In a randomized, prospective trial of 100 patients, we have studied the safety and efficacy of warfarin sodium in comparison with that of dextran 40 in the prevention of venous thrombosis in patients at high risk for deep vein thrombosis after elective total hip or knee replacement. Warfarin was given in a new two-step regimen designed to avoid bleeding complications while still preventing venous thrombosis. A low dose of warfarin was started ten to 14 days preoperatively, and the prothrombin time was regulated to between 1.5 and 3 seconds longer than control at the time of surgery; immediately after surgery, the dose was increased to prolong the prothrombin time to 1.5 times control. The overall incidence of venous thrombosis as documented by venography was less in the 53 patients treated with warfarin than in the 37 treated with dextran (21% v 51%), as was the incidence of thrombi in the femoral or popliteal veins (2% v 16%). Objective measures of blood loss showed no difference between patients treated with warfarin or dextran, and excessive postoperative bleeding was infrequent and similar in both treatment groups. This study demonstrates that two-step warfarin therapy provides highly effective prophylaxis of postoperative venous thrombosis after elective hip or knee prosthetic surgery without excessive risk of perioperative bleeding.

The effects of amiloride hydrochloride on thiazide-induced hypokalemia were evaluated. In metabolic balance studies, amiloride reversed thiazide-induced urinary potassium loss, restored plasma bicarbonate concentration and pH to pretreatment levels, and produced further increases in aldosterone secretion. Effects of long-term administration of hydrochlorothiazide and an amiloride-hydrochlorothiazide combination were compared in outpatients who had experienced thiazide-induced hypokalemia while receiving oral potassium supplements. After eight weeks, those given hydrochlorothiazide alone had an average serum potassium level of 3.01 +/- 0.08 mEq/L). Those given the amiloride-hydrochlorothiazide combination had an average serum potassium level of 3.75 +/- 0.008 mEq/L, not significantly different from the control value (3.82 +/- 0.08 mEq/L). Both groups had increased plasma aldosterone concentrations and plasma renin activity. The potassium-conserving effect of amiloride persisted with extended therapy.

To evaluate the short-term effects of an intervention that consists of stress management training and dietary changes in patients with ischemic heart disease (IHD), we compared the cardiovascular status of 23 patients who received this intervention with a randomized control group of 23 patient who did not. After 24 days, patients in the experimental group demonstrated a 44% mean increase in duration of exercise, a 55% mean increase in total work performed, somewhat improved left ventricular regional wall motion during peak exercise, and a net change in the left ventricular ejection fraction from rest to maximum exercise of +6.4%. Also, we measured a 20.5% mean decrease in plasma cholesterol levels and a 91.0% mean reduction in frequency of anginal episodes. In this selected sample, short-term improvements in cardiovascular status seem to result from these adjuncts to conventional treatments of IHD.

Over a 21-month interval, we investigated the effectiveness of immunoglobulin (lg) in preventing hepatitis A spread in day-care centers. Immunoglobulin was given to all center and employees whenever hepatitis occurred in one center child or employee or parents in two families. Immunoglobulin programs were completed in 91 centers during the trial within an average of 17 days of onset of illness in the index case. Immunoglobulin intervention caused significant reduction in the average size of a day-care hepatitis outbreaks, from 7.3 cases in historically untreated centers to 6.0 cases in Ig-treated centers. Cases in center children and employees virtually ceased two weeks after Ig intervention, while those in household contacts decreased significantly within six weeks. Reported cases of hepatitis type A or unspecified in the community decreased 75%, and the number of new hepatitis outbreaks decreased 77% during the trial. A decrease occurred not only in day-care-associated cases, but in cases not directly associated with centers, probably due to decreased tertiary spread from day-care families into the community. Use of Ig to prevent hepatitis spread in day-care centers seems to be an excellent means of controlling this disease, both within the centers and the general community.

Reserpine in different doses was assigned in random, double-blind fashion to 329 patients with mild to moderate hypertension who had not achieved normotension with chlorthalidone therapy alone. The additional reduction of BP averaged 11.0/10.4 mm Hg with chlorthalidone, 50 mg, plus reserpine, 0.25 mg (C 50+R 0.25); 9.5/9.4 mm Hg with C 50+R 0.125; 6.4/8.5 mm Hg with C 50+R 0.05; and 9.9/9.6 mm Hg with C 25+R 0.125. The percentage of patients in whom control was achieved at diastolic BP less than 90 mm Hg and at least 5 mm Hg below baseline with either chorthalidone alone or with reserpine added was 65% with C 50+R 0.25, 69% with C 50+R 0.125, 58% with C 50+R 0.05, and 56% with C 25+R 0.125. Side effects of lethargy and impotence noted by patients with the 0.05-mg dose of reserpine were only one third of those noted with the 0.25-mg dose, although the incidence of other side effects did not differ. These results indicate that hypertension in many persons can be controlled by less than customary doses of reserpine in combination with a diuretic.

Eighty-one patients with a variety of refractory disseminated malignant neoplasms have been treated in the first multiple fixed-dose phase I trial of recombinant leukocyte A interferon (IFL-rA). Each patient received IFL-rA by intramuscular injection, three times weekly for 28 days. Dosages were escalated in different patients from 1 to 136 x 10(6) units per injection. The toxic reactions seen with IFL-rA resembled those of nonrecombinant leukocyte interferon and included fever, chills, fatigue, anorexia, myalgia, headache, occasional nausea and vomiting, and dose-dependent reversible leukopenia and hepatic transaminase elevations. The pharmacokinetics of IFL-rA were also comparable with nonrecombinant leukocyte interferon. Objective evidence of antitumor activity was seen in non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Hodgkin's disease, breast cancer, and melanoma, indicating that IFL-rA, the first genetically engineered biological response modifier available for testing in cancer patients, is biologically active in vivo.

The analgesic efficacy of single 500- and 1,000-mg doses of diflunisal (Dolobid), a new nonsteroidal anti-inflammatory analgesic, was compared in a double-blind study with that of acetaminophen, 600 mg, the combination of acetaminophen, 600 mg, with codeine phosphate, 60 mg, and placebo in 159 oral surgery outpatients. Using a self-rating record, patients rated their pain and its relief hourly for 12 hours after medication. Both doses of diflunisal were significantly more effective than acetaminophen alone and produced peak analgesia comparable to that of the acetaminophen-codeine combination. Diflunisal proved to have an unusually long duration of analgesic action. Acetaminophen and the combination were significantly superior to placebo through hours 2 and 5, respectively; both doses of diflunisal were significantly superior through the end of the 12-hour observation period. None of the active treatments produced more side effects than the placebo.

As described in the preceding communication, either propranolol hydrochloride or hydrochlorothiazide were randomly allocated in a double-blind manner to 683 patients with initial diastolic BP in the range of 95 to 114 mm Hg. Of this number, 394 entered the long-term treatment phase. During the subsequent 12 months of long-term treatment, hydrochlorothiazide was more effective than propranolol in controlling BP (mean reductions, -17.5/-13.1 mm Hg with hydrochlorothiazide compared with -8.3/-11.3 with propranolol. After treatment with hydrochlorothiazide, a greater percentage of patients achieved the goal diastolic BP of less than 90 mm Hg (65.5% compared with 52.8% taking propranolol). Also during treatment, fewer patients receiving hydrochlorothiazide required termination as compared with those receiving propranolol; comparative dosage requirements were lower; additional titration during long-term treatment was required less often, and BP remained lower after withdrawal of the active drugs. However, biochemical abnormalities were greater with hydrochlorothiazide. Although not statistically significant, the antihypertensive effects of hydrochlorothiazide were greater in blacks than in whites. Whites, on the other hand, had a greater response to propranolol than blacks, although it was still less than the response of the whites to hydrochlorothiazide.

We compared hydrochlorothiazide and propranolol hydrochloride for monotherapy of hypertension by a double-blind study of 683 men who were titrated to less than 90 mm Hg diastolic BP or to 640 mg of propranolol or 200 mg of hydrochlorothiazide. Propranolol reduced systolic BP from 146.0 +/- 14.4 (SD) to 134.8 +/- 16.3 mm Hg and diastolic BP from 101.6 +/- 4.6 to 90.5 +/- 7.5 mm Hg. Hydrochlorothiazide lowered both systolic BP more effectively from 146.5 +/- 15.8 to 128.8 +/- 12.2 mm Hg and diastolic BP from 101.3 +/- 4.5 to 89.4 +/- 6.5 mm Hg. In blacks, hydrochlorothiazide lowered systolic BP 20.3 +/- 14.3 mm Hg v 8.2 +/- 12.2 mm Hg for propranolol; hydrochlorothiazide reduced diastolic BP 13.0 +/- 7.0 mm Hg v 9.5 +/- 7.0 for propranolol. In whites, the systolic BP reductions were 15.3 +/- 12.0 mm Hg for hydrochlorothiazide v 13.2 +/- 13.1 mmn Hg for propranolol; diastolic BPs were 10.9 +/- 5.7 mm Hg for hydrochlorothiazide and 12.6 +/- 6.6 mm Hg for propranolol. In blacks treated with hydrochlorothiazide, 71.3% achieved diastolic BP of less than 90 mm Hg, v 53.5% with propranolol. There was no racial difference in dose response to propranolol, but blacks required much less hydrochlorothiazide to achieve control. We conclude that in this short-term study propranolol was as efficacious as hydrochlorothiazide in whites, but the latter was more effective than propranolol in blacks.