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The clarification of lipemic serum by heparin has been observed by many investigators.l-4 Fuller5 extended the application of this property of heparin through the use of sublingual administration of the drug, thereby avoiding the inherent limitations of parenteral therapy. A particular advantage of the sublingual route is the absence of the anticoagulant effects of heparin,6 without appreciable diminution of its lipemic clearing activity. 7, 8 in an earlier study,9 we were able to confirm the lipemic serum clearing properties of sublingual heparin (Clarin) and also to demonstrate once again the absence of its anticoagulant activity.Several interesting aspects of this phenomenon arose in the course of our study with this agent which prompted our continued investigation. The clarification of lipemic serum is not equated with the lowering of serum cholesterol, a subject of much current misunderstanding. Cholesterol determinations, although unquestionably useful in the study of the epidemiology of atherosclerosis, have little predictive value for the individual.10Although there is no conclusive evidence that serum clarification will prolong the life span of the patient with cardiovascular disease, there are references to the favorable effect of prolonged heparin treatment in preventing the recurrence of myocardial infarction. 5. 1 There is, however, the positive fact that the rate of fat disappearance from the serum after a standardized fat meal is accelerated in a safe and predictable manner by sublingual heparin. What this means to the clinician and his particular patient is a question which Anfinsen may have answered when he said that the slower rate of metabolic lipid removal from circulating plasma is &dquo;perhaps the most characteristic laboratory feature of atherosclerosis. &dquo;12Our earlier study was conducted under acute, short term experimental conditions, whereas the present study is concerned with observations after administration of the drug to chronically ill patients during a period of from 1 to 2 years. We were also interested in ascertaining any secondary effects of sublingual heparin administered under the conditions of the everyday practice of medicine. EXPERIMENTAL PROCEDUREControl base line-values of the rate of serum clarification after ingestion of a standardized fat meal were obtained for a group of 40 subjects (26 men and 14 women) ranging in age of from 28 to 66 years, in the manner described in our earlier paper,9 and the values for three separate determinations (conducted a month apart) were averaged for each individual index. Sublingual heparin (Clarin) was then prescribed at a dosage level of 1500 IU, four times daily. The serum clarification rates after a test meal were studied at monthly intervals for a period of 10 months. The drug was next withdrawn for 2 months although the serum clarification rates were determined during this period. The drug was then reinstituted and the serum clarification studies continued during the next year.There was no control of diet during this study an...

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...