A Clinical Study of a Musculotropic Vasodilating Compound

Abstract

Within the past years, research in vascular disease has stimulated the development of many chemical and surgical techniques concerned with the management of peripheral arterial diseases. Because of the chronicity of vascular disease and the difficulty in measuring therapeutic benefit, the ultimate acceptance or rejection of these drugs and the various methods proposed for treating these diseases require the continued study of the different agents resulting from research.Among the drugs which have been suggested to be of value by various investigators is the mandelic acid ester of 3 , 3 , 5-trimethyl cyclohexanolf (cyclandelate) ( fig. 1), which was synthesized by Funcke.1 Cyclandelate differs from other spasmolytic, vasodilator substances in that it is relatively nonpolar with a low aqueous solubility.Using standard techniques, Funckel compared the spasmolytic activity of cyclandelate, papaverine and atropine on strips of guinea pig intestine. Against acetyl-choline induced spasm, cyclandelate was reported to be at least 5 times as active as papaverine hydrochloride, but approximately 500 times weaker than atropine sulfate. The antibarium effect of cyclandelate was at least twice that of papaverine. The antihistamine activity of cyclandelate was also more than twice as great as papaverine.Similar studies by Funckel using isolated seminal vesicle, isolated gallbladder and common bile duct of the guinea pig, and isolated rabbit intestine yielded similar results, with cyclandelate having consistently greater activity than papaverine. The early observations showing that the coronary vessels (exposed by opening of the thorax) of cats, given this agent for a number of days, were dilated in comparison to those of nontreated cats, prompted Van den Akker and co-workerg' to reinvestigate the vasodilating properties of the drug. Studies' carried out with cyclandelate showed that rats and dogs fed over 200 times the usual human dose of cyclandelate remained in good health over a six month period. The acute oral median lethal dose of the drug in rats was measured at 5 gm per kg.Initially, cyclandelate was prescribed by a number of physicians for treatment of spastic contractions of smooth muscle tissue of abdominal organs. Herschel3 studied cyclandelate in various affections of the peripheral vessels. He described the treatment of eight patients with intermittent claudication. Even though subjective improvement became manifest fairly soon, it was usually a considerable time (weeks to months) before the improvement could be demonstrated objectively by means of a tensiograph of Boulette.Doornink4 employed the drug in 18 cases of arteriosclerotic leg ulcer, concluding that the drug was a valuable aid in the medical regimen. The doses used were quite low (20 to 200 mg per day) by present standards (400 to 1600 mg per day). Nevertheless, in 10 out of 18 patients, Doornink felt that the drug helped promote closure of the ulcers. Van Wijkl reported favorably on 50 patients. For objective criteria he used claudication time measuremen...