rifampin and Body-Weight

Rifampicin has become an essential component as the first-line therapy for pulmonary tuberculosis (PTB). Several population pharmacokinetic (PK) studies on rifampicin in adult and child populations have been studied previously, therefore the aims of the systematic review were (i) to summarize the relevant published studies and significant covariates that influence the PK of rifampicin across different populations, and (ii) to identify any knowledge gap that requires additional research in the future.. A total of 121 relevant population PK articles were systematically identified using PubMed and Scopus from inception to October 2021. Review articles, in-vitro and physiological methods, animal studies and noncompartmental analysis were excluded.. Nineteen studies, of which 16 involved adults, two involved children, and one involved both adults and children, were included in the review. The structural model of rifampicin can be described as one compartment with a transient compartment absorption model and first-order elimination in most of the studies. Pharmaceutical formulation, body weight, gender, pregnancy status, diabetes and nutritional supplementation were found to be the significant covariates that affect the PK parameters. External validation of the developed PK model was only conducted in two studies.. The source of variability for PK parameters of rifampicin remains inconsistent and poorly understood even though there were many potential covariates investigated in the selected studies. Exploring other possible factors and implementing a strict sampling strategy by considering the induction effects might uncover precise and reliable information. Furthermore, external validation should be frequently conducted to produce better predictability of model performance.

Topics: Animals; Body Weight; Female; Humans; Models, Biological; Pregnancy; 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

Topics: Animals; Biological Availability; Body Weight; Dapsone; Drug Evaluation, Preclinical; Humans; Leprostatic Agents; Leprosy; Ofloxacin; Oxazines; Rifampin; Species Specificity

Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens.. Data were collected from 41 children, aged 2-16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed-effects model.. Isoniazid pharmacokinetics were described by a one-compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one-compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed-dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed-dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg. The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose-effect relationship of higher doses of rifampicin.

Topics: Adolescent; Age Factors; Antitubercular Agents; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; India; Infant; Isoniazid; Male; Metabolic Clearance Rate; Models, Biological; Rifampin; Tuberculosis

Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. A cohort of 100 TB patients (58 men; median age, 35 [interquartile range {IQR}, 29 to 40] years, and median body mass index [BMI], 18.8 [17.3 to 19.9] kg/m(2)) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (+14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC0-24) of 5.6 μg/ml and 28.6 μg · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher Cmax and AUC0-24 values of 6.4 μg/ml and 31.6 μg · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.).

Topics: Adult; Biological Availability; Body Mass Index; Body Weight; Cohort Studies; Coinfection; Dietary Supplements; Female; Genotype; HIV Infections; Humans; Male; Middle Aged; Rifampin; Tuberculosis; Weight Gain

Micronutrients play an important role in immune function. To our knowledge, there have been no comprehensive studies on the role of micronutrient supplementation in children with tuberculosis.. We assessed the effect of micronutrient supplementation in children treated with antituberculosis therapy (ATT).. A randomized, double-blind, placebo-controlled trial that used a 2 × 2 factorial design was undertaken at 2 teaching hospitals in Delhi. Children with newly diagnosed intrathoracic tuberculosis were enrolled, and they received ATT together with daily supplementation for 6 mo with either zinc alone, micronutrients without zinc, micronutrients in combination with zinc, or a placebo. Main outcomes were weight gain and an improvement in a chest X-ray (CXR) lesion assessed at 6 mo of treatment.. A total of 403 children were enrolled and randomly assigned. A microbiological diagnosis of tuberculosis was confirmed in 179 children (44.4%). The median (95% CI) increase in weight-for-age z score at 6 mo was not significantly different between subjects who received micronutrients [0.75 (0.66, 0.84)] and those who did not receive micronutrients [0.76 (0.67, 0.85)] and between subjects who received zinc [0.76 (0.68, 0.85)] and those who did not receive zinc [0.75 (0.66, 0.83)]. An improvement in CXR was observed in 285 children, but there was no difference between those receiving zinc and no zinc or between those receiving micronutrients and no micronutrients after 6 mo of ATT. However, children who received micronutrients had a faster gain in height over 6 mo than did those who did not receive micronutrients (height-for-age z score Δ = 0.08; P = 0.014).. Micronutrient supplementation did not modify the weight gain or clearance of lesions on CXR in children with intrathoracic tuberculosis. However, micronutrient supplementation during treatment may improve height gain in children with intrathoracic tuberculosis. This trial was registered at clinicaltrials.gov as NCT00801606.

Topics: Adolescent; Antitubercular Agents; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Dietary Supplements; Double-Blind Method; Ethambutol; Female; Humans; India; Infant; Isoniazid; Male; Micronutrients; Patient Compliance; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; Zinc

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

The potential of drug-drug interaction between efavirenz and rifampicin is a major concern in the treatment of HIV and tuberculosis. The optimal efavirenz dosage is still unclear. Our randomized control trial study recently reported the similar efavirenz level between efavirenz 600 and 800 mg/day in HIV-infected patients receiving rifampicin. We report the similar virological and immunological outcomes at 48 weeks between the two groups. Efavirenz 600 mg/day should be sufficient for concurrent use with rifamipicin.

Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Body Weight; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Oxazines; Rifampin; Treatment Outcome; Tuberculosis

Readily identified markers of tuberculosis relapse risk are needed, particularly in resource-limited settings. The association between weight gain or loss during antituberculosis therapy and relapse has not been well studied.. Subjects in the Tuberculosis Trials Consortium Study 22 were studied. Underweight was defined as 10% or more below ideal body weight at diagnosis. Weight change was assessed between (1) diagnosis and completion of induction phase therapy, (2) diagnosis and end of continuation phase therapy, and (3) completion of induction to completion of continuation phase therapy.. A total of 857 subjects were monitored for 2 yr, and 61 of 857 (7.1%) relapsed. Relapse risk was high among persons who were underweight at diagnosis (19.1 vs. 4.8%; p < 0.001) or who had a body mass index of less than 18.5 kg/m(2) (19.5 vs. 5.8%; p < 0.001). Among persons who were underweight at diagnosis, weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy was moderately associated with an increased relapse risk (18.4 vs. 10.3%; relative risk, 1.79, 95% confidence interval, 0.96-3.32; p = 0.06). In a multivariate logistic regression model that was adjusted for other risk factors, a weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy among persons underweight at diagnosis was significantly associated with relapse risk (odds ratio, 2.4; p = 0.03).. Among persons underweight at diagnosis, weight gain of 5% or less during the first 2 mo of treatment is associated with an increased relapse risk. Such high-risk patients can be easily identified, even in resource-poor settings. Additional studies are warranted to identify interventions to decrease risk of relapse in such patients.

Topics: Adult; Antitubercular Agents; Body Mass Index; Body Weight; Female; Humans; Isoniazid; Male; Middle Aged; Prognosis; Recurrence; Rifampin; Risk Factors; Thinness; Tuberculosis; Weight Gain

To evaluate a monthly 'pulse' of rifampicin plus pyrazinamide plus streptomycin in the continuation phase of a short-course antituberculosis regimen.. Randomised controlled trial of two 7-month chemotherapy regimens.. Inpatient chemotherapy and outpatient follow-up in Tanzania.. Smear-positive pulmonary tuberculosis.. All patients received streptomycin plus rifampicin plus isoniazid plus pyrazinamide daily for 6 weeks followed by isoniazid daily for 24 weeks; 50%, at random, received additional doses of rifampicin, pyrazinamide and streptomycin every 4 weeks in the continuation phase. Follow-up continued for 23 months after cessation of chemotherapy.. Bacteriological failure rate at the end of chemotherapy and relapse rate after stopping.. Of the 266 patients with fully sensitive strains before treatment there was one failure in each series during chemotherapy; after stopping, 5% of the 114 who received the supplement relapsed bacteriologically compared with 10% of the 113 who did not (95% CI for the difference -0.02% to + 11.3%). The results in the 37 patients with strains resistant to isoniazid pretreatment were not as good, but similar for the two regimens.. This study was not large enough to demonstrate a significant reduction in the relapse rate from 10% to 5%. If such a reduction were confirmed in a larger study it would represent an important improvement in efficacy. further, in an outpatient setting, the additional monthly doses might improve attendance.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Black People; Body Weight; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Isonicotinic Acids; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Ethambutol is said to be capable of elevating serum urate concentration. This statement was reconsidered in three investigations using strictly supervised administration of ethambutol in a single daily dose of 25 mg. per kg. of body weight: (1) In short term administration 10 healthy subjects received ethambutol for eight days. (2) In a pilot study 13 patients suffering from pulmonary tuberculosis were treated with a triple combination including thambutol for six months. (3) In a controlled trial 23 patients were randomly allocated to one of the following regiments: In the first group patients received ethambutol plus isoniazid plus rifampicin for six months. In the second group patients received streptomycin plus isoniazid plus PAS for three months and thereafter streptomycin plus isoniazid plus ethambutol for another three months. Serum urate concentrations and clearances of uric acid and of creatinine were determined periodically in all subjects. A slight increase in serum urate concentration occurring in long term therapy showed no relation to ethambutol administration, but was obviously dependant on parameters related to the course of the disease in form of increase in body weight and physical activity, or related to the well known syntropy of chronic alcoholism and tuberculosis.

Topics: Alcoholism; Body Weight; Creatinine; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Uric Acid

Topics: Adolescent; Adult; Age Factors; Aged; Antibody Formation; Body Weight; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fever; Humans; Male; Middle Aged; Rifampin; Sex Factors; Tuberculosis, Pulmonary

In a controlled clinical trial in Hong Kong, 575 Chinese adults with smear-positive isoniazid-resistant pulmonary tuberculosis, who had previously been treated with first-line chemotherapy, were allocated at random to regimens of rifampicin plus ethambutol daily (ER7), twice-weekly (ER2), once-weekly (ER1), or daily for 2 months and then once-weekly (ER7ER1), or to a standard retreatment regimen of daily ethionamide plus pyrazinamide plus cycloserine (EtZC). The ER7 patients were allocated to 12 or 18 months of chemotherapy, and the remainder to 18 months. As assessed at 18 months, a favourable response was achieved in 87 per cent of 91 ER7 patients, 79 per cent of 84 ER2, 81 per cent of 53 ER1, 87 per cent of 62 ER7ER1, and in 88 per cent of 68 EtZC patients (93 per cent of 59 EtZC patients if those with ethionamide-resistant strains pretreatment are excluded). As assessed at 18 and 30 months the ER7 regime was as effective as the control EtZC regimen, and 18 months of chemotherapy on the ER7 regimen conferred no benefit over 12 months. No patient on either regimen relapsed after 18 months. Adverse reactions were uncommon on the daily rifampicin regimen but relatively common on the intermittent and control regimens. The commonest reaction to the intermittent regimens was the 'flu' syndrome, which was associated with the presence of circulating rifampicin-dependent antibodies (P less than 0-001).

Topics: Antibody Formation; Body Weight; Clinical Trials as Topic; Cycloserine; Drug Combinations; Drug Resistance; Ethambutol; Ethionamide; Fever; Follow-Up Studies; Humans; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aminosalicylic Acids; Blood Proteins; Blood Sedimentation; Body Weight; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Mycobacterium bovis; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Body Weight; Ethambutol; Ethionamide; Female; Hemoglobins; Humans; Isoniazid; Liver; Liver Function Tests; Male; Middle Aged; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Adult; Body Weight; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Female; Follow-Up Studies; Humans; Leukocyte Count; Male; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Blood Sedimentation; Body Weight; Clinical Trials as Topic; Drug Synergism; Female; Hemoglobins; Humans; Isoniazid; Male; Middle Aged; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Topics: Body Weight; Clinical Trials as Topic; Drug Synergism; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Esaxerenone is a novel, non-steroidal mineralocorticoid receptor (MR) blocker with improved selectivity and affinity for MR. The objectives of this study were to model the population pharmacokinetics of esaxerenone in a diverse population and to evaluate the effect of covariates on pharmacokinetics parameters.. A total of 8263 plasma esaxerenone concentrations from 166 healthy volunteers, 1097 hypertensive patients and 360 patients with diabetic nephropathy were pooled. A three-compartment model with sequential zero- and first-order absorption was used to describe the time-courses of plasma esaxerenone following single and multiple doses once daily for up to 12 weeks. Covariate effects were estimated using the full covariate modeling approach. Clinical relevance of covariates was ascertained using tornado plots.. Esaxerenone was estimated to have high bioavailability (85.3%), low clearance (3.28 L/h) and relatively large distribution volume at steady state (94.8 L). Body weight (-26 to +36%) and coadministration of itraconazole (+64%) or rifampicin (-68%) were associated with a greater influence on esaxerenone exposure.. The most influential covariates on esaxerenone exposure were coadministrations of itraconazole and rifampicin, followed by body weight. The clinical relevance of effects of renal impairment, mild to moderate hepatic impairment, and age is limited.

Topics: Body Weight; Diabetes Mellitus; Diabetic Nephropathies; Essential Hypertension; Healthy Volunteers; Humans; Itraconazole; Receptors, Mineralocorticoid; Rifampin

A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Body Weight; Cigarette Smoking; Cytochrome P-450 CYP3A; Drug Combinations; Female; Food-Drug Interactions; Humans; Liver Failure; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Racial Groups; Renal Insufficiency; Rifampin; Schizophrenia; Sex Factors; Young Adult

The weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination tablets according to their weight-band. However, some analysis has shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.. Rifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median area under the curve (AUC0-24 h) after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.. The difference of median AUC0-24 h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.. Weight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.

Topics: Body Weight; Dose-Response Relationship, Drug; Humans; Rifampin; Tablets; Tuberculosis

Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden.. We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child.. We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure.. This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality.. Eunice Kennedy Shriver National Institute of Child Health and Human Development and UK Medical Research Council.

Topics: Algorithms; Antitubercular Agents; Body Weight; Child Nutrition Disorders; Child, Preschool; Drug Administration Schedule; Humans; Isoniazid; Models, Statistical; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

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

Arylbenzimidazoles have been synthesized as antimycobacterial agents. An efficient synthesis has been developed for 2-arylbenzimidazoles from o-phenylenediamines and aromatic aldehydes in molecular sieves-methanol system. The methodology is straightforward to get 2-arylbenzimidazoles (3a-3z) in excellent yields with high chemoselectivity over 2-aryl-1-benzylbenzimidazoles (4a-4z). All these benzimidazole analogues were evaluated against M. tuberculosis in BACTEC radiometric assay. The compounds 4y and 4z exhibited potential antitubercular activity against M. tuberculosis H

Topics: Administration, Oral; Animals; Antitubercular Agents; Bacterial Proteins; Binding Sites; Body Weight; DNA Gyrase; Imidazoles; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Protein Structure, Tertiary; Structure-Activity Relationship

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P

Topics: Adolescent; Age Factors; Antitubercular Agents; Body Weight; Child; Child, Preschool; Coinfection; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; Humans; India; Infant; Isoniazid; Male; Models, Biological; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

A population pharmacokinetic (PK) model was developed for cediranib to simulate cediranib exposure for different doses, including comedication with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin, in cancer patients.. Plasma concentrations and covariates from 625 cancer patients after single or multiple oral cediranib administrations ranging from 0.5 to 90 mg in 19 Phase I and II studies were included in the analysis. Stepwise covariate modelling was used to develop the population PK model. The final model was used to simulate cediranib exposure in cancer patients to evaluate cediranib target coverage and the need for dose adjustment for covariates or coadministration with rifampicin.. A two-compartment model with sequential zero- and first-order absorption and first-order elimination adequately described the cediranib concentration-time courses. Body weight and age were identified as having statistically significant impact on cediranib PK, but only <21% impact on AUC and maximum concentrations. Simulated lower bounds of 90% prediction interval or median of unbound cediranib concentrations after cediranib 15 or 20 mg exceeded the IC. No covariate was identified to require dose adjustment for cediranib. Cediranib exposure following 15 or 20 mg daily dose administration is adequate overall for inhibition of in vitro estimated vascular endothelial growth factor receptor-1, -2 and -3 activities. An increase in cediranib dose may be needed for cediranib coadministered with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin.

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Body Weight; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Female; Glucuronosyltransferase; Humans; Inhibitory Concentration 50; Male; Middle Aged; Models, Biological; Neoplasms; Polypharmacy; Protein Kinase Inhibitors; Quinazolines; Rifampin; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Young Adult

Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TB-coinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Area Under Curve; Biological Availability; Biotransformation; Body Weight; Clinical Trials as Topic; Cohort Studies; Coinfection; Computer Simulation; Ethambutol; Female; Half-Life; HIV Infections; Humans; Isoniazid; Liver; Male; Middle Aged; Models, Statistical; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Area Under Curve; Body Weight; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Isoniazid; Rifampin; Tuberculosis

To evaluate serum levels of rifampicin (RMP) in children with tuberculosis (TB) at doses administered according to India's Revised National Tuberculosis Control Programme (RNTCP) 2009 report.. Prospective, open label, non-randomised single-dose study in 20 children aged 5-12 years.. The out-patient chest clinic of a tertiary care hospital, New Delhi, India.. The median RMP dose administered was 9.56 mg/kg (range 9-12.64). Peak RMP concentration (Cmax) attained was 6.24 μg/ml (range 5.44-7.61) at time to Cmax of 3.5 h (range 3-4). RMP levels were significantly lower at 2, 3 and 4 h in children administered <10 mg/kg than those who received ⩾10 mg/kg (P < 0.05). A positive correlation between the RMP dose administered and Cmax was observed (r(2) = 0.748). RMP Cmax was <8 μg/ml in all patients, a level considered too low for therapeutic efficacy.. Low serum concentrations of RMP were attained in children under the RNTCP 2009 weight band system. Peak RMP levels appear to be lower and the single dose elimination half-life shorter in children than in adults. To optimise treatment outcomes, revisions in RMP dose in children should take into consideration age-related differences in pharmacokinetics.

Topics: Antitubercular Agents; Body Weight; Child; Child, Preschool; Female; Half-Life; Humans; India; Male; Outpatients; Prospective Studies; Rifampin; Tertiary Care Centers; Treatment Outcome; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary; World Health Organization

Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 μg/ml may result in virologic failure and above 4 μg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV.. Patients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses.. CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels.. This study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Alleles; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B; Benzoxazines; Body Weight; Case-Control Studies; Cyclopropanes; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2B6; Drug Interactions; Female; Hallucinations; Headache; Humans; Male; Models, Biological; Rifampin; Sex Characteristics; Sleep Wake Disorders; Tuberculosis; Zimbabwe

Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Age Factors; Antitubercular Agents; Body Weight; Child; Child, Preschool; Clinical Trials, Phase II as Topic; Computer Simulation; Drug Dosage Calculations; Humans; Infant; Levofloxacin; Models, Biological; Mycobacterium tuberculosis; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Meningeal

In 2010, the World Health Organization revised the recommendations for the treatment of tuberculosis (TB) in children. The major revision was to increase isoniazid, rifampicin and pyrazinamide dosages according to body weight in children. The recommendations for higher dosages are based on consistent evidence from 1) pharmacokinetic studies suggesting that young children require higher dosages than adolescents and adults to achieve desired serum concentrations; and 2) observational studies reporting that the higher dosages would not be associated with increased risk of toxicity in children. However, national tuberculosis programmes faced unforeseen challenges in implementing the revised recommendations. The main difficulty was to adapt the revised dosages for the treatment of children with drug-susceptible TB using available fixed-dose combinations (FDCs). A more suitable FDC for the intensive and continuation phases of treatment has now been developed for planned implementation in 2015. This paper explains the background and rationale for the development of a new FDC tablet for children with drug-susceptible TB.

Topics: Antitubercular Agents; Body Weight; Child; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; World Health Organization

Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese.. HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively.. From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33-0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97-9.59) in multivariate analysis.. Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations.

Topics: Adult; Aged; Aged, 80 and over; Alkynes; Anti-HIV Agents; Antitubercular Agents; Aryl Hydrocarbon Hydroxylases; Asian People; Benzoxazines; Body Weight; China; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Monitoring; Drug Therapy, Combination; Ethnicity; Female; HIV Infections; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; Young Adult

Rifampin (RIF) upregulates CYP 450 isoenzymes, potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends an EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and human immunodeficiency virus (HIV) virologic suppression in patients on EFV (600 mg) and RIF-based tuberculosis treatment in the multicenter randomized trial (ACTG A5221).. EFV Cmin was measured 20-28 hours post-EFV dose at weeks 4, 8, 16, 24 on-RIF and weeks 4, 8 off-RIF. Results were evaluated with 2-sided Wilcoxon rank-sum, χ(2), Fisher exact tests and logistic regression (5% type I error rate).. Seven hundred eighty patients received EFV; 543 provided ≥1 EFV Cmin. Median weight was 52.8 kg (interquartile range [IQR], 48.0-59.5), body mass index 19.4 kg/m(2) (IQR, 17.5-21.6), and age 34 years (IQR, 29-41); 63% were male, 74% black. Median Cmin was 1.96 µg/mL on-RIF versus 1.80 off-RIF (P = .067). Cmin were significantly higher on-RIF versus off-RIF in blacks (2.08 vs 1.75, P = .005). Weight ≥60 kg on-RIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs 2.02, P = .021). However, weight ≥60 kg was associated with more frequent HIV RNA < 400 copies/mL at week 48, compared to weight <60 kg (81.9% vs 73.8%, P = .023).. EFV and RIF-based tuberculosis therapy coadministration was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone. Patients weighing ≥60 kg had lower median EFV Cmin versus those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weight-based dosing of EFV with RIF.

Topics: Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Body Weight; Cyclopropanes; Drug Interactions; Female; HIV Infections; Humans; Male; Rifampin; Treatment Outcome; Tuberculosis; Viral Load

This study was performed to describe clindamycin, administered either orally or intravenously, concentration-time courses to patients with osteomyelitis, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme.. Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58 from oral administration and 64 from i.v. infusion). A population pharmacokinetic model was developed with MONOLIX 4 software.. A one compartment model adequately described the data. Clindamycin clearance increased significantly with body weight (BW). The typical population estimates (interindividual variability) for clearance, volume of distribution and absorption rate constant were 16.2 l h(-1) (0.39), 70.2 l and 0.92 h(-1) , respectively. The bioavailability of the oral form was estimated to be 87.6%. According to BW, theoretical doses needed to reach a C(min) of 2 mg l(-1) were then calculated.. The current recommendation of 600 mg three times daily seems to be effective up to 75 kg but the dose should be raised to 900 mg three times daily thereafter. These assumptions should be prospectively confirmed.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biological Availability; Body Weight; Clindamycin; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Models, Theoretical; Osteomyelitis; Retrospective Studies; Rifampin; Young Adult

Historically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [C(max)]), the time above the MIC (t > MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.

Topics: Antitubercular Agents; Area Under Curve; Body Weight; Drug Dosage Calculations; Ethnicity; Female; Humans; Isoniazid; Liver; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007-2010 were investigated to assess whether interventions on dosing were effective.. Lists of all notified culture positive TB cases in 2007-2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007-2010 (p<0.001). The proportion of patients treated with consistent dosing of a 3-drug fixed-dose combination (FDC) increased from 73.9% in 2003 to 87.7% in 2007-2010 (p<0.001), and that for 2-drug FDC from 76.0% to 86.1% (p = 0.024), for rifampicin (RMP) from 62.8% to 85.5% (p<0.001), and for isoniazid from 87.8% to 95.3% (p<0.001). In 2007-2010, among 2917 patients treated with either FDCs or RMP in single-drug preparation, the dosage of RMP was adequate (8-12 mg/kg) in 2571(88.1%) patients, too high in 282(9.7%), too low in 64(2.2%). In multinomial logistic regression models, factors significantly associated with adequate dosage of RMP were body weight and preparations of RMP. Patients weighting <40 kg (relative risk ratio (rrr) 6010.5, 95% CI 781.1-46249.7) and patients weighting 40-49 kg (rrr 1495.3, 95% CI 200.6-11144.6) were more likely to receive higher-than-recommended dose of RMP.. Prescribing practice in the treatment of TB in Taipei City has remarkably improved after health authorities implemented a series of interventions.

Topics: Adult; Aged; Antitubercular Agents; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Drug Prescriptions; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pyrazinamide; Rifampin; Taiwan; Tuberculosis; Young Adult

This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight-based dosage recommendations used to counteract the rifampicin-efavirenz interaction.. Efavirenz pharmacokinetics were simulated using a physiologically based pharmacokinetic model implemented in the Simcyp™ population-based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype.. Apart from the absorption phase, the simulation model predicted efavirenz concentration-time profiles reasonably well, with close agreement with clinical data. The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval 13-19) in efavirenz area under the concentration-time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status.. Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut-off for efavirenz dose increment when co-treating with rifampicin.

Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Body Weight; Computer Simulation; Cyclopropanes; Cytochrome P-450 CYP2B6; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Forecasting; HIV Infections; Humans; Models, Theoretical; Oxidoreductases, N-Demethylating; Phenotype; Rifampin; Tuberculosis

The disruption of host-symbiont interactions through the use of antibiotics can help elucidate microbial functions that go beyond short-term nutritional value. Termite gut symbionts have been studied extensively, but little is known about their impact on the termite's reproductive output. Here we describe the effect that the antibiotic rifampin has not only on the gut microbial diversity but also on the longevity, fecundity, and weight of two termite species, Zootermopsis angusticollis and Reticulitermes flavipes. We report three key findings: (i) the antibiotic rifampin, when fed to primary reproductives during the incipient stages of colony foundation, causes a permanent reduction in the diversity of gut bacteria and a transitory effect on the density of the protozoan community; (ii) rifampin treatment reduces oviposition rates of queens, translating into delayed colony growth and ultimately reduced colony fitness; and (iii) the initial dosages of rifampin had severe long-term fitness effects on Z. angusticollis. Taken together, our findings demonstrate that the antibiotic-induced perturbation of the microbial community is associated with prolonged reductions in longevity and fecundity. A causal relationship between these changes in the gut microbial population structures and fitness is suggested by the acquisition of opportunistic pathogens and incompetence of the termites to restore a pretreatment, native microbiota. Our results indicate that antibiotic treatment significantly alters the termite's microbiota, reproduction, colony establishment, and ultimately colony growth and development. We discuss the implications for antimicrobials as a new application to the control of termite pest species.

Topics: Animals; Anti-Bacterial Agents; Body Weight; Fertility; Gastrointestinal Tract; Isoptera; Longevity; Metagenome; Rifampin; Symbiosis

Altered pharmacokinetics of antituberculosis drugs may contribute to an increased risk of tuberculosis treatment failure for diabetic patients. We previously found that rifampin exposure was 2-fold lower in diabetic than in nondiabetic tuberculosis patients during the continuation phase of treatment. We now examined the influence of diabetes on the pharmacokinetics of antituberculosis drugs in the intensive phase of tuberculosis treatment, and we evaluated the effect of glycemic control. For this purpose, 18 diabetic and 18 gender- and body weight-matched nondiabetic tuberculosis patients were included in an Indonesian setting. Intensive pharmacokinetic sampling was performed for rifampin, pyrazinamide, and ethambutol at steady state. The bioavailability of rifampin was determined by comparing rifampin exposure after oral versus intravenous administration. Pharmacokinetic assessments were repeated for 10 diabetic tuberculosis patients after glycemic control. No differences in the areas under the concentration-time curves of the drugs in plasma from 0 to 24 h postdose (AUC(0-24)), the maximum concentrations of the drugs in plasma (C(max)), the times to C(max) (T(max)), and the half-lives of rifampin, pyrazinamide, and ethambutol were found between diabetic and nondiabetic tuberculosis patients in the intensive phase of tuberculosis treatment. For rifampin, oral bioavailability and metabolism were similar in diabetic and nondiabetic patients. The pharmacokinetic parameters of antituberculosis drugs were not correlated with blood glucose levels or glucose control. We conclude that diabetes does not alter the pharmacokinetics of antituberculosis drugs during the intensive phase of tuberculosis treatment. The reduced exposure to rifampin of diabetic patients in the continuation phase may be due to increased body weight and possible differences in hepatic induction. Further research is needed to determine the cause of increased tuberculosis treatment failure among diabetic patients.

Topics: Adult; Antitubercular Agents; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Ethambutol; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Seventy-one human immunodeficiency virus-infected patients with tuberculosis who were receiving a rifampin (rifampicin)-containing regimen were initiated on treatment with efavirenz at 600 mg/day plus stavudine-lamivudine. Fasting efavirenz concentrations at 12 h after dosing (C12) were monitored. The mean +/- standard deviation efavirenz C12 at weeks 6 and 12 and after rifampin discontinuation were 4.5 +/- 4.3, 3.8 +/- 3.5, and 3.5 +/- 2.7 mg/liter, respectively. High body weight was associated with a low efavirenz C12 at weeks 6 and 12 (P = 0.003, r = -0.255). The efavirenz C12 regression prediction line at 1 mg/liter intercepted a mean body weight of 57.5 kg.

Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Body Weight; Cyclopropanes; Drug Administration Schedule; Female; HIV Infections; Humans; Male; Multivariate Analysis; Rifampin; Tuberculosis

The aim of this study was to examine factors influencing plasma concentration of efavirenz and nevirapine.. Data from the Liverpool Therapeutic Drug Monitoring (TDM) registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. For each patient, the first measurement of efavirenz (600 or 800 mg/day) or nevirapine (400 mg/day) plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifampicin with log-transformed drug concentration, adjusted for time since last intake.. Data from 339 patients on efavirenz (34% black, 17% rifampicin) and 179 on nevirapine (27% black, 6% rifampicin) were included. Multivariable models revealed the following predictors for efavirenz concentration: black ethnicity (59% higher; P<0.001), weight (10% lower per additional 10 kg; P=0.002), 800 mg/day (52% higher; P=0.027), rifampicin (35% lower; P=0.039), and zidovudine (25% lower; P=0.010). Notably, without adjustment for other factors, patients on rifampicin had 48% higher efavirenz concentration, as these patients were mostly black and on 800 mg/day. For nevirapine the predictors were black ethnicity (39% higher; P=0.002), rifampicin (40% lower; P=0.002), protease inhibitor (28% higher; P=0.008) and tenofovir (22% higher; P=0.024).. We observed clear associations between ethnicity and concentrations of nevirapine and efavirenz. Our analyses confirm that concomitant rifampicin substantially decreases concentration of both efavirenz and nevirapine; however, for efavirenz this effect was more than counterbalanced by the effect of ethnicity and increased efavirenz dose. There was also an additional impact of weight, which should be considered when determining optimal dosage. Other associations from our analysis (between tenofovir or protease inhibitor and nevirapine, and zidovudine and efavirenz), require confirmation in formal pharmacokinetic studies.

Topics: Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Black People; Body Weight; Cyclopropanes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Viral Load; White People

Rifampicin, an antibacterial drug widely used in the treatment of tuberculosis and leprosy, has recently been reported to have anti-oxidative and anti-apoptotic effects. However, its anti-angiogenic effect has not been investigated. We examined its anti-angiogenic effect on tube formation and proliferation by human umbilical vein endothelial cells (HUVECs) in vitro and on retinal neovascularization in a murine oxygen-induced retinopathy model in vivo. In addition, we explored the potential mechanisms for its anti-angiogenic effect. Rifampicin significantly suppressed HUVEC tube formation and proliferation, and its effects appeared to be mediated at least in part through inhibition of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Retinal neovasuclarization was induced in neonatal mice by returning the retina to normoxia (21% O2) after exposure to hyperoxia (75% O2) from postnatal day 7 (P7) to P12. Rifampicin was given subcutaneously at 20mg/kg once a day from immediately after hyperoxia (P12) to P16. At P17, flat-mounted retinas were prepared and evaluated for pathological and physiological angiogenesis. Rifampicin significantly suppressed retinal neovascularization (versus vehicle treatment), but revascularization of the capillary-free area did not differ between vehicle and rifampicin treatment. Rifampicin has anti-angiogenic effects in vitro and in vivo, and may be useful as an anti-angiogenic agent in the treatment of retinal neovascularization diseases.

Topics: Angiogenesis Inhibitors; Animals; Body Weight; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelium, Vascular; Humans; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oxygen; Phosphorylation; Retinal Neovascularization; Rifampin

Rifampicin, an antibacterial drug, is highly effective in the treatment of tuberculosis and leprosy. Recently, it has been reported to have neuroprotective effects in in vitro and in vivo models. This study was designed to elucidate its neuroprotective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity (known as an in vivo mouse model of Parkinson's disease). Mice were injected intraperitoneally (i.p.) with MPTP (10 mg/kg) four times at 1-h intervals, and brains were analyzed 3 or 7 days later. Rifampicin at 20 mg/kg (i.p., twice) had protective effects against MPTP-induced neuronal damage (immunohistochemical changes in tyrosine hydroxylase) in both the substantia nigra and striatum. Rifampicin also protected against the MPTP-induced depletions of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the striatum. The maximal concentrations of rifampicin between 30 and 240 min after a single rifampicin injection (20 mg/kg, i.p.) were 2.6 microM (at 30 min) in plasma and 0.77 microM (at 60 min) in striatum. Next, the effects of rifampicin on oxidative stress [lipid peroxidation in mouse brain homogenates and free radical-scavenging activity against diphenyl-p-picrylhydrazyl (DPPH)] were evaluated to clarify the underlying mechanism. At 1 microM or more, rifampicin significantly inhibited both lipid peroxidation in the striatum and free radical production. These findings suggest that in mice, rifampicin can reach brain tissues at concentrations sufficient to attenuate MPTP-induced neurodegeneration in the nigrostriatal dopaminergic neuronal pathway, and that an inhibitory effect against oxidative stress may be partly responsible for its observed neuroprotective effects.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Body Weight; Brain; Brain Chemistry; Cell Count; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Free Radicals; Homovanillic Acid; Immunohistochemistry; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Parkinsonian Disorders; Rifampin; Tyrosine 3-Monooxygenase

Hepatotoxicity is one of the most serious adverse effects of antituberculosis drugs. The aim of this study was to produce a rat model of isoniazid-rifampicin (INH-RIF) induced hepatotoxicity.. Wistar rats (100-150 g) were treated with different doses of INH i.e. 25, 50 and 75 mg/kg/day with a fixed dose of RIF i.e. 50 mg/kg/day intragastrically for a period of 28 days. Serum glutamate oxaloacetate aminotransferase (SGOT), glutamate pyruvate aminotransferase (SGPT), bilirubin (Bil) and alkaline phosphatase (ALP) were estimated at 0,14, 21 and 28 days in rats. Histological analysis was carried out to assess the liver.. Treatment of rats with INH-RIF (50 mg/kg/day each) induced hepatotoxicity as judged by elevated serum SGPT, SGOT, Bil and ALP as compared with their base line. Histological evaluation of INH-RIF induced hepatotoxicity also showed liver damage.. The present study suggests that 50 mg/kg/day each of INH-RIF was selected as hepatotoxic dose (i.e. minimum dose with maximum hepatotoxicity) in wistar rats.

Topics: Administration, Oral; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Body Weight; Isoniazid; Liver; Male; Rats; Rats, Wistar; Rifampin

All 44 non-private hospitals in Malawi treating pulmonary tuberculosis (PTB) patients with an oral regimen (0.5RHZE/1.5R3H3Z3E3/6HE).. In new smear-positive PTB patients, to determine whether: 1) numbers of tablets were correctly prescribed according to pre-treatment weights, and 2) medication dosages were adequate, too low or too high.. Retrospective review of TB registers and TB treatment cards for patients registered with new smear-positive PTB between 1 October and 31 December 2001.. Of 1970 patients aged > or = 15 years, 1211 (62%) had treatment cards and pre-treatment weights. Incorrect prescriptions were given to 88 (7%), and many of these received dosages of anti-tuberculosis drugs that were too high or too low. For those receiving correct prescriptions, daily treatment in the initial and continuation phases was generally associated with adequate dosages of drugs. However, in the initial intermittent phase, between 3% and 40% of patients received anti-tuberculosis drug dosages that were too low.. A small percentage of patients receive incorrect prescriptions, which can be resolved by training and supervision. In those receiving correct prescriptions, intermittent treatment provides dosages that are sometimes too low. Weight bands for intermittent treatment should be re-examined.

Topics: Administration, Oral; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Body Weight; Communicable Disease Control; Drug Therapy, Combination; Drug Utilization Review; Ethambutol; Female; Guideline Adherence; Hospital Records; Hospitals, Public; Humans; Isoniazid; Malawi; Male; Middle Aged; Pyrazinamide; Registries; Rifampin; Tuberculosis, Pulmonary

Poor bioavailability of rifampicin (R) in combination with other anti-tuberculosis drugs such as isoniazid (H), pyrazinamide (Z), and ethambutol (E) is a subject of much concern for the last few decades. This could be due to an interaction between R and other drugs. An investigation was therefore undertaken to examine the bioavailability of R in the presence of H, Z and E or a combination of the three drugs.. The study included eight healthy volunteers, each being investigated on four occasions at weekly intervals once with R alone and with three of the four combinations on the three remaining occasions. A partially balanced incomplete block design was employed and the allocation of R or the drug combinations was random. Plasma concentrations of R at intervals up to 12 h were determined by microbiological assay using Staphylococcus aureus as the test organism. The proportion (%) dose of R as R plus desacetyl R (DR) in urine excreted over the periods 0-8 and 8-12 h was also determined. Bioavailability was expressed as an index (BI) of area under time concentration curve (AUC) calculated from the plasma concentrations or proportion of dose of R excreted as R plus DR in urine with the combinations to that with R alone.. The bioavailability indices based on AUC were 0.96 with RE, 0.76 with RH, 1.08 with RZ and 0.65 with REHZ. The indices based on urine estimations (0-8 h) were similar, the values being 0.94, 0.84, 0.94 and 0.75, respectively. A second investigation revealed that the decrease of bioavailability of R with H was not due to the excipients present in H tablets.. Isoniazid alone or in combination with E and Z reduces the bioavailability of R. Urinary excretion data offer a simple and non invasive method for the assessment of bioavailability of R.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Area Under Curve; Body Weight; Ethambutol; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Staphylococcus aureus; Time Factors

The antibacterial effects of a new benzoxazinorifamycin, KRM-1648 (3'-hydroxy-5'-(4-isobutyl-1-piperazinyl, CAS 129791-92-0), against Mycobacterium ulcerans were evaluated in vivo in mouse foot pads, and the results were compared against those obtained with rifampicin (rifampin, CAS 13292-46-1). When mice were fed with the drugs from the day of footpad inoculations, KRM-1648, at concentrations of 0.001% and higher, mixed in mouse food, was effective in inhibiting the growth of M. ulcerans in the foot pads, and the effects were bactericidal. Effects of KRM-1648 at 0.0005% were bacteriostatic. Similar results were obtained with rifampicin, but only at concentrations of 0.008% and above. In established infection, i.e., when M. ulcerans were growing actively in footpads, bactericidal effects were observed with KRM-1648 at concentrations of 0.002% and above; to obtain similar results with rifampicin, the minimum dose was 0.032%. Thus, the results suggest the superiority of KRM-1648 over rifampicin in the treatment of M. ulcerans infection. The possibility of using KRM-1648 in combination with other antimycobacterial agents is discussed.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antitubercular; Body Weight; Eating; Foot; Mice; Microbial Sensitivity Tests; Mycobacterium ulcerans; Rifampin; Rifamycins

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

Five days intraperitoneal administration of rats with chlordiazepoxide (0.4 mg/kg), griseofulvin (7 mg/kg), rifampicin (8. 6 mg/kg), phenytoin (4.3 mg/kg) and phenobarbitone (1.4 mg/kg; an established inducer of microsomal enzymes) caused a significant increase in serum triacylglycerol (P<0.001) and the activities of aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethylase (P<0.001). Aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethylase activities were increased 1.48-, 1.15- and 1.47-fold, respectively, in chlordiazepoxide-treated rats, 1.65-, 1.20- and 1.38-fold in griseofulvin-treated rats, 1.74-, 1.36- and 1.44-fold in rifampicin-treated rats, 1.56-, 1.29- and 1.62-fold in phenytoin-treated rats and 2.26-, 1.72- and 1.93-fold in phenobarbitone-treated rats. Chlordiazepoxide, griseofulvin, rifampicin, phenytoin and phenobarbitone increased the activity of cytosolic phosphatidate phosphohydrolase by 52, 58, 67, 73 and 82%, respectively, while the drugs elicited 50, 60, 60, 73 and 87% increases in the activity of the microsomal phosphatidate phosphohydrolase. Similarly, chlordiazepoxide, griseofulvin, rifampicin, phenytoin and phenobarbitone elicited 2.4-, 2.39-, 2.34-, 1.69- and 3.75-fold increases in serum triacylglycerol concentrations. The correlations between serum triacylglycerol concentrations and the activities of aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethylase were significant in all treatment groups (r=0.83, r=0.92 and r=0.87, respectively, n=30, P<0.001). Our results suggest that induction of hepatic enzymes by the administered drugs may lead to hypertriglyceridaemia as an adverse effect, possibly by inducing the activity of regulatory enzymes in the biosynthesis of triglyceride.

Topics: Aminopyrine N-Demethylase; Aniline Hydroxylase; Animals; Body Weight; Chlordiazepoxide; Cytosol; Enzyme Activation; Enzyme Induction; Enzyme Inhibitors; Griseofulvin; Inactivation, Metabolic; Liver; Male; Microsomes, Liver; Organ Size; Oxidoreductases, O-Demethylating; Phenytoin; Phosphatidate Phosphatase; Rats; Rats, Wistar; Rifampin; Triglycerides

In this study we investigated whether leptin and TNFalpha levels change with improvement in body weight with antituberculotic therapy in active tuberculosis patients. 30 patients (8 females and 22 males) with active pulmonary tuberculosis formed the patient group, and 25 sex- and age-matched healthy subjects (8 females and 17 males) served as the control group. Body weight, body mass index (BMI) and serum leptin and plasma TNFalpha levels are measured before and in the sixth month of therapy in all patients. Before the initiation of therapy, BMI of the patients was significantly lower than BMI of the controls (20.2 +/- 1.6 vs. 25.2 +/- 2.7 kg/m(2), respectively; p < 0.05). After treatment, BMI of the patients increased significantly to 21.4 +/- 1.9 kg/m(2) (p < 0.05), but was still lower than that of the controls (p < 0.05). Pretreatment serum leptin (4.5 +/- 0.9 vs. 2.1 +/- 0.2 ng/ml, respectively; p < 0.05) and plasma TNFalpha (27.9 +/- 3.4 vs. 23.9 +/- 3.0 pg/ml, respectively; p < 0.05) levels of the patients were significantly higher than those of the controls. After treatment, serum leptin levels increased to 6.7 +/- 2.2 ng/ml, but this rise was not statistically significant (p > 0.05). Treatment did not result in any significant change in TNFalpha levels, either. Delta leptin was highly related to Delta BMI in patients with tuberculosis (r = 0.68, p = 0.02). In the pretreatment period, there was a significant correlation between leptin and TNFalpha levels in the whole patient group (r = 0.78, p < 0.001), and in female (r = 0.74, p < 0.001) and male patients separately (r = 0.74, p = 0.035). In conclusion, leptin and TNFalpha may be responsible for the weight loss in pulmonary tuberculosis patients, but their levels do not change with improvement in body weight with antituberculotic treatment.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Body Mass Index; Body Weight; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Leptin; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

Topics: Antitubercular Agents; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Ethambutol; Humans; Isoniazid; Optic Neuritis; Practice Guidelines as Topic; Pyrazinamide; Rifampin; South Africa; Streptomycin; Tuberculosis

P-glycoprotein (pgp), the protein product of the multidrug resistance (mdr) gene family, can confer a multidrug resistance (mdr) phenotype to cells in which it is expressed. One member of the pgp family, pgp2, is located on the hepatocyte biliary pole where it may have a role in biliary excretion. Using primates we sought to determine if mdr gene expression and pgp levels were affected by xenobiotics excreted via the bile in man. Five drugs were studied in male and female rhesus monkeys: erythromycin, rifampicin, tamoxifen, diethylstilbesterol (DES), and probenecid. For each xenobiotic, with the exception of DES, an increase in mdr2 mRNA was observed. The results suggest that expression of mdr2 is responsive to xenobiotics, or their metabolites, that require biliary excretion. We speculate that the mdr2 gene may be a member of a class of xenobiotic responsive genes coding for proteins that actively excrete xenobiotics and/or their metabolites into the bile.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Body Weight; Densitometry; Diethylstilbestrol; Drug Resistance, Multiple; Electrophoresis, Polyacrylamide Gel; Erythromycin; Female; Gene Expression Regulation; Liver; Macaca mulatta; Male; Organ Size; Probenecid; Rifampin; RNA, Messenger; Tamoxifen

Intravesical bacillus Calmette-Guérin (BCG) is widely used for the treatment of transitional cell carcinoma of the bladder. Although it is usually well tolerated, sepsis can occur, which has resulted in at least eight deaths [3]. The survival of Connaught BCG-infected mice treated with single and combination antibiotic and steroid therapy was evaluated. Triple-drug therapy with isoniazid, rifampin, and prednisolone resulted in 53% survival compared with 25% survival in the control group (P = 0.0209). A survival of only 10.5% was observed with treatment using prednisolone alone. This survival was worse than that of the control group (25%), and approached statistical significance (P = 0.0669). Our data suggest that BCG sepsis probably has components of both a hypersensitivity reaction and bacterial sepsis; they support the current use of combination antibiotic and steroid therapy for treatment of BCG sepsis in humans, but argue against treatment with steroids alone.

Topics: Animals; Body Weight; Cycloserine; Drug Combinations; Isoniazid; Mice; Mice, Inbred C3H; Mycobacterium bovis; Prednisone; Rifampin; Survival Analysis; Tuberculosis

Tuberculosis may be diagnosed too late, especially in HIV-infected patients, with consequences on bacillus transmission and survival. Empiric antibuberculosis treatment (EATT) may be started before diagnosis of tuberculosis is confirmed. As rifampicin is a broad spectrum antibiotic, EATT including rifampicin may be effective in infections other than tuberculosis, leading to misdiagnosis.. To define the efficiency criteria of EATT with or without rifampicin.. Between 1988 and 1991, 20 febrile patients with suspected tuberculosis (including 15 who were HIV-positive) were started on EATT in the absence of bacteriological or histological proof of tuberculosis. 10 patients (50%) received a 4-drug non-specific EATT including rifampicin, isoniazid, pyrazinamide and ethambutol, and 10 (50%), received a 3-drug specific EATT without rifampicin.. In 10 patients (50%), the diagnosis of tuberculosis was confirmed by positive cultures within a mean of 32 days (15-57 days) after the beginning of EATT (group TB 1). Of the 10 patients whose cultures remained negative, 4 (20%) became afebrile and showed improvement under EATT (group TB 2), and 6 (30%) remained febrile and did not improve (group No TB). Patients from groups TB 1 and TB 2 became afebrile within a mean of 11 days (1-54 days). This delay was not different between patients receiving specific or non-specific EATT. In patients receiving specific EATT, rifampicin was added to the initial 3-drug treatment after resolution of fever.. EATT appears to be a useful method for rapid presumptive diagnosis and treatment of tuberculosis.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Body Weight; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Fever; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

Rabbits, infected with M paratuberculosis of caprine origin, were treated with streptomycin sulphate and rifampicin in combination with levamisole hydrochloride for a period of 2 months. Marked clinical response including significant rise in total serum protein, albumin and globulin were recorded in treated groups. Highly significant higher leucocyte migration inhibition indicating enhanced CMI reaction, occurred in rabbits treated for 4 weeks. Complete elimination of M. paratuberculosis from faeces, intestines and mesenteric lymph nodes was observed. They were also absent from spleen, kidneys, lungs and liver of rabbits treated with rifampicin and levamisole, whereas were present in lungs of the rabbits administered with streptomycin and levamisole. Absence of characteristic lesions of paratuberculosis and evidence of regenerative reaction were observed in visceral organs of rabbits treated with rifampicin and levamisole. Effectiveness of rifampicin is attributed to its effect on lymphocyte, the primary cell involved in cell mediated immunity. Rifampicin-levamisole combination appeared superior to streptomycin-levamisole in eliminating the infection of M. paratuberculosis from infected rabbits. Approximate cost of treatment was calculated to be Rs 8.50 per kg body weight. Cattle, sheep and goats, if treated in early stage of infection may recover from paratuberculosis.

Topics: Animals; Body Weight; Drug Therapy, Combination; Female; Levamisole; Male; Paratuberculosis; Rabbits; Rifampin; Streptomycin

The in vivo efficacy of streptomycin (STR), doxycycline (DOX), rifampin (RIF), ciprofloxacin (CIP), and their combinations was evaluated for a Brucella melitensis experimental infection in a mouse model. Animals were infected with 2 x 10(4) to 4 x 10(4) CFU of B. melitensis intraperitoneally on day 0 and were randomized to receive, starting on day 7, STR alone at 75, 150, or 300 mg/kg of body weight per day intraperitoneally or DOX at 6 mg/kg/day orally, RIF at 3 mg/kg/day orally, or CIP at 200 mg/kg/day orally, each of the last three drugs alone or in combination with STR at 75, 150, or 300 mg/kg/day, for 14 days. Therapy failure (defined as nonsterile spleens) was observed in all animals treated with STR at all doses and with CIP given as monotherapy. Mean log CFU isolated from the spleens remaining infected following monotherapy with STR or CIP were not different from those in control mice. RIF at a low dose did not have an effect on cure rates; however, a reduction in CFU relative to the CFU in untreated animals was obtained. DOX at low levels achieved a 35% cure rate and a reduction in CFU in animals not cured. All animals treated with DOX or RIF combined with any STR dose were cured, but none of the animals receiving the STR-CIP combinations was cured, and the splenic CFU remained similar to those in the controls. These results demonstrate that the combinations DOX-STR and RIF-STR are synergistic against B. melitensis, while the combination STR-CIP is indifferent and ineffective in the management of acute murine brucellosis. The results also appear to support the clinical superiority of combination drug therapy over monotherapy.

Topics: Animals; Body Weight; Brucella; Brucellosis; Ciprofloxacin; Colony Count, Microbial; Doxycycline; Drug Synergism; Drug Therapy, Combination; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Organ Size; Rifampin; Spleen; Streptomycin

An analysis carried out on the dosage schemes adopted in several controlled clinical trials in tuberculosis has indicated that preestablishing the daily doses of isoniazid, rifampicin, and pyrazinamide in the initial intensive phase results in large deviations of the doses administered from those considered appropriate in mg/kg body weight. This is due partly to the variations in the patients' body weight and partly to the restrictions in terms of fine adjustments of dosage imposed by the unitary content of active principle in the available individual preparations of the drugs. The availability of a fixed-triple combination of the same 3 drugs where the content of each component is established multiplying the mg/kg requirement of each drug by 10, allows a complete coincidence between the appropriate and the administered dose simply administering 1 tablet every 10 kg of body weight. The implications of the large overdosing in light patients if the conventional approach is followed are discussed in terms of toxicity and drug purchasing cost, both being of great relevance for Third World countries where the majority of patients are of low body weight.

Topics: Antitubercular Agents; Body Weight; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Tablets; Time Factors; 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

A 12-day-experimental study of rifampicin (RMP) on male rats followed both the biochemical indices signalling disorder of metabolic equilibrium in the organism, and distribution of RMP in the tissues. The study showed the RMP concentration to be manifold higher in the liver than in the blood and other organs; in epididymal fat the concentration in one half of that in the blood. RMP adversely affects the energy metabolism, i.e. intake and resorption of nutrients, especially metabolically and calorically important lipids and sugars. RMP is harmful also for liver parenchyma.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Fatty Acids; Liver; Rats; Rats, Inbred Strains; Rifampin

The steatogenic effect on the liver of Rifampicin, a potent inhibitor of the DNA-dependent RNA polymerase in bacteria, was investigated in male and female rats which received either 200 mg or 400 mg of Rifampicin/kg/24 h for 8 days. The determination of total lipids (TL), triglycerides (TG), total cholesterol (TC) and phospholipids (PL) showed a significant increase of TL, TG and TC in the liver at a dose of 400 mg. There was better reproducibility in the male whose blood TG and PL were significantly decreased. These results showed that fatty liver can be induced by very high doses of Rifampicin in rats. A blockage of the very low density lipoproteins (VLDL) biosynthesis and/or secretion can be expected. As a potent steatogenic toxin, alpha-amanitin, is a strong inhibitor of RNA polymerase II in eukariotic cells, a relationship between the RNA polymerase inhibition induced by both of substances and a subsequent inhibition of the biosynthesis of the protein moiety of lipoproteins can be considered. Nevertheless Rifampicin is at present not considered as an inhibitor in eukariotic cells and it will be of great interest to test such a possibility with the high doses used in these experiments, in further work.

Topics: Animals; Body Weight; DNA-Directed RNA Polymerases; Eukaryotic Cells; Fatty Liver; Female; Lipid Metabolism; Liver; Male; Organ Size; Rats; Rifampin

Topics: Adolescent; Adult; Body Height; Body Weight; Child; Crohn Disease; Female; Flucytosine; Humans; Male; Middle Aged; Prednisone; Rifampin; Tetracycline

Following oral pretreatment with rifampicin over 3 and 9 days, the exocrine pancreatic function was studied in urethane-anaesthetized rats under exocrine stimulation. The volume and electrolyte content, and especially the protein and amylase outputs of the pancreatic secretion showed a virtually dose- and time-dependent decrease. Histologically, there was a corresponding decline of the zymogen granules in the acinar cells. The suggested explanation for the observed disorders of the pancreatic exocrine function is primarily an inhibition of protein synthesis due to rifampicin.

Topics: Animals; Body Weight; Male; Pancreas; Rats; Rifampin

Rifampin, a broad-spectrum antibiotic able to penetrate intracellularly, was used for treatment of infections with Brucella melitensis in mice and Brucella abortus in guinea pigs. Treatments were administered for seven, 14, or 21 days; mice were given 25 mg of rifampin/kg per day, and guinea pigs 100 mg/kg per day. Efficacy of the drug was determined by comparison of rifampin-treated animals with saline-treated controls and with tetracycline-treated mice (200 mg/kg per day) according to the following criteria: (1) primary infections of the spleen and (in guinea pigs) of the lymph nodes; (2) residual infections of the spleen, i.e., infections shown after complementary treatment with suspensions of killed Corynebacterium parvum or with cortisone; (3) splenomegaly; and (4) serological response (in guinea pigs). Treatment with rifampin, even for one or two weeks, drastically reduced the number of infections by all of these criteris, and treatment for three weeks cured nearly all mice; the incidences of primary and residual infections in rifampin-treated mice after three weeks were 0 and 8.5%, respectively, as compared with 70.3% and 73.5%, respectively, in tetracycline-treated mice. Of 25 guinea pigs treated with rifampin for three weeks, spleen infection was shown in one, and lymph node infections in 10.

Topics: Animals; Antibodies; Body Weight; Brucella abortus; Brucellosis; Female; Guinea Pigs; Mice; Organ Size; Rifampin; Spleen

Topics: Animals; Body Weight; Drug Evaluation, Preclinical; Guinea Pigs; Liver; Lung; Mice; Organ Size; Rifampin; Spleen; Time Factors; Tuberculosis

The total minimal inhibitory dose of rifampicin determined in the experimental mouse model, was found to be 10 mg/kg body weight, administered once a week for 6 weeks or once every 2 weeks for 12 weeks. From these and other results it is suggested that administration of RMP in human treatment can be reduced to a total amount of 7.2 either as a 600 mg dose once a week for 12 weeks or as a 900 mg dose once a week for 8 weeks. At present these regimens can only be used as an introductory treatment for multibacillary cases and are still too expensive for developing countries, but their efficacy should be evaluated in the field as sole treatments in tuberculoid cases, since they could signify a substantial economy for the management of the majority of leprosy infections.

Topics: Animals; Body Weight; Disease Models, Animal; Humans; Leprosy; Mice; Mice, Inbred Strains; Mycobacterium leprae; Rifampin; Time Factors

Topics: Animals; Asparaginase; Body Weight; Dose-Response Relationship, Drug; Female; Graft vs Host Reaction; Immunosuppressive Agents; Indomethacin; Lymph Nodes; Male; Medroxyprogesterone; Methotrexate; Methylprednisolone; Rats; Rats, Inbred Strains; Rifampin; Skin Transplantation; T-Lymphocytes; Transplantation, Homologous

Streptovaricins (Sv), ansa macrolide antibiotics, inhibited Rauscher leukemia virus (RLV) splenomegaly by 25-50%. All streptovaricins tested were effective when administered orally either by diet ad lib or by intubation from infection to time of killing. When delivered by intubation, Sv was measurable in plasma for up to 6 h. SvC, at 300 mg/kg/day, reduced mean spleen weight of infected mice from 478 plus or minus 51 (SE) mg to 300 plus or minus 55 (SE) mg. Rifampicin, at 250 mg/kg/day, had no similar activity. Decrease in caloric intake and in body-weight gain also resulted in an inhibition of RLV splenomegaly; although Sv-treated mice gained weight, the increase was usually slightly less than controls. However, mice treated with a Sv diet for a week prior to infection, after an initial period of weight loss, gained at a rate equivalent to control group, and when killed had a marked reduction in splenomegaly. The selectivity of streptovaricins and specificity for viral events was suggested by several observations: (1) Splenomegaly and mortality, induced by L1210 or a non-infective transplantable tumor of RLV origin, was not inhibited. (2) No inhibition of normal hematopoietic spleen colonies was observed. (3) Host immune responses, including cellular and humoral immunity and interferon production and action, were not inhibited. Thus, although the effect of slightly decreased weight and intake could not be unequivocally established, the findings were most compatible with a selective inhibition of RLV splenomegaly by Sv.

Topics: Animals; Antibodies, Neoplasm; Body Weight; Cell Line; Erythrocytes; Female; Graft vs Host Reaction; Hemagglutination Tests; Immunity, Cellular; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasm Transplantation; Rauscher Virus; Rifampin; Serum Albumin, Bovine; Sheep; Splenomegaly; Streptovaricin

Topics: Administration, Oral; Animals; Blood Cell Count; Blood Pressure; Body Weight; Cats; Depression, Chemical; Digestive System; Dose-Response Relationship, Drug; Female; Heart; Injections, Intraperitoneal; Kidney; Lipids; Liver; Liver Glycogen; Lung; Male; Mice; Neuromuscular Junction; Organ Size; Rats; Respiration; Rifampin; Sex Factors; Thyroid Gland; Transaminases; Urea

Topics: Administration, Oral; Animals; Body Weight; Cochlea; Dose-Response Relationship, Drug; Electrodes, Implanted; Eye Movements; Female; Guinea Pigs; Male; Rifampin; Sound; Time Factors; Vestibule, Labyrinth

Topics: Adult; Body Weight; Drug Therapy, Combination; Ethambutol; Exanthema; Female; Fever; Follow-Up Studies; Gastrointestinal Diseases; Hemorrhage; Humans; Male; Middle Aged; Pain; Pyrazinamide; Recurrence; Rifampin; Shock; Sputum; Time Factors; Tuberculosis, Pulmonary

Topics: Body Weight; Drug Therapy, Combination; Ethambutol; Female; Fever; Headache; Humans; Male; Nausea; Pain; Purpura, Thrombocytopenic; Rifampin; Time Factors; Tuberculosis, Pulmonary; Vomiting

Topics: Anti-Bacterial Agents; Body Weight; Chloramphenicol; Female; Humans; Male; Novobiocin; Rifampin; Sex Factors; Tetracycline; Time Factors

Topics: Animals; Body Weight; Coal; Dust; Guinea Pigs; Lung; Lung Diseases; Macrophages; Mycobacterium; Mycobacterium Infections; Organ Size; Pneumoconiosis; Pulmonary Fibrosis; Radiography; Rifampin; Silicon Dioxide; Tracheal Diseases

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

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Antitubercular Agents; Body Weight; Ethambutol; Ethionamide; Injections, Intramuscular; Kanamycin; Lung; Mice; Organ Size; Pyrazinamide; Rifampin; Spleen; Tuberculosis; Viomycin

Topics: Antitubercular Agents; Body Weight; Drug-Related Side Effects and Adverse Reactions; Ethambutol; Humans; Isoniazid; Rifampin; Time Factors; Tuberculosis

Topics: Acute Disease; Animals; Bacteriuria; Behavior, Animal; Body Weight; Cephaloridine; Depression, Chemical; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Female; Kidney; Organ Size; Pyelonephritis; Rats; Rifampin

Topics: Animals; Body Weight; Drug Combinations; Drug Resistance, Microbial; Evaluation Studies as Topic; Guinea Pigs; Humans; Lung; Mice; Microbial Sensitivity Tests; Mycobacterium; Mycobacterium bovis; Mycobacterium tuberculosis; Organ Size; Rifampin; Spleen; Sputum; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

Topics: Acute Disease; Administration, Oral; Animals; Atrophy; Body Weight; Chronic Disease; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Organ Size; Piperidines; Rats; Rifampin; Sex Factors; Testis

Topics: Administration, Oral; Animals; Body Weight; Brain; Male; Optic Nerve; Piperidines; Rats; Rifampin

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Female; Fetus; Maternal-Fetal Exchange; Pregnancy; Rabbits; Rats; Rifampin

Topics: Animals; Body Weight; Female; Guinea Pigs; Piperidines; Rifampin; Tuberculosis

Topics: Administration, Oral; Alkaline Phosphatase; Animals; Antitubercular Agents; Body Weight; Ethambutol; Female; Injections, Intraperitoneal; Kanamycin; Kidney; L-Lactate Dehydrogenase; Leucyl Aminopeptidase; Male; Rats; Rifampin; Streptomycin

Topics: Adult; Antitubercular Agents; Body Weight; Humans; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Animals; Body Weight; Drug Synergism; Ethambutol; Guinea Pigs; Isoniazid; Rifampin; Tuberculosis

Topics: Adolescent; Adult; Blood Sedimentation; Body Weight; Female; Humans; Male; Middle Aged; Radiography; Rifampin; Tuberculosis, Pulmonary

Topics: Animals; Animals, Newborn; Blood Pressure; Body Weight; Dogs; Female; Kidney; Male; Mice; Organ Size; Pregnancy; Rabbits; Rats; Reproduction; Respiration; Rifampin; Species Specificity