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Biomedical subjects

M G Bogaert

Publications and source records attributed to M G Bogaert.

At least 73 records · Page 4Linked to original sources
PubMed1988

Effect of inflammation on the metabolism of antipyrine, lidocaine and propranolol in isolated rat hepatocytes.

A decrease of the hepatic intrinsic clearance could contribute to the increase of the plasma concentrations of alpha 1-acid glycoprotein-bound drugs such as propranolol in animals and humans with inflammation. Therefore, the influence of inflammation upon the metabolism of propranolol and another high clearance drug, lidocaine, and of the low clearance drug antipyrine, was studied in isolated rat hepatocytes. For comparative purposes, the influence of the enzyme inhibitor SKF 525A (100 mg/kg i.p.) was also evaluated. Turpentine pretreatment of the rats significantly decreased the metabolism of the three drugs by the hepatocytes; the decrease was least pronounced for propranolol. The inhibitory effect of turpentine-induced inflammation was somewhat lower than that of SKF 525A. These results are in agreement with the results found for the same drugs in the 9,000-g supernatant fraction of the rat liver and point to a marked decrease of intrinsic clearance in some types of inflammation.

Animals↗
PubMed1988

Influence of food on steady state serum concentrations of theophylline from two controlled-release preparations.

The influence of food on the bioavailability of the controlled-release theophylline preparations Theostat and Theolair was studied in 12 healthy subjects after multiple dosing (b.i.d. for 6 days). On the morning of days 5 and 6, the volunteers took these products once after overnight fasting and once after a high-fat breakfast. For Theostat, serum theophylline levels and pharmacokinetic parameters were not affected by the intake of breakfast. For Theolair, serum theophylline concentrations were markedly lower after breakfast, with a significant decrease of Cmax and AUC. This study confirms the necessity of studying the influence of food on the bioavailability of theophylline controlled-release preparations.

Adult↗
PubMed1988

Alteration of the pharmacokinetics and metabolism of propranolol and antipyrine elicited by indwelling catheters in the rat.

It has been shown that catheter implantation in rats increases concentrations of propranolol and this is usually explained by the increased serum protein binding of propranolol, as a consequence of the higher serum alpha-1-acid glycoprotein concentration. We investigated in this study whether this increase in propranolol concentration after p.o. administration is not also due to a decreased first pass metabolism. We therefore studied in rats the pharmacokinetics and the in vitro metabolism by hepatocytes, of propranolol and antipyrine, 2 and 48 hr after catheter implantation. After p.o. administration of propranolol, the area under the serum concentration time curve 48 hr after catheter implantation was increased 4-fold as compared to 2 hr. As the unbound propranolol fraction was decreased only by a factor of two, it can be concluded that the hepatic intrinsic clearance was decreased, and this was confirmed by a decreased metabolizing activity in the isolated hepatocytes of these animals. After i.v. administration of antipyrine, the systemic clearance was decreased, the volume of distribution was unchanged and the half-life was increased 48 hr after catheter implantation. As antipyrine is a low extraction drug and is not bound to serum proteins, the decreased systemic clearance suggests a lower hepatic intrinsic clearance, and this was again confirmed by a decreased metabolizing activity in the isolated hepatocytes. These results confirm the important effect of the presence of indwelling catheters on the serum concentrations of antipyrine and propranolol, and suggest that this effect is the result of both an increased serum binding and a decreased hepatic metabolism.

Animals↗
PubMed1987

Alpha 1-acid glycoprotein and serum binding of drugs in healthy and diseased dogs.

Inter-individual variation in drug serum protein binding was studied in healthy dogs and in dogs with inflammatory diseases for lidocaine, oxprenolol and propranolol, which bind mainly to alpha 1-acid glycoprotein (alpha 1-AGP), and for diazepam, digitoxin and phenytoin, which bind mainly to albumin. For the drugs mostly bound to alpha 1-AGP, in both groups of dogs binding varied considerably, and it was markedly higher in dogs with inflammatory disease. For the other drugs, the variation in binding was smaller and did not differ between the two groups of dogs. In both groups of dogs, the alpha 1-AGP concentration varied widely; it was higher in the serum of the dogs with inflammation, while the concentration of albumin was lower in these animals. There was a significant negative correlation between percentage free lidocaine, oxprenolol or propranolol and alpha 1-AGP concentration, suggesting that the inter-individual variation in binding of these drugs is due to the variation in alpha 1-AGP concentration. There was a marked intra-individual variation in lidocaine binding and in serum alpha 1-AGP concentration, studied over a period of 3 weeks in healthy dogs; a significant negative correlation between percentage free lidocaine and alpha 1-AGP concentration was obtained.

Animals↗
PubMed1987

In-vitro biotransformation of antipyrine, lignocaine and propranolol in the liver of rats with turpentine-induced inflammation.

In rats with inflammation induced by turpentine injection, changes in drug disposition occur in-vivo and in the perfused isolated liver. Therefore the biotransformation of a low extraction drug, antipyrine, and of two high extraction drugs, lignocaine and propranolol, has been evaluated in the 9000g supernatant fraction of the liver of turpentine-treated rats. Aminopyrine N-demethylase activity and cytochrome P450 content were also measured. Turpentine treatment significantly reduced the in-vitro breakdown of the three drugs; aminopyrine N-demethylase activity and cytochrome P450 content were also decreased. Similar results were found in the proadifen-treated rats, except that in those, the cytochrome P450 content was slightly increased. The changes in drug disposition seen after turpentine-induced inflammation, could therefore be due in part to a change in hepatic enzymatic activity.

Aminopyrine N-Demethylase↗
PubMed1987

Effect of inflammation and proadifen on the disposition of antipyrine, lignocaine and propranolol in rat isolated perfused liver.

The effect of inflammation, induced in rats by injection of turpentine oil, on drug disposition has been evaluated in rat isolated perfused livers. The drugs studied were a low extraction drug, antipyrine, and two high extraction drugs, lignocaine and propranolol. Turpentine significantly increased the half-life of antipyrine and of propranolol, but not that of lignocaine. Proadifen (SKF 525A) significantly increased the half-life of all three drugs. Turpentine decreased the clearance of antipyrine significantly by about 50% and that of propranolol non-significantly by about 20%, but did not affect the clearance of lignocaine. Proadifen significantly decreased the clearance of all three drugs, but this was most pronounced for antipyrine. In both turpentine- and proadifen-treated rats a significant increase in volume of distribution of propranolol was observed. The results show that, as with proadifen, turpentine-induced inflammation affects the hepatic clearance of antipyrine in the rat isolated perfused liver. With both high extraction drugs, the effect of inflammation on their clearance was low or absent, in contrast to the effect of proadifen. This suggests that a possible effect of inflammation on intrinsic clearance is not large enough to influence the hepatic clearance of the high extraction drugs.

Animals↗
PubMed1987

Clinical pharmacokinetics of glyceryl trinitrate following the use of systemic and topical preparations.

Glyceryl trinitrate has been used for more than a century for the treatment of angina pectoris and, more recently, for the treatment of congestive heart failure. The introduction of transdermal delivery systems has renewed the controversy regarding the efficacy of the drug, mainly in the light of the development of tolerance. With concentrations of the order of 1 microgram/L or less, the measurement of glyceryl trinitrate in plasma is not easy: gas chromatography with electron capture detection has been used widely but recently gas chromatography-mass spectrometry has provided satisfactory results. Assay problems are most likely to be responsible for some of the unexpected results reported. Further factors which may confound the results of the study of plasma concentrations are the rapid metabolism of glyceryl trinitrate in blood in vitro, adsorption to containers and infusion sets, and the uptake and/or metabolism in vessel walls. From the intravenous infusion data, the large interindividual variability in plasma concentrations of glyceryl trinitrate is apparent. The plasma half-life is about 2 to 3 minutes; plasma clearance values reported vary from 216 to 3270 L/h, indicating extensive non-hepatic metabolism. With transdermal administration, mainly with the transdermal controlled delivery systems, plasma concentrations of glyceryl trinitrate appear to be maintained for up to 24 hours, with large interindividual variations. Despite the ability to maintain, for example with the transdermal delivery systems, relatively constant concentrations of glyceryl trinitrate, it has not been possible to find a relationship between plasma concentrations and pharmacological or clinical effects. This is in part due to the attenuation of the effects with time; from the available data it is clear that this attenuation occurs at a pharmacodynamic level (reflex adaptation and tolerance) and not at the pharmacokinetic level.

Humans↗
PubMed1987

Identification and characterization of peripheral neuronal dopamine receptors in the rat.

The effects of local administration of the dopamine receptor agonists apomorphine and pergolide were investigated in the isolated autoperfused hindquarters, renal and superior mesenteric vascular beds of the rat, in order to assess whether presynaptic dopamine receptors in these vascular regions could play a role in the hypotensive effect of these agents. In the three vascular beds, local infusion of apomorphine and pergolide did not influence perfusion pressure per se, but clearly reduced the pressure response to electrical stimulation of the sympathetic innervation. Increases in perfusion pressure induced by local administration of noradrenaline were not influenced by apomorphine and pergolide. The inhibitory effect of apomorphine and pergolide on stimulation-evoked pressure responses was completely antagonized by the dopamine receptor antagonist haloperidol. The alpha 2-adrenoceptor antagonist rauwolscine, which completely blocked the inhibitory effect of the alpha 2-adrenoceptor agonist UK-14,304-18 on neurogenic vasoconstriction, had no influence on the inhibitory effect of apomorphine and pergolide. Like haloperidol, the DA2-receptor antagonist domperidone antagonized the inhibition of neurogenic vasoconstriction by apomorphine in the three vascular beds; the DA1-receptor antagonist SCH 23390 had no influence. These results indicate that inhibitory DA2-receptors are present on the sympathetic innervation to the hindquarters, renal and superior mesenteric vascular beds of the rat.

Animals↗
PubMed1987

Influence of enhanced alpha-1-acid glycoprotein concentration on protein binding, pharmacokinetics and antiarrhythmic effect of lidocaine in the dog.

The pharmacokinetics and the antiarrhythmic effect of lidocaine were studied in healthy dogs on three occasions: before administration of rifampicin, on the 14th day of treatment with rifampicin and 4 weeks after stopping rifampicin treatment. On each occasion a loading and a maintenance infusion of lidocaine were given to obtain steady-state concentrations. Blood and plasma concentrations of lidocaine, alpha-1-acid glycoprotein plasma concentrations and percentage of free lidocaine in plasma were determined at the end of the maintenance infusion. The antiarrhythmic effect of lidocaine was evaluated by measuring the arrhythmogenic dose of epinephrine. Blood concentrations and, consequently, the total blood clearance of lidocaine were comparable on the three occasions. Total plasma concentrations were significantly higher after rifampicin administration as compared to the two control periods. Percentage of free lidocaine decreased from about 50 to about 30%, accompanied by a nearly 3-fold increase of alpha-1-acid glycoprotein concentrations. Free plasma concentrations were slightly lower after rifampicin treatment. The epinephrine dose ratio (before/after) paralleled the changes in free lidocaine concentrations. The correlation between free plasma concentrations and epinephrine dose ratio was much stronger than between total plasma concentrations and epinephrine dose ratio. The plasma elimination half-life of lidocaine was markedly shortened after rifampicin treatment, due to a diminished volume of distribution. It is concluded that, under steady-state conditions, marked increases in the protein binding of lidocaine are accompanied by only slight decreases of free plasma concentrations and of antiarrhythmic effect.

Animals↗
PubMed1987

SKF 525A displaces drugs from serum alpha 1-acid glycoprotein binding sites.

In vivo treatment of rats with beta-diethylaminoethyl-diphenylpropylacetate hydrochloride (SKF 525A), an inhibitor of hepatic monooxygenases, decreases the serum binding of oxprenolol and propranolol, which bind mainly to alpha 1-acid glycoprotein, but not that of phenytoin, which is bound to albumin. The effect was maximal 40 min after treatment and had disappeared after 6 hr, when enzyme inhibition was still present. A displacing effect was also observed when SKF 525A was added in vitro to serum of rats, dogs and humans and to human alpha 1-acid glycoprotein, whereas binding to human serum albumin was not affected. SKF 525A was found to be equipotent with tris(2-butoxyethyl)phosphate, a known displacer of binding of drugs from alpha 1-acid glycoprotein. When studying the pharmacokinetics or the effects of drugs after SKF 525A pretreatment, the possibility that altered protein binding may influence the findings should be considered.

Aminopyrine N-Demethylase↗
PubMed1986

Inhibition of noradrenergic neurotransmission by apomorphine and pergolide in the in situ autoperfused rat renal and superior mesenteric vascular beds.

In vitro studies have provided evidence that presynaptic dopamine receptors are present in the rat renal and superior mesenteric vascular beds. To confirm this in vivo, the effects of locally administered apomorphine and pergolide were studied in the in situ autoperfused renal and superior mesenteric vascular beds. Local infusion of apomorphine (1 microgram X kg-1 X min-1 for 5 min) or pergolide (1 microgram X kg-1 X min-1 for 5 min) into either the renal or the superior mesenteric artery had no effect on perfusion pressure per se. In the renal vascular bed, the pressure response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) was reduced to 49.8 +/- 4.8% by apomorphine and to 54.8 +/- 2.7% by pergolide; in the mesenteric vascular bed, apomorphine reduced the pressure response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) to 53.8 +/- 2.9, pergolide to 52.0 +/- 1.8%. Increases of perfusion pressure in the renal and in the mesenteric vascular bed induced by locally administered noradrenaline were not modified by apomorphine or pergolide. In both vascular beds, the inhibition of the stimulation-evoked pressure responses by apomorphine or pergolide was completely antagonized by local administration of the dopamine receptor antagonist haloperidol in a dose (1 microgram X kg-1) which did not influence the inhibitory effect of the alpha 2-adrenoceptor agonist UK-14,304; the alpha 2-adrenoceptor antagonist rauwolscine, in a dose (100 micrograms X kg-1) which completely antagonized the inhibitory effect of UK-14,304, did not antagonize the inhibitory effects of apomorphine and pergolide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Pharmacological characterization of neuronal dopamine receptors in the rat hindquarters, renal and superior mesenteric vascular beds.

The present study was designed to characterize the neuronal dopamine receptors involved in the inhibitory effect of apomorphine on neurogenic vasoconstriction in the isolated autoperfused hindquarters, renal and superior mesenteric vascular beds of the rat. In the three vascular beds, the inhibitory effect of apomorphine on neurogenic vasoconstriction was antagonized by the selective DA2-receptor antagonist domperidone, but not by the selective DA1-receptor antagonist SCH 23390. Local administration of these antagonists had no effect on the perfusion pressure per se or on the pressure response to electrical stimulation of the sympathetic innervation. These results show that the neuronal dopamine receptors present in the rat hindquarters, renal and superior mesenteric vascular beds can be classified as DA2-receptors.

Animals↗
PubMed1986

Binding to serum alpha 1-acid glycoprotein and effect of beta-adrenoceptor antagonists in rats with inflammation.

The beta-blocking effect of 4 beta-adrenoceptor antagonists with different pharmacokinetic properties was studied after intravenous and intraportal administration to control rats and to rats with experimental inflammation. In rats with inflammation the effects of propranolol and oxprenolol, which are mainly bound to alpha 1-acid glycoprotein (alpha 1-AGP), were significantly less after intravenous administration, but not after intraportal administration. In contrast, for metoprolol and atenolol, which are only negligibly serum bound, no difference was observed between control rats and rats with inflammation for either route of administration. Total and unbound serum concentrations of propranolol were measured 20 min after intravenous and intraportal administration. After intravenous administration, in the rats with inflammation total concentrations of propranolol were more than twice, and unbound concentrations less than half those of control rats. After intraportal administration the total concentrations were 8 times, and the unbound concentrations 3 times higher in the rats with inflammation. There was a significant correlation between the beta-blocking effect and the unbound concentrations of propranolol after intravenous administration, but not after intraportal administration. The latter finding is probably because the unbound concentrations were supramaximal.

Adrenergic beta-Antagonists↗
PubMed1986

Neither morphine nor clonidine influence the non-adrenergic, non-cholinergic inhibitory response in the rat gastric fundus.

Morphine and clonidine are among the few agents reported to modulate non-adrenergic, non-cholinergic (NANC) responses in different tissues. They were therefore tested for their effect on the NANC inhibitory response in the rat gastric fundus. Neither morphine (10(-5) M), nor clonidine (10(-5) M in the presence of prazosin 10(-6) M to avoid its own relaxatory effect) modified the NANC response in the rat gastric fundus.

Animals↗
PubMed1986

In-vitro study of the enkephalinergic hypothesis for non-adrenergic, non-cholinergic innervation in the cat stomach.

It has been suggested that enkephalins are involved in the gastric relaxation induced by stimulation of the non-adrenergic, non-cholinergic vagal fibres in the cat stomach. Experiments were therefore performed on strips of cat stomach. With longitudinal and circular gastric fundus and corpus strips from reserpinized cats, non-adrenergic, non-cholinergic relaxatory responses could be elicited by transmural electrical stimulation in Tyrode solution containing atropine and 5-hydroxytryptamine. Morphine, leu-enkephalin and met-enkephalin did not influence the tone of the strips or the relaxation evoked by stimulation at 8 Hz, and neither did the opioid antagonist, naloxone. These results do not support the enkephalinergic hypothesis for the non-adrenergic, non-cholinergic vagal fibres in the cat stomach.

Animals↗
PubMed1986

Converting enzyme inhibition: search for additional mechanisms of action.

Although the therapeutic usefulness of angiotensin converting enzyme (ACE) inhibitors in patients with hypertension and congestive heart failure has been clearly demonstrated, important unanswered questions remain about these drugs, including patient selection criteria, side effects, long-term effects, and especially their precise mechanism of action. The principal explanation of the effect of ACE inhibitors remains the inhibition of the renin-angiotensin system (RAS). However, in chronic treatment with ACE-inhibitory drugs, this relationship may not held true. Additional mechanisms of action postulated to explain the effect of ACE-inhibitors include inhibition of angiotensin II formation in the central RAS, neutralization of renin activity in the vascular wall, blockade of vasoconstrictor response to sympathetic nerve stimulation, and possible involvement of prostaglandins linked, for instance, to bradykinin accumulation. The search for additional mechanisms of action should lead to clinically important findings, provide a better understanding of the pathophysiology of cardiovascular disease, and improve patient treatment with ACE inhibitory drugs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

Inhibitory effects of apomorphine and pergolide on neurogenic vasoconstriction in the hindquarters of the rat.

The effects of locally administered apomorphine and pergolide were studied in the isolated autoperfused hindquarters of the rat, in an attempt to assess the possible role of presynaptic dopamine receptors at that level in the hypotensive effect of these dopamine agonists. Local infusion of apomorphine (1 micrograms . kg-1 . min-1 for 5 min) or pergolide (1 micrograms . kg-1 . min-1 for 5 min) [into the hindquarters] did not alter perfusion pressure per se, but reduced the pressor response to electrical stimulation of the lumbar sympathetic chains for the whole frequency range used during a cumulative frequency-response curve (0.25-16 Hz, 1 ms, supramaximal voltage). Apomorphine and pergolide reduced the pressor response elicited by 4 Hz electrical stimulation (applied until maximum response was reached) to 54.8 +/- 7.1% and 53.9 +/- 1.7% respectively, but they did not modify similar increases of perfusion pressure produced by locally administered noradrenaline. The inhibition by apomorphine and pergolide of the 4 Hz stimulation-evoked pressor response was completely antagonized by local administration of the dopamine antagonist haloperidol (1 microgram . kg-1), but was not influenced by the alpha 2-antagonist rauwolscine (100 micrograms . kg-1). This dose of rauwolscine antagonized the inhibitory effect of the alpha 2-agonist UK-14,304, which was not influenced by haloperidol. Local administration of rauwolscine increased the pressor response to stimulation at 4 Hz by 37.4-46.2%. In contrast, local administration of haloperidol did not influence the 4 Hz stimulation-evoked pressor response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗