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PubMedDate not supplied

[The relationship between the chemical structure and anti-arrhythmia action of a number of omega-aminoacyl-3-carbalcoxyaminodibenzazepines].

The antiarrhythmic activity of 20 derivatives of dibenzazepine (the effects on the maximal effective rabbit heart auricle contraction rate, aconitine-induced arrhythmia in rats under or without anesthesia) was studied. It was shown that the most active compounds are those with carbethoxyamine group in position 3 in combination with dimethylamino- or diethylamino-acetyl groups in position 5 of dibenzazepine ring. 5-dimethyl-aminoacetyl-10,11-dihydro-5H-dibenz b, f azepine (GS-015, bonnecor) was selected for the further detailed investigation.

Aconitine↗

PubMed1990

[Glaucoma following the antidepressant mianserin].

Mianserin HC1 (Bolvidon) is a new antidepressant agent of the diperazino-azepine group, not related chemically to the tricyclic antidepressants. It lacks the basic side-chain considered to be responsible for the anticholinergic activity, including mydriasis, of the tricyclic antidepressants. Nevertheless, a 60-year-old woman developed acute angle closure glaucoma following administration of the drug. After the acute attack we performed argon laser iridotomies, followed with mianserin, without deleterious effects. We think that acute angle closure glaucoma might be a rare complication of mianserin in narrow angle glaucoma patients, in whom laser iridotomy is advisable.

Acute Disease↗

PubMed1988

In vitro and in vivo studies of the non-sedating antihistamine epinastine.

Epinastine (3-amino-9,13b-dihydro-1H-dibenz [c,f]imidazo[1,5-a]azepine hydrochloride, WAL 801 CL) was tested in vitro and in vivo in comparison with other H1-receptor antagonists. In the guinea pig ileum and in receptor binding studies the test substance showed a high affinity to H1-receptors. The following rank order was determined: WAL 801 CL greater than astemizole greater than terfenadine. These results were confirmed in vivo. The studies were carried out with oral and intravenous administration of WAL 801 CL to assess the inhibition of histamine-induced reactions in the skin or the lung of rats, dogs and guinea pigs. 10- to 100fold antihistaminic doses of WAL 801 CL showed no effect on the sleeping-waking behaviour of cats. From this and other results it is suggested that the compound does not penetrate in the central nervous system. The action pattern of WAL 801 CL as a non-sedating antihistamine corresponds more to that of terfenadine than that of ketotifen.

Animals↗

PubMed1989

Metabolism of trimipramine in man.

This paper describes studies on the metabolism of the tricyclic antidepressant 5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (trimipramine, Stangyl) in man. The metabolites were identified after cleavage of conjugates, extraction and derivatisation by acetylation in human urine using gas chromatography-mass spectrometry. Besides the unchanged trimipramine (T), the following 15 metabolites could be identified: mono- and dihydroxy-T, hydroxy-methoxy-T; iminodibenzyl (I), mono- and dihydroxy-I, hydroxy-methoxy-I; nor-T (NT), mono- and dihydroxy-NT, hydroxy-methoxy-NT; bis-nor-T (BNT), mono- and dihydroxy-BNT and hydroxy-methoxy-BNT. Therefore 3 overlapping metabolic pathways can be postulated: N-dealkylation of the nitrogen in the iminodibenzyl ring, 1- and 2-fold N-demethylation of the nitrogen in the side chain and 1- and 2-fold aromatic hydroxylation of the iminodibenzyl ring. The dihydroxy metabolites are partly methylated at one of the hydroxy groups. The hydroxy metabolites are conjugated additionally.

Biotransformation↗

PubMed1989

Pharmacological profile of the new anticonvulsant etazepine.

The pharmacological profile of the new anticonvulsant etazepine (5,6-dihydro-5-methyl-11H-11-ethoxy-dibenzo[b,e]azepin-6-one) was investigated. It protected mice and rats from a wide variety of convulsant agents (maximal electroshock, pentetrazol (metrazole), bicuculline, strychnine, 3-mercaptopropionic acid, nicotine, cefazoline and kainic acid) at doses about 16-45 times lower than those exerting neurotoxic effects (depending on the test used). The anticonvulsant effect of etazepine was long-acting (more than 24 h) and did not seem to develop tolerance. Moreover, etazepine did not prolong thiopental-induced sleeping time. Based on pharmacological studies etazepine seems to exert its anticonvulsant effects by activating the GABAergic system.

5-Hydroxytryptophan↗

PubMedDate not supplied

Characterization of glucuronide metabolites of carbamazepine in human urine by gas chromatography and mass spectrometry.

Glucuronide metabolites of carbamazepine (5 H-dibenz[b,f]azepine-5-carboxamide) were identified in human urine following chromatography on XAD-2 resin, permethylation, and combined gas chromatography and mass spectrometry with an SE-30 capillary column. Eight glucuronide metabolites, previously unidentified in man, were characterized as their permethylated derivatives. These included carbamazepine N-glucuronide (M+. 482), three isomers of dihydroxycarbamazepine O-glucuronide (M+. 542), three isomers of hydroxymethoxycarbamazepine O-glucuronide (M+. 542), and one isomer of hydroxycarbamazepine O-glucuronide (M+. 512). Other glucuronide metabolites, previously identified following enzymatic hydrolysis, were characterized as the unhydrolyzed, permethylated glucuronides, 10,11-dihydro-10,11-di--hydroxy carbamazepine O-glucuronide (M+. 544), and three isomers of monohydroxycarbamazepine O-glucuronide (M+. 512).

Biotransformation↗

PubMedDate not supplied

Involvement of postsynaptic adrenergic mechanism(s) in the ATP-contractions of the rat anococcygeus muscle and the effect of extracellular Ca2+.

Clonidine, ICI-106270 (6-aryl 2,367 tetrahydro 5-H-pyrrolo(1,2-a)-imidazole derivative), B-HT-920 (6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiozolo = [4,5-d]azepine-dihydrochloride, and guanfacine, agonists at alpha 2-adrenoceptors, produced concentration-dependent contractions of the rat anococcygeus muscle. The order of potency of these agonists in producing the response was clonidine greater than ICI-106270 greater than guanfacine greater than B-HT 920. Yohimbine (10(-6) M) competitively antagonized the contractile response due to these agents acting at alpha 2-adrenoceptors. ATP (10(-6) M-10(-4) M) also produced concentration-dependent contractions of the rat anococcygeus muscle. Prazosin (10(-8) M) an alpha 1-blocker, significantly antagonized ATP-induced contractions in a competitive manner. ATP (10(-7) M) in a concentration that had no effect on basal tension of the preparation, tends to potentiate phenylephrine responses, though not significantly. The sensitivity of the anococcygeus muscle to ATP was enhanced after 24 hr (maximum catecholamine depletion period) of reserpine (5 mg/kg, i.p.) treatment. Yohimbine (10(-6) M), a selective alpha 2-blocker, significantly antagonized ATP-induced contractions and shifted the ATP concentration-response curve towards right. The antagonism was found to be competitive. The ATP-contractions were also sensitive to inhibition by reduced calcium contents (quarter or calcium free) in the Krebs bicarbonate solution. However, it was observed that ATP was capable of producing contractions of anococcygeus muscle even in Ca-free Krebs bicarbonate solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMedDate not supplied

Effect of diet and gavage on the absorption and metabolism of fluperlapine in the rat.

Fluperlapine, Sandoz compound NB 106-689, 3-fluoro-6-(4-methyl-1-piperazinyl)-11H-dibenz[b,e]azepine, in a 12-week toxicity study exhibited liver toxicity (moderate to severe hyperlipidosis) when administered to rats in the diet at 40 mg/kg/day and at 80 mg/kg/day, but not by gavage at 80 mg/kg/day. In order to elucidate those factors which might explain these differences in toxicological findings, the effect of mode of administration (diet vs. gavage) on the absorption and metabolism was investigated in rats. Although the peak concentration of radioactivity was earlier (2 hr vs. 15 hr) and higher (3.3 micrograms eq/ml vs. 1.6 micrograms eq/ml) by gavage than by diet, the extent of absorption based on AUC values and excretion of radioactivity was the same. Analysis of plasma and liver extracts for metabolites showed that although the metabolic pathways were the same after diet or gavage, the relative composition of drug and metabolites present was a function of the mode of administration. In the liver, the target organ, after multiple oral doses by the diet mode, 96% of the identified products represented hydroxylation; a minor amount of parent drug was present. After gavage, the drug (32%) and desmethylfluperlapine (25%) together accounted for 54% of the mixture, and hydroxylation accounted for 44%. In plasma after multiple oral doses, a similar trend was observed; there was a greater percentage of the hydroxylated metabolites compared to the nonhydroxylated metabolites after diet administration and an almost similar proportion of these products after gavage administration. It is possible that the observed differences in toxicity could be due to a difference in the exposure of the target organ to drug and metabolites.

Animals↗

PubMed1988

Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity.

SCH39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl- 5H-benzo[d]naptho-(2,1-b)azepine] is a benzonaphthazepine that has been evaluated as a selective D1 dopamine receptor antagonist. In vitro, SCH39166 (Ki = 3.6 nM) inhibited the binding of [3H]SCH23390 (a D1 specific compound) and blocked dopamine-stimulated adenylate cyclase (Ki = 9.1 nM); in contrast the Ki for SCH39166 to displace [3H]spiperone (D2) was greater than 1 microM and its Ki vs. [3H]-ketanserin (5-hydroxytryptamine2) binding was greater than 300 nM. In vivo, SCH39166 inhibited both rat and squirrel monkey conditioned avoidance responding (minimal effective dose = 10 and 1.78 mg/kg p.o., respectively) and had a duration of at least 6 hr in both species. In addition, SCH39166 antagonized apomorphine-induced stereotypy in rats (minimal effective dose = 10 mg/kg p.o.). These in vivo actions of SCH39166 are similar to the activity of typical dopamine antagonists. However, in contrast to D2-selective antagonists, SCH39166 failed to increase plasma prolactin levels, did not block apomorphine-induced emesis in the dog and had minimal effects on the striatal levels of homovanillic acid or dihydroxyphenylacetic acid. Furthermore, although immobility was seen after p.o. administration of SCH39166 using the inclined screen test, the drug did not cause catalepsy at doses up to 10 times its minimal effective dose in the rat conditioned avoidance response test. Additionally, SCH39166 inhibited apomorphine-induced climbing at lower doses than it inhibited apomorphine-induced sniffing in mice. The results from these latter two tests suggest that SCH39166 may have a reduced liability to produce extrapyramidal side effects. Therefore, based on this profile of activity, SCH39166 is a selective D1 dopamine receptor antagonist both in vitro and in vivo. Additionally, because this compound is longer acting in the primate than previously available D1 antagonists, it has potential utility as a clinically useful drug.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

Molecular structure of Ro15-1788 and a model for the binding of benzodiazepine receptor ligands. Structural identification of common features in antagonists.

Ligands that bind to the benzodiazepine receptor have three possible effects. The ligand can be an agonist and reduce anxiety, an antagonist and have no biological effect, or an inverse agonist and promote convulsions. This receptor complex is unique in its spectrum of response to ligands, and conformational changes in the receptor are implicated. The x-ray crystal structure of an imidazobenzodiazepine antagonist ligand, Ro15-1788, was determined and compared to the structures of the 1,4-benzodiazepine agonists and to two other types of antagonists, beta-carbolines and a pyrazoloquinolinone, CGS-8216. The antagonists were found to have similar arrangements of binding features including an aromatic ring, a carbonyl oxygen atom, and a hydrophobic side chain. The structures of these antagonists could be superimposed in a model binding site with three common features for all of the antagonists and a fourth hydrogen-bonding site for the pure antagonists (or inverse agonists), the beta-carbolines, and CGS-8216. A comparison of the shapes of the antagonist benzodiazepine, Ro15-1788, and several agonists showed that RO15-1788 has a unique azepine ring conformation that distorts the usual arrangement of the aromatic A ring, carbonyl oxygen atom, and imine N atom of the agonists. A conformational adjustment in the receptor would be required to accommodate both of these types of ligands. A summary of the superpositions of typical agonists and the antagonists leads to a model with 7 conformationally mobile binding points. Inverse agonists are distinguished from antagonists by the length of the hydrophobic side chain. Antagonists are distinguished from agonists in part by the lack of a binding feature similar to the imine N atom of the diazepine ring. This model accounts for the key features found in ligands for the benzodiazepine receptor and provides an explanation for the spectrum of responses elicited by receptor binding.

Benzodiazepinones↗

PubMed1977

[Studies on cardio-circulatory effects of carpipramine. Results of a double-blind study (author's transl)].

For eight weeks 30 psychotic patients with a healthy cardiovascular system received 3 X 50 mg 1-[3-(10,11-dihydro=5H-dibenz[b,f]-azepin-5-yl]-propyl]-4-piperidiono-piperdine-4-carboxamide dihydrochloride-monohydrate (carpipramine) per day with a placebo phase of three weeks either previous to the medication of succeeding it. In addition there was a group of similar patients without any medication. From this study it was concluded that carpipramide has no depressive effect on the cardiovascular system. The differences in blood pressure and heart rate after the change from medication to placebo indicate a certain vegetative lability in this phase. In the ECG, no irregularities of the atrioventricular and intraventricular conduction and its repolarisation in form of a lengthening were observed; only the WPW-syndrome noticed with one patient might be related to the medication since it occurred at the end of the three weeks during which carpipramine had been administered.

Adult↗

PubMed1988

Investigations on the intraindividual constancy of the ratio of carbamazepine to carbamazepine-10,11-epoxide in man.

The constancy of the ratio of carbamazepine (5H-dibenzo[b,f]azepine-5-carboxamide) to carbamazepine-10,11-epoxide was investigated in epileptic patients receiving carbamazepine (Tegretal) monotherapy. We observed a significant interindividual difference, but not between the times in a single patient. Together with the similarly evaluated concordance coefficient, this indicates a certain intraindividual constancy of the ratio between carbamazepine and its epoxide. The carbamazepine:carbamazepine epoxide ratio was dose-dependent, while a sex difference could not be demonstrated.

Adolescent↗

PubMedDate not supplied

[The place of mianserin among the antidepressants (author's transl)].

The originality of mianserin lies mainly in its chemical formula ; it is a tetracyclic piperazino-azepine compound. Moreover its pharmacological profile differs from that of other antidepressant drugs because it is devoid of central anticholinergic effects, it inhibits 5-hydroxytryptophane (the precursor of serotonine) and contrary to the tricyclics it does not affect the re-uptake of the amine-transmitters but increases the turnover of noradrenaline. It has been shown in a clinical trial that mianserin induces a hypomania in some manic-depressed patients. Regarding the antidepressive effect, mianserin is superior to placebo and as effective as imipramine and amitriptyline. It simultaneously works on anxiety, psychomotoric retardation and suicidal tendency; sleep improves under mianserin's influence. The value of mianserin is proved by its safety in use. It has no cardiotoxic effect and does not interact with coumarin-type anticoagulants. Since there are no anticholinergic effects, mianserin can be given to patients suffering from glaucoma or prostatic hypertrophy. Finally it appears that mianserin lowers the suicidal risk through its sedative properties.

Animals↗

PubMed1985

[Characteristics of the anti-arrhythmic action of 3-carbethoxyamino-5-dimethylaminoacetyl-imino-dibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015)].

The action of GS 015, a substance out of the series of the novel 5-(dialkyl-amino-acyl)-3-carbalkoxyamino-10,11-dihydro-5H-dibenz[b ,f]azepines, on the alteration of the bioelectric activity in the sympathetic nerves of the heart in case of disturbed cardiac rhythm and ventricular fibrillation was tested on anaesthetized cats. The arrhythmias were induced by two different methods: Artificial electric induction by high-frequency electrical stimulation of the ventricles, occlusion and reperfusion of the anterior descending branch of the arteria coronaria sinistra. GS 015 decreases the tonic bioelectric activity in the sympathetic nerves of the heart and prevents their activation in case of disturbed rhythm which is provoked or by electric stimulation or by occlusion of the coronary artery. With an electric stimulation of the ventricles GS 015, given at doses of 0.5, 1.0, and 2.0 mg/kg, decreases the maximally reproducible frequency in dependence on the dose, which corresponds to an increase of the effective refractory period. At the same time the fibrillation threshold of the ventricles is enhanced in a very intense and long-lasting manner excelling considerably the action of the reference preparations Ethmozin and lidocaine. It may be concluded from the present results that the antiarrhythmic and antifibrillatory effects of GS 015 are basing not only on its immediate action on the myocardial cell but also on a decrease of the activity in the sympathetic nerves of the heart.

Animals↗

PubMed1985

[Circulatory action and adverse effects of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) in the dog and cat].

The haemodynamic and cardiac effects of GS 015, a substance of the series of the novel 5-(dialkyl-aminoacyl)-3-carbalkoxyamino-10,11-dihydro-5H-dibenz-[b ,f]-azepines with very potent antifibrillatory and antiarrhythmic actions, are studied on anaesthetized dogs and cats by means of the catheter technique. The clinical symptoms and the therapeutic range were tested on conscious animals. On the strength of the present results it can be stated that GS 015, given at pharmacodynamically effective doses, does not cause any circulatory side effects. A negative inotropic effect appears only at increased doses. Like other antiarrhythmic drugs, GS 015 possesses a limited therapeutic range which should be taken into consideration particularly in case of cardiac insufficiency. But an application seems possible also in patients during the acute stage of myocardial infarction.

Anesthesia↗

PubMed1985

[Absorption, distribution, metabolism and excretion of bacmecillinam. I. Absorption, distribution, metabolism and excretion of 14C-bacmecillinam following oral administration to rats].

The pharmacokinetics of bacmecillinam (KW-1100), a new semisynthetic penicillin, was studied. Plasma levels, tissue distribution, metabolites and urinary and biliary excretion of mecillinam after oral administration of KW-1100 were studied in rats given a dose of 20 mg/kg (as mecillinam). The absorption of 14C-KW-1100 was so rapid that the level in blood was found to reach the peak 30 minutes after administration. 14C-KW-1100 was distributed widely into various tissues and relatively high distribution was noted in liver, kidney, adrenal gland and spleen. No accumulation of 14C-KW-1100 in any tissue was found. It was excreted rapidly from each tissue. Within 24 hours after administration of KW-1100, approximately 86% of the given dose was excreted. And within 72 hours, approximately 97% of the dose was excreted. Excretions in urine and feces within 72 hours after KW-1100 administration were 39.5 and 57.4% of the given dose, respectively. Biliary excretion was 2.0% of the given dose within 24 hours after administration of KW-1100. The major metabolite in the plasma at peak time (30 minutes) was mecillinam (50.5%). The major metabolite in the urine (0 approximately 8 hours) was mecillinam (52.2%), too. The minor metabolites were 5,5-dimethyl-2-(1'-formamidomethyl)-thiazolidine-1',4-dicarboxylat e(M-1), 6-beta-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicilloic acid (M-6) and M-4.

Administration, Oral↗

PubMed1985

[Absorption, distribution, metabolism and excretion of bacmecillinam. III. Absorption, metabolism and excretion of 14C-bacmecillinam following oral administration to dogs].

The pharmacokinetics (i.e., blood level, biological half-lives and excretion) of bacmecillinam (KW-1100) was investigated. KW-1100 was orally administered to dogs at the dose of 20 mg/kg (as mecillinam). Biological half-lives (radioactivity) of 14C-KW-1100 in plasma were 1.2 hours (T1/2 alpha) and 52 hours (T1/2 beta). The Cmax and Tmax were 8.4 micrograms/ml and 2 hours. The biological half-life (microbiological activity) of KW-1100 in plasma was 0.9 hour. The Cmax and Tmax were 5.6 micrograms/ml and 1 hour. The urinary and fecal excretion of 14C-KW-1100 were approximately 46% and 49% (0 approximately 72 hours), respectively. The major metabolites in the urine (0 approximately 8 hours) were mecillinam, 5,5-dimethyl-2-(1'-formamidomethyl)-thiazolidine-1',4-dicarboxy lat e (M-1) and 6-beta-[(hexahydro-1 H-azepin-1-yl)-methyleneamino]penicilloic acid (M-6), each distribution ratio of which was 57.2, 24.2 and 12.0% of the total radioactivity in the sample, respectively. The major metabolite in the plasma at peak time (2 hours) was mecillinam (56.2%).

Administration, Oral↗

PubMed1985

[Absorption, distribution, metabolism and excretion of bacmecillinam. IV. Metabolites of bacmecillinam in human urine].

Bacmecillinam (KW-1100) metabolites and their excretion in human urine were investigated in the 3 male volunteers. After administration of KW-1100 capsules containing 80 mg (2 X 40 mg) as mecillinam to men, the urine samples up to 8 hours were collected for every 2 hours and analysed by high performance liquid chromatography and gas chromatography. The major metabolites in the human urine were mecillinam and 6-beta-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicilloic acid (M-6), and minor quantities of M-4 and M-1 were also detected as the metabolites. Total recoveries of administered dose for the 3 volunteers were approximately 62, 81 and 73%, respectively. And M-1 excretion rate was lower than that in the case of rats and dogs. Hexamethyleneimine (HMI) as metabolite from the side chain was detected.

Administration, Oral↗