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PubMed1998

High performance liquid chromatographic determination of isoniazid, pyrazinamide and rifampicin in pharmaceutical preparations.

lsoniazid (IS) individually or in the presence of pyrazinamide and rifampicin has been determined by high performance liquid chromatography (HPLC) after derivatization with 6-methyl-2-pyridinecarboxaldehyde. Pyrazinamide and rifampicin separate completely from isoniazid derivative and are determined simultaneously. The chromatography is carried out from YMC-ODS column with elution with methanol: water: isopropanol: acetonitrile: sodium acetate (1 mM) 51:42:3:2:2: v/v/v/v/v/) with flow rate 1.7 ml/min and UV detection at 333 nm. The method is applied for the analysis of Isoniazid B.P Rambuzid and Myrene-p tablets.

Journal Article↗
PubMed2004

Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a cost-effectiveness analysis based on a multicenter clinical trial.

Two months of treatment with rifampin-pyrazinamide (RZ) and 9 months of treatment with isoniazid are both recommended for treatment of latent tuberculosis infection in adults without human immunodeficiency virus infection, but the relative cost-effectiveness of these 2 treatments is unknown. We used a Markov model to conduct a cost-effectiveness analysis to assess the impact on life expectancy and costs based on the results of a recent clinical trial that compared the rates of adverse events and completion of the 2 treatment regimens. Compared with no treatment, both regimens increased life expectancy by 1.2 years, but RZ cost 273 dollars more per patient. Sensitivity analyses showed that, assuming equal efficacy between the 2 regimens, there was no threshold completion rate for RZ at which the 2 treatments would be of equal net cost. Under most circumstances, treatment of latent tuberculosis infection with isoniazid is cost-saving than treatment with RZ.

Adolescent↗
PubMed2006

Potential tuberculostatic agent: micelle-forming pyrazinamide prodrug.

Pyrazinamide was condensed with the poly(ethylene glycol)-poly(aspartic acid) copolymer (PEG-PASP), a micelle-forming derivative was obtained that was characterized in terms of its critical micelle concentration (CMC) and micelle diameter. The CMC was found by observing the solubility of Sudan III in Poly(ethylene glycol)-poly(pyrazinamidomethyl aspartate) copolymer (PEG-PASP-PZA) solutions. The mean diameter of PEG-PASP-PZA micelles, obtained by analyzing the dynamic light-scattering data, was 78.2 nm. The PEG-PASP-PZA derivative, when assayed for anti-Mycobacterium activity, exhibited stronger activity than the simple drug.

Antitubercular Agents↗
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↗
PubMed2002

Investigation of the effects of concomitant caffeine administration on the metabolic disposition of pyrazinamide in rats.

The utility of pyrazinamide (PZA) in the short-course antituberculous treatment is well established. All available data support the idea that the PZA metabolite pyrazinoic acid (PA) is the active compound against M. tuberculosis. This situation warranted a deeper investigation of possible interactions with respect to its metabolic disposition. Caffeine, which is widely used as a drug and is a common constituent of most diets, shares with PZA the same metabolic enzyme, xanthine oxidase (XO). This study investigated if, and in what manner, concomitant administration of caffeine affects PZA metabolism. PZA and caffeine, in various doses (PZA=50 or 100 mg kg(-1) and caffeine= 0, 50, 100, and 150 mg kg(-1)), were administered to female Sprague-Dawley rats. PZA and its three main metabolites were quantified in 24 h urine samples by reversed phase-HPLC Concomitant administration of 100 mg kg(-1) caffeine and 50 mg kg(-1) PZA increased from the excretion (p<0.05) of the most water-soluble and the least toxic PZA metabolite 5-hydroxypyrazinoic acid (5-OH-PA) from 66.18+/-10.87 to 94.56+/-8.65 micromol/24 h. This effect was more pronounced when 100 mg kg(-1) of PZA was administered increasing excretion of 5-OH-PA from 113.28+/-70 to 173.23+/-17.82 micromol/24 h. These results show that the metabolic disposition of PZA is affected by concomitant caffeine intake.

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↗
PubMedDate not supplied

Rapid radiometric method for pyrazinamide susceptibility testing of Mycobacterium tuberculosis.

Pyrazinamide (PZA) is one of the most important drugs in modern chemotherapy of tuberculosis. Since PZA is active only at an acid pH, testing the susceptibility of Mycobacterium tuberculosis to PZA is difficult and timeconsuming. Therefore, we evaluated the BACTEC system for rapid testing of PZA susceptibility at pH 6. A total of 91 M. tuberculosis strains and 2 different strains of M. bovis BCG were screened for susceptibility to PZA. Each strain was tested in special 7H12 broth supplemented with polyoxyethylene stearate containing 25, 50 and 100 micrograms PZA/ml. Strains resistant to 100 micrograms/ml were retested against 25-100 micrograms/ml and at an extended range of PZA concentrations from 200-6,400 micrograms/ml. The MIC was determined with all strains within 4-20 (mean 7) days. Of the 77 susceptible strains, based on the pyrazinamidase test, MIC were less than or equal to 25 micrograms/ml for 34 strains, 50 for 38 and 100 for 2 strains. Three pyrazinamidase-positive strains had still higher MIC, 1 at 800 and 2 at 3,200 micrograms/ml. PZA-resistant strains had MIC of 800 or greater. Monoresistance to PZA has not been detected to date. The clear bimodal distribution of MIC in this method could enable the routine clinical microbiology laboratory to perform PZA susceptibility testing as easily as the 4 drugs now tested in the BACTEC system.

Evaluation Studies as Topic↗
PubMed1994

4-, 5- and 6-month regimens containing isoniazid, rifampicin, pyrazinamide and streptomycin for treatment of pulmonary tuberculosis under program conditions in Hong Kong.

SETTING: Ten full time urban government chest clinics in Hong Kong. OBJECTIVE: To assess the effectiveness of 4-, 5- and 6-month fully supervised thrice-weekly regimens containing 4 months of isoniazid, rifampicin, pyrazinamide and streptomycin followed by nil, 1 or 2 months of isoniazid and rifampicin for the treatment of smear-negative culture-negative, smear-negative culture-positive and smear-positive pulmonary tuberculosis. DESIGN: Retrospective study of the 3 antituberculosis treatment regimens given under program conditions during a 6-month period in 1983. RESULTS: Of the 1616 patients assessed, 953 (59%) completed their treatment strictly as planned, 443 (27%) had their treatment prolonged, 107 (7%) had their treatment modified and 113 (7%) defaulted or did not complete their treatment as planned. There were 2 treatment failures at the end of chemotherapy. At 60 months of follow-up, 67 patients died, 2 from the sequelae of tuberculosis. Of 1287 patients assessable up to 60 months, a total of 47 (3.7%) patients relapsed and were eventually treated successfully. 11 (20%) relapses occurred among the 55 patients who had defaulted and did not complete treatment as planned. CONCLUSION: The effectiveness of the 3 treatment regimens depended very much on the patient's adherence to treatment. The necessity of prolongation of treatment is not known and requires further assessment.

Adolescent↗
PubMed2006

Synthesis of pyrazinamide Mannich bases and its antitubercular properties.

A series of pyrazinamide (PAZ) Mannich bases has been synthesized by reacting PAZ, formaldehyde, and various substituted piperazines using microwave irradiation with the yield ranging from 46% to 86%. The synthesized compounds were evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-4-((pyrazine-2-carboxamido)methyl)piperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (17) was found to be the most active compound in vitro with MIC of 0.39 and 0.2 microg/mL against MTB and multidrug-resistant MTB, respectively. In the in vivo animal model 17 decreased the bacterial load in lung and spleen tissues with 1.86 and 1.66-log10 protections, respectively.

Animals↗
PubMed2004

Genetic and phenotypic characterization of pyrazinamide-resistant mycobacterium tuberculosis complex isolates in Japan.

The pncA gene mutations associated with pyrazinamide (PZA) resistance in Mycobacterium tuberculosis complex were determined in 26 PZA-resistant isolates in Japan. Of the 26 PZA-resistant isolates included, 21 were negative for pyrazinamidase (PZase). Of these, 20 isolates had various pncA mutations, resulting in alteration of primary amino acid sequence. However, 1 PZase-negative isolate did not have any mutation on pncA gene. The remaining 5 PZA-resistant isolates were positive for PZase and had identical pncA alleles with PZA-susceptible isolates. IS6110 RFLP analysis demonstrated various distinct IS6110 types and 5 pairs of isolates were very close to each other (>90% identical pattern). This study demonstrates that most of the PZA resistance is a result of various mutations on pncA resulting in loss of PZase activity. Further investigation, particularly on PZase-positive but PZA-resistant isolates and a PZase-negative isolate with no mutation on pncA, should be urgently done.

Amidohydrolases↗