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Biomedical subjects

I Janků

Publications and source records attributed to I Janků.

At least 19 recordsLinked to original sources
PubMed1997

Kidney function changes in rats after single-dose administration of borocaptate sodium.

Kidney function changes after single-dose administration of borocaptate sodium (mercaptoundecahydro-closododecaborate, B12H11SH, BSH) were studied in rats. Changes of glomerular filtration rate (GFR) measured as 14C-inulin clearance, renal plasma flow rate (3H-p-aminohippuric acid clearance) and urine flow rate (UFR) after a slow intravenous injection of BSH (25 mg/kg b.w.) were investigated in rats under pentobarbital anaesthesia. It was found that a slow BSH injection induces a gradual decrease of renal plasma flow and glomerular filtration rate resulting in an almost constant reduction of the filtration fraction. These alterations were accompanied by a temporary increase of urine flow rate. Although a direct effect of BSH on the nephron cannot be excluded, it is suggested that the observed changes in kidney function might at least partly be mediated by disturbances in the function of the cardiovascular system following BSH injection. The role of the dianionic sulfhydryl group present in the borocaptate molecule in inducing these renal functional changes is discussed.

Animals↗
PubMed1995

The disposition of new arabinosylcytosine derivative-- 5'-chloro-5'-deoxy-arabinosylcytosine--in rats.

1. Pharmacokinetic properties of a new derivative of the widely used and very potent antileukemic agent arabinosylcytosine (araC)--5'chloro-5'-deoxy-arabinosylcytosine (5'-Cl-araC)--were investigated after intraperitoneal (i.p.) and oral routes of administration in rats and compared with the equimolar dose of araC administered orally. 2. It was found that substitution of the hydroxyl group at position 5' resulted in a change of pharmacokinetic parameters. 3. There is a large difference in average serum concentrations of 5'-Cl-araC administered by the i.p. and oral routes; the average serum concentration obtained after i.p. injection being several times higher in comparison to those after oral administration. 4. However, the latter are, at the same time, lower than the average serum concentrations of araC administered by the same route in an equimolar dose. 5. On the other hand, the apparent volume of distribution is much larger, and the area under the curve of serum concentration of 5'-Cl-araC is smaller, after oral as compared to the i.p. route of administration indicating more extensive tissue distribution together with higher tissue binding of 5'-Cl-araC when compared to the parental drug araC.

Administration, Oral↗
PubMed1993

Nephrotoxicity of borocaptate after short-term administration in rabbits.

Fifteen Chinchilla rabbits were treated by seven daily i.v. injections of two doses (25 or 50 mg/kg body wt.) of sodium borocaptate (Na2B12H11SH), an agent now widely investigated for potential use in Boron Neutron Capture Therapy (BNCT) of malignant brain tumors. Definite nephrotoxic lesions hyperemic and dilated glomeruli, degenerative necrobiosis with desquamation of tubular epithelium, granular casts in the distal convoluted and collecting tubuli were detected by histopathological examination in the kidneys of all animals without relation to dose of borocaptate. The accumulation of urea in blood and a reduction in red blood cell counts were, however, statistically significant only in rabbits receiving the higher dose (50 mg/kg body wt.) of borocaptate. In the brain the prevalent finding was dilation of perivascular (Virchow-Robin's) spaces. The growth of the animals was retarded and three animals died after injection of the 5th daily dose of borocaptate. With respect to these findings borocaptate sodium can by no means be regarded as an agent which is fully devoid of activity towards healthy non-tumor tissue. Therefore, recent proposals to enhance the effectiveness of BNCT by repeated borocaptate treatment should be considered with caution.

Alanine Transaminase↗
PubMed1993

Physiological modelling of renal drug clearance.

A physiological model of renal drug clearance is presented with the aim of establishing a basis for adjusting drug dosing regimens in renal insufficiency. In agreement with the morphology of blood supply to the nephron, the model assumes serial arrangement of the processes involved in drug excretion. Fractional extraction by filtration in the glomeruli is defined in terms of the product of the unbound fraction of the drug, the filtration fraction being responsible for the limited extraction efficiency of this process. For a description of the limitations of the tubular secretory process by plasma flow through peritubular capillaries, the parallel tube model is utilized. The assumption of direct proportionality between the transport maximum of the secretory process and filtrate flow in the tubules permits a quantitative comparison of the intrinsic tubular secretion clearance and the effectiveness of the filtration process. Provided that the secretory mechanism is highly effective, renal clearance becomes dependent only on kidney plasma flow and the fraction of drug not reabsorbed in the tubules. Tubular reabsorption results only in a proportional decrease in renal clearance. The model predicts proportionality of renal drug clearance to GFR, which as a rule is used for dosage adjustment of drugs in renal insufficiency, only for compounds exclusively excreted by filtration. Compounds also excreted by tubular secretion in general exhibit a curvilinear relationship. The curvature is less pronounced as an increasing fraction of the drug is protein bound in blood. Therefore, for dosage adjustment of drugs secreted in the tubules and highly bound in blood, proportionality between renal clearance and GFR can serve as a reasonable approximation.(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular Filtration Rate↗
PubMed1993

Quantitative analysis of drug handling by the kidney using a physiological model of renal drug clearance.

Published data on the renal clearance of creatinine, p-aminohippuric acid (PAH) and kanamycin in relation to glomerular filtration rate (GFR) in patients with various renal diseases were analysed by a physiological model of renal clearance. Fitting of the data by the general linear equation representing the model proposed by Levy [10] resulted in insignificant intercepts with the ordinate, indicating the unsuitability of the model for the detection of tubular secretory activity. Use of this model also did not lead to significant improvement in goodness of fit compared to simple proportionality of renal clearance and GFR. On the other hand, parameter estimates of the physiological model obtained from the data by nonlinear regression analysis revealed statistically significant tubular secretion both of PAH and creatinine. The much lower tubular secretory activity estimated from the kanamycin data did not reach statistical significance. For compounds exhibiting statistically significant tubular secretion, use of the physiologically based relationship between renal clearance and GFR significantly improved the goodness of fit to the data as compared to simple proportionality of both variables. It is concluded that analysis of the relationship between renal clearance of drugs and GFR using the physiological model of renal clearance can contribute to our knowledge of drug handling by the kidney, and may facilitate drug classification according to total extraction by this organ.

Aminohippuric Acids↗
PubMed1992

Disposition kinetics and concentration-effect relationship of metipranolol in patients with cirrhosis and healthy subjects.

The disposition kinetics and heart rate reducing effect of deacetylmetipranolol (DMP), the active form of the beta-adrenoreceptor blocking agent metipranolol (MP), administered as a single 40 mg oral dose have been compared in 6 patients with cirrhosis and 6 healthy volunteers. The mean maximal DMP concentration was significantly higher and the time to reach the peak level shorter in the patients compared to the healthy subjects. There was also a significantly higher AUC of DMP, a shorter half-life of the rapid phase of the decline in DMP concentrations, a smaller central compartment and lower apparent DMP clearance in patients. A correlation with the albumin level was observed in cirrhotics for individual values of apparent DMP clearance (r = 0.92) and AUC (r = -0.89). The maximal reduction in heart rate was recorded in patients at plasma DMP levels which were already significantly lower than the peak levels. Median inhibitory concentrations (IC50) and maximum possible heart rate reductions (delta HRmax), obtained by fitting individual plots of the plasma DMP concentration-effect relationship to the inhibitory Emax model in the postdistributional phase of DMP disposition were significantly higher in cirrhotics than in healthy subjects. It is conjectured that down-regulation of adrenoreceptors due to chronic sympathetic activation in hepatic cirrhosis contributes to decreased sensitivity to the reduction in heart rate following a single dose of the beta-blocker.

Adult↗
PubMed1992

Dose-dependent disposition kinetics and tissue accumulation of boron after intravenous injections of sodium mercaptoundecahydrododecaborate in rabbits.

Kinetics of boron disposition after single intravenous injections of two different doses (25 and 50 mg/kg) of mercaptoundecahydrododecaborate sodium (Na2B12H11SH; BSH) was studied in rabbits. Residual boron concentrations in various organs and tissues (heart, lungs, liver, spleen, kidney, adrenals, and brain) were also determined after seven daily injections of the same doses of BSH. Boron blood and tissue concentrations were measured by atomic emission spectrometry. In the majority of animals, the decline of boron blood concentrations after a single intravenous injection of either dose was biphasic, being consistent with a two-compartment model of boron disposition in the body. Although mean boron blood concentrations were roughly proportional to the BSH dose delivered, the mean total body clearance of boron from the body was 3 times lower (6.5 +/- 1.9 ml min-1 kg-1) after a dose of 50 mg/kg than after the injection of 25 mg/kg (22.4 +/- 7.9 ml min-1 kg-1), the difference between the means being statistically significant (P less than 0.05). Moreover, the mean terminal half-life of boron in blood was prolonged after the injection of 50 mg/kg (14.5 +/- 5.5 h) as compared with that found after the 25-mg/kg dose (3.5 +/- 0.9 h). On the other hand, the different BSH doses did not result in marked differences in the mean values obtained for the volume parameters - the volume of the central compartment (1.3 +/- 0.4 vs 1.3 +/- 0.5 l kg-1) and the volume of distribution at steady state (4.7 +/- 1.3 vs 6.0 +/- 4.0 l kg-1) - both of which were high, indicating extensive binding of the compound not only in the blood but also in tissues. Residual concentrations of boron found after seven daily injections of both doses of BSH were highest in the kidneys, the difference in the mean values being relatively small (33.6 +/- 6.1 vs 39.0 +/- 10.7 micrograms/g tissue). In the majority of other organs (heart, lung, liver, spleen, brain, adrenals), the residual concentrations after a dose of 50 mg/kg were disproportionately higher than those measured after the injection of 25 mg/kg, and the mean values corresponded to the reduced total body clearance rather than to the increased BSH dose. The saturability of BSH binding to blood and tissue proteins is suggested as a possible explanation for the dose dependency of the total clearance of boron from the body and the accumulation of BSH in organs and tissues.

Animals↗
PubMed1992

[Chronopharmacokinetics of digoxin in compensated cardiac patients].

The authors provided evidence that the pharmacokinetics of digoxin are influenced by daily rhythms. Using doses of 0.125 mg digoxin by the oral route, after 12 hours they found a statistically higher serum digoxin concentration in the minimum before administration of the morning dose and in the maximum concentration after this dose, as compared with the minimal and maximal concentration before and after administration of the same dose in the evening. The other pharmacokinetic parameters--the area beneath the curve of serum concentrations, the time before the maximum concentration was attained and the total plasma clearance of digoxin did not differ. This chrono-pharmacokinetic relationship in compensated cardiac patients was comparable with data in the literature pertaining to healthy volunteers. To conclude it may be said that on administration of major does in the morning there is a greater risk of serum concentrations beyond the therapeutic range than during the administration of the same amount of digoxin in the evening.

Aged↗
PubMed1991

Pharmacokinetic profile of the immunomodulating compound adamantylamide dipeptide (AdDP), a muramyl dipeptide derivative in mice.

A pharmacokinetic profile of 14C-AdDP with uniformly labelled alanine was investigated. It was shown that the distribution phase after an i.v. administration is very short with a half-life of 2.1 min. The half-life of elimination phase after the i.v. administration is about 2.85 hours, that is longer than those of MDP and its derivatives. The total body clearance (30 ml/min/kg) is caused predominantly by metabolism of the compound. All the radioactivity found in urine in a 48 hours interval after a s.c. administration represents only 3.1% of the administered dose. Only a smaller part of the excreted radioactivity is formed by unmetabolised AdDP. The concentration curve after a s.c. administration is characterized by a very fast absorption with a half-life shorter than 1 minute. The distribution and elimination phases are prolonged (20 min, 11 hours respectively) in comparison with an i.v. injection. The decreased absolute bioavailability after a s.c. administration (65%) is probably not biologically significant because of a slower release of the compound from the site of the s.c. administration. A relatively very high radioactivity was found in liver, kidney, thymus, spleen and brain very soon which suggest a very good penetration into tissues. It is an agreement with the high apparent distribution volume of peripheral compartment and higher lipophilicity of AdDP as compared to MDP.

Adjuvants, Immunologic↗
PubMed1991

The effect of some immunomodulators administration to rats on palmitic and oleic acids incorporation into the lipids of liver cell organelles.

The incorporation of equimolar doses of [14C]-palmitic and [3H]-oleic acids into the lipid moiety of hepatocytes after muramyl dipeptide (MDP), adamantylamide dipeptide (AdDP) and levamisole (LM) administration were investigated. The utilization of [14C]-palmitic acid for the synthesis of neutral lipids and phospholipids of crude nuclear fraction increased significantly after MDP and AdDP administration and to a lesser extent after LM. While the incorporation of [3H]-oleic acid did not change significantly after MDP and AdDP, LM significantly increased the incorporation of this acid into the phospholipids of nuclear and microsomal fractions. The changes in the incorporation of saturated palmitic and unsaturated oleic acids suggest a possible influence on deacylation-reacylation mechanisms. These changes could alter the physical properties of membrane and affect certain membrane functions, including the activity of membrane bound enzymes and transport mechanisms.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

[Possibilities of predicting serum levels of lithium and subsequent correction of its dosage].

The objective of the present work was to evaluate the practicability of several procedures used for prediction of the serum concentration of lithium in a steady state which will make it possible to adjust the dosage in the early period of treatment. The group comprised nine men where prophylactic lithium treatment was indicated on account of maniomelancholy. The authors assessed in each patient the theoretically calculated and actually assessed value of minimal lithium concentrations in a steady state. In all applied predictive methods the predicted values were always higher than the actually assessed lithium concentrations. The least suitable method was that based on individualization of the population average of the velocity constant of elimination. The predictive value of the procedure based on a non-individualized single-point estimate was higher. A statistically significant correlation of predicted and assessed values was provided by the method which, based on two collected samples of lithium serum concentrations, makes it possible to estimate the individual value of the cumulative factor.

Adult↗
PubMed1990

A set of simple aids to drug dosage adjustment in renal insufficiency.

A set of graphical aids to drug dosage adjustment is presented, consisting of 1) a nomogram for evaluation of the dosage adjustment factor, 2) a nomogram for estimation of the creatinine clearance from the serum creatinine level, 3) decision tables for selection of a clinically acceptable adjustment of the dosing regimen. The set is accompanied by a list of percentage fractions excreted unchanged in urine for selected drugs and requiring adjustment of the dosing regimen in renal insufficiency. An example of the utilization of the set is demonstrated in comparison with the usual procedures of dosing regimen adjustment.

Creatinine↗
PubMed1989

The effect of structural modifications of 5-fluorouracil derivatives on their transport and biodegradation by isolated rat jejunum.

The continuous-perfusion technique was used in an isolated segment of everted rat jejunum to study transport and biotransformation processes in a series of cancerostatic derivatives of 5-fluorouracil. Metabolic alterations during penetration of the intestinal wall were assessed by high-performance liquid chromatography (HPLC). Octanol-buffer partition coefficients were measured, and the lipophilicity of the study compounds and fragmental constants for their sugar moieties were assessed. In the present series of 5-fluorouracil derivatives, there was no correlation between lipophilicity and metabolic cleavage to 5-fluorouracil, but a correlation was found between lipophilicity and the transport rate. Remarkable stability of the nucleoside bond and high biotransport were observed with 5'-chloro-5-fluorouridine, suggesting a different mode of activation for this derivative.

Animals↗
PubMed1988

Comparative study of cyclocytidine and arabinosylcytosine disposition in rats.

The stability of cyclocytidine (II) in aqueous solutions decreased with increasing pH and temperature. After intravenous injection to rats the biphasic decline of cyclocytidine in the serum was accompanied by simultaneous formation of arabinosylcytosine. Since under physiological conditions (37 degrees C, pH 7.2) the half-lifetime of cyclocytidine dissolved in water was 5 hours, the very early appearance of arabinosylcytosine in the serum of rats suggests that various hydrolytic enzymes may also be responsible for the conversion of cyclocytidine in to arabinosylcytosine in vivo. An equimolar dose of arabinosylcytosine (I) injected to rats produced serum levels which were several times higher than those of cyclocytidine under the same conditions. Since the rate constant of overall elimination was similar for both compounds, this difference in serum levels may most probably be explained by a much higher distribution volume of cyclocytidine resulting also in a higher plasmatic clearance of this compound.

Ancitabine↗
PubMed1987

Morphine and dynorphins in lipid mobilization in rats in vitro.

In vitro lipid-mobilizing activities of morphine (MO) and dynorphin-(1-10) amide (DYA) were compared using adipocytes of young adult rats (body weight 170-200 g, age 50-60 days, diameter of adipocytes 54 +/- 1.12 microns) and of 20-month-old rats (body weight 500-690 g, diameter of adipocytes 99.5 +/- 3.0 microns). The adipokinetic activities of adenosine deaminase (ADA) and dynorphin-(1-13) (DY) were also tested. In the experiments 0.16 units of ADA did not influence basal or stimulated lipolysis, whereas DY exerted a slight but statistically significant adipokinetic effect. In three experimental series the EC50 of MO ranged between 0.89 and 14.60 mumol l-1, the EC50 of DYA in young rats was estimated as 0.8 mumol l-1 and in old animals, 1.3 mumol l-1. Statistically significant differences in the lipid-mobilizing potency between DYA and MO could be observed only in one experimental series in young rats. Expressed in percent of maximum lipolysis induced by isoprenaline, the maximum lipolytic response to DYA in young animals was significantly lower (Emax 26.1 +/- 1.9) when compared to the maximum effect of MO (Emax 76.3 +/- 8.5 and 68.9 +/- 3.5, respectively). Adipocytes of old rats seemed to be more sensitive not only against MO but also against DYA. When studying lipolysis no signs of competitive dualism could be observed in the interaction between MO and DYA. The possibility of two or more independent lipid-mobilizing mechanisms in the effect of the two opioids compared cannot be excluded.

Adenosine Deaminase↗