Since isoniazid is metabolized in man to several derivatives with little or no specific activity against the tubercle bacillus, its rate of inactivation in the body may have an important bearing on its efficacy as an antituberculosis drug. The inactivation rate, though constant in any one person, is known to vary from individual to individual and from race to race. A series of studies on the rate of inactivation of isoniazid in Indian patients with pulmonary tuberculosis has recently been undertaken at the Tuberculosis Chemotherapy Centre, Madras. The present paper describes the first of these studies, in which the concentration of isoniazid in the serum of patients admitted to a controlled comparison of four domiciliary chemotherapeutic regimens was determined by microbiological assay four-and-a-half hours after administration of a standard dose of isoniazid (3 mg/kg body-weight). Patients with serum levels of 0.58 mug/ml or more were classified as slow inactivators of isoniazid and those with levels below 0.58 mug/ml as rapid inactivators. By this definition, 195 (61%) of the 321 patients studied were found to be slow inactivators and 126 (39%) rapid inactivators. A relationship was shown between sex and the rate of inactivation, there being a significantly higher proportion of rapid inactivators among the females than among the males. The observed estimates of the error of the microbiological assay procedure are discussed and possible ways of reducing the error suggested.

Antitubercular Agents↗

PubMed1961

Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis. 3. Serum concentrations of isoniazid produced by three regimens of isoniazid alone and one of isoniazid plus PAS.

A series of studies on the rate of inactivation of isoniazid in Indian patients with pulmonary tuberculosis in a 1-year comparison of four domiciliary chemotherapeutic regimens-three of isoniazid alone, either in moderate (HI-1 and HI-2 regimens) or in low (H regimen) dosage, and one of isoniazid in low dosage plus p-aminosalicylic acid (PAS) (PH regimen) -has recently been undertaken by the Tuberculosis Chemotherapy Centre, Madras. This paper-the third of the series-presents information on the length of time during which inhibitory concentrations of isoniazid (0.2 mug/ml or more) were maintained in the serum and on the estimated peak serum concentrations of isoniazid produced by the four regimens and relates these factors to the therapeutic effectiveness of the different regimens.THE RESULTS SUGGESTED THAT: (a) the therapeutic superiority of the PH regimen over the isoniazid-alone regimens was only in part due to the effect of PAS in enhancing the serum levels of isoniazid; (b) the therapeutic superiority of the HI-1 regimen (moderate dosage, given in one dose a day) over the HI-2 and H regimens (moderate and low dosage, respectively, given in two doses a day) was due to the higher peak serum concentration of isoniazid produced rather than to the period minimal inhibitory concentrations of isoniazid were maintained in the serum; and (c) there was a possibility that raising the peak serum concentration of isoniazid above a critical concentration of about 3 mug/ml had a greater therapeutic effect than similar proportional increases below this concentration. It also appeared that the slightly better therapeutic response observed in the slow inactivators of isoniazid than in the rapid inactivators was due to the higher peak serum concentrations of isoniazid produced; the enhanced therapeutic effect was approximately the same as would be expected from a 50% increase in isoniazid dosage.

Humans↗

PubMed1961

Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis. 2. Clinical implications in the treatment of pulmonary tuberculosis with isoniazid either alone or in combination with PAS.

A series of studies on the rate of inactivation of isoniazid in Indian patients with pulmonary tuberculosis undergoing domiciliary chemotherapy with isoniazid, alone or in combination with p-aminosalicylic acid, has recently been undertaken by the Tuberculosis Chemotherapy Centre, Madras. In the first study, the serum isoniazid levels of the patients were determined four-and-a-half hours after intramuscular administration of a standard dose of 3 mg/kg body-weight of isoniazid and, according to whether the serum level was 0.58 mug/ml or above, or less than 0.58 mug/ml, the patient was classified as a slow or as a rapid inactivator. The present paper describes the second of these studies, in which the response to treatment of the slow and the rapid inactivators was compared. The results of this investigation suggested that there might be an association between response to treatment and rate of inactivation of isoniazid, since the slow inactivators were more often culture-negative during treatment and showed a higher proportion of individuals with bacteriologically quiescent disease at 12 months and a lower proportion with radiographic deterioration at six months than the rapid inactivators, while the slow inactivators who deteriorated radiographically or clinically to an extent warranting a change of treatment during the two years did so later than the corresponding rapid inactivators. There was slight evidence that the slow and the rapid inactivators differed in the speed of conversion to bacteriological negativity of those patients whose disease was bacteriologically quiescent at 12 months, but no evidence that they differed in the degree of positivity of sputum specimens that were positive on culture at six, nine or 12 months, or in the frequency with which the patients showed moderate or greater radiographic improvement at six months.

Humans↗

PubMed1961

Progress in the second year of patients with quiescent pulmonary tuberculosis after a year of domiciliary chemotherapy, and influence of further chemotherapy on the relapse rate.

This study from the Tuberculosis Chemotherapy Centre, Madras, summarizes the progress during the second year of those patients in a 1-year comparison of four domiciliary chemotherapeutic regimens (isoniazid plus PAS and three regimens of isoniazid alone) whose pulmonary tuberculosis had attained bacteriological quiescence at the end of the year of chemotherapy. During the second year, about half of the patients received further chemotherapy, with isoniazid alone, and the remainder received a placebo, calcium gluconate. The main objects of the study were to determine the influence on the progress during the second year of (a) a second year of chemotherapy with isoniazid alone, (b) residual cavitation at the end of the first year, and (c) the chemotherapeutic regimen received during the first year, and to compare the results with those obtained in an earlier study by the Centre of the progress during the second year of patients with quiescent pulmonary tuberculosis after a year's chemotherapy with isoniazid plus PAS at home or in sanatorium.The results of the present study, which was planned on the same lines as the earlier one, showed that relapse in the second year was unrelated to the chemotherapeutic regimen received in the first year, and it was therefore permissible to amalgamate the findings in the two studies. The amalgamated results showed that the relapse rate in the second year was low (5.9%) and that a second year of treatment with isoniazid alone was of definite value for the patients with no residual cavitation at the end of the first year, but had no effect on the relapse rate of those with residual cavitation. The combined data from the two studies have thus clarified the position with regard to the effectiveness of isoniazid in preventing bacteriological relapse in patients without residual cavitation, slight evidence of which was apparent in the earlier study.

Aminosalicylic Acid↗

PubMed1960

Peripheral neuritis due to isoniazid.

It is well known that in the treatment of tuberculosis with isoniazid the complication of peripheral neuritis may arise. This complication is normally rare when small dosages of the drug are used, but a high incidence of the neuropathy has recently been observed in East Africa in a group of malnourished tuberculous patients receiving isoniazid in comparatively low dosage (4-6 mg/kg body-weight daily). The present paper reports on 20 cases of peripheral neuritis encountered in Madras, India, among 338 poorly nourished tuberculous patients during a trial of four isoniazid regimens, two of low and two of high dosage (3.9-5.5 and 7.8-9.6 mg/kg body-weight daily, respectively). Nineteen of the 20 cases occurred in the two groups of patients receiving the high dosage and these 19 patients were found to have a higher mean serum level of free isoniazid than the patients in the same groups who did not develop the complication. The authors consider that dosages of 7.8-9.6 mg/kg body-weight daily should not be used for the mass therapy of poorly nourished patients unless steps are taken to prevent the development of peripheral neuritis. Pyridoxine has been reported to be an effective preventive, but is too expensive for use on a large scale. This study indicates, however, that administration of the cheaper vitamin B complex might give satisfactory results and warrants further investigation.

Africa, Eastern↗

PubMed1958

[The detection of isoniazid in urine].

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Body Fluids↗