In vitro and in vivo pharmacological characterization of BIIL 284, a novel and potent leukotriene B(4) receptor antagonist.

BIIL 284 is a new LTB(4) receptor antagonist. It is a prodrug and has negligible binding to the LTB(4) receptor. However, ubiquitous esterases metabolize BIIL 284 to the active metabolites BIIL 260 and BIIL 315, the glucuronidated form of BIIL 260.

Comparative effects of a glucocorticosteroid, theophylline and the peptido-leukotriene-antagonist CGP 45715A on antigen-induced early and late phase airway response and inflammatory cell influx in sensitised guinea pigs.

A novel model of allergic early and late-phase reaction in the airways of conscious guinea pigs was developed and the effect of established and novel antiasthmatic drugs on peak of immediate response, late phase response and associated inflammatory cell influx investigated. Guinea pigs were sensitised twice in adjuvant (50 mg/kg silica + 0.1 ml/kg Bordetella pertussis).

Characterisation of a novel airway late phase model in the sensitized guinea pig which uses silica and Bordetella pertussis as adjuvant for sensitization.

The objective of the present investigation was to validate a novel model of allergic late phase reaction in the airways of conscious guinea pigs by monitoring airway function with CO2-forced respiration. In addition airway inflammation as one possible cause for the development of airway late phase reaction was characterized by a novel technique which consists of bronchoalveolar lavage via the orotracheal route. Guinea pigs were sensitized twice at 2-week intervals with ovalbumin in silica and Bordetella pertussis.

Pharmacological characterisation of a new model of antigen-induced pulmonary late-phase reaction in the conscious guinea pig which uses additional polymyxin B inhalation.

The aim of the present study was to develop a new model of allergic late-phase reaction in the airways of conscious guinea pigs (GPs) and to characterise it by pharmacological intervention. GPs were pretreated with cyclophosphamide and sensitized with ovalbumin (OA) in Al(OH)3. Weekly inhalations of polymyxin B were performed before and during sensitization and continued throughout the study period.

Synthesis and biological evaluation of 14-alkoxymorphinans. 11. 3-Hydroxycyprodime and analogues: opioid antagonist profile in comparison to cyprodime.

A series of 3-hydroxy-substituted analogues (3-7) of the mu selective opioid antagonist cyprodime has been synthesized in order to evaluate the role of a hydroxy group at C-3 concerning mu opioid antagonist selectivity. Compounds 3-7 were tested in bioassays (electrical stimulated mouse vas deferens preparation and myenteric-plexus longitudinal muscle preparation of the guinea pig ileum) and opioid receptor binding assays. Antagonism of mu receptor-mediated responses induced by the mu selective agonist DAMGO afforded equilibrium dissociation constants in the mouse vas deferens preparation (Ke values) for compounds 3-7 which agreed closely with their affinities as determined by opioid receptor binding assays (Ki values).

Dissociation of airway responsiveness and bronchoalveolar lavage (BAL) cell composition in sensitized guinea-pigs after daily inhalation of ovalbumin.

The association between inflammatory cell influx, cell activation status and change of airway responsiveness to acetylcholine (ACh) after daily inhalation of ovalbumin (OA) in sensitized guinea-pigs was investigated. Starting 3 weeks after sensitization (OA at 50 mg/kg s.c.

Synthesis and biological evaluation of 14-alkoxymorphinans, V: 6-Deoxyocyprodime, an opioid antagonist with decreased mu receptor selectivity in comparison to cyprodime.

N-Cyclopropylmethyl-4,14-dimethoxymorphinan (4) and N-cyclopropylmethyl-4-hydroxy-14-methoxymorphinan (5) have been prepared from cyprodime (1) by Wolff-Kishner reduction. Pharmacological studies (mouse vas deferens and guinea pig ileum preparations) revealed that there was no significant decrease of 4 in antagonist activity but in mu selectivity when compared with 1. The phenol 5 showed partial agonism at mu, kappa and delta receptors.

Evidence for a specific effect of BHT 920, an azepine derivative, on tyrosine hydroxylase in the dopaminergic system of the rat.

The effect of BHT 920, a putative presynaptic dopamine receptor agonist, on tyrosine hydroxylase was investigated in rats. The activity of the high affinity (BH4) form of striatal tyrosine hydroxylase was investigated dose-dependent manner in rats treated with BHT 920. This effect was pronounced in the dopaminergic system and was not observed to the same extent in the adrenal medulla.

N-(3-acetylaminophenyl)piperazine hydrochloride (BEA 1654), a putative 5-HT1 agonist, causes constriction of arteriovenous anastomoses and dilatation of arterioles.

Using 3H-ligands and radioactive microspheres we studied the binding characteristics and the effects on the distribution of carotid arterial blood flow of n-(3-acetylaminophenyl)piperazine hydrochloride (BEA 1654). The compound had a Ki value of 32 nM (5-HT: 8 nM) on 5-HT1 but no or very weak affinity for 5-HT2, alpha 1- and alpha 2-adrenoceptor sites in rat cerebral cortex homogenates. Intracarotid infusions of BEA 1654 (0.

Redistribution of carotid artery blood flow by 5-HT: effects of the 5-HT2 receptor antagonists ketanserin and Wal 1307.

The study concerned effects of ketanserin and a new 5-HT2 receptor antagonist, Wal 1307, on the responses to 5-hydroxytryptamine (5-HT) in the porcine common carotid vascular bed. More than 80% of the total carotid blood flow (208 +/- 18 ml; n = 12) bypassed the tissues via arteriovenous anastomoses. Intracarotid infusions of 5-HT (2 micrograms X kg-1 X min-1) reduced the total carotid blood flow by about 50% and arteriovenous anastomotic flow by 85% but extracerebral tissue (nutrient) blood flow more than tripled.

Mr 2033 CL--a novel non-morphine-like opioid analgesic.

Mr 2033 CL is a very potent non-morphine-like opioid analgesic as shown in different test models and animal species. On a weight for weight basis, it is about 20 times more potent than morphine. The analgesic effects of Mr 2033 CL are supposed to be different from those of morphine and bremazocine because of individual sensitivity against selective antagonists like naloxone and Mr 2266 CL.

[Isolation of cytostatically active proteins from seeds of Ricinus communis, Abrus praecatorius and Canavalia ensiformis (author's transl)].

The extraction and isolation of, as yet, uninvestigated antitumor active protein mixtures from the seeds of Abrus praecatorius, Canavalia ensiformis and especially Ricinus communis is reported. By means of membrane ultrafiltration of crude ricin a low-molecular weight protein mixture, Ro 413, could be obtained, which showed, in comparison to ricin-toxin, a reduced toxicity but with the same cytostatic action. An almost complete separation of Ro 413 into the individual components was achieved using preparative disc electrophoresis.

[Experimental studies on the effect of pyloroplasty on gastric emptying, serum gastrin and duodenogastric reflux in selective proximal vagotomy (SPV)].

The influence of selective proximal vagotomy (SPV) and of an additional pyloroplasty (Heineke-Mikulicz) on gastric emptying, acid and gastrin secretion, and duodenogastric reflux was examined experimentally. After SPV, gastric emptying of fluids and a solid meal was significantly faster than before surgery. An additional pyloroplasty did not influence gastric emptying time significantly.

[Manometry and gastro-esophageal closure mechanism. An attempt at evaluation (author's transl)].

The registration of resting pressures and motility activity has considerably increased our knowledge of the normal functioning of the esophagus. We have not jet solved all the methodological problems of manometry; however perfusion manometry, which is used today, has enabled us to make an exact cassification of functional disorders and adequate therapy. An understanding of the methodological problems involved is necessary for the correct use of the manometric method and the correct interpretation of its results.

The effect of clonidine on gastric acid secretion in rats and dogs.

The effect of clonidine on gastric acid secretion was investigated using rats and dogs. In the stomach lumen perfused rat basal gastric acid secretion was increased by clonidine in the anaesthetized rat but inhibited in the conscious animal. Clonidine also reduced the basal gastric acid secretion in rats with chronic gastric fistula, (ED50 12 microng/kg p.

Somatostatin mode of action on gastric acid secretion in dogs.

The aim of the present study was to investigate the mode of the inhibitory effect of somatostatin on gastric acid secretion. This was done in Heidenhain-pouch dogs studying the effect of somatostatin on cumulative dose response curves of pentagastrin, carbachol and histamine. Somatostatin inhibited gastric secretion after all three stimuli, with decreasing potency against carbachol, pentagastrin and histamine.

The relationship between serum IRG levels and LES Pressure under various conditions.

In investigations with various groups of patients there was no correlation between fasting serum IRG levels and LES pressures in individual subjects with undisturbed for disturbed sphincters. After food ingestion a short phase of LES pressure increase (from 13.5 +/- 1.

The effect of pressure changes inside the antrum on lower esophageal sphincter (LES) pressure in man and dog.

The pressure change inside the lower esophageal sphincter (LES) in response to pressure changes inside the antrum was investigated in man and in dogs with antral pouches. In dogs with innervated antral pouches a pressure increase of 20 cm H2O inside the antrum produced an increase in LES pressure of 14 +/- 7 mm Hg, whereas an antral pressure of 80 cm H2O caused a decrease of 26 +/- 12 mm Hg in LES pressure (x +/- SD). Truncal vagotomy abolished LES response to the various antral pressures.

Experimental hypergastrinaemia in the dog.

In order to investigate chronic hypergastrinaemia in dogs, studies with various excluded antrum preparations were performed. Gastric secretion was collected from denervated fundic pouches and gastrin levels were measured pre- and postoperatively by radioimmunoassay. In some samples the gastrins were separated according to their molecular size.

Motilin effects on gastrointestinal motility and lower esophageal sphincter (LES) pressure in dogs.

Natural porcine motilin induces phasic contractions of the lower esophageal sphincter in dogs. These contractions are related to gastric contractions, which have the characteristics of interdigestive-motility patterns. Duodenal alkalinization produces an insignificant LES pressure increase after 5 minutes.

The effect of intravenous infusion of synthetic human gastrin-I on lower esophageal sphincter (LES) pressure in the dog and its relation to gastrin level.

To demonstrate the relation between gastrin level and lower esophageal sphincter (LES) pressure, experiments with intravenous infusions of synthetic human gastrin-I (SHG-I) were performed in anaesthetized dogs. The results show that infusions with 5 mug-kg-1-h-1 SHG-I have an initially increasing effect on LES pressure but produce unphysiologically high gastrin blood levels. Physiological levels of gastrin were measured only using an infusion dose of 0.

The motor-stimulating effect of natural motilin on the lower esophageal sphincter fundus, antrum and duodenum in dogs.

Natural motilin was investigated for its effect on gastrointestinal motor activity in anesthetized dogs. In doses starting from 10 ng/kg as single injection and 100 ng/kg-h as intravenous infusion, motilin induced phasic pressure changes in the lower esophageal sphincter (LES) and in the lumen of the fundus, antrum, and duodenum. Tachyphylaxis was seen in 6 out of 10 dogs.