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PubMed1977

[Experimental investigation of psychophysiological effect of a new antidepressant (lofepramine) as compared to imipramine and placebo (author's transl)].

Using 24 non-selected healthy male students the effects of imipramine (single dose of 100 mg orally) and 4'-chloro-2-[3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-propyl]-methylamino]-acetophenone-hydrochloride (lofepramine, Gamonil) (single dose of 140 mg orally) in comparison to placebo (doubleblind) on subjective, physiological and performance variables were examined. All subjects (Ss) received the three drugs in a completely counterbalanced sequence. On the basis of their scores on the Depression Scale of the Freiburger Personality Inventory (FPI, Fahrenberg) Ss were divided into two groups of 12 Ss each, "high depression" and "low depression" group. Two-way analyses of variance were computed. Imipramine and Lofepramine elevate scores in the mood scale, but only for the "high depression" group. For the Ss scoring lower in depression no such effect can be demonstrated. The physiological effects are similar. Reported side effects are less for lofepramine than for imipramine.

Antidepressive Agents↗
PubMed1981

Effects of azelastine hydrochloride, a new antiallergic drug, on the gastrointestinal tract.

Effects of 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-(2H)-phthalazinone hydrochloride (azelastine hydrochloride), a new antiallergic drug, on the gastrointestinal tract were experimentally studied in comparison with diphenhydramine and clemastine. In the isolated guinea pig ileum, the dose-response curve for histamine was shifted to the right by 10(-8) mol/l of diphenhydramine, clemastine or azelastine to the same degree. Clemastine and azelastine reduced the maximum response in the dose-response curve, while diphenhydramine caused a parallel shift. In addition to the potent antihistamine action, azelastine at higher dose antagonized serotonin action and clemastine markedly inhibited the contractile responses of isolated intestinal preparations to acetylcholine and bradykinin. Azelastine and clemastine (50 mg/kg intraduodenally) reduced gastric secretion in pylorus ligated rats. Azelastine (5 mg/kg i.v.), clemastine (1 mg/kg i.v.) and diphenhydramine (1 mg/lg i.v.) depressed gastrointestinal motility in conscious rats. Biliary and pancreatic secretions of anesthetized rats were not affected by 1 mg/kg i.v. of azelastine or clemastine.

Animals↗
PubMed1981

Effects of azelastine hydrochloride, a novel anti-allergic drug, on the central nervous system.

The effects of 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone hydrochloride (azelastine hydrochloride), a new anti-allergic drug, on the central nervous system were studied in mice, rats and rabbits in comparison to clemastine, chlorpheniramine and diphenhydramine. In mice, azelastine showed a definite central action with the same dose range (10--40 mg/kg p.o.) as the reference drugs. However, the central action profile of azelastine was considerably different from those of the reference antihistaminics. Clemastine and diphenhydramine produced potent anti-tremorine and anti-pilocarpine activities, while azelastine was less active than the two drugs. Chlorpheniramine and diphenhydramine produced a marked anti-reserpine activity and a marked potentiation of the caffeine-induced hypermotility, while clemastine had little effect in this animal model; on the contrary, 40 mg/kg of azelastine suppressed the caffeine-induced hypermotility. In rats, a high dose of 100 mg/kg azelastine produced a slight suppression of the paradoxical sleep. But the drug affected neither the rectal temperature nor the conditioned avoidance response at oral doses up to 100 mg/kg. In unanesthetized and restrained rabbits, azelastine in a dose of 0.5 to 8 mg/kg i.v. showed no significant change in the spontaneous EEG activity and in the susceptibility of the ascending reticular activating system, whereas an i.v. dose of 2 mg/kg clemastine produced a marked high voltage and slow wave pattern in EEG activity and suppressed the reticular activating system.

Aggression↗
PubMed1981

Effect of azelastine hydrochloride on vascular permeability in hypersensitivity reaction skin site in guinea pig.

4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1-(2H)-phthalazinone hydrochloride(azelastine) is a new compound promising anti-allergic effect, which was tested on increased vascular permeability in two types of hypersensitivity skin reaction in guinea pigs. The reversed passive Arthur (RPA) reaction was induced by bovine serum albumin and its heterologous or homologous antibody IgG. A monophasic permeability response, shown by amount of extravasated Evan's blue, was considerably suppressed by pretreating the animals orally with azelastine at different concentrations. In contrast, antihistamines such as triprolidine, chlorpheniramine and pyrilamine had no effect on the vascular response. Thus the potent antiexudative action of azelastine was demonstrated for the RPA reactions in guinea pigs as the model. However, the vascular response in tuberculin reaction in guinea pigs was not influenced by azelastine suggesting a different permeability mechanism.

Animals↗
PubMed1981

Pharmacokinetic and biopharmaceutical studies on azelastine hydrochloride in beagle dogs by quantitative selected-ion monitoring.

A quantitative selected-ion monitoring method for the determination of plasma concentrations of the new potent antiallergic agent, 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone hydrochloride (azelastine hydrochloride, A 5610), using N-methyl deuterium labelled azelastine as the internal standard, has been developed. This specific method has a lower limit of sensitivity of about 0.5 ng/ml plasma. The utility of this method was demonstrated by pharmacokinetic studies in the beagle dog after a single oral 20 mg dose as aqueous solution or as sugar-coated tablets, and after a single 10 mg i.v. dose. Plasma concentration-time curves following i.v. dose were satisfactorily described by a bi-exponential equation, and the mean values of half-lives (t 1/2) for the distribution and elimination phases were 17.5 +/- 5.0 min and 160 +/- 14 min, respectively. From the comparison of the areas under the curves after the p.o. dose of aqueous solution and tablet to that after i.v. dose, the absolute availabilities were estimated to be 16.6 +/- 2.5% and 19.6 +/- 0.4%, respectively. These low availabilities could be explained on the basis of a first-pass effect. From the analysis according to the Loo-Riegelman method, the absorption rate was revealed to be described by a first-order process. The absorption half-lives were 48.1 +/- 10.2 min for the solution and 58.4 +/- 21.8 min for the tablet. The lag times before onset of absorption were 18.2 +/- 2.1 min and 40.9 +/- 10.8 min, respectively. This seemed to be due to the difference in gastric emptying time or disintegration time of the tablets in the gastro-intestinal tract.

Animals↗
PubMed1982

Correlation between phosphatidylinositol labeling and contraction in rabbit aorta: effect of alpha-1 adrenergic activation.

Activation of rabbit aortic strips with alpha adrenergic agonists increased the labeling (with [32P]Pi) of phosphatidylinositol (PI) and phosphatidic acid and contracted the vascular preparations in dose-related fashion. Epinephrine, norepinephrine and methoxamine produced maximal effects, whereas clonidine behaved as partial agonist and B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazole-[5,4-d] azepin dihydrochloride) was almost without activity in the two experimental models used. Phenylephrine was a full agonist in producing contraction, but failed to elicit the maximal increase in PI labeling. The EC50 values to produce contraction of aortic strips were lower for all agonists than those required to increase the incorporation of radioactive phosphate into PI, but there was a good correlation between the two sets of data. The increased PI labeling and contraction of aortic strips induced by epinephrine were antagonized by prazosin and yohimbine in dose-related fashion, but the first alpha blocker was about three orders of magnitude more potent than the second in antagonizing the two effects. The present results indicate that both stimulation of PI labeling and contraction are mediated through activation of alpha-1 adrenoceptors in rabbit aorta.

Adrenergic alpha-Agonists↗
PubMed1984

Pharmacology of fluperlapine compared with clozapine.

3-Fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz [b,e]azepine ( fluperlapine , NB 106-689) resembles clozapine qualitatively and quantitatively in that it causes sedation, muscle relaxation, anticholinergic effects, no catalepsy, has little effect on apomorphine- and amphetamine-induced behaviour, does not induce apomorphine supersensitivity, and increases dozing and spindle activity in the rat's EEG. In the striatum of rats, it binds less to dopamine (DA) D2-receptor sites, but it enhances DA-turnover more than clozapine. Like clozapine and unlike haloperidol, it is equally active in the striatum, the nucl . accumbens and the cortex. Unlike clozapine, it does not significantly enhance norepinephrine (noradrenaline, NA)- or 5-hydroxytryptamine turnover and it does not increase prolactin blood levels significantly. Of the two compounds, only fluperlapine has some effects in common with antidepressants, i.e. tetrabenazine-antagonism and NA-uptake inhibition in slices of rat brain in vitro and ex vivo.

Animals↗
PubMed1984

Pharmaco-EEG studies with fluperlapine.

In the first of 2 studies, the effects of 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine , NB 106-689) 5 and 10 mg, clozapine 5 and 10 mg, and placebo on the EEG and on subjective mental and emotional state were investigated in 8 healthy male volunteers. The study was carried out as a double-blind within-subject comparison, with randomized sequence of treatments. Quantitative spectral analysis of the EEG revealed that changes after fluperlapine were strikingly similar to those after clozapine, i.e. an increase in delta and theta and a decrease in alpha activity. These changes were associated with a reduction in self-rated "wakefulness" and are evidence of a sedative effect. The drugs' effects differed only in the magnitude of the increase in beta activity in the 20-40 cps frequency band (beta 2), which was greater after fluperlapine than after clozapine. Since increased beta 2 activity has been reported with tricyclic antidepressants, it is suggested that fluperlapine , besides possessing neuroleptic properties, might also have some properties of a (sedative) antidepressants. It is estimated from the EEG findings that, at equal doses, fluperlapine (capsules) has approximately one half of the sedative potency of clozapine (tablets). A second study in schizophrenic patients revealed strong correlations between EEG effects and blood levels of unchanged fluperlapine during long-term treatment.

Adult↗
PubMed1984

Results of a multicenter AMDP study with fluperlapine in schizophrenic patients.

In an open multicenter trial (7 hospitals) 85 schizophrenic patients were treated with 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine , NB 106-689) during 20 days. Symptomatology was documented with the AMDP system on days 0, 1, 5, 10, 15 and 20. A mean daily dosage of about 400 mg caused a significant antipsychotic effect and pronounced improvement of depressive symptoms. Fluperlapine was well tolerated. Extra-pyramidal side-effects were very rare.

Adolescent↗
PubMed1984

Fluperlapine in 104 schizophrenic patients. Open multicenter trial.

Twelve parallel, open, uncontrolled therapeutic studies on 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine , NB-106 689) were performed as a multicenter trial using standardized protocol/case report forms and inclusion and global assessment criteria. 66% of 104 medium to severe acute or relapsed schizophrenic patients showed a very good or good overall benefit (responder rate 80%) with 200-400 mg fluperlapine daily, median 300; 20-1200 mg; 6 weeks. Ratings ( FSCL -NL = (Fischer Symptom Check List Neuroleptics, BPRS = Brief Psychiatric Rating Scale, FSUCL = Fischer Somatic Symptoms and Untoward Effects Check List) showed a quick onset of action (25% improvement in 5 days) and a very good improvement of all important and secondary single symptoms or symptom groups. FSCL -NL and BPRS were highly correlated (R = 0.87). Tolerability was very good or good in 88% of patients (very good in 65%, poor or bad in 12%), mild to moderate fatigue being the most prominent untoward effect (means 25% of patients, max. 31 per control) followed by dizziness, tremor, dry mouth (10%). No drug-induced Parkinsonism was seen. No recurrent or relevant abnormalities in relation to fluperlapine were observed in safety data (circulation, blood, kidney or liver function). Several times paroxysmal dysrhythmias/sharp waves were seen in the EEG, and in our studies 2 patients experienced epileptiform seizures of short duration after overdosage. In one patient showing a granulocytopenia before starting fluperlapine , an agranulocytosis was seen, which normalized quickly after stopping fluperlapine .

Adult↗
PubMed1984

A short survey on untoward effects of fluperlapine.

The adverse drug reaction profile of 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine -NB 106-689), a possible successor drug of clozapine, is presented based on, first, the results of the open multicentre trial of the AMDP group, and second, on two open multicentre trials initiated by the manufacturers. In general, side-effects of fluperlapine seem to be very similar to those of clozapine, i.e. anticholinergic and sedative effects as well as marked EEG-changes can be observed in most of the patients. However, in contrast to clozapine, so far no evidence for the occurrence of hypersalivation, or increase of body temperature has been obtained, although an increased white blood cell count around day 15 could be seen in quite a number of patients. Hypotensive effects were less than expected from corresponding trials with clozapine.

Animals↗
PubMed1984

Synthesis of some substituted benzodiazepines as possible CNS depressant drugs.

A new series of 2,3-cyclopentano-3,4-dihydro-4-spirocyclopentano-1,5-benzodi azepine which are substituted in 5-position with beta-N-heterocycloethyl or gamma-N-heterocyclo-n-propyl groups have been synthesized and evaluated for their CNS depressant activity including anticonvulsant, analgesic and pentobarbital induced hypnosis. These compounds were also investigated for their ability to inhibit in vitro succinate dehydrogenase (SDH). In most of the compounds an appreciable CNS depressant activity has been found to be associated with the compounds possessing good SDH inhibitory activity. Low toxicity of these compounds was reflected by their high approximate LD50 values.

Analgesics↗
PubMed1981

Inhibition by azelastine of the immunologically induced histamine release from isolated guinea pig mast cells.

4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone (azelastine, A 5610) did not affect the spontaneous histamine release but inhibited effectively the allergic histamine release from isolated mesenteric mast cells of actively sensitized guinea pigs. At 10(-6) mol/l concentration the inhibition was almost equal to that caused by adrenaline (10(-8) mol/l).

Animals↗
PubMed1978

Mianserin: a decade of scientific development.

1 Mianserin is a tetracyclic piperazino-azepine compound synthesized in 1966 for its peripheral anti 5-hydroxytryptamine properties. Animal screening showed that mianserin was centrally active, but the profile did not indicate possible antidepressant activity. Following clinical observations of sedative and possible mood-lifting effects, a quantitative electroencephalogram (EEG) study showed that the EEG effects of mianserin are similar to those of amitriptyline. 2 Subsequent clinical and pharmacological studies have indicated that mianserin is an effective antidepressant which differs from the tricyclic antidepressants not only chemically but also in its pharmacological and clinical profile. Mianserin seems to lack anticholinergic and cardiotoxic properties, and has unusual effects on monoamine metabolism. 3 On the basis of the initial profile a series of clinical and pharmacological studies has been carried out, and the results of many of these studies are presented in these Proceedings.

Amines↗
PubMed1982

[Comparative study on clinical effectiveness of mecillinam and pivmecillinam versus ampicillin in acute urinary infections (author's transl)].

30 outpatients suffering from acute urinary infections underwent oral treatment with pivaloyloxymethyl-(2S,5R,6R)-6-(perhydroazepin-1-ylmethylenamino)penicillinate (pivmecillinam) (n = 15) or ampicillin (n = 15) in a first study. In a second study 6-beta-(hexahydro-1H-azepin-1-yl)-methylenamino penicillanic acid (mecillinam) (n = 16) or ampicillin (n = 14) were applied i.v. to 30 patients with pretreated urinary infections. The tolerance of the drugs proved to be comparatively good in both studies. The clinical and antibacterial effectiveness were equally good in the first study. However, in the second study the effectiveness of mecillinam However, in the second study the effectiveness of mecillinam seemed to be comparatively inferior.

Amdinocillin↗
PubMed1978

[Comparative study of the pharmacological and clinical effects of clorimipramine and metaprimine (19560 R.P.)].

Although its pharmacology is virtually identical with that of the tricyclic antidepressants, metapramine (19560 R.P.), i.e. methyl-5 methylamino-10 dihydro-10, 11 dibenzo (b,f) azepine, differs biochemically from the tricyclics in that it markedly enhances the turnover of norepinephrine without notably inhibiting the re-uptake of this amine. Differences in the therapeutic effects of metapramine and clorimipramine have been investigated in a double-blind clinical test. The possible relationship between these differences and the biochemistry of both compounds is discussed in terms of the monoaminergic hypotheses.

Adult↗
PubMed1984

Strain and sex differences in N-nitrosohexamethyleneimine carcinogenesis in NZB, NZC, NZO, and NZY mice.

The carcinogenic activity of N-nitrosohexamethyleneimine [(NHEX) CAS: 932-83-2; hexahydro-1-nitroso-1H-azepine] was studied in male and female mice of the four inbred strains NZB/BlGd, NZC/BlGd, NZO/BlGd, and NZY/BlGd. A total of 158 mice received NHEX treatment; 1,338 untreated controls were used, all kept under identical laboratory conditions for their natural life-spans. Beginning at age 50 days a 1.56-mM NHEX solution (200 mg/liter) was given instead of drinking water for 8 weeks, which resulted in nearly the same total dosage of 0.7 +/- 0.04 g or 5.7 +/- 0.2 mmol NHEX/kg body weight in both sexes of all four strains. In both sexes of all four strains the main types of tumors after NHEX treatment were squamous papillomas and carcinomas of the esophagus, squamous stomach, and oropharynx and hepatocellular carcinomas. Tumors of the hepatic bile ducts, glandular stomach, and lung and malignant lymphomas were also induced by NHEX, but these tumors had a predilection for certain strains only. The incidences of other tumors characteristic of the untreated mice in each particular strain, such as tumors of the ovary in NZC, tumors of the breast in NZY, and tumors of the duodenum in NZO, were not increased significantly by NHEX treatment. The incidence of main tumor types in NHEX-treated mice varied greatly between strains, e.g., esophageal papillomas and carcinomas in 81% of male NZC versus 32% in male NZB mice. Some marked sex differences also emerged in NHEX-treated animals, e.g., the occurrence of liver angiosarcomas only in males of three strains and the 53% incidence of hepatocellular tumors in male NZY mice compared to the absence of liver tumors in female NZY mice.

Animals↗
PubMed1983

[Synthesis of 14C-azelastine hydrochloride].

The synthesis of 4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone hydrochloride (14C-azelastine hydrochloride, Asta A 5610) is described Starting material was 14C-phthalic anhydride.

Carbon Radioisotopes↗