SEARCH · Search PubMed

Results for “PYRAZINAMIDE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed2002

Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis.

BACKGROUND: The current Canadian and US guidelines for the treatment of multidrug-resistant latent tuberculosis infection advocate the use of pyrazinamide and a fluoroquinolone as a first-line treatment option. However, there is very little information in the literature that describes the use of these agents together. This case series describes the probable association between multiple adverse events and the use of pyrazinamide and levofloxacin in the treatment of individuals with suspected latent multidrug-resistant tuberculosis infection. METHODS: We studied a case series of 17 individuals with suspected latent multidrug-resistant tuberculosis infection in Hamilton, Ont., who were being treated with pyrazinamide and levofloxacin. The Naranjo scale was used to assess patients for musculoskeletal, central nervous system, gastrointestinal and dermatological adverse events. Hepatocellular events were assessed and defined using criteria established by the Council for International Organizations of Medical Sciences. Laboratory abnormalities and adverse events that were documented during combination drug therapy were evaluated to determine the likelihood of an association. RESULTS: Fourteen individuals developed musculoskeletal adverse effects (11 were deemed to be probably related to combination therapy). There were 8 reports of central nervous system effects (5 of which were assessed as being probably associated with therapy). Hyperuricemia and gastrointestinal and dermatological effects were also common; the use of pyrazinamide and levofloxacin was believed to be probably responsible for the emergence of these adverse effects. There were 5 cases of hepatocellular injury. Therapy was discontinued in all individuals. INTERPRETATION: The combination of pyrazinamide and levofloxacin appears to be a poorly tolerated regimen. The mechanism of a possible interaction is not yet understood. Given the severity of some of the adverse events, a better understanding of dosing and clearer guidelines for monitoring therapy are imperative if these drugs are to be prescribed together.

Adolescent↗

PubMed1978

Bioassay of pyrazinamide for possible carcinogenicity.

A bioassay of the tuberculostatic drug pyrazinamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered pyrazinamide at one of two doses, either 5,000 or 10,000 ppm, for 78 weeks, and then observed for an additional 26 or 27 weeks. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. High-dose male mice died or were killed by week 92; all other surviving animals were killed at weeks 104 or 105. Mean body weights of the dosed male rats were slightly lower than those of the matched controls, while mean body weights of the dosed females were more nearly comparable to those of the controls. A sufficient number of rats in each group was at risk to termination of the study at weeks 104-105 for the development of late-appearing tumors. In mice, administration of pyrazinamide had no consistent effect on mean body weights. Survival to termination of the study was low, particularly among the control groups. In rats, no lesions could clearly be related to administration of the chemical. In mice, interstitial and suppurative myocarditis in the dosed animals and suppurative bronchopneumonias in both dosed and matched control mice of each sex were associated with increased deaths. In the females, there was a significant positive dose-related trend (P=0.037) in the incidence of lymphoma (matched controls 0/13, low-dose 2/25, high-dose 6/29); however, the incidences in each of the dosed groups were not significant when compared with that in the matched controls. In addition, the poor survival and the small size of the control group precluded making a clear association of the incidence of these tumors with administration of the chemical. It is concluded that under the conditions of this bioassay, the early deaths and small size of the control group precluded a conclusion regarding the carcinogenicity of pyrazinamide in female B6C3F1 mice. Pyrazinamide was not carcinogenic for Fischer 344 rats or for male mice.

Journal Article↗

PubMed2004

Pyrazinamide induced hyperuricemia in patients taking anti-tuberculous therapy.

OBJECTIVE: To record the effect of pyrazinamide on uric acid in patients of tuberculosis. DESIGN: Descriptive and observational study. PLACE AND DURATION OF STUDY: Chandka Medical College Hospital, Larkana from February 2000 to January 2003. PATIENTS AND METHODS: All patients receiving anti-tuberculosis drugs with pyrazinamide were included. Serum uric acid levels were monitored at weeks 0, 2, 8 and 12 of therapy. Serum creatinine was done at weeks 0, 8 and 12. RESULTS: Results were reported on 216 patients. Mean uric acid and creatinine levels at the start of therapy, i.e., week '0' were 5.07 -/+ 0.57 mg/dl and 0.87 -/+ 0.11 mg/dl respectively. The results show significant increase in uric acid levels from week '0' to week '2', at the end of week '8', the levels remained elevated and there was no statistical significant difference from that at week '2'. The uric acid levels reduced at week '12' after pyrazinamide was stopped and the difference was significant. Despite that renal function steadily improved with the treatment of tuberculosis to the extent that comparable pre-treatment values were obtained at the end of treatment. CONCLUSION: Anti-tuberculous therapy with pyrazinamide affects the uric acid levels early. This change is reversible after the withdrawal of the agent.

Adult↗

PubMed1981

Serum uric acid concentrations and arthralgia among patients treated with pyrazinamide-containing regimens in Hong Kong and Singapore.

The serum uric acid concentrations of patients being treated in Hong Kong and Singapore with a daily regimen consisting of streptomycin, isoniazid, rifampicin and pyrazinamide or a control regimen of daily streptomycin, p-amino-salicylic acid (PAS) and isoniazid were determined by the phosphotungstate method. Arthralgia and elevated serum uric acid levels were encountered only during the period that patients were being treated with pyrazinamide. Although daily treatment with pyrazinamide increased serum uric acid concentrations approximately 2.5-fold, the concentrations of the 6 patients who developed arthralgia were closely similar to those of matched controls without arthralgia. This fails to confirm a previous suggestion that patients with arthralgia might have higher values. Rifampicin appeared not to influence the hyperuricaemic effect of pyrazinamide.

Humans↗

PubMed1993

Effect of pyrazinamide on rifampicin kinetics in patients with tuberculosis.

Rifampicin and pyrazinamide constitute an important part of drug regimens advocated for tuberculosis therapy, along with INH and streptomycin/ethambutol. The International Union against Tuberculosis and Lung Disease has also suggested the inclusion of these two drugs as part of short course chemotherapy for tuberculosis. Hence this study was undertaken to evaluate the influence of pyrazinamide on rifampicin kinetics when the two are given together. In a randomized, cross-over, single dose study, 16 patients with untreated pulmonary tuberculosis, after an overnight fast, were administered either rifampicin 450 mg + INH 300 mg (study A) or rifampicin 450 mg + INH 300 mg+pyrazinamide 1500 mg (study B). Blood samples were collected for serum rifampicin estimation at 0, 0.5, 2, 4, 6 and 8 h. Various pharmacokinetic parameters (Cmax, Tmax, t1/2, Kel, area under plasma concentration time curve (AUC), Vd & Cpl of rifampicin) were calculated. It was observed that rifampicin concentration in study A in contrast to study B was significantly higher at 6 h (P < 0.01) and 8 h (P < 0.05), while there were no significant differences in serum rifampicin concentration at 0.5, 2 and 4 h. A significant difference was also observed in AUC and Cpl. In study A, AUC was higher (P < 0.05), while Cpl was lower (P < 0.02), than in study B. From the above data it appears that on concomitant administration of pyrazinamide in patients on rifampicin therapy, AUC of rifampicin is decreased while its clearance is increased.

Adult↗

PubMed2004

Comparative bioavailability of rifampicin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels.

Fixed dose combination (FDC) formulations became popular in the treatment of tuberculosis (TB) because of the better patient compliance, reduced risk of monotherapy and emergence of drug resistance in contrast to treatment with separate formulations of two to four first-line drugs. However, its successful implementation in national programs is limited by probable bioinequivalency of rifampicin if present in FDC form. In this regard, World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. Hence, bioequivalence study of four drug FDC tablet was conducted using 22 healthy male volunteers according to WHO recommended protocol to determine bioavailability of rifampicin, isoniazid and pyrazinamide compared to standard separate combination at the same dose level. The study was designed as two period, two treatment crossover experiment with a washout period of 1 week. Bioequivalence of rifampicin was estimated by plasma and urinary method for both rifampicin and its active metabolite, des-acetyl rifampicin whereas isoniazid and pyrazinamide were estimated from plasma. Mean concentration time profiles and all the pharmacokinetic parameters of rifampicin, isoniazid and pyrazinamide from FDC tablet were comparable to individual formulations and passed the bioequivalence test with power of the test above 95%. Further, bioequivalence of both rifampicin and isoniazid shows that in vitro interaction of rifampicin and isoniazid is clinically insignificant. Thus, it was concluded that FDC formulation is bioequivalent for rifampicin, isoniazid and pyrazinamide and ensures the successful treatment of TB without compromising therapeutic efficacy of any of these components of anti-TB therapy.

Administration, Oral↗

PubMed2005

Mechanistic explanation to the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and isoniazid in anti-TB FDCs.

Rifampicin and isoniazid are known to interact with each other in solid formulation environment to yield isonicotinyl hydrazone (HYD). In earlier studies, this reaction was indicated to be catalyzed by pyrazinamide and ethambutol hydrochloride, the two other co-drugs present in oral anti-tuberculosis fixed-dose combination (FDC) formulations. Accordingly, the present study was carried out to understand the catalytic role of pyrazinamide and ethambutol hydrochloride on the reaction between rifampicin and isoniazid. For the purpose, organic bases and amides similar in structure to pyrazinamide and ethambutol hydrochloride were combined individually with rifampicin and isoniazid. The compounds employed were pyrazine, piperdine, pyrollidine, pyridine, triethylamine, diisopropylethylamine, picolinamide, benzamide, ethylenediamine, ethanolamine, diethanolamine, and triethanolamine. An additional study was also carried out in the presence of free base of ethambutol. The mixtures were exposed to accelerated stability test condition of 40 degrees C/75% RH for 15 d. The nature of the products formed and the changes in relative concentrations of the drugs and products were followed by HPLC. The drugs showed different extent of degradation, yielding HYD, and in some cases degradation products of rifampicin. The results confirmed the catalytic role of pyrazinamide and ethambutol hydrochloride. The catalysis is postulated to involve intra-molecular proton transfer during transhydrazone formation process, entailing a tetrahedral mechanism.

Amides↗

PubMed1998

Pyridine nucleotide levels in liver of rats fed clofibrate- or pyrazinamide-containing diets.

Hepatic NAD+, NADH, and NADPH were increased significantly 3 days after feeding rats with a 0.25% clofibrate diet, increased further after 8 days, and stayed at the same levels 14 days after feeding the diet. The NAD+/NADH ratio was decreased significantly by feeding the clofibrate diet for 8 days, while the ratio remained unchanged with a 1% pyrazinamide diet. Hepatic quinolinate phosphoribosyltransferase (QAPRTase) (EC 2.4.2.19) activity was increased to 1.8 and 1.3 times that of the control animals in the clofibrate- and the pyrazinamide-fed rats, respectively, while hepatic aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) (EC 4.1.1.45) activity was decreased to 0 and 19% of that of the control animals. The heat-treated liver homogenate from the pyrazinamide-fed rats contained inhibitory activity toward ACMSDase, while no inhibitory activity was found in the liver homogenate of the clofibrate-fed animals. We conclude that these changes of enzyme activities, which seem due to different mechanisms, may contribute to the increase of pyridine nucleotides in the liver of rats fed clofibrate or pyrazinamide.

Animals↗

PubMed1994

Enhancement of cyclophosphamide cytotoxicity in vivo by the benzamide analogue pyrazinamide.

The ability of pyrazinamide to enhance the in vivo cytotoxicity of cyclophosphamide in Lewis lung and RIF-1 tumours was investigated. Using an in vivo/in vitro excision assay a large single dose of pyrazinamide (500 mg kg-1 i.p.) was shown to enhance the tumour cell killing by cyclophosphamide. This enhancement was greatest when pyrazinamide was administered before the alkylating agent and had a dose-modifying effect on all cyclophosphamide doses tested, giving rise to a mean (+/- 1 s.e.) enhancement ratio (ER) of 1.54 (+/- 0.15) for the Lewis lung and 1.24 (+/- 0.08) for the RIF-1 tumour. Pyrazinamide also increased the cytotoxic action of cyclophosphamide in a normal tissue, namely white blood cell counts. However, the ER was only 1.14 (+/- 0.08), which although not significantly different from the value seen in RIF-1 was significantly less than the ER obtained with Lewis lung, suggesting the possibility of a therapeutic gain. This benzamide analogue did not appear to inhibit recovery from cyclophosphamide-induced potentially lethal damage in tumours, nor did it alter the bioactivation of cyclophosphamide or the subsequent clearance of the cytotoxic species from the plasma, so the mechanism for this chemosensitisation remains unclear.

Animals↗

PubMed1997

Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children.

BACKGROUND: This prospective study was performed to evaluate the tolerance of pyrazinamide in short course chemotherapy in children. METHODS: A total of 114 children ages 6 months to 15 years (4.5 +/- 3.4 years) with diagnosed pulmonary tuberculosis from 1985 to 1995 entered the trial. A 2-month regimen of isoniazid, rifampin and pyrazinamide, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to all children. Clinical adverse effects specifically investigated were gastrointestinal disturbances, rash, signs of hepatotoxicity and arthralgias. Laboratory toxicity data (number of leukocytes, erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and serum uric acid) were collected before treatment and 1, 3 and 5 months after the beginning of chemotherapy. RESULTS: Clinical adverse effects were mild in all cases. Three children (2.6%) had fever and 5 (4.4%) had gastrointestinal disturbances. Aspartate aminotransferase and alanine aminotransferase mean values showed no differences along time and no patients had clinical signs of hepatotoxicity. Only 11 children (19.6%) showed a slight increase in alanine aminotransferase (< 194 units/l). Serum uric acid increased in 92.2% of the children compared with pretreatment values. This increase remained within the normal range in all but 9.8% of patients. There was a significant increase in uric acid mean concentrations after 1 month of therapy (from 3.7 +/- 0.7 mg/dl to 5.7 +/- 1.6 mg/dl, P < 0.05), which fell again (4.0 +/- 1.1) 1 month after pyrazinamide was stopped. There were no signs of gout or arthralgias. In no case was the treatment interrupted. CONCLUSION: The addition of pyrazinamide in chemotherapy for pulmonary tuberculosis in children was found to be safe. The slight increase in uric acid concentration during its administration had no recognized adverse consequences.

Adolescent↗

PubMed1996

Erythema multiforme due to pyrazinamide.

Drug-induced erythema multiforme is reported with many antimicrobial and antipyretic medications. We present one patient who experienced erythema multiforme and urticaria after administration of pyrazinamide for treatment of cutaneous tuberculosis. The side-effects of pyrazinamide include hepatic or dermatologic disorders, but erythema multiforme has not yet, to our knowledge, been described. Clinical features and discontinuation and reintroduction of the drug led us to consider pyrazinamide the cause of the erythema multiforme, but allergologic studies remained negative, except for the presence of circulating immune complexes. The mechanism of this eruption remains obscure, and definite withdrawal of pyrazinamide seems to be the best therapeutic choice.

Aged↗

PubMed1997

Mutations associated with pyrazinamide resistance in pncA of Mycobacterium tuberculosis complex organisms.

A gene (pncA) with mutations associated with pyrazinamide resistance in Mycobacterium tuberculosis complex members was characterized in 67 pyrazinamide-resistant and 51 pyrazinamide-susceptible isolates recovered from diverse geographic localities and anatomic sites and typed by IS6110 profiling. All pyrazinamide-susceptible organisms had identical pncA alleles. In striking contrast, 72% of the 67 resistant organisms had pncA mutations that altered the primary amino acid sequence of pyrazinamidase. A total of 17 previously undescribed mutations were found, including upstream mutations, missense changes, nucleotide insertions and deletions, and termination mutations. The mutations were arrayed along virtually the entire length of the gene. These data are further evidence that most drug resistance in M. tuberculosis is due to simple mutations occurring in chromosomally encoded genes rather than to acquisition of resistance genes by horizontal transfer events.

Amidohydrolases↗

PubMed2006

Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection.

Recent pharmacokinetic studies that included children found that serum drug levels were low compared to those of adults for whom the same dosages were used. This study aimed to characterize the pharmacokinetics of pyrazinamide and ethambutol in Malawian children and to examine the impact of age, nutritional status, and human immunodeficiency virus (HIV) infection. We conducted a pharmacokinetic study of children treated for tuberculosis with thrice-weekly pyrazinamide (n = 27; mean age, 5.7 years) and of a separate group of children treated with thrice-weekly ethambutol (n = 18; mean age, 5.5 years) as portions of tablets according to national guidelines. Malnutrition and HIV infection were common in both groups. Blood samples were taken just prior to oral administration of the first dose, and subsequent samples were taken at intervals of 2, 3, 4, 7, 24, and 48 h after drug administration. Serum drug levels were low in all children for both drugs; in almost all cases, the maximum concentration of the drug in serum (Cmax) failed to reach the MIC for Mycobacterium tuberculosis. The Cmax of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The Cmax of pyrazinamide was also lower for HIV-infected children and children with severe malnutrition, but these differences did not reach statistical significance. No differences were found for ethambutol in relation to age, HIV infection, or malnutrition, but the Cmax was <2 mg/liter in all cases. Studies of pharmacokinetic parameters and clinical outcomes obtained by using higher dosages of drugs for treatment of childhood tuberculosis are needed, and recommended dosages may need to be increased.

Adolescent↗

PubMed1992

Pyrazinamide sterilizing activity in vitro against semidormant Mycobacterium tuberculosis bacterial populations.

Previously, we reported that pyrazinamide has very poor bactericidal activity against M. tuberculosis growing in broth at pH 5.6. In the present study, cultivation at pH 4.8 to 5.0 in 7H12 broth prevented an increase in the number of viable bacteria, but the cultures remained metabolically active. The presence of 50 micrograms/ml pyrazinamide in semidormant cultures led to a sharp decline in the number of viable bacteria, by more than 1,000-fold. This unfavorable environment probably made the bacilli especially vulnerable to pyrazinamide, whose mode of action remains unclear. To distinguish this effect of pyrazinamide on the semidormant bacteria from its mostly bacteriostatic activity against actively multiplying bacteria, we suggest interpreting the in vitro effect as "sterilizing."

Culture Media↗

PubMed1981

Pyrazinamide deamidase activity in tuberculous disease.

To investigate whether pyrazinamide deamidase activity is suppressed in tuberculosis, serial serum concentrations of pyrazinamide, following 40 mg of pyrazinamide per kg, were determined in 10 patients with sputum positive pulmonary tuberculosis and in 10 control subjects without disease. The concentrations and the half-lives of pyrazinamide were similar in the 2 groups, suggesting no suppression of the deamidase activity in tuberculous patients.

Antitubercular Agents↗

PubMed1986

The bioavailability of isoniazid, rifampin, and pyrazinamide in two commercially available combined formulations designed for use in the short-course treatment of tuberculosis.

The bioavailability of isoniazid, rifampin, and pyrazinamide in 2 combined formulations of the 3 drugs (Rifater) for use primarily in the short-course chemotherapy of tuberculosis has been studied in Chinese patients in Singapore and Hong Kong. One formulation, containing 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide per tablet is suitable for daily use, whereas the other, containing higher proportions of isoniazid and pyrazinamide, is designed for intermittent treatment, each tablet containing 125 mg isoniazid, 100 mg rifampin, and 375 mg pyrazinamide. Appropriate dosages for the Chinese patients, whose average weight was approximately 50 kg, were 5 and 6 tablets, respectively. Plasma concentrations of the 3 drugs after giving such dosages of the 2 combined formulations were compared in 16 patients, 8 in Singapore and 8 in Hong Kong, by means of a crossover study, with the concentrations obtained when identical doses of the 3 drugs were given using standard separate drug formulations. The concomitant urinary excretions of the drugs and their major metabolites were also estimated. Very similar results were obtained whether the drugs were given as the combined preparations or in their standard separate formulations, demonstrating the excellent bioavailability of all 3 drugs in each of the 2 combined formulations.

Acetylation↗

PubMedDate not supplied

A case of pyrazinamide-associated myoglobinuric renal failure.

A 50-year-old man developed myoglobinuric renal failure after taking pyrazinamide. Both serum and urine myoglobin levels were elevated and tubulo-interstitial nephropathy was demonstrated on renal biopsy. After pyrazinamide was discontinued, the myoglobin concentrations were normalized and his renal function ameliorated. The rhabdomyolysis was considered to be caused by pyrazinamide. To our knowledge, this is the first reported case of rhabdomyolysis associated with pyrazinamide.

Acute Kidney Injury↗

PubMed1999

Chemotherapy of tuberculosis in mice using single implants of isoniazid and pyrazinamide.

OBJECTIVE: To establish the chemotherapeutic value of a depot drug preparation of isoniazid and pyrazinamide against experimental tuberculosis. DESIGN: To see whether sustained levels of pyrazinamide are available for prolonged periods after a single subcutaneous administration of a biodegradable polylactic-glycolic acid (PLGA) polymer containing the drug, studies were done to ascertain whether a single administration of isoniazid and pyrazinamide in separate PLGA polymers could offer chemotherapeutic protection against a heavy intravenous challenge of susceptible mice with a virulent strain of Mycobacterium tuberculosis similar to that rendered by daily administration of the two drugs for 8 weeks. RESULTS: Even with three times the daily dose of pyrazinamide contained in the single PLGA polymer implant, no abnormally high (burst) levels of the drug were evident after administration, but sustained levels of the drug were seen up to 54 days. The chemotherapeutic activity of the single PLGA polymer implants was similar to that obtained with standard oral treatment with the two drugs given daily for the entire 8 weeks, as judged by mortality and colony forming unit (CFU) counts of tubercle bacilli from lungs and spleen. CONCLUSION: Treatment with single implants of the PLGA polymer containing anti-mycobacterial drugs offers a strong possibility of circumventing the compliance problem.

Administration, Oral↗