John W. Ward

Is 5-hydroxytryptamine involved in the mechanism of action of fenfluramine?

The present investigations show that the injection of either hormone into the hind-limb has an immediate effect on blood flow but that angiotensin I is much less effective than angiotensin 11. We have found in other investigations that both hormones used in the present studies are removed equally by the hind-limb of the sheep. A possible explanation for the present findings is that much of the angiotensin I is inhibited or destroyed rather than converted to angiotensin I1 when it is removed from the circulation. Our findings in the sheep differ from those of Ng & Vane (1968) in the dog and they are in agreement with those reported in several species by the earlier workers. These studies were made in the Dr. Leonard West Research Laboratory of Sully Hospital, Sully, Glamorgan, and we gratefully acknowledge the expert technical assistance of Mr. J. Wilson, Mr. 0. F. Mason and Mr. P. Stock.

Effects of fenfluramine on sleep-wakefulness in cats.

Five cats were prepared with chronically implanted electrodes for recording sleep-wakefulness patterns. Four of these animals received fenfluramine at each of three dose levels and data was recorded for the following 12 hours. Percent of time in paradoxical sleep was significantly reduced by 2.5 and 7.5 mg/kg, but not by 0.5 mg/kg, of fenfluramine. The higher doses also increased slow-wave sleep and, at 7.5 mg/kg (an anorexigenic dose), total sleep time was significantly increased. Under similar conditions amphetamine, at an anorexigenic dose of 1 mg/kg, significantly suppressed both paradoxical sleep and slow-wave sleep in three cats.Rebound of paradoxical sleep after suppression induced by 2.5 mg/kg of fenfluramine was not seen in either of two cats studied when sleep patterns were recorded for 48 hours. After 7.5 mg/kg of the drug, however, rebound was seen on days 3 and 4 after suppression of paradoxical sleep which lasted for over 26 hours. In two animals, daily administration of 2.5 mg/kg of fenfluramine for 16 consecutive days, followed by saline administration for three days, indicated that tolerance was developing to the suppression of paradoxical sleep produced by the drug.

Cardiovascular and autonomic effects of fenfluramine hydrochloride

Fenfluramine hydrochloride (N‐ethyl‐α‐methyl‐3‐trifluoromethylphenethylamine hydrochloride; AHR‐965) administered orally or intravenously to anaesthetised or unanaesthetised dogs, caused a predominant rise in arterial blood pressure, tachycardia, an increase in myocardial contractile force and cardiac output, and an enhanced total peripheral resistance. Fenfluramine was qualitatively like dexamphetamine in its cardiovascular effects; however dexamphetamine was 10 to 20 times more potent as a pressor agent.

Unusual, rod-shaped cytoplasmic inclusions (Hirano bodies) in a cerebellar hemangioblastoma.

SummaryThe present study reports unusual, long, tubular, rod-shaped cytoplasmic inclusions found in the stromal cells of a cerebellar hemangioblastoma, associated with von Hippel-Lindau syndrome. These inclusions have two layers of circular, laminated filaments, and longitudinally arranged filaments; and appear similar to the so-called “Hirano bodies”, which have been previously found in normal and various pathologic conditions of the brain tissue, skeletal muscle cells in myopathy, and interstitial cells of the testis. A review of previous ultrastructural studies of cerebellar hemangioblastoma shows several different types of cytoplasmic inclusions, but none are found to be identical to the present report.

Toxicologic studies of fenfluramine.

Abstract An account of toxicologic studies of fenfluramine HCl ( N -ethyl-α-methyl-3-trifluoromethylphenethylamine hydrochloride), an appetite suppressant, is presented. Mice, rats, guinea pigs, rabbits, monkeys, dogs, and cats, and the iv, ip and po (capsule and diet) routes of administration were involved in acute, subchronic, chronic, reproduction, and teratologic studies. Effects noted in acute studies were tremors, clonic convulsions, rigidity of the limbs, opisthotonus, mydriasis, lacrimation, chromodacryorrhea, salivation, vocalization, cutaneous hyperemia, piloerection, and hyperresponsiveness to tactile stimuli. Animals in subchronic and chronic studies were less active and showed slight bradycardia (dogs) and a slight to moderate reduction in food consumption and weight gain. Results were essentially negative with regard to clinical studies, gross findings at autopsy, changes in organ to body weight ratios, and histopathology. Most deaths were apparently due to respiratory failure. Teratologic information was negative. Reproduction studies showed decreases in rate of conception and in survival weight at weaning among animals at higher dose levels of fenfluramine. Weight gain was reduced during gestation in treated females.

Toxicologic studies of doxapram hydrochloride

Doxapram HCl (3,3-diphenyl-1-ethyl-4-[β-morpholinoethyl]-2-pyrrolidinone hydrochloride monohydrate: Dopram®: AHR-619), a new respiratory stimulant, was studied in several species to characterize its toxicity and assess its safety. The intravenous LD50 in mice, rats, dogs, and cats was approximately 75 mg/kg; the intraperitoneal LD50 was about twice as great; and the subcutaneous and oral LD50s were three to four times the intravenous value. Sex differences were not apparent in mice. Newborn rats appeared more suceptible than older animals, whereas newborn dogs did not. One-month subchronic studies were conducted as follows: rats, by intubation, at 40, 80, or 160 mg/kg/day; rats, intravenously, at 20 mg/kg/day; dogs, by capsule, at 2.5, 5, 10, 20, 50, or 125 mg/kg/day; dogs, intravenously at 2.5, 5, 10, or 20 mg/kg/day. Respiratory stimulation, pressor activity, and tachycardia were observed in dogs at lower does; hyperactivity, hyperthermia, emesis, salivation, lacrimation, defecation, urination, diarrhea, tremors, opisthotonus, and convulsions were observed at high doses. Deaths occurred in dogs at 50 mg/kg/day and above. Hypoxia was observed histologically in the brain at doses of 20 mg/kg/day and above, apparently the result of hyperventilation. Hemograms, blood chemical values, and urinalyses were normal. Reproductive and teratologic studies in rats gave results that were within normal limits. Tissue irritation was produced by subcutaneous injection in rabbits but not by intramuscular injection. Liver triglycerides were elevated in dogs and rats, apparently as a result of sympathetic stimulation by the compound.

Contrasting effects of two 5-hydroxytryptamine-depleting drugs on sleep patterns in cats

Abstract Slow-wave sleep increased in cats after administration of a 5-hydroxytryptamine (5-HT)-depleting dose of fenfluramine while it was decreased by p-chlorophenylalanine (pCPA), another 5-HT-depleting drug. Fenfluramine reversed the reduction in sleeping time resulting from pCPA administration and this reversal was blocked by AHR-3009, a 5-HT antagonist. These data suggest that although brain 5-HT levels may not be involved in the sedative action of fenfluramine, sleep was induced by an action on a tryptaminergic pathway.

Inhibition of release of slow-reacting substance by arsenic

Abstract The effects of arsenic, in the form of Fowlers solution, on sensitized guinea-pigs have been studied in an attempt to explain the previously reported beneficial effects of the metal in the treatment of patients with asthma. Arsenic was found to prevent the release of SRS-A and histamine in isolated perfused lungs in the presence of specific antigen. It also blocked the contraction of isolated, sensitized ileum in contact with antigen. Arsenic did not markedly inhibit the action of SRS-A, histamine or acetylcholine on isolated ileum. Some animals treated with arsenic survived anaphylactic shock whereas all untreated animals died. It was concluded that arsenic is effective in the treatment of asthmatic patients because the release of histamine and SRS-A in the lungs is blocked. Arsenic does not appear to block the union of antigen with antibody and must inhibit a later step in the reaction. The possible mechanism of action is discussed.

A condensed format for reporting toxicologic data--results of studies on glycopyrrolate.

Abstract A format is proposed for concise but comprehensive reporting of toxicologic information. It is used for presenting the toxicology of glycopyrrolate (1-methyl-3-pyrrolidyl α-phenylcyclopentaneglycolate methobromide; Robinul ® ), a potent anticholinergic agent. Mice, rats, rabbits, and dogs, and the intravenous, intraperitoneal, oral (capsule and diet), topical, intramuscular, and subcutaneous routes of administration were involved in acute, subchronic, and chronic, reproduction, teratologic, and irritation studies. No effects were produced in animals offered drug in the diet. Mydriasis, cycloplegia, and xerostomia were noted in all other studies. Additional effects seen were: acute studies—decreased motor activity, hypersensitivity, labored respiration, tremors and convulsions; subchronic studies—occasional tachycardia and emesis; and chronic studies—occasional lacrimation, injection of sclera, and rhinorrhea. Results were essentially negative with regard to clinical studies, changes in body weight and food consumption, gross findings at autopsy, changes in organ to body weight ratios, and histopathology. Most deaths were observed and apparently resulted from respiratory failure. Teratologic information was negative, reproduction studies showed decreases in rate of conception and survival rate at weaning, and minimal effects were noted in irritation studies.

Species-dependent effects of fenfluramine on the central nervous system

The cortical effects of fenfluramine and a metabolite, norfenfluramine, were studied in rabbits and cats. The parent compound produced slow waves in the e.e.g. which were compatible with sedation in cats. Norfenfluramine also produced slow waves and apparent sedation in cats, but neither compound produced marked changes in the cortical waves of rabbits. When cortical waves in both species were slowed with pentobarbitone, fenfluramine increased the frequency of the waves in rabbits but did not alter the frequency in cats. Both fenfluramine and the metabolite blocked cortical after‐discharges in both species. There is no apparent explanation for the differences in the action of the two drugs in the two species.