PubMed Health⌕ Search

Biomedical subjects

T Trnovec

Publications and source records attributed to T Trnovec.

At least 19 recordsLinked to original sources
PubMed1991

Pharmacokinetics of stobadin and of the sum of its metabolites in rats during repeated administration.

Stobadin dihydrochloride was administered p.o. to rats at a dose of 1 mg kg-1 once daily for 25 consecutive days. The peak and trough concentrations of the sum of stobadin metabolites, determined from Days 6-16 of treatment, demonstrated a steady-state. The mean daily excretion of 3H-radioactivity during this period was 43 per cent and 52 per cent of the administered dose into urine and faeces, respectively. The terminal half-life of stobadin in plasma following a 25-day chronic treatment was 78.3 min, which was shorter than the value of 95.3 min, determined in a single dose experiment. The data indicate that no accumulation of stobadin and of its labelled metabolites occurs in the course of repeated administration of 3H-stobadin.

Administration, Oral↗
PubMed1991

Interaction of propafenone enantiomers with human alpha 1-acid glycoprotein.

The interaction of propafenone enantiomers with human alpha 1-acid glycoprotein was studied using high-performance liquid chromatography. Each of the two optical antipodes interacted with one class of high-affinity binding sites characterized by Ka(R) = (6.18 +/- 0.93) x 10(5) M-1, n(R) = 1.34 +/- 0.09 for the (R)-isomer and Ka(S) = (8.93 +/- 1.82) x 10(5) M-1, n(S) = 0.99 +/- 0.08 for the (S)-isomer. Nonspecific binding to secondary low-affinity high-capacity binding site(s) was only slightly greater in the case of the (S)-enantiomer (n'k'(S) = (1.06 +/- 0.09) x 10(4) M-1) compared to the (R)-enantiomer (n'k'(R) = (6.87 +/- 0.72) x 10(3) M-1). It was concluded that both enantiomers interact with common single class of high-affinity binding sites on AAG (along with nonspecific binding) exhibiting only slight stereoselectivity for propafenone.

Chromatography, High Pressure Liquid↗
PubMed1991

Interaction of pirprofen enantiomers with human serum albumin.

The interaction of pirprofen enantiomers with human serum albumin (HSA) was investigated by means of high-performance liquid chromatography (HPLC), circular dichroism (CD), and 1H NMR spectroscopy. HPLC experiments indicated that both pirprofen enantiomers were bound to one class of high-affinity binding sites (n(+) = 1.91 +/- 0.13, K(+) = (4.09 +/- 0.64) x 10(5) M-1, n(-) = 2.07 +/- 0.13, K(-) = (6.56 +/- 1.35) x 10(5) M-1) together with nonspecific binding (n'K'(+) = (1.51 +/- 0.21) x 10(4) M-1, n'K'(-) = (0.88 +/- 0.13) x 10(-4) M-1). Slight stereoselectivity in specific binding was demonstrated by the difference in product n(+)K(+) = (0.77 +/- 0.08) x 10(6) M-1 vs. n(-)K(-) = (1.30 +/- 0.21) x 10(6) M-1, i.e., the ratio n(-)K(-)/n(+)K(+) = 1.7. CD measurements showed changes in the binding sites located on the aromatic amino acid side chains (a small positive band at 315 nm and a pronounced negative extrinsic Cotton effect in the region 250-280 nm). The protein remains, however, in its predominantly alpha-helical conformation. The 1H NMR difference spectra confirmed that both pirprofen enantiomers interacted with HSA specifically, most probably with site II on the albumin molecule.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

The effect of high energy electron irradiation on blood-brain barrier permeability to haloperidol and stobadin in rats.

The heads of rats were irradiated by 4 MeV electrons in doses 90, 180, and 360 Gy. The observed times of deaths ranged 120-600, 60-420, and 150-370 min after 90, 180, and 360 Gy, respectively. A dose dependent decrease of the brain uptake index of haloperidol was observed 1 and 3 h post radiation. On the other hand an increased brain uptake index was found for stobadin after head irradiation with doses of 180 and 360 Gy. Regional cerebral blood flow, blood pressure, and heart rate were not significantly altered in the period following irradiation with 180 Gy. The observed changes in blood-brain barrier (BBB) permeability seem to be the result of the damaged function of morphological structures forming the BBB rather than altered regional blood flow.

Animals↗
PubMed1991

The immunoadjuvant effect of soluble glucan derivatives in mice.

We examined the effect of soluble derivatives of yeast glucan on the humoral immune response of various strains of inbred mice after administration of different doses according to various schedules. Glucan was injected i.v. or s.c. in a single dose or repeatedly. The immune response was examined by determining the titres of serum hemagglutinins against sheep erythrocytes (SRBC-Ab). The immunoadjuvant effect of glucan derivatives depends on the inbred strain used, on the dose of glucan, mode and time of administration with respect to antigen injection. The results have shown that the stimulatory effect of glucan derivatives occurred already after a single injection, the optimum dose being 10-20 mg/kg. Intravenous injection was more efficient than the subcutaneous one. In some cases, a slight increase of the spleen mass was observed.

Adjuvants, Immunologic↗
PubMed1991

Hepatobiliary elimination of bendamustin (Cytostasan) in rats.

Biliary excretion of bendamustin (Cytostasan, 5-[bis(2-chloroethyl)amino]-i-methylbenzimidazole-2-butyric acid; 1) and its metabolites was studied in rats after i.v. administration of 14C-1. The most significant finding was the rapid excretion of 1 related radioactivity in the bile occurring shortly after injection. While radioactivity eliminated by bile within 2 h was 41.8%, in the course of subsequent 22 h it amounted only to 3.2%. Bile samples analyzed by TLC indicated that the total amount of radioactivity was excreted in the form of conjugates and two hydroxy metabolites. A significant amount of radioactivity was excreted in urine. The diversion of bile by cannulation of the bile duct led to a significant decrease of elimination by feces.

Animals↗
PubMed1991

Disposition of lypophilized (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles in rats and their effect on zoxazolamine paralysis time.

The fate of lyophilized (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles was studied in male Wistar rats after p.o. administration. It was found that at least 4% of the dose of 14C was absorbed from the gastrointestinal tract after a single dose with these nanoparticles. Some radioactivity (less than 0.15% of dose) was found 7 d after administration in lung, spleen and liver. As expected excretion of the label was predominated via the feces. Ten d of p.o. treatment of rats with lyophilized nanoparticles (1 g/kg of body weight) was shown to prolong significantly zoxazolamine paralysis time. This result suggests that lyophilized nanoparticles decreased elimination of zoxazolamine.

Acrylates↗
PubMed1990

Irradiation of the head by 60Co opens the blood-brain barrier for drugs in rats.

The passage of 6 model drugs; acetylsalicylic acid, chloramphenicol, ethimizol, carbisocaine, heptacaine, and diazepam, through the blood-brain barrier, was determined in unirradiated control rats and in animals 1, 3, and 7 days after irradiation of the head only with a dose of 25 Gy from a 60Co source. The brain uptake index (BUI), which compares the uptake of the test substance with that of 3H2O 5 s after their injection into the common carotid artery, was significantly increased in comparison with unirradiated controls 7 days after irradiation, for all substances tested except for ethimizol. For acetylsalicylic acid and chloramphenicol it was also significantly increased in the other time intervals. The less lipophilic substances showed a greater relative increase of BUI than the more lipophilic ones.

Animals↗
PubMed1990

Effects of inducers and inhibitors of mixed-function oxidases on the biliary excretion of pentacaine metabolites.

The biliary excretion of 3H-pentacaine and its metabolites was studied in rats pretreated with an inducer or inhibitor of mixed-function oxidases. Over one-fourth (25.8 per cent) of a 2 mg kg-1 intraportal dose of 3H-pentacaine was excreted in bile in urethaneanaesthetized control rats within 3 h. The radioactivity appeared in the form of the parent drug, basic metabolites, and metabolite conjugates, 3.1, 86.5, and 10.4 per cent of the total radioactivity excreted, respectively. Pretreatment of rats with phenobarbital enhanced only slightly the biliary excretion of basic metabolites, and pretreatment with 3-methylcholanthrene had no effect. Phenobarbital also increased the initial rate of excretion of conjugates, but this effect was not sustained. 3-Methylcholanthrene had a tendency to impair excretion of conjugates by bile. Pretreatment of rats with SKF 525-A decreased the biliary excretion of both basic metabolites and conjugates while cimetidine did not alter significantly the biliary excretion of pentacaine metabolites. These results suggest that the canalicular transport of metabolites may be the most important factor in controlling pentacaine metabolite excretion in bile.

Animals↗
PubMed1990

Kinetics of biliary elimination of pentacaine in rats.

Pentacaine, a local anaesthetic of the carbanilate type, administered intravenously as 3H-pentacaine, 2 mg kg-1 to rats, was eliminated in the bile mainly in the form of metabolites (20.5 +/- 1.5 per cent of the dose) and as parent drug (0.1 per cent of the dose) within 3 days. In control rats 32.2 +/- 2.5 and 37.8 +/- 2.5 per cent of 3H-dose, representing pentacaine metabolites, were excreted in the urine and faeces, respectively. In bile-duct-cannulated rats 35.7 +/- 6.8, 11.2 +/- 3.4, and 20.5 +/- 1.5 per cent of 3H-dose were excreted in the urine, faeces, and bile, respectively. The high 3H recovered in faeces in animals with diverted bile flow indicated passage of pentacaine metabolites through the intestinal wall. The excretion of pentacaine and its metabolites in bile was an active process, since the ratio bile/plasma concentration rapidly attained values approaching 10. In rats with ligated ureters the biliary elimination of pentacaine and its metabolites was enhanced, compensating for impaired urinary excretion. This was accompanied by increased plasma and brain levels of 3H compared with untreated controls.

Animals↗
PubMed1990

Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances.

Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultra-structural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. Either an increase or a decrease of BBB permeability, or both, occurring in a certain time sequence, was observed. The mechanism of hyperpermeability after irradiation is not fully understood, but the activation of vesicular transport offers one possible explanation. Even less understood is the mechanism of decreased permeability. The response of the BBB to ionizing radiation is most probably nonspecific and its nature may be assumed to be similar to its responses to other physical or chemical noxious factors.

Blood-Brain Barrier↗
PubMed1990

Survival after intramuscular or inhalation administration of gentamicin in neutropenic guinea pigs infected by Klebsiella pneumoniae.

Guinea pigs were infected by intranasal administration of Klebsiella pneumoniae on day 7 after irradiation with a dose of 4 Gy and treated on days 8-10 by gentamicin 4 mg/kg bd im or by inhalation leading to estimated systemically absorbed doses of 5.9 mg/kg/day. All animals died; however, gentamicin treatment significantly (P less than 0.05, Fisher's exact test) delayed death in the specific time intervals: 7-13 days (with the exception of day 11) and 12-26 days after im and inhalation administration respectively. Comparison of the two treatments by Fisher's exact test showed a significant advantage (P less than 0.05) for im vs inhalation treatment on days 9 and 10 only. The log rank test gave somewhat different results in that the delay of death after im administration was highly significantly (P less than 0.002) different from control whereas results after inhalation were not significantly different from control (P = 0.06). Moreover, according to the log rank test, im administration delayed death significantly (P = 0.04) better than inhalation. In conclusion these data do not show any advantage of inhalation over im administration for treatment of experimental pneumonia, indeed they are compatible with im administration being marginally more effective.

Administration, Inhalation↗
PubMed1990

Effect of gamma-irradiation on disposition of the local anaesthetic, carbisocaine in rabbits.

14C Labelled carbisocaine, a local anaesthetic agent, has been administered intravenously in a dose of 2 mg kg-1 to rabbits 7 days after whole-body 60Co gamma-irradiation with a dose of 5 Gy (1.9 Gy min-1) and to control rabbits. The plasma carbisocaine concentration-time courses were approximated by biexponential equations. The estimated pharmacokinetic parameters obtained when the data were fitted to an open two-compartment model were significantly different for the irradiated group relative to control animals, indicating a radiation-induced slower elimination rate of carbisocaine: AUC: 0.37 vs 0.29% dose min mL-1, CLtot: 109.8 vs 155.4 mL min-1, Vdss: 27.6 vs 33.2 mL kg-1, kel: 0.0259 vs 0.0307 min-1, MRT: 251.7 vs 214.6 min. The total excreted amount of 14C radioactivity in the irradiated group was lower in comparison with controls: 6.5 vs 8.7% in bile and 18.3 vs 23.7% in urine. However, lower carbisocaine concentrations were recorded in the heart, lungs, liver, and kidneys of irradiated rabbits compared with controls.

Anesthetics, Local↗
PubMed1990

Plasma concentration, tissue distribution and excretion of the prospective cardioprotective agent cis-(-)-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dihydrochloride in rats.

Pharmacokinetics of cis-(-)-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl- 1H-pyrido-[4,3-b]indole dihydrochloride (Stobadin; in the following briefly called STB), a pharmacologically active stereoisomer of the gamma-carboline carbidine, was studied using a 3H-labelled product. Determination of STB in biological material was based on liquid-liquid extraction from alkaline media into n-heptane. The plasma concentration of STB following i.v. administration to rats was approximated by a biexponential function. An open two-compartment pharmacokinetic model was conferred to the data with the following parameter estimates: terminal elimination half-life 85.6 min, distribution volume at steady state 4.78 l/kg, total body clearance 105.3 ml/min/kg. The systemic availability of orally given STB dihydrochloride in solution was 19.7%. The brain uptake index of STB was 78.2%. Autoradiography in rats injected i.v. showed a heterogenous distribution of the label in the tissues. STB showed strong affinity to the lung tissue and kidneys and was evenly distributed in the cortex and medulla of the latter organ. During 72 h after i.v. administration, 64.6% and 11.0% of the 3H dose was excreted into urine and faeces, respectively, and after oral administration, the excretion was 62.0% and 21.9%, respectively.

Administration, Oral↗
PubMed1989

Different binding of propranolol enantiomers to human alpha 1-acid glycoprotein.

The binding of propranolol enantiomers to human alpha 1-acid glycoprotein was studied using high performance liquid chromatography in order to provide insight into binding models and to describe individual binding parameters of both enantiomers. The binding of (-)-propranolol was shown to be saturable with one major binding site (n = 0.81, k = 2.73 x 10(5)/M). The saturation process achieved its upper asymptotic value at drug/protein molar ratio of approximately 1. In the case of the opposite (+)-enantiomer the binding isotherm did not show evidence of saturation even at higher drug/protein molar ratios (up to 50). The individual binding parameters for (+)-enantiomer were n = 0.38, k = 3.4 x 10(6)/M and n'k' = 1.39 x 10(4)/M for the saturable and nonsaturable binding component, respectively. At drug/protein molar ratio 2 the circular dichroism measurements confirmed the existence of different binding models for individual propranolol enantiomers.

Chromatography, High Pressure Liquid↗