Biomedical subjects

H F Pitschner

Publications and source records attributed to H F Pitschner.

61 records · Page 4Linked to original sources

PubMed1989

Selective antagonists reveal different functions of M cholinoceptor subtypes in humans.

Effects of atropine and of the subtype selective mAChR antagonists pirenzepine (PZ) and AF-DX 116 were studied in humans. Dose- or time-response curves were established for heart rate and salivary flow. Plasma samples were drawn in parallel with the effect measurements and analysed for drug concentrations. Subtype-selective radioreceptor assays of the samples served to estimate the respective receptor occupancy in vivo. It is shown that low doses of PZ (M1-selective blockade) cause cholinomimetic effects indicated by bradycardia and increase in salivary flow. After high doses of PZ or atropine, tachycardia and inhibition of salivary flow are observed in parallel with occupancy of both the M2 and M3 subtypes. AF-DX 116 induces a tachycardia together with an increased salivary flow in agreement with its selectivity profile (M2 greater than M1 greater than M3). The diagnostic and therapeutic applications of M1- or M2-selective blockade by low dose PZ or AF-DX 116 respectively are discussed.

Humans↗

PubMed1988

Complex dose-response curves of atropine in man explained by different functions of M1- and M2-cholinoceptors.

In the present study we set out to explain the complex atropine dose-response curves in man in relation to M-cholinoceptor subtype occupancy. In healthy volunteers the effects of atropine on heart rate and salivary flow were quantified. M-cholinoceptor subtype occupancy by antagonist present in plasma samples was detected in an in vitro radioreceptor assay. Atropine effects were studied without and after propranolol (240 mg oral dose) and without and after pirenzepine (1.1 mg i.v.) to differentiate beta-adrenoceptor and M-cholinoceptor subtype mediated effects. 1. In receptor binding studies, M-cholinoceptors in bovine cerebral cortex membranes were labelled with 3H-pirenzepine (pKd = 8.05), M-cholinoceptors in rat salivary gland membranes with 3H-N-methylscopolamine (pKd = 9.02). Atropine competed for binding of these ligands with a small (2.1-fold) preferential selectivity via the cerebral in comparison to the glandular receptors (pKi = 9.18 versus 8.86). Pirenzepine showed a marked selectivity (40-fold) in this respect with pKi-values of 8.05 (M1: cerebral cortex) and 6.45 (M2: salivary glands). 2. At heart rate and at salivary flow, bivalent dose-response curves of atropine were observed with opposite effect vectors. The typical antagonist effects at M-cholinoceptors (i.e. an increase of heart rate and an inhibition of salivary flow) were observed at doses greater than 1 microgram/kg, whereas "paradoxical" cholinomimetic effects of atropine became apparent at lower doses. From a superposition of two isotherms with opposite effect vectors ED50-values were calculated, which were in the range of half-maximal M-cholinoceptor occupancy in the in vitro radioreceptor assay of plasma samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Dose-response curves of pirenzepine in man in relation to M1- and M2-cholinoceptor occupancy.

The aim of the present study was to investigate the M-cholinoceptor subtype selectivity of pirenzepine in man. In parallel with effects on the heart rate and salivary flow, M-cholinoceptor subtype occupancy by antagonist present in plasma samples was detected in radioreceptor assays. Bovine cerebral cortex membranes labelled with 3H-pirenzepine (M1) and rat salivary gland membranes labelled with 3H-N-methylscopolamine (M2) were used in these in vitro assays. A half-maximal occupancy of M1-cholinoceptors in the in vitro assay of plasma samples was detected after 0.25 mg of pirenzepine i.v. The respective half-maximal M2-cholinoceptor occupancy was observed after 10 mg. Doses less than 3 mg decreased the heart rate by maximally 10.7 beats/min with an ED50 of about 0.1 mg. An increase in heart rate (relative to control values) was observed at doses greater than 10 mg. This bivalent dose-response relationship was also observed after beta-blockade. Salivary flow tended to increase at doses less than 1 mg and was half-maximally inhibited after 10 mg. Combining the in vitro and in vivo results, the typical antimuscarinic effects (tachycardia and inhibition of salivary flow) can be attributed to the blockade of M2-cholinoceptors, whereas the reduction of heart rate coincides with the blockade of the M1-subtype. With respect to the typical antimuscarinic effects, pirenzepine was 70-fold less potent than atropine; in contrast, with respect to the reduction of heart rate, pirenzepine was equipotent with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Transdermal delivery of bupranolol: pharmacodynamics and beta-adrenoceptor occupancy.

Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6-15 nmol/l (equivalent to 1.5-4 ng/ml in plasma) at beta 1- (rat salivary gland) and beta 2-adrenoceptors (rat reticulocytes) in receptor binding studies with 3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t 1/2 = 2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Administration, Cutaneous↗

PubMed1985

Receptor binding of propranolol is the missing link between plasma concentration kinetics and the effect-time course in man.

In a double-blind, placebo-controlled study in 6 healthy volunteers, the correlation between beta-adrenoceptor binding, the time course of the effect and plasma concentration kinetics was investigated from 0 to 48 h after a single oral dose of propranolol 240 mg. First, the in vitro beta-adrenoceptor interaction of propranolol was investigated. Propranolol inhibited beta-adrenoceptor binding to rat parotid (beta 1) and reticulocyte (beta 2) membranes in the presence of pooled human plasma with a Ki of about 8 ng/ml plasma. After oral administration of 240 mg propranolol, concentration kinetics in plasma could be described by a Bateman function with a fictive concentration at time 0 of 275 ng/ml plasma, and a mean elimination half-life of 3.5 h. Using the concentration kinetics of propranolol in plasma together with its in vitro beta-adrenoceptor binding characteristics in the presence of placebo plasma from each individual, the time course of antagonism against beta-adrenoceptor mediated effects was predicted. The latter was in agreement with the time course of propranolol-induced inhibition of tachycardia due to orthostasis. After bicycle ergometry, however, the time course of inhibition of tachycardia was shorter than was predicted. Plasma sampled at various times after propranolol administration inhibited beta-adrenoceptor binding of the radioligand 3H-CGP 12177 to rat reticulocyte membranes in a fashion reflecting the time course of inhibition of exercise tachycardia observed in the volunteers. A direct, linear relation was shown between the in vitro inhibition of beta-adrenoceptor binding by the plasma samples withdrawn after propranolol administration and the inhibition of exercise tachycardia observed in parallel. The results show that the concentrations of antagonist present in plasma are representative of the concentrations in the effect compartment. Deep compartments of drug distribution appear irrelevant to the effects of the drugs. The relation between the plasma concentration of propranolol and the reduction in heart rate at various levels of physical effort shows no significant inhibition at rest and increasing IC50-values from orthostasis to 2 min and to 4 min of ergometry. IC50-values after orthostasis are in the range of the Ki-values from in vitro receptor binding studies, whereas the IC50-values after exercise are shifted 2- to 3-fold to the right relative to the Ki-values. This finding is in agreement with increased beta-adrenoceptor stimulation with increasing effort (release of endogenous noradrenaline), which shifts the antagonist concentration-effect curve to the right.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1985

Receptor binding characteristics and pharmacokinetic properties as a tool for the prediction of clinical effects of beta-blockers.

The clinical effects of a single dose of beta-adrenoceptor antagonists (beta-blockers) lasts longer than the respective half-lives in plasma will suggest. This apparent discrepancy is easily explained by a superimposition of the function of plasma concentration kinetics and the function for competitive antagonism at beta-adrenoceptors according to the law of mass action. By taking data from literature as well as those from receptor binding studies and clinical investigations from our laboratories this model was confirmed. Furthermore it can be stated: The plasma concentrations of beta-blockers are representative for the drug concentration at the beta-adrenoceptor in human. "Tight" receptor binding is not the reason for the prolonged effects, but rather the relation between drug concentration and the resp. EC50-value at the respective time of measurement. The extent of antagonism of beta-blockers in vivo can be predicted from ligand binding studies in vitro. Using the time-concentration profile in plasma in addition, the time course of clinical effects can be delineated. This holds true for the non-selective beta-blocker propranolol as well as atenolol, which shows selectively higher affinity at the beta 1-subpopulation. Deviations from the model suggested for the correlation between plasma concentration kinetics, time course of clinical effects and interaction between drug and receptor for beta-blockers may be indicative of additional compartments, active metabolites, partial agonist activity, counterregulatory processes, adaptive mechanisms and must be verified if taken for modelling. In general, any drug acting on the basis of the law of mass action should obey to the described relation between the time course of plasma concentrations and clinical effect (e.g. cardiac glycosides).

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Down-regulated beta-adrenoceptors in severely failing human ventricles: uniform regional distribution, but no increased internalization.

In chronic heart failure cardiac beta-adrenoceptors are decreased. In this study we investigated whether a) in severely failing human ventricles beta-adrenoceptors are uniformly decreased or regional variations exist, and b) the beta-adrenoceptor decrease is caused by increased internalization or is a real loss in beta-adrenoceptors. For this purpose we assessed beta-adrenoceptor number and subtype distribution in a particulate fraction (mainly sarcolemmal plasma membranes) and a light vesicle fraction of right and left ventricular segments (obtained by cutting transversal rings of 2 cm from the midventricular regions) of explanted hearts from 2 patients with end-stage congestive dilated cardiomyopathy (DCM) and one patient with end-stage ischemic cardiomyopathy (ICM). In all three hearts ventricular beta-adrenoceptor number was very low (7.5-10 and 21-26 fmol/mg protein in DCM, 15-22 fmol/mg protein in ICM compared to 68-74 fmol/mg protein in non-failing ventricles). beta-Adrenoceptors were uniformly decreased over the whole ventricular region and no considerable regional variations existed. The same held true for beta 1- and beta 2-adrenoceptors. In ICM decrease in beta-adrenoceptors was due to a concomitant reduction in beta 1- and beta 2-adrenoceptors, in DCM it was mainly caused by beta 1-adrenoceptor down-regulation. In all ventricular segments investigated light vesicle beta-adrenoceptors amounted to about 5-7% of total ventricular beta-adrenoceptors, and this was not significantly different from non-failing left ventricles. We conclude that a) in severely failing human ventricles beta-adrenoceptors are evenly down-regulated and no regional variations exist, and b) the decrease in beta-adrenoceptors is not due to enhanced internalization but is a real loss of beta-adrenoceptors.

Adult↗