Danazol, an androgen derivative, was evaluated for its effectiveness in preventing attacks of hereditary angioedema in a double-blind study with nine patients. Of 47 placebo courses, 44 ended with attacks, but during 46 danazol courses only one attack occurred. Side effects were minimal, and virilization was not observed in the women studied. C1 esterase inhibitor levels increased three to four times, and levels of the fourth component of complement (C4) increased 15 times. These changes began during the first day of therapy and were maximal by one to two weeks. After therapy was stopped, C1 esterase inhibitor and C4 levels rapidly decreased. Danazol effectively prevents attacks in hereditary angioedema and acts to correct the underlying biochemical abnormality.

Two types of surgical therapy of bleeding esophageal varices were evaluated in 48 patients by a randomized controlled trial: 24 were randomized for a total shunt and 24 for the selective shunt. In two of the latter, a total shunt had to be performed for technical reasons. The fatality rates (six in the 24 total, and six in 22 selective [performed], and seven in 24 selective [randomized]), the frequency of shunt occlusion (two in each group), and of recurrent gastronintestinal bleeding (three in each group) were similar. Encephalopathy developed more often after a total shunt -- 10 of 24, or one per 58 patient-months -- than after selective (performed) -- one of 22, or one per 593 patient-months (P less than 0.005). Total shunts consistently diverted the hepatopetal mesenteric-portal flow from the liver. Deterioration of hepatic function (maximum rate of urea synthesis) was greater after total than selective shunt (P less than 0.05).

To determine whether intravenous 3.5 per cent amino acid solution enhanced the rate of albumin synthesis in postoperative patients, we measured the albumin synthesis rate by the (14C) carbonate technic in 10 patients on the fourth day after elective gastrointestinal-tract operations. Five patients were randomized to receive a 3.5 per cent solution of essential and non-essential amino acids, and five to receive 5 per cent glucose. A mean (+/-S.E.M.) of 75.0+/-2.0 per day of amino acids or 111.0+/-12.4 glucose was given. In the amino acid group the mean (+/-S.E.M.) albumin synthesis rate was 237+/-24 mg per kilogram per day, in comparison to 157+/-23 in the glucose group (P less than 0.05). The infused amino acids were apparently more effective than plain glucose in promoting albumin synthesis.

To evaluate earlier observations, including our own, showing usefulness of vitamin C for managing the common cold, we performed a double-blind trial of vitamin C versus placebo in 868 children. There was no difference in number becoming ill (133 versus 129), number of episodes (166 versus 159) or mean illness duration (5.5 versus 5.8 days) between the groups. Children receiving vitamin C had fewer throat cultures yielding beta-hemolytic streptococcus (six versus 13, P less than 0.10), but no difference in overall complicated illness rate (24 versus 25). Plasma ascorbic acid levels were higher in the vitamin group 24 to 26 hours after supplementation (1.28 versus 1.04 mg per 100 ml, P less than 0.01). Children with high plasma ascorbic acid concentrations had longer mean illness (6.8 versus 4.0 days, P less than 0.05) than those with low levels. Vitamin C does not seem to be an effective prophylactic or therapeutic agent for upper respiratory illness.

Chlorambucil, in combination with prednisone, was compared with prednisone alone in a randomized controlled trial in 21 children with either steroid-dependent or frequently relapsing nephrotic syndrome to assess its effect on the duration of remission and the rate of relapse. All control patients treated with prednisone alone continued to relapse at the same rate, with all patients experiencing a return of proteinuria by seven months. Conversely, those who received the same prednisone therapy along with chlorambucil for six to 12 weeks remained in complete remission, without further medication, during 12 to 34 months of follow-up observation. Complications were minimal. Immediate side effects commonly reported with cyclophosphamide were not seen with chlorambucil. Comparison with published reports also suggests that remission induced by chlorambucil is more stable than that after cyclophosphamide. Chlorambucil appears to be of value in the frequently relapsing nephrotic patient, adding an effect that is unattainable with prednisone alone.

In spite of the controversy over the role of randomized clinical trials in medical research, the rationale underlying such trials remains persuasive as compared to recent suggestions for alternative non-randomized studies such as those relying on the use of historical controls and adjustment technics. Others have suggested that recent statistical innovations for improving clinical trials, including adaptive allocation of treatment to patients and sequential stopping procedures, are underutilized. These innovations, though theoretically interesting, are not easily adapted to large-scale, complex medical trials in which there may be multiple end points and delayed response times. Ethical considerations suggest that randomized trials are more suitable than uncontrolled experimentation in protecting the interests of patients. Randomized clinical trials remain the most reliable method for evaluating the efficacy of therapies.

We studied the antihypertensive effect of propranolol alone and in combination with diuretics in 13 patients with high, 18 with normal and nine with low-renin essential hypertension whose blood-pressure response to diuretics was previously established. Propranolol (160 mg daily) significantly lowered mean arterial pressure in high-renin (129 +/- 2.6 to 114 +/- 2.1 mm Hg) and normal-renin (131 +/- 2.7 to 119 +/- 3.5 mm Hg) patients but not in low-renin patients. A positive correlation (r = 0.36, P less than 0.05) between fall in pressure and fall in plasma renin activity occurred at this dose when the whole group was considered. An antihypertensive effect occurred in both high-renin and low-renin hypertension during large-dose (320 to 960 mg daily) propranolol therapy. This effect was independent of changes in plasma renin activity. The antihypertensive effects of propranolol and diuretics were additive in normal-renin and high-renin hypertension. These data suggest that propranolol's pressure-lowering activity is due to both renin-dependent and renin-independent effects.