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Biomedical subjects

J B SELKON

Publications and source records attributed to J B SELKON.

At least 19 recordsLinked to original sources
PubMed1964

THE EMERGENCE OF ISONIAZID-RESISTANT CULTURES IN PATIENTS WITH PULMONARY TUBERCULOSIS DURING TREATMENT WITH ISONIAZID ALONE OR ISONIAZID PLUS PAS.

Previous reports from the Tuberculosis Chemotherapy Centre, Madras, have described a comparison of four regimens (three of isoniazid alone and one of isoniazid plus PAS) in the treatment of pulmonary tuberculosis and an investigation of the serum isoniazid levels in the patients concerned. The present report studies the emergence of isoniazid-resistant organisms in these patients during treatment. All patients with an unsatisfactory response to treatment yielded resistant cultures, showing that the isoniazid dosage was never too low to inhibit sensitive organisms. From the degree of resistance of the first resistant cultures and of the six-month cultures from the patients treated with isoniazid alone it was concluded that resistance emerged in two stages. In the first stage, very earlyin treatment, highly resistant mutant bacilli grew freely whatever the isoniazid dosage, but mutants of lower resistance were prevented from growing to an extent dependent on the peak isoniazid concentration in the serum. Consequently, when the isoniazid dosage was increased the proportion of patients with resistant organisms decreased, since fewer low-resistance strains were able to develop. In the second stage, organisms with relatively low resistance continued to multiply, though still partially inhibited by isoniazid, and became more resistant, particularly in slow inactivators. The first-stage events determined the results of treatment since, once resistance had emerged, its extent was unrelated to the patient's eventual progress. These findings emphasize the importance of early intensive chemotherapy and adjustment of the isoniazid dosage according to peak serum concentrations rather than concentrations measured three or six hours after the dose. Concomitant administration of PAS prevented emergence of isoniazid resistance in many patients and in others delayed its emergence and reduced its degree, possibly because growth in the second stage was slow.

Aminosalicylic Acid↗
PubMed1963

A COMPARISON OF THE VIRULENCE IN THE GUINEA-PIG OF TUBERCLE BACILLI FROM THAI AND BRITISH PATIENTS.

Recent work carried out at the Tuberculosis Chemotherapy Centre, Madras, and at the Postgraduate Medical School of London has shown that isoniazid-sensitive cultures of tubercle bacilli obtained before the start of chemotherapy from South Indian patients with pulmonary tuberculosis are of lower average virulence than corresponding cultures from British patients. The present paper from the Centre extends these studies to areas outside India by comparing isoniazid-sensitive cultures from 81 Thai patients and 67 British patients for their guinea-pig virulence. As assessed by the amount of disease visible at post-mortem examination six weeks after intramuscular injection of the cultures, by the mortality of the guinea-pigs and by the results of spleen culture, the Thai cultures were less virulent than the British cultures. However, a retrospective comparison with the earlier studies suggests that the Thai cultures were intermediate in their virulence between British and Indian cultures. These findings contribute to the over-all study of the geographical distribution of attenuated tubercle bacilli.

Animals↗
PubMed1962

The course of pulmonary tuberculosis in patients excreting organisms which have acquired resistance. Response to continued treatment for a second year with isoniazid alone or with isoniazid plus PAS.

This study from the Tuberculosis Chemotherapy Centre, Madras, summarizes the progress during the second year of the patients in a concurrent comparison of four domiciliary chemotherapeutic regimens (isoniazid plus PAS and three regimens of isoniazid alone) who had bacteriologically active or bacteriologically relapsed pulmonary tuberculosis, with isoniazid-resistant organisms, at the end of the first year of treatment.Of the 57 patients who continued on the same chemotherapy during the second year, nine had attained bacteriological quiescence by the end of that year, 15 still had bacteriologically active disease and 33 had during the year had a serious radiographic deterioration necessitating a change of treatment. An association was observed between the response to treatment in the second year and both the extent of cavitation and the degree of culture-positivity at the end of the first year, but no association was found between the response to treatment in the second year and the level of isoniazid-resistance, the catalase activity, the susceptibility to hydrogen peroxide or the virulence in the guinea-pig of cultures isolated in the last months of the first year.It is concluded that persisting bacteriological positivity at the end of one year's treatment with isoniazid, either alone or in combination with PAS, is likely to lead to serious radiographic deterioration, irrespective of the level of isoniazid-resistance or of the catalase activity of the cultures of tubercle bacilli, and that, consequently, treatment of patients with bacteriologically active pulmonary tuberculosis must aim at rendering the sputum culture-negative in all instances.

4-Aminobenzoic Acid↗
PubMed1961

The virulence in the guinea-pig of tubercle bacilli isolated before treatment from South Indian patients with pulmonary tuberculosis. 2. Comparison with virulence of tubercle bacilli from British patients.

A series of studies has been undertaken by the Tuberculosis Chemotherapy Centre Madras, with the ultimate object of finding out whether differences in the virulence of the tubercle bacilli isolated from Indian tuberculous patients before the start of chemotherapy are related to the severity of the patients' disease and to the subsequent response to treatment. This paper-the second in the series-presents the results of a comparative investigation of the virulence in the guinea-pig of tubercle bacilli obtained from Indian and from British tuberculous patients before treatment. In this investigation, which was carried out at the Centre and at the Microbiological Research Establishment, Porton, England, the virulence of the Indian and the British cultures was assessed by guinea-pig mortality, by the "root-index of virulence" (based on the post-mortem tuberculous disease score and the survival period of the animal), and by the results of spleen culture. The Indian cultures were found, on the average, to be less virulent and to show a w der range of virulence than the British cultures, both in the Porton and in the Madras series of experiments. A further indication of the heterogeneity of the Indian tubercle bacilli was provided by the results of tuberculin tests: whereas the British cultures appeared to be homogeneous in their ability to induce tuberculin allergy in the guinea-pig, the Indian cultures showed considerable variation in this respect.

Animals↗
PubMed1961

Response of patients infected with isoniazid-resistant tubercle bacilli to treatment with isoniazid plus PAS or isoniazid alone.

This study from the Tuberculosis Chemotherapy Centre, Madras, compares patients infected with isoniazid-resistant tubercle bacilli ("R" patients) with those infected with isoniazid-sensitive tubercle bacilli ("S" patients) as regards, first, their pretreatment status and, secondly, their response to a year's chemotherapy, either with isoniazid plus p-aminosalicylic acid (PAS) or with isoniazid alone. With regard to the first comparison, there was, on admission to treatment, little difference between the R and S patients in terms of the extent of the radiographic lesion, the extent of cavitation or the bacterial content of the sputum, but there were major differences in the age and sex distributions, the R patients showing a greater preponderance of young males than the S patients. As to the second comparison, statistically significant differences in the bacteriological response to treatment of the S and the R patients were observed in both the isoniazid-plus-PAS and the isoniazid-alone series, the response of the S patients being much better than that of the R patients. When the response to treatment was assessed in terms of radiographic progress and weight changes, however, hardly any difference was observed between the progress of the S and the R patients. The reasons for the response in the R patients are discussed.

Bacillus↗
PubMed1961

Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis.

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

The virulence in the guinea-pig of isoniazid-sensitive tubercle bacilli isolated from South Indian patients before treatment and after three months of chemotherapy.

In order to find out whether chemotherapy with isoniazid affects the virulence in the guinea-pig of tubercle bacilli that do not develop resistance to the drug, virulence tests were carried out on isoniazid-sensitive cultures obtained from 20 South Indian tuberculous patients before treatment and after three months of chemotherapy with isoniazid. No significant difference in virulence was observed between the cultures obtained on admission to treatment and those obtained after three months of chemotherapy. This is a finding with important implications for large-scale surveys of the distribution of attenuated strains of tubercle bacilli from untreated patients in India and other countries. Detailed and repeated inquiries as to previous chemotherapy are not important in such surveys, provided that sensitivity tests are done on all the cultures.

Bacillus↗
PubMed1961

Identification of tubercle bacilli from Indian patients with pulmonary tuberculosis.

Pretreatment cultures of bacilli from Indian patients with active pulmonary tuberculosis admitted to a controlled domiciliary chemotherapy study by the Tuberculosis Chemotherapy Centre, Madras, were subjected to a series of in vitro tests designed to identify the bacilli as human or bovine tubercle bacilli, or as anonymous mycobacteria. For the purposes of comparison, pretreatment cultures from British patients with pulmonary tuberculosis were examined by the same series of identification tests.Cultures identifiable as mammalian tubercle bacilli were obtained from all the 341 Indian patients admitted to the chemotherapy study. Tests for niacin production were carried out on the cultures from 277 of these patients; all gave positive results, indicating that the bacilli in question were Mycobacterium tuberculosis var. hominis. The cultures from the Indian patients yielded results similar to those of the cultures from the British patients in all the in vitro tests except the thiacetazone-sensitivity test. In this test the Indian cultures differed from the British cultures, being on the average less sensitive and showing greater variation in sensitivity among themselves.

Animals↗
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↗
PubMed1961

The virulence in the guinea-pig of tubercle bacilli isolated before treatment from South Indian patients with pulmonary tuberculosis. I. Homogeneity of the investigation and a critique of the virulence test.

A series of studies on the virulence in the guinea-pig of tubercle bacilli isolated before treatment from Indian tuberculous patients admitted to a controlled comparison of different regimens of domiciliary chemotherapy has recently been undertaken by the Tuberculosis Chemotherapy Centre, Madras. The main object of these studies was to determine whether the differences in virulence of the tubercle bacilli obtained from Indian patients before the start of chemotherapy were related to the severity or type of the patients' disease at that time and to the subsequent response to treatment. Before these relationships could be investigated, however, it was necessary to find out whether the results of the virulence tests, which were carried out over a period of two-and-a-half years at the Centre and at the Microbiological Research Establishment, Porton, England, could be considered as a unified whole-that is, as if they had all been done on the same day in the same laboratory.A proportion of the cultures was stored at - 20 degrees C for 44-78 weeks, but this did not affect their virulence. Inter-experimental variation was found to be small in the Porton series of tests and undetectable in the Madras series, and the results in the latter series could be successfully adjusted to those in the former by allowing for differences in the means and standard deviations of the distributions for the two series. The measure of virulence used was found to be reasonably acceptable for the analysis of variance technique. Suggestions are made as to ways of improving the efficiency of the experimental design in future studies.

Bacillus↗