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PubMed1989

Hypouricemia due to familial isolated renal tubular uricosuria. Evaluation with the combined pyrazinamide-probenecid test.

A Jewish Iraqi woman with familial isolated renal tubular uricosuria, urate clearance of 60.5 +/- 5.7 ml/min and hypouricemia of 1.0 +/- 0.2 mg/dl is described. The combined pyrazinamide-probenecid test suggested a presecretory defect in urate reabsorption. Four offspring were moderately affected. This family represents the sixth Jewish Iraqi family with familial isolated presecretory uricosuria, and emphasizes the marked prevalence of this disease among the Iraqi Jewish population. Since the inheritance of the presecretory defect is autosomal recessive, we suggest that this family is an example of pseudodominant transmission. The combined pyrazinamide-probenecid test may cause a reduction in glomerular filtration rate and filtered load of urate and thereby affect urinary excretion rate of urate in patients with urate wasting.

Creatinine↗
PubMed1988

Pyrazinamide and rifampicin regimens for patients on maintenance dialysis.

We measured pyrazinamide and rifampicin plasma concentrations in five patients with pulmonary tuberculosis and end stage renal failure treated by haemodialysis or continuous ambulatory peritoneal dialysis. Using conventional daily doses of oral pyrazinamide and rifampicin, we found that the drugs were removed efficiently by both dialysis methods, so that plasma levels were sub-optimal for maximal bactericidal action. These findings suggest that in patients with tuberculosis on maintenance dialysis, treatment should be either with higher doses of these two drugs, or with additional replacement doses given after each dialysis. Further detailed pharmacokinetic studies on larger numbers of patients are indicated.

Adolescent↗
PubMed1987

Clinical pharmacokinetics and metabolism of pyrazinamide in healthy volunteers.

Eight healthy volunteers were treated with a single dose of pyrazinamide 35 mg/kg. The aim of the study was to evaluate the pharmacokinetic profile of the product and of its metabolites. Urine and blood samples were collected till the 60th h. The kinetics of pyrazinamide could be characterized as follows: CPmax = 50.1 micrograms/ml, tmax less than 1 h, t1/2 alpha = 3.2 h, t1/2 beta = 23 h, U(0-60 h) = 1.6% of the dose administered. The kinetics of the main metabolite, the pyrazinoic acid, gave the following values: CPmax = 66.6 micrograms/ml, tmax = 4 h, t1/2 beta = 12.3 h, U(0-60 h) = 37.5%, of the administered dose.

Adult↗
PubMed1968

Toxicity of pyrazinamide, administered once weekly in high dosage, in tuberculous patients.

The success of a twice-weekly regimen of streptomycin plus isoniazid, reported earlier from the Tuberculosis Chemotherapy Centre, Madras, prompted an investigation at the Centre of various once-weekly regimens of chemotherapy. In this context, a pilot study was undertaken in 19 patients to assess the toxicity of high-dosage pyrazinamide (70 mg/kg of body-weight), when administered once weekly, together with isoniazid (14 mg/kg of body-weight) and streptomycin (1 g), for at least 6 months. Serial estimations of SGOT and SGPT activity, urine tests for urobilin and bilirubin and haematological investigations were undertaken at frequent intervals. None of the patients showed any clinical evidence of hepatotoxicity; however, there was a slight and transient elevation in aminotransferase activity, probably of a non-specific nature, at 2 weeks. These findings are encouraging for the use of high-dosage pyrazinamide in once-weekly regimens of chemotherapy.

Adult↗
PubMed1980

[Toxicity of pyrazinamide in antituberculous treatments (author's transl)].

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

Chemical and Drug Induced Liver Injury↗
PubMedDate not supplied

Hepatotoxicity after a short course of low-dose pyrazinamide.

We report on a patient who developed extensive centrolobular liver necrosis after a treatment with low-dose (25 mg/kg/d) pyrazinamide for only 4 weeks, combined with rifampicin, 600 mg/d). In the past, the patient already developed severe aminotransferase elevations under isoniazid treatment. After prompt withdrawal of the drugs, a gradual decline of the aminotransferases was observed. No signs of hepatic failure developed. Pyrazinamide has to be used with caution, even in low-dose, especially when combined with rifampicin.

Adult↗
PubMedDate not supplied

[Hepatic functional changes induced by the combined use of isoniazid, pyrazinamide and rifampicin in the treatment of pulmonary tuberculosis].

Antituberculosis therapy commonly used for pulmonary tuberculosis in Brazil include isoniazid (440 mg), rifampicin (600 mg) both for six months plus pyrazinamide (2 g) together in the first two months. Such therapy may induce acute or chronic liver damage in some individuals. The purpose of this study is to evaluate 1096 patients treated with antituberculous drugs, being 773 males and 323 females. Clinical and laboratory signs of hepatic cell injury was present in 66 patients. Serum bilirubin and transaminase levels were evaluated in 21 (31.81%) and 45 (68.19%) respectively, with a female preponderance. Early return to normal values occurred more frequently among alcoholic drinkers and non-cigarette smokers. Liver injury was characterized as being mild and moderate and the type of injury associated was represented by pure cholestasis and hepatocanalicular lesions. Probably, rifampicin is the drug responsible for this kind of evolution aggravating the hepatotoxicity induces by isoniazid and pyrazinamide.

Adult↗
PubMed1998

Bioavailability of rifampicin, isoniazid and pyrazinamide from fixed-dose combination capsules.

SETTING: The absorption of rifampicin, isoniazid and pyrazinamide was tested after administration of each drug in free combinations and in a fixed-dose combination of the three drugs, known as Trifazid. OBJECTIVE: To examine the relative bioavailability of rifampicin, isoniazid and pyrazinamide after oral administration of the drugs given alone in comparison to that of the same drugs after administration of Trifazid. DESIGN: An open, randomized, cross-over study comprising 16 healthy volunteers. RESULTS: The pattern of absorption, plasma concentrations and pharmacokinetic parameters were very similar after administration of the drugs in free and fixed combinations. CONCLUSION: The triple combination of antituberculosis drugs could replace the separate drugs in the treatment of tuberculosis.

Administration, Oral↗
PubMedDate not supplied

Metabolic disposition of pyrazinamide in the rat: identification of a novel in vivo metabolite common to both rat and human.

Only limited studies have been reported on the disposition and pharmacokinetics of pyrazinamide (PZA) in both animals and humans. The metabolism of PZA has never been completely elucidated, consequently the metabolites of PZA, pyrazinoic acid (PA), 5-hydroxypyrazinoic acid (5-HOPA), and 5-hydroxypyrazinamide (5-HOPZA) were characterized and the disposition of PZA was examined following administration of 150 mg kg-1 of 14C-PZA to male Wistar rats. Comparable t1/2 for total radiolabel 14C (1.45 +/- 0.06 h) and PZA (1.39 +/- 0.04 h) in the blood compartment were observed. Cumulative 48 h excretion in urine and faeces accounted for 82.6 +/- 3.2 per cent and 11.0 +/- 1.3 per cent, respectively, of the dose administered. In the 0-6 h urine collections PA, 5-HOPA, 5-HOPZA, and PZA, respectively, accounted for 25.4 +/- 1.7, 17.7 +/- 1.2, 11.6 +/- 0.8, and 2.7 +/- 0.2 per cent of the administered dose. In the 6-12 h urine samples the proportions of PA and 5-HOPA increased statistically over the 0-6 h excretion whereas 5-HOPZA decreased. Administration of PZA to humans indicated 5-HOPZA was a major urinary metabolite in human. These data suggested that direct hydroxylation of PZA was an alternative pathway in the oxidation of PZA of importance to both human and rat.

Animals↗
PubMed1987

Fulminant hepatitis during treatment with rifampicin, pyrazinamid and ethambutol.

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

Cervical Vertebrae↗
PubMedDate not supplied

Pharmacokinetics of pyrazinamide in plasma and CSF of rabbits following intravenous and oral administration.

The pharmacokinetics of pyrazinamide (PZA) in cerebrospinal fluid (CSF) and plasma of 10 rabbits were studied after separate intravenous (i.v.) and oral (p.o.) administration, in a cross-over study. Concentrations of PZA in biological fluids were determined by high performance liquid chromatography (HPLC). After p.o. dose PZA was absorbed rapidly and peak plasma concentration was attained at 0.5 h post administration. After i.v. dose, the plasma PZA concentrations declined rapidly within 10 min and subsequently more slowly following a bi-exponential manner. No difference was observed in the area under plasma concentration-time curves indicating oral absorption was complete and no apparent first-pass metabolism occurred. The (mean +/- S.D.) elimination t1/2 after i.v. (1.04 +/- 0.18 h) was significantly shorter (P less than 0.0005) than that after oral (1.95 +/- 0.63 h) dose and the apparent volume of distribution was also significantly smaller (P less than 0.005) after i.v. (3.211 +/- 0.412 l) than after oral (5.936 +/- 1.607 l) administration. The elimination t1/2 of PZA in CSF was nearly identical to that in plasma after either i.v. (1.07 +/- 0.20 h) or p.o. (1.84 +/- 0.56 h) administration. There is no apparent barrier in rabbits for the penetration of PZA into CSF from the general circulation.

Administration, Oral↗
PubMed1977

The effect of the interaction of pyrazinamide and probenecid on urinary uric acid excretion in man.

Complex interactions occur between pyrazinamide (PZA) and probenecid in man involving both the metabolism and distribution of the drugs, and their effects on renal tubules. Pretreatment with PZA prolonged the half-life (T 1/2) of probenecid without changing its plasma-binding. As the rate of probenecid metabolism is decreased, its uricosuric action tends to be prolonged and the effect of PZA lessened. The PZA-suppressible urate level is increased to values well above control after the administration of probenecid; it is less after alkalinization of urine, although still larger than the value for PZA-suppressible urate after the administration of PZA alone. Urinary probenecid excretion is much greater when urine is alkalinized. These observed drug interactions, plus the known effect of probenecid to block secretion of PZA, have to be considered in evaluating the effect of the two drugs given together, compared to the effect of each drug given separately.

Adult↗
PubMed1975

Controlled trial of 6- and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong.

A comparison has been made between 6- and 9-month regimens of streptomycin, isoniazid and pyrazinamide given daily, 3 times a week or twice a week from the start of chemotherapy, in the treatment of newly-diagnosed, smear-positive, pulmonary tuberculosis in Chinese patients. At 6 months the twice-weekly regimen was marginally inferior in that 5 (4 per cent) of 126 patients with drug-sensitive strains pretreatment had an unfavourable bacteriological status compared with only 2 (1 per cent) of 141 on the 3 times weekly and none of 137 of the daily regimen. Of a total of 211 patients treated for 9 months, only 1 of 74 on the twice-weekly regimen relapsed bacteriologically between 6 and 9 months. The bacteriological relapse rates in the first 6 months of follow-up after 6 months' chemotherapy were 13 per cent on the daily, 16 per cent on the 3 times weekly, and 18 per cent on the twice-weekly regimen, and after 9 months' chemotherapy they were 3 per cent, 4 per cent and 4 per cent respectively. All 33 relapses were with strains sensitive to isoniazid and streptomycin, and 76 per cent of them occurred in the first 3 months after the end of chemotherapy. Although patients with drug-resistant strains pretreatment fared less well, about two-thirds had a favourable bacteriological status at 6 months, and all 3 regimens given for 9 months had low relapse rates. The implications of these findings are discussed.

Adolescent↗
PubMed1979

Double blind controlled comparison of aspirin, allopurinol and placebo in the management of arthralgia during pyrazinamide administration.

Chinese patients with arthralgia during treatment with an antituberculosis regimen containing pyrazinamide were allocated at random to 3 anti-arthralgia treatment series in a controlled double-blind study. One series (18 patients) received soluble aspirin 2.4 g daily, the second (23 patients) allopurinol 200 mg daily, and the third (19 patients) placebo only, for 8 weeks. The response was assessed both by independent assessors and by the patients themselves using a diary card. The serum uric acid concentration was measured before and during anti-arthralgia treatment. The joints most commonly affected were the shoulders, the knees and the fingers, and symptoms and signs were in general neither severe nor protracted. For most of the patients in all 3 series the joint symptoms and signs improved during the 8 weeks, but a higher proportion of patients in the aspirin and placebo series than in the allopurinol series experienced improvement, this being most rapid in the aspirin series. Only in the aspirin series was the mean serum uric acid concentration lower during treatment than before it, and this effect was related to the dose in mg per kg. It is concluded that the arthralgia was often self-limiting, that aspirin had a small beneficial effect, that allopurinol, in the dosage studied, may have had a slightly deleterious effect, but that it would be worth studying larger dosages of allopurinol because the dosage studied did not affect the serum uric acid concentration.

Adolescent↗
PubMed1991

Efficacy of intermittent pyrazinamide in experimental murine tuberculosis.

CFLP mice were infected intravenously with Mycobacterium tuberculosis strain H37Rv and the progress of chemotherapy was followed by counts of viable bacilli in the lung and spleen. After spleen counts had reached log10 7.0, 12 experimental groups, each containing 10 mice, were treated for 8 weeks with pyrazinamide (PZA) given in mean daily dosages of 100, 200 or 400 mg/kg/day, with the interval between the doses within each dosage group being 1, 2, 4 or 8 days. All mice were also given 25 mg isoniazid/kg daily. An increase in the mean daily dosage from 100 mg PZA/kg to 400 mg PZA/kg resulted in a decrease of spleen viable counts at the end of treatment from log10 4.2 to log10 3.8. The organ counts, averaged over the full dosage range, were little altered by spacing out the interval between doses from 1-4 days, while increasing dose size proportionately: the counts with low mean dosages tended, however, to decrease (indicating improved efficacy) while those with high mean dosages increased (P less than 0.001). Counts increased when the interval was 8 days. Spacing out the doses while keeping the dose size constant resulted in progressive loss of efficacy. These findings suggest that, if PZA is given intermittently, the size of the dose should be increased, though not quite proportionately, to maintain full efficacy. Even with such an increase in dose, however, once weekly treatment would be less effective.

Animals↗
PubMed1994

Comprehensive assay for pyrazinamide, rifampicin and isoniazid with its hydrazine metabolites in human plasma by column liquid chromatography.

A comprehensive assay for determination of pyrazinamide (PZA), rifampicin (RIF), isoniazid (INH) and hydrazine metabolites is described. The method involves organic solvent extraction of PZA and RIF, followed by derivatization of INH, monoacetylhydrazine (mHYD) and hydrazine (HYD) with salicylaldehyde and extraction with diethyl ether. Acetylisoniazid (acINH) and diacetylhydrazine (dHYD) were hydrolyzed to INH and mHYD, respectively, and processed as above. Using a gradient solvent programmer, PZA and RIF were analyzed on a C8 (5 microns) column at 248 nm, while INH and metabolites were analyzed on a C18 (5 microns) ODS2 column at 280 nm.

Chromatography, High Pressure Liquid↗