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Biomedical subjects

R K Müller

Publications and source records attributed to R K Müller.

At least 37 records · Page 2Linked to original sources
PubMed1988

Epidermal growth factor content of submandibular glands is increased in rats with experimentally induced gastric lesions.

Occurrence and growth-promoting effect suggest that epidermal growth factor (EGF) is involved in the maintenance of the gastrointestinal mucosa. The aim of this study was to ascertain whether rats with gastric lesions, induced by cold-water stress, ethanol, or indomethacin, have altered EGF levels in their gastrointestinal tract compared with controls. For this purpose we established a solid-phase enzyme immunoassay and measured the amount of immunoreactive EGF (IR-EGF) in extracts of the submandibular gland, stomach, duodenum, jejunum, ileum, and colon. In the submandibular glands of control rats the IR-EGF content was 100-400 times higher than in the gastrointestinal tract. In animals with experimentally induced ulcer the IR-EGF content was increased in the submandibular glands (1480 versus 423 ng/g), duodenum (11.4 versus 5.8 ng/g), and colon (4.1 versus 1 ng/g), whereas no change was observed in the stomach and jejunum. When the formation of lesions was prevented by omeprazole (stress) or prostaglandin E2 (ethanol and indomethacin), the IR-EGF increase in submandibular glands and duodenum was abolished. This indicates that mechanisms regulating the synthesis and secretion of submandibular EGF might be of importance in the development of gastric and duodenal ulcers.

Animals↗
PubMed1987

Ro 18-5364, a potent new inhibitor of the gastric (H+ + K+)-ATPase.

The sulfoxide agent Ro 18-5364 is an extremely potent and rapid inhibitor of the gastric mucosal (H+ + K+)-ATPase with an apparent Ki of 0.1 microM at pH 6. The inhibition of both enzymatic activity and vesicular proton transport in membrane preparations is concentration- and time-dependent. Comparative studies with the two enantiomers of Ro 18-5364 indicated no enantiomeric preference. Marked differences were seen between Ro 18-5364 (sulfoxide) and Ro 18-5362 (sulfide) with regard to inhibitory activity. Even at concentrations as high as 0.1 mM Ro 18-5362 failed to affect significantly (H+ + K+)-ATPase activity and associated proton translocation. Similarly, Ro 17-5380 demonstrated an apparent Ki of 20 microM for inhibition of the (H+ + K+)-ATPase whereas its reduced derivative Ro 17-4749 was inactive. Addition of a single methyl group in the pyridine moiety of Ro 18-5364 noticeably decreased the inhibitory potency. The inhibitory action of Ro 18-5364 on (H+ + K+)-ATPase activity was markedly higher at low incubation medium pH in comparison to physiological or alkaline values. The results of incorporation studies paralleled that of enzymatic inhibition. The extent of Ro 18-5364 incorporation was dependent on time, concentration, and medium hydrogen ion concentration, with a decrease in medium pH resulting in increased binding. While ATP and GTP had little effect on the binding rates, reduced lipoic acid methyl ester, mercaptoethanol and dithiothreitol were capable of displacing the radiolabel to different extents. Autoradiography of electrophoresed Ro-18-5364-labeled gastric microsomal membranes confirmed that the radiolabel was associated with polypeptides of approximately 100 kDa. The incorporation was reversed upon subjection of the membranes to reducing conditions.

Adenosine Triphosphatases↗
PubMed1986

Gastric (H+ + K+)-ATPase: modulation of the inhibitory properties of the novel potent antisecretagogue Ro 18-5364 by sulfhydryl reagents and nucleotides.

The sulfoxide Ro 18-5364, a potential metabolite of the IND Ro 18-5362, is a powerful inhibitor of gastric mucosal (H+ + K+)-ATPase, decreasing enzymatic activity with an apparent Ki of 0.1 microM. Exposure of Ro 18-5364-treated gastric membranes to dithiothreitol fully restored (H+ + K+)-ATPase activity. ATP protected the enzyme against Ro 18-5364-induced inactivation of enzymatic activity. In addition, Ro 18-5364 inhibited vesicular proton uptake. In proton translocation experiments reduced lipoic acid methyl ester partially restored transport properties. Dithiothreitol and mercaptoethanol were without effect. The results are discussed with respect to the possible location of essential sulfhydryl groups for enzyme activity and proton transport.

Adenosine Triphosphatases↗
PubMed1985

Inhibition of canine gastric secretion by the prostanoid Ro 22-6923.

The synthetic prostanoid, Ro 22-6923, was studied for its effects on canine gastric secretion. Histamine-stimulated acid secretion was inhibited for up to 8 hr after an orally administered dose of 0.25 mg/kg Ro 22-6923. In the Amdrup (modified Pavlov) pouch model, Ro 22-6923 significantly inhibited food-stimulated acid secretion at an oral dose of 0.5 mg/kg. The effect lasted for 4 hr and was of greater intensity than that observed with 5 mg/kg cimetidine. The ED50 for Ro 22-6923 in this model was 0.25 mg/kg and 0.09 mg/kg for oral and intrapouch administration, respectively. Natural prostaglandin E2 was inactive up to 1 mg/kg orally, but had an ED50 of 0.08 mg/kg when administered directly into the pouch. The results indicate that Ro 22-6923 is a potent, long-acting antisecretory drug that may be useful in the therapy of peptic ulcer disease in man.

Animals↗
PubMed1985

Inhibition of acid secretion and gastric lesions in rats by the prostanoid Ro 22-6923.

The synthetic prostanoid Ro 22-6923 was studied for its ability to inhibit gastric secretion and to protect the gastric mucosa against the injurious effects of stress, indomethacin and ethanol. Ro 22-6923 inhibited basal acid secretion when administered intragastrically or intraduodenally to animals with a gastric fistula. The pH of the gastric juice promptly increased and remained above 5 for 3 h after an intragastric dose of 10 micrograms/kg and the pH remained above 4 for more than 3 h after this dose given intraduodenally. The increase in pH was associated with reduction of acid concentration and H+ output. Ro 22-6923 inhibited histamine-stimulated gastric secretion in a perfused stomach preparation with an ED50 of 15 micrograms/kg compared to values of 43, 126 and 289 micrograms/kg for prostaglandin (PG)E2, ranitidine and cimetidine, respectively. The synthetic prostanoid protected the gastric mucosa from the injurious effects of stress (oral ED50 values of 0.2 and greater than 1.0 mg/kg for Ro 22-6923 and PGE2, respectively) and indomethacin (oral ED50 0.07 and 0.06 mg/kg for Ro 22-6923 and PGE2, respectively). Cimetidine and ranitidine, at high doses, were effective against the mucosal damage produced by stress (ED50 values greater than 100 mg/kg) and indomethacin (ED50 values greater than 10 mg/kg). Ro 22-6923, but not PGE2 or 16, 16-dimethyl PGE2, inhibited dibutyryl cyclic AMP-induced [14C]aminopyrine accumulation by isolated parietal cells, indicating that the prostanoid has a direct inhibitory effect on H+ secretion. The results on the antisecretory and cytoprotective properties of Ro 22-6923 suggest this drug could be potentially useful in the pharmacotherapy of peptic ulcer disease.

Aminopyrine↗
PubMed1985

Effect of the synthetic prostanoid Ro 22-6923 on gastric secretion and blood flow in Heidenhain pouch dogs.

The synthetic trimethyl prostanoid Ro 22-6923 was studied for its effects on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. The prostanoid (at a p.o. dose as low as 0.05 mg/kg) produced significant inhibition of gastric acid secretion induced by 12 micrograms/kg/h of histamine for 5 h. A dose of 0.5 mg/kg p.o. produced a significant antisecretory effect within 45 min that lasted for 8.5 h. Cimetidine (5 mg/kg p.o.) produced an inhibitory effect on acid output equivalent to the 0.5-mg/kg dose of Ro 22-6923, but the duration of the cimetidine effect was less than 6 h. Administration of Ro 22-6923 i.v. (0.25 mg/kg) inhibited acid output for longer than 8 h. Against a 25-micrograms/kg/h histamine challenge, Ro 22-6923 (0.5 and 1.0 mg/kg) inhibited acid output to an equal degree but for a longer duration than cimetidine (5 mg/kg). Pepsin output was totally inhibited by 0.5 mg/kg of Ro 22-6923, whereas 5 mg/kg of cimetidine inhibited pepsin output by approximately 60%. Pepsin activity in the gastric juice was reduced by Ro 22-6923 and was increased by cimetidine. Blood flow, as estimated by the aminopyrine clearance technique, was reduced slightly by Ro 22-6923 and cimetidine. However, the ratio of clearance to acid secretory rate increased with both compounds, suggesting a direct effect of Ro 22-6923 and cimetidine on acid secretion at the parietal cell level. The results suggest that Ro 22-6923 may be a useful therapeutic agent for peptic ulcer disease in humans.

Animals↗
PubMed1983

Biochemical investigation of cells from keratoconus and normal cornea.

Collagen is the major structural protein in the cornea. In keratoconus the central cornea is thin, opaque and weak. Collagen synthesis was investigated in cells derived from the stroma of cornea with keratoconus and from controls. No difference was found in the ratio of collagens type I and type III synthesized, which were investigated as procollagens and after conversion to collagen as well. The alpha 1/alpha 2 ratio in type I collagen was similar in keratoconus cells and controls.

Cells, Cultured↗
PubMed1982

Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects.

In neurological and behavioral studies in mice, rats, dogs and squirrel monkeys, the imidazobenzodiazepinone Ro 15-1788 acted as a potent benzodiazepine antagonist. The antagonistic activity was both preventive and curative and seen at doses at which no intrinsic effects were detected. It was highly selective in that it acted against CNS effects induced by benzodiazepines but not against those produced by other depressants, such as phenobarbitone, meprobamate, ethanol, and valproate. The onset of action was rapid even after oral administration. Depending on the animal species studied, the antagonistic effects lasted from a few hours to 1 day. The acute and subacute toxicity of Ro 15-1788 was found to be very low. Benzodiazepine-like effects were not seen.

Animals↗
PubMed1982

Pharmacological properties of carprofen.

Carprofen, a new non-steroidal anti-inflammatory agent, showed marked anti-inflammatory and analgesic effects in various relevant experimental models. The analgesic activity was restricted to conditions where pain was provoked by an inflammatory process. Induction of intestinal ulcers was the only side effect recognizable in animals and occurred only after high doses. Inhibition of prostaglandin (PG) synthesis by carprofen was slight in relation to its anti-inflammatory and analgesic potency. As ulcerogenicity of non-steroidal anti-inflammatory agents is correlated with inhibition of the PG-synthesis, the insignificant impairment of the PG-synthesis in therapeutically effective doses may explain the good gastrointestinal tolerance repeatedly reported for carprofen in clinical trials.

Administration, Oral↗
PubMed1982

[Parameters of the liquid-liquid extraction of toxicologically relevant organic compounds. Part 1: Methodology of the experimental determination of partition constants and pH-dependent partition quotients; results obtained with acidic compounds].

Though liquid-liquid extraction is most widely used technique for isolating organic compounds (drugs, poisons), its fundamental parameters (partition constants and dissociation constants) are not determined explicitly in most cases; they are mostly estimated indirectly together with other factors in the form of resultants (total yield, detection sensitivities). For this reason we determined the partition quotients and their pH-dependence for more than 300 slightly volatile organic compounds (mainly drugs) in two-phase systems (aqueous buffer solution/solvent non-miscible with water). Nearly all the determinations were performed using diethyl ether and chloroform; other organic solvents were applied especially in studying slightly extractable compounds. The results obtained with 63 acidic compounds are reported.

Acids↗
PubMed1981

Pharmacology of midazolam.

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

Anesthetics↗
PubMed1979

Syntheses and biological activities of methoxinine-analogues of the C-terminal octapeptide of cholecystokinin-pancreozymin.

The C-terminal octapeptide of cholecystokinin-pancreozymin and its analogues in which the methionine residues were successively replaced by methoxinine have been synthesized. When these analogues were tested for their gallbladder-contraction activity in an in vitro system the following relative potencies were observed: [Mox3]-CCK-PZ 8 (95%), [Mox6]-CCK-PZ 8 (5%) and [Mox3, Mox6]-CCK-PZ 8 (2%).

Amino Acid Sequence↗
PubMed1979

Relation between ulcerogenic activity of various NSAID and their potency as inhibitors of prostaglandin synthesis in vivo.

A series of non-steroidal anti-inflammatory drugs (NSAID) and a few other agents were evaluated for their ability to: 1) reduce the acute toxicity of intravenously injected arachidonic acid (AA) in mice; 2) prevent castor oil-induced diarrhoea in mice; 3) enhance the formation of gastric mucosal erosions by a water stress in rats. A correlation between the activity in the three tests has been found for most NSAID studied, and the results point to inhibition of cyclooxygenase as a common mechanism of action.

Animals↗