A double blind placebo controlled crossover study of prostacyclin in man.

Prostacyclin sodium (PGI₂) was administered in a double blind crossover trial to 6 normal males at infusion rates of 2, 4 and 8 ng/kg/minute. Substantial (p < 0.001) shifts of the log dose response curve of ADP induced platelet aggregation occured during the highest infusion rate of PGI₂. This was associated with a small but significant fall in diastolic blood pressure (?6.3± 1.6 mm Hg, p < 0.01) and a rise in heart rate (+25.5 ± 6.5 beats/minute, p < 0.001). Plasma renin activity rose in a dose related manner with PGI₂ but plasma aldosterone and plasma norepinephrine did not change. Marked facial flushing occured with PGI₂.     

Progesterone and the premenstrual syndrome: a double blind crossover trial.

A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos''s menstrual distress questionnaire, Beck et al''s depression inventory, Spielberger et al''s state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.     

Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial.

OBJECTIVE--To investigate the possible therapeutic role of omeprazole, a powerful proton pump inhibitor, in unselected patients presenting with upper gastrointestinal bleeding. DESIGN--Double blind placebo controlled parallel group study. Active treatment was omeprazole 80 mg intravenously immediately, then three doses of 40 mg intravenously at eight hourly intervals, then 40 mg orally at 12 hourly intervals. Treatment was started within 12 hours of admission and given for four days or until surgery, discharge, or death. SETTING--The medical wards of University and City Hospitals, Nottingham. SUBJECTS--1147 consecutive patients aged 18 years or more admitted over 40 months with acute upper gastrointestinal bleeding. MAIN OUTCOME MEASURES--Mortality from all causes; rate of rebleeding, transfusion requirements, and operation rate; effect of treatment on endoscopic appearances at initial endoscopy. RESULTS--Of 1147 patients included in the intention to treat analysis, 569 received placebo and 578 omeprazole. No significant differences were found between the placebo and omeprazole groups for rates of transfusion (302 (53%) placebo v 298 (52%) omeprazole), rebleeding (100 (18%) v 85 (15%)), operation (63 (11%) v 62 (11%)), and death (30 (5.3%) v 40 (6.9%)). However, there was an unexpected but significant reduction in endoscopic signs of upper gastrointestinal bleeding in patients treated with omeprazole compared with those treated with placebo (236 (45%) placebo v 176 (33%) omeprazole; p less than 0.0001). CONCLUSIONS--Omeprazole failed to reduce mortality, rebleeding, or transfusion requirements, although the reduction in endoscopic signs of bleeding suggests that inhibition of acid may be capable of influencing intragastric bleeding. Our data do not justify the routine use of acid inhibiting drugs in the management of haematemesis and melaena.     

Effect of enterocoated cholestyramine on bowel habit after ileal resection: a double blind crossover study.

Ileal resection causes malabsorption of bile acid; the increased load of bile acids in the colon induces increased secretion of salt and water and hence diarrhoea. A study was carried out to test the effect of an enterocoated cholestyramine tablet designed to disintegrate in the colon and sequester the bile acids there, thereby minimising diarrhoea induced by bile acids while having no effect on malabsorption of bile acid and jejunal fat absorption. The study comprised 14 patients who had undergone ileal resection of 40-150 cm for Crohn''s disease. A double blind crossover trial was performed with placebo and cholestyramine enterocoated with cellulose acetate phthalate. During treatment with cholestyramine the daily faecal output decreased, the number of defecations each week decreased, and the intestinal transit time increased. Acceptability of the tablets was high, in contrast with general clinical experience with cholestyramine powder. No change was observed in the total faecal output of bile acids or fat. Cholestyramine tablets caused a reduction in diarrhoea without noticeably interfering with the metabolism of fat or bile acid.     

Sulphasalazine in ankylosing spondylitis: a double blind controlled study in 60 patients.

Sulphasalazine has been reported to be effective in ankylosing spondylitis with peripheral arthritis, but its efficacy in spondylitis is unknown. Thus 60 patients with active ankylosing spondylitis without peripheral arthritis or gastrointestinal symptoms were randomly allocated to one of two therapeutic groups. One group received 2 g sulphasalazine daily for six months and the other a placebo. Thirteen patients (six given placebo and seven given sulphasalazine) dropped out of the trial and were considered to be treatment failures. After six months'' follow up efficacy was rated as good or very good by 15 of the 30 patients given sulphasalazine and by only six of the 30 given placebo (p less than 0.02). Furthermore, in the patients given sulphasalazine the daily consumption of non-steroidal anti-inflammatory drugs, functional index, and plasma IgG concentrations had fallen significantly. These data suggest that sulphasalazine may be a safe and effective treatment for spondylitis in ankylosing spondylitis.     

Co-amoxiclav in recurrent acute otitis media: placebo controlled study.

OBJECTIVE--To determine the efficacy of coamoxiclav in children aged 6 months to 12 years with recurrent acute otitis media. DESIGN--A randomised double blind placebo controlled clinical trial. SETTING--General practice in the Netherlands. PATIENTS--121 children with recurrent acute otitis media, defined by onset of otalgia and otoscopic signs of middle ear infection within four to 52 weeks after the previous attack. Confirmation of diagnosis and randomisation was done by otolaryngologists. INTERVENTION--Oral co-amoxiclav or placebo in weight related doses for seven days. MAIN OUTCOME MEASURE--An irregular clinical course defined as the presence of otalgia or a body temperature greater than or equal to 38 degrees C, or both, after three days. RESULTS--Eleven (16%; 95% confidence interval 9% to 28%) children had an irregular course in the co-amoxiclav group and 10 (19%; 9% to 31%) in the placebo group (difference not significant). Age, dichotomised at 2 years, was the only significant prognostic factor for irregular course of the disease (odds ratio 5.9; 1.8 to 19.1). Among children aged below 2 years, 28% (4/14) in the co-amoxiclav group and 58% (7/12) in the placebo group had irregular courses. For children 2 years and older these percentages were 13% (7/52) and 7% (3/41). CONCLUSION--Children with recurrent acute otitis media are at greater risk of an irregular clinical course of the disease than children with a first episode of acute otitis media. Co-amoxiclav has no significant benefit over placebo in treating children over 2 years with acute otitis media.     

Effect of long-term treatment with salmeterol on asthma control: a double blind,randomised crossover study.

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers

Background and Rationale

Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.

Methodology/Principal Findings

A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18–30 years old, BMI 18.5–25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.

Conclusions/Significance

Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00741026","term_id":"NCT00741026"}}NCT00741026     

Zinc supplementation during pregnancy: a double blind randomised controlled trial.

OBJECTIVE--To see whether zinc supplementation during pregnancy improves maternal and fetal outcome. DESIGN--Prospective study started at booking and continued till discharge of mother and baby from the maternity hospital. Mothers were randomly assigned to receive zinc supplementation or placebo in a double blind trial. SETTING--Mothers booking at one hospital. PATIENTS--Women booking before 20 weeks of gestation who agreed to take part in the study. 494 Mothers were followed up till the end of pregnancy. There was no difference between the groups given zinc and placebo in their social or medical backgrounds. INTERVENTIONS--Mothers in the active treatment group received one capsule of 20 mg elemental zinc daily and those in the placebo treated group a capsule identical in appearance and taste with the active capsule but which contained inert substances. MAIN OUTCOME MEASURE--Various adverse outcomes were tested, including maternal bleeding, hypertension, complications of labour and delivery, gestational age, Apgar scores, and neonatal abnormalities. The main outcome measure was birth weight. RESULTS--There were no differences whatsoever between mothers given a zinc supplement and those given a placebo. CONCLUSION--Zinc supplementation in pregnancy in the United Kingdom does not seem to offer any benefits to the mother or her fetus.     

Reversal of postmenopausal vertebral bone loss by oestrogen and progestogen: a double blind placebo controlled study

Because of uncertainty about the place of hormones in the treatment of postmenopausal bone loss vertebral and forearm bone loss was measured by absorptiometry in early post-menopausal women before and after continuous or sequential treatment with combined oestrogen and progestogen in a double blind placebo controlled trial. Treatment with hormones significantly reversed the vertebral bone loss. The net gain in vertebral bone density amounted to 6·4% a year with continuous supplementation and 5·4% a year with sequential supplementation; the net gain in forearm bone density was lower (3·6% with continuous and 3·7% with sequential supplementation).Before a policy of supplementation with hormones can be recommended to all postmenopausal women with the aim of reducing the incidence of vertebral crush fractures further studies with different doses and combinations of hormones, administered over several years, are needed.     

Single dose vitamin A treatment in acute shigellosis in Bangladesh children: randomised double blind controlled trial.

OBJECTIVE: To evaluate the efficacy of a single large oral dose of vitamin A in treating acute shigellosis in children in Bangladesh. DESIGN: Randomised double blind controlled clinical trial. SETTING: Dhaka Hospital, International Centre for Diarrhoeal Disease Research, Bangladesh. SUBJECTS: 83 children aged 1-7 years with bacteriologically proved shigellosis but no clinical signs of vitamin A deficiency; 42 were randomised to treatment with vitamin A and 41 formed a control group. INTERVENTION: Children were given a single oral dose of 200,000 IU of vitamin A plus 25 IU vitamin E or a control preparation of 25 IU vitamin E. MAIN OUTCOME MEASURES: Clinical cure on study day 5 and bacteriological cure. RESULTS: Baseline characteristics of the subjects in the two treatment groups were similar. Significantly more children in the vitamin A group than in the control group achieved clinical cure (19/42 (45%) v 8/14 (20%); chi 2 = 5.14, 1 df, P = 0.02; risk ratio = 0.68 (95% confidence interval; 0.50 to 0.93)). When cure was determined bacteriologically, the groups had similar rates (16/42 (38%) v 16/41 (39%); chi 2 = 0.02, 1 df, P = 0.89; risk ratio = 0.98 (0.70 to 1.39)). CONCLUSIONS: Vitamin A reduces the severity of acute shigellosis in children living in areas where vitamin A deficiency is a major public health problem.     

Salmeterol in nocturnal asthma: a double blind,placebo controlled trial of a long acting inhaled beta 2 agonist.

OBJECTIVE--To determine whether inhaled salmeterol, a new long acting inhaled beta adrenergic agonist, reduces nocturnal bronchoconstriction and improves sleep quality in patients with nocturnal asthma. DESIGN--Randomised, double blind, placebo controlled crossover study. SETTING--Hospital outpatient clinics in Edinburgh. SUBJECTS--Twenty clinically stable patients (13 women, seven men) with nocturnal asthma, median age 39 (range 18-60) years. INTERVENTIONS--Salmeterol 50 micrograms and 100 micrograms and placebo taken each morning and evening by metered dose inhaler. Rescue salbutamol inhalers were provided throughout the run in and study periods. MAIN OUTCOME MEASURES--Improvement in nocturnal asthma as measured by peak expiratory flow rates and change in sleep quality as measured by electroencephalography. RESULTS--Salmeterol improved the lowest overnight peak flow rate at both 50 micrograms (difference in median values (95% confidence interval for difference in medians) 69 (18 to 88) l/min) and 100 micrograms (72 (23 to 61) l/min) doses twice daily. While taking salmeterol 50 micrograms twice daily patients had an objective improvement in sleep quality, spending less time awake or in light sleep (-9 (-4 to -44) min) and more time in stage 4 sleep (26 (6-34) min). CONCLUSIONS--Salmeterol is an effective long acting inhaled bronchodilator for patients with nocturnal asthma and at a dose of 50 micrograms twice daily improves objective sleep quality.     

Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind,randomised controlled study.

OBJECTIVE--To assess the diagnostic value and safety of the benzodiazepine antagonist flumazenil in patients with coma of unclear origin with suspected poisoning. DESIGN--Double blind, placebo controlled, randomised study. SETTING--Intensive care unit at a major teaching hospital. PATIENTS--105 Unconscious adults admitted consecutively with suspected drug overdosage during 18 months from a total of 362 cases of poisoning. Exclusion criteria were pregnancy, epilepsy, obvious poisoning with drugs identified unequivocally from information from relatives or others as other than benzodiazepines, and coma score greater than 10 on a scale graded from 4 to 20. Patients were allocated randomly to receive flumazenil (21 men and 32 women) or placebo (25 men and 27 women). INTERVENTIONS--Intravenous injection of flumazenil (10 ml, 0.1 mg/ml) or placebo (10 ml vehicle alone) given double blind over three minutes. MAIN OUTCOME MEASURES--Serum and urine concentrations of benzodiazepines, antidepressants, and several other agents; blood gas tensions; standardised evaluation on admission and five minutes after the injection by means of coma scale score and urgent diagnostic or therapeutic interventions indicated according to the history and clinical examination; standardised interview after the injection to try to ascertain further information; and adverse reactions. RESULTS--Benzodiazepines were found in the serum in 36 of the 53 patients in the flumazenil group and in 37 of the 52 who received placebo. The average coma scale score increased significantly after injection in the flumazenil group (6.4 v 12.1, p less than 0.001) but not in the placebo group. In the flumazenil group several interventions were rendered unnecessary by the injection: gastric lavage and urinary catheterisation (19 patients each), intubation (21), artificial ventilation and computed tomography of the brain (three patients each), blood culture and lumbar puncture (one patient each), and electroencephalography (two). In the placebo group the indications for these procedures did not change in any patient after injection. The 95% confidence interval for the difference in reduction of the frequency of indications for gastric lavage after injection between the two groups was 21% to 51%, that for intubation 25% to 55%, and that for urinary catheterisation 21% to 51%. In the flumazenil group 21 patients gave valuable information on their drug ingestion within 10 minutes after injection compared with only one in the placebo group (p less than 0.001). Nine adverse reactions were recorded in the flumazenil group, eight of which were graded as mild and one severe. The safety of the antagonist was acceptable, even though 60% of the patients in the flumazenil group had multiple drug poisoning including benzodiazepine. No epileptic seizures or arrhythmias were recorded. CONCLUSION--Flumazenil is a valuable and safe differential diagnostic tool in unclear cases of multiple drug poisoning.     

Randomised,double blind,crossover challenge study of allergenicity of peanut oils in subjects allergic to peanuts.

OBJECTIVE: To determine the in vivo allergenicity of two grades of peanut oil for a large group of subjects with proved allergy to peanuts. DESIGN: Double blind, crossover food challenge with crude peanut oil and refined peanut oil. SETTING: Dedicated clinical investigation unit in a university hospital. SUBJECTS: 60 subjects allergic to peanuts; allergy was confirmed by challenge tests. OUTCOME MEASURES: Allergic reaction to the tested peanut oils. RESULTS: None of the 60 subjects reacted to the refined oil; six (10%) reacted to the crude oil. Supervised peanut challenge caused considerably less severe reactions than subjects had reported previously. CONCLUSIONS: Crude peanut oil caused allergic reactions in 10% of allergic subjects studied and should continue to be avoided. Refined peanut oil did not pose a risk to any of the subjects. It would be reasonable to recommend a change in labelling to distinguish refined from crude peanut oil.     

Randomised,double blind,placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea

Objective To determine the efficacy of oral morphine in relieving the sensation of breathlessness in patients in whom the underlying aetiology is maximally treated.Design Randomised, double blind, placebo controlled crossover study.Setting Four outpatient clinics at a hospital in South Australia.Participants 48 participants who had not previously been treated with opioids (mean age 76, SD 5) with predominantly chronic obstructive pulmonary disease (42, 88%) were randomised to four days of 20 mg oral morphine with sustained release followed by four days of identically formulated placebo, or vice versa. Laxatives were provided as needed.Main outcome measures Dyspnoea in the morning and evening as shown on a 100 mm visual analogue scale, quality of sleep, wellbeing, performance on physical exertion, and side effects as measured at the end of the four day treatment period.Results 38 participants completed the study; three withdrew because of definite and two because of possible side effects of morphine (nausea, vomiting, and sedation). Participants reported significantly different dyspnoea scores when treated with morphine: an improvement of 6.6 mm (95% confidence interval 1.6 mm to 11.6 mm) in the morning and of 9.5 mm (3.0 mm to 16.1 mm) in the evening (P = 0.011 and P = 0.006, respectively). During the period in which they were taking morphine participants also reported better sleep (P = 0.039). More participants reported distressing constipation while taking morphine (9 v 1, P = 0.021) in spite of using laxatives. All other side effects were not significantly worse with morphine, although the study was not powered to address side effects.Conclusions Sustained release, oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in the community setting.     

Effect of naloxone on exercise-induced angina pectoris: a randomized double blind crossover trial

To determine whether endogenous opioids play a role in modulating the appreciation of chest pain in angina pectoris, the specific opioid antagonist, Naloxone, was used. The hypothesis was that the appearance time of ischemic myocardial pain should decrease after Naloxone if centrally mediated pain perception is significantly influenced by the endorphin system in angina pectoris. A randomized double blind clinical trial was conducted in 5 men with effort-induced angina pectoris associated with ST segment changes. Three multi-stage exercise tests, using the Bruce protocol were performed on the same day and time, on three successive weeks. Chest pain was reported 4.3 +/- 0.3 (SEM) minutes after starting exercise on the first or baseline test. On subsequent tests patients received either Naloxone 2 mg IV or a similar volume of saline placebo. Angina pectoris occurred significantly (p. less than 0.05) earlier (1.6 +/- 0.2 minutes) after Naloxone compared to placebo. There were no significant differences in myocardial ischemia indicated by ST segment changes and no significant differences in resting or exercise blood pressure and heart rate between Naloxone and placebo. Thus, these data focus attention on a neglected area of myocardial ischemic pain and suggest that endogenous opioids play a significant role in the recognition of the pain of effort-related angina pectoris.     

Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial.

OBJECTIVE--To investigate the apparent increased risk of severe hypoglycaemia associated with use of human insulin by comparing the pattern of symptoms of hypoglycaemia with human insulin and porcine insulin. DESIGN--Randomised controlled double blind crossover trial of treatment with human insulin and porcine insulin, with two treatment periods of six weeks. SETTING--Diabetes outpatient department of a university teaching hospital in Berne, Switzerland. PATIENTS--44 patients (25 men, 19 women) aged 14 to 60 years, with insulin dependent diabetes mellitus. All patients met the following criteria: receiving treatment with fast acting soluble insulin and long acting protamine insulin; performing multiple daily fingerstick blood glucose self measurements; and had stable glycaemic control with about one mild hypoglycaemic episode a week during the preceding two months. INTERVENTION--Patients were randomised to receive either human or porcine insulin for six weeks and were then changed over to the other type of insulin for a further six weeks. MAIN OUTCOME MEASURE--Questionnaire recording "autonomic" and "neuroglycopenic" symptoms that occurred during hypoglycaemic episodes confirmed by a blood glucose concentration less than or equal to 2.8 mmol/l. RESULTS--Insulin doses and blood glucose, glycated haemoglobin A1c, and fructosamine concentrations were similar during the two treatment periods. 493 questionnaires on hypoglycaemia (234 during treatment with human insulin and 259 during treatment with porcine insulin) were analysed. With human insulin patients were more likely to report lack of concentration (52% v 35%, p = 0.0003) and restlessness (53% v 45%, p = 0.004) and less likely to report hunger (33% v 42%, p = 0.016) than during treatment with porcine insulin. The difference in the pattern of symptoms during the two treatments was similar to that between the 12 patients with a history of recurrent hypoglycaemic coma and the 32 patients without such a history. CONCLUSIONS--The pattern of symptoms associated with human insulin could impair patients'' ability to take appropriate steps to avoid severe hypoglycaemia. Caution should be exercised when transferring patients from animal insulin to human insulin, and a large scale randomised trial of the two types of insulin may be justified.     

Acyclovir given as prophylaxis against oral ulcers in acute myeloid leukaemia: randomised,double blind,placebo controlled trial.

OBJECTIVES--To evaluate (a) the prophylactic effect of the antiherpetic drug acyclovir on oral ulcers in patients with acute myeloid leukaemia receiving remission induction chemotherapy and thus (b), indirectly, the role of herpes simplex virus in the aetiology of these ulcers. DESIGN--Randomised, double blind, placebo controlled trial. SUBJECTS--74 herpes simplex virus seropositive patients aged 18-84. Thirty seven patients received acyclovir (800 mg by mouth daily) and 37 placebo. The patients were examined daily for 28 days. MAIN OUTCOME MEASURES--Occurrence of herpes labialis, intraoral ulcers, and acute necrotising ulcerative gingivitis. RESULTS--The two populations were comparable in age, sex, type of antineoplastic treatment, and history of herpes labialis. Acute oral infections occurred in 25 of the acyclovir treated patients and 36 of the placebo treated patients (relative risk 0.69 (95% confidence interval 0.55 to 0.87)). This difference was due to a reduction in the incidence of herpes labialis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)), intraoral ulcers excluding the soft palate (one case versus 13 cases; relative risk 0.08 (0.01 to 0.56)), and acute necrotising ulcerative gingivitis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)). However, ulcers on the soft palate were diagnosed with similar frequency in the two groups. Isolation of herpes simplex virus type 1 in saliva was reduced from 15 cases in the placebo group to one case in the acyclovir group (relative risk 0.07 (0.01 to 0.48)). CONCLUSION--Intraoral ulcers excluding the soft palate are most often due to infection with herpes simplex virus, whereas ulcers on the soft palate have a non-herpetic aetiology. The findings suggest that acute necrotising ulcerative gingivitis may also be due to herpes simplex virus. Prophylaxis with acyclovir should be considered for patients with acute myeloid leukaemia during remission induction therapy.