In a controlled trial of streptokinase in acute myocardial infarction, 512 of 2338 patients at 11 European centers were stratified according to clinical severity. Three hundred fifteen patients allocated to medium-risk and high-risk groups were randomized to a 24-hour infusion of streptokinase or glucose. There were no essential differences in the severity of illness in the two groups before infusion. The overall mortality rates within six months were significantly lower (P less than 0.01) in the streptokinase group (15.6 per cent) than in the control group (30.6 per cent). Bleeding complications were more frequent in the streptokinase group; except for two nonfatal cerebral hemorrhages these complications were clinically unimportant. The treatment was generally well tolerated. We tolerated. We conclude that streptokinase given under the conditions of this trial -- to medium-risk patients admitted to a coronary-care unit within 12 hours of onset of symptoms -- reduces mortality at six months. (N Engl J Med 301:797-802, 1979)

Previously untreated patients with myeloma were randomized to initial treatment with melphalan and prednisone (and to cyclophosphamide or carmustine if relapse or progression occurred)(Group A, 125 patients), melphalan, cyclophosphamide, carmustine and prednisone in alternating (Group B, 123 patients) or concurrent (Group C, 116 patients) schedules. The groups were similar with respect to known prognostic factors. Response rates and survival were also similar. We were unable to identify a subgroup of patients who responded or survived better on melphalan-cyclophosphamide-carmustine and prednisone than on melphalan and prednisone. We conclude that the combination of the four drugs is not better than melphalen and prednisone for inducing responses or prolonging the survival of patients with myeloma. Myelomas producing only gamma chains have a poorer prognosis (P greater than 0.001) than IgG, IgA, or kappa myeloma. Acute leukemia has developed in 14 patients. The actuarial risk of developing acute leukemia, has increased rapidly to 17.4 per cent at 50 months.

One hundred and fifty patients with advanced cancer participated in a controlled double-blind study to evaluate the effects of high-dose vitamin C on symptoms and survival. Patients were divided randomly into a group that received vitamin C (10 g per day) and one that received a comparably flavored lactose placebo. Sixty evaluable patients received vitamin C and 63 received a placebo. Both groups were similar in age, sex, site of primary tumor, performance score, tumor grade and previous chemotherapy. The two groups showed no appreciable difference in changes in symptoms, performance status, appetite or weight. The median survival for all patients was about seven weeks, and the survival curves essentially overlapped. In this selected group of patients, we were unable to show a therapeutic benefit of high-dose vitamin C treatment.

Since platelet cyclo-oxygenase is much more sensitive to inactivation by aspirin than is the enzyme in the arterial wall and low doses of aspirin may prevent thrombosis by blocking thromboxane synthesis, we conducted a randomized, double-blind trial of aspirin (160 mg per day) vs. placebo in 44 patients on chronic hemodialysis. The study was continued until there were 24 patients with thrombi and both groups had been under observation for a mean of nearly five months. Thrombi occurred in 18 of 25 (72 per cent) of patients given placebo and 16 of 19 (32 per cent) of those given aspirin (P less than 0.01). The incidence of thrombosis was reduced from 0.46 thrombi per patient month in the placebo group to 0.16 thrombi per patient month in the aspirin group (p less than 0.005). A dose of 160 mg of aspirin per day is an effective, nontoxic antithrombotic regimen in patients on hemodialysis.

To determine whether analysis of lymphocyte surface markers adds clinically useful information to the Lukes-Collins classification of lymphomas, tumors from 107 adults were histologically classified and studied for surface markers. Ninety-six cases were histologically classified as Lukes-Collins B-cell lymphomas; 87 showed B and one showed T surface markers, whereas eight had neither marker. Eleven lymphomas were histologically T-cell tumors; four of the 11 showed T surface markers, and seven had neither marker. Both the Lukes-Collins classification and surface markers identified patient groups with different clinical characteristics, chemotherapeutic responsiveness and survival. However, by combining surface markers and histologic features, additional important therapeutic and prognostic information was obtained. In each histologic class, patients whose lymphomas failed to express immunologically the histologically predicted marker had fewer responses to chemotherapy and shorter survivals than patients whose lymphomas expressed the predicted marker. Our data suggest that the analysis of surface markers in combination with the Lukes-Collins classification identifies many patients who respond poorly to current therapy and who thus require new therapeutic approaches.

Gonococci that resist standard penicillin regimens by production of a penicillinase are now well established in certain areas of the world. Because cefoxitin, a semisynthetic cephamycin, resists gonococcal penicillinase in vitro, we compared procaine penicillin G and cefoxitin in treatment of gonorrhea in an area where 40 per cent of isolates produce penicillinase. One hundred and seven men with culture-proved gonococcal urethritis were given a single dose of either procaine penicillin G, 4.8 million U, or cefoxitin, 2 g, intramuscularly. Both groups took 1 g of probenecid orally; cefoxitin was given with lidocaine to reduce pain at the injection site. In men infected with penicillinase-negative gonococci, both cefoxitin and penicillin were highly effective. Penicillin failed in 77 per cent of men with penicillinase-positive strains, whereas cefoxitin was completely successful. Cefoxitin is an effective alternative to spectinomycin for single-session therapy of urethritis caused by penicillinase-producing Neisseria gonorrhoeae.

A double-blind crossover study of the efficacy of disodium cromoglycate given by mouth to control the cutaneous, gastrointestinal and central-nervous-system manifestations of systemic mastocytosis was carried out in five patients for periods of eight to 32 months. In 15 of 18 trials, disodium cromoglycate produced marked amelioration of the clinical manifestations of pruritus, whealing, flushing, diarrhea, abdominal pain and disorders of cognitive function. By contrast, in all 19 trials with placebo, there was no improvement in these symptoms and signs. Histaminuria and peripheral-blood eosinophilia were unrelated to disease activity and were unaffected by drug therapy. Although it is poorly absorbed after administration by mouth, disodium cromoglycate is of clinical benefit to patients with systemic mastocytosis.

Two dose levels of ticrynafen, a new uricosuric diuretic, and of hydrochlorothiazide were randomly assigned, double-blind to 240 men with initial diastolic blood pressures in the range of 95 to 114 mm Hg. A dose of 500 mg of ticrynafen once daily exerted an antihypertensive effect comparable to that of 50 or 100 mg of hydrochlorothiazide. Whereas serum uric acid levels rose in patients treated with hydrochlorothiazide, they fell markedly in those receiving ticrynafen. Otherwise, both diuretics produced similar chemical changes in serum. Patients tolerated ticrynafen as well as they did hydrochlorothiazide over a period of six months of observation, and there was no evidence of serious toxicity or loss of therapeutic effect with ticrynafen. This antihypertensive agent, in appropriate doses, appears to be as effective and well tolerated as hydrochlorothiazide, and in addition ticrynafen prevents hyperuricemia.

Microneurosurgical procedures on the trigeminal-nerve root are often followed by reactivation of herpes simplex virus infection, manifested by herpes labialis or oropharyngeal herpesvirus shedding or both. In a double-blind study of the ability of human leukocyte interferon to prevent this reactivation, patients with a history of herpes labialis were given 7 x 10(4) U of interferon per kilogram of body weight per day or placebo for five days beginning on the day before operation. In 18 patients treated with placebo, herpes labialis developed in 10, and virus shedding in the oropharynx in 15. In 19 patients treated with interferon, lesions developed in five, and shedding in eight. The frequency of reactivation as measured by lesions or positive throat cultures or both was significantly reduced by interferon (P less than 0.05). Of 127 daily throat-wash cultures in the placebo group, 42 per cent were positive for herpesvirus, but of 134 in the interferon group, only 9 per cent were positive (P less than 0.001). We conclude that interferon at a well-tolerated dosage reduces reactivation of latent herpes simplex virus infection after a potent operative stimulus.

Little is known about the frequency with which various research designs appear in the clinical literature and how this frequency has changed in recent years. This study describes the research designs used in 612 articles randomly selected from original research published in three general medical journals from 1946 to 1976. Cross-sectional studies increased from 25 to 44 per cent, cohort studies declined from 59 to 34 per cent, and clinical trials increased from 13 to 21 per cent of articles (P less than 0.001). Randomized controlled trials comprised 5 per cent of articles published in 1976 and were not represented 30 years before. In 1976, 37 per cent of articles reported on 10 subjects or less, and this number has not changed substantially since 1946. The frequency of studies with weak research designs has increased in these general medical journals over the past 30 years. The trend deserves critical attention.

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.

A double-blind, placebo-controlled trial of interferon prophylaxis against viral infections was conducted in renal-transplant recipients receiving standard immunosuprressive therapy with or without antithymocyte globulin. Interferon was administered for six weeks, beginning on the day of transplantation. Cytomegalovirus excretion began earlier and viremia was more frequent in placebo-treated than in interferon-treated patients. Cytomegalovirus viremia correlated with clinical syndromes was more frequent in recipients of antithymocyte globulin. In contrast, neither interferon nor antithymocyte globulin altered excretion of herpes simplex virus. Reversible leukopenia and thrombocytopenia occurred in seven interferon recipients. Patient and graft survival were comparable in interferon and placebo groups. There preliminary results suggest that a six-week course of prophylactic interferon delays shedding of cytomegalovirus and decreases the incidence of viremia after transplantation. In contrast, antithymocyte globulin appears to increase the severity of infection from cytomegalovirus among these patients.

Two double-blind, crossover trials comparing the antiemetic effectiveness of nabilone, a new synthetic cannabinoid, with that of prochlorperazine were conducted in patients with severe nausea and vomiting associated with anticancer chemotherapy. Of 113 patients evaluated, 90 (80 per cent) responded to nabilone therapy, whereas only 36 (32 per cent) responded to prochlorperazine (P less than 0.001). Complete relief of symptoms was infrequent, occurring only in nine patients (8 per cent) given nabilone. When both drugs were compared, both nausea (P less than 0.01) and vomiting episodes (P less than 0.001) were significantly lower in patients given nabilone. Moreover, patients clearly favored nabilone for continued use (P less than 0.001). Predominant side effects noted by patients were similar for both agents and included somnolence, dry mouth and dizziness but were about twice as frequent and more often severe in patients receiving nabilone. In addition, four patients (3 per cent) taking nabilone had side effects (hallucinations in three, hypotension in one) that required medical attention. Euphoria associated with nabilone was infrequent (16 per cent) and mild.

The ability of topical 10 per cent adenine arabinoside 5'-monophosphate to decrease the severity and frequency of recurrent herpes simplex labialis was evaluated in a double-blind, randomized study of 233 patients at three collaborating institutions. Nine clinical and four virologic measurements were used to evaluate drug efficacy during a single episode. No statistically significant improvement in any measurement was seen in the drug-treated patients. Analyses according to institution and age, stage and size of lesion before therapy also indicated no benefit attributable to the drug. There was no effect of the drug on the rate of recurrence of herpes simplex labialis. We conclude that, despite activity against herpes simplex virus infection in tissue culture and in some laboratory animal models, topical use of the drug is ineffective against recurrent herpes simplex labialis. This may be due to failure of the drug to penetrate the skin.

We observed the frequent occurrence of persistent middle-ear effusion in children with acute otitis media and followed them according to standard procedures for otologic diagnosis. We performed a life-table analysis to identify risk factors for such persistent disease. Sixty-two patients were free of middle-ear effusion at one or more clinic visits two to 13 weeks after presentation and were considered cured; 45 had effusion at all clinic visits during this period and were defined as having persistent effusion. The life-table analysis showed that the relative risk for persistence was 3.8 times higher in children less than 24 months of age as compared with children 24 months of age or older (P less than 0.001) and that this risk was 2.8 times greater for white as compared with black children (P less than 0.01). Other factors examined were not identified as significant risk factors. Persistent middle-ear effusion may be associated with impaired hearing and appears to be the most important sequela of otitis media.