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Biomedical subjects

R Gomeni

Publications and source records attributed to R Gomeni.

89 records · Page 5Linked to original sources
PubMed1977

Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat.

1 Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.2 Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.3 Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.4 Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 mug/ml for desipramine and from 0.04 to 1.2 mug/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40 degrees rotation were 1.35 mug/ml (desipramine) and 1.75 mug/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 mug/ml for desipramine and 3.6 mug/ml for protriptyline.5 Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.

Animals↗
PubMed1976

An integrated approach for the evaluation of psychotropic drug in man. I. Studies on amphetamine. Relationship between drug levels and psychophysiological measurements.

Following an integrated approach based on the contemporary recording of drug plasma levels, central (CNS) and peripheral responses and performance tests, the effects of two different amphetamine formulations were evaluated in healthy volunteers. Interesting relationships were observed between amphetamine initial rate of entry into the blood stream and both incidence of side effects (S.E.) and rise in arterial blood pressure. Minimal thresholds for CNS (5 ng/ml) and peripheral (20 ng/ml) effects could also be determined. It appeared also that the personality of the subject may have some bearing on both incidence of side effects and performance. The described methodology seems valuable in valuating psychotropic drug effects in man through a comprehensive integrated approach.

Adult↗
PubMed1976

Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment.

Propranolol blood and plasma levels were measured after a single oral dose of 40 mg in patients with chronic renal failure, in patients undergoing regular dialysis treatment, and in healthy volunteers. Peak levels were observed in all cases within 1.5 to 3 hours. However, peak blood and plasma concentrations of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 +/- 41 ng/ml) than those observed in the dialysis patients (47 +/- 9 ng/ml) and in the healthy volunteers (26 +/- 1 ng/ml). The apparent plasma clearance was also significantly reduced in the patients with chronic renal failure. The data suggest a reduced hepatic extraction in chronic renal failure patients. A significant increase in the fraction of the dose available to the systemic circulation was also found, together with a modification of apparent plasma half-life and volume of distribution in regular dialysis patients during the dialysis day as compared with the after-dialysis day. No extraction of propranolol by the dialyzer was noticed. Marked fluctuations in propranolol blood concentrations were also observed in patients on regular dialysis following continuous propranolol treatment. The suppressive effect of propranolol on plasma renin activity did not fully correlate with the hypotensive effect of the drug. On the basis of the reported data, propranolol should be used with great caution and at low doses in chronic renal failure.

Adult↗
PubMed1976

Carbamazepine pharmacokinetics in young, adult and pregnant rats. Relation to pharmacological effects.

Adult, male, female and pregnant rats were treated with single and repeated doses of carbamazepine (CBZ). The time course of the drug concentrations in plasma and tissues was followed. In all cases, data on plasma levels were subjected to pharmacokinetic analyses. Attempts were made to relate pharmacokinetic properties of carbamazepine to its effect on pentobarbital sleeping time and on protection against electroshock, after acute and repeated administration: --it was found that male rats eliminate carbamazepine faster than females: the total body clearance (TBC) was 16 ml/min/kg and 9.4 ml/min/kg, respectively. Two dose levels (25 and 50 mg/kg) had the same pharmacokinetic properties in young rats. Pregnant rats clear CBZ to a lesser extent than controls. --CBZ was found to accelerate its own elimination after repeated administration in both adult and young rats as revealed by the shortening of its half-life and an increase of 50% in clearance. Moreover, the protection against electroshock was significantly reduced after repeated administration, compared with a single-dose administration. Repeated administration of CBZ in rats shortens pentobarbital sleeping time and decreases the pentobarbital brain level significantly.

Aging↗
PubMed1975

Pharmacokinetics of N-demethyldiazepam in patients suffering from insomnia and treated with nortriptyline.

1 Hospitalized patients suffering from insomnia were treated with N-demethyldiazepam (30 mg p.o.) for 10 days, while continuing treatment with nortriptyline (75 or 100 mg daily). 2 Clinical evaluation performed by objective rating scales showed a positive therapeutic effect. No correlation was found however between drug plasma levels and clinical efficacy. A high inter-individual variability was observed. 3 In three cases the N-demethyldiazepam disappearance curve showed a biexponential decay, with a slow first component followed by a faster one. 4 Compared with diazepam the tested drug has a longer plasma apparent half-life and a lower relative clearance.

Adult↗
PubMedDate not supplied

Pharmacokinetic aspects of the sublingual administration of vincamine.

The sublingual absorption of vincamine used as tracer occurs in two successive absorption steps: true sublingual absorption and absorption in the gastrointestinal tract of the drug dissolved in the saliva and not absorbed through the buccal mucosa. This is confirmed by a pharmacokinetic study and simulation. These two successive absorptions can explain the increase in the amounts of drug absorbed.

Administration, Oral↗
PubMedDate not supplied

Elimination kinetics of desmethyldiazepam in two young and two elderly subjects.

Pinazepam (P) (10 mg) was orally administered to two young (22-23 years) and two elderly (74-80 years) healthy volunteers. Also, desmethyldiazepam (DD) (10 mg) was orally administered to the same young volunteers on a separate occasion. P was almost completely converted into DD 24 h after administration. Plasma levels of DD were measured in all subjects. In all cases, the DD concentration-time curve showed a biphasic decay (a first slow decay was followed by a fast one) which closely fitted by a Michaelis-Menten equation. Vmax and km constant were computed for all subjects. The kinetic analysis relative to the young subjects showed that T 1/2 of both the slow and fast decay as well as the area under the curve (AUC) were reduced when P was administered instead of DD. Comparison of DD kinetics between young and elderly subjects showed an increase of half-life in the elderly, while AUC was found unchanged.

Adult↗
PubMedDate not supplied

Ritodrine sulphation in the human liver and duodenal mucosa: interindividual variability.

The beta2-adrenoceptor agonist ritodrine has a bioavailability of 30% due to its presystemic metabolism and sulphation is an important metabolic route. The interindividual variability in the rate of ritodrine sulphation in 100 specimens of human liver and duodenum is reported. The final concentrations of ritodrine were 2 mM (duodenum) and 20 mM (liver). The mean estimates of ritodrine sulphation rate were 490 pmol x min(-1) x mg(-1) (duodenum) and 140 pmol x min(-1) x mg(-1) (liver). There was a 4-5-fold variation within +/- 2 SD units in the hepatic and duodenal rates of ritodrine sulphation. Statistical analysis revealed the presence of at least two subgroups of ritodrine sulphation. In the liver, 30% and 70% of the population fell into two subgroups with the mean estimates of ritodrine sulphation rate of 114 and 149 pmol x min(-1) x mg(-1), respectively (P < 0.05). In the duodenum, 25% and 75% of the population fell into two subgroups and the mean estimates of ritodrine sulphation rate were 332 and 538 pmol x min(-1) x mg(-1), respectively (P < 0.05). The rates of ritodrine and 4-nitrophenol sulphation correlated highly in the liver (r = 0.865; P < 0.001) and the rates of ritodrine and dopamine sulphation correlated highly (r = 0.914; P < 0.001) in the duodenum. In both tissues, the rates of ritodrine and (-)-salbutamol sulphation underwent a similar extent of variation and correlated highly. The intrinsic clearance of ritodrine sulphation was over one order of magnitude higher in the duodenum than in the liver suggesting that the duodenum is an important site of ritodrine sulphation.

Adrenergic beta-Agonists↗
PubMedDate not supplied

A population approach to the forecasting of amikacin plasma and urinary levels using a prescribed dosage regimen.

We retrospectively analyzed amikacin pharmacokinetics in 19 critically ill patients who received amikacin intravenously. Fourteen subjects (577 serum amikacin concentrations, 167 urine measurements) were studied to obtain data for population modeling, while 5 patients (267 serum amikacin concentrations, 68 urine measurements) were studied for the assessment of predictive performance. The population analysis was performed using serum and urine amikacin measurements; the renal clearance of amikacin was expressed as a function of creatinine clearance. A two-compartment model was fitted to the population data by using NONMEM. The population characteristics of the pharmacokinetic parameters (fixed and random effects) were estimated using the FOCE method. The population pharmacokinetic parameters with the interindividual variability (CV%) were as follows: slope (0.254, 126%) and intercept (3 l/h, 59.6%) of the linear model which relate the amikacin renal clearance to the creatinine clearance, initial volume of distribution (17.1 l, 22.2%), intercompartment clearance (5.22 l/h, 104%), steady state volume of distribution (55.2 l, 64.1%) and urinary elimination (67.5%, 36.3%). The Bayesian approach developed in this study accurately predicts amikacin concentrations in serum and urine and allows for the estimation of amikacin pharmacokinetic parameters, minimizing the risk of bias in the prediction.

Amikacin↗
PubMedDate not supplied

Mechanism of antihypertensive activity of orally administered prazosin in spontaneously hypertensive rats.

In conscious, spontaneously hypertensive rats (SHR) oral prazosin (0.03-3.0 mg/kg) resulted in dose-related reductions of systolic blood pressure measured with a tail cuff. In SHR whose tail artery blood pressure was continuously monitored the antihypertensive effect of prazosin (1.0 mg/kg, p.o.) was accompanied by a significant increase in heart rate. Several groups of SHR were pithed 2 hr after oral prazosin (1.0 mg/kg) or placebo. In this preparation the mean carotid blood pressure increases following i.v. injections of angiotensin II or 5-hydroxytryptamine and the positive chronotropic responses to i.v. norepinephrine or electrical stimulation of the spinal cord were similar in control and prazosin-pretreated animals. However, the dose-pressor response curves to i.v. norepinephrine or electrical stimulation of the spinal cord from prazosin-pretreated SHR lay to the right of the control curves. In addition, the slopes of the linear portion of these curves were flatter after prazosin and remained so even after i.v. propranolol was given alone or with cocaine. Prazosin-pretreated SHR responded to phenylephrine with a fall followed by a rise in carotid blood pressure. The depressor effect was abolished and the pressor phase enhanced by i.v. propranolol. The pressor responses to i.v. cirazoline or clonidine were significantly inhibited by prazosin. Finally, prazosin failed to significantly modify the negative chronotropic effects of clonidine observed in pithed SHR whose heart rate was raised by continuous electrical stimulation of the thoracic spinal cord. These results indicate that oral prazosin exerts pronounced antihypertensive effects in the SHR. This action apparently results from impairment of the sympathetic nervous system at the level of vascular postsynaptic alpha-adrenoceptors.

Administration, Oral↗
PubMedDate not supplied

The metabolism and kinetics of tiflorex in the rat.

14C-Tiflorex given either orally or intravenously to male rats (10 mg/kg; 250 microCi) was well absorbed orally; greater than 70% of the dose was excreted in the urine in the first 48 hr after dosing by either route of administration. Inasmuch as part of the dose (10%) was excreted in the feces after iv administration, it is probable that biliary excretion is a route of elimination. This was shown to be so by cannulation of the bile duct. The major route of metabolism was S-oxidation to give the sulfoxides and sulfones of tiflorex (7% each) and nortiflorex (10 and 20%, respectively) which were excreted together with the unchanged drug (1%) in the 0- to 48-hr urine. Examination of the plasma for the unchanged drug and its metabolites showed the drug to be rapidly absorbed orally, maximum levels being attained within 30 min. The plasma half-life for the elimination phase of the unchanged drug was relatively long (7.5 hr) compared with the metabolites (2.5 hr) with the exception of nortiflorex sulfone (9.8 hr) and two as yet unidentified metabolites which had half-lives in excess of 24 hr. The latter three compounds were responsible for the relatively long plasma half-life of total radioactivity (ca. 13 hr). The ratio of the areas under the plasma curve for unchanged drug indicated a low bioavailability (30%). It appears that the predominant route of metabolism of this group of compounds in the rat, p-hydroxyltation had been blocked by the trifluoromethylthio group, with consequent emphasis on S-oxidation.

Animals↗
PubMedDate not supplied

Population kinetics and conditional assessment of the optimal dosage regimen using the P-PHARM software package.

The adjustment of individual dosage regimen is an adaptive control process based upon an individual response to a pharmacokinetic model. To attain this objective, it is very helpful to know the characteristics of the population to which the subject belongs, in terms of mean parameters and interindividual variability. Usually the available information consists of incomplete and sparse data. For this reason it is essential to employ a computational methodology based on non-linear mixed-effect procedures in order to obtain a population parameter estimate. A Bayesian methodology can then be applied from the population parameters to the specific data for the individual requiring a dosage adjustment (such data includes drug concentration(s) of the active drug, demographic data, etc). The result of the Bayesian calculation supplies the required individual pharmacokinetic parameters. An optimal dosage regimen can be defined on the basis of therapeutical criteria (concentration ranges) as well as practical constraints such as: the size of available unitary drug dosages, feasible drug intake times, penalties associated with expected concentrations falling outside the therapeutic concentration ranges. In this paper we present the methodology and results obtained using the P-Pharm software tool. P-Pharm implements a non-linear mixed-effect population parameter estimation algorithm based on the EM algorithm. This method allows the inclusion of explicit variables into the calculations, it implements an individual Bayesian parameter estimation procedure and also an algorithm for the conditional assessment of the optimal dosage regimen given a list of practical constraints.

Algorithms↗