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At least 19 recordsLinked to original sources

PubMed1976

Observations on the reduction of the renal elimination of urate in man caused by the administration of pyrazinamide.

The urinary excretion of pyrazinamide, pyrazinoic acid, 5-hydroxypyrazinoic acid and uric acid were determined in a healthy subject after giving single or multiple doses of pyrazinamide or its metabolite pyrazinoic acid. The results obtained demonstrated that 5-hydroxypyrazinoic acid is a major metabolite of pyrazinoic acid in man and supported previous evidence indicating that the retention of uric acid caused by the administration of pyrazinamide is mediated by pyrazinoic acid. After giving 3 g pyrazinamide the urinary excretion of uric acid was maximally suppressed for 24 hours and partially reduced for a further 24 hours. Prolonged exposure to pyrazinoic acid resulted in a net reduction in the urinary excretion of uric acid. The findings suggested that the degree of uric acid retention in patients treated with pyrazinamide-containing regimens could be reduced by giving pyrazinamide intermittently.

Humans↗

PubMed1976

Adverse reactions to short-course regimens containing streptomycin, isoniazid, pyrazinamide and rifampicin in Hong Kong.

Three studies of drug toxicity were made in Chinese adults with pulmonary tuberculosis admitted concurrently to short-course antituberculosis regimens. The first was of streptomycin plus isoniazid plus pyrazinamide given daily (SHZ regimen), three times a week (S3H3Z3 regimen) or twice a week (S2H2Z2 regimen). The second was of pyrazinamide in the SHZ regimen and PAS in the standard daily combination of streptomycin plus isoniazid plus PAS (SPH regimen). The third was of the SHZ regimen and these 3 drugs plus rifampicin daily (SHRZ regimen). In study 1 (174 SHZ, 185 S3H3Z3, 182 S2H2Z2 patients), the incidence of arthralgia was associated with the number of doses per week (P less than 0.001). The incidence of other reactions, most of which were cutaneous or vestibular, or symptomless increases in the serum alanine transaminase (AIT) concentration, was similar on all 3 regimens. In study 2 (142 SHZ, 137 SPH patients), hepatic reactions occurred on the SHZ but not on the SPH regimen (P less than 0.002), serum AIT concentrations were distributed over a higher range on the SHZ regimen, and 2 patients had jaundice. Gastrointestinal reactions were more frequent on the SPH regimen (P = 0.06). Arthralgia was commoner on the SHZ regimen (P less than 0.05). In study 3 (38 SHZ, 41 SHRZ patients), the incidence of hepatic reactions, jaundice and arthralgia was similar in the 2 regimens. On the pyrazinamide regimens combined, hepatic reactions were marginally more frequent in patients with Australia antigen or antibody either before or during chemotherapy (P = 0.09). Serum uric acid concentrations were higher in patients on daily than on intermittent pyrazinamide (P less than 0.005), and in patients with arthralgia on the daily pyrazinamide regimen than in matched controls (P = 0.07).

Aminosalicylic Acids↗

PubMed1977

Inhibition of probenecid uricosuria by pyrazinamide and para-aminohippurate.

Both para-aminohippurate (PAH) and pyrazinamide inhibited the uricosuric response to probenecid administration. The mechanism of this inhibition of probenecid uricosuria was assessed in 18 male subjects. The decrease in uricosuria was assessed in 18 male subjects. The decrease in uricosuric response to probenecid observed after pyrazinamide administration or PAH infusion occurs by different mechanisms. Administration of PAH and probenecid together resulted in reduced excretion of both drugs. PAH was weakly uricosuric and did not appear to inhibit urate secretion. PAH inhibition of probenecid uricosuria is accounted for by inhibition of probenecid secretion. Probenecid excretion was not affected by pyrazinamide administration. Inhibition of probenecid-induced uricosuria by pyrazinamide is most likely due to inhibition of urate secretion. The urate secretory carrier inhibited by pyrazinamide appears to be independent of that responsible for secretion of probenecid and PAH. Probenecid secretion appears to be required for its uricosuric effect.

Adolescent↗

PubMed1992

The combined effect of rifampin and pyrazinamide within the human macrophage.

A recent study in the murine model suggested that a combination of rifampin and pyrazinamide used as preventive therapy might shorten the duration of treatment time. Clinical trials using this combination have been initiated, but significant results will not be available for many years. The ex vivo human macrophage model has been instructive in expanding our knowledge of the activity of chemotherapeutic agents against intracellular virulent tubercle bacilli. Prior studies have shown rifampin to have a bactericidal effect in this model while even at clinically unachievable levels, pyrazinamide had only a bacteriostatic impact. This study finds an enhanced bacteriostatic effect when low, nonbactericidal levels of rifampin are combined with clinically achievable levels of pyrazinamide but not with higher bactericidal levels of rifampin. Adding pyrazinamide 2 days after the introduction of rifampin clearly enhanced the combined killing effect. However, reversing the order and adding rifampin 2 days after the introduction of pyrazinamide produced a result weaker than introducing the agents simultaneously. Our findings do not support the use of these agents as a potentially effective preventive therapy combination, but they suggest that the timing of the administration of these chemotherapeutic agents could be an important factor in their effectiveness.

Colony Count, Microbial↗

PubMed1978

The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Acetylation↗

PubMed2026

The effect of metformin on the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide in adults with tuberculosis.

Metformin is under investigation as adjunctive host-directed therapy for tuberculosis (TB), which might interact with first-line TB treatment. We used population pharmacokinetic modeling to assess whether metformin alters first-line TB-drug pharmacokinetics in HIV/TB-coinfected adults without diabetes. Rifampicin, isoniazid, and pyrazinamide pharmacokinetics were investigated in participants from a randomized clinical trial of adjunctive metformin (500 mg twice daily to week 12) in adults starting HIV-associated TB treatment. Antiretroviral therapy (ART)-naïve participants initiated dolutegravir-based ART within 8 weeks. Intensive and semi-intensive sampling was conducted at week 5; concentration-time data were analyzed using non-linear mixed-effects modeling. Data from 78 individuals (43 receiving metformin, median weight 60.8 kg, 62.8% male, 79.5% on ART) were analyzed. Rifampicin and pyrazinamide were described by one-compartment models with linear elimination; typical clearances were 15.8 L/h (95% CI: 13.5-18.7) and 3.88 L/h (95% CI: 3.54-4.08), respectively. Isoniazid followed a two-compartment model with a mixture model for acetylator status; clearance was 10.5 L/h (95% CI: 9.44-11.9) in slow acetylators and 28.8 L/h (95% CI: 25.6-31.0) in fast/intermediate acetylators. Metformin reduced isoniazid bioavailability by 15.6% (95% CI: 4.45-26.4%, P < 0.009) and rifampicin bioavailability by 24.0% (95% CI: 7.83-36.3%, P < 0.007), decreasing the area under the curve from 0 to 24 h from 18.2 to 15.6 mg·h/L and from 35.9 to 27.1 mg·h/L, respectively. No significant effect on pyrazinamide was detected. We found that non-diabetic patients on metformin had lower isoniazid and rifampicin bioavailability. Lowered rifampicin exposure might be clinically relevant; simulations suggest that this could be offset by a single 150 mg rifampicin dose.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04930744.

Humans↗

PubMed1992

Two cases in whom pyrazinamide does not inhibit the uricosuric action of benzbromarone.

The 2 subjects were a diabetic male with renal hypouricemia and a healthy male with normouricemia. In these subjects, 200 mg of benzbromarone increased fractional uric acid clearance (FUa) and 3.0 g of pyrazinamide decreased FUa. However, pyrazinamide did not inhibit the uricosuric action of benzbromarone at all on the administration of 3.0 g of pyrazinamide together with 200 mg of benzbromarone. These results indicated that in these cases, the relative role of each component could not be determined on the basis of the hypothetical four-component model.

Adult↗

PubMed1978

Study of urinary pyrazinamide metabolites and their action on the renal excretion of xanthine and hypoxanthine in a xanthinuric patient.

A chromatographic technique on anion exchange column was developed. It permets to determine unmetabolized pyrazinamide and three major metabolities: pyrazinoic acid, 5-hydroxypyrazinoic acid and an unidentified compound. In a xanthinuric patient only traces of 5-hydroxypyrazinoic acid were found 12 hours after 3 g pyrazinamide were given. These finding confirms that pyrazinoic acid is oxidised through the the action of xanthine oxidase. Both the clearances of hypoxanthine and of xanthine are as rapid as that of endogenous creatinine in a xanthinuric patient. But the effects of pyrazinamide are different on both purine bases. Urinary excretion of hypoxanthine is slightly but not significantly reduced while excretion of xanthine is decreased by about 75%. Evidence was demonstrated that pyrazinoic acid is likely the agent causing xanthine retention. These results suggest that the mechanisms of renal transport of xanthine and hypoxanthine are different.

Chromatography, Ion Exchange↗

PubMed1978

Mass fragmentographic determination of pyrazinamide and its metabolites in serum and urine.

A combined gas chromatographic-mass spectrometric technique is described for the simultaneous determination of pyrazinamide and its two main metabolites, pyrazinoic acid and 5-hydroxypyrazinoic acid. Serum (200 microliter) is deproteinized and evaporated to dryness; urine (20 microliter) is evaporated. The crude residues are silylated and selected ions are monitored in the chemical-ionization mode with isobutane as both chromatographic carrier and reagent gas. The sensitivity is 10 ng/ml for pyrazinamide and pyrazinoic acid and 20 ng/ml for the 5-hydroxy metabolite in a single analysis. Nicotinic acid and nicotinamide are internal standards. Both unchanged drug and metabolites were identified and quantified in the serum and urine of human subjects.

Gas Chromatography-Mass Spectrometry↗

PubMed1976

Use of pyrazinamide to assess renal uric acid transport in the rat: a micropuncture study.

Free-flow micropuncture studies were performed to evaluate renal uric acid transport in control and pyrazinamide-treated rats. In all studies [2-14C]uric acid and [methoxy-3H]inulin were administered. [2-14C]uric acid was determined after column chromatographic separation from its labeled oxidation product in tubular fluid, plasma, and urine. Tubular fluid collections were obtained from the early and late proximal tubule under hydropenic conditions and from the early proximal tubule during volume expansion induced with 0.9% sodium chloride. These studies indicate that pyrazinamide, in the dose employed, provokes a uniform reduction in fractional uric acid excretion but simultaneously inhibits both net uric acid reabsorption and secretion in the early and late proximal tubule, respectively. In addition, these experiments unmasked uric acid reabsorption within the late proximal tubule and bidirectional transport beyond this nephron site. These studies also suggest at least two mechanisms for uric acid reabsorption; one sodium dependent, the other independent of sodium and water transport.

Animals↗

PubMed1977

Familial hypouricemia due to isolated renal tubular defect. Attenuated response of uric acid clearance to probenecid and pyrazinamide.

A 37-year-old female was found to have hypouricemia (1.1-1.9 mg%) with markedly increased uric acid clearance (24.7039.5 ml/min). Uric acid excretion was only slightly affected by pyrazinamide, a drug which suppresses renal tubular uric acid secretion, and by probenecid, a drug which inhibits tubular uric acid reabsorption. The attenuated response in this subject to both drugs suggest a renal tubular defect in the proximal high capacity-high affinity uric acid reabsorption mechanism. No other renal tubular or metabolic abnormalities were detected. A survey of the family-three sisters and two brothers, revealed two similarly affected sisters. The abnormality described in this family is defined as familial renal hypouricemia due to an isolated renal tubular defect with attenuated response of uric acid clearance to probenecid and pyrazinamide.

Adult↗

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↗

PubMed1975

The penetration of dapsone, rifampicin, isoniazid and pyrazinamide into peripheral nerves.

1 Dapsone, rifampicin, isoniazid and pyrazinamide were shown to penetrate readily into the sciatic nerves of the dog and sheep. 2 These findings suggest that the continued persistence of viable drug-sensitive leprosy bacilli in the peripheral nerves of patients treated for long periods with either dapsone or rifampicin is not due to inadequate intraneural drug penetration.

Animals↗

PubMed1977

Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months.

A comparison was made between 6-month and 9-month regimens of streptomycin plus isoniazid plus pyrazinamide given daily, 3 times a week, or twice a week in the treatment of newly diagnosed, smear-positive pulmonary tuberculosis in Chinese patients. At 6 months, the twice-weekly regimen was marginally inferior; treatment failed for 5 (4 per cent) of 126 patients with drug-susceptible strains before treatment compared with 2 (1 per cent) of 141 on the 3-times-weekly regimen and none of 137 on the daily regimen. The results for patients with pretreatment strains resistant to isoniazid, to streptomycin, or to both drugs were not as good, treatment failing for 10 (30 per cent) of 33 on the daily regimen, 15 (37 per cent) of 41 on the 3-times-weekly regimen, and 14 (39 per cent) of 36 on the twice-weekly regimen. In contrast, the relapse rates after chemotherapy were similar for patients with drug-susceptible and drug-resistance strains before treatment and for patients on the daily and intermittent regimens. By 30 months, 35 (21 per cent) of 167 patients with susceptible strains who were treated for 6 months and 10 (6 per cent) of 179 treated for 9 months had relapsed, all with strains still susceptible to isoniazid and streptomycin. The relapse rates for patients with resistant strains were 7 (24 per cent) of 29 and 1 (4 per cent) of 26, respectively. Drug toxicity was not a special problem.

Adolescent↗

PubMed1977

Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide alone and in combination against Mycobacterium Tuberculosis.

Log-phase cultures of Mycobacterium tuberculosis in Tween-albumin medium were exposed to streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide in concentrations in the range likely to be present in serum during treatment of patients. The bactericidal activity of the drugs was measured as the decrease in viable counts at 4 and 7 days. The activity of single drugs was highest for streptomycin and next highest for rifampin and isoniazid, but ethambutol only started to kill after 4 days. When exposed to 2 drugs, bactericidal synergism was found with streptomycin/isoniazid and isoniazid/ethambutol; additivity, with streptomycin/rifampin; indifference, with isoniazid rifampin and streptomycin/ethambutol; and antagonism, with rifampin/ethambutol and isoniazid/pyrazinamide. When cultures were exposed to the 3 drugs, isoniazid, rifampin, and ethambutol, marked antagonism was found between isoniazid and rifampin, whereas the addition of isoniazid or an increase in its concentration increased the bactericidal activity.

Drug Interactions↗

PubMed1978

[Determination of the sensitivity of mycobacteria to pyrazinamide and nicotinamide (author's transl)].

Since pyrazinamide (PZA) has had a come-back in therapy of tuberculosis a simple and reliable method for sensitivity tests has been necessary. A comparison of resistance tests to PZA in acid Löwenstein-Jensen-medium and in fluid medium with those to nicotinamide (NSA) showed a clear superiority of the NSA method, recommended by BRANDER. Also in routine sensitivity tests the use of NSA instead of PZA has stood the test. Another advantage of the method is the possibility to integrate it in the simplified proportion method without any additional work.

Drug Resistance, Microbial↗