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PubMed1984

Niacin, nitrate and pyrazinamide studies using Middlebrook 7H10 Broth.

An innovative and rapid method for testing mycobacteria was developed using Middlebrook 7H10 Tween Broth in place of conventional media. Niacin production, nitrate reduction and the breakdown of pyrazinamidase were determined in 198 mycobacteria isolates. Less than nine days were required to obtain positive test results, and the correlation of tween broth with conventional test methods exceeded 98%.

Amidohydrolases↗
PubMed2001

[Effectiveness and problems of PZA-containing 6-month regimen for the treatment of new pulmonary tuberculosis patients].

One third of the world population has been infected with Mycobacterium tuberculosis, and the number of tuberculosis will increase worldwide without more effective programs of tuberculosis control. Despite of the presence of very potent anti-tuberculosis drugs the global tuberculosis situation is still very serious, and such gloomy feature are caused, at least partly, by the failures in the treatment of tuberculosis. The most important factor for the failure in chemotherapy is incompliance of the patients to the regimens. History of the chemotherapy of tuberculosis can be said as the history of the efforts to reduce such defaulters. Modern chemotherapy of tuberculosis has started from the discovery of streptomycin. Streptomycin monotherapy could improve temporally symptoms and bacteriological status, but could not cure the patients with moderately advanced pulmonary tuberculosis because of the emerge of drug-resistant tuberculosis. This problem was overcome by combining use of para-aminosalicylate and/or isoniazid developed later on. About 97% of patients with pulmonary tuberculosis became bacteriologically quiescent by the 12 months of streptomycin, para-aminosalicylate and isoniazid. Since 1950s through 1970s three drug combination of streptomycin, para-aminosalicylate and isoniazid had been the standard regimen for the treatment of tuberculosis. By the introduction of rifampicin, the duration of chemotherapy could be shortened to 9 months. Subsequent to the successful animal experiments carried out by Grosset which demonstrated that the addition of pyrazinamide for initial 2 months to the standard two-drug combination (isoniazid and rifampicin) could remarkably shorten the duration of chemotherapy, many clinical trials have been done all over the world to compare the efficacy and safety of pyrazinamide-containing intensified short-course regimen with those of standard regimen without pyrazinamide. Sputum negative conversion rates after 2 months of treatment with PZA-regimen was 70-95%, and the relapse rates after the completion of the treatment course were less than 4%. The incidence of adverse events was less than 4%. The pyrazinamide-containing 6 months short-course regimens has been established as a new standard regimen for the initial treatment of pulmonary tuberculosis worldwide. But, in Japan, this regimen had not been adapted as the standard until April 1996 because of undue fear for high incidence of liver toxicity induced by pyrazinamide. However, in many clinical trials carried out in various parts of the world did not show any causative relationship between the higher incidence of liver toxicity and pyrazinamide. According to our own experience in Fukujuji Hospital, Japan Anti-tuberculosis Association, the frequency of drug induced hepatitis among 632 patients with normal liver function at the onset of chemotherapy was 7.9 percent (50/632) when treated with pyrazinamide-containing regimens, and was similar to that among 412 patients treated with other regimens without pyrazinamide (7.3 percent 30/412). These figures were higher than those reported in the literatures. The risk factors of drug-induced hepatitis so far reported included elderly, positive hepatitis C virus antibody, low serum albumin and so on. Such known risk factors could not wholly explain the higher rate of liver dysfunction observed among our Japanese patients. We have examined additional factors affecting the frequency of drug-induced hepatitis in our hospital, and noticed that the past history of gastrectomy and over-dosing of isoniazid (> or = 7.5 mg/kg) and/or pyrazinamide (> or = 30 mg) were relating to the higher incidence of drug-induced hepatitis. Another important finding is that the relapse rate among patients complicated with diabetes mellitus is significantly higher than that of the patients without diabetes mellitus (6.31/100 person-years vs 0.90/100 person-years, P < 0.001). Further research will need whether the patients complicated with diabetes mellitus have any immunological deficient to kill Mycobacterium tuberculosis. WHO, CDC and ATS recommended that 4-drug regimen including pyrazinamide for the initial treatment of all cases of tuberculosis. Considering that the incidence of initial resistance to isoniazid is 4.4% in Japan, we should start to treat all cases of newly diagnosed tuberculosis with pyrazinamide-containing regimen (isoniazid, rifampicin, pyrazinamide, plus streptomycin or ethambutol). To do this, further studies on the risk factors of drug-induced hepatitis are urgently needed.

Animals↗
PubMed1973

Evidence for a postsecretory reabsorptive site for uric acid in man.

The effects of administration of drug combinations on uric acid excretion were studied in order to test the hypothesis that a portion of renal tubular reabsorption of uric acid occurs distal to the uric acid secretory site. Oral administration of pyrazinamide (3 g) during probenecid uricosuria (probenecid 500 mg every 6 h) decreased urate excretion from 463 mug/min following probenecid medication alone to 135 mug/min following probenecid plus pyrazinamide (P < 0.01). When a greater uricosuric effect was induced with a 2 g oral dose of probenecid, the decrement in urate excretion which followed pyrazinamide administration (3 g) was more pronounced (2,528 mug/min following probenecid alone, 574 mug/min following probenecid plus pyrazinamide). Results were similar when an 800 mg oral dose of sulfinpyrazone was given in place of probenecid (1,885 mug/min following sulfinpyrazone alone, 475 mug/min following sulfinpyrazone plus pyrazinamide). Thus, apparent urate secretion (measured as the decrease in excretion of urinary uric acid resulting from pyrazinamide administration) appeared to vary, depending upon the degree of inhibition of reabsorption produced by probenecid or sulfinpyrazone. When small doses of aspirin were administered in place of pyrazinamide to produce secretory inhibition, the results were similar. Neither probenecid nor pyrazinamide significantly altered urate excretion when administered to patients with serum salicylate levels above 14 mg/100 ml. These results are interpreted as suggesting that renal tubular reabsorption of uric acid occurs at least in part at a postsecretory site and that a portion of secreted urate is reabsorbed. During maximum probenecid- or sulfinpyrazone-induced uricosuria, inhibition of urate secretion with either pyrazinamide or low doses of aspirin resulted in a decrease in uric acid excretion which exceeded total urinary uric acid during control periods by two- to fourfold. This suggests that renal tubular secretion of urate may greatly exceed uric acid excretion and that a large fraction of secreted urate is reabsorbed. The pyrazinamide suppression test underestimates urate secretion. Uricosuria induced by some drugs, including probenecid, sulfinpyrazone, and iodinated radioopaque dyes, appears to represent, at least in part, inhibition of postsecretory urate reabsorption.

Absorption↗
PubMed1982

Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report: the results up to 24 months. Hong Kong Chest Service/British Medical Research Council.

Five 6-month antituberculosis regimens, allocated at random to patients with acid-fast bacilli in their sputum on microscopy, were studied. Four, given 3 times a week throughout, contained isoniazid and rifampicin together with 1. streptomycin, pyrazinamide and ethambutol, 2. streptomycin and pyrazinamide, but no ethambutol, 3. streptomycin and ethambutol, but no pyrazinamide, 4. pyrazinamide and ethambutol, but no streptomycin. The fifth was a daily regimen of isoniazid, rifampicin, pyrazinamide and ethambutol. All 833 patients with drug-sensitive strains of tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy, and the bacteriological relapse rate during 18 months after stopping chemotherapy was 1% for the three-times-weekly regimens containing streptomycin and pyrazinamide in addition to isoniazid and rifampicin (regimens 1 and 2, above) and for the daily regimen, 2% for the regimen of isoniazid, rifampicin, pyrazinamide and ethambutol three times a week (regimen 4), but 8% for the only regimen which did not contain pyrazinamide (regimen 3). The results achieved by the 4 pyrazinamide regimens were practically as good for the 110 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment as they were for the patients with drug-sensitive strains.

Adolescent↗
PubMed1996

Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status.

The standard antitubercular regimen currently includes a combination of 3 antitubercular agents: isoniazid, rifampicin (rifampin) and pyrazinamide. Administration of a fourth agent, ethambutol, is recommended when isoniazid resistance is suspected. Two of these 4 agents (isoniazid and pyrazinamide) are major hepatotoxins. The remaining 2 agents (rifampicin and ethambutol) are rarely or not hepatotoxic. However, rifampicin, which is a powerful enzyme inducer, may enhance the hepatotoxicity of isoniazid. In patients receiving a combination of isoniazid, rifampicin and pyrazinamide, 2 patterns of fulminant liver injury can be observed. The first pattern is characterised by an increase in serum transaminase activity that occurs soon (usually within the first 15 days) after initiation of treatment. This pattern is likely to be caused by rifampicin-induced isoniazid hepatotoxicity. The prognosis is good in most cases. The second pattern is characterised by an increase in serum transaminase activity that occurs late (usually more than 1 month) after the initiation of treatment. It has been suggested that this pattern may be related to pyrazinamide hepatotoxicity. The prognosis of this type of hepatitis is generally poor. In order to reduce the risk of severe hepatic adverse effects during antitubercular treatment, several measures are proposed. First, patients with underlying liver test abnormalities should not be given pyrazinamide. Second, isoniazid and pyrazinamide should be administered at the lowest dosage within their respective therapeutic ranges. Third, serum transaminase levels should be determined twice weekly during the first 2 weeks of treatment, every 2 weeks during the rest of the first 2 months, and every month thereafter. When serum transaminase levels increase to greater than 3 times the upper limit of normal, therapy with isoniazid, rifampicin and pyrazinamide should be stopped. After serum transaminase levels have returned to normal, isoniazid can be re-introduced at a low daily dose, without rifampicin. Pyrazinamide may not be re-introduced because of the risk of recurrence and the poor prognosis of pyrazinamide-induced hepatitis. Although it is nephrotoxic, streptomycin is an alternative in patients with liver test abnormalities during antitubercular treatment.

Antitubercular Agents↗
PubMed2004

Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis.

In a recent experimental study using the mouse model of tuberculosis, treatment with a combination of rifampin, moxifloxacin, and pyrazinamide was able to shorten the time to negative lung cultures by up to 2 months compared with the standard regimen of rifampin, isoniazid, and pyrazinamide. To confirm that this substitution of moxifloxacin for isoniazid permits a shorter duration of treatment, a second study was performed in which mice were assessed for relapse after treatment with combination therapy for 3, 4, 5, or 6 months. Although no relapse was observed among mice treated for at least 4 months with rifampin, moxifloxacin, and pyrazinamide, mice treated with rifampin, isoniazid, and pyrazinamide required 6 months of treatment before no relapse could be detected. For mice treated with rifampin, moxifloxacin, and pyrazinamide, similar efficacy was noted whether pyrazinamide was administered for 1 month, 2 months, or the entire duration of therapy. These results suggest that the use of rifampin, moxifloxacin, and pyrazinamide may substantially shorten the duration of therapy needed to cure human tuberculosis and that the full benefit of pyrazinamide in this regimen may be realized after just 1 month of treatment.

Animals↗
PubMed1981

A controlled trial of six months chemotherapy in pulmonary tuberculosis. First Report: results during chemotherapy. British Thoracic Association.

The results of six-month courses of chemotherapy with daily isoniazid and rifampicin, supplemented for the first two months by either streptomycin and pyrazinamide (EHRZ6 regimen), or by ethambutol and pyrazinamide (EHRZ6 regimen), in patients with culture-positive pulmonary tuberculosis have been studied. These results have been compared with those of a nine-month regimen of daily isoniazid and rifampicin supplemented by ethambutol for the first two months (EHR9 regimen). All patients in the three regimens achieved negative cultures before the end of chemotherapy but the rate of sputum conversion was significantly more rapid with the two pyrazinamide-containing regimens. Of the 287 patients on the SHRZ6 and EHRZ6 regimens who completed chemotherapy, 77% had achieved negative cultures at two months and 98% at three months, compared with 64% and 88% respectively of the 157 patients on the EHR9 regimen. Adverse drug reactions were not a serious problem. Of the 234 patients who started treatment with the SHRZ6 and EHRZ6 regimens, 14 (4%) developed hepatitis; among the 177 patients in the EHR9 group (who did not receive pyrazinamide), the incidence of hepatitis was also 4%. Thus the addition of pyrazinamide to regimens containing rifampicin and isoniazid did not increase the incidence of hepatitis. However, the incidence of adverse effect other than hepatitis was increased in the pyrazinamide-containing regimens, the most common being skin rashes. These results indicate that six-month regimens containing pyrazinamide do not produce undue toxicity and are worthy of further study. Their usefulness in routine clinical practice will not become clear until a further period of follow-up of patients in this study had established the incidence of subsequent relapse.

Adolescent↗