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Biomedical subjects

D A Mitchison

Publications and source records attributed to D A Mitchison.

At least 55 records · Page 3Linked to original sources
PubMed1994

Effect of vaccines in a murine model of dormant tuberculosis.

SETTING: The value of Mycobacterium vaccae vaccine in immunotherapy is of current interest. OBJECTIVE: A series of 3 experiments was carried out using the Cornell model of dormant tuberculosis in the mouse to see whether M. vaccae and BCG vaccines would alter the rate of relapse to active disease. DESIGN: In each experiment, BALB/c mice were infected intravenously with M. tuberculosis strain H37Rv and the disease was allowed to progress for 2 weeks to the point where the spleens yielded about 10(7) colony forming units (cfu). Treatment with 25 mg isoniazid/kg and 1000 mg pyrazinamide/kg in the diet was given for 14 weeks when the spleens and lungs usually yielded negative cultures only (the sterile state). The mice were then divided into 3 groups each of 30-49 mice, one of which received a heat-killed M. vaccae vaccine, another BCG vaccine and the third a control saline injection. The mice were killed 3 months later and the spleens and lungs cultured. RESULTS: Neither of the vaccines altered the relapse rate from the sterile state. CONCLUSION: Immunotherapy does not influence relapse from the dormant state and probably therefore human endogenous reactivation. However, vaccine dosage was not studied, nor do mice necessarily model human response.

Animals↗
PubMed1993

DNA analysis demonstrates that mycococcus forms are not mycobacteria.

Previous experimental evidence has suggested that the mycobacteria may exist in morphological forms other than the well characterised acid-fast bacillus. However none of these studies have been able to show conclusively that these variant forms are derived from the mycobacteria and therefore much debate has centered around the exact nature of these organisms. In this study we have examined stored cultures of the mycococcus form of Mycobacterium bovis BCG and M. phlei which were prepared by Csillag in 1972 and 1969. Restriction fragment patterns of the DNA of the variant forms and the parent mycobacteria were not similar and chromosomal DNA from the parent mycobacteria did not hybridise with the DNA of the variant forms. Furthermore biochemical studies indicate that the variant forms are environmental contaminants. Although this study shows conclusively that the mycococcus is not derived from the mycobacteria, we believe that the search for variant morphological or metabolic forms of the mycobacteria should remain an active area of investigation, but that no study should be considered complete without the full use of newer molecular technology.

Animals↗
PubMed1993

Application of DNA fingerprinting with IS986 to sequential mycobacterial isolates obtained from pulmonary tuberculosis patients in Hong Kong before, during and after short-course chemotherapy.

A total of 266 Mycobacterium tuberculosis isolates were subjected to DNA RFLP analysis. They were obtained from monthly sputum cultures from patients treated with short-course chemotherapy and then followed up for 2 years. They originated from 42 patients who relapsed after short-course chemotherapy and from a further 42 patients who yielded a single isolated positive culture after chemotherapy. The isolates consisted of one obtained pretreatment and the last obtained during chemotherapy, together with either two isolates cultured at least 2 months apart during relapse or the single post-chemotherapy isolate. They were coded before DNA RFLP analysis and assigned to groups with identical or near identical band patterns on visual inspection. After decoding, it was evident that almost every patient was infected with a strain with a different band pattern (fingerprint). In 100 comparisons of either the pretreatment isolate against the last positive isolate obtained during chemotherapy, or of the first relapse isolate against the second relapse isolate, 15 had been recorded as different; 4 of these were retrospectively found to be due to reading error (error rate 1.5%), leaving 11 (11%) with marked differences. For 5 (12%) of the 42 patients who relapsed, the fingerprint of the relapse isolate was markedly different from that of the pretreatment isolate. In contrast, the isolated positive culture was markedly different from that initially present in 36 (90%) of 40 comparisons. The relative contributions by clinical mixed infection and laboratory cross-contamination to the remaining 10-12% discrepancy rates could not be assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitubercular Agents↗
PubMed1993

Turning intermittent regimens into daily regimens using blister-packs. An exploration in murine tuberculosis.

SETTING: Blisterpacks might be used to present low cost intermittent regimens while maintaining an easily remembered daily frequency of opening blisters, by alternating blisters containing 2 of the drugs of a 4-drug regimen with blisters containing the remaining 2 drugs. OBJECTIVE: The efficacy of the alternating regimens was examined in murine tuberculosis. DESIGN: 2 weeks after infection with Mycobacterium tuberculosis H37Rv, groups of mice were treated with rifampicin (R) 15 mg/kg, isoniazid (H) 25 mg/kg, pyrazinamide (Z) 300 mg/kg, ethambutol (E) 100 mg/kg three times weekly (RHZE3); RH/ZE, an alternating regimen of RH on days 1, 3 and 5 of the week and ZE on days 2, 4 and 6, RZ/HE or RE/HZ. RESULTS: Spleen and lung bacillary counts at 7 and 12 weeks indicated large differences in the efficacy of the regimens: RZ/HE > RE/HZ > RHZE3 > RH/ZE. Serum assays showed that Rifampicin (RMP) levels were much lower after HRZE and slightly lower after RZ, RE and RH than after R alone, whereas levels were similar when R was given before the remaining drugs; also, the absorption of Z was slightly increased by R. A second experiment used the same 4 regimens but gave R before other drugs. The organ colony forming units counts at 6 and 12 weeks were then similar. A third experiment examined continuation phase regimens of R3, R2, R2H2 and R2H6 given after daily RHZ treatment for 4 weeks. It found R2H2 only slightly superior to R2H6 and R3 much better than R2. CONCLUSION: 1. Alternating initial phase regimens were as effective as conventional intermittent regimens. 2. R3H6 might be an optimal continuation phase regimen for blisterpacks.

Animals↗
PubMed1993

The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts: a new method of drug assessment.

The activity of rifabutin and rifampicin against rapidly growing, extra-cellular Mycobacterium tuberculosis in cavity walls was measured by counting colony-forming units (cfu) in the sputum of 74 patients with newly diagnosed, severe pulmonary tuberculosis during the first 2 days of daily chemotherapy. The fall in counts, (log10 cfu/mL sputum/day), was termed the early bactericidal activity (EBA). The EBA, a highly reproducible measure within groups of 10-13 patients, was -0.015 for a low EBA reference group (who received no chemotherapy) and 0.495 for a high EBA reference group (who received 300 mg isoniazid daily). The EBAs in patients receiving 300 and 600 mg rifabutin were 0.014 and 0.075, and for those taking 150, 300 and 600 mg rifampicin 0.021, 0.150 and 0.204, respectively. Weight-for-weight, the ratio rifabutin to rifampicin producing the same EBA was estimated to be 2.73 (95% confidence limits 1.96-3.78). Determination of the EBA is a rapid and economical method of comparing the potency in human lesions of drugs of the same type before embarking on a conventional clinical trial.

Adolescent↗
PubMed1993

Monocyte antimycobacterial activity before and after Mycobacterium bovis BCG vaccination in Chingleput, India, and London, United Kingdom.

Monocytes from purified protein derivative S Mantoux-negative children and young adults inhibited intracellular growth of Mycobacterium microti more in Chingleput than in London. Mycobacterium bovis BCG vaccination did not enhance bacteriostasis with the Indians but did so with the Londoners. No evidence was found for involvement of cytokines such as macrophage-activating factor and granulocyte macrophage colony-stimulating factor in the differences.

BCG Vaccine↗
PubMed1992

Activity of two long-acting rifamycins, rifapentine and FCE 22807, in experimental murine tuberculosis.

The efficacy of the long-acting rifamycins, rifapentine (RPE) and FCE 22807 (FCE) in experimental murine tuberculosis was studied by counting viable bacilli in spleens. At 2 weeks after infection with Mycobacterium tuberculosis, strain H37Rv, treatment with isoniazid 25 mg/kg, rifampicin 10 mg/kg and pyrazinamide 150 mg/kg was given daily for 6 weeks. The mice were then divided into groups given RPE or FCE at intervals of 1, 2 or 3 weeks with spleen counts after 18 and 24 weeks of chemotherapy. The first experiment showed the great effect of the size of the dose of RPE, which, in once-weekly regimens, caused rapid sterilization at 16 mg/kg, less rapid sterilization at 10 mg/kg and incomplete activity at 6.25 mg/kg. Regimens of RPE given every 2 or 3 weeks were less effective, though 16 mg/kg fortnightly was as good as 6 mg/kg once-weekly. The second experiment compared RPE and FCE each given at 12 or 8 mg/kg. The results were similar though, at 8 mg/kg every 2 or 3 weeks, FCE was slightly more effective than RPE. Serum assays showed that the levels with 8 and 12 mg/kg FCE were lower than those produced even by 6.25 mg/kg RPE, suggesting that FCE would be a better drug than RPE if its bioavailability could be improved, and that the levels following 16 mg/kg RPE were similar to those found in man after 8 mg/kg RPE taken with a fat-rich meal, suggesting good prospects for effective once-fortnightly human treatment. The potential for long-acting rifamycins in the management of pulmonary tuberculosis is discussed.

Animals↗
PubMed1992

The early bactericidal activity of rifabutin measured by sputum viable counts in Hong Kong patients with pulmonary tuberculosis.

Previously untreated patients with smear-positive pulmonary tuberculosis were randomly allocated to treatment with 600, 300, 150 or 75 mg doses of rifabutin (LM427, ansamycin), 600, 300 or 150 mg of rifampicin, 300 mg isoniazid or to no drug daily for 2 days. The fall in viable counts of Mycobacterium tuberculosis in sputum collections during the 2 days, termed the early bactericidal activity (EBA), was estimated from counts of colony-forming units (cfu) on selective 7H-11 agar medium. The EBA for rifabutin ranged from -0.039 (an increase in counts) to 0.049 log10 cfu/ml/day whereas the EBA increased from 0.071 for 150 mg rifampicin to 0.293 log10 cfu/ml/day for 600 mg rifampicin and was 0.43 log10 cfu/ml/day for 300 mg isoniazid. The difference between the EBAs for rifabutin and rifampicin just attained significance (P = 0.05) suggesting that rifabutin was inactive or less active than rifampicin against the extracellular bacilli in pulmonary cavities. Peak plasma concentrations of rifabutin after the initial doses were found to be proportional to dose size and were approximately 7 times lower than those after the same dose size of rifampicin. The lower EBA of rifabutin as compared to rifampicin is probably due to the low plasma concentrations which are not fully compensated for by slightly greater antituberculosis activity of rifabutin in vitro.

Adolescent↗
PubMed1992

The pattern of mycobacterial antigen recognition in sera from Mantoux-negative individuals is essentially unaffected by bacille Calmette-Guérin (BCG) vaccination in either south India or London.

Paired sera were obtained before and 8 weeks after routine BCG vaccination from 20 PPD-S Mantoux-negative individuals who were living adjacent to the Chingleput BCG vaccine trial area in Tamil Nadu and from seven Mantoux-negative school-children in London, UK. Most subjects became Mantoux-positive after vaccination. In ELISA tests against soluble extracts of BCG or Mycobacterium tuberculosis H37Rv or against PPD-S, pre-vaccination antibody titres of South Indian subjects were about twice those of British subjects but there was no increase in titre of antibodies after vaccination of either population. Western blotting showed that even before vaccination, and even in British subjects, antibodies were present that recognized numerous antigenic components in extracts of BCG and M. tuberculosis. There was no consistent difference between band patterns with South Indian and British subjects and any effect of vaccination on the patterns was minimal.

Adolescent↗
PubMed1992

Activity in vitro of rifabutin, FCE 22807, rifapentine, and rifampin against Mycobacterium microti and M. tuberculosis and their penetration into mouse peritoneal macrophages.

The activities of the rifamycins, rifabutin, FCE 22807, rifapentine, and rifampin, were studied within unstimulated peritoneal macrophages infected with Mycobacterium microti and in cultures of M. microti and M. tuberculosis in 7H-9 medium without Tween 80. In macrophage cultures, serial rifamycin concentrations were added after a 2.5 h phagocytosis period, and viable counts were done after incubation for 5 to 6 days. To ensure comparability with the daily drug replacements in the macrophage experiments, the period of exposure to serial rifamycin concentrations in 7H-9 medium was kept to only 3 days. The MICs of M. microti and M. tuberculosis were similar. The MICs of rifabutin and FCE 22807 were 2.5 times lower and that of rifapentine 1.7 times lower than the MIC of rifampin. None of the rifamycins were concentrated in macrophages, the MICs being higher in the macrophages than in vitro by a factor of 2-fold for rifabutin, 6.7-fold for rifampin, 20-fold for FCE 22807, and 26-fold for rifapentine.

Animals↗