liver transaminase level of >/= 120 IU/L, occurred more frequently in HBsAg carriers (9 of 110 carriers; 8%) than in control subjects (4 of 97 control subjects; 4%), although this was not a statistically significant discrepancy (p = 0.230). More importantly, HBsAg carriers (n = 9; 8%) who received antituberculosis therapy evidenced a higher proportion of moderate-to-severe drug-induced hepatotoxicity when compared with the control subjects (n = 2; 2%; p = 0.05). Isoniazid and rifampin were reintroduced as therapy after AST/ALT levels returned to baseline values in 10 patients (6 HBsAg carriers and 4 control subjects) among the 13 patients exhibiting drug-induced hepatotoxicity, and these retrials proved to be successful in 7 patients (5 HBsAg carriers and 2 control subjects).. Tuberculosis treatment in HBsAg-positive and HBeAg-negative inactive carriers could be pursued in the usual manner, using standard short-course regimens of isoniazid, rifampin, ethambutol, and/or pyrazinamide, with the condition that monthly liver function tests are performed.

Topics: Adult; Antitubercular Agents; Carrier State; Case-Control Studies; Chemical and Drug Induced Liver Injury; Ethambutol; Female; Hepatitis B; Hepatitis B Surface Antigens; Humans; Incidence; Isoniazid; Male; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors

Topics: Chemical and Drug Induced Liver Injury; Drug Labeling; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Rifampin; United States; United States Food and Drug Administration

Topics: Chemical and Drug Induced Liver Injury; Drug Industry; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Rifampin; Ritonavir; Saquinavir; United States

The present report showed the hepatoprotective property of a 50% hydroalcoholic extract of the fruits of Emblica officinalis (fruit) (EO-50) against antituberculosis (anti-TB) drugs-induced hepatic injury. The biochemical manifestations of hepatotoxicity induced by rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA), either given alone or in combination were evaluated. In vitro studies were done on suspension cultures of rat hepatocytes while sub-acute studies were carried out in rats. The hepatoprotective activity of EO-50 was found to be due to its membrane stabilizing, antioxidative and CYP 2E1 inhibitory effects.

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Fruit; Hepatocytes; Humans; Isoniazid; Male; Phyllanthus emblica; Phytotherapy; Plant Extracts; Protective Agents; Pyrazinamide; Rats; Rats, Wistar; Rifampin; Tuberculosis, Pulmonary

Cases of severe and fatal liver injury were reported after a 2-month course of rifampin-pyrazinamide therapy was recommended in 2000 as an alternative to isoniazid for treatment of latent tuberculosis infection. We estimated rates of rifampin-pyrazinamide-associated liver injury and compared these with historical rates for isoniazid.. We conducted a survey of state and city tuberculosis programs and other health care settings in the United States where rifampin-pyrazinamide was prescribed. The number of rifampin-pyrazinamide therapy initiations was collected, as well as the number of occurrences of (1) asymptomatic aspartate aminotransferase serum concentration >5 times the upper limit of normal, (2) symptomatic hepatitis (in which the patient was not hospitalized), (3) hospitalization for liver injury, (4) death with liver injury, and (5) treatment completion. We also searched a national pharmacy claims database (Verispan). Rates of these events were calculated.. Among 139 programs, 110 (79%) responded; 87 (79%) had initiated rifampin-pyrazinamide therapy for a total of 8087 patients between January 2000 and June 2002. Rates per 1000 rifampin-pyrazinamide therapy initiations during this period were 25.6 (95% confidence interval [CI], 22.3-29.3) for asymptomatic aspartate aminotransferase level >5 times the upper limit of normal and 18.7 (95% CI, 15.9-21.9) for hepatitis. Seven fatalities and 23 hospitalizations occurred, with rates of 0.9 (95% CI, 0.4-1.9) and 2.8 (95% CI, 1.8-4.3) per 1000 rifampin-pyrazinamide therapy initiations, respectively. Of 8087 patients, 64% completed rifampin-pyrazinamide therapy. The Verispan search revealed 1 rifampin-pyrazinamide-associated hospitalization (2.9 hospitalizations per 1000 rifampin-pyrazinamide therapy initiations; 95% CI, 0.1-18.4) and no deaths. Articles on the use of isoniazid therapy for latent tuberculosis infection that were published after 1990 reported fatality rates of 0.0-0.3 deaths per 1000 persons.. Rates of liver injury, hospitalization, and death associated with rifampin-pyrazinamide therapy exceed rates reported for isoniazid therapy. Because earlier randomized trials of rifampin-pyrazinamide lacked adequate statistical power to detect fatal events, the Centers for Disease Control and Prevention recommends that rifampin-pyrazinamide generally should not be used for treatment of latent tuberculosis infection.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Health Surveys; Hospitalization; Humans; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis; United States

Two months of rifampin and pyrazinamide (RIF/PZA) for tuberculosis prevention has been advocated as a way to improve adherence in mobile populations, such as recent immigrants. However, RIF/PZA requires intensive patient and laboratory monitoring for hepatotoxicity.. To describe the feasibility and outcomes of using RIF/PZA for TB prevention during a tuberculosis outbreak in a Mexican immigrant community, where 23 adults and 11 children were treated with RIF/PZA between August 2001 and October 2001.. Retrospective chart review and interviews with health department employees were conducted to assess completion rates, hepatotoxicity, cost, and feasibility of monitoring.. Ten (91%) children and 13 (57%) adults completed RIF/PZA. One child (9%) and four adults (17%) developed drug-induced hepatitis. Cultural barriers affected care. The adults resisted the biweekly blood draw, believing it would "drain them of energy." RIF/PZA, plus monitoring, was twice as costly as 4 months of rifampin.. RIF/PZA was associated with significant hepatotoxicity, poor completion, and cultural barriers to monitoring, and was more costly than standard therapy. Tuberculosis prevention must address potential clinical, cultural, and economic barriers to completion and monitoring of short-course therapy in immigrants.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Disease Outbreaks; Drug Therapy, Combination; Emigration and Immigration; Female; Humans; Interviews as Topic; Male; Mexican Americans; Mexico; Middle Aged; Patient Compliance; Pyrazinamide; Rifampin; Tuberculosis; United States

To investigate the role of CYP2E1 in isoniazid (INH)-induced hepatotoxicity and the influence of rifampicin (RFP) on INH-induced liver injury.. Rats were treated with INH alone (100 mg/kg, ip) or co-administered with RFP (100 mg/kg, ig) for 10 d and 21 d. Hepatotoxicity was assayed by plasma enzymes (sALT, sAST) and histopathological examinations. Hepatic CYP2E1 activity was measured by aniline hydroxylase (ANH), and CYP2E1 mRNA expression was determined by RT-PCR. Plasma hydrazine concentration was determined by RP-HPLC.. For a 10 d INH-treatment, hepatic CYP2E1 level was increased to 3.7-fold over the control; liver impairment appeared after 21 d treatment, while CYP2E1 and plasma hydrazine were, respectively, increased to 4.6-fold and 1.7-fold. However, in INH-RFP group for 10 d, CYP2E1 and plasma hydrazine were, respectively, decreased by 13 % and 18 % over INH group; similarly, hepatic injury is equal to INH group appeared after 21 d, and CYP2E1 was further decreased by 26 %. Correlation analysis showed that sALT had a positive correlation with plasma hydrazine and with CYP2E1 activity; CYP2E1 activity was also markedly correlated with plasma hydrazine. And compared with control, there is no difference in changes of CYP2E1 mRNA expression in INH and INH-RFP treatment for 21 d.. The metabolite of INH, hydrazine, plays an important role in INH-induced hepatotoxicity in rats. The induction of CYP2E1 by hydrazine is involved in the hepatotoxicity of INH. RFP does not exacerbate INH-induced hepatotoxicity in short term, which relates to down-regulation of CYP2E1.

Topics: Alanine Transaminase; Animals; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Down-Regulation; Hydrazines; Isoniazid; Liver; Male; Rats; Rifampin; RNA, Messenger

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Liver Diseases; Pyrazinamide; Rifampin

Severe liver injury has been attributed to preventive treatment of latent tuberculosis infection with a 2-month course of rifampin-pyrazinamide.. A retrospective cohort study in The Netherlands compared the hepatotoxicity of preventive treatment with rifampin-pyrazinamide with that of preventive treatment with isoniazid, and also with that of treatment for active tuberculosis containing at least isoniazid, rifampin, and pyrazinamide.. Preventive treatment with rifampin-pyrazinamide caused severe hepatotoxicity more often than did preventive treatment with isoniazid (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.26-5.39; P=.012), especially in patients <25 years old. It also caused severe hepatotoxicity more often than triple- or quadruple-drug tuberculosis treatment (OR, 2.61; 95% CI, 1.21-5.59; P=.016), especially if the pyrazinamide dose was > or =30 mg/kg. Preventive treatment with rifampin-pyrazinamide was more hepatotoxic even when the advised pyrazinamide dose of up to 20 mg/kg for preventive treatment was compared with the pyrazinamide dose of 30 mg/kg for tuberculosis treatment.. Preventive treatment with rifampin-pyrazinamide causes severe hepatotoxicity more often than does preventive treatment with isoniazid or curative treatment for tuberculosis.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Cohort Studies; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Netherlands; Prospective Studies; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis

In 2000, results of a multinational trial demonstrated that a 2-month course of rifampin and pyrazinamide (RZ) was as effective as isoniazid (INH) in reducing tuberculosis in human immunodeficiency virus (HIV)-infected individuals with latent tuberculosis infection (LTBI). After the release of new guidelines, the Centers for Disease Control and Prevention received reports of severe hepatotoxicity associated with the use of the RZ regimen for the treatment of LTBI in the general population. To better understand the occurrence of hepatotoxicity in an HIV-infected population, we conducted a more detailed analysis of the liver function test results obtained in the multinational trial of RZ.. At study entry, patients were required to have a bilirubin level of < or =2.5 mg/dL and both an aspartate aminotransferase (AST) level and an alkaline phosphatase level of < or =5 times the upper limit of normal. Patients with acute hepatitis were excluded. At months 1 and 2 of the study, all patients had bilirubin and AST levels measured.. There was no difference between the RZ and INH groups with regard to AST level or bilirubin level at baseline. An increase in the AST level of > or =40 U/L was associated with the use of INH and older age; and an increase in the bilirubin level of > or =0.5 mg/dL was associated with the use of RZ, male sex, and nonwhite race (P<.05). An absolute AST level of >250 U/L occurred in 12 of 745 INH recipients and in 15 of 721 RZ recipients (P=.56), and an absolute bilirubin level of >2.5 mg/dL occurred in 5 of 743 INH recipients and 13 of 718 RZ recipients (P=.06).. These data demonstrate very little liver injury associated with either INH or RZ in the HIV-infected subjects, leaving unclear the reasons for serious RZ-related liver damage in the general population.

Topics: Adolescent; Adult; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; HIV Infections; Humans; Isoniazid; Liver; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Pyrazinamide; Randomized Controlled Trials as Topic; Regression Analysis; Rifampin; Tuberculosis

An alternative regimen for the treatment of latent tuberculosis infection is 2 months of rifampin and pyrazinamide, but some patients have died of hepatitis associated with this therapy. One hundred fourteen patients received rifampin/pyrazinamide in Wake County, North Carolina, between December 1999 and May 2002; 60.5% of these patients were homeless, and at least 17% drank alcohol to excess. Seventy-seven patients (67.5%) completed a full 2-month course. Nine patients had a history of viral hepatitis or chronic liver disease. Four of 114 (3.5%; 95% confidence interval, 1.0-8.7%) patients developed hepatitis on therapy, and another two had symptoms consistent with hepatitis but did not report for laboratory testing (total confirmed plus suspected hepatitis rate 5.3%; 95% confidence interval, 2.0-11.1%). No patient who developed hepatitis had a history of viral hepatitis or liver disease, and none had been previously treated with isoniazid. No patients died or were hospitalized due to drug side effects. Rifampin/pyrazinamide was associated with a significantly higher rate of hepatitis than previously described with isoniazid therapy for latent tuberculosis but resulted in a high completion rate. The rifampin/pyrazinamide regimen for latent tuberculosis infection may be useful for high-risk, traditionally nonadherent patient groups, but careful monitoring for toxicity is required.

Topics: Adolescent; Adult; Aged; Alcoholism; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cohort Studies; Comorbidity; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Hepatitis B; Hepatitis C; Humans; Ill-Housed Persons; Infant; Liver Diseases; Male; Middle Aged; North Carolina; Pyrazinamide; Rifampin; Safety; Treatment Outcome; Tuberculosis

American Thoracic Society guidelines recommend a 9-month course of therapy with isoniazid for treatment of persons with latent tuberculosis infection who are at high risk for reactivation of disease. Major liver injury has been reported with the alternative regimen, a 2-month course of pyrazinamide and rifampin.. To evaluate the rate of completion and incidence of hepatotoxicity of a short regimen of pyrazinamide and rifampin for latent tuberculosis as compared with standard isoniazid therapy before and after instituting an intensive monitoring program.. Prospective cohort study of 224 patients in a community setting between 1999 and 2001.. Daily pyrazinamide and rifampin for 2 months or daily isoniazid for 6 months.. Treatment completion, hepatotoxicity (fourfold increase of alanine transaminase [ALT]), severe hepatotoxicity (40-fold increase in ALT).. Treatment was completed by 71% (78 of 110 patients) in the pyrazinamide/rifampin group and by 59% (67 of 114 patients) in the isoniazid group (p = 0.07). Hepatotoxicity (ALT > 160 U/L) was documented in 13% (14 of 110 patients) in the pyrazinamide/rifampin group and in 4% (5 of 114 patients) in the isoniazid group (p = 0.03). Severe hepatotoxicity (ALT > 1,600 U/L) occurred in 2 of 43 patients (5%) receiving pyrazinamide/rifampin prior to instituting intensive monitoring. Once more intensive monitoring of liver enzymes was implemented, severe hepatotoxicity occurred in none of 67 patients.. The risk of hepatitis in patients receiving pyrazinamide/rifampin for prevention of latent tuberculosis is increased threefold as compared to patients receiving isoniazid. When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance (p = 0.15).

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Prospective Studies; Pyrazinamide; Rifampin; Severity of Illness Index; Tuberculosis, Pulmonary

Major adverse reactions to antituberculosis drugs can cause significant morbidity, and compromise treatment regimens for tuberculosis (TB). Among patients treated for active TB we estimated the incidence, and risk factors, of major side effects from first-line anti-TB drugs. Side effects, resulting in modification or discontinuation of therapy, or hospitalization, were attributed on the basis of resolution after withdrawal, and/or recurrence with rechallenge. Among 430 patients treated between 1990 and 1999, the incidence of all major adverse effects was 1.48 per 100 person-months of exposure (95% confidence interval [95% CI], 1.31 to 1.61) for pyrazinamide, compared with 0.49 (95% CI, 0.42 to 0.55) for isoniazid, 0.43 (95% CI, 0.37 to 0.49) for rifampin, and 0.07 (95% CI, 0.04 to 0.10) for ethambutol. Occurrence of any major side effect was associated with female sex (adjusted hazard ratio, 2.5; 95% CI, 1.3 to 4.7), age over 60 years (adjusted hazard ratio, 2.9; 95% CI, 1.3 to 6.3), birthplace in Asia (adjusted hazard ratio, 2.5; 95% CI, 1.3 to 5.0), and human immunodeficiency virus-positive status (adjusted hazard ratio, 3.8; 95% CI, 1.05 to 13.4). Pyrazinamide-associated adverse events were associated with age over 60 years (adjusted hazard ratio, 2.6; 95% CI, 1.01 to 6.6) and birthplace in Asia (adjusted hazard ratio, 3.4; 95% CI, 1.4 to 8.3), whereas rifampin-associated adverse events were associated with age over 60 years (adjusted hazard ratio, 3.9; 95% CI, 1.02 to 14.9) and human immunodeficiency virus-positive status (adjusted hazard ratio, 8.0; 95% CI, 1.5 to 43). The incidence of pyrazinamide-induced hepatotoxicity and rash during treatment for active TB was substantially higher than with the other first-line anti-TB drugs, and higher than previously recognized.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Ethambutol; Female; HIV Seropositivity; Humans; Incidence; Isoniazid; Male; Middle Aged; Proportional Hazards Models; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Drug Resistance, Bacterial; Emigration and Immigration; Health Care Costs; Humans; Pyrazinamide; Rifampin; Tuberculosis

To investigate the secular change in the incidence rate of drug-induced hepatitis (DIH) due to anti-tuberculosis chemotherapy including isoniazid (INH) and rifampicin (RFP), but not including pyrazinamide (PZA), we retrospectively studied the incidence rates of DIH in patients treated with chemotherapy including INH and RFP in four periods 1980-83, 87-88, 91-92, and 1998-2000. The criteria for selection of the patients were as follows. 1. The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before, and one month (20-40 days) and 2 months (45-75 days) after starting anti-tuberculosis chemotherapy. When the serum AST and ALT were measured twice or more during period 20-40 days or 45-75 days after starting anti-tuberculosis chemotherapy, the data obtained nearest to 30 or 60 days after were chosen as those of one or two months after starting chemotherapy, respectively. 2. The serum AST and ALT were within normal range before starting anti-tuberculosis chemotherapy. The normal range of serum AST and ALT were < or = 40 K-A and < or = 35 K-A (in 1980-83) or < or = 31 IU/l and 34 IU/l (in 1987-2000), respectively. 3. Chronic active hepatitis and cirrhosis patients were excluded. 4. All alive after completion of anti-tuberculosis chemotherapy. The numbers of the subjects who fulfilled the above criteria were 113, 135, 128 and 154 in 1980-83, 1987-88, 1991-92 and 1998-2000, respectively. DIH was defined serologically by serum AST > or = 40 K-A and/or ALT > or = 35 K-A (in 1980-83), or AST > or = 40 IU/l and/or ALT > or = 40 IU/l (1987-2000). The DIH incidence rate of the subjects classified by the year of treatment and age were examined, and the contributions of the risk factors for DIH, such as age, sex, alcoholics, previous liver disease history, HBs ag positivity, anti-HCV ab positivity, and hypoalbuminenia were studied, and none except the age over 80 y.o. was found to be a risk factor to DIH, in our subjects. In patients with the age over 80 y.o., daily doses of antituberculosis drugs RFP, INH and ethambutol (EB) were significantly higher in patients with DIH than those without DIH, but body weight and serum albumin level were not significantly different between these two groups. There was no risk factor to DIH in our patients less than 80 y.o. and this could be explained by the above-mentioned criteria of study patients selection. To exclude the age dependence of the incidence rate of DIH in our subjects, the incidence

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Ethambutol; Female; Humans; Incidence; Isoniazid; Japan; Male; Middle Aged; Retrospective Studies; Rifampin; Risk Factors; Time Factors

We report a case of severe hepatotoxicity associated with rifampin-pyrazinamide preventative therapy that required liver transplantation in a closely monitored, human immunodeficiency virus-uninfected individual who had no risk for hepatotoxicity. Because hepatotoxicity associated with this treatment appears to be idiosyncratic, we recommend closer monitoring of liver enzyme levels than do the Centers for Disease Control and Prevention guidelines, as well as at least temporary interruption of treatment during any elevation of liver enzyme levels greater than the normal value.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Chemical and Drug Induced Liver Injury; Humans; Liver Function Tests; Male; Organ Transplantation; Pyrazinamide; Rifampin; Risk; Tuberculosis; United States

CDC has reported previously surveillance data of severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month regimen of rifampin with pyrazinamide (RZ). On the basis of these initial reports, CDC cautioned clinicians in the use of this therapy with advised additional monitoring. To estimate the incidence of RZ-associated severe liver injury and provide more precise data to guide treatment for LTBI, CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI during January 2000-June 2002 and for whom data were reported to CDC through June 6, 2003. This report summarizes the analysis, which found high rates of hospitalization and death from liver injury associated with the use of RZ. On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI. The revised ATS/CDC recommendations described in this report have been endorsed by the Infectious Diseases Society of America (IDSA). Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI. Rifampin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Pyrazinamide; Retrospective Studies; Rifampin; Tuberculosis; United States

Topics: Centers for Disease Control and Prevention, U.S.; Chemical and Drug Induced Liver Injury; Communication; Humans; Pyrazinamide; Rifampin; Tuberculosis; United States; United States Public Health Service

To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suitable for nebulization.. Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs.. The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 +/- 0.11 microm, favourable for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained therapeutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability [compared to intravenous (i.v.) administration] was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles containing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit.. Nebulization of nanoparticles-based ATDs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.

Topics: Administration, Inhalation; Aerosols; Animals; Antibiotics, Antitubercular; Antitubercular Agents; Area Under Curve; Biological Availability; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry, Physical; Colony Count, Microbial; Drug Carriers; Drug Combinations; Drug Compounding; Female; Guinea Pigs; Half-Life; Injections, Intravenous; Isoniazid; Lactic Acid; Lung; Male; Microspheres; Mycobacterium tuberculosis; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Pyrazinamide; Rifampin; Tuberculosis

Our objective was to clarify risk factors associated with the development of severe hepatotoxicity during antituberculosis chemotherapy in Japanese children.. In a retrospective analysis in a 350-bed referral children's hospital in a metropolitan area, the medical charts of all pediatric patients who received antituberculosis chemotherapy between January 1995 and November 1999 were surveyed. Univariate and multivariate analyses were performed to find any demographic parameters (ie, sex, age, height, and body weight), clinical characteristics (ie, nutritional or developmental status, co-infection with hepatitis viruses [B or C] or human immunodeficiency virus, presence of extrapulmonary tuberculosis, or medical history of liver disease), or individual antituberculosis agents used that would be associated with the likelihood of development of severe hepatotoxicity during antituberculous chemotherapy. Severe hepatotoxicity (defined as an elevation of ALT and AST levels that were greater than 5 times the respective reference values) was attributed to the chemotherapy when it developed in children with normal pretreatment values for these parameters and no other potential causes were identified. Those who had abnormal ALT or AST values before treatment were excluded from analysis.. Among the 117 patients surveyed (58 males and 59 females; age range, 0 to 16 years), 18 were excluded from the analysis because of abnormal baseline ALT and AST values. Severe hepatotoxicity developed in 8 of the 99 eligible children, and all 8 of those children were younger than 5 years old. The univariate analysis revealed that the children in whom hepatotoxicity developed were significantly (P <.05) younger, were predominantly male, had extrapulmonary tuberculosis, and were given pyrazinamide more often than those who had no hepatotoxicity. However, the multivariate logistic regression analysis revealed that only age and the administration of pyrazinamide would have a significant contribution (P <.05) to the development of severe hepatotoxicity, with odds ratios of 143 (95% confidence interval, 4.2 to 4934.9) and 0.60 (95% confidence interval, 0.39 to 0.90), respectively: the estimated probability of development of hepatotoxicity in a typical pediatric patient at 1, 5, and 10 years receiving pyrazinamide with rifampin (INN, rifampicin) and isoniazid would be 0.95, 0.72, and 0.16, respectively.. This study indicated that intensive monitoring of hepatotoxicity should be performed for younger children (<5 years) receiving pyrazinamide for antituberculosis chemotherapy.

Topics: Adolescent; Analysis of Variance; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Isoniazid; Japan; Liver; Male; Medical Records; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Liver Function Tests; Male; Pyrazinamide; Rifampin

Reports of fatal and severe liver injury associated with treatment of latent tuberculosis infection (LTBI) with the drug combination rifampin and pyrazinamide (RZ) prompted CDC to issue revised guidelines for the use of this regimen on August 31, 2001. To determine if these revised guidelines were effective in reducing morbidity and mortality, CDC has continued to collect reports on adverse effects associated with this regimen. This update summarizes the results of this ongoing investigation.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; United States

Three municipal tuberculosis (TB) clinics.. Reports of liver injury in patients treated with a 2-month regimen of daily rifampin and pyrazinamide (2RZ) for latent TB infection have raised concern about its safety. We aimed to evaluate the safety and tolerability of 2RZ and identify risk factors for hepatotoxicity.. We reviewed charts of adults started on 2RZ between 1999 and 2001. Cases with grade 3 hepatotoxicity (AST or ALT >5.0-20.0 x upper limit of normal) and grade 4 hepatotoxicity (AST or ALT >20.0 x upper limit of normal) were identified.. Of 148 patients prescribed 2RZ, 85 (57.4%) completed therapy. Grade 3 or 4 hepatotoxicity occurred in 14 patients (eight grade 4 cases). In multivariate analysis, hepatotoxicity was associated with female sex (odds ratio [OR] 4.1; 95% confidence interval [CI] 1.2-14.3) and with presumed recent infection (recent tuberculin skin test conversion or contact with a TB case) (OR 14.3; 95%CI 1.8-115), but not with alcohol use, illicit drug use, age, race, or pyrazinamide dose.. Hepatotoxicity occurred in a high proportion of patients prescribed 2RZ, and was more common among females and those with recent infection. Caution is warranted in using 2RZ in populations where its safety has not been established.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care Facilities; Anti-Bacterial Agents; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Chicago; Drug Therapy, Combination; Female; Hospitals, Public; Humans; Liver; Liver Function Tests; Male; Middle Aged; Odds Ratio; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; United States

There is evidence to suggest that rifampicin is an effective second line therapy for controlling pruritus in patients with chronic cholestatic liver disease. It is most widely used as an antipruritic agent in the autoimmune cholestatic liver disease, primary biliary cirrhosis (PBC). Rifampicin has been reported as causing hepatitis in patients being treated for tuberculosis. Most reports of this have been confounded however by the concurrent use of other hepatotoxic antitubercular therapy. Here we report a single centre experience of the use of rifampicin in PBC, and describe three cases of significant hepatitis associated with rifampicin therapy. Two of these patients had significant impairment of liver synthetic function (necessitating liver transplantation in one case). These are the first reports of impaired hepatic synthetic function due to rifampicin monotherapy. Rifampicin caused significant hepatitis in 7.3% (95% confidence interval 2.5-19.4%) of patients treated for cholestatic liver disease in our centre.

Topics: Adult; Antipruritics; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Cirrhosis, Biliary; Middle Aged; Pruritus; Rifampin

Neurologic damage is usual after central nervous system (CSN) tuberculosis recovery. Treatment is long, difficult and prone to complications. Many factors are enrolled as prognostic determinants. This study aimed to describe the treatment and outcome of 52 children with CNS tuberculosis of a tertiary pediatric hospital. All of them received standard triple drug regimen, and 41 (78.8%) received corticosteroids as adjunctive therapy. Hydrocephalus was common (28 of 41 tested), but only 8 (15.4%) patients underwent ventricular shunt surgery. Hepatotoxicity to anti tuberculosis drugs occurred in 32 (61.5%) cases, but in only 3 (9.4%) drug substitution was necessary. There were 8 (15.4%) deaths and 24 (46.1%) cases developed neurologic damage after therapy. Patients who did not receive steroids during treatment and those with advanced neurological involvement at diagnosis showed a tendency to worse prognosis.

Topics: Adolescent; Adrenal Cortex Hormones; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydrocephalus; Hyponatremia; Infant; Isoniazid; Male; Prognosis; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Central Nervous System

One of the recommended treatments for latent tuberculosis infection (LTBI) is a 9-month regimen of isoniazid (INH); a 2-month regimen of rifampin (RIF) and pyrazinamide (PZA) is an alternative in some instances. In September 2000, a man in New York died of hepatitis after 5 weeks of RIF-PZA, and in December, a woman in Georgia was admitted to a hospital because of hepatitis after 7 weeks of this regimen. This report summarizes the findings of the investigations of these incidents, which underscore the need for clinical monitoring for adverse effects in all patients receiving treatment for LTBI.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Fatal Outcome; Female; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Georgia; Humans; Liver Function Tests; Male; Middle Aged; New York; Pyrazinamide; Rifampin; Tuberculosis

Short course regimens; 2HRZ (E)(S)/4HR (E), 6HRS (E)/3-6HR and 6-9HR have been accepted as a standard chemotherapy (SC) for initial treatment of pulmonary tuberculosis in Japan. We studied the frequency of the treatment completion, the causes of the treatment failure and the outcome of the patients in whom INH or RFP was discontinued within 6 months after starting SC. The subjects included 597 newly diagnosed culture positive pulmonary tuberculosis patients admitted to 16 national hospital in 1996. Results were as follows. 1. In 47 (7.9%) of the 597 patients, either INH (19; 3.2%) or RFP (33; 5.5%) was discontinued. These 47 cases were defined as a SC incompleted group and the other 550 as a SC completed group. 2. The patients in the SC incompleted group were seen more frequently in the ages of 20s (11.9%), 50s (10.9%), 60s (11.7%) or 70s (11.4%). 21 (13.6%) of 154 female patients and 26 (5.9%) of 443 male patients were in the SC incompleted group. 3. The causes of cessation of INH or RFP were drug side effects (33; 5.5%), drug resistance (10; 1.7%) and complications or underlying diseases (8; 1.3%). 4. Fever or eruption (19; 3.2%) and drug induced hepatitis (12; 2.0%) were frequently seen as drug related side effects causing the cessation of INH or RFP. 5. The rate of culture negative conversion of TB bacilli at 6 months after the start of the treatment was 98.9% in the SC completed and 88.9% in the SC incompleted group respectively. In the SC incompleted group, there were three cases continuously positive and two other patients who relapsed and became culture positive again. In these five patients, INH or RFP was discontinued because of drug resistance.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Female; Fever; Humans; Isoniazid; Male; Middle Aged; Rifampin; Sex Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Drug Combinations; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; United States

Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis

Topics: Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Health Personnel; Humans; Policy Making; Pyrazinamide; Rifampin; United States

During February 12-August 24, 2001, a total of 21 cases of liver injury associated with a 2-month rifampin-pyrazinamide (RIF-PZA) regimen for the treatment of latent tuberculosis infection (LTBI) was reported to CDC. These 21 cases are in addition to two previously reported RIF-PZA-associated cases. Cases of liver injury have occurred each year since 1999. CDC also received reports of 10 cases associated with other LTBI treatment regimens; however, risk for liver injury cannot be compared among treatment regimens in part because the number of patients treated for LTBI with each treatment regimen is unknown. This report provides preliminary information about the 21 cases associated with RIF-PZA and the revised recommendations on selecting appropriate LTBI therapy for patients and monitoring the use of RIF-PZA to treat LTBI. In most instances, the 9-month isoniazid (INH) regimen is preferred for the treatment of patients with LTBI. RIF-PZA may be used in selected cases and requires more intensive clinical and laboratory monitoring than previously recommended.

Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis

Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP).. To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity.. Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation.. Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95% CI 1.94-6.06) for intermediate-type and 28.0 (95%CI 26.0-30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types.. Slow NAT2* genotype significantly affected the development of INH + RMP-induced hepatotoxicity. This suggests the possibility that NAT2* genotyping prior to medication may be useful in evaluating patients with high risk for INH + RMP-induced hepatotoxicity.

Topics: Adult; Aged; Antitubercular Agents; Arylamine N-Acetyltransferase; Asian People; Chemical and Drug Induced Liver Injury; Female; Genotype; Humans; Isoniazid; Japan; Male; Middle Aged; Prospective Studies; Rifampin; Tuberculosis, Pulmonary

Rifampicin has been shown to increase during activities of serum transaminases and to decrease in cytochrome P-450-mediated monooxygenase activities in livers of mice treated with carbon tetrachloride (CCl4). Although these findings suggest that rifampicin prevents hepatocyte damage caused by CCl4, detailed information on the protective effects is not available.. We injected first rifampicin and then CCl4 into mice and examined denaturation and fragmentation of hepatocyte DNA by in situ nick translation, in situ end labeling, and in situ hybridization. Furthermore, expressions of p53, a cytoplasmic marker for apoptosis, and bcl2, an anticell death factor, were examined immunohistochemically. In addition, a major ethanol-inducible P-450 isoform in liver homogenates or microsomes, CYP2E1, was examined by Western blotting, because the enzyme metabolizes CCl4 and forms free radicals to injure perivenular hepatocytes in which the enzyme is restrictedly expressed.. Rifampicin prevented the denaturation and fragmentation of DNA caused by CCl4 in perivenular hepatocytes except for those located within two or three cell layers surrounding the central venule. Furthermore, CYP2E1 decreased in liver homogenates or microsomes from rifampicin-treated animals. It is therefore likely that rifampicin suppresses expression of CYP2E1 and protects CCl4-mediated DNA damage of hepatocytes by inhibiting formation of free radicals. In addition, perivenular hepatocytes except for those surrounding the venule showed negative immunoreaction for p53 and bcl2 in rifampicin+CCl4-treated animals.. The drug did not alter the mechanism of cell death from necrosis to apoptosis and did not promote recovery of hepatocytes from CCl4-mediated damage.

Topics: Animals; Blotting, Western; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; DNA Damage; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Gene Expression; In Situ Hybridization; In Situ Nick-End Labeling; Liver; Liver Diseases; Male; Mice; Microsomes, Liver; Poly A; Rifampin

Incidence of tuberculosis worldwide will increase progressively unless the effective program is implemented immediately. In Japan, the decreasing of tuberculosis incidence has been very slow since 1977 and this trend has not been improved till now. Six-month regimens for the treatment of tuberculosis were recommended by IUATLD, ATS, CDC, and WHO and have been adopted in most developed countries since late 1980s, but not adopted in Japan till April, 1996. We studied effectiveness of 6-month regimen including pyrazinamide (2HRZS or E/4HRE) on newly diagnosed pulmonary tuberculosis who started the treatment in the Fukujuji Hospital, Japan Anti-Tuberculosis Association (JATA). From January 1991 to December 1997, 726 newly diagnosed pulmonary tuberculosis patients started treatment with 6-month regimen. Bacillary negative conversion rate among 424 patients whose bacilli were susceptible to both isoniazid and rifampicin, was 92.9% after 2 months of treatment and who completed treatment without change of treatment regimen. Among 726 cases, 593 (81.7%) succeeded, 48 (6.6%) defaulted, 53 (7.3%) were referred to other doctors, and 32 (4.4%) died. The relapse rate after completion of the treatment was 3.2 percent among 345 patients whose bacilli were susceptible to both isoniazid and rifampicin and who completed the treatment without change of regimen. The relapse rate among the patients complicated with diabetes mellitus (DM) was higher than that among non-DM patients (6.31/100 person-years vs 0.90/100 person-years) (P < 0.001). When drug-induced hepatitis was defined as the elevation of serum liver enzyme levels with the clinical symptoms of hepatitis or their elevation over 5 times of normal upper limit, the incidence of drug-induced hepatitis among the patients treated with pyrazinamide-containing 6-month regimen was not higher than that among the patients treated with 9-month regimen without pyrazinamide (6HRS or E/3HR) (7.9% vs 7.3%). The risk factors for drug-induced hepatitis included elderly, history of gastrectomy, hypoalbuminemia, the higher dose of isoniazid over than 7.5 mg/kg, higher than 30 mg/kg of pyrazinamide and positive HCV antibody. The effectiveness of 6-month regimen on the patients whose organisms were resistant to isoniazid and susceptible to rifampicin was studied. The average duration of the treatment for the patients started 6-month regimen was 3.2 months shorter than for the patients started 9-month regimen (10.2 months vs 13.4 months).

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Diabetes Mellitus; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Risk Factors; Time Factors; Tuberculosis, Pulmonary

The role of N-acetylcysteine (NAC), a glutathione (GSH) precursor, was investigated in protection against isoniazid- (INH) and rifampicin- (RIF) induced oxidative hepatic injury in young Wistar rats. The hepatotoxic dose of INH and RIF was 50 mg kg(-1) day(-1) each and the hepatoprotective dose of NAC was 100 mg kg(-1) day(-1). All drugs were administered intraperitoneally (i.p.) in sterile water (4.0 ml kg(-1) day(-1)) over a period of 3 weeks. Status of oxidative/antioxidative profiles was the mechanistic approach to assess the hepatotoxicity and/or hepatoprotection. The oxidative injury in INH-RIF co-exposed animals was closely associated with significant decline of GSH and related thiols, as well as with compromised antioxidant enzyme system. The oxidative stress was further supported by increased lipid peroxidation observed in these animals. The co-administration of NAC prevented the induction of oxidative stress in INH-RIF co-exposed animals. The amelioration of oxidative stress by NAC was faithfully reflected as normal morphology in these animals, except the presence of mild degree of portal triaditis in one animal co-exposed to INH-RIF and NAC. In contrast, the animals co-exposed to INH-RIF alone showed histological lesions which ranged from intralobular inflammation to patchy necrosis. These results suggest that INH-RIF-induced oxidative injury can be prevented by supporting the cellular antioxidant defense mechanism by NAC.

Topics: Acetylcysteine; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Catalase; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Drug Interactions; Injections, Intraperitoneal; Isoniazid; Lipid Peroxidation; Liver; Male; Oxidative Stress; Rats; Rats, Wistar; Rifampin; Superoxide Dismutase

Oral treatment with the ethanol extract of Hemidesmus indicus roots (100 mg/kg, for 15 days) significantly prevented rifampicin and isoniazid-induced hepatotoxicity in rats.

Topics: Administration, Oral; Animals; Chemical and Drug Induced Liver Injury; Isoniazid; Magnoliopsida; Male; Medicine, Ayurvedic; Mitochondria, Liver; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar; Rifampin

The usefulness of the lymphocyte transformation test (LTT) for the analysis of adverse reactions to antituberculous drugs was evaluated. - The LTT was performed with isoniazid and rifampicin in 15 tuberculosis and 2 MOTT (Mycobacteria other than tuberculosis)-infection patients who suffered drug reactions, in 23 patients without any adverse reactions, in 7 controls previously exposed to antituberculous drugs, and in 14 controls who had never been exposed. 4/15 of the hepatotoxic reactions only showed a positive LTT with rifampicin, 3/15 only with isoniazid, and in 8/15 the LTT was negative. In an anaphylactoid shock reaction the LTT was extremely exaggerated for both rifampicin and isoniazid. In patients without any side effects only one slightly increased LTT due to isoniazid was observed. Two healthy controls with previous contact to these drugs showed a positive LTT for isoniazid, one of those with both rifampicin and isoniazid. The LTT was negative in all control persons without any former contact to antituberculous medications. In most cases hepatotoxicity seems to be a pure toxic reaction without the participation of cellular immune mechanisms. LTT can be useful for identifying the drug responsible for immunological side effects.

Topics: Adult; Anaphylaxis; Anti-Bacterial Agents; Antitubercular Agents; Bromodeoxyuridine; Cells, Cultured; Chemical and Drug Induced Liver Injury; DNA Replication; Drug Eruptions; Drug Hypersensitivity; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunity, Cellular; Isoniazid; Kidney Diseases; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Mycobacterium kansasii; Nervous System Diseases; Rifampin; Tuberculosis

The incidence of tuberculosis in Japan, 33.7 per 100,000 in 1997, is very high compared with USA or Western European countries. The decrease in the incidence has slowed down from the early 1980s, and the average annual rate of decrease has been 3.8% in the last 5 years. About 9 percent of tuberculosis patients defaulted from the nine-month regimen (6HRS or E/3HR) in urban areas. Regimens shorter than nine-month are needed to achieve high effectiveness of tuberculous chemotherapy. Out of 1128 new pulmonary tuberculosis patients, six-hundred twenty started treatment with six-month (2HRZS or E/4HRE) in Fukujuji Hospital, JATA, in Tokyo from January 1991 to December 1996. Out of 620, four-hundred twenty eight were both smear and culture positive, 136 were smear negative and culture positive and 56 were bacilli negative. Out of 564 bacilli positive cases, 530 were susceptible to INH and RFP. Out of 530 drug susceptible cases three hundred ninety-three patients completed the regimen. Ninety-three percent of these patients had converted to negative at two months of chemotherapy and all of them at five months. Out of 450, two-hundred ninety five completed 6-month regimen, one-hundred fifty-five were changed their regimen or prolonged duration of chemotherapy. Out of 295, nine patients (3.1%) relapsed after the completion of 6-month chemotherapy. Mean follow-up period was 17.2 months and the median was 15.5 months. The relapse rate was 2.2 per 100 person-years. Six of the relapsed cases were complicated with Diabetes Mellitus. Relapse rate was higher in patients with Diabetes Mellitus than in patients without (6/54, 7.9 per 100 person-years vs 3/237, 0.8 per 100 person-years) (p < 0.001). Drug-induced hepatotoxicity was defined as elevated serum transaminase level with clinical symptoms of hepatitis or elevated serum transaminase level more than 5 times of upper limit of normal range with or without symptoms. Drug-induced hepatotoxicity developed in 43 (8.0%) of 535 with initial normal liver function test results, this rate was similar to that in patients treated with nine-month regimen (34/420, 8.1%). But the frequency of hepatotoxicity of more than 400 IU/ml of serum transaminase level was higher in patients treated with PZA-containing regimen than with nine-month regimen (16/536, 3.0% vs 4/420, 1.0%), but this deference was not statistically significant. Hepatotoxicity developed in 13/85 (15.3%) of patients treated with PZA-containing regimen with abnormal live

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Diabetes Complications; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Patient Acceptance of Health Care; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Acute Kidney Injury; Adult; Chemical and Drug Induced Liver Injury; Humans; Leprostatic Agents; Leprosy, Tuberculoid; Male; Rifampin

Monomethyl fumarate, isolated for the first time from the methanolic extract of the whole plant of Fumaria indica, was characterised and screened for its antihepatotoxic activity in albino rats. The compound showed significant (P < 0.01) antihepatotoxic activity against thioacetamide in vitro, and against hepatotoxicities induced by carbon tetrachloride, paracetamol and rifampicin in vivo to an extent almost similar to that of silymarin, a known antihepatotoxic agent.

Topics: Acetaminophen; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Female; Fumarates; Galactosamine; Liver; Male; Maleates; Plant Extracts; Rats; Rats, Wistar; Rifampin; Silymarin; Thioacetamide

Isoniazid prophylaxis for 12 months effectively prevents tuberculosis in HIV-infected persons and may decrease the incidence of other HIV-related disease and mortality. Recent clinical trials have found that some short-course regimens also effectively prevent tuberculosis.. To compare the benefits, risks, and cost-effectiveness of isoniazid prophylaxis and short-course prophylaxis regimens.. Decision and cost-effectiveness analysis.. United States.. Hypothetical patients who are HIV-infected and have CD4 counts of 200 cells/mm3 or less and positive results on tuberculin skin tests.. Isoniazid prophylaxis lasting 12 months and six short-course prophylaxis regimens of isoniazid, rifampin, and pyrazinamide alone or in combination.. 5-year survival rate, life expectancy, lifetime incidence of tuberculosis, and cost per quality-adjusted life-year saved.. Compared with no prophylaxis, the 12-month isoniazid regimen increased 5-year survival rates by 9% and life expectancy by 8.7 months, decreased incidence of tuberculosis by 27%, and saved 4 medical care dollars for every 1 spent on prophylaxis. Regimens of isoniazid for 6 months, isoniazid and rifampin for 3 months, and rifampin and pyrazinamide for 2 months had similar results: 6.2- to 8.6-month increases in life expectancy, 19% to 26% reductions in incidence of tuberculosis, and 1 to 7 medical care dollars saved for every 1 spent on prophylaxis. A 3-month regimen of isoniazid, rifampin, and pyrazinamide resulted in fewer clinical benefits and was the only regimen tested that did not save medical care dollars.. Prophylaxis decreases the incidence of tuberculosis and increases life expectancy for HIV-infected patients. Some regimens save medical care dollars, and some short-course regimens have clinical and economic benefits similar to those of the 12-month isoniazid regimen. Short-course prophylaxis is a reasonable alternative to the 12-month isoniazid regimen.

Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Decision Trees; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Quality-Adjusted Life Years; Rifampin; Survival Rate; Tuberculosis

We report the case of a patient with nausea, loss of appetite and increase of the aminotransferase levels to eight times the upper normal limit occurring two weeks after she was started on isoniazide, rifampicine and pyrazinamide for treatment of tuberculosis. Isoniazide is the most likely cause of liver injury occurring during combined antituberculosis therapy, whereas pyrazinamide or rifampicine are only rarely responsible. The case presented is used to review and compare the different recommendations concerning the monitoring of patients receiving antituberculous therapy and the clinical management of patients developing liver injury.

Topics: Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Combinations; Female; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

The role of oxidative-stress as a mechanism of hepatotoxicity caused by combination of isoniazid (INH) and Rifampicin (RMP) was investigated in young growing rats. A successful model of hepatotoxicity was produced by giving 50 mg/kg/day each of INH and RMP in two weeks. Liver showed type II hepatocellular changes (microvesicular fat deposition) with mild portal triaditis. The glutathione and related thiols were significantly decreased in both blood and liver tissues with combination of INH and RMP treatment. Superoxide dismutase, glutathione peroxidase, catalase and glutathione-S-transferases with CDNB and DCNB as substrates were decreased in the combination treated group. Glutathione reductase, glutathione-S-transferase with ethacrynic acid as substrate and lipid peroxidation exhibited a significant increase with treatment. The altered profile of antioxidant enzymes with increased lipid peroxidation indicated the enhanced oxidative-stress in combination of INH and RMP treatment. All the findings are faithfully reflected in the blood tissue except superoxide dismutase which showed significant enhancement in this tissue. INH and RMP hepatotoxicity is thus appeared to be mediated through oxidative-stress.

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Isoniazid; Lipid Peroxidation; Liver Diseases; Male; Oxidative Stress; Rats; Rats, Wistar; Rifampin

To evaluate the risk factors involved in antituberculosis treatment-induced hepatotoxicity. In a retrospective study we analyzed the rate of drug-induced hepatotoxicity in a sample of 456 patients. Patients received a combination of drugs including isoniazid, rifampin, pirazinamide and streptomycin or ethambutol. The association among hepatotoxicity and several risk factors (age, sex, alcoholism and HIV infection) was studied by univariate methods, stratified analysis and the multiple logistic regression model. Signs of liver injury were found in 9.86% of the treated patients. In the logistic model, the adjusted odds ratios (OR) and significance were found as follows: a) for alcoholism, OR = 17.31 (95% CI: 6.35-47.16), p < 0.001; b) for HIV infection, OR = 3.23 (95% CI: 1.47-7.11), p = 0.003 and c) for female sex, OR = 2.44 (95% CI: 1.22-4.86), p = 0.011. Age was not significantly associated with hepatotoxicity. Alcoholism, HIV infection and female sex were associated with an increased risk of hepatotoxicity in this study.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Ethambutol; Female; Humans; Isoniazid; Logistic Models; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Streptomycin

To explore the relationship between clinical manifestations and pathological changes of liver injury resulting from rifampin and isoniazid.. 194 cases treated with rifampin and isoniazid, among them liver biopsies were done once in 28 cases, twice in 17 cases, were observed.. 21 of 59 cases with positive HBVM and 13 out of 135 cases with negative HBVM showed abnormal liver function after treatment, and the elevation of ALT was in accordance with the degree of liver pathological injury. Elevated ALT and liver pathological injury returned to normal within 6 weeks after rifampin and isoniazid were stopped or reduced in doses. No significant difference was found between chronic hepatis B and rifampin, isoniazid in causing liver pathological injury, but two different points were noted in their manifestations: 1. The cells mainly caused portal inflammation were lymphocytes in the former, while eosinophils in the latter. 2. The incidence of intrahepatic cholestasis was higher in the latter.. The incidence of liver injury in HBVM positive group is higher than that in HBVM negative group because liver injury exists in the former before treatment, and the mechanisms causing liver injury may be different.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Biopsy; Chemical and Drug Induced Liver Injury; Female; Hepatitis B Antigens; Humans; Isoniazid; Liver; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Side effects of the most commonly used first-line antituberculosis drugs range from minor gastrointestinal symptoms to severe hepatotoxicity. If unrecognized, they can lead to increased morbidity and mortality as well as to higher healthcare costs. Side effects are most evident in patients with underlying compromise in hepatic function. Erratic treatment protocols not only promote secondary drug resistance but also offset all gains in tuberculosis control. Recognition of this problem, mandatory directly observed therapy, judicious standardized follow-up planning, and implementation of modified treatment protocols when needed may play a dominant role in treating and controlling tuberculosis and may also prevent the morbidity and mortality sometimes associated with tuberculosis treatment. In view of the changing epidemiology of tuberculosis and its global impact, the American Thoracic Society and the Centers for Disease Control and Prevention may need to look closely into the issues outlined here to develop a consensus and establish more specific guidelines.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Liver; Liver Diseases; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

Bispebjerg Hospital, Department of Pulmonary Medicine, tuberculosis referral center for the Municipality of Copenhagen.. To evaluate routine procedure for the management of liver injury during antituberculosis treatment.. From 1983-1993, 765 patients for whom we could trace 752 files (98%) were treated at our ward with standard Danish treatment for tuberculosis. From 1983-1986 they received a three-drug (9-month) regimen and from 1986-1993 a four-drug (6-month) regimen consisting of isoniazid, rifampicin, ethambutol + pyrazinamide. Data from a retrospective chart review.. An increase in aspartate aminotransferase (AST) of more than twice the upper limit of normal (ULN) was recorded in 127 patients (16%). 66 had elevated AST before treatment; most of these were men with a daily alcohol consumption in excess of 60 g. In the remaining 61 patients (8%) AST increased during antituberculosis treatment. 30 of these patients were excessive alcohol consumers, and seven had alcoholic liver cirrhosis. Despite an increase in AST of median 6 x ULN (range 2-25 x ULN), it was possible to continue treatment in 31 (15 excessive alcohol consumers) or reintroduce it fully in 14 (12 excessive alcohol consumers). Only 16 patients (2%), including 11 women with no daily alcohol consumption, needed a modified regimen. These patients were older (P < 0.05), seven were jaundiced, and one had alcoholic liver cirrhosis. Hepatotoxicity was confirmed by challenge with pyrazinamide (n = 7), isoniazid (n = 6) and combined isoniazid/rifampicin (n = 1). No deaths were caused by hepatotoxicity.. In spite of an increase in AST levels to approximately 6 x ULN during antituberculosis treatment, the drugs can be continued or reintroduced in full in most cases. Risk factors of hepatotoxicity included old age, female sex and extensive tuberculosis, and not alcohol consumption. Overall, hepatotoxicity during antituberculosis treatment can be monitored and managed easily.

Topics: Adolescent; Adult; Aged; Alcohol Drinking; Antitubercular Agents; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Jaundice; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin

Hepatotoxicity by antituberculous drugs is well known. Nonetheless, severe liver involvement is infrequent. Several series of fulminant hepatitis by antituberculous drugs have recently been reported with a much greater frequency than previously reported. The present study describes the authors' experience which, similar to other groups, has shown a marked increase with respect to previous experience. During 1994 5 patients with acute severe hepatitis associated to antituberculous drugs were admitted to the authors' unit. The mean age of the patients was 43 years (range: 25-62). Two patients were healthy HBsAg carriers, one undergoing enzymatic inducer treatment and was anti-HIV positive. Another patient presented compensated liver cirrhosis by HCV. The 5 cases received combined isoniazid and rifampicin and four had also received pyrazinamide. Four patients presented hepatic encephalopathy. Of these cases, three could not undergo emergency liver transplantation because of contraindications and died due to complications of acute severe liver failure. Another patient evolved favorably following emergency liver transplantation. The only patient who presented good evolution with conservative treatment and who did not present hepatic encephalopathy had discontinued isoniazid because of the finding of slight hypertransaminasemia during a routine analytical control. Several risk factors have been reported for the appearance of hepatotoxicity by antituberculous drugs. The factor of greatest clinical importance for the development of severe hepatotoxicity is probably continuation of the treatment once hepatic dysfunction has initiated. The important increase in cases of severe toxicity urges the need for strict analytical monitoring following initiation of treatment.

Topics: Acute Disease; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Hepatic Encephalopathy; Humans; Isoniazid; Liver; Liver Failure; Liver Transplantation; Male; Middle Aged; Pyrazinamide; Rifampin

To determine the incidence of hepatotoxicity due to isoniazid and rifampin in inner-city patients with active tuberculosis.. A hospital-based review of 70 consecutive in-patients in a 770-bed, inner-city hospital. The patient population is primarily African-American and Hispanic.. Fifty-eight men and 12 women were followed from 2-12 wk (median 4 wk). Patients had to be treated for at least 2 wk to be eligible for the study. Patients were excluded if they had been on any anti-tuberculous or any other hepatotoxic drug during the 2-month period before their hospitalization. Aminotransferases, alkaline phosphatase, bilirubin, and albumin were obtained at least every 2 wk.. Hepatocellular toxicity, defined as AST and/or ALT greater than 200 IU/L, occurred in eight out of 70 (11.4%) patients. The mean age of these patients was 38.9 yr (22-58 yr). Patients with AIDS were significantly more likely to develop hepatotoxicity than those with any other risk factor (p < 0.01).. Baseline aminotransferases followed by monitoring may be necessary in AIDS patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Alanine Transaminase; Alcoholism; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Female; Humans; Incidence; Isoniazid; Liver Function Tests; Male; New York City; Poverty Areas; Rifampin; Risk Factors; Time Factors; Tuberculosis, Pulmonary

We evaluated whether elderly patients with pulmonary tuberculosis and without apparent preexisting liver disease are at an increased risk to develop hepatotoxicity from an isoniazid-rifampin regimen and require regular liver function tests in comparison with younger patients. We analyzed the data of 131 patients treated in the period 1980-1985 of whom 64 (49%) were at least 60 yr of age. Subsequent increases of transaminases (measured weekly for as long as 4 wk after the start of treatment and later on when symptoms suggestive of hepatotoxicity occurred) above baseline values were found more frequently in the elderly (38 versus 18%, p < 0.05) and were also more pronounced in them (p < 0.01). The ratio of the highest transaminase value over the baseline value was called the transaminase index (TI). A TI of at least 5 was found in 22% of elderly and 8% of younger patients (p = NS), but ratios as high as 10 were mostly asymptomatic and always normalized progressively without treatment adjustment. Only symptomatic patients with a TI > or = 10 (five elderly and three younger) required temporary or definitive treatment adjustment. We conclude that repeated liver function test evaluations are generally unnecessary, except for symptomatic elderly and younger patients alike, in order to detect those with a TI > or = 10, thus requiring drug adjustment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

A 35 year old black Somalian woman with miliary tuberculosis developed hepatotoxicity after a few days of treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol. After withdrawal of all drugs the liver profile returned to normal and remained so after challenge with isoniazid. Hepatotoxicity recurred when rifampicin was added, but it was well tolerated when reintroduced without isoniazid.

Topics: Adult; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Rifampin; Tuberculosis, Miliary

Anti tubercular drug related hepatotoxicity is common. The mechanism of injury and factors predisposing to its development are not fully understood. Forty patients with anti tubercular drugs related hepatotoxicity were studied to see the clinical and biochemical profile of these patients and to find out the significance of acetylator phenotype in the development of hepatotoxicity. Mean age of patients with liver damage (37.82 +/- 10.0 years) was similar to those without liver damage (36.48 +/- 12.5 years). Pyrazinamide appeared to increase the hepatotoxicity of isoniazid and rifampicin. The percentage of rapid acetylators and slow acetylators among patients with hepatotoxicity (70% and 30% respectively) was similar to controls (66.6% rapid and 33.3% slow acetylators). Acetylator phenotype probably has no role in anti tubercular drugs induced hepatotoxicity.

Topics: Acetylation; Adult; Antitubercular Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoniazid; Liver; Liver Function Tests; Male; Middle Aged; Phenotype; Pyrazinamide; Rifampin

An elderly patient with borderline tuberculoid Hansen's disease (leprosy) developed the diaminodiphenylsulphone syndrome after approximately 8 weeks of multi-drug therapy comprising dapsone and rifampicin. Postmortem histological examination, following autopsy, demonstrated features consistent with drug-induced hepatitis, tubulo-interstitial nephritis and myocarditis. Although these could have been engendered by dapsone toxicity, it was thought that a concommitant adverse reaction to rifampicin, which is known to be hepatotoxic, nephrotoxic and possibly capable of predisposing to the dapsone syndrome, could not be excluded.

Topics: Acute Kidney Injury; Aged; Chemical and Drug Induced Liver Injury; Dapsone; Diagnosis, Differential; Drug Therapy, Combination; Fatal Outcome; Humans; Kidney; Leprosy; Liver; Male; Myocarditis; Myocardium; Nephritis, Interstitial; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Fever of Unknown Origin; Humans; Isoniazid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Liver Function Tests; Male; Middle Aged; Rifampin; Time Factors

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Hypersensitivity; Ethambutol; Humans; Isoniazid; Male; Middle Aged; Purpura; Pyrazinamide; Rifampin; Streptomycin; Thrombocytopenia; Tuberculosis, Pulmonary

We report two cases of fulminant hepatitis induced by antitubercular drugs. The mechanism is both immunoallergic and toxic. The fatal case appears in patient with acquired immunodeficiency syndrome. Liver tests must be realized during antitubercular treatment, that is difficult in sub-Saharan Africa.

Topics: Adult; Anti-Bacterial Agents; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Fatal Outcome; Female; HIV Infections; Humans; Isoniazid; Liver Function Tests; Pyrazinamide; Rifampin; Tuberculosis, Miliary; Tuberculosis, Pulmonary

Topics: Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Hepatic Encephalopathy; Humans; Isoniazid; Rifampin; Risk Factors

Topics: Antibodies, Antinuclear; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Humans; Male; Middle Aged; Rifampin

Department of Chest Diseases, Gazi University Faculty of Medicine and Atatürk Chest Diseases Hospital, Ankara, Turkey.. The primary purpose of this study was to assess the contributory role of viral hepatitis in antituberculosis drug hepatotoxicity.. Serologic markers for viral hepatitis were studied in 57 patients who developed acute hepatitis during antituberculosis therapy with rifampicin and isoniazid.. Among 705 adult tuberculous patients, 57 (8.1%) developed acute hepatitis during therapy with rifampicin and isoniazid. Serologic markers confirmed the presence of hepatitis B in 6 (10.5%) and hepatitis C in 4 (7%) of the 57 patients. Acute hepatitis A was not diagnosed in any of the patients.. Hepatitis occurring during antituberculosis therapy may not be drug-induced in all patients. Apart from the other factors mentioned above the endemicity of viral hepatitis in developing countries could be responsible for the higher incidence of antituberculosis-drug hepatitis.

Topics: Acute Disease; Adolescent; Adult; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Drug Therapy, Combination; Female; Hepatitis B; Hepatitis C; Hepatitis, Viral, Human; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin

In order to determine the efficacy of short course chemotherapy (SCC) for tuberculosis in children, 83 newly diagnosed cases in children < 12 years old were given SCC and were prospectively followed for 1-3 years. Seventy-one cases were treated for 6-9 months as they had mild to moderate involvement. Twelve cases were treated for 12 months as they had meningitis (7), disseminated tuberculosis (2), or miliary tuberculosis (3). The results showed that none of the children, at the end of follow up, showed evidence of active tuberculosis. All children tolerated the drugs well, with side effects noticed being mild, namely transient hepatitis (4), vomiting (1), and skin rash (1). It is suggested that SCC for 6-9 months using isoniazid (INH) and rifampicin along with other drugs when necessary is highly effective in most cases of tuberculosis in children and has several advantages over conventional chemotherapy of 18 months or longer duration.

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Pyrazinamide; Rifampin; Skin Diseases; Streptomycin; Tuberculosis; Vomiting

Topics: Chemical and Drug Induced Liver Injury; Clinical Protocols; Contraindications; Humans; Isoniazid; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

One hundred and ninety-nine cases of hepatic injury related to antituberculous treatment were analysed in order to assess the role played by each drug and to look for predisposing factors. This is a retrospective study of 169 cases reported in the literature and 30 cases reported to the regional pharmacovigilance centre of Paris Saint-Antoine. The mortality rate was related to the dose of isoniazid: it was 43 percent with a daily dose higher than 300 mg, and 9 percent with a daily dose of 300 mg or less (P < 0.001). Hepatic injury appeared significantly earlier in the case of rifampicin combination: 11 weeks without rifampicin and 2 weeks with rifampicin (P < 0.01). The role of pyrazinamide was difficult to determine because isoniazid and pyrazinamide were always used in combination. The influence of a preexisting liver disease could not be evaluated because of the small number of cases reported (8 cases). Alcoholism did not increase the mortality rate. Our results confirm the dose-dependent toxicity of isoniazid. Because of the short time elapsed before the apparent onset of hepatitis observed with the rifampicin combination, a close supervision of the patients should be exerted during the first weeks of treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethambutol; Female; Humans; Infant; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis

Topics: Chemical and Drug Induced Liver Injury; Child; Drug Interactions; Epilepsy; Female; Humans; Isoniazid; Phenytoin; Rifampin; Tuberculosis

Twenty-nine patients with extensive pulmonary tuberculosis and drug-induced hepatitis were treated with ofloxacin along with other relatively non-hepatotoxic drugs, either during the interim phase to await recovery of liver function in some, or as definitive therapy as required by the compromised hepatic status of others. No adverse drug reactions were noted and no treatment failures were observed. This preliminary experience indicates the exceedingly good tolerance of ofloxacin when utilized in treatment of extensive pulmonary tuberculosis in the face of deranged liver function tests. Due to the small number of patients and numerous variables, no definite conclusion can be drawn on the specific efficacy of ofloxacin against Mycobacterium tuberculosis. However, it is concluded that acquisition of further clinical experience is warranted for similar patients.

Topics: Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver Function Tests; Male; Middle Aged; Ofloxacin; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

After i.v. and i.p. injections of isoniazid (Iso) 40 mg.kg-1 to male Wistar rats, the plasma levels of Iso, acetylisoniazid (AcIso), and acetylhydrazine (AcHz) were determined by spectrophotometric method and gas chromatography. The results suggested that the pharmacokinetic behavior of Iso in rats belonged to a 2-compartment model. The plasma levels of AcHz in rifampicin (Rif 30 mg.kg-1)-pretreated rats were lowered vs the control (P < 0.05 or < 0.01). The T1/2 of AcHz was shortened by Rif (control group 3.3 h, Rif-pretreated group 1.4 h) after i.v. injection of AcHz 10 mg.kg-1 to rats and the results showed that AcHz was converted to its active metabolites quickly by increasing the oxidative elimination rate of AcHz, which is related to the higher incidence of liver necrosis caused by Iso and Rif in combination.

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Interactions; Hydrazines; Isoniazid; Male; Rats; Rats, Wistar; Rifampin

Side-effects of leprosy treatment with dapsone are said to be uncommon, with drug allergy occurring in only one of every several hundred patients treated with dapsone. The dapsone or sulphone syndrome (DDS) has been recognized since the earliest days of sulphone therapy but until recently its incidence had been decreasing. In Vanuatu, during the years 1988-1991, nine leprosy patients have developed the dapsone syndrome, four of whom have died. During the last 4 years only 37 patients were started on treatment, which is an incidence of the dapsone syndrome of 24% with a fatality rate of 11%. All the patients were being given multi-drug treatment (MDT) of daily dapsone (100 mg) and clofazimine (50 mg) and monthly rifampicin (600 mg) and clofazimine (300 mg). There has been speculation that the increased incidence of what was previously described as a rare reaction is due to the use of MDT, and the reasons for this are discussed. We feel the increase in the number of reactions in Vanuatu since starting MDT is probably due to the high starting dose of 100 mg of dapsone, possibly enhanced by the combination with clofazimine and rifampicin and a genetic susceptibility of the Melanesian population.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Clofazimine; Dapsone; Drug Eruptions; Drug Synergism; Drug Therapy, Combination; Female; Humans; Incidence; Leprosy; Male; Middle Aged; Rifampin; Syndrome; Vanuatu

A plasmapheresis (PA) model was developed to be used in chronic rabbit experiments. Test results obtained in 96 generalized tuberculosis animals demonstrated a more benign tuberculosis process in animals subjected to plasmapheresis, which was confirmed by parameters of the coefficients of mass and indices of animals' organ affecting, findings of the cation-lysosomal test and peptide molecules content in the peripheral blood. Rabbit studies involving registration of bromsulphalein half-life, hepatic blood flow and relative parenchymatous clearing showed that the isoniazide and rifampicin action significantly decreased under the PA influence. Studies in a hospital accommodating 90 patients with different renal tuberculosis forms and poor tuberculostatic tolerance showed that PA promoted restoration of tolerance to specific preparations and renal function improvement. PA was found to be practicable and safe method which relieves side effects of antituberculous preparations and contributes to tuberculosis treatment efficiency.

Topics: Animals; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Disease Models, Animal; Drug Tolerance; Humans; Isoniazid; Mycobacterium bovis; Plasmapheresis; Rabbits; Rifampin; Tuberculosis, Pulmonary; Tuberculosis, Renal

A 42-year-old woman was admitted because of cough, sputum, and fever. A chest roentgenogram revealed a nodular density in the left upper lung field with satellite lesions compatible with tuberculoma. Mycobacterium tuberculosis was detected from sputum. Five weeks after starting the treatment with 0.4 g/day of isoniazid, 0.45 g/day of rifampicin, and 0.75 g/day of streptomycin, she showed itching erythema in the trunk. The white blood cell count was 4,500/mm3 with 14% eosinophils, and serum transaminases were slightly increased (GOT 101 U/L, GPT 74 U/L). Although isoniazid and rifampicin were stopped, the erythema with exfoliation spread to her extremities, suggesting exfoliative dermatitis. The white blood cell count reached 15,990/mm3 with 68% eosinophils (10,810/mm3). Stimulation indices measured with the lymphocyte stimulation test (LST) were 109% with rifampicin, 140% with isoniazid, and 275% with streptomycin, suggesting streptomycin-induced allergy. After cessation of streptomycin, the symptoms gradually improved. After the reaction had subsided, the treatment with isoniazid, rifampicin, and ethambutol was resumed, but she showed no further adverse reactions. LST seems to be very useful to identify the drug or drugs responsible for the reactions occurred during the treatment by antituberculosis drugs.

Topics: Adult; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Therapy, Combination; Eosinophilia; Female; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Isoniazid, rifampicin and ethambutol administered in equimolecular dosages (50, 250 and 100 mg/kg, respectively) for 4 days caused liver affection. This was manifested by elevated activity of serum aminotransferases and alkaline phosphatase, inhibition of lipid peroxidation of hepatocyte membranes and antioxidative system dysfunctions. Isoniazid and rifampicin were proved to be most hepatotoxic. The combined use of antituberculous drugs increases their membrane-damaging action, especially when isoniazid and rifampicin are used together, but mostly when isoniazid in combination with rifampicin and ethambutol is applied.

Topics: Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Ethambutol; Isoniazid; Liver; Liver Function Tests; Male; Rats; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Rifampin; Risk Factors

Two-week administration of isoniazid, rifampicin (50 mg/kg and pyrazinamide (1,5 g/kg) to white rats brings about liver affection characterized by a higher activity of alanine and aspartate aminotransferases, lipid peroxidation activation and bile production inhibition. With the liver affected by antituberculous drugs, protective action is provided by acetate tocopherol an antioxidant, and piracetam riboxin and pyriditol, antihypoxic agents.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Hepatitis, Animal; Inosine Diphosphate; Isoniazid; Male; Piracetam; Pyrazinamide; Rats; Rifampin; Vitamin E

Serologic markers for hepatitis viruses were studied in 40 children who developed acute hepatitis during antituberculosis therapy with rifampin and isoniazid, with the aim of assessing the contributory role of these viruses toward producing hepatic injury. Hepatitis A and B were confirmed in 7.5 and 35% patients, respectively, by IgM antibodies. Epidemiologic evidence suggested the possibility of non-A, non-B hepatitis in at least a few of the remaining 23 children. Hepatitis B was seen more often in children with severe tubercular disease (72%) and was largely (92.8%) parenterally transmitted. The study highlights that the endemicity of viral hepatitis in developing countries, among other factors, could also be responsible for the reported higher incidence of hepatotoxicity from developing countries and also for the increased risk of hepatotoxicity seen in severe tubercular disease.

Topics: Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Hepatitis A; Hepatitis B; Hepatitis C; Humans; Infant; Isoniazid; Liver; Male; Rifampin; Tuberculosis

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Protocols; Humans; Isoniazid; Liver Diseases; Pyrazinamide; Rifampin

In Zimbabwe patients with pulmonary tuberculosis who are acid-fast bacilli (AFB) negative in the sputum are treated in the two month intensive phase with isoniazid, thiacetazone pyrazinamide and streptomycin (regimen A). Sputum positive patients receive regimen A plus rifampicin (regimen B). Both groups continue treatment with isoniazid and thiacetazone. 21 patients on regimen A and 19 on regimen B had clinical assessment and liver function tests performed at weeks 0, 2, 4, 8, and 12 weeks of treatment (during and four weeks after, the intensive phase of 8 weeks). Acetylator status was also assessed, no significant difference was found between patients on regimen A or B (41 per cent and 45 per cent fast acetylators respectively). Liver function tests results (alanine aminotransferase and alkaline phosphatase) showed a persisting rise during the intensive phase on both regimens, and further rise after four weeks in the continuation phase, this further rise reaching statistical significance in regimen B. These results are unexpected when compared to other studies but the regimens under investigation are not used elsewhere. The significant rise after stopping intensive therapy in regimen B suggests some protective effect of rifampicin against the hepatotoxicity of the regimen, possibly the isoniazid/thiacetazone component. Acetylator status did not influence the degree of hepatotoxicity.

Topics: Alanine Transaminase; Alkaline Phosphatase; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Zimbabwe

From January 1984-December 1987, 1783 patients received combination therapy of isoniazid, rifampin, and ethambutol for the control of tuberculosis. Forty-two developed symptomatic hepatitis during the period of treatment. Fifteen were hepatitis B virus carriers, and the remaining 27 were noncarriers. The peak serum transaminase and bilirubin levels were higher in carriers. Seven carriers died of fulminant or subacute hepatic failure, and only 1 noncarrier died. Eleven carriers had detectable serum hepatitis B virus deoxyribonucleic acid during the acute stage of hepatitis. The roles of isoniazid-rifampin combination therapy and hepatitis B virus in the adverse outcomes of carriers were discussed.

Topics: Carrier State; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Hepatitis B; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

We investigated the pharmacokinetic interaction of RMP (administered from the first day of treatment onwards), PZA (given from the second day onwards), and INH (day 17 onwards) in ten, previously untreated patients with pulmonary tuberculosis (five slow acetylators and five fast acetylators). In the case of the slow acetylators, higher INH and acetylhydrazine concentrations were measured than in the fast acetylators. RMP revealed the well-known autoinduction of its metabolism. During the course of continuing treatment, the PZA levels increased. No increased incidence of hepatoxic reactions was to be seen.

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Infusions, Intravenous; Isoniazid; Metabolic Clearance Rate; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

To determine the efficacy of combination drug therapy for disseminated Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome (AIDS).. Prospective, nonrandomized, before-after comparison.. Outpatient clinics at three university medical centers.. Seventeen patients with at least two consecutive blood cultures positive for M. avium complex who had not been previously treated with antituberculous medications. Fifteen of the seventeen patients completed at least 4 weeks of treatment.. Patients received daily intravenous amikacin (7.5 mg/kg body weight) for the first 4 weeks plus the following oral medications for at least 12 weeks: ciprofloxacin, 750 mg twice daily; ethambutol, 1000 mg daily; and rifampin, 600 mg daily.. The baseline geometric mean colony count from blood cultures decreased from 537/mL to 14/mL (P less than 0.001) after 4 weeks of therapy. The microbiologic suppression was sustained while on treatment and was associated with a decrease in systemic symptoms related to M. avium complex infection. Premature withdrawal from treatment (less than 12 weeks) occurred in 7 of 17 patients. The commonest reasons for early withdrawal were gastrointestinal intolerance and hepatic toxicity.. Mycobacterial load and systemic symptoms in patients with AIDS and disseminated M. avium complex infection can be effectively reduced by a regimen containing amikacin, ethambutol, rifampin, and ciprofloxacin.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Amikacin; Chemical and Drug Induced Liver Injury; Ciprofloxacin; Drug Therapy, Combination; Ethambutol; Female; Humans; Infusions, Intravenous; Male; Mycobacterium avium-intracellulare Infection; Rifampin; Vomiting

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Miliary

Forty-seven Gabonese children with tuberculosis either limited to the lung or associated with other localizations were treated with isoniazid-rifampin (INH + RIF). They had liver tests done during the first 6 months of treatment. In 30 patients (63.8%) there was an increase in aminotransferase levels [over 100 UI/l in 14 (29.2%)]. The main factors increasing the risk of hepatic toxicity was a high dosage of INH and overall malnutrition. In fact, the weights of patients presenting with signs of hepatic toxicity were significantly lower than those in children who had no alterations of liver function. 68% of the severely malnourished (marasmus of kwashiorkor) presented with high ALAT or ASAT levels during treatment. The eventual role of the chronic HBV carrier state is discussed as 2 children presented with a chronic form of hepatitis at the time the treatment was initiated.

Topics: Adolescent; Africa; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Combinations; Female; Hepatitis B; Humans; Infant; Isoniazid; Liver; Male; Nutrition Disorders; Rifampin; Transaminases; Tuberculosis, Pulmonary

A 58-year-old woman with tuberculosis received antituberculous drugs which included isoniazid, rifampicin, and ethambutol. Nausea and anorexia were initial symptoms while jaundice and abdominal pain were late manifestations. She became comatose and died 7 weeks after therapy. Autopsy revealed submassive necrosis of the liver and active advanced pulmonary tuberculosis. It is, thus, necessary for the physician to be alert for this serious complication in prescribing a combination of these antituberculous drugs.

Topics: Chemical and Drug Induced Liver Injury; Female; Hepatic Encephalopathy; Humans; Isoniazid; Liver; Middle Aged; Necrosis; Rifampin

Experiments on rats showed that 14-day exposure of the animals to pyrazinamide in a dose of 1.5 g/kg induced marked disorders in cholopoiesis and lowering of the reduced glutathion levels in the liver. When pyrazinamide was used in combination with isoniazid or rifampicin a marked increase in the activity of aspartate and alanine aminotransferases in blood serum and induction of lipid peroxidation in the liver were observed in addition to the disorders in cholopoiesis and lowering of the reduced glutathion levels. Combined use of pyraxinamide, isoniazid and rifampicin induced disorders in the liver state not differing significantly from those observed with using pyrazinamide in combination with isoniazid or rifampicin.

Topics: Animals; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Synergism; Isoniazid; Liver; Male; Pyrazinamide; Rats; Rifampin

Topics: Acute Kidney Injury; Adult; Chemical and Drug Induced Liver Injury; Humans; Male; Rifampin; Seizures

Topics: Acetaminophen; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Hypersensitivity; Humans; Infant; Isoniazid; Rifampin

Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

The possible development of hepatotoxic effects as a result of high dosages of isoniazid, rifampin, pyrazinamide, and ethionamide was assessed in 56 young children (median age, 22 months) treated for severe tuberculous meningitis (TBM). Only one of the 56 children became jaundiced, probably as result of hepatitis A infection. Of 33 children observed for at least eight weeks, only five (15%) had normal serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase levels throughout, but in only three patients were AST or ALT values greater than 200 U/L, and enzyme levels tended to normalize toward the end of the period. In this group of 33 children, those at stage III TBM had higher enzyme levels than did those at stage II. The remaining 23 children were observed for a mean period of only four weeks, and 18 (75%) had at least one abnormal liver function test result.

Topics: Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child, Preschool; Drug Combinations; Ethionamide; gamma-Glutamyltransferase; Humans; Infant; Isoniazid; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Rifampicin pharmacokinetics in rats with acute affection of the liver with carbon tetrachloride did not alter. Chronic affection with carbon tetrachloride resulted in retarded elimination of the antibiotic from blood. There was observed no relationship between increased activities of transamination enzymes such as alanine aminotransferase and aspartate aminotransferase in blood serum of animals and changes in rifampicin pharmacokinetics.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Female; Liver; Rats; Rifampin

A 10-year-old girl with cervical tuberculosis was treated with Isoniazid, Rimfampicin and Ethambutol. After 2 weeks of treatment a hepatotoxic reaction developed. Withdrawal of therapy resulted in complete clinical improvement and in normalization of all laboratory measurements. Treatment was restarted with Rifampicin, Pyrazinamid and Ethambutol. Liver enzyme levels were monitored weekly. Seven weeks after this three-drug regiment was started, all therapy was discontinued because of elevated liver enzyme levels. However, the patient died 2 weeks later of progressive fulminant hepatitis.

Topics: Cervical Vertebrae; Chemical and Drug Induced Liver Injury; Child; Drug Therapy, Combination; Ethambutol; Female; Humans; Pyrazinamide; Rifampin; Tuberculosis, Spinal

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Humans; Isonicotinic Acids; Prothionamide; Rifampin

The causes and frequency of occurrence of toxic hepatitides determined by isoniazid and rifampicin, were analysed in 551 patients with primary tuberculosis detected by clinical pharmacological methods. The intravenous mode of drug administration was shown to be indicated for prevention of isoniazid hepatitides in patients with a fast type of acetylation. Doses and methods of therapy with isoniazid and streptomycin leading to their high concentrations in the patients' body should be avoided to prevent liver affection with rifampicin. Since rifampicin hepatitides develop in persons with a slow type of acetylation, rifampicin and isoniazid with streptomycin should be injected with a 6-hour interval to prevent them.

Topics: Acetylation; Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Acetylation; Asian; Chemical and Drug Induced Liver Injury; Drug Combinations; Drug Interactions; Humans; Isoniazid; Peripheral Nervous System Diseases; Rifampin; Risk; Time Factors; Tuberculosis

We studied the relationship between acetylation phenotype and the appearance of biochemical and clinical signs of liver damage in 73 tuberculous children treated with isoniazid and rifampin. No significant differences were found with respect to the distribution of acetylation phenotype between tuberculous patients and a control group consisting of 256 children. Hepatotoxicity manifested in 27 cases (37%), of which only five (7%) had clinical signs. Application of the Fisher exact probability test did not show a relationship between acetylation phenotype and hepatotoxicity.

Topics: Acetylation; Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Liver Function Tests; Male; Phenotype; Rifampin; Time Factors; Tuberculosis, Pulmonary

The effect of daily administration of rifampin on the direct conversion of isoniazid to isonicotinic acid and hydrazine by isoniazid hydrolase was investigated in 6 slow and 8 rapid acetylators of isoniazid. The proportion of isoniazid metabolized through this direct pathway during the first 6 h was estimated from the ratio of total isonicotinic acid formed to acetylisoniazid in urine after administration of isoniazid or acetylisoniazid. In slow acetylators, this proportion was approximately 3% when isoniazid alone was administered and approximately 6% during the maximal phase of induction caused by the daily administration of rifampin in addition to isoniazid (p less than 0.001); in rapid acetylators, the proportions were considerably less (less than 1 and 2.5%, respectively), suggesting that isoniazid hydrolase was induced by rifampin. The increased formation of hydrazine, a known hepatotoxic agent in animals, could explain the substantially higher frequency of the occurrence of hepatitis in slow than in rapid acetylators among tuberculous patients treated with daily rifampin and isoniazid.

Topics: Acetylation; Chemical and Drug Induced Liver Injury; Drug Combinations; Humans; Hydrazines; Isoniazid; Rifampin; Tuberculosis

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Humans; Infant; Isoniazid; Jaundice; Liver; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Meningeal; Tuberculosis, Pulmonary; Tuberculosis, Spinal

The incidence and types of adverse reactions to rifampicin (in combination with isoniazid, pyrazinamide, and ethambutol) have been studied in 86 South-East Asian refugees treated for tuberculosis in Australia. Most patients received daily therapy initially (mean 3.5 months) followed by supervised thrice-weekly treatment (mean 4.6 months). Minor adverse reactions occurred with similar frequencies during daily (5%) and intermittent (5%) treatment but in no case was modification of rifampicin dosage required. Withdrawal of pyrazinamide was necessary in two patients (2.3%) with clinical hepatitis.

Topics: Adolescent; Adult; Aged; Asia, Southeastern; Australia; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Prospective Studies; Pyrazinamide; Refugees; Rifampin; Tuberculosis, Pulmonary

Because a 13% incidence of hepatotoxicity was observed in a first study of multibacillary leprosy patients treated daily with dapsone, rifampin, and 10 mg/kg thioamide, the patients were treated in a second study with 5 mg/kg thioamide in daily combination with dapsone and rifampin. In this study, monthly assessments of liver function were performed in order to detect early hepatic disturbances. Despite the reduced dosage of thioamide, a 16.5% incidence of hepatotoxicity was observed among 110 multibacillary patients. However, jaundice was observed in only 2 out of 18 cases of hepatotoxicity (11%); whereas it was observed in 5 out of the 7 cases of hepatotoxicity (71%) in the first study (p less than 0.05). The decrease in the thioamide dosage and the performance of monthly assessments of liver function did not decrease the incidence of hepatotoxicity but did decrease its severity. It is concluded that thioamide should not be used in daily combination with rifampin unless the daily dose is 5 mg/kg and monthly assessments of liver function are routinely performed.

Topics: Adolescent; Adult; Aged; Body Weight; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isonicotinic Acids; Leprosy; Liver; Male; Middle Aged; Prothionamide; Rifampin

We report the cases of 2 female patients aged 69 and 61 yr, suffering from fulminant hepatitis induced by pirprofen, a new nonsteroidal antiinflammatory drug. The duration of pirprofen administration before the onset of hepatitis was long, 7 and 9 mo, respectively. Hepatitis was not preceded or accompanied by hypersensitivity manifestations. The liver lesion consisted of massive, predominantly centrilobular hepatic cell necrosis and microvesicular steatosis. One patient died of liver failure. Although the risk of fulminant hepatitis is very low, we recommend that, in patients taking pirprofen for more than 2 mo and complaining of asthenia, nausea, or vomiting, serum aminotransferase levels should be measured and administration of the drug should be interrupted as soon as an increased level is noted.

Topics: Aged; Alanine Transaminase; Amikacin; Chemical and Drug Induced Liver Injury; Female; Humans; Middle Aged; Phenylpropionates; Rifampin; Spondylitis, Ankylosing; Staphylococcal Infections; Vancomycin

It was shown in experiments on male albino rats that rifampicin potentiated the hepatotoxicity of isoniazid. As compared to the use of isoniazid alone, its combination with rifampicin resulted in a higher activity of transaminases and alkaline phosphatases and a higher rate of inhibition of biliary secretion and synthesis and excretion of bile acids, bilirubin and cholesterol with bile. Moreover, an increase was observed in the level of lipid peroxidation products of the hepatocyte membranes in liver homogenates and blood, which was indicative of an increased intensity of lipid peroxidation. The increased hepatotoxicity of isoniazid was evident from a more pronounced decrease in the number of sulfhydryl groups accompanied by an increase in the number of disulfide ones in the liver and blood. The authors suggest that potentiation of isoniazid hepatotoxicity under the action of rifampicin was due to its inducing activity with respect to the microsomal oxidation enzymes.

Topics: Animals; Bile; Chemical and Drug Induced Liver Injury; Depression, Chemical; Drug Synergism; Free Radicals; Isoniazid; Lipid Peroxides; Liver; Male; Rats; Rifampin

Possible toxic side-effects of antituberculous chemotherapy are studied in 718 children affected with pulmonary tuberculosis. 26 (3.62%) presented adverse side-effects and one drug had to be changed in 8 (1.11%). Treatment had to be stopped in one (0.13%) due to toxicity. Liver toxicity was specially studied, showing that younger age is a risk factor (p less than 1 X 10(-10). In 44 cases (16.54%) transient increases of no more than triple of maximum normal value, were found in SGOT and/or SGPT. Toxicity observed in controlled clinical studies and guides for treatment are exposed.

Topics: Adolescent; Antitubercular Agents; Blood Coagulation Disorders; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Eruptions; Drug Therapy, Combination; Humans; Infant; Infant, Newborn; Isoniazid; Nausea; Nervous System Diseases; Rifampin; Tuberculosis, Pulmonary

The general medical community in the United States has been rather slow in adopting short-course bactericidal chemotherapy for tuberculosis despite the clear demonstration of the advantage by several carefully controlled clinical trials. Reported herein is experience between January 1976 and December 1982 in 1,028 patients with bacteriologically proved pulmonary tuberculosis treated for nine months with isoniazid (300 mg) and rifampin (600 mg) daily for one month followed by twice-weekly isoniazid (900 mg) and rifampin (600 mg) for the other eight months. They were treated by 45 local practitioners and supervised by public health nurses through 60 Arkansas Department of Health chest clinics in the state. Outpatient therapy was mostly self-administered in the routine treatment program. Overall success was achieved in 95 percent of the 751 patients who completed therapy; in 21 (2.8 percent), sputum cultures failed to convert to negative, and 15 (2.1 percent) have had relapse since therapy was stopped. Therapy could not be completed in 26.9 percent due to deaths, drug toxicities, relocation, refusal, etc. Of 21 bacteriologic failures, 18 patients developed isoniazid resistance and were treated with additional two bactericidal drugs. Most of the relapses (nine of 15) occurred within 12 months after chemotherapy was stopped. However, four relapses occurred quite late during follow-up. Only three of 15 patients with relapse showed isoniazid resistance. Side effects of the drugs were encountered in 10.3 percent, but major toxicities occurred in 3.2 percent (hepatitis in 2.6 percent, hematologic effects in 0.6 percent). Clinical surveillance for toxicity is preferred over routine and regular biochemical monitoring. Patient acceptance of the regimen was excellent, and compliance was good. Short-course chemotherapy is effective, with low drug toxicity, reduced cost of drugs, and ease of direct supervision when needed, and is acceptable to patients in routine treatment.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Patient Compliance; Recurrence; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Humans; Rifampin; Urinary Tract Infections

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Humans; Infant; Isoniazid; Nutrition Disorders; Rifampin

Topics: Amphotericin B; Animals; Bile Acids and Salts; Calcium; Chemical and Drug Induced Liver Injury; In Vitro Techniques; Liver; Male; Mycotoxins; Oligopeptides; Peptides, Cyclic; Phalloidine; Rats; Rats, Inbred Strains; Rifampin; Sodium; Transaminases; Valinomycin

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; China; Drug Therapy, Combination; Female; Humans; Isonicotinic Acids; Leprosy; Male; Middle Aged; Prothionamide; Rifampin

With reference to an observation of porphyria variegata, which was complex and unusual as all such observations are, the direct responsibility of rifampicin is underscored. Porphyria variegata should be considered in two situations. The first of these is a dramatic acute neuroabdominal picture: the diagnosis of acute hepatic porphyria is established by the measurement of urinary porphyrins; the second step is to distinguish between the three acute hepatic porphyrias by looking for cutaneous manifestations and determining the respective proportions of coproporphyrins and protoporphyrins in the stools. In porphyria variegata, fecal protoporphyrins are significantly increased. The second situation is cutaneous involvement suggestive of late-onset cutaneous porphyria: porphyria variegata as well as hereditary coproporphyria in the cutaneous phase must be considered. Diagnosis can be established only through measuring fecal porphyrins. Porphyria variegata is a genetic enzymatic disorder inherited on an autosomal dominant basis. A study of the family is required in all cases, but the conventional methods for detecting heterozygotes for porphyria variegata are not satisfactory. Carriers will be unequivocally distinguished from healthy subjects only through measuring the defective enzyme activity.

Topics: Acute Disease; Adult; Chemical and Drug Induced Liver Injury; Feces; Humans; Liver Diseases; Male; Polyradiculoneuropathy; Porphyrias; Porphyrins; Rifampin; Skin Diseases

To estimate rates of hepatotoxicity in the United States among children treated for tuberculosis, we conducted a retrospective survey of health departments and individual practitioners. We received 874 reports suitable for analysis of children treated during 1977 to 1979. A total of 16 hepatotoxic reactions were reported; 14/430 (3.3%) children receiving isoniazid and rifampin had a hepatotoxic reaction, which approximates the rate seen in adults taking these drugs. Half of the reactions occurred during the first month of therapy, and all of the well-documented reactions were noted during the first 10 weeks. Because the likelihood of hepatotoxicity may be increased with higher drug doses, limiting the dose of isoniazid to 10 mg/kg and that of rifampin to 15 mg/kg may help minimize hepatotoxic reactions. Because more serious disease, especially disseminated tuberculosis, may further increase the risk of hepatotoxicity, close monitoring of such children receiving isoniazid and rifampin should help minimize serious hepatotoxicity. Routine biochemical monitoring may not be necessary for all children, eg, those with mild forms of disease and those with normal pretreatment liver function who are treated with lower drug doses.

Topics: Adolescent; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Humans; Infant; Isoniazid; Liver Function Tests; Retrospective Studies; Rifampin; Time Factors; Tuberculosis, Pulmonary; United States

A 58-year-old man with a history of tuberculosis had been treated with anticonvulsant drugs for a long period and presented with a small lesion in the apex of the left lung. Prior to thoracotomy treatment with isoniazid and rifampicin was started. Fulminant hepatitis developed and the patient died on the 7th postoperative day, 9 days after starting the drugs. The risk of hepatotoxicity from isoniazid is increased when it is given concomitantly with anticonvulsants, halothane or rifampicin, all of which induce microsomal enzymes.

Topics: Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Between January 1976 and June 1981, 814 patients with pulmonary tuberculosis were treated for 9 months with isoniazid (INH) and rifampin (RIF), daily for 1 month and twice weekly for the other 8 months. Overall success was achieved in 95% of the 586 patients who completed therapy: in 15 patients (2.9%), sputum cultures failed to convert to negative during therapy, and 10 patients (1.7%) have relapsed since stopping the chemotherapy. Major toxic effects occurred in 22 patients; in 14 during the daily phase and in 8 during the twice-weekly phase. Hepatic toxicity occurred in 13 patients during daily and in 5 during twice-weekly treatment, and it was caused by RIF in 5, INH in 10, and was undetermined in 3. Hematologic abnormalities developed in 4 patients: in 1 during the daily and in 3 during the twice-weekly phase. Minor side effects, which were not life threatening, were encountered in 62 patients: in 35 during the daily and in 27 during the twice-weekly therapy. These were gastrointestinal intolerance in 18, drug fever in 27 (including 11 with "flu-syndrome" during twice-weekly administration), cutaneous rashes in 14, and headache, general malaise, and weakness in 3. These side effects were produced by RIF in 43, by INH in 18, and the responsible drug was not identified in 1. Hypersensitivity reactions to twice-weekly administration of RIF were infrequent. Clinical surveillance for toxicity is preferred over routine and regular biochemical monitoring.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Fever; Gastrointestinal Diseases; Hematologic Diseases; Humans; Isoniazid; Male; Middle Aged; Rifampin; Skin Diseases; Tuberculosis, Pulmonary

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethanol; Isoniazid; Male; Phospholipids; Rats; Rifampin

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethambutol; Liver; Organothiophosphorus Compounds; Rabbits; Rifampin; Tuberculosis

A 13% incidence of hepatitis was observed among 54 cases of multibacillary leprosy treated daily with the three-drug combination of dapsone, rifampin, and a thioamide (ethionamide or prothionamide). No hepatitis was observed among 109 cases of paucibacillary leprosy treated daily with the two-drug combination of dapsone and rifampin. Symptoms were jaundice in five cases and nausea plus vomiting associated with a significant increase of transaminase levels in two cases. In five cases, the symptoms appeared during the first two months of therapy and in two cases, later. Discontinuing treatment with rifampin and the thioamide but not dapsone resulted in recovery. When rifampin was resumed without the thioamide, the hepatitis did not recur. Viral etiology could be eliminated in six cases. Neither sex, age, weight nor the fact that the patient was a new case or a relapse case appeared to be a contributing factor. Hepatotoxicity caused by administration of a thioamide might have been potentiated by the concurrent administration of rifampin.

Topics: Adolescent; Adult; Aging; Amides; Chemical and Drug Induced Liver Injury; Dapsone; Drug Therapy, Combination; Female; Humans; Leprosy; Male; Middle Aged; Rifampin; Sex Factors; Thioamides

Topics: Chemical and Drug Induced Liver Injury; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Interactions; Hepatic Encephalopathy; Humans; Isoniazid; Liver; Male; Middle Aged; Necrosis; Rifampin

Since 1973, when the incidence and pattern of adverse reactions to antituberculosis therapy were described by Rossouw and Saunders, para-amino-salicylic acid, the major cause of drug-induced hepatitis, has been withdrawn from the regimen used in Cape Town and replaced with pyrazinamide (PZA). Our study in the same hospital indicates that although the substitution has resulted in a significant reduction in the incidence of all side-effects (4,1% v. 9%; P less than 0,001), the incidence of hepatitis is unchanged (0,3%). PZA is currently the major cause of hepatitis associated with antituberculosis therapy.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Alcoholism; Chemical and Drug Induced Liver Injury; Ethambutol; Fatty Liver; Humans; Isoniazid; Male; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Child; Drug Therapy, Combination; Humans; Isoniazid; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Rifampin

Topics: Adult; Age Factors; Aged; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Evaluation; Ethambutol; Humans; Isoniazid; Kidney Diseases; Middle Aged; Optic Neuritis; Rifampin; Risk; Streptomycin; Tuberculosis

In 95 patients with active tuberculosis, we investigated in a prospective study the influence of the acetylator phenotype on the hepatotoxic side effects of the antituberculous regimen isoniazid (INH) 10 mg/kg, rifampicin (RMP) 10 mg/kg, and ethambutol (EMB) 25 mg/kg. Besides a much higher incidence of isoniazid hepatitis (SGOT, SGPT greater than 200 U/l) in 12.6% of patients treated--as compared to the incidence reported in large chemoprophylaxis trials with isoniazid monotherapy in the range of 0.5%-1% (IUAT 1969, U.S.P.H.S. 1971)--we observed a significant, higher risk of isoniazid-induced hepatotoxicity in slow acetylators (p less than 0.01): in 26 of 56 slow acetylators (= 46.4%), but only in 4 of 30 rapid acetylators (=13.3%) were transaminases in the serum elevated greater than 50 U/l. The 12 patients with the most severe hepatotoxic side effects (SGOT, SGPT greater than 200 U/l) were all slow acetylators. Women developed severe hepatic injury more often than men (p less than 0.05). In cases with isoniazid hepatitis, triple therapy was either stopped or reduced to a combination RMP, EMB. In cases with less severe liver injury, triple therapy was continued. In all patients transaminases normalized within 2-4 weeks. On return to full triple therapy, none of the patients developed new elevation of transaminases. The constant occurrence of isoniazid hepatitis during the 2nd-4th week (19 +/- 7 days) as well as the normalization without any new hepatotoxic reaction suggest that there may be an interaction between RMP and isoniazid metabolism limited to the early phase of chemotherapy.

Topics: Acetylation; Chemical and Drug Induced Liver Injury; Ethambutol; Humans; Isoniazid; Phenotype; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Mixed Connective Tissue Disease; Rifampin

Topics: Biotransformation; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Diagnosis, Differential; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Kinetics; Liver; Rifampin; Transaminases

Topics: Adult; Aminosalicylic Acid; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Halothane; Humans; Iproniazid; Isoniazid; Middle Aged; Nitrofurantoin; Phenytoin; Prognosis; Rifampin; Sulfonamides

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethambutol; Humans; Isoniazid; Liver; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Hydrazines; Isoniazid; Liver; Male; Phenobarbital; Rats; Rats, Inbred Strains; Rifampin

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Poland; Rifampin; Time Factors; Tuberculosis, Pulmonary; United States

Topics: Chemical and Drug Induced Liver Injury; Child, Preschool; Humans; Isoniazid; Liver; Male; Parotid Diseases; Rifampin; Tuberculosis; Tuberculosis, Oral

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Male; Middle Aged; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Child; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Pleural; Tuberculosis, Pulmonary

Thirty four children with tuberculous meningitis were treated with rifampicin (mean, 17 mg/kg/day) and isoniazid (mean, 18 mg/kg/day). Fifteen (44%) showed rise in transaminase GOT and GPT values and four cases (11.7%) developed jaundice, hepatomegaly and low prothrombin levels. Rifampicin was removed in only nine of these 15 cases with signs of liver disfunction, but complete normalization of liver function and disappearance of symptoms occurred in all cases even when the treatment was not interrupted. Children are more sensitive to hepatic injury during rifampicin and isoniazid combination therapy than adults. Our results indicate very good prognosis for this hepatopathy and suggest that rifampicin need not be withdrawn in the benign situations. Removal of the rifampicin treatment may delay recovery of serious cases of tuberculous meningitis.

Topics: Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Hepatomegaly; Humans; Infant; Isoniazid; Liver Diseases; Rifampin; Transaminases; Tuberculosis, Meningeal

Topics: Acute Disease; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin

Topics: Chemical and Drug Induced Liver Injury; Humans; Infant; Isoniazid; Male; Rifampin; Tuberculosis, Pulmonary

In order to determine the hepatotoxicity of rifampicin in children treated for tuberculosis, a survey was performed of 18 children receiving this medicine in combination with isoniazid. Fifteen of the 18 children (83%) showed a rise in ASAT values and 11 (61%) in ALAT values exceeding 29U/L. Seven children with maximal ASAT values between 40 and 100 U/L were treated without any changes in the regimen and the transaminases normalized later in the treatment. Six out of the eight children with ASAT values over 100 U/L were allowed a three-week pause in their therapy, one was given the same dose of rifampicin, and in one the treatment was discontinued entirely. The therapy was discontinued in an additional three children because of a second high rise in the transaminase values. Liver injury can occur at any time during treatment, and thus makes continuous follow-up tests necessary.

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Humans; Infant; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Epilepsy; Female; Hepatic Encephalopathy; Humans; Isoniazid; Phenobarbital; Rifampin; Tuberculosis, Miliary

Topics: Acute Disease; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Chemical and Drug Induced Liver Injury; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

The authors report a new case of acute renal insufficiency with Rifampicin. They evoke the clinical background which is characteristic of these anuric tubular nephritis. They recall the different complications with Rifampicin to which they can be associated and the different mechanisms which can be at the origin of this affection as well as the difficulties to reveal them. Then, they insist on the prevention of renal accidents within the frame of our present knowledge.

Topics: Acute Kidney Injury; Anuria; Chemical and Drug Induced Liver Injury; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Lung Diseases; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Certain drugs are transformed into reactive metabolites by cytochrome P-450, a hepatic microsomal enzyme. The reactive metabolites covalently bind to hepatocyte macromolecules, thus determining liver lesions. Induction of microsomial enzymes increases the formation of reactive metabolites and exaggerates hepatotoxicity of these drugs.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Glutathione; Glycolates; Humans; Hydrazines; Isoniazid; Monoamine Oxidase Inhibitors; Pharmaceutical Preparations; Rifampin

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Hematologic Diseases; Humans; Isoniazid; Liver; Peripheral Nervous System Diseases; Psychoses, Substance-Induced; Rheumatic Diseases; Rifampin; Streptomycin; Tuberculosis

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Liver; Rifampin; Tuberculosis, Pulmonary

It is generally accepted that hepatitis occurring during treatment with INH and rifampicine results from the hepatotoxicity of INH metabolites. A case is reported of cholestatic hepatitis occurring during such treatment, in which there was a previous history of an isolated hepatic affection. The administration of INH and rifampicin caused cholestasis alone, which reoccurred after rifampicin administration only. No immuno-allergic phenomenon has been shown to be involved in rifampicin toxicity. This observation suggests that rifampicin may be hepatotoxic itself, especially in patients with previous hepatic affections.

Topics: Aged; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Liver Diseases; Peritonitis, Tuberculous; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aminosalicylic Acid; Antitubercular Agents; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Interactions; Ethambutol; Female; Humans; Immunosuppression Therapy; Isoniazid; Optic Neuritis; Phenytoin; Pregnancy; Rifampin; Streptomycin; Thrombocytopenia

Topics: Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Synergism; Humans; Rifampin; Thrombocytopenia; Tuberculin Test

We report a case of hepatorenal failure complicating rifampicin administration in which rifampicin-dependent antibodies were demonstrated. Hepatorenal failure during rifampicin treatment has been reported before but in none of the previous cases were rifampicin-dependent antibodies described.

Topics: Acute Kidney Injury; Adult; Antibodies; Chemical and Drug Induced Liver Injury; Humans; Liver Diseases; Male; Rifampin

Topics: Animals; Biotransformation; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Liver; Microsomes, Liver; Necrosis; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver; Phospholipids; Rifampin; Tuberculosis, Pulmonary

The complications of isoniazid (INH) were studied in 1033 patients, who had received INH for at least 18 months, with or without other drugs. Hepatitis developed in 25 patients; this was attributed to rifampicin, (15 cases); infectious hepatitis (three cases); INH alone, (three cases); IHN possibly exacerbating chronic liver disease, (two cases); and multiple drug treatment, (two cases). Central nervous system disorders (mainly peripheral neuropathy) due to INH occurred in 12 patients, all of whom were over the age of 40 years. Hypersensitivity to INH developed in 12 patients. Some difficulties in distinguishing hepatitis due to rifampicin from that due to INH are discussed. When the risk of hepatitis was compared with the risks of developing, or dying from, tuberculosis, it was found that the benefits of INH chemoprophylaxis outweighed the risks, particularly in patients who were less than 50 years of age.

Topics: Adult; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Female; Hepatitis, Viral, Human; Humans; Isoniazid; Liver Diseases; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Age Factors; Chemical and Drug Induced Liver Injury; Female; Humans; Infant; Infant, Newborn; Male; Rifampin; Tuberculosis, Meningeal; Turkey

Topics: Adult; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Rifampin

Topics: Acute Kidney Injury; Adult; Chemical and Drug Induced Liver Injury; Humans; Knee Injuries; Knee Joint; Liver; Male; Radiography; Rifampin; Tuberculosis, Osteoarticular

Seventy-five patients who developed mild hepatic reactions (serum transaminase concentrations of 45 to 149 units per liter) and 50 patients who showed more serious liver damage (serum transaminase values greater than 150 units per liter) were compared with 261 consecutive patients who had no liver reactions during treatment with rifampin and isoniazid. Generally, liver toxicity occurred in 18 per cent of patients receiving combined anti-tuberculous drug therapy. Small increases in transaminase occurred in 14 per cent of the patients; large increases occurred in 4 per cent. Elderly women comprised a risk group. Among patients exhibiting a more serious hepatic lesion (transaminase values greater than 150 units per liter), alcoholics, mostly men, formed another risk group, together with other patients with a history of previous liver or biliary disease. Of 261 patients who did not develop a liver reaction, 57 per cent were slow INH acetylators. In this study, the groups with small and large increases in transaminase were clearly separated; in the former group there was no preponderance of phenotype, whereas in the latter group, slow acetylators clearly dominated among early (first 4 weeks of treatment) hepatic reactions (P less than 0.01). Studies of single-drug regimens of isoniazid have shown that neither slow nor rapid acetylation has any causal influence on isoniazid-induced hepatitis. Because the metabolism of rifampin is independent of the acetylation process, rifampin and isoniazid in combination seem to cause a toxic hepatitis that differs from the hepatitis induced by either drug separately.

Topics: Acetylation; Adult; Age Factors; Alanine Transaminase; Alcoholism; Aspartate Aminotransferases; Biliary Tract Diseases; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Male; Middle Aged; Phenotype; Rifampin; Risk; Sex Factors; Time Factors; Tuberculosis, Pulmonary

A case of acute renal insufficiency associated with acute hepatitis that arose in the course of intermittent rifampicine management is reported. Specific reagin-type antibodies were noted in the circulating blood. The clinical, morphological and pathogenetic aspects of the case are compared with those of kidney disease caused by penicillin. While certain clinical features appear in both situations, the histological and immunofluorescence data suggest that two separate pathological entities are involved.

Topics: Acute Kidney Injury; Chemical and Drug Induced Liver Injury; Humans; Liver; Male; Middle Aged; Rifampin

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethambutol; gamma-Glutamyltransferase; Humans; Isoniazid; Liver; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Liver; Rifampin

The authors report 6 cases of fulminant hepatitis in patients treated with isoniazid and rifampin. In 4 of these patients, the treatment had been started within 3 days after a general anesthesia. The course of the disease was remarkably similar in all 6 patients: (1) the time interval from the beginning of the isoniazid-rifampin administration to the onset of jaundice was 6 to 10 days; (2) disorders of consciousness appeared less than 3 days after the onset of jaundice; (3) serum transaminases were 26 to 80 times the upper limit of normal; (4) the main liver lesion was centrilobular necrosis; (5) hypersensitivity manifestations were absent; (6) all 6 patients recovered. Fulminant hepatitis might be attributable to a hepatotoxic metabolite of isoniazid, the production of which would be attributable to a hepatotoxic metabolite of isoniazid, the production of which would be increased as a consequence of the enzyme-inducing effect of rifampin and, possibly, other drugs administered for general anesthesia.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Enzyme Induction; Female; Humans; Isoniazid; Liver; Male; Microsomes, Liver; Rifampin

Five children with tuberculosis were treated with isoniazid (20 mg./Kg./day) and rifampin (15 mg./Kg./day). After five to twenty seven days of treatment they presented anorexia, vomiting and jaundice. Hepatomegaly was found in two of them. High indirect bilirubin, S.G.O.T. and S.G.P.T. and low prothrombin levels were present in all of them. Eight to thirty one days after withdrawal of rifampin, all patients were well and their laboratory data was normal.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Child; Diagnosis, Differential; Female; Humans; Isoniazid; Male; Rifampin; Tuberculosis

A case report is given on two patients receiving halothane anesthesia while beeing treated with isoniacid, ethambutol and rifampicin. Following halothane anesthesia, both patients developed a severe liver disease with encephalopathy grade III. We observed a moderate increase of bilirubin and SGOT and a more severe increase of serum ammonia. Histologically, both patients had alterations compatible with drug hepatitis. Within 14 days remission occurred spontaneously. The two case reports do not fit with typical isoniacid hepatitis or typical halothane hepatitis. The possibility of combined drug toxicity on liver during halothane and isocianid treatment is discussed.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Ethambutol; Female; Halothane; Hepatic Encephalopathy; Humans; Isoniazid; Middle Aged; Rifampin; Time Factors

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Child; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Three studies of drug toxicity were made in Chinese adults with pulmonary tuberculosis admitted concurrently to short-course antituberculosis regimens. The first was of streptomycin plus isoniazid plus pyrazinamide given daily (SHZ regimen), three times a week (S3H3Z3 regimen) or twice a week (S2H2Z2 regimen). The second was of pyrazinamide in the SHZ regimen and PAS in the standard daily combination of streptomycin plus isoniazid plus PAS (SPH regimen). The third was of the SHZ regimen and these 3 drugs plus rifampicin daily (SHRZ regimen). In study 1 (174 SHZ, 185 S3H3Z3, 182 S2H2Z2 patients), the incidence of arthralgia was associated with the number of doses per week (P less than 0.001). The incidence of other reactions, most of which were cutaneous or vestibular, or symptomless increases in the serum alanine transaminase (AIT) concentration, was similar on all 3 regimens. In study 2 (142 SHZ, 137 SPH patients), hepatic reactions occurred on the SHZ but not on the SPH regimen (P less than 0.002), serum AIT concentrations were distributed over a higher range on the SHZ regimen, and 2 patients had jaundice. Gastrointestinal reactions were more frequent on the SPH regimen (P = 0.06). Arthralgia was commoner on the SHZ regimen (P less than 0.05). In study 3 (38 SHZ, 41 SHRZ patients), the incidence of hepatic reactions, jaundice and arthralgia was similar in the 2 regimens. On the pyrazinamide regimens combined, hepatic reactions were marginally more frequent in patients with Australia antigen or antibody either before or during chemotherapy (P = 0.09). Serum uric acid concentrations were higher in patients on daily than on intermittent pyrazinamide (P less than 0.005), and in patients with arthralgia on the daily pyrazinamide regimen than in matched controls (P = 0.07).

Topics: Aminosalicylic Acids; Arthritis; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Therapy, Combination; Gastrointestinal Diseases; Hong Kong; Humans; Isoniazid; Labyrinth Diseases; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

In 1971, rifampin was approved for treatment of pulmonary tuberculosis and asymptomatic carriers of Neisseria meningitidis. At present, the approved indications remain the same. However, rifampin in conjunction with at least one other antituberculous drug may be of great value in therapy of extrapulmonary tuberculosis and infections due to other susceptible mycobacteria. In addition, results of clinical trials in leprosy have been highly encouraging. Rifampin appears to induce light chain proteinuria in a majority of patients and has been implicated in suppression of both humoral and cell-mediated immune responses. However, these effects appear to have been of little consequence to treated patients. A variety of possibly immunologically mediated reactions to rifampin has been closely associated with irregular administration of the drug. These reactions and hepatic toxcity may be preventable in many patients. Rifampin or one of its congeners, alone or in combination with other antibiotics, may prove useful in treatment of various infectious, and possibly malignant, diseases.

Topics: Animals; Antibody Formation; Antineoplastic Agents; Antiviral Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Forecasting; Humans; Immunity, Cellular; Immunosuppressive Agents; Leprosy; Liver; Meningococcal Infections; Mycobacterium Infections; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

Topics: Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Function Tests; Pemphigus; Prednisone; Remission, Spontaneous; Rifampin; Tuberculosis, Renal

In a retrospective study the following was found: Out of 111 patients suffering from tuberculosis and receiving a combined INH-therapy without Rifampicin 23% showed an increase of serum-transmainase activities, on the other hand out of 105 patients, treated with a combination including Rifampicin 74% did so. A pathological De Ritis ratio GOT/GPT was found in 31 among 59 comparable cases of Rifampicin-treated patients, and a pathological ratio GOT + GPT/AP in 22 among 37 cases before the transaminase-activities rose above normal. Development of a distinct toxic hepatic damage has to be anticipated in those cases, which show a De Ritis ratio below 0,5 or a GOT + GPT/AP ratio above 1,0 while transaminase-activity still is only slightly elevated. Liver biopsies taken from 10 patients showed no regular relation to the biochemical data.

Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Isoniazid; Retrospective Studies; Rifampin; Time Factors; Tuberculosis

A large number of chemical agents, administered for therapeutic or diagnostic purposes, can produce various types of hepatic injury by several mechanisms. Some agents are intrinsically hepatotoxic, and others produce hepatic injury only in the rare, uniquely susceptible individual. Idiosyncrasy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberation of the host permitting the accumulation of hepatotoxic metabolites. The syndromes of hepatic disease produced by drugs have been classified hepatocellular, hepatocanalicular, mixed and canalicular. Measurement of serum enzyme activities has provided a powerful tool for studies of hepatotoxicity. Their measurement requires awareness of relative specificity, knowledge of the mechanisms involved, and knowledge of the relationship between known hepatotoxic states and elevated enzyme activities.

Topics: Anti-Bacterial Agents; Anticonvulsants; Antidepressive Agents; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Contraceptives, Oral, Hormonal; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Ethanol; Female; Humans; Liver Diseases; Mitochondria, Liver; Rifampin; Steroids; Tetracycline; Tranquilizing Agents

Topics: Animals; Chemical and Drug Induced Liver Injury; Humans; Liver; Rats; Rifampin

Topics: Animals; Bile; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Liver; Rats; Rifampin

Topics: Adult; Aged; Biopsy; Chemical and Drug Induced Liver Injury; Ethambutol; Female; Humans; Liver; Male; Middle Aged; Rifampin; Tuberculosis

Three cases of children who developed hepatic toxicity of different degree while on antituberculous treatment with isoniazid and rifampicin are reported. The clinical picture is presented and the pathogenesis of the hepatic damage is discussed. The pathological findings in the liver are those of a drug induced hepatitis. The combined treatment of tuberculosis in children with isoniazid and rifampicin is potentially dangerous and should be reserved for cases in which resistance to other drugs has been demonstrated.

Topics: Adult; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Isoniazid; Liver; Male; Rifampin

Report on a 24 years old first pregnant woman with chronic pyelonephritis, treated for 1 1/2 years, also during pregnancy, with high doses of rifampicin (1200 mgs/day). After normal delivery in the 42 th. week of pregnancy there were bleedings both in mother and newborn with demonstrable temporary disturbances in liver-function and coagulation system. Especially the coagulation factors produced in the liver were concerned. The complications after rifampicin carried out the conclusion that rifampicin should be given in pregnancy only with exact indication.

Topics: Blood Coagulation Disorders; Chemical and Drug Induced Liver Injury; Chronic Disease; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Pregnancy; Pregnancy Complications, Infectious; Pyelonephritis; Rifampin

Topics: Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Galactosamine; Isoniazid; Liver; Male; Rats; Rifampin

Seventy-nine consecutive patients receiving rifampicin in combination with isoniazid and another drug, were found to have an 8-3% incidence of acute clinical liver disease. Half the patients (36) were advanced alcoholics and almost all cases of hepatitis came from this group. Fifteen of the 36 were thought to have evidence of pre-existing liver disease and were studied by means of serial liver biopsies. Most of those with pre-treatment abnormalities of liver function developed abnormalities in their biopsies, not attributable to alcohol. In one patient active chronic hepatitis is believed to have followed irregularly taken rifampicin. Those patients with both normal pretreatment liver function and biopsies did not develop histological abnormalities. The dangers of irregularly taken self-administered rifampicin are stressed. It is suggested that rifampicin is contraindicated in alcoholics with initial abnormal liver function tests.

Topics: Adult; Aged; Alcoholism; Chemical and Drug Induced Liver Injury; Humans; Liver; Liver Diseases; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Topics: Acute Kidney Injury; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Hemolysis; Humans; Liver; Rifampin; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Animals; Antitubercular Agents; Capreomycin; Chemical and Drug Induced Liver Injury; Cycloserine; Deafness; Drug Hypersensitivity; Ethambutol; Ethionamide; Gastrointestinal Diseases; Goiter; Humans; Isoniazid; Kanamycin; Liver; Mental Disorders; Mice; Nervous System Diseases; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis; Viomycin

1. Thioctic acid used clinically in poisoning by A. phalloides, protected perfused livers and also isolated hepatocytes against phalloidin, when given in high concentrations. 2. Some SH-compounds like coenzyme A, dimercaprol, cysteine and cysteamine were found to be protective in different concentrations. 3. Rifampicin protects mice against lethal doses of phalloidin, and inhibits poisoning of isolated hepatocytes at low concentrations. 4. Some choleretic drugs like dehydrocholate, temoebilin (extr. cucumae xanth.), ethacrynic acid influenced phalloidin poisoning by inhibition of binding. 5. Doses of 0.2 to 4.0 mg dexamethasone added to 100 ml of perfusion medium did not protect perfused rat livers against 0.5 mg phalloidin. 6. Pretreatment of female rats with estrogens effected protection against phalloidin in vivo. The same procedure resulted in moderate decrease of phalloidin effects when the livers of pretreated animals were poisoned in vitro. In male rats estrogen pretreatment was less effective. Castration did not augment the protective effect. 7. Secophalloidin, a biologically inactive derivative, did not influence phalloidin poisoning in perfused livers, even when applied in excessive concentrations. 8. Concanavalin A, probably bound in the neighborhood of binding sites for phalloidin, did not protect perfused livers against phalloidin. 9 Diethyldithiocarbamate, a compound protecting livers against carbon tetrachloride and halothane, was ineffective in phalloidin poisoning. 10. Further protective actions of Evans blue, of some phenanthrolines and of EDTA are discussed. 11. Pretreatment of animals with hepatotoxic compounds (CCl4, CHCl3, cinchophen) decreased the toxicity of phalloidin in vivo. Possible mechanisms are discussed.

Topics: Animals; Chelating Agents; Chemical and Drug Induced Liver Injury; Chloroform; Cholagogues and Choleretics; Coenzyme A; Concanavalin A; Cysteamine; Cysteine; Dexamethasone; Dimercaprol; Estradiol; Female; Male; Oligopeptides; Phalloidine; Rats; Rifampin; Sulfhydryl Compounds; Thioctic Acid

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Hepatic Encephalopathy; Humans; Isoniazid; Liver; Liver Function Tests; Male; Rifampin; Tuberculosis, Pleural; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Ethambutol; Humans; Isoniazid; Rifampin; Risk; Tuberculosis, Pulmonary; United States

Topics: Aged; Aortic Valve Stenosis; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Liver; Lung Diseases; Lung Diseases, Obstructive; Male; Mycobacterium Infections; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Patient Compliance; Rifampin; Streptomycin; Tuberculosis

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Liver; Liver Function Tests; Male; Methods; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Alcoholism; Biopsy; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Liver Function Tests; Male; Middle Aged; Prednisolone; Rifampin; Staining and Labeling; Streptomycin; Tuberculosis, Pulmonary

Topics: Capreomycin; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cycloserine; Depression; Drug Hypersensitivity; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Hospitalization; Humans; Isoniazid; Kanamycin; Kidney Diseases; Optic Neuritis; Patient Education as Topic; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Enzyme Induction; Female; gamma-Glutamyltransferase; Humans; Leucyl Aminopeptidase; Liver; Male; Middle Aged; Rifampin

Topics: Adult; Ambulatory Care; Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Drug Resistance, Microbial; Ethambutol; Humans; Infant; Isoniazid; Kidney Function Tests; Liver Function Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Aspartate Aminotransferases; Biopsy; Cell Membrane; Chemical and Drug Induced Liver Injury; Cytoplasm; Drug Therapy, Combination; Ethambutol; Humans; Long-Term Care; Microscopy, Electron; Middle Aged; Mitochondria, Liver; Rifampin

Topics: Aminosalicylic Acids; Antitubercular Agents; Arthritis; Chemical and Drug Induced Liver Injury; Child; Cycloserine; Drug Hypersensitivity; Drug Resistance, Microbial; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Liver; Lupus Vulgaris; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis; Viomycin

Topics: Adult; Bilirubin; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoenzymes; Isoniazid; Jaundice; L-Lactate Dehydrogenase; Male; Oxidoreductases; Rifampin; Transaminases; Tuberculosis

Topics: Adult; Aged; Autopsy; Biopsy; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Jaundice; Liver; Middle Aged; Rifampin

Topics: Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Hepatitis A; Humans; Hyperbilirubinemia; Jaundice; Liver Diseases; Pruritus; Rifampin; Tuberculosis

Topics: Aged; Alanine Transaminase; Anesthesia, Inhalation; Aspartate Aminotransferases; Biopsy; Chemical and Drug Induced Liver Injury; Cholecystectomy; Drug Therapy, Combination; Female; Halothane; Humans; Liver; Liver Function Tests; Postoperative Complications; Rifampin; Surgical Wound Dehiscence; Tuberculoma

Topics: Acute Kidney Injury; Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Middle Aged; Pain; Rifampin; Shock, Septic; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Clinical Enzyme Tests; Drug Therapy, Combination; Ethambutol; Fatty Liver; Female; Humans; Isoniazid; Liver Diseases; Liver Function Tests; Male; Middle Aged; Necrosis; Rifampin; Sulfobromophthalein; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Drug Combinations; Drug Interactions; Female; Humans; Isoniazid; Liver; Male; Rifampin; Statistics as Topic; Transaminases; Tuberculosis

Topics: Antigen-Antibody Reactions; Chemical and Drug Induced Liver Injury; Drug Interactions; Female; Humans; Hyperbilirubinemia; Isoniazid; Male; Prognosis; Rifampin; Statistics as Topic; Transaminases; Tuberculosis

Topics: Adolescent; Adult; Alanine Transaminase; Aspartate Aminotransferases; Biopsy; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Male; Middle Aged; Rifampin; Rifamycins; Staining and Labeling; Tuberculosis, Meningeal

Topics: Aminosalicylic Acids; Biopsy, Needle; Chemical and Drug Induced Liver Injury; Child; Drug Eruptions; Ethambutol; Fever; Humans; Isoniazid; Liver; Male; Pain; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adult; Biopsy, Needle; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Tolerance; Female; Hepatitis A; Humans; Isoniazid; Jaundice; Liver; Male; Middle Aged; Rifampin; Tuberculosis

Topics: Bilirubin; Biopsy; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethambutol; Humans; Isoniazid; Liver; Phosphoric Monoester Hydrolases; Rifampin; Transaminases; Tuberculosis

Topics: Acute Disease; Acute Kidney Injury; Adult; Ambulatory Care; Amylases; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Hematologic Diseases; Humans; Isoniazid; Liver; Male; Pancreatitis; Prednisolone; Recurrence; Rifampin; Stimulation, Chemical; Streptomycin; Transaminases; Tuberculosis, Pulmonary

Topics: Adult; Cells, Cultured; Cerebral Hemorrhage; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Male; Purpura, Thrombocytopenic; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cycloserine; Ethambutol; Ethionamide; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin

Topics: Adult; Aged; Alanine Transaminase; Aspartate Aminotransferases; Bilirubin; Biopsy; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Middle Aged; Rifampin

Topics: Animals; Chemical and Drug Induced Liver Injury; Isoniazid; Liver; Rats; Rifampin; Time Factors

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Male; Middle Aged; Rifampin; Tuberculosis

Topics: Chemical and Drug Induced Liver Injury; Ethambutol; Humans; Jaundice; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Animals; Chemical and Drug Induced Liver Injury; Cholangitis; Cholecystitis; Evaluation Studies as Topic; Humans; Liver; Liver Function Tests; Male; Middle Aged; Rifampin

Topics: Administration, Oral; Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Time Factors; Tuberculosis

Topics: Chemical and Drug Induced Liver Injury; Humans; Jaundice; Liver; Rifampin; Tuberculosis

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Combinations; Humans; Infant; Isoniazid; Liver; Rifampin; Transaminases; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Humans; Liver; Rifampin; Tuberculosis, Pulmonary

Topics: Alkaline Phosphatase; Bilirubin; Blood Proteins; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Synergism; Female; Humans; Isoniazid; Liver; Liver Function Tests; Male; Rifampin; Transaminases; Tuberculosis, Pulmonary

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Liver Function Tests; Male; Rifampin; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Child, Preschool; Cholestasis; Humans; Isoniazid; Jaundice; Liver; Male; Rifampin; Tuberculosis, Miliary

Topics: Capreomycin; Chemical and Drug Induced Liver Injury; Drug Combinations; Ethambutol; Gastrointestinal Diseases; Rifampin; Tuberculosis

Topics: Adolescent; Adult; Aged; Bilirubin; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Transaminases

Topics: Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Imipramine; Isoniazid; Jaundice; Liver; Male; Middle Aged; Rifampin; Tuberculosis; Tuberculosis, Miliary

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cycloserine; Drug Eruptions; Drug Hypersensitivity; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Ethionamide; Female; Gastrointestinal Diseases; Humans; Hypothyroidism; Isoniazid; Kanamycin; Male; Microbial Sensitivity Tests; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Viomycin

Topics: Adult; Chemical and Drug Induced Liver Injury; Diarrhea; Drug Resistance, Microbial; Female; Fever; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sweating; Temperature; Tuberculosis, Pulmonary

Topics: Acute Disease; Adolescent; Adult; Aged; Atrophy; Chemical and Drug Induced Liver Injury; Female; Hepatitis A; Humans; Jaundice; Liver; Male; Rifampin; Transaminases; Tuberculosis, Pulmonary

Topics: Animals; Chemical and Drug Induced Liver Injury; Glucosyltransferases; Humans; Hyperbilirubinemia; Iodobenzenes; Liver; Novobiocin; Rats; Rifampin

Topics: Chemical and Drug Induced Liver Injury; Humans; Liver; Liver Function Tests; Rifampin; Tuberculosis

Topics: Adult; Aged; Animals; Biopsy; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Liver; Liver Function Tests; Male; Mice; Middle Aged; Rifampin

Topics: Aged; Biopsy; Chemical and Drug Induced Liver Injury; Ethionamide; Female; Humans; Isoniazid; Jaundice; Liver; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Drug Synergism; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary; Tuberculosis, Splenic

Rifampicin (usually 600 mg per day, with ethambutol 1 gm or isoniazide) was given to 106 patients with tuberculosis: 6 during pregnancy, 4 of whom were taking estrogen and progestagens for hormonal imbalance , 14 women taking oral contraceptives or steroids, 25 women with increased estrogen levels, and 5 elderly women taking testosterone. Particular attention was paid to liver function considering reports of jaundice in pregnancy, oral contraception, and use of rifampicin with isoniazide. The 6 pregnancies resulted in 5 normal infants (1 with meconium staining) and 1 fetal death at 6 months. During pregnancy there were 3 incidents of elevated serum glutamic-pyruvate transaminase (SGPT) 30-150 units, and 1 of liver toxicity. The authors' concluded that there was no proof that rifampicin caused the hormonal imbalance or fetal death, and it can be prescribed safely, especially after the first 3 months. In 12 progestagen and estrogen users, there were 1 jaundice treated by stopping rifampicin but not the pill, and 4 incidents of elevated SGPT of 35-90 units. The authors recommended following those taking pills and rifampicin with regular SGPT tests. 5 patients received cyclofenil, 400 or 800 mg per day, in addition to rifampicin to induce ovulation or treat menopausal symptoms: this resulted in 1 case of hepatic toxicity. Cyclofenil is preferred over estrogen for treating menopausal symstoms in patients on rifampicin. 5 postmenopausal women received methyl-testosterone and ethinyl estradiol without any change in SGPT.

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Contraceptives, Oral; Cystitis; Drug Resistance, Microbial; Female; Fetus; Humans; Infant; Infant, Newborn; Liver; Male; Menopause; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Contraceptives, Oral; Drug Hypersensitivity; Drug Tolerance; Female; Humans; Kidney Function Tests; Rifampin; Tuberculosis; Uterine Hemorrhage; Vision Disorders

Topics: Chemical and Drug Induced Liver Injury; Female; Humans; Rifampin; Transaminases; Tuberculosis

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Hepatitis; Hepatitis A; Hepatitis B virus; Humans; Liver; Rifampin

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Hepatitis; Humans; Liver; Rifampin

Topics: Adult; Bilirubin; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Middle Aged; Rifampin; Transaminases; Tuberculosis, Pulmonary

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Humans; Liver; Liver Function Tests; Punctures; Rifampin

Topics: Aged; Chemical and Drug Induced Liver Injury; Hepatic Encephalopathy; Humans; Male; Rifampin; Tuberculosis, Pulmonary

Topics: Aged; Alkaline Phosphatase; Chemical and Drug Induced Liver Injury; Drug Synergism; Female; Humans; Isoniazid; Liver; Liver Function Tests; Middle Aged; Rifampin; Tuberculosis

Topics: Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Jaundice; Liver; Rifampin; Transaminases

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Jaundice; Liver; Male; Middle Aged; Rifampin

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary