Effect of administration of rifampicin on the adrenocortical function in patients with pulmonary tuerculosis

The ACTH (synacthen) stimulation test was performed on admission and after 4 weeks of treatment in 17 pulmonary tuberculosis patients receiving daily Rifampicin regimen (R-7), 22 patients on a twice-weekly Rifampicin regimen (R-2) and 19 patients on a daily non Rifampicin regimen (NR-7). A positive response to synacthen was observed in 8 R-7, 16 R-2 and 8 NR-7 patients on admission and in 7, 15 and 15 patients respectively at 4 weeks. The increase in the proportion of positive responders among the NR-7 patients was significant (P = 0.02). Three R-7 and 2 R-2 patients who were positive responders to synacthen on admission became negative responders at 4 weeks, a phenomenon not observed in the NR-7 patients. These findings suggest that Rifampicin probably exerts a deleterious effect on the adrenocortical function

Genetic control of drug metabolism and drug action in man

The study of genetic factors that modify the individual response to drugs, referred to as "pharmacogenetics" is relatively new field, a discipline at the interface between genetic and clinical pharmacology. In the short period since Motulsky (1) emphasized the importance of genetics to pharmacology and Vogel coined the term "pharmacogenetics", an impressive number of examples in man has accumulated in which inherited differences account for strikingly exaggerated responses to drugs, novel drug effects, or lack of effectiveness of drugs given in the usual dosage. More recently, we have come to realize that genetic factors are in large measure responsible for the individual variability in response to drugs conferring on each patient a "pharmacologic individuality". The objectives of pharmacogenetics include the identification of genetically controlled variations in response to drugs and the study of the molecular basis for these conditions, their clinical significance, and most important, the development of simple methods by which susceptible individuals can be recognized before the drug is administered

Effect of Anti-tuberculosis Drugs on the Iron- Sequestration Mechanisms of Mycobacteria

The effect of sub-lethal concent-rations of isoniazid, ethambutol, rifampicin and pyrazinamide on the growth in vitro and the production of both exochelins and mycobactins by the high virulent and the South Indian low virulent strains of M. tuberculosis was examined under iron-deficient and iron-rich conditions. There was a marked decrease in the growth of both strains in the presence of increasing concentrations of all four drugs, the inhibition being total in the presence of minimal inhibitory concentrations of the drugs. It was also observed that the growthinhibitory effect of all four drugs was slightly reversed in the presence of high concentration of iron in the medium. A significant increase was observed in the concentrations of both siderophores in the presence of all four drugs, under both iron-deficient (or) iron-rich conditions

Siderophore-mediated iron uptake in mycobacteria

Iron is vital for the survival and proliferation of microorganisms, while mycobacteria also require this element for their survival within the host. To meet the demand for iron, mycobacteria synthesise and utilise specific high-affinity iron-binding compounds (siderophores) which help them grow in the’ iron-restricted conditions of the host [1, 2] and also participate in the uptake of iron across the thick lipid cell wall [3]. Two types of siderophores are produced by mycobacteria [3]. Exochelin occurs extracellularly to act as a scavenger, and mycobactin occurs on the cell wall to act as a transporter. Specific membrane proteins are also produced by several mycobacteria for the transport of siderophore-ferric iron complexes [4]. Recent work [5] demonstrated that the growth of Mycobacterium tuberculosis strains was increased with increasing concentrations of iron in the medium and that the concentrations of exochelins and mycobactins, which are highest under iron-deficient conditions, registered marked decreases. It does not follow, however, that exochelins are involved in the uptake of iron by mycobacteria. We have therefore studied the uptake of iron by four strains of mycobacteria in the absence and in the presence of exochelins released by these strains

Effect of haemoglobin on the growth of mycobacteria and production of siderophores

Hemoglobin is known to support the growth of several bacterial species. The growth and the production of siderophores by 4 strains of mycobacteria in the presence of hemoglobin was studied in vitro. The findings were compared with those obtained in the presence of equivalent concentrations of iron in the medium. Increase in the concentrations of hemoglobin caused an appreciable increase in the growth of all 4 strains. This was however, accompanied by a significant decrease in the production of both exochelins and mycobactins. It was also observed that hemoglobin supported the growth of all strains as well as that with free iron and the concentrations of both siderophores was significantly higher in the presence of hemoglobin than in that of free iron

Effect of iron on the growth and siderophore production of mycobacteria

To gain a better understanding of the role of iron in the pathogenesis of tuberculosis, the growth and production of siderophores were studied in the presence of different concentrations of free iron in vitro with M. smegmatis and virulent, avirulent and low virulent strains of M. tuberculosis. Increase in the concentrations of iron caused an appreciable increase in the growth (as assessed by cell dry-weight and log viable counts) of all 4 strains. This was, however accompanied by a significant decrease in the production of both exochelins and mycobactins, suggesting that these siderophores are necessary only under iron-deficient conditions. The growth and production of siderophores were significantly higher with the virulent strain of M.tuberculosis than with the avirulent (or) the low virulent strains

Uric acid disposition during intermittent chemotherapy of pulmonary tuberculosis with regimens containing pyrazinamide & rifampicin

Uric acid disposition during intermittent chemotherapy of pulmonary tuberculosis was studied in 13 patients allocated to a thrice-weekly regimen containing pyrazinamide in addition to rifampicin, isoniazid and streptomycin and in 19 patients allocated to a twice-weekly regimen of the same four drugs; the dosage of pyrazinam ide was 50 mg/kg in the former and 70 mg/kg in the latter. In the thrice-weekly series, the mean serum uric acid concentration ½ h before drug administration at 2 months (5.5 mg/dl) was significantly higher (P< 0.001) than that on admission (3.2 mg/ dl); hyperuricaemia (>7 mg/dl) was observed in none of the patients on admission and in 3 at 2 months. In the twice-weekly series, the two values (3.4 and 3.1 mg/dl, respectively) were similar, and none of the patients bad hyperuricaemia. The mean concentrations 5 h after drug administration at 2 months were significantly higher (P< 0.001) than those before drug administration in both the series (6.6 and 4.8 mg/dl, respectively), and hyperuricaemia was observed in 4 patients, all in the thrice weekly series

Methods for the estimation of pyrazinamide and pyrazinoic acid in body fluids

zinoic acid in urine using an anion-exchange resin (Dowex-1) have been described. Recoveries were quantitative, and the sensitivity was 5 μg/ml for ail 3 estimations. In serum, pyrazinoic acid at a concentration of 50 μg/ml did not interfere with the estimation of pyrazinamide. In urine, pyrazinamide and pyrazinoic acid could be separated from each other and estimated even when the 2 compounds were present together at concentrations of 2000 μg/ml each

Acute phase proteins in tuberculous patients

The serum concentrations of some acute phase proteins were determined on admission, during treatment, at the end of treatment and at 12 months after stopping treatment in 20 patients with pulmonary tuberculosis. Measurements were also made, on admission and at the end of treatment, in 19 patients with abdominal tuberculosis, and 11 children with tuberculous meningitis. All 20 patients with pulmonary TB had quiescent disease by the end of treatment and none had a bacteriological relapse during the followup period of 12 months. The response to treatment was considered favorable in 18 of the 19 patients with abdominal TB, and the CSF findings had returned to normal in 9 of 11 patients with TB meningitis. There was a significant decrease with treatment in the concentrations of C-reactive protein, ceruloplasmin, haptoglobin and a1 -acid glycoprotein in all 3 groups of patients. While there was an increase in the concentrations of transferrin in patients with pulmonary and abdominal TB, there was a significant decrease in those with TB meningitis, a2- macroglobulin did not appear to function as an acute phase reactant in any of the 3 groups. Amalgamating the findings in all 3 groups of tuberculous patients, the proportions of patients with abnormal values on admission and at the end of treatment were 62% and 14% for C-reactive protein, 78% and 50% for ceruloplasmin, 86% and 26% for haptoglobin and 92% and 6% for a1- acid glycoprotein, respectively

Self-induction of rifampicin metabolism in man

Self-induction of rifampicin metabolism caused by daily administration of the drug was studied in 7 healthy subjects. Rifampicin 600 mg was administered daily for 10 days and additional doses were administered on the 4th and 8th days after drug administration ceased. The mean serum half-life of rifampicin decreased from 4.9 h on the 1st day to 3.5 h on the 4th day (P<0.01), to 2.7 h on the 7th day (P<0.001), and 2.5 h on the 10th day (P<0.001). The difference between the mean values on the 7th and the 10th days was not significant. The mean value on the 8th day after stopping drag administration (3.8 h), was significantly higher than that on the last day of daily administration (P=0.02), but was still lower than that on the 1st day (P=0.05). There was a decrease in the excretion of both rifampicin and desacetylrifampicin in urine on induction, followed by a gradual return to normal when drug administration was stopped