Effects of age, BMI, smoking and contraception on levels of Cu, Se and Zn in the blood of the population in the Czech Republic.

Variations in the levels of Cu, Se and Zn in blood were analyzed in relation to gender, age, BMI, smoking and hormonal contraception. The blood samples were collected from 3,207 blood donors (2,362 men, 845 women) during years 1996-2003. Blood concentrations of these elements were in the same range as those found for populations of other European countries. Significant differences exist between men and women, in blood concentration, for Cu (840 microg Cu.l(-1) vs. 970 microg Cu.l(-1), p<0.01) and Zn (6,780 microg Zn.l(-1) vs. 6,235 microg Zn.l(-1), p<0.01) only. The level of Cu in relation to age is increasing in men, but decreasing in women. The level of Se in relation to age increases regardless of sex. Concentrations of Zn rise with age in women group, only. Positive correlation was found between BMI and level of Cu only for group of men. For Se levels and BMI differences exist only in men namely between groups <20 and >35 (82 microg Se.l(-1) vs. 92 microg Se.l(-1)). Slight positive correlations exist between Zn concentration and BMI in women only. The significant differences were found between smokers and non-smokers for Cu in men (850 microg Cu.l(-1) vs. 830 microg Cu.l(-1)) and Se (81 microg Se.l(-1) vs. 84 microg Se.l(-1)). The smoking has not significant influence on concentration of Zn in the blood. The hormonal contraception significantly increases the concentration of Cu in blood (920 microg Cu.l(-1) vs. 1,270 microg Cu.l(-1), p<0.01). The levels of Se and Zn in blood are not influenced using hormonal contraception.

Toxicity of morphazinamide compared with pyrazinamide.

In a toxicological study on rats two derivatives of pyrazine: morphazinamide (MZA) and pyrazinamide (PZA) were compared with the objective to verify the possibility of using MZA as a substitute for the hepatotoxic PZA. The daily recorded weight and food intake of the rats were statistically significantly changed in the experimental groups with MZA as well as those with PZA, as compared with the control group and the group fed parallelly, already after the sixth dose of MZA and PZA 2.5 g per kg body weight, and similarly changed were also the various biochemical blood and liver tissue tests. Yet, certain differences were observed between the action of MZA and PZA. Some explanation was obtained from PZA blood and tissue concentrations, determined in the course of 24 hours following the administration of the sixth dose of both drugs. A repeated administration of MZA led to a PZA cumulation in the blood and organs of the rats. The study demonstrated that both drugs are hepatotoxic and, in high doses, also nephrotoxic. Moreover, MZA decreases the concentration of plasmatic iron and causes spleen atrophy. It will not be, therefore, a suitable substitute for the hepatotoxic PZA.

Pharmacokinetics of antituberculosis drugs after oral isolated and simultaneous administration in triple combination.

On the basis of a mathematical analysis of the time course of the drug distributed in the organism there were studied pharmacokinetics of antituberculosis drugs after an isolated oral administration of doses used in daily treatment of tuberculosis, in INH, RMP, EMB, PZA, ETA, CS and TZ, and after a simultaneous--single and repeated--administration of INH, RMP, EMB in a triple combination, after the usual daily doses and after increased intermittent doses administered twice weekly. At first there were determined, with the use of chemical methods, blood concentrations of the antituberculosis drugs studied and their excretion with urine in an unchanged form. The results were analyzed pharmacokinetically by means of a one- compartment model with absorption. By an iteration process, based on non-linear regression analysis, the following pharmacokinetic parameters were calculated: Vd, Ka, Ke, T0.5 abs, T0.5 el, Tmax, Cmax, Clp tot and AUC. Their comparison revealed the following facts: The microbiologically most effective antituberculosis drugs--INH and RMP--are comparable even from the point of view of pharmacokinetics on account of similar pharmacokinetic parameters; in comparison with them EMB has half the size of the AUC, characterizing the efficacy of the drug. In this parameter PTA exceeds more than twice ETA; CS and TZ have a low Ke as well as Clp tot and a high T0.5 el, which is indicative of an insufficient excretion of both drugs. Pharmacokinetic parameters of PZA confirm the possibility of using the dose of 25 mg/kg in the treatment of tuberculosis. A simultaneous administration of the triple drug combination under study influences pharmacokinetic parameters of all the three antituberculosis drugs--it significantly decreases Ka as well as Ke, increases T0.5 el, Tmax, Vd and in INH also Clp tot, but only after a repeated administration. An intermittent administration of the mentioned triple drug combination significantly increases the area under the curve AUC in all the three antituberculosis drugs. This explains the same efficacy of higher doses of antituberculosis drugs, administered twice weekly, in comparison with a daily administration of lower doses of the same combination. The pharmacokinetic process of orally administered antituberculosis drugs can be analyzed according to a one-compartment model of pharmacokinetics, although the kinetics of certain antituberculosis drugs probably proceed in the organism in a more complicated way.

Causes for rifampicin toxicity--experimental study.

A 12-day-experimental study of rifampicin (RMP) on male rats followed both the biochemical indices signalling disorder of metabolic equilibrium in the organism, and distribution of RMP in the tissues. The study showed the RMP concentration to be manifold higher in the liver than in the blood and other organs; in epididymal fat the concentration in one half of that in the blood. RMP adversely affects the energy metabolism, i.e. intake and resorption of nutrients, especially metabolically and calorically important lipids and sugars. RMP is harmful also for liver parenchyma.

Factors influencing the effects of the initial phase of tuberculosis chemotherapy.

Two groups of patients suffering from extensive pulmonary tuberculosis treated with daily or twice-weekly regimens of isoniazid (INH) plus rifampicin (RMP) plus ethambutol (EMB) were formed by random selection. The effectiveness of treatment was expressed by the slope of regression line calculated for each patient in terms of quantitative time dependent decrease of mycobacteria isolated by culture per 1 ml of sputum. Chemically serum concentrations of drugs in five time intervals following simultaneous administration were established. It was shown that the rate of decrease of mycobacteria did not significantly vary in the compared groups. Negativity was reached in 48 day on the average. The mean regression line with double standard deviation allocated patients with rapid, normal or slow sputum conversion. Rapid convertors were the youngest, excreted largest amounts of mycobacteria before the start of treatment, and their x-ray showed predominantly changes of exudative character. Slow convertors excreted least amounts of mycobacteria. In the group of slow convetors with daily regimen was significantly higher number of rapid INH inactivators compared with groups of rapid and normal convertors. Analysis of multiple correlation and variance of the ratio of mycobacterial decrease rate and of the parameters of the biological availability of drugs as expressed by the area under the curve of drug serum levels reveal the rate of mycobacterial decrease to be dependent always on the drug out of the combination. In daily regimen the decrease rate was controlled by INH, in the intermittent regimen by RMP. The speed of negativization could therefore be increased in daily regimen by increased doses of INH, chiefly in rapid INH inactivators. The most important share of RMP in the mycobacterial decrease rate during intermittent administration can be judged from dependence of biological availability on the dose of RMP. Under the experimental circumstances of this study the pharmacological means for speeding up negativization were best utilized. Further shortening of time necessary for obtaining negativity would be practicable only when residual factors are involved presumably existing beyond the region of pathogen and drug relationship.