Therapeutic monitoring of metipamide during antihypertensive therapy.

The aim of our study was to monitor metipamide during a two-month period of treatment and to determine whether the whole-blood levels estimated by high-performance liquid chromatography provide a relevant indicator of possible accumulation of the drug. We also analysed antihypertensive activity and biochemical changes in the blood of twenty hypertonic patients. The results of our clinical trial showed that metipamide is an effective first-line antihypertensive agent, in that it combines satisfactory reduction of blood pressure with a low frequency of side-effects and a simple once-daily dosage regime.

Study of the effect of Edikron on the immune system.

Using the nucleolar test, the authors investigated the effects of the new Czechoslovak cytostatic agent Edikron (gamma, gamma-bis[4-ethylphenyl]-alpha, beta-dibromisocrotonic acid] on Wistar rats. The test showed that Edikron, administered perorally in the dose of 100 mg/kg BW per day for 5 days, affects neither the number of leukocytes nor the proteosynthetic activity of peripheral lymphocytes. The serum levels of Edikron, assessed with the aid of HPLC method 90 min after its last administration, averaged 14.03 +/- 1.63 micrograms/ml serum. Histological examination of the spleen, lymph nodes and thymus of the experimental and control groups also failed to detect any changes. However, the administration of Edikron elicited a statistically significant rise of erythrocytes in the experimental group, but the reason for that has not so far been ascertained.

Pharmacokinetics of Damvar.

The pharmacokinetics of granulated Damvar (delta-(2-amino-6-hydroxy-3,4-dihydro-4-oxo-5-pyrimidinyl) valeric acid) after a single oral dose of 1000 mg was studied in 10 subjects with neoplastic disease. The rate of Damvar absorption from the digestive tract is not very fast. Maximal serum levels (13.5 micrograms/ml) were recorded 3 h after administration with minor interpersonal variations. The time course of Damvar serum concentrations coincides with its distribution in a two-compartmental pharmacokinetic model with biological half-life of 9.72 +/- 0.84 h. Only a small amount of Damvar is eliminated in urine during a period of 24 h (3.1% of the administered dose). Its renal clearance is also low (0.05 ml/s). The analysis of Damvar excretion in urine shows that kidneys play a minor role in its elimination from the body. Therefore the attention should be concentrated on the effect of Damvar administration in patients with disturbed metabolic functions.

[Binding of butocin to serum proteins (author's transl)]. / Die Bindung von Butocin an Serumeiweisskörper.

The binding of N-[-5-(6-purinylthio)-valeryl]-glycin ethylester (butocin, PVG) to serum proteins and pure human albumin was studied using the method of equilibrium dialysis. Its binding to protein in sera diluted 1:1 of 10 patients with malignant disease averaged 48.4 +/- 7.07%. At the butocin concentration of 20 micrograms/ml an average of 36% of butocin were bound to pure albumin. Only a small portion was bound to globulin fractions. Measurements of the saturation curve showed butocin to be bound to albumin molecule by one binding centre with a microscopic association constant kappa = 1.7 . 10(3) mol/l.

Clinical localization of tubular transport of exogenous substances exhibiting urine flow dependence excretion.

The proposed method is based on the assumption that a fluid flow dependent tubular transport process in the distal (diluting) segment of the nephron can be influenced by water diuresis as well as osmotic diuresis. If the fluid flow dependent transport process is localized in the proximal part of the nephron only, the urinary excretion of such a substance can be increased by proximal osmotic diuresis but not by water diuresis. By means of this method the localization of fluid flow dependent tubular transport processes of chloramphenicol and its metabolites (arylamines and total nitro compounds) has been studied in 17 healthy volunteers. The results indicate that the flow dependent transport processes of substances under study may be localized in the diluting segment.

The effects of functional adaptation of residual nephrons on the urinary excretion of drugs.

In patients with chronic renal failure due to glomerulonephritis, pyelonephritis or polycystic kidneys the urinary clearance of free chloramphenicol (C(CHL)) was depressed proportionally to GFR (C(In)). The ordinate intercept of the regression line of C(CHL) on C(In), however, consistently was positive (+3 to +5 ml/min). The fractional excretion of chloramphenicol in renal failure increased from its normal value of 50 percent as an exponential function of the decrease of GFR, and as a linear function of the fractional excretion of water or of sodium. Dietary sodium restriction had no influence on C(CHL) in the patients, while water diuresis, in normal subjects, enhanced the urinary excretion of chloramphenicol. The data suggest that chloramphenicol is reabsorbed by back-diffusion and that increases of the rate of flow of urine and tubular fluid prevent back-diffusion.

The influence of ethacrynic acid, hydrochlorothiazide and clopamide on the renal excretion of chloramphenicol and its metabolites.

Simultaneous administration of chloramphenicol (1 g orally) and ethacrynic acid (150 mg orally), hydrochlorothiazide (25 mg orally) or clopamide (40 mg orally) increased the urinary excretion of chloramphenicol and its metabolites (aryl amines and total nitro compounds). The administration of diuretics did not change the time course of serum concentrations of substances under study. Since the urinary excretion of chloramphenicol and its metabolites is a urine flow-dependent process, the influence of the tested diuretics can be explained as a consequence of decreased tubular water reabsorption.

Pharmacokinetics of butocine.

The pharmacokinetics of Butocine (glycine, N-[1-oxo-5-(1H-purin-6-ylthio)pentyl], ethyl ester) was studied in 8 individuals with malignant tumor after a single oral dose of 500 mg. Butocine is quickly absorbed from the alimentary tract. Highest serum levels were found 45 minutes after administration. Its urinary excretion is very low (2.5 per cent in 15 hours), 1.7 per cent being eliminated 3 hours after administration. Its renal clearance is likwise very low, i.e. 1.5 ml/min compared with endogenous creatinine clearance of 81.2 ml/min.

The consequences of osmotic diuresis in residual nephrons for urinary drug excretion.

The renal clearance of chloramphenicol (calculated per 100 ml of inulin clearance) increased in linear relation to fractional sodium and water excretion. The renal excretion of chloramphenicol may be influenced by changes in fractional water excretion without changes in fractional sodium excretion. The low sodium diet did not significantly change chloramphenicol urinary excretion in patients with chronic renal insufficiency. The results obtained are compatible with the view that osmotic diuresis in residual nephrons, the development of which is in part accounted for by an adaptive decrease in tubular sodium reabsorption, affects urinary excretion of drugs, the tubular transport of which depends on fractional water reabsorption.

Interaction of tolbutamide and chloramphenicol in diabetic patients.

In study 1 we investigated 8 diabetic female patients treated with tolbutamide who received chloramphenicol to combat urinary tract infections. In 5 patients, chloramphenicol was found to produce a distinct decrease of glycemia. Evaluation of the whole series revealed that the latter averaged 31.5%. No patient developed a marked hypoglycemia. With one exception, the values of immunoreactive insulin (IRI) in serum were within normal. In study 2 we investigated another series of 8 diabetic patients. Given chloramphenicol, 7 patients registered an almost twofold increase in the mean morning tolbutamide level in serum and glycemia decreased by one fourth. No patient developed severe hypoglycemia. Tolbutamide increase in serum was not associated with a rise of IRI level in serum. All patients displayed steady chloramphenicol level in serum. Potential reasons for the development of hypoglycemia during the treatment with sulphonylurea antidiabetics are discussed.

The binding of chloramphenicol to serum proteins in patients with chronic renal insufficiency.

The binding (r) of chloramphenicol to serum proteins is significantly lower in patients with chronic renal failure than in normal subjects. Before hemodialysis, the mean r value in patients with chronic renal insufficiency was 0.165 mg/g (+/-0.003) versus 0.188 mg/g (+/-0.004) in healthy individuals. Hemodialysis produced a significant rise in r (to 0.182 mg/g, +/-0.004). Decrease in the serum concentration of albumin in patients with chronic renal insufficiency does not seem to be the sole factor responsible for decreased r.

Urinary excretion of drugs in chronic renal impairment with respect to changes their tubular handling by residual nephrons.

Decrease of the relative value of the renal clearance (the ratio between the value observed and the normal value) of a drug may be slower than the decrease of the relative value of the glomerular filtration rate. A slower decrease of drug renal clearance may be due to an increase in its effective secretion or a decrease in its effective reabsorption by residual nephrons. The mechanisms underlying these changes still remain obscure. One of the factors is assumed to be sodium osmotic diuresis in residual nephrons (associated with functional adaptation).

Comparison of renal excretion of chloramphenicol in patients with chronic pyelonephritis, glomerulonephritis and polycystic kidneys.

In patients with chronic pyelonephritis, glomerulonephritis and polycystic kidneys, decrease in renal clearance of chloramphenicol (CCHL) is related to a decrease in the clearance of inulin (Cin). The rate of decrease of CCHL is relatively slower than that of Cin. The findings attest to an increased excretion of chloramphenicol by residual nephrons. The groups investigated did not display any significant differences in the relation between CCHL and Cin. The findings indicate that changes in the excretion of chloramphenicol by residual nephrons are not related to the primary pathological process responsible for the impairment of the renal parenchyma.

Effect of 6-azauridine on calcium metabolism in rats.

After 12 days of intramuscular administration of 6-azauridine (500 mg/kg b.w.) rats displayed a significant decrease in plasma calcium, inorganic phosphorus, and total hydroxyproline levels and alkaline and acid phosphatase activity. The biological method employed revealed no changes in calcitonin activity. 6-Azauridine reduced the citric acid concentration in the kidneys, liver, heart and bones. Alkaline phosphatase activity in the kidneys, heart and liver was unaffected. The results indicate that 6-azauridine inhibits calcium resorption from the bones and interferes with collagen synthesis. It cannot be ruled out that the described changes are elicited by the antimetabolic effect of this cytostatic drug.