Safety evaluation of cimetidine: report at the termination of a seven-year study in dogs.

Cimetidine in tablet form was administered orally daily to eight male and four female beagle dogs at a dose level of 144 mg kg-1 for 385 weeks. Four male and two female control dogs received placebo tablets. Treatment with cimetidine did not affect the clinical condition of the dogs, but was associated with a slightly less rapid weight gain. Five dogs (two cimetidine-treated and three controls) were killed during the course of the study for reasons not related to treatment. Treatment with cimetidine did not affect haematological, clinical chemical, urinalysis or electrocardiographic parameters. Multiple biopsies of gastric mucosa taken at intervals of approximately six months from Week 177 to Week 363 showed no change which could be attributed to treatment with cimetidine. There were no toxic effects on the gastric mucosa of any dog. At necropsy no treatment-related findings were reported except for reduction in prostate size in 6/8 males receiving cimetidine. This was expected in view of previous experience with cimetidine.

Cimetidine does not demasculinize male rat offspring exposed in utero.

Cimetidine has weak antiandrogenic activity in rats, but does not affect fertility in male rats at daily doses up to 950 mg/kg. Literature reports have claimed that giving cimetidine to pregnant rats in the drinking water caused feminization of male pups, small sex organs, low libido, and low serum testosterone. In the present study these effects were tested by giving large groups of pregnant rats 180 mg/kg/day cimetidine in the drinking water from Day 12 of pregnancy until the end of lactation, or a combination of drinking water and gavage treatment. Estimations included anogenital distance exactly 24 and 120 h after birth; serum testosterone at 55 and 110 days of age; mating performance at 110 days and (after castration and testosterone implantation) at 143 days; and testis, prostate, and seminal vesicle weights at 55 and 147-148 days. Maternally administered cimetidine was completely without effect on all the parameters measured in the male offspring. Thus, giving cimetidine to pregnant rats did not affect the masculinity of their male offspring.

The effect of phorbol esters on human erythrocyte morphological discocyte-echinocyte transitions.

12-O-Tetradecanoylphorbol-13-acetate (TPA) (100 nM) when incubated with human erythrocytes under conditions of ATP depletion, delayed the onset of the morphological transition from discocytes to echinocytes so that at 2 h, when control incubations were estimated to contain 65% echinocytes, those treated with TPA contained 23% echinocytes. TPA did not alter the subsequent rate of the transition which was complete by 3 h in control cells and 5 h in TPA-treated cells. Addition of 100 nM TPA to ATP-depleted erythrocytes at 2.5 h (greater than 80% echinocytes) for 0.5 h at 37 degrees C resulted in 17% reversal to a discocyte morphology, but as the time of incubation under conditions of ATP depletion was extended, the level of the reversal fell. TPA had no significant effect on the fall in ATP concentrations over the time course of the experiments (5 h). Preincubation of discocytes with TPA for 10 min also prevented, by approx. 50%, the echinocytosis induced by the calcium (0.2 mM) loading of discocytes using 5 microM A23187. TPA was unable to reverse the echinocyte morphology of calcium-loaded cells back to discocytes. The less potent tumour promotor 4-phorbol-12,13-didecanoate had no effect on this discocyte-echinocyte transition. Incubation of discocytes with the diacylglycerol 1-oleoyl-2-acetylglycerol (OAG) (1-10 microM) had complex effects on morphology, and the ATP-induced morphological transition, ranging from stomatocyte formation to echinocyte formation, depending upon the concentration of the agent and the time of incubation.

Dyspnoea and thoracic spinal deformation in rats after oral prizidilol (SK&F 92657-A2).

Prizidilol (SK&F 92657-A2), an anti-hypertensive agent, has undergone a range of prescribed toxicity studies required for the investigation of possible adverse drug effects. During the second year of the 2-year rat oral study, a variety of symptoms were exhibited by males receiving 1600 mg of the compound day-1kg-1 by gavage. These animals became lethargic, slouched and developed dyspnoea which became progressively more severe during the course of the study. Necropsy of the affected rats revealed severely haemorrhagic lungs, cardiac hypertrophy and lordosis of the spine into the thoracic cavity. At the 2-year terminal kill, a proportion of the male rats receiving 100 and 400 mg of prizidilol day-1kg-1 were identified with similar but less severe spinal deformation. No female was found with spinal changes but all the rats receiving prizidilol showed haemorrhagic lungs and enlarged hearts. The lordosis of the affected males was always confined to the thoracic spine and this, along with the cardiac hypertrophy, presumably led to marked reduction in the volume of the thoracic cavity, inducing the dyspnoea. Thoracic vertebral body damage, possibly a precursor to the spinal deformities, was found in male rats from both drug-treated and control groups. The nature of the spinal lesion is at present under investigation.

Cardiotoxicity of a new inotrope/vasodilator drug (SK&F 94120) in the dog.

The cardiotoxicity and haemodynamic changes induced by IV administration of high doses of SK&F 94120, a novel positive inotrope/vasodilator, were studied in the dog. Inotropism was observed at a dose of 0.375 mg/kg. Mean blood pressure was reduced in a dose-related manner, reaching a nadir of 43.7 mm Hg at 24 mg/kg. Heart rate was increased at doses of 1.5 mg/kg and above. ECG examination revealed a shortening of PR interval and an increase in T-wave amplitude. At doses of 15 mg/kg and above, occasional AV dissociation with accrochage were sometimes seen shortly after the start of the infusion. Ventricular extrasystoles were only seen at doses of 120 mg/kg and above. A dose-related increase in severity and incidence of haemorrhages, deposition of haemosiderin and fibroplasia were seen in the left ventricular endocardium and atrioventricular valves at doses of 15 mg/kg and above. Focal myocardial necrosis, predominantly of the left ventricular papillary muscle, and mild periarteritis of medium-sized extramural arteries, mostly in the right atrium, were seen at doses of 45 mg/kg and above. Intimal proliferation of intra- and extramural coronary vessels was observed. A necrotising peri/panarteritis of these arteries was noted at doses of 200 and 400 mg/kg. The cardiotoxicity observed was considered to be due to the exaggerated pharmacologic effects seen at these high dose levels.

Discolouration of the optic disc in baboons during treatment with prizidilol (SK&F 92657), a novel antihypertensive agent.

Prizidilol (SK&F 92657-A2 X H2O) is the dihydrochloride salt of D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazi ne, a molecule combining the properties of precapillary vasodilatation and beta-adrenoceptor blockade. Prizidilol was administered to baboons daily for up to 1 year at sustained doses up to 800 mg/kg. During the 16th week of a 26-week study ophthalmoscopic examination revealed an orange tinge at the periphery of the normally pale pink optic disc in all high-dose (800-1225 mg/kg) baboons. The colour became more intense as the study progressed. By week 25 orange discolouration was seen in all baboons at 350 mg/kg and three out of six baboons at 100 mg/kg. The findings, except those at 100 mg/kg, were confirmed in a 12-month study. Optic disc discolouration was correlated with darkening of internal organs at necropsy. Discolouration of the optic disc did not appear to affect visual function. Slow regression of discolouration was demonstrated after withdrawal of treatment with 800 mg of prizidilol/kg at 6 months. No histological abnormalities were present in the optic discs of affected baboons. The study demonstrates the value of regular ophthalmoscopy in toxicity studies, combining the facility for the early detection of an unusual lesion with the ability to follow its time-course.

Toxicology of cimetidine.

Cimetidine has been shown to have low acute toxicity in dogs and rodents. Repeated-dose studies of up to 24 months' duration in rodents at doses up to 950 mg day-1 kg-1 showed few adverse effects. Liver weight was consistently increased at the highest dose and testis, prostate and seminal vesicle weights were reduced in a dose- and time-related fashion. Cimetidine was not carcinogenic in the rat. In tests of up to 1 year's duration in dogs two animals receiving 504 mg day-1 kg-1 had to be killed before the end of the study. They had degenerative changes in the liver and renal tubular nephrosis. These and other dogs at 504 mg day-1 kg-1 had elevated serum transaminases. No such changes were seen at 366 mg day-1 kg-1 or less. Prostate weights were reduced in a dose- and time-related fashion. In a 7-year study in dogs, specifically designed for the purpose, no changes of the stomach mucosa were seen during regular biopsy. Although shown to be a mild anti-androgen, cimetidine produced no significant adverse effects in reproductive studies. The large body of evidence that cimetidine is not a risk for gastric cancer is reviewed. Over 30 million patients have so far been treated with cimetidine and the prediction from the animal studies that it would be an extremely safe therapeutic agent has been borne out in practice.

Short-term toxicological studies with impromidine (SK&F 92676): a specific histamine H2-receptor agonist.

Impromidine is a specific, potent histamine H2-receptor agonist. The present paper describes the results of acute and short-term repeated-dose toxicity studies with impromidine in rodents and dogs. The intravenous LD50 was 9.6 mg kg-1 in male mice, 12.7 mg kg-1 in female mice and 25.5 mg kg-1 in rats. The minimum lethal dose in dogs after 30 min intravenous infusion was 27.7 mg kg-1 during the infusion and 4 mg kg-1 within 14 days. In 12- or 14-day tests in rats by the intravenous (maximum dose 3.24 mg per kg per day) and subcutaneous (maximum dose 20 mg per kg per day) routes, impromidine had no serious toxicological effects. In 12- or 14-day studies in dogs by the i.v. (maximum dose 0.259 mg per kg per day) and intramuscular (maximum dose 0.5 mg per kg per day) routes, impromidine caused vasodilation, tachycardia and vomiting. In a few dogs, at the highest dose levels, there was erosion and irritation of the gastrointestinal tract and myocardial damage. Other minor pathological changes were seen in the liver, kidneys and pancreas. No changes were seen other than those to be expected from the pharmacological actions of impromidine as an H2-receptor agonist. Studies in anaesthetized rats, either spontaneously respiring or sustained by artificial respiration, indicate that, at acute doses, impromidine causes death by respiratory failure.

Safety evaluation of cimetidine: 54 month interim report on long-term study in dogs.

Cimetidine [N"-cyano-N-methyl-N'-2[(5-methylimidazol-4-yl)methylthio]ethyl guanidine] was administered orally to eight male and four female beagle dogs at a dose level of 144 mg per kg bodyweight per day. Four males and two females received placebo tablets. Dosing began in March 1976. During the first 26 months of dosing the animals became obese--the control animals more so than the cimetidine-treated. Since month 27 feeding time was restricted and there has been an overall weight loss. Some control animals are still obese. One control male and one dosed female have been killed because they developed convulsions. No treatment-related effects on haematology, clinical biochemistry, urinalysis, electrocardiography or clinical condition have been seen. Three out of the five surviving control animals but none of the 11 surviving cimetidine-dosed animals have developed cataracts. Biopsies of gastric mucosa taken during endoscopy in months 41, 47 and 53 have shown no changes attributable to cimetidine treatment.