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PubMed1988

Management and outcome of pulmonary tuberculosis in adults notified in England and Wales in 1983. Medical Research Council Tuberculosis and Chest Diseases Unit.

The management and outcome of treatment were studied, two years or more after notification, in previously untreated adult patients of white and Indian subcontinent (Indian, Pakistani, and Bangladeshi) ethnic origin with pulmonary tuberculosis notified in England and Wales in the first six months of 1983. Of the 1068 patients, 10% had died, 3% defaulted, and 1% left the UK before completing chemotherapy. Of the 917 patients who completed chemotherapy, 90% were prescribed rifampicin and isoniazid throughout, most having ethambutol in addition either in the initial phase only (72%) or throughout (3%); 18% had pyrazinamide. The outcome of chemotherapy at the time the patient was last seen was reported by the clinician. Of those completing treatment, most were classified as cured after the primary course of chemotherapy (86%) or after modification of chemotherapy because of toxicity (10%) or therapeutic failure (2%). Altogether, 28 patients were classified as therapeutic failures because of a slow response, deterioration, or failure during chemotherapy or relapse after stopping chemotherapy. A further 151 patients, however, failed to complete chemotherapy, some for reasons attributable to a failure of the routine clinical services. This should prompt continued efforts to maximise the efficiency of the services for tuberculosis. The main differences between the findings of this survey and those of the previous Medical Research Council survey (of patients starting chemotherapy in 1978-9) were an increased use of pyrazinamide and a reduction in the duration of the chemotherapy prescribed.

Adolescent↗
PubMed1976

Uric acid excretion by the pig kidney.

The handling of uric acid by the pig kidney has been investigated during continuous urate infusion in unrestrained, unanesthetized animals. Urate-to-inulin clearance rates in excess of 1 were found under all experimental conditions, demonstrating only net secretion by the pig kidney. The demonstration of a secretory maximum was precluded owing to a progressive reduction in the GFR associated with high rates of urate infusion. Urate clearance was independent of urine flow rate up to 10 ml/min. The administration of probenecid inhibited urate secretion, but urate-to-inulin clearance ratios below unity were not observed. Pyrazinamide or pyrazinoic acid, at doses which either inhibited secretion or promoted uricosuria in other species, did not alter urate excretion in the pig. Probenecid together with pyrazinamide exerted the same inhibitory effect on urate secretion as probenecid alone. Pyrazinoic acid was reabsorbed at all infusion rates. It is concluded that the pig kidney eliminates uric acid by filtration and secretion only.

Animals↗
PubMed1979

Mechanism of the uricosuric activity of ticrynafen.

Studies employing pyrazinamide, which have included the measurements of clearances of pyrazinamide and pyrazinoate, as well as of ticrynafen itself and its principal metabolite, have lent support to the hypothesis that ticrynafen inhibits the tubular reabsorption of both filtered and secreted urate by nephrons of the human kidney. The inhibition of the reabsorption of secreted urate by ticrynafen appears to be quantitatively important for eliciting its uricosuric and hypouricemic responses. Because the uricosuric and natriuretic responses correlate with urinary ticrynafen concentrations, the drug appears to inhibit tubular reabsorption after gaining access to tubule fluid. As a consequence of its extensive binding to plasma proteins, clearance data suggest that tubular secretion of ticrynafen is necessary for its action.

Diuretics↗
PubMed1987

Familial renal hypouricemia with intact reabsorption of uric acid.

Three patients with renal hypouricemia in the same family are described. Serum urate levels in the mother were in the low normal range and were below normal in her 2 sons. In all 3 patients, the ratios of renal urate clearance to creatinine clearance were abnormally elevated. Clear responses to either pyrazinamide or probenecid administration were observed in these ratios. These results suggest that these 3 patients had renal hypouricemia with normal reabsorption of urate as judged by the criteria for differentiating abnormalities in renal urate handling. This corresponds to the previously postulated mechanism as renal urate hypersecretion. Possible limitations to the diagnostic use of probenecid and pyrazinamide are also discussed.

Adult↗
PubMed1992

Two cases of persistent hypouricemia associated with diabetes mellitus.

Two patients with diabetes mellitus had persistent hypouricemia due to increased urate clearance; the degree of the apparent renal hypouricemia with uricosuria was quite mild. At the onset of diabetes, their serum urate levels were normal. Even after good diabetes control in both cases, hypouricemia continued. Based on the pharmacological evaluation in both patients, pyrazinamide administration could partially decrease urate clearance, however, suppression by pyrazinamide was less than in normal subjects, and probenecid increased urate clearance. These results suggest that the present cases had a renal abnormality affecting tubular presecretory reabsorption of urate, which might be due to diabetes mellitus.

Aged↗
PubMed1993

Evidence of defective tubular reabsorption and normal secretion of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone.

The mechanisms responsible for the increased renal clearance of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are not fully clarified. Studies using either pyrazinamide or probenecid, or both drugs but at an interval of several days, could not undoubtedly distinguish the 'hypersecretory theory' from the one favoring a defect in either post- or presecretory reabsorption. We decided to do a combined pyrazinamide and probenecid test in 5 patients with hyponatremia due to SIADH in order to evaluate more clearly the respective importance of these different pathways. Our results allow the conclusion of a diminished presecretory and mainly postsecretory reabsorption (80 +/- 4.6 and 14 +/- 3% of filtered load, respectively). As far as the secretion of uric acid is concerned (17 +/- 10% of filtered load), we may say that this pathway is adapted to the amount of hypouricemia.

Absorption↗
PubMed1993

Renal hypouricemia due to enhanced tubular secretion of urate associated with urolithiasis: successful treatment of urolithiasis by alkalization of urine K+, Na(+)-citrate.

We encountered a case of hypouricemia with increases both in urate clearance (Cur) and in the ratio of Cur to creatinine clearance (Cur/Ccr), the normal daily urinary excretion of urate, and urolithiasis. Pyrazinamide markedly decreased Cur and Cur/Ccr, and both probenecid and benzbromarone markedly increased Cur and Cur/Ccr, however, benzbromarone did not increase either Cur or Cur/Ccr under pretreatment with pyrazinamide in the patient. Thus, the diagnosis was made of renal hypouricemia due to enhanced tubular secretion of urate. The urinary pH of the patient tended to be acidic. Three months after the start of alkalization of the patient's urine by K+, Na(+)-citrate, both urolithiasis and the symptoms related to urolithiasis disappeared. These results suggest that renal hypouricemia due to enhanced tubular secretion of urate can result in urolithiasis and the alkalization of urine may be an effective treatment for uric acid stones.

Benzbromarone↗
PubMed1988

Antimycobacterial drugs and the production of reactive oxidants by polymorphonuclear leucocytes in vitro.

The effect of five antimycobacterial drugs isoniazid, rifampicin, streptomycin, pyrazinamide and ethambutol on the generation of reactive oxidants by polymorphonuclear leucocytes was investigated in vitro, using N-formyl-L-methionyl-L-leucyl-phenylalanine (FMLP) activated and spontaneous luminol-enhanced chemiluminescence and myeloperoxidase-mediated iodination. Streptomycin, pyrazinamide and ethambutol had no effect on the assays at the concentrations investigated. Isoniazid as concentrations of 1.25 and 5 micrograms/ml and rifampicin at 100 micrograms/ml significantly inhibited iodination. Rifampicin also caused dose-dependent inhibition of chemiluminescence which was partly due to its light-absorbing activities. It is concluded that isoniazid, and to a lesser extent, rifampicin at therapeutic concentrations possess anti-oxidative properties.

Antitubercular Agents↗
PubMed1976

Exacerbation of porphyria during treatment of pulmonary tuberculosis.

Several attacks of acute intermittent porphyria complicated the treatment of a patient with pulmonary tuberculosis. To determine whether the attacks were drug-induced, the ability of a variety of antituberculous drugs to induce (delta)-amino-levulinic acid synthetase activity in a rat liver model was assessed. Pyrazinamide was found to be capable of significantly inducing amino-levulinic acid synthetase activity; the other antituberculous drugs caused either slight or no induction of amino-levulinic acid synthetase. The data suggest that pyrazinamide was capable of causing an exacerbation of the patient's porphyria. Tuberculosis, by causing debility, may also have aggravated this patient's previously latent porphyria.

5-Aminolevulinate Synthetase↗
PubMed1976

Controlled clinical trial of four 6-month regimens of chemotherapy for pulmonary tuberculosis. Second report. Second East African/British Medical Research Council Study.

A comparison has been made of the relapse rates between 7 and 30 months for four 6-month regimens. Streptomycin plus isoniazid plus rifampicin had a relapse rate of 2 per cent of 171 patients; isoniazid plus rifampicin had a relapse rate of 7 per cent of 164. An initial 2 months of streptomycin, isoniazid, rifampicin, and pyrazinamide, when followed by thiacetazone plus isoniazid, had a relapse rate of 7 per cent of 179, and when followed by streptomycin plus isoniazid plus pyrazinamide twice a week the relapse rate was 4 per cent of 159 patients. Of the 36 relapses, 32 occurred in the first 6 months after stopping chemotherapy and 35 were with drug-susceptible organisms. The difference between the relapse rate on the streptomycin plus isoniazid plus rifampicin regimen and the isoniazid plus rifampicin and thiacetazone plus isoniazid regimens approached significance (P =0.06 for both comparisons).

Adolescent↗
PubMed1979

Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis.

In a study in Singapore, Chinese, Malay, and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed either by daily treatment with isoniazid, rifampin, and pyrazinamide (SHRZ/HRZ regimen) or by daily administration of isoniazid and rifampin (SHRZ/HR regimen) allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli before treatment had a favorable bacteriologic response during chemotherapy. During the first 6 months after the end of chemotherapy, there was only a single bacteriologic relapse among 84 SHRZ/HRZ and 80 SHRZ/HR patients treated for 6 months, but 8 (10 per cent) of 80 SHRZ/HRZ and 4 (5 per cent) of 74 SHRZ/HR patients treated for 4 months relapsed. Of a total of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs before treatment, only one had an unfavorable response during chemotherapy, and none of 31 patients relapsed during the first 6 months after stopping chemotherapy. The incidence of adverse reactions was low; 11 (3 per cent) of 397 patients had hepatitis, but not all episodes were attributable to drug toxicity, and one patient had thrombocytopenic purpura.

Adolescent↗
PubMed1979

The cost of antituberculous drug regimens.

The relative costs of several highly effective short-course regimens have been compared for a developing and a developed country both for 1976 and 1978, with particular reference to the proportion of the total cost due to individual drugs. A convenient method of calculating costs for any individual country is provided. Of isoniazid, pyrazinamide, and rifampin, the 3 most important drugs in short-course chemotherapy, the cost and duration of the latter two have a major effect on the total cost. A decrease in the duration of a regimen from 9 to 6 months may decrease therapeutic effectiveness by as little as 5% or as much as 20%; the decrease in cost is often not proportional, because it depends on the drugs used in the continuation phase. The duration of pyrazinamide therapy has a considerable influence on cost, but the benefit of giving it beyond 2 months now needs to be re-evaluated. Factors that influence the choice of regimens are discussed. The importance of quality of the drugs, including purity and bioavailability, is stressed.

Antitubercular Agents↗
PubMed1982

Successful intermittent treatment of smear-positive pulmonary tuberculosis in six months: a cooperative study in Poland.

One hundred nineteen patients 15 to 70 yr of age, all with smear-positive, previously untreated, pulmonary tuberculosis, were treated with a 6-month regimen containing isoniazid and rifampin, supplemented during the initial 2 months with streptomycin and pyrazinamide. The 4 drugs were administered daily in the hospital during the initial 2 months, followed by isoniazid and rifampin administered twice weekly on an outpatient basis during the next 4 months. Adverse reactions to the drugs were seen in 19 patients, but only 6 had toxic reactions requiring withdrawal of drugs for 7 days or more. Three of the toxic reactions were attributed to streptomycin, 2 to rifampin, 1 to isoniazid, and none to pyrazinamide. Eighty-five (71%) of the 119 eligible patients completed treatment. After the first 2 months of therapy, 91% of these patients had negative sputum cultures, and all of them had negative cultures by the end of the third month of treatment. No relapses have occurred among the 84 patients observed for 18 months after therapy was completed.

Adolescent↗
PubMed1982

A controlled trial of six months chemotherapy in pulmonary tuberculosis. Second report: results during the 24 months after the end of chemotherapy. British Thoracic Association.

Two 6-month regimens of isoniazid and rifampicin supplemented for the first 2 months by streptomycin and pyrazinamide or by ethambutol and pyrazinamide were compared with a 9-month regimen of isoniazid and rifampicin supplemented for the first 2 months by ethambutol. All 444 patients who completed chemotherapy had negative sputum cultures by the end of treatment. Of these, 393 have been followed for 24 months after the end of chemotherapy. Relapse has occurred in 1 of 125 SHRZ6 patients, 3 of 132 EHRZ6, and 2 of 136 EHR9 patients. These observations suggest that both 5-month regimens are as effective as the currently recommended 9-month regimen and have the advantages of being shorter, cheaper, and equally well tolerated.

Antitubercular Agents↗
PubMed1985

Pharmacokinetic studies on antituberculosis regimens in humans. I. Absorption and metabolism of the compounds used in the initial intensive phase of the short-course regimens: single administration study.

The absorption and metabolism of streptomycin, isoniazid, rifampicin, and pyrazinamide were evaluated after administration of each drug alone and in combination. In the combination sessions, isoniazid, rifampicin, and pyrazinamide were administered orally, either individually or in a single fixed-ratio triple preparation. The results have shown that the pattern of absorption and metabolism (acetyl-isoniazid, desacetyl-rifampicin, and pyrazinoic acid) found after administration of each drug alone did not differ from that found after administration of the drugs in free and fixed combination. The 3 orally administered drugs given in a fixed combination resulted in a reduction of the order of 50% of the total number of tablets to be ingested.

Absorption↗
PubMed1986

Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis.

The response to short-course chemotherapy of patients with pulmonary tuberculosis caused by drug-resistant Mycobacterium tuberculosis was examined in 12 controlled trials carried out during the past decade in Africa, Hong Kong, and Singapore. Among those with initial resistance to isoniazid and/or streptomycin, failures during chemotherapy were encountered in 17% of 23 patients given a 6-month regimen of isoniazid and rifampin and in 12% of 264 patients given rifampin only in an initial 2-month intensive phase of their regimen. The proportion of failures fell as the number of drugs in the regimen and the duration of treatment with rifampin were increased, to reach 2% of 246 patients receiving 4 or 5 drugs including rifampin in 6-month regimens. The sterilizing activity of the regimens, whether these included rifampin or pyrazinamide, was little influenced by initial resistance, because the sputum conversion rate at 2 months was similar to that in patients with initially sensitive bacilli, and the relapse rates after chemotherapy were only a little higher. The response in the 11 patients with initial rifampin resistance was, however, much less good, failure during chemotherapy occurring in 5 and relapse afterwards in a further 3 patients. This review demonstrates the value of rifampin in preventing failure caused by the emergence of resistance during treatment and the greater sterilizing activity of rifampin and pyrazinamide compared with that of isoniazid and streptomycin.

Antitubercular Agents↗
PubMed1986

A controlled clinical trial of 3- and 5-month regimens in the treatment of sputum-positive pulmonary tuberculosis in South India. Tuberculosis Research Centre, Madras, and National Tuberculosis Institute, Bangalore.

A controlled comparison of 3 short-course regimens was undertaken in patients with newly diagnosed, sputum-positive, pulmonary tuberculosis in South India. The regimens were: R3: rifampin plus streptomycin plus isoniazid plus pyrazinamide daily for 3 months; 5: the same as regimen R3 followed by streptomycin plus isoniazid plus pyrazinamide twice weekly for 2 months; Z5: the same as regimen R5 but without rifampin. The distributions of various pretreatment characteristics were similar in the 3 series. At the end of treatment, 6 patients (3 R3, 3 Z5) of 694 (228 R3, 230 R5, 236 Z5) with drug-sensitive organisms initially were classified as having an unfavorable response. By 24 months (21 months of follow-up for the R3 regimen and 19 months for the R5 and Z5 regimens), a bacteriologic relapse requiring treatment occurred in 20% of 200 R3, 4% of 187 R5, and 13% of 199 Z5 patients, the difference between the R3 and R5 series being highly significant (p = 0.00001). Considering patients with cultures initially resistant to isoniazid, 4 of 57 in the R3 and R5 series combined had an unfavorable response to treatment compared with 13 of 26 in the Z5 series (p less than 0.0001). Of the 4 patients with an unfavorable response in the R3 and R5 series combined, resistance to rifampin emerged in 2. Complaints of arthralgia were made by 45% of the R3 and R5 patients combined and 70% of the Z5 patients (p less than 0.00001). However, chemotherapy was modified in only 5 and 12%, respectively. Jaundice occurred in 7% of the R3 and R5 patients and 1% of the Z5 patients (p less than 0.00001).

Adolescent↗
PubMed1986

American Thoracic Society. Medical Section of the American Lung Association: Treatment of tuberculosis and tuberculosis infection in adults and children.

Treatment of tuberculosis: A 6-month regimen consisting of isoniazid, rifampin, and pyrazinamide given for 2 months followed by isoniazid and rifampin for 4 months is effective treatment in patients with fully susceptible organisms who comply with the treatment regimen. It may be advisable to include ethambutol in the initial phase when isoniazid resistance is suspected. A 9-month regimen consisting of isoniazid and rifampin is also highly successful. The need for an additional drug in the initial phase is not certain unless isoniazid resistance is suspected, in which case ethambutol should be included until susceptibility tests have been reported. In the presence of documented resistance to isoniazid, rifampin and ethambutol, perhaps supplemented initially by pyrazinamide, should be given for minimum of 12 months. Children should be treated in essentially the same ways as adults using appropriately adjusted doses of the drugs. However, consideration must be given to the important differences in the approach to management in children. Extrapulmonary tuberculosis should be managed according to the principles and with the drug regimens outlined to pulmonary tuberculosis. The major determinant of the outcome of treatment is patient compliance. Careful attention should be paid to measures designed to foster compliance and to ensure that patients take the drugs as prescribed. Treatment of tuberculous infection: Preventive therapy with isoniazid given for 6 to 12 months is effective in decreasing the risk of future tuberculosis. (ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗