Malignant eccrine neoplasms of the foot.

Eccrine cancers are uncommon, but potentially recurrent, metastatic and fatal. Rarely, they are primary foot lesions. The literature records 46 foot cases, with age and sex given for 41. Various eccrine cancer types (most on the sole), affected all races, males predominating. Average age at diagnosis was approximately 55. A podiatric facility recorded eight cases among approximately 30,000 skin biopsies, during 15 years. Seven arose in women. Five arose in the great toe area. Three are porocarcinomas. Five are "adenocarcinomas" varying in degree of differentiation. None of the eight patients presented recurrence or metastasis during follow-up 0.5-13.4 years. Of the combined 49 literature and podiatric cases, 28 (57.1%) arose in men, mostly between ages 41 and 70. Most were slow growing, long standing, and mildly symptomatic. No clinical features distinguished eccrine cancers from other pedal tumors.

Lovastatin and the human lens; results of a two year study. The MSDRL Study Group.

Lovastatin has been associated with development of subcapsular cataract in dogs given high doses. To test the cataractogenic potential of lovastatin in humans, 192 patients were divided into 2 groups, A (N = 94) and B (N = 98), 1 taking 40 mg/day of lovastatin and 1 taking placebo. Both groups were enrolled for 2 years in this double-blind, randomized study and were followed with eye examinations including assessment of visual function, Lens Opacities Classification System II (LOCS II) cataract and nuclear color classification, and computerized lens image analysis. There were no statistically significant differences in visual function between the two groups. Similarly, cataract progression, assessed by LOCS II measurement and by computerized measurements of cataract, showed no important differences between the treatment groups. These data show no cataractogenic effect of lovastatin in humans.

Efficacy and tolerability of lovastatin in 3390 women with moderate hypercholesterolemia.

OBJECTIVE: To evaluate the efficacy and safety of lovastatin in women with moderate hypercholesterolemia. DESIGN: The Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, in which participants were randomly assigned to receive placebo or lovastatin at doses of 20 or 40 mg once daily, or 20 or 40 mg twice daily for 48 weeks. SETTING: Ambulatory patients recruited by 362 participating centers throughout the United States. PATIENTS: Women (n = 3390) from the total cohort of 8245 volunteers. MEASUREMENTS: Plasma total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, and triglycerides; and laboratory and clinical evidence of adverse events monitored periodically throughout the study. RESULTS: Among women, lovastatin (20 to 80 mg/d) produced sustained (12- to 48-week), dose-related changes (P < 0.001): decreases in LDL cholesterol (24% to 40%) and triglycerides (9% to 18%), and increases in HDL cholesterol (6.7% to 8.6%). Depending on the dose, from 82% to 95% of lovastatin-treated women achieved the National Cholesterol Education Program goal of LDL cholesterol levels less than 4.14 mmol/L (160 mg/dL), and 40% to 87% achieved the goal of 3.36 mmol/L (130 mg/dL). Successive transaminase elevations greater than three times the upper limit of normal occurred in 0.1% of women and were dose dependent above the 20-mg dose. Myopathy, defined as muscle symptoms with creatine kinase elevations greater than 10 times the upper limit of normal, was rare and associated with the highest recommended daily dose of lovastatin (80 mg). Estrogen-replacement therapy appeared to have no effect on either the efficacy or safety profile of lovastatin. CONCLUSION: Lovastatin is highly effective and generally well tolerated as therapy for primary hypercholesterolemia in women.

Comparative effects of simvastatin and lovastatin in patients with hypercholesterolemia. The Simvastatin and Lovastatin Multicenter Study Participants.

The efficacy, safety profile, and tolerability of the HMG-CoA reductase inhibitors simvastatin and lovastatin were compared in a multicenter, randomized, double-blind study in patients with moderate hypercholesterolemia. Commonly prescribed doses of these two drugs were used by 544 men and women, who followed an American Heart Association phase I diet during a 6-week baseline period and for the 24 weeks of active treatment. Simvastatin 10 mg and lovastatin 20 mg produced statistically significant reductions in total and low-density lipoprotein cholesterol (LDL-C). Patients receiving simvastatin 10 mg once daily and lovastatin 20 mg once daily experienced similar reductions in LDL-C and total cholesterol; however, simvastatin 20 mg was statistically superior to lovastatin 40 mg in decreasing these lipid fractions. For all treatment groups, increases in high-density lipoprotein cholesterol were inversely related to baseline levels. Moderate decreases in triglycerides occurred with all doses. Lipoprotein(a) levels, measured in a subset of patients, were similar before and after treatment. Both drugs were well tolerated.

The case for unstable angina pectoris as a primary end point in primary prevention studies.

Coronary artery disease (CAD) primary end point definitions used in previous prevention trials are reviewed, as well as trends over time for CAD mortality, incidence and hospital discharges to see if new primary end points should be considered. CAD mortality has shown a dramatic decline in the U.S. in the last 20 years, whereas the decrease in the incidence of acute myocardial infarction (AMI) is less consistent. The decline in CAD incidence and mortality has been attributed to changes in lifestyle and increased medical/surgical intervention. Hospital discharge rates for CAD have risen during the past decade. In addition, although the rate of discharge for AMI appears to have stabilized, the rates for angina, and more dramatically for unstable angina, have increased. Unstable angina made up 4% of CAD discharges in 1980, and increased to 25% of CAD discharges in 1989. Because of these trends, future trials that rely solely on AMI as a primary end point will not reflect the actual experience with CAD presentation in the U.S. Given the greater availability of methods to diagnose unstable angina more accurately, and because of its high risk pathology, it is concluded that unstable angina should receive serious consideration as a primary end point in future primary prevention trials.

[Extended worldwide experience. HMG-CoA reductase inhibitors: lovastatin and simvastatin]. / Expérience étendue au monde entier. Les inhibiteurs de l'HMG-CoA réductase: lovastatine et simvastatine.

Lovastatin and simvastatin are the first licensed compounds of a potent new class of lipid lowering drugs whose mechanism of action is to inhibit HMG-CoA reductase, a rate-limiting enzyme in the cholesterol biosynthetic pathway in the liver. Inhibition of cholesterol synthesis leads to upregulation of LDL-receptors in the liver and subsequent increased LDL clearance. Both agents are pro-drugs (lactones) which undergo extensive first-pass hepatic metabolism to the beta-hydroxyl acid form. These drugs are liver specific and have low systemic exposure as open-acid forms (plasma concentration < 5% of oral dose). Thus, theoretically both drugs have low potential for systemic adverse events. They are potent and effective agents for the treatment of primary hypercholesterolemia. The adverse experiences reported for both drugs demonstrate an excellent safety profile.

Extended clinical safety profile of lovastatin.

Lovastatin has been available for prescription use in the United States for about 20 months (as of June 1989). Over 1 million patients have received the prescription drug, and approximately 14,000 patients have participated in clinical trials. It is estimated that 500,000 patients have received lovastatin continuously for at least 1 year. This report reviews the extended safety experience from all clinical trials and prescription use. At least 645 patients have received lovastatin for more than 3 years. There are new data from a recently completed 1 year, placebo-controlled trial in 8,245 patients (Expanded Clinical Evaluation of Lovastatin study) and 20 months of health professionals' reports on spontaneous adverse events associated with large prescription usage. Data from recent large clinical trials suggest that the risk of myopathy and asymptomatic sustained liver transaminase elevations is less than reported in prior studies. The early clinical trials enrolled very high risk patients receiving lovastatin at a usual dose of 80 mg/day and often receiving concomitant hypolipidemic agents including gemfibrozil and niacin. After more than 42 months' long-term clinical trial experience, data have not established adverse effects from lovastatin on the human lens. Possible new types of rare drug-related adverse events observed with large prescription use include hypersensitivity reactions such as arthralgia, thrombocytopenia, symptomatic hepatitis and interaction with warfarin. No new, unique adverse-event profile has emerged with extended clinical use, including use in a few patients who have received therapy for more than 5 years. The lovastatin extended safety profile is that of a generally well-tolerated drug.

Clinical experience with lovastatin.

New information on the tolerability of lovastatin has emerged from an ongoing study of long-term therapy; preliminary results from a large, 48-week clinical trial; and spontaneous reports of adverse events observed during prescription use of the drug in the United States. As of June 1989, 744 patients had received lovastatin for an average duration of 3.6 years in the long-term study. Drug-attributable adverse events necessitated withdrawal of 17 patients (2.3%) from the study. These adverse effects were asymptomatic elevations of transaminases (10), skin rash (3), gastrointestinal symptoms (2), myopathy (1) and insomnia (1). No effect of lovastatin on the human lens was observed. In the 48-week study, 8,245 patients were randomized into 5 equal groups to receive placebo or lovastatin 20 or 40 mg once or twice daily on a double-blind basis. Only 3 cases of myopathy were observed, all in patients taking lovastatin 40 mg twice daily. The incidence of withdrawal from the study because of raised transaminases was approximately 0.1% in the placebo group vs 0.1, 0.7, 0.6 and 1.5% in patients taking lovastatin in doses of 20 mg once daily, 40 mg once daily, 20 mg twice daily and 40 mg twice daily, respectively. Lovastatin has been available in the United States since September 1987. By June 1989, the drug had been prescribed for approximately 1 million patients. Drug-attributable adverse events not observed in clinical trials (such as hypersensitivity reactions and symptomatic hepatitis) have been reported, but the incidence of each appears to be extremely low.

Effects of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia. Multicenter Group I.

Simvastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was compared with cholestyramine resin in a randomized open-label 12-week multicenter study of 251 high-risk patients with familial or nonfamilial hypercholesterolemia. Simvastatin, 20 mg and 40 mg daily, produced mean reductions in total cholesterol of 26% and 33%, respectively, and reductions in low-density lipoprotein cholesterol level of 32% and 40%. Cholestyramine resin, 4 to 12 g twice daily, reduced total cholesterol and low-density lipoprotein cholesterol levels 15% and 21%, respectively. High-density lipoprotein cholesterol levels were increased 8% to 10% by all treatments. Plasma triglyceride levels were moderately decreased by simvastatin treatment, while triglyceride levels increased with cholestyramine treatment. Simvastatin was better tolerated than cholestyramine, which had numerous gastrointestinal tract side effects. No patient had a serious drug-related adverse event.

Effects of simvastatin and probucol in hypercholesterolemia (Simvastatin Multicenter Study Group II).

This 12-week, randomized, double-blind, multicenter study compared the efficacy, tolerability and safety of simvastatin (a potent HMG-CoA reductase inhibitor) and probucol. Two doses of simvastatin, 20 or 40 mg once daily, were compared to probucol, 500 mg twice daily. Both simvastatin doses were significantly more effective than probucol in improving the plasma lipid profile. Mean reduction in low density lipoprotein (LDL) cholesterol was 34% with 20-mg simvastatin and 40% with the 40-mg dosage, compared to a mean reduction of 8% with probucol. Simvastatin significantly decreased total cholesterol, triglycerides and apolipo-protein B, and increased high density lipoprotein (HDL) cholesterol and apolipoprotein A-I. Probucol caused some reduction in LDL cholesterol but significantly decreased HDL cholesterol. Both simvastatin and probucol were well tolerated and no serious drug-related events occurred. Simvastatin appears to be a well-tolerated and effective new agent used once-a-day as an adjunct to diet in the management of patients with hypercholesterolemia.

Lipid lowering drugs in atherosclerosis--the HMG-CoA reductase inhibitors.

Arteriosclerosis, particularly coronary heart disease, is the leading cause of morbidity and mortality in many areas of the world. Elevated cholesterol, particularly LDL-cholesterol, has been shown to be one of the major modifiable factors in reducing coronary events. Standard hypolipidemic therapies include resin, fibrates and niacin. This review emphasizes a significant new therapeutic class of hypolipidemic agents, namely the HMG-CoA reductase inhibitors. These are potent cholesterol lowering agents. Lovastatin is the first agent of this class to receive clinical approval in the U.S.A. Simvastatin, an analog of lovastatin, is also approved in several countries. Both these agents are administered as lactones and hydrolyzed to the open acid forms. Another HMG-CoA reductase inhibitor pravastatin has recently been filed for registration in several countries. A fourth compound (SRI-62-320) which is currently in clinical investigation is a totally synthetic structure. If long-term safety remains good and clinical efficacy as demonstrated by reduction of cardiovascular events is proven, the HMG-CoA reductase class of agents will be a significant advance in the treatment of cardiovascular disease.

The effect of various dose regimens of famotidine on basal nocturnal and meal-stimulated gastric secretion.

The antisecretory profile of the H2-receptor antagonist famotidine was studied with various oral doses and regimens in 10 healthy volunteers with high basal acid output (greater than or equal to 5 mEq/hr). Doses included 10, 20, and 40 mg at 9 PM and 9 AM and also 40 mg at 9 PM only. In the 22 hours after the PM doses, overnight (midnight to 7 AM) basal acid secretion was evaluated. Daytime meal-stimulated secretion was assessed at 7 AM, 12 noon, and 5 PM. Doses of 10, 20, and 40 mg inhibited fasting nocturnal basal secretion by 69%, 86%, and 83% to 94%, respectively (P less than 0.01). Meal-stimulated secretion at 7 AM (10 hours after administration) was inhibited by 28% and 39% (P less than 0.01) by only the 40 mg doses. The response to the 12 noon meal was inhibited by the 9 AM doses of 10, 20, and 40 mg by 45%, 75%, and 85%, respectively (P less than 0.01). The effect of a 40 mg dose given at 9 PM only had dissipated by breakfast (7 AM). The response to the 5 PM meal was suppressed by the 20 and 40 mg doses given at 9 AM by 22% and 35%, respectively (P less than 0.05). Suppression was present in only eight of the subjects after the 20 mg dose but in all 10 after the 40 mg dose. The effect on basal gastric aspirate pH values paralleled those seen on acid output. An association was found between mean plasma concentrations of famotidine and mean inhibition of meal-stimulated acid secretion. However, individual values may not be predictive.

A multicenter, double-blind, randomized, placebo-controlled comparison of nocturnal and twice-a-day famotidine in the treatment of active duodenal ulcer disease.

The efficacy and safety of famotidine, a potent new long-acting H2-receptor antagonist, was compared with placebo in a multicenter, double-blind, randomized, placebo-controlled study in the United States. A total of 384 patients with endoscopically proven acute duodenal ulcer disease were enrolled. Patients received either famotidine or a placebo. The patients receiving famotidine were treated with one of three dose regimens, 40 mg h.s., 40 mg b.i.d., or 20 mg b.i.d. Patients were reassessed by endoscopy at 2, 4, and 8 wk if ulcer healing had not occurred sooner. A diary was kept to record the duration and intensity of the day and night pain and the amount of Gelusil antacid (Parke-Davis, Morris Plains, N.J.) ingested. Three hundred sixty-three patients met the evaluation criteria. The results revealed a 4-wk healing rate of 70%, 75%, 67%, and 31% for the famotidine 40 mg h.s., 40 mg b.i.d., 20 mg b.i.d., and placebo groups, respectively. The 8-wk healing rates for the same respective groups were 83%, 82%, 82%, 45%. Ulcer pain and antacid consumption occurred less often in the famotidine groups. The clinical and laboratory safety profile of the famotidine groups was similar to that of the placebo group. Famotidine appears to be an effective and safe once-a-day therapy for the treatment of acute duodenal ulcer disease. The recommended dosage is 40 mg h.s.

Maintenance therapy of duodenal ulcer with famotidine. A multicenter United States study.

The decision to treat a patient with duodenal ulcer should be based upon the following: severity of disease; effectiveness of treatment; and risk and cost of treatment. A number of drugs are effective for this condition. When administration of the drug is discontinued, a recurrence of the ulcer occurs most often within three months, with the rate approaching 90 percent at one year. Maintenance therapy has evolved as a method of preventing recurrence. A double-blind, randomized, multicenter study was done to compare 40 mg of famotidine at bedtime, 20 mg of famotidine at bedtime, and placebo in the maintenance treatment of patients with recently healed duodenal ulcer. In 37 centers in the United States, 303 patients received randomly allocated treatment with 40 mg of famotidine at bedtime (107 patients), 20 mg of famotidine at bedtime (97 patients), or placebo (99 patients). The treatment groups were comparable as to the risk factors and other characteristics. Esophagogastroduodenoscopies were scheduled at three, six, and 12 months of treatment. Additional endoscopies could be done at any time if symptoms suggested a relapse. Cumulative relapse rates were significantly lower in the famotidine groups than in the placebo group at all time points (p less than 0.01). The cumulative life-table relapse rates at three, six, and 12 months were 9.2, 20.9, and 24.8 percent for the 40-mg famotidine group; 13.5, 16.1, and 23.3 percent for the 20-mg famotidine group; and 39.3, 51.5, and 56.8 percent for the placebo group. No significant difference between the two famotidine groups was observed. Within each period, the relapse rate was lower with famotidine than with placebo. Famotidine is more effective than placebo as maintenance therapy. It is generally well tolerated for periods of up to one year. A dose of 20 mg at bedtime is proposed as the maintenance dose. Fewer relapses occurred in non-smokers, in females, and in patients in whom healing occurred with placebo. More relapses occurred in patients under 40 years of age, patients with a long ulcer history, or patients who were younger than 40 years of age at onset of ulcer disease.

The effect of eugenol on oral mucous membranes.

Eugenol, in the 100 percent concentration in commercial use, was applied to a circumscribed area, 3 mm in diameter, of rat labial mucosa for 1 minute. Reaction periods of 15 minutes, 1, 2, 4 and 6 hours were then permitted. Using routine histological procedures for processing the experimental tissues, it was observed that eugenol caused denaturation of cytoplasmic proteins and loss of staining capacity of epithelium, loss of cell boundaries, swelling and cell necrosis. In addition, vesicle formation, edema in the corium, and striated muscle dissolution were observed.