Serc - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Manufacture: Abbott Laboratories
Country: Angola
Condition: Vertigo
Class: Antiemetic/antivertigo agents
Form: Tablets
Ingredients: Betahistine dihydrochloride, Citric acid, Colloidal anhydrous silica, Mannitol, Microcrystalline cellulose, Talc.

Pharmaceutical Information

Drug Substance

Proper name: betahistine dihydrochloride
Chemical name: 2-[2-(methylamino)ethyl]pyridine dihydrochloride
Molecular formuland molecular mass: C8H12N2•2HCl                             209.1
Structural formula:
Physicochemical properties: Betahistine dihydrochloride is a white to almost white crystalline product which is very hygroscopic. The product is very soluble in water, freely soluble in methanol and 96% methanol, and slightly soluble in isopropanol. The pKa values are 3.5 and 9.7. The substance melts at about 152°C.

Detailed Pharmacology

Animal

Pharmacodynamics

In vitro

In studies on a variety of isolated organs and isolated tissues, betahistine dihydrochloride produced responses similar to those induced by histamine. Betahistine dihydrochloride had little or no affinity for histamine H2-receptors as confirmed by its activity in tests using rat uterine muscle, rabbit and guinea pig hearts and atrial pairs, and isolated guinea pig ileum.

In vivo

In evaluations of its effects on the circulation of the inner ear, betahistine dihydrochloride was found to produce greater effects than histamine. Betahistine dihydrochloride increased blood flow in the labyrinthine arteries of dogs by 60.9% following a dose of 100 mcg. Circulation in the stria vascularis and spiral ligament of guinea pigs and chinchillas was increased by a mean of 50% when betahistine dihydrochloride was administered at doses as low as 0.1 mg/animal. In guinea pigs, cochlear blood flow was increased for 30 minutes following a dose of 0.2 mg/kg.

In cats, betahistine dihydrochloride was also found to have a dose dependent inhibiting effect on spike generation of neurons in lateral and medial vestibular nuclei. Betahistine dihydrochloride at 60 and 120 times the normal human dose accelerates the vestibular recovery after unilateral neurectomy. Taken together these properties may contribute to its beneficial therapeutic effects in Ménière's disease and vestibular vertigo.

Betahistine dihydrochloride increases histamine turnover and release likely by blocking presynaptic H 3-receptors and inducing H3-receptor downregulation. This effect on the histaminergic system could provide an explanation for the efficacy of betahistine dihydrochloride in the treatment of vertigo and vestibular diseases.

Studies of the effects on the cardiovascular system, the pulmonary system, the renal system, the gastrointestinal system, and the central nervous system all indicated that betahistine dihydrochloride produced effects similar to, but less potent than, those of histamine.

Following rapid intravenous (iv) administration of betahistine dihydrochloride, a brief fall in blood pressure was evoked in rats, guinea pigs, dogs, and cats. This hypotensive effect could be blocked by the administration of histamine H1-antagonists, but not by histamine H2-antagonists. When betahistine dihydrochloride was injected slowly into anaesthetized dogs, general blood pressure decreased while basilar blood flow increased by up to 200%. Pronounced increases in blood flow were found in the coronary (225%), labyrinthine (161%), and communicating hepatic arteries (156%).

Intravenous doses of 0.2 to 0.4 mg/kg given to anaesthetized guinea pigs produced an increase in pulmonary resistance while large doses induced bronchoconstriction. Parenteral administration to guinea pigs at a dose of 0.2 mg/kg induced vasopermeability. Administration of an intraperitoneal dose of 40 mg/kg caused death by respiratory failure.

In the perfused baboon kidney, the addition of betahistine dihydrochloride to the perfusate produced increases in urine flow, osmotic clearance, urea and creatinine clearance.

Betahistine dihydrochloride doses of 80 to 1600 mcg/kg/min administered as a continuous infusion to dogs with Heidenhain pouches produced a slight increase in the rate of acid secretion corresponding to 8.8% to 17.6% of the maximum response to histamine. In dogs with gastric fistulae, an increase in acid secretion was obtained with a subcutaneous dose of 20 mg/kg betahistine dihydrochloride. This increase corresponded with that produced by 30 mcg /kg of histamine.

The effect of betahistine dihydrochloride on continuous avoidance behaviour in rats was compared with that of histamine. Betahistine dihydrochloride injected intraventricularly at a dose of 0.32 mg/animal and histamine at a dose of 0.08 mg/animal produced a significant increase in the avoidance rate; an increase was also observed after an intraperitoneal dose of 4.0 mg/kg betahistine dihydrochloride, but this did not achieve statistical significance. Betahistine dihydrochloride did not affect the righting reflex when given to newborn chicks at a dose of 100 mg/kg, while a dose of 50 mg/kg histamine produced sleep characterized by loss of the righting reflex.

Pharmacokinetics

The absorption, distribution, metabolism, and excretion of betahistine dihydrochloride were studied in female rats.

Absorption

After oral administration, betahistine dihydrochloride is completely absorbed from the gastrointestinal tract.

Distribution

The distribution of radio-labelled betahistine dihydrochloride was evaluated at 0.5, 1, 3, 6, 24 or 48 hours after the oral or intravenous administration of a 1 mg dose. Following intravenous administration, radioactivity was distributed rapidly throughout the body, with immediate and intensive secretion into the stomach and intestines. There was a transient accumulation of radioactivity in the liver and the portal vein. After oral administration, radioactivity was distributed throughout the body, with high accumulation in the stomach and intestines. Levels of radioactivity in excess of blood levels were observed in the bronchial epithelium, the eye, and the preputial gland. At 24 hours, only the preputial gland and the alimentary system still showed evidence of accumulated radioactivity. By 48 hours, there was no remaining activity.

Metabolism

The metabolite pattern in rat urine showed only one main metabolite – 2 pyridylacetic acid.

Excretion

Following the oral or intravenous administration of 0.5 mg radio-labelled compound, total excretion of the radioactive label was 80 to 90%, about 67% of which was in the urine. Of the total excretion which took place, 98.5% appeared in the urine within 24 hours.

Toxicology

Acute Toxicity

The oral LD50 (Lethal Dose; LD50 is the amount of compound, given at a single dose, which causes the death of 50% [one half] of a group of test animals) for betahistine dihydrochloride is 3040 mg/kg in the albino rat. The intravenous LD50 is 5.1 mg/kg in the rabbit. Side effects in the nervous system were seen in dogs and baboons after intravenous doses at and above 120 mg/kg. Signs of toxicity included ataxia, salivation, inactivity, hyperpnoea, tremors, and cyanosis. Severe gastroenteritis was noted during pathology.

Long-Term Toxicity

Rat and Dog

In a six month study, dogs were given doses of up to 25 mg/kg/day. There were no significant abnormalities noted in any of the parameters assessed. In rats given doses of up to 500 mg/kg/day for 18 months, there were no significant abnormalities noted in any of the parameters assessed. Oral dosing up to and above 250 mg/kg, in dogs and in rats respectively, of betahistine dihydrochloride administered during 3 months did not result in adverse effects.

In investigational studies with betahistine dihydrochloride in rats over 6 months with doses starting at 13 mg/kg and above, hyperemia in some tissues was reported, namely liver, spleen and kidneys. Data presented in the literature are limited, therefore, the impact of this finding is not clear.

Dog and Baboon

Emesis was observed at 300 mg/kg and 120 mg/kg following oral and iv dosing respectively in dogs and sporadically in baboons.

Mutagenicity and Carcinogenicity

In the studies conducted with betahistine dihydrochloride, no mutagenic effects have been observed.

Special carcinogenicity studies were not performed with betahistine dihydrochloride. However, in two 18 month chronic toxicity studies in rats there was no indication of any tumors, neoplasms or hyperplasia in the histopathological examination. Therefore, betahistine dihydrochloride up to a dose of 500 mg/kg did not show any evidence for carcinogenicity in these limited 18 month studies.

Reproduction and Teratology

Limited data are available for betahistine dihydrochloride on reproduction. In a one-generation study in rats, an oral dose of approximately 250 mg/kg/day betahistine dihydrochloride had no adverse effect on male and female fertility, implantation of foetuses, parturition and viability of pups during lactation. No abnormalities were noted in weaned rats. In pregnant rabbits treated orally with 10 or 100 mg/kg betahistine dihydrochloride from mating (gestation day 0) to gestation day 28, slight increases in fetal loss were observed in the two test groups and a slight increase in the incidence of reduced or unossified sternebrae and extra ribs were observed compared to untreated rabbits. Both effects were non-significant and within historical control data. No adverse effects were noted on implantations, vitality or weight of foetuses.