Lectopam - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Lectopam - Scientific Information

Manufacture: Roche
Country: Canada
Condition: Anxiety, Neurosis
Class: Anxiolytics, sedatives, and hypnotics
Form: Tablets
Ingredients: Iron oxide red, Lactose monohydrate, Magnesium stearate, Microcrystalline cellulose, Talc, Indigotine aluminum lake, Iron oxide yellow

Pharmaceutical Information

Drug Substance

Proper name: Bromazepam
Chemical name: 7-bromo-1,3-dihydro-5-(2-pyridinyl)-2H-1,4-benzodiazepine-2-one
Molecular formula and molecular mass: C14H10BrN3O, 316.2
Structural formula:


Detailed Pharmacology

Bromazepam is a benzodiazepine with CNS depressant properties. In laboratory animals, it has shown anti-anxiety, sedative, muscle relaxant and anticonvulsant properties. In a “conflict” test, bromazepam was active in restoring suppressed lever-pressing behaviour (punishment induced suppression) at a minimum effective dose (MED) of 0.16 mg/kg orally in rats. This activity was demonstrated over a dose range which did not involve either depression or stimulation of unpunished control patterns of lever-pressing behaviour. At 2.5 mg/kg, a dose 16 times greater than the MED, bromazepam produced the first decrease in unpunished lever-pressing. In rats, utilizing the Sidman continuous avoidance test, an MED of 1.7 mg/kg i.p. decreased the rate of avoidance of shock, and 5.6 mg/kg i.p. prevented the rat from turning off the shock.

A marked reduction in aggressive behaviour was observed in vicious cynomolgus monkeys after an oral dose of 1 mg/kg and a taming effect at a dose of 2.5 mg/kg p.o. In the inclined screen test in mice the ED50 for bromazepam was 30 mg/kg p.o. In cats, the minimal effective taming dose of bromazepam was 0.2 mg/kg p.o.

Doses of 0.72 to 0.94 mg/kg p.o. of bromazepam protected mice against metrazol (125 mg/kg) induced convulsions. Bromazepam administered at doses of 3.90 to 34.2 mg/kg and 65 to 133 mg/kg p.o. protected mice against maximal and minimal electroshock-induced convulsions, respectively. A single dose of bromazepam (0.25 to 0.50 mg/kg p.o.) produced sedation or ataxia and modified the sleep cycle in cats. An increase in the amplitude of the electrical patterns of the caudate nucleus was observed.

A decrease in blood pressure was observed after the intravenous administration of bromazepam to anesthetized cats (1 mg/kg) and dogs (5 mg/kg). However, in hypertensive rats, little or no antihypertensive effect was detected. Bromazepam exhibited no diuretic, anti-obesity, anti-diabetic or anti-emetic activity.

Metabolism

The metabolites of bromazepam were studied in the mouse, rat and dog using 14C labelled drug. The quantitative determination of the metabolites indicates that marked differences in the excretion patterns exist in these species. In the mouse and dog, the major metabolite is 3-hydroxybromazepam, although it is only present as a minor metabolite in the rat. Both 2-(2-amino-5-bromobenzoyl) pyridine and its 3-hydroxy derivative are found as metabolites of bromazepam in all three species. In the dog, a separate biotransformation occurs, such that the nitrogen atom, at the 4-position of the diazepam ring, is oxidized to bromazepam 4-oxide. In rats, over 80% of an administered oral dose of bromazepam is excreted in four days, whereas in the dog, excretion is much slower. In rats, biliary excretion and in dogs, urinary excretion is the predominant route of elimination.

Toxicology

Acute Toxicity

LD50 (mg/kg):

p.o. i.p. s.c. i.v.
Mice (CFI)
Rats - mature (Wistar)
Rats - neonatal (Wistar)
Rabbits (Wistar)
Dogs
2,350
3,050
110
1,690
≥1,280
550
2,300


7,400



13.7



Signs of toxicity included decreased motor activity, ataxia, loss of righting reflex and lacrimation.

Chronic Toxicity

Bromazepam was administered in the diet to rats for a period of 18 months at doses of 0, 5, 20 and 80 mg/kg/day. No deviations from normal were observed except for an increase in the liver weight at necropsy at the time of the interim kill (18 months). Differences were not found in animals killed at the end of the study (24 months, after 6 months recovery) except for an increase in the ratio of liver to body weight. Histopathological examination revealed centrolobular hepatocellular hypertrophy in the treated groups.

Daily doses of 0, 5, 20 and 80 mg/kg were administered in the diet to dogs for a period of one year. In the high-dose group, untoward effects were slight-to-moderate sedation and ataxia, which decreased as the study progressed. Isolated brief convulsive seizures were observed and an occasional elevation in serum alkaline phosphatase, a borderline increase in SGPT and a slight increase in liver weights occurred in a few dogs in the 80 mg/kg dosage group.

Reproductive Studies

Reproductive, teratological, perinatal and postnatal studies in rats receiving bromazepam at levels of 5 and 50 mg/kg/day p.o. revealed an increase in fetal mortality in the 50 mg/kg group. However, a second reproductive study, in which rats were administered either 10 or 25 mg/kg/day, revealed an increase in the stillbirth rate and a reduction in pup survival at both doses during the first four days following delivery. In another rat study, the daily oral administration of 1 mg/kg, through two successive matings, did not affect the reproductive processes. Bromazepam, at doses of 10 mg/kg/day produced a slight decrease in the number of pregnancies and in the postpartum survival of the offsprings following the second matings. When 100 mg/kg/day was given through three successive matings, a decrease in the number of pregnancies in the parent generation and in the postpartum survivability of the offsprings was observed in all instances. Bromazepam was given to pregnant rabbits at doses of 5 and 50 mg/kg/day p.o. The following effects were noted: a reduction in maternal weight gain, a reduction in fetal weight and an increase in the incidence of resorptions in both treated groups. In a second study in rabbits, at dose levels of 5 and 80 mg/kg/day p.o., no teratogenic effects were observed. Pregnant mice were administered bromazepam orally, by stomach tube, from day 7 through 13 or 16 of pregnancy at dose levels of 5, 10, 50 and 125 mg/kg/day. No teratogenic effects were detected.