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Excerpt Six years have elapsed since the first report on the clinical use of dicumarol.1Since that time there have been a number of clinical reports by ourselves and others. The literature has been...

The successful use of dicumarol in the prevention of intravascular thrombosis and subsequent embolism has led to the investigation of other coumarin compounds as therapeutic anticoagulants. 4-Hydroxycoumain anticoagulant No. 63 is such a compound. Like dicumarol, it induces hypoprothrombinemia and daily tests of prothrombin time are necessary as a guide to dosage. Our experience indicates that a less fluctuating and somewhat more consistent therapeutic hypoprothrombinemia can be established and maintained with anticoagulant No. 63 than with dicumarol. The potential disadvantage of the prolonged hypoprothrombinemia after administration is stopped is counter balanced by the strong and relatively rapid antagonistic effect of vitamin K 1 .

Nicotinic acid was administered orally to 33 patients with hypercholesterolemia in doses varying from 1.5 to 6.0 Gm. per day for periods of 3 months to 1½ years. Significant, sustained, and reproducible decreases in the concentration of cholesterol and total lipids in the plasma and of serum beta-lipoprotein cholesterol were observed in a majority of patients. This form of therapy appears to be effective, practical, and probably free from serious harmful effects.

We have reported a series of thirteen cases of peripheral vascular disease affecting chiefly the legs and feet which seems to us to be best classified under the term “livedo reticularis,” as described in the literature. The clinical manifestations differ distinctly from those of Raynaud's disease, acrocyanosis, and thromboangiitis obliterans. These patients did not have evidence of tuberculosis or syphilis, and the circulatory disturbance developed during adult life. The etiology in our cases is not known. The available data in our cases and others indicate that in livedo reticularis there are usually organic changes in the arterioles of the skin, with chronic vasospasm, which result in regional atony and dilatation of capillaries and slowing of the blood flow. The condition may be complicated by ulceration of the legs and superficial gangrene of the toes. Lumbar sympathetic ganglionectomy resulted in definite improvement in circulation and prevention of further attacks of gangrene in two of our cases and was unsuccessful in one case. It is our opinion that sympathectomy is a justifiable procedure in cases of livedo reticularis in which (1) no definite etiological factor can be found, and (2) superficial gangrene is present.

The following is an attempt to summarize the value of the Sanders bed in the treatment of occlusive arterial diseases of the extremities, based on the effects observed in the eighty-eight cases. We have found no contraindications to the use of this method of treatment, with the possible exception of the presence of marked infection in association with gangrene. The bed can be used for comparatively short periods, or patients can be kept on it continuously for days or weeks. In comparison with other mechanical methods of treatment of peripheral circulatory diseases, it possesses the advantage of avoiding any constriction of the leg or obstruction to the venous circulation. It can be used in conjunction with vasodilating procedures, such as artificially induced fever, drugs given by mouth, or increased environmental heat. To secure the best effects, it is necessary to vary the position and timing of the cycle in accordance with the needs of the individual patient. This form of treatment produces slight objective improvement in circulation, and slight, but incomplete, vasodilatation. Its most striking therapeutic effect appears to be the immediate relief of pretrophic pain, the pain of ischemic neuritis, and the pain of ulceration and gangrene. Relief of these types of pain is not necessarily maintained when the treatment is discontinued. The bed apparently has minimal, if any, beneficial effects on the pain which causes intermittent claudication. It constitutes a valuable addition to the armamentarium for the treatment of peripheral arterial diseases, but it should not supplant other methods of treatment.

Nicotinic acid, in doses of 1.5 to 6 gm. a day by mouth, has been administered to sixty-six persons with hypercholesteremia. A direct dose-response relationship was demonstrated. Eighty per cent of the fifty-one persons treated for at least one year, whose mean pretreatment value for plasma cholesterol was 327 mg. per 100 ml., had a mean value of less than 250 mg. per 100 ml. for plasma cholesterol during the three month interval of optimal response. The hypocholesteremic effect of nicotinic acid was sustained with continued treatment and was associated with a decrease of fatty acids and of the ratio of cholesterol to phospholipid in the plasma. Although subjective improvement in respect to symptoms of coronary and peripheral arterial insufficiency was noted by many persons during treatment with nicotinic acid, objective evidence of improvement in regard to clinical signs of atherosclerosis was lacking, and death from the complications of atherosclerosis occurred in eleven persons during or after treatment. Side effects, particularly gastrointestinal irritation and cutaneous flushing, abnormal results in tests of hepatic function and carbohydrate tolerance, occurrence of hyperuricemia and, more rarely, of jaundice, have been associated with use of large doses of nicotinic acid. The mechanism by which this substance decreases plasma lipids or causes many of the side effects noted is unknown. The continued careful use of this agent in the investigative treatment of hypercholesteremia is warranted and may ultimately provide insight into the possible value of lowering elevated levels of cholesterol in the blood as a means of treatment or prevention of atherosclerosis.

Dicumarol is a potent and valuable anticoagulant drug. When used properly it appears to prevent intravascular thrombosis in almost all patients. There is considerable and unpredictable variation in sensitivity to dicumarol among different patients. Dosage of dicumarol must be guided by the effect produced in each patient as indicated by the degree and duration of prothrombin deficiency which develops and is indicated by determinations of the concentration of prothrombin in the blood. It is unwise to use dicumarol unless adequate facilities for determining the prothrombin time are available. If the prothrombin is kept between 10 and 30 per cent of normal by administration of dicumarol, thrombosis will almost certainly be prevented and serious bleeding is very unlikely to occur. The action of dicumarol is delayed. When a rapid anticoagulant effect is desired concurrent heparinization is necessary for the first few days. We have found that dicumarol has prevented fatal pulmonary embolism and recurrence or extension of venous thrombosis in patients who have had postoperative nonfatal pulmonary embolism or thrombophlebitis. There is some incomplete evidence to the effect that it will prevent peripheral thrombosis, pulmonary embolism and further coronary thrombosis in patients who have had acute myocardial infarction. Dicumarol with preliminary heparinization is valuable in the treatment of acute arterial occlusion of the extremities. It has also been used safely in patients in whom thrombophlebitis and pulmonary embolism complicated the puerperium and various diseases, in patients with idiopathic recurrent thrombophlebitis and in those with chronic occlusive arterial disease. While statistical confirmation is lacking, it is our impression that in many of these patients thrombosis and embolism have been prevented by administration of dicumarol.

The anticoagulant drugs, heparin and dicumarol, have been of great value in the prevrention and treatment of peripheral thromboembolic disease. The use of both drugs requires individualization of dosage based on the results of the appropriate tests of their effect on coagulation. The risk of bleeding is very small if heparin and dicumarol are properly used. New anticoagulant drugs are being studied and evaluated clinically in an effort to increase even further the effectiveness and safety of anticoagulant therapy.

The deficiency in the conversion of prothrombin to thrombin which develops after administration of dicumarol appears to be due largely to decreased cothromboplastin activity. Both the development of this deficiency and the recovery from it tend to precede the accompanying changes in prothrombin itself, as measured by the two-stage method. In terms of deviation from normal, the deficiency in conversion often exceeds in magnitude the deficiency of prothrombin itself.

Summary No satisfactory routine procedure has been devised for the prevention of postoperative thrombophlebitis. Certain measures have been discussed which will help to minimize the three essential factors of local vein injury, slowing of venous blood flow and alteration in the coagulability of the blood. Postoperative thrombophlebitis Inay be successfully treated in the acute stage by adequate elevation of the limb and the use of extensive hot wet packs locally. It is advisable to get the patient up as soon as the temperature has been normal for three days, swelling below the knee has subsided and local tenderness in the involved veins has disappeared. As soon as the patient is out of bed it is necessary to equip him with an adequate leg support and for this a heavy pure rubber bandage is recommended. The bandage can usually be discarded in from three to twelve months without the subsequent appearance of any signs or sy-nlptoms of chronic venous insufficiency. Once the clinical picture of acute postoperative femoral or iliac thrombophlebitis has appeared, the danger of fatal pulmonary embolism is small.

Cerebral infaretion currently is the third leading cause of death in the United States. Since atherosclerosis of the cerebral arteries is the basis for the majority of strokes, the authors undertook to define more accurately the distribution of such atherosclerosis, its relation to coronary atherosclerosis, and its relation to such other factors as hypertension, obesity, and cerebral infarction. The results of their study are presented here.

The pathogenesis of intravascular thrombosis involves 1 or a combination of 3 factors: an endothelial lesion, a disturbance of blood flow, and hypercoagulability of the blood. The fate of fresh thrombi is probably dependent on the fibrinolytic activity of the plasma. While some tests for coagulation factors have given some positive results among patients with various types of thrombosis, no test has consistently demonstrated its value in predicting a thrombosing tendency. Carefully administered anticoagulant therapy has been effective in the prevention of thrombosis in many patients. Such therapy requires individualization on the basis of frequent laboratory tests and is usually justified only after the patient has suffered one or more episodes of clinical thrombosis. Treatment of acute thrombosis by intravascular injections of fibrinolysins is still in the experimental stage. Recent advances in surgical technic have led to successful restoration of continuity of some of the large arteries previously occluded by thrombosis.

SummaryThis study indicates that protamine sulfate is an active antagonist of paritol in the human subject. Larger doses than those used in neutralizing the effect of heparin are required to counteract the defect produced by paritol. Large amounts of protamine sulfate may produce toxic symptoms and therefore should be used with caution.

The coagulation time of 1 c.c. of venous blood placed in a 10 by 75 mm. Wassermann-type glass tube and inverted every thirty seconds has been obtained on fifty control subjects and seventy patients before and after the intravenous injection of 25 mg. of heparin in 2.5 c.c. of liquid. The results of the determinations of coagulation time on samples of venous blood withdrawn at ten-minute intervals for variable periods indicated that the maximal response to the intravenous injection of heparin occurred ten minutes after injection. Of the individuals without evidence of intravascular thrombosis, including the control subjects, 5 per cent were hyper-reactors; 88 per cent, normal reactors; 7 per cent hyporeactors, and none were nonreactors. Of the individuals with evidence of intravascular thrombosis (categories 1 to 4 in Table III), none were hyper-reactors, 31 per cent were normal reactors, 30 per cent were hyporeactors and 39 per cent were nonreactors.

In 10 patients with hypercholesteremia who were not restricted in amount or type of dietary fat, treatment with large oral doses of nicotinic acid (niacin) was more effective in lowering plasma cholesterol than was that with either safflower oil or sitosterol. The simultaneous administration of niacin and sitosterol was more effective than the use of either agent alone, and their combined effects were nearly additive. As compared with safflower oil or sitosterol in the treatment of hypercholesteremia, niacin has several practical advantages in that the drug is inexpensive, is simple to administer, and does not require alterations in the patient's dietary habits. However, the safety of such long-term use of niacin must be established before this form of therapy can be regarded as other than an investigational procedure.

The experiments of Goldblatt 1 and others 2 who have shown that hypertension may be produced in dogs by partial constriction of the renal arteries by means of metal clamps have stimulated a more careful search for primary localized renal disease, particularly chronic pyelonephritis, in human beings with so-called essential hypertension. Although there is no evidence of chronic pyelonephritis in the majority of cases of essential hypertension, several investigators (Longcope, 3 Butler 4 and Weiss and Parker 5 ) have felt that the association of these conditions was frequent enough to be more than incidental. Butler has reported a case in which hypertension was associated with unilateral chronic pyelonephritis in a child aged 7 years. Surgical removal of the affected kidney was followed by return of blood pressure to normal; the pressure had remained normal for twenty months at the time of Butler's report. Barney and Suby 6 have reported a

Excerpt In the past two years two patients have been observed at the clinic who presented the clinical picture of occlusive arterial disease of the legs, xanthoma tuberosum of the skin and marked l...

The 5-year survival rate for 422 patients having chronic atherosclerotic occlusive disease of the femoral artery was 54 per cent for the diabetic patients and 75 per cent for the nondiabetic. Ischemic ulceration without gangrene occurred in 12 per cent of the diabetic and in 5 per cent of the nondiabetic group; gangrene had developed in 40 per cent of the diabetic and in 9 per cent of the nondiabetic. Intermittent claudication was the predominant symptom on initial examination. Amputation was required in 27 per cent of the diabetic but in only 7 per cent of the nondiabetic patients.

In spite of warnings by Buerger, 1 Brown, 2 Allen and others, the vulnerability of the toes of patients with peripheral occlusive arterial disease has not been sufficiently emphasized. At the Mayo Clinic, approximately 20 per cent of such patients have definite gangrene of the toes or feet on admission. In a series of 171 consecutive cases of thrombo-angiitis obliterans in which the patients when first seen had definite gangrene of the toes or feet, ninety-four patients (55 per cent) stated that the gangrene had occurred spontaneously, and seventeen (10 per cent) stated that it had followed accidental, mechanical or thermal trauma; on the other hand, sixty (35 per cent) stated that it had followed therapeutic procedures instituted for painful toes or feet when gangrene or ulceration had not previously been present. These figures are still more appalling when it is added that thirty-two, or more than 50 per cent

There is a group of diseases which involve primarily the legs, characterized by the presence of nodules and sometimes by ulceration and which are associated with varying degrees of involvement of the blood vessels and fibrosis. These diseases, which have many features in common, are nodular vasculitis, erythema induratum, erythrocyanosis and pernio, erythema nodosum, panniculitis, recurrent idiopathic thrombophlebitis, and indurated cellulitis and ulceration secondary to chronic venous stasis. Our especial interest in these diseases was aroused because they have certain clinical features in common which often make a differential diagnosis difficult or impossible on clinical grounds alone. Likewise it is difficult to correlate the vascular involvement, which may be of varying degree and sometimes of different types in each disease with the clinical findings. Furthermore, histopathologic studies of tissue excised from the nodules and ulcers have not simplified the problem, especially as to the etiologic relationship of tuberculosis in some

Bishydroxycoumarin (dicumarol®) has been used clinically as an anticoagulant for 10 years. 1 Recently two other coumarin compounds, ethyl biscoumacetate (tromexan®) 2 and 4-hydroxycoumarin anticoagulant No. 63 3 (hereafter in this paper designated as anticoagulant No. 63), have been investigated experimentally and clinically with the hope that they might have advantages over bishydroxycoumarin for clinical use in anticoagulant therapy (Fig. 1). Like bishydroxycoumarin, these two coumarin compounds induce hypoprothrombinemia, which is defined for this paper as that coagulation defect indicated by prolongation of the one-stage prothrombin time. Also, as is the case with bishydroxycoumarin, other effects or untoward reactions not related to the coagulation defect have not been noted, except for rare mild allergic reactions and occasional mild gastrointestinal irritation. It is well known that the response of the one-stage prothrombin time varies greatly among different patients who receive certain fixed doses of bishydroxycoumarin. Body weight, nutritional status, gastrointestinal disease

Excerpt For many years physicians who have been particularly interested in vascular diseases have had a definite clinical impression that the smoking of tobacco, and particularly of cigarettes, has...