Search PubMed⌕ Search

Biomedical subjects

R Hammer

Publications and source records attributed to R Hammer.

At least 73 records · Page 4Linked to original sources
PubMed1981

[Pharmacokinetics of AR-L 115 BS in rabbits and dogs].

The pharmacokinetics of 2-[(2-methoxy-4-methylsulfinyl) phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) were investigated in the rabbit and the dog. The rabbits were dosed with 1 mg/kg 14C-AR-L 115 BS i.v. or p.o and the dogs with 1 mg/kg i.v. or 5 mg/kg p.o. following i.v. administration the blood levels in the two investigated species are described by a 3-exponential decline, during which the preponderant amount of radioactivity is eliminated in the first two phases. The half-lives are 0.25 h and 6 h in the rabbit and 0.2 h and 0.6 in the dog. Following oral administration the radioactivity is absorbed rapidly and quantitatively. Blood level peaks occur after 1 h p.a. amounting to 0.07--0.1 microgram Eq/ml in the rabbit (1 mg/kg) and 2.7 +/- 0.3 micrograms Eq/ml in the dog (5 mg/kg). The elimination behaviour is comparable to that after i.v. dosing. The plasma radioactivity in the dog is not protein bound. On average the urinary excretion amounts to 45% (i.v) and 40% (p.o.) in the rabbit, with a further 52% (both application routes) in the faeces up to 144 h p.a. In the dog the mean urinary excretion is 24% (i.v.) and 29% (p.o.). Faecal elimination is 63% (i.v.) and 56% (p.o.) up to 96 h p.a.

Administration, Oral↗
PubMed1980

Binding of an imidazolidine (clonidine), an oxazoloazepin (B-HT 933) and a thiazoloazepin (B-HT 920) to rat brain alpha-adrenoceptors and relation to cardiovascular effects.

The specific binding to alpha-adrenoceptors in crude plasma membrane preparations of the rat brain was studied by means of 3H-clonidine (specific radioactivity 26.7 Ci/mmole). Equilibrium binding of 3H-clonidine could be described adequately according to a two-site model with a minor population of high affinity sites (KD1 = 0.4 nM) and a major population of low affinity sites (KD2 = 6.1 nM). The heterogeneity of 3H-clonidine binding was also indicated by a biphasic association rate in kinetic binding studies. In competition experiments with 3H-clonidine concentrations of 0.5 or 4.0 nM respectively, concentration-dependent displacement was observed with the non-radioactive compounds: clonidine, B-HT 920 (2-amino-6-allyl-5, 6, 7, 8-tetrahydro-4H-thiazolo-[5, 4-d]-azepin-dehydrochloride) and B-HT 933 (2-amino-6-ethyl-4, 5, 7, 8-tetrahydro-6H-oxazolo-[5, 4-d]-azepin-dihydrochloride). IC50 values of 3, 21 and 160 nM or 10, 63 and 380 nM respectively were thereby evaluated. Cardiovascular effects were estimated in rats. The blood pressure increase in spinal animals was taken as parameter for alpha-adrenoceptor stimulation at peripheral vascular sites. The bradycardic effect in vagotomized animals was taken as parameter for central nervous sympathoinhibition. The ranking order of the potency of the three drugs was the same in both in vivo tests and parallels the in vitro binding affinities at both binding sites: clonidine greater than B-HT 920 greater than B-HT 933. These results indicate the similarity of the alpha-adrenoceptor structures in brain membrane preparations, at peripheral vascular sites and at central sympathoinhibitory sites.

Animals↗
PubMed1980

Pirenzepine distinguishes between different subclasses of muscarinic receptors.

Some antagonists exhibit tissue selectivity in their pharmacological antagonism of muscarinic responses. However, the affinity constants for equilibrium binding of classical antagonists to muscarinic receptors in subcellular preparations have shown only small variations in different peripheral tissues and regions of the brain. The binding curves do not deviate significantly from the simple Langmuir isotherm, indicating apparent homogeneity of the receptor population in any given region. In contrast, heterogeneity has been detected by agonist binding studies but this may arise from different environmental or coupling restraints on the agonist-induced conformational change and cannot be taken as evidence for different receptor subtypes. We report here binding studies using a new anti-muscarinic drug, pirenzepine, in which we found heterogeneity of binding that correlates well with the pharmacological activity.

Animals↗
PubMed1980

Pirenzepine--a ligand with original binding properties to muscarinic receptors.

Pirenzepine has been shown to evoke a variety of antimuscarinic effects in animals. However, in contrast to classical antimuscarinic drugs, pirenzepine inhibits gastric acid secretion at much lower doses than those required to block smooth muscle action and to cause tachycardia. To investigate this novel behaviour we have compared the binding properties of pirenzepine to muscarinic receptors with those of a classical muscarinic antagonist, N-methyl-scopolamine. Binding has been determined in subcellular preparations of the sublingual, submandibular, parotid and lacrimal glands, smooth muscle of ileum and stomach, heart and several brain regions of the rat. Whereas N-methyl-scopolamine binds to an apparently uniform population of muscarinic receptors with little regional variation in affinity constant, the binding of pirenzepine in peripheral tissues is characterised by its low affinity in smooth muscle and the heart and considerably higher affinities to muscarinic receptors in exocrine glands and fundus mucosa, in agreement with the pharmacological profile of the drug. Furthermore, within the central nervous system and some exocrine glands, pirenzepine distinguishes between subclasses of muscarinic receptors which are not detected by classical antagonists. This evidence suggests that the unusual receptor binding properties of pirenzepine may make its selective antimuscarinic action possible.

Animals↗
PubMed1980

An international pharmacokinetic study on pirenzepine following a single oral dose.

Pirenzepine is a very hydrophilic compound. As a consequences its penetration through biomembranes and hence its absorption after oral administration is limited. The variability in plasma pirenzepine after a single oral dose of 50 mg (2 x 25 mg tablet) was investigated in ten countries in a total of 87 volunteers. Pirenzepine was measured by a specific radioimmunoassay. Plasma level profiles were similar in every country with a peak of about 50 ng/ml within two hours after the dose. The mean terminal half-life of disposition was 11 hours. Although the area under the plasma level curve was not normally distributed throughout the population, there was a narrow distribution around the median. It is often accepted that drugs or drug formulations with low bioavailability show high variations in the rates and extent of absorption. Pirenzepine, however, shows consistently uniform plasma level profiles, well within the therapeutic range after multiple dosing (50 mg, twice daily). Only a small proportion of the population may need individual adjustment of the conventional dose regimen.

Administration, Oral↗
PubMed1980

Muscarinic receptors in the stomach.

Using tritiated N-methyl-scopolamine (3H-NMS), muscarinic receptor binding was demonstrated in broken cell preparation of mucosa and smooth muscle of the fundus of the canine stomach. Binding curves of pirenzepine were established in competition experiments against 3H-NMS. Pirenzepine shows a considerably higher affinity to muscarinic receptors from fundic mucosa than those from smooth muscle, suggesting a difference of muscarinic receptors in these two regions of the stomach. Different properties of mucosal and smooth muscle receptors could be further substantiated by agonist binding studies. Whilst carbachol binding to muscarinic receptors from fundic smooth muscle was modulated by guanine nucleotides, no such effect was found in fundic mucosa. Direct binding studies with 3H-NMS demonstrated muscarinic receptors in peripheral ganglia (sympathetic trunk ganglia from the calf, stellate ganglia from the dog). These are characterized by high affinity pirenzepine binding so that besides its direct action on gastric secretory glands, pirenzepine may influence indirectly gastrointestinal functions via peripheral, presumably intramural, ganglia.

Animals↗
PubMed1979

Spontaneous rupture of the liver. A complication of oral anticoagulant therapy.

Therapeutic doses of oral anticoagulants have been associated with spontaneous hemorrhage and rupture of apparently normal abdominal viscera. To our knowledge, this is the second reported case of such rupture involving the liver. The patient had sudden severe epigastric pain and signs of acute abdomen and shock. Discrete microscopic changes in the liver may precede massive hemorrhage.

Aged↗
PubMed1979

Inhibition of gastric acid secretion by pirenzepine (LS 519) in man.

Pirenzepine is a new tricyclic drug used in the treatment of peptic ulcer disease. The effect of two doses of pirenzepine (25 mg twice daily and 50 mg thrice daily) was examined in ten healthy volunteers during basal acid secretion and under stimulation with two doses of pentagastrin (0.166 microgram/kg . h and 1 microgram/kg.h given as continuous intravenous infusion). Serum drug concentrations were determined by radioimmunoassay, and parallel studies of the salivary function were performed. Pirenzepine, 25 mg twice daily, reduced basal acid output by 50% and 55%, respectively, and inhibited stimulated acid output by 31% and 26%, respectively. The higher dose of pirenzepine, 50 mg thrice daily, augmented the effect insignificantly despite markedly increased serum drug levels. The recommended therapeutic dose of 25 mg twice daily gave no salivary inhibition. Pirenzepine may have an anticholinergic effect on the parietal cell, although systemic side effects were not seen. Pirenzepine does not competitively inhibit pentagastrin-stimulated acid secretion.

Adult↗
PubMed1979

The pharmacokinetic profile of pirenzepine.

This paper gives a brief review of the pharmacokinetic studies performed on pirenzepine (L S 519 Cl2, Gastrozepin hitherto. Particular attention will be paid thereby to the clinical significance of the pharmacokinetic parameters.

Animals↗