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Biomedical subjects

G B Leslie

Publications and source records attributed to G B Leslie.

At least 19 recordsLinked to original sources
PubMed1992

[Effects of environmental tobacco smoke on prenatal development. (Review of the medical literature)].

For near thirty years, epidemiological studies have coped with the search of possible noxious consequences of an involuntary exposure of pregnant women to environmental tobacco smoke on the gestation and the intrauterine development of embryo and foetus. These studies were mainly retrospectives; a careful study of the methods used (questionnaires, evaluation of exposure, and so on ...) gives evidence that they can rarely avoid serious criticism. As possible effects of intrauterine exposure to environmental tobacco smoke, low birth weight and impairing of other body parameters, perinatal mortality, frequency of abnormalities have been reviewed. As a potential cause, the role of the father tobacco smoking has been especially examined. As a whole, the consequences of a prenatal exposure to environmental tobacco smoke are an extremely controversial subject and no obvious effect has yet been universally recognized. The critical analysis of the studies has shown that, frequently, the epidemiological studies have been interpreted in order to find links between and involuntary exposure to tobacco smoke and some troubles of reproduction, particularly in offspring. As a matter of facts, fundamentally, the noted actually correlations, even if they are statistically significant, are not able to move such links. They are only able to indicate the existence of an association and only, if the eventual role of confounding factors has been properly treated. An interesting case is the potential effects of the father's tobacco smoking. The hypotheses emerging from these examined inquiries remain to be more precisely defined and thoroughly by new studies, preferentially prospective, and, when necessary, completed by animal experiments. It is suggested that a special effort shall be applied to the measurement of the exposure of pregnant women to define toxic compounds originating from environmental tobacco smoke. Presently, it is not possible to draw a conclusion on the noxious or innoxious influence of the involuntary exposure of pregnant women to environmental tobacco smoke, particularly as far as potential risks for foetus are concerned.

Abortion, Spontaneous↗
PubMed1988

Improved oral dosing technique for rats.

In a department assessing the safety of potential medicines, it was found that gavage-related death in rats could be virtually eliminated by the use of a modified dosing cannula. It had previously been found with a series of potential therapeutic agents that a number of rodents died with dyspnea following administration by gavage. It was known that this was not due to technical error; gavage with water in control groups led to death with similar symptoms in only one case per 220 rat years, or one in 80,520 doses. Accidental aspiration of small volumes of the oral dose was considered to be responsible for the drug-related deaths. Hypertonic, acidic sodium chloride solutions, used as a control, tonicity- and pH-matched to a compound solution in a long-term study, had similar effects. It was shown in a small experiment that the intratracheal lethal dose was approximately 1/200 the published oral LD50 of NaCl. Cannulae of various diameters, lengths, and materials were tested in order to devise a safer dosing method, which would not cause trauma but would allow economical dosing speeds to be achieved. For adult rats, a steel cannula 70-mm-long, with a maximum tip diameter of 4 mm, was chosen. Lighter rats could be dosed using cannulae of smaller tip diameter according to body weight. The adoption of our method, developed using a few rats, could save many unnecessary deaths in laboratory rodents as well as many spurious "treatment-related" pulmonary symptoms.

Administration, Oral↗
PubMed1988

An improved simple technique for the collection of blood samples from rats and mice.

The technique of blood collection from the lateral caudal vein has been improved. The method requires only moderate skill and no anaesthesia is necessary. Collection of blood samples causes little trauma and can be repeated at frequent (8 h) intervals thus making the method particularly suitable for pharmacokinetic and hormonal studies. Blood samples are uncontaminated by tissue fluids. Large volumes can be obtained, in mice up to 1.5 ml and in Wistar rats over 4 ml.

Animals↗
PubMed1987

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.

Animals↗
PubMed1986

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.

Adrenergic beta-Antagonists↗
PubMed1985

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.

Administration, Oral↗
PubMed1985

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.

Animals↗
PubMed1982

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.

Animals↗
PubMed1981

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.

Administration, Oral↗
PubMed1978

Characterization and development of cimetidine as a histamine H2-receptor antagonist.

The concept of two classes of histamine receptor, H1 and H2, is introduced and the chemical derivation of histamine H2-receptor antagonists is outlined briefly. Starting from the structure of histamine, chemical modification led eventually to burimamide, the first described histamine H2-receptor antagonist. Further stepwise modifications ultimately afforded metiamide and cimetidine. In vitro studies show that cimetidine is a specific competitive histamine H2-receptor antagonist. In vivo, it is a potent inhibitor of histamine-stimulated gastric acid secretion in rats and dogs after both intravenous and oral administration. It is equally potent as an inhibitor of pentagastrin-stimulated secretion. The evidence suggests that cimetidine inhibits gastric acid secretion through blockade of histamine H2-receptors in the gastric mucosa. Cimetidine has been shown to have low acute toxicity. Repeated dose studies of up to 24 months in rats and up to 12 months in dogs have been carried out and the results are presented and discussed. There is no known toxic effect which would limit the usefulness of cimetidine in man.

Androgen Antagonists↗
PubMed1977

The in vitro and in vivo activity of taurolin against anaerobic pathogenic organisms.

An antibacterial agent, taurolin, formed by the combination of 2 molecules of taurine with 3 molecules of formaldehyde has been tested against anaerobes in vitro and in vivo. In vitro, taurolin is highly active against Bacteroides species and anaerobic Streptococci as measured by the minimum inhibitory concentration. In vivo, small dosages of taurolin given intraperitoneally increase the mortality in mice with Bacteroides peritonitis. However, by increasing the dosage of taurolin, survival is prolonged and mortality reduced. Intravenously administered taurolin protects rabbits from the effects of Bacteroides fragilis infection whether the organisms are given intravenously or intraperitoneally.

Animals↗
PubMed1976

Animal models of peritonitis.

A reproducible animal model of peritonitis has been developed. It uses standard animals, standardized cultures of bacteria and simple techniques. Use of this model would facilitate comparison of data from workers in this field. The use of small rodents permits the use of comparatively large populations for statistical evaluation. The method is cheap and economic of laboratory space and does not require surgical expertise.

Animals↗