Pharmacological action of some known and possible metabolites of brotizolam.

The two major metabolites of brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) in man are the hydroxylation products We 964 (hydroxylation in the methyl group at 9-position) and We 1061 (hydroxylation in 6-position). A structural isomer originating from the latter, We 1064, was found in the urine of dogs. In the same species the demethylation product We 956 was identified. In line with this demethylation the oxidation product Web 1175 might also be formed but was not yet detected. The dihydroxylated product Web 1073 which could arise either from We 964 or from We 1061 was discovered in monkeys. All compounds were investigated with respect to their pharmacological and acute toxicological properties in various experimental situations in mice and rats, and exhibited a profile of action quite similar to brotizolam. Effects of other kinds did not occur. None of the examined metabolites had a longer duration of action than the parent substance. The strength of activity in the various tests was, with very minor exceptions, less than that of brotizolam. All findings favor the conclusion that the various actions of brotizolam are mainly caused by the latter itself and not by its active metabolites. Also, the duration of action of brotizolam is not substantially determined by the pharmacokinetics of its metabolites.

Therapeutic safety studies of brotizolam in animals.

Comparing dose levels for pentetrazol antagonism or antiaggressive activity with those causing motorial side effects in mice brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-alpha]-1,4-diazepine, We 941, Lendormin) showed consistently larger dose ranges than diazepam. This gives evidence that brotizolam may offer the advantage of not causing motorial side effects during therapeutic use as do many other diazepines.

General pharmacology of brotizolam in animals.

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) is a thienotriazolo-diazepine with profound sedative and hypnogenic properties. The side effects of the drug on general behavior, motocoordination, feeding pattern, body temperature, uropoietic and gastrointestinal functions, cardiovascular system, and respiration, as well as interactions with some biogenic amines are reported and discussed. The findings correlate with those known for other diazepines. Accordingly, effects on motocoordination were prominent, but were limited to an ataxia, whereas even extremely high doses scarcely eliminated the postural reflexes. Sleeping animals could invariably be woken and were capable of locomotion; thus, no comatose condition developed. The cardiovascular functions were not appreciably altered by brotizolam in anesthetized cats, while in conscious dogs minor fluctuations of blood pressure and heart rate occurred. Respiration was clearly inhibited when brotizolam was given intravenously. The cardiovascular effects of acetylcholine, norepinephrine, epinephrine, isoprenaline, and histamine were only slightly modulated. The orexigenic and hypothermic effects equalled those of other diazepines. The functions of kidney, stomach, and intestines were not affected. The entirety of the observations procured in ten different species suggest that brotizolam is well tolerated when given orally.

Interactions of brotizolam and diazepam with some psychotropic drugs on motor performance in mice.

The interaction of brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin) and diazepam with ethanol, phenobarbital, haloperidol and desipramine was investigated in a motor performance test (rotarod) in mice. Brotizolam and diazepam were tested at dose levels which partially impaired the motor performance. In combination with ethanol and phenobarbital only the anticipated additive effect was observed. Brotizolam and diazepam partially overcame the cataleptic effect of haloperidol. A combined treatment with brotizolam and desipramine did not alter the effect obtained with brotizolam alone. In a second experiment the loss of righting reflexes induced by ethanol and hexobarbital was prolonged by brotizolam and diazepam depending on the dose. From this it is concluded that in combination with ethanol brotizolam and diazepam may be effective at antiemotional and anticonvulsant doses. In combination with hexobarbital brotizolam is expected to have a greater "therapeutic range".

Antiemotional and anticonvulsant activity of brotizolam and its effects on motor performance in animals.

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) is a thienotriazolo diazepine with predominantly sleep-inducing properties. Additionally, brotizolam, attenuated conflict behavior in rats and inhibited aggressive behavior in mice and cats. Brotizolam prevented audiogenic seizures in mice, seizures provoked by electroshock in rats and inhibited convulsions elicited by electrical stimulation in the limbic system of cats. Furthermore, brotizolam antagonized seizures induced by the convulsant drugs pentetrazol, bicuculline and strychnine in mice. Motocoordination was not impaired within the effective dose range. Muscle relaxant effects appeared at higher doses only. The onset of effect of brotizolam occurred in the different experiments within 15-30 min, thus indicating a fast enteral absorption and penetration of the blood-brain barrier. The duration of action within the therapeutic dose range was between 2-6 h. The effect of brotizolam was compared with other diazepine derivatives. Brotizolam was more active than diazepam, nitrazepam, estazolam, flurazepam and clonazepam and nearly as active as triazolam.

Pharmacological and neurochemical properties of 1,4-diazepines with two annelated heterocycles ('hetrazepines').

1,4-Diazepines with two annelated heterocycles ('hetrazepines') such as brotizolam (WE 941), WE 973 and WE 1008 bind with high affinities to benzodiazepine receptors in the central nervous system. Brotizolam has a pharmacologic spectrum of action similar to clinically useful benzodiazepines, while the closely related derivatives WE 973 and WE 1008 appear to lack hypnotic action. Unlike other benzodiazepine receptor ligands which share common pharmacologic properties with the benzodiazepines, the apparent affinities of WE 973 and WE 1008 are not increased significantly in the presence of GABA, even at an elevated incubation temperature. Furthermore, the apparent affinities of these compounds do not appear to be reduced as a result of increasing the incubation temperature. Brotizolam, like the benzodiazepines, facilitates GABAergic transmission in zona recitulata neurons of the substantia nigra. In contrast, at a dose which inhibits cell firing, WE 973 does not appear to significantly augment the inhibitory action of GABA in these cells. These observations suggest that the so-called 'GABA shift' may not be a valid means of distinguishing benzodiazepine-like compounds in vitro. Furthermore, these data suggest that facilitation of GABAergic transmission may be necessary for the hypnotic action of benzodiazepine receptor ligands, but not for the anticonflict or the anticonvulsant actions of such compounds.

Pharmacology and hypnogenic properties of brotizolam in animals.

Brotizolam differs in pharmacological profile from other diazepines by virtue of its hypnogenic potency. It increases, whereas other diazepines reduce, sleep in the cat. With increasing doses, the latency to rapid eye movement sleep is lengthened and the proportion is reduced. Brotizolam has anxiolytic, anticonvulsant and muscle relaxant properties. The effective anxiolytic and muscle relaxant doses are somewhat lower than those of diazepam, and the effective anti-convulsant dose is ten times lower. Barbiturate synergism in mice is lower with brotizolam than with diazepam, while alcohol-induced coma is prolonged over the same dose range. Side-effects of brotizolam are similar to those of other diazepines, but the therapeutic range is more favourable. Physical dependence as tested in the monkey seems to be low.