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Biomedical subjects

T Walle

Publications and source records attributed to T Walle.

At least 91 records · Page 5Linked to original sources
PubMed1986

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis.

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.

Administration, Oral↗
PubMed1986

Partial metabolic clearances as determinants of the oral bioavailability of propranolol.

The objective of this study was to determine the relationships between the total oral clearance of propranolol and the partial clearances through its primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Seven young, white males were given single 80 mg oral doses of the drug together with tritium-labelled propranolol. Plasma propranolol was measured by GC/MS and fourteen metabolites were measured in urine by h.p.l.c. with radiometric detection. The total oral clearance of propranolol in these subjects varied about three-fold, from 27.5 to 71.4 ml min-1 kg-1. The clearance through glucuronidation was very similar in all subjects, ranging from 6.8 to 9.9 ml min-1 kg-1. The clearance through side-chain oxidation varied 2.4-fold, from 10.9 to 25.8 ml min-1 kg-1. Increased clearance through this pathway correlated with increased total oral clearance (r = 0.84; P less than 0.02). The clearance through ring oxidation varied as much as 5.6-fold, from 7.5 to 41.8 ml min-1 kg-1. Increased clearance through this pathway correlated highly with increased total oral clearance (r = 0.94; P less than 0.002). These observations indicate that the intersubject variability in the oral clearance of propranolol in young, white males is due mainly to differences in the activity of the ring oxidation pathway, to some extent in the side-chain oxidation pathway, but not to differences in the glucuronidation pathway. The partial metabolic clearance approach adopted in this study may be useful in the investigation of factors influencing the oral bioavailability of propranolol.

Administration, Oral↗
PubMed1986

Acute hypotensive effects of oral and intravenous propranolol: early alterations in peripheral resistance.

The effects of single oral and intravenous doses of propranolol on blood pressure and hemodynamics were measured in normal volunteers. Systolic and diastolic blood pressure decreased 10% within 3 hours after the oral dose and by 3%-5% after the intravenous dose. Cardiac output decreased 16% after the intravenous dose and 10% after the oral dose. Total peripheral resistance transiently increased by 23% after the intravenous, but not after the oral dose. Change in mean arterial pressure was positively correlated with change in total peripheral resistance after both the oral and intravenous doses. In contrast, change in mean arterial pressure was negatively correlated with change in cardiac output after the intravenous dose. Single oral and intravenous doses of propranolol lowered blood pressure within 3 hours after administration, and the reduction was correlated with change in total peripheral resistance and not with change in cardiac output. At least part of the adaptation in peripheral resistance occurs within the first 3 hours after both oral and intravenous single doses of propranolol.

Administration, Oral↗
PubMed1985

Influence of food on the intravenous and oral dose kinetics of propranolol in the dog.

The intravenous and oral dose kinetics of propranolol were studied in the dog both in a fasted state and immediately after a meal consisting of 100 g of cooked beef liver. Fifty microCi of 3H-propranolol was administered intravenously simultaneously with a 40-mg oral dose of unlabeled propranolol. Plasma 3H-propranolol was measured by specific extraction and liquid scintillation spectrometry, and unlabeled plasma propranolol was determined by gas chromatography-mass spectrometry. Feeding significantly reduced (25%) the elimination half-life and increased (52%) the systemic clearance of intravenous propranolol. The increase in the systemic clearance of propranolol after feeding was mostly due to an increase (60%) in apparent hepatic blood flow, which appeared to remain elevated for 5-7 hr. The meal had no influence on the apparent volume of distribution or plasma binding. Feeding did not affect the area under the concentration-time curve of oral propranolol, but significantly delayed the rate of oral propranolol absorption, shifting the time to reach peak plasma levels from 60 to 158 min. The results of this study suggest that feeding alters the disposition of propranolol in the dog by producing a sustained increase in hepatic blood flow.

Administration, Oral↗
PubMed1985

Synthesis of 4'-hydroxypropranolol sulfate, a major non-beta-blocking propranolol metabolite in man.

4'-Hydroxypropranolol sulfate was recently identified as a major metabolite of propranolol (Inderal). In order to confirm the structure and to further study disposition and biological activity, we have synthesized 8 with use of 1,4-naphthoquinone as the starting material. Reduction and alkylation with benzyl iodide gave 4-(benzyloxy)naphthol. Sulfation and chlorosulfuric acid in N,N-dimethylaniline gave potassium 1-(benzyloxy)-4-naphthol sulfate. Catalytic hydrogenation, alkylation with [[[(trifluoromethyl)sulfonyl]oxy]methyl]oxirane, and amination in isopropylamine gave 8. Racemic 8 was found to be 100-1000 times less potent than racemic propranolol as a beta-adrenergic receptor blocking agent in the dog.

Adrenergic beta-Antagonists↗
PubMed1985

Biologic determinants of propranolol disposition: results from 1308 patients in the Beta-Blocker Heart Attack Trial.

Our objective was to identify biologic determinants of propranolol serum levels in 1308 patients after myocardial infarction (MI). Patients had had their MI within the previous month. A steady-state propranolol dosage of 40 mg every 8 hours produced a mean trough concentration of 42 ng/ml with extremely great (fiftyfold) interindividual variability. Univariate and multivariate analyses suggested that this variability was the result of many biologic factors. Serum levels were higher in women, in older patients, and in patients receiving concomitant therapy with other antiarrhythmic drugs. Serum levels were also higher in patients with elevated serum creatinine and lactate dehydrogenase levels. Serum levels were lower in black patients than in white patients. Also, serum levels in smokers were lower than those in nonsmokers, but only markedly so in the outpatient setting (6 months after the MI). The influence of sex and race on drug disposition has not previously been reported for beta-blocking drugs. Although a genetic deficiency in the oxidative metabolism of propranolol has been indicated, the frequency distribution of serum propranolol levels did not demonstrate a bimodal distribution for genetically distinct populations.

Adult↗
PubMed1985

[Plasma exchange and hyperthyroidism. Current indications].

Serious thyrotoxicosis must be treated quickly and efficiently. Plasma exchange (PE) takes place when ordinary treatment is not suitable in emergency cases. Several methods of plasma clearing have already been practiced successfully. PE is the best one. It quickly removes a great amount of thyroid hormones and occasionally pathological immunoglobulins. Risks have not to be underestimated. The most serious accidents are particularly linked with the substitution fluids. Hemoperfusion, peritoneal dialysis, transfusion exchanges can be used too. Thyrotoxicosis crisis, as far as life prognosis is concerned, is an appropriate indication of PE, either as a first line treatment or after the classical treatment has failed. Serious hyperthyroidism due to iodine overload is not improved with common treatment. In this case PE might be worthwhile. In malignant exophthalmia, unimproved with an usual treatment PE can be successfully used, every time ocular prognosis is concerned.

Graves Disease↗
PubMed1984

Stereoselective clearance and distribution of intravenous propranolol.

Our objective was to determine the kinetics of (+)- and (-)-propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium-labeled (+)-propranolol and unlabeled (-)-propranolol. Plasma concentrations of (+)- and (-)-propranolol as measured by gas chromatography-mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)-propranolol, 1.21 +/- 0.15 l/min; (-)-propranolol, 1.03 +/- 0.12 l/min; P less than 0.01] and apparent volume of distribution (Vd) [(+)-propranolol, 4.82 +/- 0.34 l/kg; (-)-propranolol, 4.08 +/- 0.33 l/kg; P less than 0.001], but no difference in distribution or elimination t1/2s (t1/2 beta 3.5 hr). The higher Cls of (+)-propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)-propranolol is mainly related to its lower plasma binding [(+)-propranolol, 20.3 +/- 0.8% unbound; (-)-propranolol, 17.6 +/- 0.7% unbound; P less than 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.

Adult↗
PubMed1984

Stereoselective ring oxidation of propranolol in man.

The objective of this study was to elucidate stereoselective mechanisms of propranolol metabolism in man. Five normal subjects were given single 80 mg oral doses of deuterium-labeled pseudoracemates of propranolol, and the stereochemical composition of propranolol and its major metabolites in urine was determined by GC/MS. The (-)/(+)-enantiomer ratios for unchanged propranolol, 1.50 +/- 0.10 (mean +/- s.e. mean), and propranolol glucuronide, 1.76 +/- 0.10, were similar to previous findings in plasma. All products of side-chain oxidation also consisted mainly of the (-)-enantiomer, with an overall (-)/(+) ratio of 1.61 +/- 0.11. A (-)/(+) ratio of 1.04 +/- 0.17 for 4-hydroxypropranolol did not indicate stereoselectivity in ring oxidation. However, the ratio for its glucuronic acid conjugate of 1.78 +/- 0.19 and for its sulphate conjugate of 0.27 +/- 0.03 suggested stereoselectivity in either the glucuronidation or sulphation of 4-hydroxypropranolol, or both. When the stereoselectivity in these secondary pathways was taken into consideration, the overall ring oxidation strongly favoured (+)-propranolol with a (-)/(+)-enantiomer ratio of 0.59 +/- 0.09. The composite observations of the stereochemistry of propranolol metabolism in man are consistent with stereoselective ring oxidation of (+)-propranolol, leading to a greater bioavailability of the pharmacologically more active (-)-propranolol and subsequent preferential side-chain oxidation and glucuronidation of this enantiomer.

Adult↗
PubMed1983

Gas chromatographic analysis of chloroquine after a unique reaction with chloroformates.

A specific method for the gas chromatographic determination of chloroquine (CQ) after derivatization with chloroformates, using 9-bromophenanthrene as the internal standard and a column filled with 3% OV-17 on 80-100 mesh Supelcoport is described. Derivatization with chloroformates produced a pyrrolidine derivative, 4-(2-methyl-1-pyrrolidyl)-7-chloroquinoline with CQ, and a carbamate with desethylchloroquine. The chloroformate reaction for CQ is thus selective in the presence of CQ metabolites. The method based on flame ionization detection is highly suitable for quantitation of CQ in urine.

Aminoquinolines↗
PubMed1983

Combined effects of propranolol and ethanol on human psychomotor performance.

Twelve male subjects were given placebo or 160 mg propranolol, in divided doses, during a 24-hr period before drinking a beverage containing 0 or 50 ml ethanol/70 kg body weight. Tests designed to measure mental and motor performance were administered 75 min after the last dose of propranolol. The tests performed included the wobble board (WB), pursuit meter (PM), delayed auditory feedback (DAF), pegboard (PB), tapping, time estimation (TE), and a modified Cornell medical index (CMI). A mean blood ethanol concentration of 48.0 +/- 9.1 mg/dl and a mean plasma propranolol level of 33.1 +/- 13.1 ng/ml were achieved. Ethanol alone significantly impaired performance in 12 out of 20 tests (p less than 0.05). Propranolol significantly (p less than 0.05) antagonized the decrement in psychomotor performance induced by ethanol on the PM. In all other tests, there was no significant interaction between ethanol and propranolol. Propranolol alone had no significant effect on the psychomotor tests. When the drugs were combined, the subjective symptoms, as measured by the CMI, showed a trend toward being additive. This study suggests that no adverse interaction occurs between therapeutic doses of propranolol and minimum impairment doses of ethanol.

Adult↗
PubMed1983

Stereoselective binding of propranolol to human plasma, alpha 1-acid glycoprotein, and albumin.

Our aim was to determine possible stereoselectivity in the plasma binding of propranolol. Equilibrium dialysis with plasma from seven healthy subjects and a deuterium-labeled pseudoracemate of propranolol was used. Plasma binding of the propranolol enantiomers differed with the unbound fraction of (-)-propranolol (22 +/- 2%; mean +/- SE) being smaller than that of (+)-propranolol (25.3 +/- 1.9%). The (-)/(+)-propranolol ratio for the unbound fraction, a measure of the stereoselectivity, was 0.86 +/- 0.02. There was an inverse correlation between the unbound (-)/(+)-propranolol ratio in individual subjects and overall binding of (+/-)-propranolol, indicating greater stereoselectivity at higher total binding. To assess the site of the stereoselective binding to plasma proteins, the binding of (+)- and (-)-propranolol to human alpha 1-acid glycoprotein (AGP) and human serum albumin (HSA) was examined. The binding to AGP was stereoselective for (-)-propranolol with a (-)/(+)-propranolol ratio for the unbound fraction of 0.79 +/- 0.01, whereas (+)-propranolol was bound to a greater extent to HSA with a (-)/(+)-propranolol ratio for the unbound fraction of 1.07 +/- 0.01. Although these results demonstrate opposite stereoselectivity in the binding of (+)- and (-)-propranolol to AGP and HSA, the stereoselective binding of (-)-propranolol to AGP predominates in plasma. This stereoselective plasma binding of the (-)-enantiomer of propranolol could limit the access of this more active enantiomer to beta-receptors or other active sites. The uptake of propranolol by red blood cells was not stereoselective.

Adult↗
PubMed1983

Exercise-induced increments in plasma levels of propranolol and noradrenaline.

Exercise-induced changes in the plasma levels of propranolol and noradrenaline were determined in nine volunteers. Total plasma propranolol levels were increased during submaximal treadmill exercise, with exercise-induced increments of 13 +/- 4% at 4 h after the last dose, 18 +/- 7% at 9 h and 41 +/- 5% at 16 h. Exercise-induced increments in plasma propranolol were observed after single as well as repeated doses. During exercise, increments in plasma propranolol were correlated temporally with changes in plasma noradrenaline. Exercise-induced increments in plasma noradrenaline were greater during propranolol administration than during placebo periods. The changes in plasma propranolol concentration during exercise may reflect a redistribution of propranolol at its site(s) of action.

Humans↗