Marcus Bogaert

Binding ofβ-adrenoceptor blocking drugs to human serum albumin, to α1-acid glycoprotein and to human serum

SummaryThe binding of 8 β-adrenergic blocking drugs to human serum albumin, to α1-acid glycoprotein and to serum from normal volunteers and from patients with rheumatoid arthritis was studied. Protein binding was determined in vitro using equilibrium dialysis of labelled drug at 25° C. Oxprenolol and propranolol were highly bound to serum, alprenolol, pindolol and timolol to a lesser degree, and atenolol, metoprolol and sotalol were negligibly bound. For the five compounds which were appreciably bound, the mean binding was significantly higher in serum from patients with rheumatoid arthritis than in serum from normal volunteers. For those drugs, binding to α1-acid glycoprotein was higher than to human serum albumin, and binding to a mixture of both proteins approached that to serum from healthy volunteers. For each of these drugs there was a strong correlation between the serum α1-glycoprotein concentration and the percentage binding.

Vascular effects of the dinitrate and mononitrate esters of isosorbide, isomannide and isoidide

SummaryThe vasodilator potency of different isomeric organic nitrates was tested on the perfused hindleg of the dog. The dinitrates and mononitrates of isosorbide, isomannide and isoidide have an increased potency if the nitrate groups are in the exo-position; for the mononitrates, potency is increased if the hydroxy group assumes the same position as the nitrate group.

EFFECT OF TURPENTINE-INDUCED INFLAMMATION ON THE DISPOSITION KINETICS OF PROPRANOLOL, METOPROLOL, AND ANTIPYRINE IN THE RAT

Summary— Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first‐pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine‐induced inflammation: propranolol, which is bound extensively to α1‐acid glycoprotein (α1‐AGP); metoprolol, another high extraction drug, but which is negligibly bound to α1‐AGP; and antipyrine, a low extraction drug, not bound to serum proteins.

Toxicokinetics of methyl parathion and parathion in the dog after intravenous and oral administration

Methyl parathion (20 mg · kg−1 intravenously and orally) and parathion (5 mg · kg−1 intravenously and 10 mg · kg−1 orally) were given to non-anesthetized dogs and the serum concentrations were followed in function of time. For both substances a low bioavailability after oral administration was found.In other dogs radioactivity was followed in urine after oral and after intravenous administration of labeled methyl parathion or parathion. The results suggest a good gastro-intestinal absorption of the substances.In anesthetized dogs which were given methyl parathion or parathion intravenously, high hepatic extraction ratios were found, suggesting that the low systemic availability after oral administration can be explained by an important hepatic first-pass extraction.Binding of methyl parathion and parathion to dog serum, to human serum and to a solution of human albumin was determined with equilibrium dialysis. In both species a high binding (>90%) was found for both substances and there was no concentration-dependency in the concentration range used (0.2–30 μg · ml−1). In man and in dog the serum protein binding of parathion was about 5% higher than that of methyl parathion.

Influence of acute renal failure on the protein binding of drugs in animals and in man

SummarySerum protein binding of phenylbutazone has been measured in the rat, guinea pig, cat, rabbit and dog, and the influence on it of renal failure induced by uranyl nitrate injection has been studied. In all species a clearcut decrease in binding was observed after the occurrence of renal failure; the time course of the fall in binding correlated well with development of renal failure. In further experiments, serum protein binding of two acidic drugs (phenylbutazone, warfarin), two basic drugs (papaverine, quinidine) and one neutral drug (digitoxin) was studied in rabbits with experimental renal failure, and the results compared with those obtained in patients with acute renal failure. In the rabbits, a decrease in the binding of phenylbutazone, warfarin, papaverine and quinidine was found, whereas protein binding of digitoxin was unchanged. In man, there was a definite fall in protein binding of phenylbutazone and digitoxin, a small decrease for warfarin and papaverine, and a slight increase for quinidine.

Plasma levels in man of nitroglycerin after buccal administration

levels may be increased for a longer time in the former group than in the latter, since we observed that the anticataleptic action of L-dopa was shorter in rats pretreated with Ro 4-4602, and the action decreased during the 2 h observation period. Spiroperidol-induced catalepsy seems to be particularly resistant to the antagonistic action of L-dopa and is not antagonized by apomorphine (unpublished results). We would like to thank Dr. Janssen for generous giftsof spiroperidol andpimozide.

In vitro study of the inhibitory effects of dopamine on the rat gastric fundus

SummaryThe influence of dopamine was studied on strips of the rat stomach fundus, contracted either by electrical stimulation (1 Hz) or by methacholine.Dopamine (3 · 10−5 M), like noradrenaline (3 · 10−7 M), inhibited the electrically induced contraction more than the methacholine-induced contraction. The inhibition by dopamine of the response to electrical stimulation was partially antagonized by phentolamine but less so by propranolol; the opposite was true for the inhibition by dopamine of the methacholine-induced contraction. Domperidone and four other dopamine antagonists slightly changed the inhibitory effect of dopamine, but had a similar influence on the inhibition caused by noradrenaline.The presence of cocaine as well as reserpine pretreatment reduced markedly the inhibitory effect of dopamine on the response to electrical stimulation. To further characterize the α-receptors on the cholinergic neurons, experiments were performed in the presence of cocaine, hydrocortisone and propranolol. Dopamine, noradrenaline, clonidine and phenylephrine concentration-dependently inhibited the contraction induced by electrical stimulation, clonidine being more potent than phenylephrine. However, the inhibitory effect of dopamine on the response to transmural stimulation was equally blocked by rauwolscine and by prazosin, as were the inhibitions caused by noradrenaline and clonidine.Our findings indicate that the inhibitory effect of dopamine in the rat stomach fundus can be explained by interaction with prejunctional β-receptors on the smooth muscle cells and prejunctional α-receptors on the intramural cholinergic neurons. No arguments for the existence of specific dopamine receptors were found. The inhibition by dopamine is largely indirect, through uptake in sympathetic nerve endings and liberation of endogenous noradrenaline. The results obtained with α-agonists and-antagonists suggest that the α-receptors on the intramural cholinergic neurons combine the characteristics of both subtypes of α-receptors, or that the receptor population consists of a mixture of α1-and α2.

DOPAMINE-INDUCED NEUROGENIC VASODILATATION IN THE INTACT HINDLEG OF THE DOG

1The dopamine‐induced neurogenic vasodilatation, previously described in the isolated perfused hindleg of the dog, has been studied in anaesthetized dogs with intact circulation in the hindleg. Dopamine was administered intravenously and/or intra‐aortically, either as a bolus injection of 4 or 16 μg/kg, or as a continuous infusion of 4, 8, 16 or 32 μg kg−1 min−1.

Effect of penicillin on the clinical course of streptococcal pharyngitis in general practice.

SummaryThe aim of the study was to explore whether penicillin was superior to placebo in altering the clinical course of proven streptococcal pharyngitis. A randomised, parallel, double blind placebo controlled trial of 10 days duration was undertaken in 42 general practices in the Gent region (Flemish part of Belgium). Phenoxymethylpenicillin (adults 250 mg t. i. d. and children 125 mg t.i.d.) or placebo were administrated to 173 patients, aged 5 to 50 y, with acute sore throat and a positive culture for Group Aβ-haemolytic streptococci. Penicillin and placebo tablets were identical. Patient compliance was monitored by assay of penicillin in urine (Sarcina lutea method).The primary outcome variable was sore throat as recorded by the physician on Day 3. The experiences of the patients themselves over the 10 day period were also assessed. Secondary outcome variables were other local and general symptoms and signs of streptococcal throat infection.In the penicillin group on Day 3,23.2% of the patients still complained of sore throat versus 65.9% in the placebo group: difference 42.7% (C. I. 29.4%, 56.1%). This finding was confirmed by survival analysis of the symptom ‘sore throat’, as recorded by the patients. The physicians recorded on Day 3 a significant positive effect on another symptom (malaise:P < 0.04) and certain clinical signs (abnormal throat:P < 0.07; and redness of throat:P < 0.003). Penicillin had more adverse effects than placebo (P < 0.007). It also inhibited the rise in ASLO (P < 0.001).In this study in general practice, penicillin had a slight but definitive positive effect on the clinical evolution of streptococcal pharyngitis. The clinical importance of this finding is not certain, as the physician in the community may lack the means to distinguish between viral and bacterial pharyngitis.

Therapeutic effectivenss and plasma levels of aprindine, a new antidysrhythmic drug

Summary41 patients with stable, frequent, chronic premature ventricular contractions have been treated with aprindine, and its therapeutic effectiveness evaluated by continuous electrocardiographic recording on tape. Excellent results (total suppression of the dysrhythmia) were obtained in 29 patients (71%), in whom the minimal effective plasma level ranged from 0.73 to 2.55 µg/ml (mean 1.35 µg/ml). Neurological side effects developed in 9 patients (22%), with plasma levels from 1.19 to 4.13 µg/ml (mean 2.65 µg/ml). The value of plasma level determinations is discussed.