rifampin and Liver-Diseases

Tuberculosis (TB) has been a human disease for centuries. Its frequency is increased manyfold in patients with liver cirrhosis. The gold standard of TB management is a 6-mo course of isoniazid, rifampicin, pyrazinamide and ethambutol. Although good results are seen with this treatment in general, the management of patients with underlying cirrhosis is a challenge. The underlying depressed immune response results in alterations in many diagnostic tests. The tests used for latent TB have many flaws in this group of patients. Three of four first-line antitubercular drugs are hepatotoxic and baseline liver function is often disrupted in patients with underlying cirrhosis. Frequency of hepatotoxicity is increased in patients with liver cirrhosis, frequently leading to severe liver failure. There are no established guidelines for the treatment of TB in relation to the severity of liver disease. There is no consensus on the frequency of liver function tests required or the cut-off used to define hepatotoxicity. No specific treatment exists for prevention or treatment of hepatotoxicity, making monitoring even more important. A high risk of multidrug-resistant TB is another major worry due to prolonged and interrupted treatment.

Topics: Antitubercular Agents; Ethambutol; Humans; Immune System Diseases; Isoniazid; Latent Tuberculosis; Liver; Liver Cirrhosis; Liver Diseases; Liver Failure; Liver Function Tests; Liver Transplantation; Prevalence; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Bile formation at the canalicular membrane is a delicate process. This is illustrated by inherited liver diseases due to mutations in ATP8B1, ABCB11, ABCB4, ABCC2 and ABCG5/8, all encoding hepatocanalicular transporters. Effective treatment of these canalicular transport defects is a clinical and scientific challenge that is still ongoing. Current evidence indicates that ursodeoxycholic acid (UDCA) can be effective in selected patients with PFIC3 (ABCB4 deficiency), while rifampicin reduces pruritus in patients with PFIC1 (ATP8B1 deficiency) and PFIC2 (ABCB11 deficiency), and might abort cholestatic episodes in BRIC (mild ATP8B1 or ABCB11 deficiency). Cholestyramine is essential in the treatment of sitosterolemia (ABCG5/8 deficiency). Most patients with PFIC1 and PFIC2 will benefit from partial biliary drainage. Nevertheless liver transplantation is needed in a substantial proportion of these patients, as it is in PFIC3 patients. New developments in the treatment of canalicular transport defects by using nuclear receptors as a target, enhancing the expression of the mutated transporter protein by employing chaperones, or by mutation specific therapy show substantial promise. This review will focus on the therapy that is currently available as well as on those developments that are likely to influence clinical practice in the near future.

Topics: Adenosine Triphosphatases; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Bile; Bile Canaliculi; Biliary Tract Surgical Procedures; Biological Transport, Active; Cholestyramine Resin; Genetic Therapy; Humans; Lipoproteins; Liver Diseases; Liver Transplantation; Models, Biological; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mutation; Rifampin; Ursodeoxycholic Acid

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

Pruritus is often the most troublesome symptom in patients with chronic liver disease, particularly when cholestasis is a prominent feature. The exact pathogenesis is unknown, but empirical treatment, such as cholestyramine, based on a liver-based origin of pruritus, has been used for many years. Recently, evidence for a central mechanism for pruritus has been obtained and opioid antagonists have been tried clinically with some benefit, but their use is not widespread. In addition, the pruritus associated with intrahepatic cholestasis of pregnancy can now be alleviated in many cases by ursodeoxycholic acid. As it also improves foetal outcome, this should become first-line therapy. We review the pathogenesis and therapy of pruritus, highlighting practical aspects to help with patients with seemingly intractable pruritus.

Topics: Anion Exchange Resins; Antipruritics; Cholagogues and Choleretics; Humans; Liver Diseases; Narcotic Antagonists; Ondansetron; Pruritus; Rifampin; Ursodeoxycholic Acid

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.

Topics: Adult; Aged; Blood Glucose; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Hypoglycemic Agents; Liver Diseases; Male; Piperidines; Renal Insufficiency; Rifampin

We report two new cases of hepatic brucelloma in addition to the 22 previously reported cases in the literature. Our analysis of these cases reveals certain characteristics. Hepatic brucelloma is a rare localization that follows previously undetected acute brucellosis. Brucelloma is a result of caseification of a granulomatous reaction induced by persistent Brucella in macrophages. Clinical manifestations can mimic malignant liver tumors or pyogenic, amebic liver abscess. Diagnosis is based on the association of characteristic imaging features (central calcification and peripheral necrotic areas), positive serology and hepatic granulomas. Brucella is rarely isolated in the blood or liver. Awareness of this clinical variant can prevent unnecessary laparotomy. Treatment should begin with rifampicine (900 mg per day) and doxycyclin (200 mg per day) for 3 months. If medical treatment is unsuccessful, percutaneous or surgical drainage should be performed. A cure should be achieved in all cases.

Topics: Anti-Bacterial Agents; Brucellosis; Diagnosis, Differential; Doxycycline; Granuloma; Humans; Liver Diseases; Macrophages; Male; Middle Aged; Rifampin

We reviewed 19 cases of hepatosplenic cat-scratch disease at Texas Children's Hospital (Houston). The range of the patients' ages was 2 years 4 months to 11 years 8 months. The chief complaint was fever for all patients. The duration of fever before diagnosis was 7 to 56 days (mean, 22 days). Abdominal pain was present in 13 patients (68%). Thirteen children were treated with rifampin alone, and three received rifampin therapy plus gentamicin or trimethoprim-sulfamethoxazole. Once rifampin therapy was initiated alone or in combination, improvement was noted within 1 to 5 days (mean, 2.6 days) for patients who had had prolonged fever the duration of which before rifampin therapy averaged 3 weeks. The most common dosage and duration for our patients were 20 mg/[kg x d] every 12 hours and 14 days, respectively. Rifampin should be considered in the initial antimicrobial treatment of hepatosplenic cat-scratch disease.

Topics: Animals; Anti-Bacterial Agents; Cat-Scratch Disease; Cats; Child; Child, Preschool; Humans; Liver Diseases; Rifampin; Splenic Diseases

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

Numerous factors such as changes in plasma protein binding, tissue binding, hepatic blood flow, hepatic metabolism, and distribution may occur in hepatic disease. The impact of these physiologic changes on pharmacokinetic and pharmacodynamic parameters of anti-infective agents is likely to be clinically significant. Unfortunately, these issues have not been thoroughly investigated. Even within the same type of liver disease, there is considerable interpatient variability in pharmacokinetic variables, rendering it difficult to predict drug disposition accurately. Pharmacokinetics of selected anti-infective agents are altered in hepatic disease, necessitating careful monitoring and dosage titration to avoid enhanced drug concentrations and risk of toxicity.

Topics: Anti-Infective Agents; Chloramphenicol; Clindamycin; Fluoroquinolones; Humans; Isoniazid; Liver Diseases; Metabolic Clearance Rate; Rifampin

Topics: Aminoglycosides; Anti-Bacterial Agents; Chloramphenicol; Clindamycin; Humans; Isoniazid; Kinetics; Lincomycin; Liver Diseases; Penicillins; Rifampin

Topics: Alcoholism; Analgesics; Anesthetics; Blood Proteins; Chronic Disease; Drug Interactions; Ethanol; Hormones; Humans; Immunity; Liver Diseases; Methadone; Prolactin; Respiration; Rifampin; Serum Albumin; Substance-Related Disorders; United States

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

This analysis was conducted to investigate factors that affect 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics after administration of fesoterodine sustained release tablets to Westerners and East Asians. Ten pharmacokinetic studies and three efficacy/safety studies in overactive bladder (OAB) patients were pooled for the population pharmacokinetic analysis. The plasma 5-HMT concentration data were described by a 1-compartment model with first order absorption and a lag time. Creatinine clearance (CLCR), hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were identified as influential covariates. It was estimated that decreasing of CLCR from 80 to 15 mL/min resulted in a 39.5% reduction in 5-HMT apparent oral clearance (CL/F). Hepatic impairment, CYP2D6 poor metabolizer, and CYP3A inhibitor were estimated to reduce CL/F by about 60%, 40%, and 50%, respectively. CYP3A inducer resulted in about fourfold increase in CL/F. Although sex and Japanese ethnicity were selected as covariates on CL/F, each resulted in only about 10% decrease and increase of CL/F, respectively. Of the influential covariates of 5-HMT CL/F, CLCR, hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were of significance, whereas sex and Japanese ethnicity covariates were considered not to have clinically significant impact on exposures of 5-HMT.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Benzhydryl Compounds; Creatinine; Cresols; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Delayed-Action Preparations; Female; Genotype; Humans; Ketoconazole; Liver Diseases; Male; Middle Aged; Models, Biological; Muscarinic Antagonists; Rifampin; Tablets; Urinary Bladder, Overactive; Urological Agents; White People; Young Adult

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

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

Regional lymphotropic therapy involving 10% isoniazid administration was included into multimodality treatment in 250 patients with pulmonary tuberculosis and comorbidity. The findings have indicated that the lymphotropic therapy during the use of rifampicin, streptomycin, ethambutol enhances the efficiency of chemotherapy in different forms of pulmonary tuberculosis, including the latter concurrent with hepatic lesion or diabetes mellitus. Lymphotropic therapy is particularly beneficial to patients with poor drug tolerability. The use of lymphotropic isoniazid in the multimodality treatment of pulmonary tuberculosis leads to the earlier disappearance of the symptoms of tuberculous intoxication (by 1-1.5 months) in 80-92% of the patients, to abacillation in the same periods, to the increased frequency of decay cavity closure by an average of 15% as compared to the conventional treatment, and, in most cases, to the normalization of the biochemical parameters of hepatic function.

Topics: Administration, Oral; Antitubercular Agents; Diabetes Complications; Ethambutol; Humans; Hypoglycemic Agents; Injections, Intralymphatic; Injections, Intramuscular; Insulin; Isoniazid; Liver Diseases; Lymphatic System; Rifampin; Streptomycin; Tuberculosis, Pulmonary

In this open-label investigation, the pharmacokinetics of rifapentine and its active metabolite, 25-desacetyl-rifapentine, were characterized in patients with varying degrees of hepatic dysfunction. Eight patients with mild-to-moderate chronic, stable hepatic dysfunction and seven patients with moderate-to-severe hepatic dysfunction received single oral 600-mg doses of rifapentine. Maximum plasma concentration of rifapentine was lower, time to maximum plasma concentration (tmax) was greater, and elimination half-life (t 1/2) was longer in the patients with moderate-to-severe hepatic dysfunction than in those with mild-to-moderate dysfunction. However, mean area under the concentration-time curve extrapolated to infinity (AUC0-infinity) for the two groups was similar. AUC0-infinity values in patients with hepatic dysfunction were 19% to 25% higher than values previously reported for healthy volunteers. The 25-desacetyl metabolite appeared in plasma slowly after the single oral dose of rifapentine. Similar to findings for the parent drug, comparable plasma exposures of 25-desacetyl-rifapentine based on AUC0-infinity were found in the two groups of patients with mild-to-moderate and moderate-to-severe hepatic dysfunction. Rifapentine was well tolerated in this patient population, irrespective of the etiology or severity of hepatic dysfunction. These safety and pharmacokinetic results suggest that no dosage adjustments for rifapentine are needed in patients with hepatic impairment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Area Under Curve; Female; Humans; Liver Diseases; Male; Middle Aged; Rifampin

We investigated the effect of rifampin on pruritus in 12 patients with chronic liver disease: non-A, non-B hepatitis (n = 3), alcoholic cirrhosis (n = 4), primary biliary cirrhosis (n = 4), and primary sclerosing cholangitis (n = 1). The study was a crossover, randomized, double-blind trial where placebo and drug were given daily in identical capsules (300 mg) for 2 weeks each, with a 1 week washout before and after each cycle. Mean duration of pruritus was 1.6 years (range of 4 months-5 years). Blood tests were done weekly and patients used a visual analogue scale (VAS) from 0 to 100 to mark their level of itchiness daily. Only transaminases were significantly lower while the patients were on rifampin. VAS scores were minimally affected by either rifampin or placebo. At the end of the trial, four patients said they were less itchy on rifampin and three preferred placebo. Of these seven patients, small falls in VAS scores occurred in two patients on rifampin and two on placebo; there was no change in the remaining three. There was little change in serum bile salt levels during the trial. No patient became jaundiced and deepening of jaundice did not occur in the four patients with initially elevated bilirubin. We conclude that a daily 300 mg dose of rifampin was not effective in relieving pruritus in a variety of chronic liver diseases.

Topics: Adult; Aged; Chronic Disease; Double-Blind Method; Female; Humans; Liver Diseases; Male; Middle Aged; Monitoring, Physiologic; Pruritus; Randomized Controlled Trials as Topic; Rifampin

Topics: Bilirubin; Chronic Disease; Clinical Trials as Topic; Drug Combinations; Drug Interactions; Humans; Isoniazid; Liver; Liver Diseases; Rifampin; Time Factors

Hepatic impairment (HI) is known to modulate drug disposition and may lead to elevated plasma exposure. The aim of this study was to quantitate the in vivo OATP1B-mediated hepatic uptake activity in populations with varying degrees of HI. First, we measured baseline levels of plasma coproporphyrin-I, an endogenous OATP1B biomarker, in an open-label, parallel cohort study in adult subjects with normal liver function and mild, moderate, and severe HI (n = 24, 6/cohort). The geometric mean plasma concentrations of coproporphyrin-I were 1.66-fold, 2.81-fold (P < 0.05), and 7.78-fold (P < 0.0001) higher in mild, moderate, and severe impairment than those healthy controls. Second, we developed a dataset of 21 OATP1B substrate drugs with HI data extracted from literature. Median disease-to-healthy plasma area under the curve (AUC) ratios for substrate drugs were ~ 1.4, 3.0, and 6.4 for mild, moderate, and severe HI, respectively. Additionally, significant linear relationship was noted between AUC ratios of substrate drugs without and with co-administration of rifampin, a prototypic OATP1B inhibitor, and AUC ratios in moderate (P < 0.01) and severe (P < 0.001) HI. Third, a physiologically-based pharmacokinetic model analysis was conducted with 10 substrate drugs following estimation of relative OATP1B functional activity in virtual disease population models using coproporphyrin-I data and verification of substrate models with rifampin drug-drug interaction data. This approach adequately predicted plasma AUC change particularly in moderate (9 of 10 within 2-fold) and severe (5 of 5 within 2-fold) HI. Collective findings indicate progressive reduction, by as much as 90-92%, in OATP1B activity in the HI population.

Topics: Adult; Area Under Curve; Biomarkers; Cohort Studies; Coproporphyrins; Drug Interactions; Humans; Liver Diseases; Pharmaceutical Preparations; Rifampin

A metabolomic study of hepatolithiasis has yet to be performed. The purpose of the present study was to characterize the metabolite profile and identify potential biomarkers of hepatolithiasis using a metabolomic approach.. We comprehensively analyzed the serum metabolites from 30 patients with hepatolithiasis and 20 healthy individuals using ultra-high performance liquid chromatography-tandem mass spectrometry operated in negative and positive ionization modes. Statistical analyses were performed using univariate (Student's t-test) and multivariate (orthogonal partial least-squares discriminant analysis) statistics and R language. Receiver operator characteristic (ROC) curve analysis was performed to identify potential predictors of hepatolithiasis.. We identified 277 metabolites that were significantly different between hepatolithiasis serum group and healthy control serum group. These metabolites were principally lipids and lipid-like molecules and amino acid metabolites. The steroid hormone biosynthesis pathway was enriched in hepatolithiasis serum group. In all specific metabolites, 75 metabolites were over-expressed in hepatolithiasis serum group. The AUC values for 60 metabolites exceeded 0.70, 4 metabolites including 18-β-Glycyrrhetinic acid, FMH, Rifampicin and PC (4:0/16:2) exceeded 0.90.. We have identified serum metabolites that are associated with hepatolithiasis for the first time. 60 potential metabolic biomarkers were identified, 18-β-Glycyrrhetinic acid, FMH, Rifampicin and PC (4:0/16:2) may have the potential clinical utility in hepatolithiasis.

Topics: Biomarkers; Chromatography, High Pressure Liquid; Glycyrrhetinic Acid; Humans; Lithiasis; Liver Diseases; Metabolome; Metabolomics; Rifampin; Tandem Mass Spectrometry

The use of rifampicin for cholestatic pruritus is accompanied by concerns over safety, but the availability of real-world prescribing data is relatively limited.. We sought to describe the rate and characteristics of rifampicin-induced hepatitis in a mixed aetiology cohort of patients with established liver disease and cholestatic pruritus.. Retrospective review of records for out-patients commenced on rifampicin for pruritus 2012-2016 inclusive. Rifampicin-induced hepatitis was recorded where alanine aminotransferase activity (ALT) increased to both ≥5 × baseline and ≥5 × upper limit of normal (ULN), or to both ≥3 × baseline and ≥3 × ULN with concurrent elevation in serum bilirubin to ≥2 × baseline and ≥2 × ULN, in addition to a Roussel-Uclaf Causality Assessment Method score of "probable" or "highly probable" for rifampicin causality.. After exclusions, we reviewed 105 patients who took rifampicin for a median of 131 days. Most had primary biliary cholangitis or primary sclerosing cholangitis; 40 (38.1%) were men and median age was 44 years (IQR: 32-57). 44 (41.9%) patients had baseline serum bilirubin ≥2 × ULN and 28 (26.7%) ALT ≥3 × ULN. 5 (4.8%) developed rifampicin-induced hepatitis at a median of 70(range 27-130) days after drug initiation. No individual or laboratory baseline characteristics were significantly associated with subsequent development of hepatitis. All cases of hepatitis recovered after drug cessation, although one patient was hospitalised and received corticosteroids.. Given the efficacy of rifampicin for an important sub-group of those with cholestatic pruritus, adult patients, including those with jaundice, can be counselled that 95% of prescriptions are safe, and where hepatitis occurs, including at long latency, drug cessation appears effective.

Topics: Adult; Cholestasis; Cohort Studies; Female; Humans; Liver Diseases; Male; Middle Aged; Pruritus; Rifampin; Risk Factors

Topics: Alkaline Phosphatase; Anticholesteremic Agents; Cholestasis; Cholestyramine Resin; Female; Humans; Liver; Liver Diseases; Liver Function Tests; Male; Practice Guidelines as Topic; Primary Health Care; Pruritus; Rifampin

Topics: Anti-Bacterial Agents; Azithromycin; Bronchial Fistula; Cysts; Ethambutol; Humans; Hydropneumothorax; Immunocompromised Host; Liver Diseases; Lung; Lung Diseases; Male; Middle Aged; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Pleura; Rifampin; Tomography, X-Ray Computed

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

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

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

Topics: Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Bartonella henselae; Cat-Scratch Disease; Cats; Child; Humans; Liver Diseases; Male; Rifampin; Splenic Diseases; Treatment Outcome

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

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

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

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

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

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

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

Exclusion of occult diseases in the donor organ and prevention of infectious disease transmission are minimal requirements in organ transplantation. We report here a case of hepatic graft tuberculosis, which was most likely transmitted by the graft from the living-related donor. The course of the recipient included tuberculosis, rejection, and other infections, which led to vanishing bile duct syndrome. Due to various infections and tuberculosis, as well as a strong interaction between rifampicin and tacrolimus, the patient died of pneumonia on day 273 after transplantation. This case emphasizes the importance of care in the selection of a living-related donor for liver transplantation.

Topics: Adult; Drug Interactions; Fatal Outcome; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Function Tests; Liver Transplantation; Living Donors; Mothers; Postoperative Complications; Rifampin; Tacrolimus; Tuberculosis

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

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

Rifampicin conferred significant protection against carbon tetrachloride (CCl4)-induced liver injury. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were not markedly altered and only hepatocellular fatty degeneration was found in mice pretreated with rifampicin (200 mg/kg), whereas severe centrilobular necrosis was observed and serum ALT and AST activities were as high as 281 and 271 I.U./l, respectively, in the control group following administration of CCl4 (400 microliters/kg). The contents and activities of microsomal drug-metabolizing enzymes in rifampicin-pretreated animals were also much higher than those of the controls. CCl4-mediated malondialdehyde (MDA) formation was increased in rifampicin-treated liver microsomes, demonstrating that rifampicin was capable of increasing the NADPH-dependent metabolism of CCl4 catalyzed by P-450 2E1 to produce free radicals. However, MDA formation was obviously depressed by rifampicin at varying concentrations from 2 to 32 x 10(-6) M in an in vitro cytochrome P-450 (P-450) enzyme system. On the other hand, NADPH oxidation in the metabolism of CCl4 and aniline hydroxylation were not suppressed in the presence of rifampicin in this systems, suggesting that rifampicin did not influence the biotransformation of CCl4 by P-450 2E1 in vitro. Therefore, the protective effect of rifampicin against CCl4 hepatotoxicity appeared to result from the direct inhibition of lipid peroxidation generated by CCl4-derived free radicals.

Topics: Animals; Carbon Tetrachloride; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Lipid Peroxidation; Liver Diseases; Male; Mice; Mice, Inbred Strains; Phenobarbital; Rifampin; Transaminases

Pruritus in hepatic cholestasis has been suggested to be secondary to a high concentration of serum bile acids. Rifampicin, which inhibits the uptake of bile acids by hepatocytes, has been used to treat pruritus. To determine the efficacy of rifampicin as a treatment for refractory pruritus, the medical records of 33 children (median age 25 months, range 4-135; 19 boys) with chronic cholestasis liver disease (21 with Alagille's syndrome, eight with progressive intrahepatic cholestasis, one with extrahepatic biliary atresia, one with an inborn error of bile acid metabolism, and one with cryptogenic cirrhosis) were reviewed retrospectively. The median dose of rifampicin was 5(4-10) mg/kg/day. The median duration of intake was 36(4-120) weeks. Complete relief of pruritus was noted in five (15%) patients and a partial response in 12 (36%). Overall, no significant difference was noted in the laboratory parameters before and after treatment with rifampicin. In the 21 patients with Alagille's syndrome, however, a significant decrease in alkaline phosphatase was seen before and after one and six months of starting treatment. No adverse side effects were seen. Rifampicin appears to be effective in the treatment of refractory pruritus. A prospective study is warranted to assess further the effect of rifampicin treatment in children with hepatic cholestasis.

Topics: Child; Child, Preschool; Cholestasis; Female; Humans; Infant; Liver Diseases; Male; Pruritus; Retrospective Studies; Rifampin; Treatment Outcome

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

Topics: Antibodies, Bacterial; Cat-Scratch Disease; Child, Preschool; Female; Fluorescent Antibody Technique; Follow-Up Studies; Humans; Liver Diseases; Rickettsieae; Rifampin; Splenic Diseases

We present a patient acutely ill from severe tuberculous meningo-encephalitis, in whom acute hepatic and renal failure, due to intercurrent septic shock, precluded the administration of full systemic dosage of antituberculous drugs. Daily direct intraventricular administration of 5 mg rifampicin, via a subcutaneous Ommaya reservoir connected to a catheter placed in the right lateral cerebral ventricle, resulted in rapid improvement without neurological sequelae. Intraventricular rifampicin administration for 50 consecutive days was well-tolerated without local or systemic side-effects. In well-selected patients with severe tuberculous meningo-encephalitis, intraventricular rifampicin may safely and highly effectively be added to systemic antituberculous therapy.

Topics: Acute Kidney Injury; Catheters, Indwelling; Cerebral Ventricles; Humans; Infusion Pumps, Implantable; Liver Diseases; Male; Meningoencephalitis; Middle Aged; Rifampin; Shock, Septic; Tuberculosis, Meningeal

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

Topics: Age Factors; Aminosalicylic Acid; Antitubercular Agents; Biological Availability; Dosage Forms; Drug Interactions; Humans; Isoniazid; Kidney Diseases; Liver Diseases; Rifampin; Streptomycin

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

Topics: Humans; Isoniazid; Liver Diseases; Rifampin; Tuberculosis

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

The pharmacology of ketoconazole was studied in patients with fungal infections. After administration of 50-, 100-, and 200-mg doses of ketoconazole, there was a linear increase in the area under the curve of serum concentrations; this was not apparent when higher doses of ketoconazole were given. An increase in the area under the curve occurred in patients receiving 200 mg daily who were restudied after 1 to 12 months of therapy. However, normalized area under the curve appeared to decrease after higher doses were administered chronically. The half life ranged from 2.0 to 3.3 h. Peak serum concentrations up to 50 micrograms/ml were detected in this study, and potentially therapeutic concentrations were detectable up to 26 h after high doses. Ketoconazole penetrated the saliva and inflamed joint fluid and meninges, although variably, and could be demonstrated in some other tissue compartments. In the presence of renal failure, ketoconazole disposition was not altered, whereas in the presence of hepatic insufficiency, an alteration in disposition was suggested. The interactions of ketoconazole and other drugs were studied. Of note, antacids did not significantly affect ketoconazole pharmacokinetics (nor did meals), and ketoconazole and warfarin did not appear to affect the pharmacokinetics of the other.

Topics: Administration, Oral; Adult; Antacids; Antifungal Agents; Child; Drug Interactions; Humans; Imidazoles; Ketoconazole; Kidney Diseases; Kinetics; Liver Diseases; Male; Piperazines; Rifampin; Saliva; Tissue Distribution

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

Glucocorticoids are used in physiological and pharmacological amounts in the management of a variety of clinical conditions. Concomitant utilisation of other drugs or the presence of some diseases may affect the physiological action of the steroid in the tissues. Phenytoin, phenobarbitone, ephedrine and rifampicin accelerate the metabolism of glucocorticoids thereby decreasing their biological activity. A similar phenomenon occurs in patients with hyperthyroidism. In contrast, glucocorticoid action is enhanced in hypothyroid patients and in those with hepatic damage as the result of a defect in the clearance of the hormone from blood. In turn, glucocorticoids antagonise the effects of cholinesterase inhibitors and ganglion blocking agents. The above mentioned effects should be kept in mind whenever glucocorticoids are utilised in the diagnosis and management of endocrine or non-endocrine conditions.

Topics: Anticonvulsants; Cholinesterase Inhibitors; Contraceptives, Oral; Cushing Syndrome; Dexamethasone; Diuretics; Drug Interactions; Ephedrine; Ganglionic Blockers; Glucocorticoids; Humans; Hypnotics and Sedatives; Insulin; Kinetics; Liver Diseases; Pancuronium; Rifampin; Salicylates; Thyroid Diseases

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

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

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

During treatment of active pulmonary tuberculosis with isoniazid, rifampicin and ethambutol in 15 patients transaminase activity increased in seven to levels of 60-340 U/l (group I). In the other eight the laboratory values remained within normal limits (group II). Rifampicin levels in group I were significantly raised at 2 and 5 hours after administration of 10 mg/kg body weight on proven fasting. There was no significant difference between the two groups for isoniazid. Estimated half-life of rifampicin was significantly longer in the first than the second group. If there is evidence of chronic liver disease (by history or by chemical tests) the rifampicin dose should be decreased to less than 10 mg/kg body weight.

Topics: Adult; Aged; Ethambutol; Female; Humans; Isoniazid; Liver Diseases; Male; Prospective Studies; Rifampin; Time Factors; Transaminases; Tuberculosis, Pulmonary

Topics: Binding Sites; Biotransformation; Drug Interactions; Enzyme Induction; Epilepsy; Humans; Liver; Liver Diseases; Phenobarbital; Phenytoin; Rifampin

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

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

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: Adolescent; Adult; Aged; Female; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Rifampin

Topics: Ethambutol; Humans; Isoniazid; Jaundice; Liver; Liver Diseases; Rifampin; Sulfobromophthalein; Tuberculosis, Pulmonary

Topics: Animals; Bile; Carbon Tetrachloride Poisoning; Disease Models, Animal; Female; Liver Diseases; Male; Rats; Rifampin

Topics: Bilirubin; Dose-Response Relationship, Drug; Half-Life; Hepatitis; Humans; Kinetics; Liver; Liver Cirrhosis; Liver Diseases; Rifampin; Time Factors

Topics: Anuria; Diagnosis, Differential; Female; Humans; Hypothermia; Jaundice; Kidney Diseases; Liver Diseases; Necrosis; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Bilirubin; Body Weight; Dose-Response Relationship, Drug; Half-Life; Humans; Kinetics; Liver; Liver Diseases; Rifampin

Topics: Alanine Transaminase; Aspartate Aminotransferases; Bilirubin; Drug Combinations; Drug Resistance, Microbial; Humans; Isoniazid; Liver Diseases; Liver Function Tests; Male; Middle Aged; Radiography; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Chronic Disease; Ethambutol; Hepatitis; Humans; Liver Diseases; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Alanine Transaminase; Alcoholism; Aspartate Aminotransferases; Bilirubin; Biopsy; Chronic Disease; Drug Combinations; Follow-Up Studies; Humans; Jaundice; Liver; Liver Diseases; Liver Function Tests; Radiography; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Aged; Chronic Disease; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Female; Humans; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Alanine Transaminase; Analysis of Variance; Aspartate Aminotransferases; Bilirubin; Drug Combinations; Ethambutol; Humans; Isoniazid; Liver; Liver Diseases; Liver Function Tests; Rifampin; Time Factors

Topics: Aminosalicylic Acids; Anti-Infective Agents; Creatinine; Gentamicins; Humans; Kidney Failure, Chronic; Liver Diseases; Rifampin

Topics: Humans; Injections, Intravenous; Liver; Liver Diseases; Liver Function Tests; Rifampin

Topics: Humans; Liver Diseases; Liver Function Tests; Rifampin; Sulfobromophthalein

Topics: Humans; Kidney Diseases; Liver Diseases; Respiratory Tract Diseases; Rifampin