Megestrol acetate for anorexia in patients with far-advanced cancer: a double-blind controlled clinical trial

The aim of this study was to evaluate a low-dose regimen of megestrol acetate (MA; 320 mg/day) on appetite in advanced cancer patients. Out-patients with far-advanced non-hormone responsive tumours and loss of appetite were randomised in a phase III trial, with two consecutive phases: a 14-day double-blind placebo controlled phase (phase A) and a 76-day open phase (phase B). During phase A, patients were treated with MA, two 160 mg tablets/day, or placebo. In phase B, the MA dose was titrated to clinical response in both groups. Appetite, food intake, body weight, performance status, mood and quality of life were evaluated with standardised measures; patients' global judgement about treatment efficacy was also requested. Of 42 patients entering the study, 33 (17 MA and 16 placebo) were evaluable for efficacy. The appetite score improved significantly with MA after 7 days (P = 0.0023), and this effect was still significant at 14 days (P = 0.0064). Patients judged the treatment with MA effective in 88.2% of cases (14th day), whilst placebo was considered effective by 25% (P = 0.0003). None of the other measures showed significant changes during treatment. The remarkable effect on appetite evident after 7 days, without serious side-effects, shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease.     

Effects of influenza vaccination in HIV-infected adults: a double-blind, placebo-controlled trial

Annual influenza vaccine is recommended for persons with HIV infection. Recent reports indicate that immunizations may increase HIV replication in infected individuals. Forty-seven HIV-infected patients were randomized to influenza vaccine or saline placebo using a double blind study design. One month after vaccination, plasma HIV-1 RNA increased in the vaccinated but not placebo group (p = 0.029). At 3 months, CD4% dropped an average of 1.6 points in the vaccinated group compared to an increase of 0.1 points in the placebo group (p = 0.039). Patients on stable antiretroviral regimens had CD4% drop an average of 2.3 points in the vaccinated group at 3 months versus 0.1 points in the placebo group (p = 0.015). It is concluded that HIV-infected patients are at risk for increased HIV replication and decreases in CD4% following influenza vaccination. Since influenza has not been associated with significant morbidity in this population, further study of routine influenza vaccination for HIV-infected patients is warranted.     

Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: The objective of this study was to evaluate the effects of daily dietary supplementation with 1.25 g or 2.5 g of docosahexaenoic (DHA), in the absence of eicosapentaenoic acid (EPA), on serum lipids and lipoproteins in persons with combined hyperlipidemia (CHL) [serum low-density lipoprotein cholesterol (LDL-C) 130 to 220 mg/dL and triglycerides 150 to 400 mg/dL]. METHODS: After a 6-week dietary stabilization period, subjects entered a 4-week single-blind placebo (vegetable oil) run-in phase. Those with adequate compliance during the the run-in were randomized into one of three parallel groups (placebo, 1.25, or 2.5 g/day DHA) for 6 weeks of treatment. Supplements were administered in a triglyceride form contained in gelatin capsules. Primary outcome measurements were plasma phospholipid DHA content, serum triglycerides, high-density lipoprotein cholesterol (HDL-C). LDL-C and non-HDL-C. RESULTS: The DHA content of plasma phospholipids increased dramatically (2 to 3 fold) in a dose-dependent manner. Significant (p < 0.05) changes were observed in serum triglycerides (17 to 21% reduction) and HDL-C (6% increase) which were of similar magnitude in both DHA groups. Non-HDL-C [+1.6 (NS) and +5.7% (p < 0.04)] and LDL-C [+9.3% (NS) and +13.6% (p < 0.001)] increased in the DHA treatment groups. All lipid effects reached an apparent steady state within the first 3 weeks of treatment. CONCLUSION: Dietary DHA, in the absence of EPA, can affect lipoprotein cholesterol and triglyceride levels in patients with combined hyperlipidemia. The desirable triglyceride and HDL-C changes were present at a dose which did not significantly increased non-HDL-C or LDL-C. These preliminary findings suggest that dietary supplementation with 1.25 g DHA/day, provided in a triglyceride form, may be an effective tool to aid in the management of hypertriglyceridemia.     

Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial

BACKGROUND/AIMS: Silymarin has protective effects in different experimental conditions, but its efficacy in human liver cirrhosis has not been completely established. Therefore, this study was carried out to determine the effect of silymarin in alcoholics with liver cirrhosis with respect to survival and clinical and laboratory changes. METHODS: From February 1986 to June 1989, we enrolled 200 alcoholics with histologically or laparoscopically proven liver cirrhosis in a randomized, double-blind multicenter trial comparing 450 mg of silymarin (150 mg/ three times per day) with placebo. The primary outcome was time to death, and the secondary outcome was the progression of liver failure. Additional analyses were also performed in 75 patients in whom anti-hepatitis C virus antibodies were measured after completion of the trial. RESULTS: One hundred and three patients were assigned to receive silymarin and 97 to receive placebo. The two groups were well matched for demographic and baseline clinical and laboratory features. A 2-year study period was completed in 125 patients (57 receiving silymarin and 68 receiving placebo). Twenty-nine patients (15 receiving silymarin, and 14 receiving placebo) died during the trial. Survival was similar in patients receiving silymarin or placebo. The effect of silymarin on survival was not influenced by sex, the persistence of alcohol intake, the severity of liver dysfunction or by the presence of alcoholic hepatitis in the liver biopsy. Silymarin did not have any significant effect on the course of the disease. No relevant side-effects were observed in any group. CONCLUSIONS: The results of this study indicate that silymarin has no effect on survival and the clinical course in alcoholics with liver cirrhosis.     

The end of antibiotic treatment in adults with acute sinusitis-like complaints in general practice? A placebo-controlled double-blind randomized doxycycline trial

BACKGROUND: Acute sinusitis-like complaints are very common and are usually treated with antibiotics in spite of the lack of evidence for the effectiveness of antibiotic therapy and the increasing number of resistant strains. AIM: To assess the effectiveness of doxycycline in adults with acute sinusitis-like complaints in general practice. METHOD: The effects of doxycycline in a placebo-controlled, double-blind, randomized trial were assessed in adults consulting their general practitioner (GP) with complaints after a common cold or influenza, pain in the head when bending forward, purulent nasal discharge, predominantly unilateral maxillary pain, toothache, or pain when chewing. Primary outcome events were the resolution of facial pain and the resumption of daily activities. Treatment differences were assessed by means of Kaplan-Meier curves and hazard ratios. The follow-up period was 42 days. RESULTS: No significant difference was found in time to recover between the doxycycline-treated group and the placebo-treated group. However, the adjusted hazard ratio for the group receiving doxycycline was 1.17 (95% CI = 0.87-1.57) for the resolution of pain and 1.31 (95% CI = 0.96-1.78) for the resumption of daily activities. After 10 days, 85% of all patients reported improvement and 60% were completely cured. Side effects were reported by 17% of the doxycycline-treated group, with two patients withdrawing because of side effects. CONCLUSIONS: Data from this study indicate that doxycycline does not add to the effectiveness of decongestive nose drops and steam inhalation in treating acute sinusitis-like complaints in general practice adults.     

Enoximone in chronic stable angina: a double-blind placebo-controlled cross-over trial

Enoximone, a phosphodiesterase inhibitor (PDEI), has both positive inotropic and vasodilatory properties. We examined the effect of a single oral dose of enoximone as compared with placebo on myocardial ischaemia and global left ventricular (LV) function using both exercise ECG and Doppler measurements of aortic blood flow, respectively. Twenty patients (16 men, 4 women) with a mean age of 59 years and stable angina were studied. Total exercise duration was significantly longer after enoximone as compared with placebo treatment, with a mean difference of 22.8 s (p = 0.003). Times (mean +/- SD) to onset of angina and development of significant ST-segment decrease were similar after placebo (454 +/- 101 and 352 +/- 155 s, respectively) or enoximone (500 +/- 155 and 413 +/- 192 s, respectively), although both showed trends in favour of enoximone. As compared with placebo, significantly higher heart rate (HR) was measured for enoximone both at rest (75 +/- 18 vs. 90 +/- 22 beats/min, p < 0.01) and on recovery from exercise (81 +/- 18 vs. 89 +/- 19 beats/min, p < 0.05). Enoximone had no significant effect on systolic or diastolic blood pressure (SBP, DBP) or rate-pressure product (RPP) generated at rest or during exercise. Changes in both acceleration and velocity of aortic blood flow during exercise were similar after administration of enoximone or placebo. We showed that a single oral dose of enoximone is well tolerated in patients with ischaemic heart disease, improving both exercise capacity and favourably influencing ST-segment changes with no increase in adverse events or significant haemodynamic disturbances.     

Albendazole in human loiasis: results of a double-blind, placebo-controlled trial

To assess the filaricidal activity and clinical safety of albendazole in human loiasis, a double-blind, placebo-controlled study was conducted in an endemic area in Benin, Africa. Twenty-three men with microfilaremia (100-30,000/mL) were randomly assigned to receive albendazole (200 mg; n = 11) or placebo (n = 12) twice daily for 21 days; 1 patient from each group withdrew from the study. There were no clinical adverse effects and no observed hepatotoxicity, renal toxicity, or hematologic abnormalities attributable to the drug. In the albendazole group, microfilarial levels began to decrease at day 14 after treatment and by 6 months had fallen to a geometric mean of 20% of pretreatment levels (vs. 84.8% in the placebo group). Blood eosinophil levels and anti-filarial IgG and IgG4 also fell significantly in response to albendazole. Taken together, these data suggest that albendazole has a primary (possibly embryotoxic) effect on the adult parasite, resulting in a slow decrease in microfilaremia.     

Long-term clinical effect of nilvadipine in patients with chronic heart failure: a double-blind placebo-controlled study

The long-term effect of calcium channel blockers on chronic heart failure is disappointing, probably because of reflex sympathetic activation through arterial vasodilation. However, nilvadipine may be beneficial for treatment of chronic heart failure since this drug has minimal effects on sympathetic activation. In this study, the effects of 12-week administration of nilvadipine or placebo on symptoms of heart failure and cardiac function were investigated in 23 patients with mild-to-moderate chronic heart failure in a double-blind trial. The patients were randomly assigned to either a nilvadipine group (16 mg daily) or a placebo group. Intergroup comparisons did not show significant differences in any parameters. Serious adverse effects were not observed during the study. Thus, this study failed to show any beneficial effect of nilvadipine in the long-term treatment of patients with chronic heart failure. We conclude that the long-term administration of nilvadipine (16 mg daily) is neither effective nor harmful in the treatment of patients with chronic heart failure.     

A double-blind placebo-controlled phase II trial of thalidomide in asymptomatic HIV-positive patients: clinical tolerance and effect on activation markers and cytokines

A randomized double-blind, placebo-controlled study was performed to determine the safety, efficacy, and effect of thalidomide on a variety of immunological and biochemical parameters in asymptomatic human immunodeficiency virus (HIV)-positive patients. Nineteen male patients with elevated markers of immune activation and CD4 cell counts above 400/mm3 were randomized to either placebo or thalidomide at 100 mg/day for 24 weeks. However, only 3 (of 10) patients receiving thalidomide completed all 24 weeks compared to 6 (of 9) patients receiving placebo. This was mainly due to fatigue (somnolence is a recognized side effect), although this was also seen to a lesser extent in the placebo group and so may not be drug attributable. No significant changes in CD4/CD8 count, activation markers, TNF-alpha, or TNFR1 were observed. However, a nonsignificant trend toward inhibition of mitogen-induced TNF-alpha production was observed in the thalidomide arm. The lack of systemic effect and the lower tolerance of thalidomide (at this dose) in asymptomatic patients highlights the need for pharmacokinetic analysis to address possible absorption problems and the need for more potent and less toxic TNF-alpha inhibitors to be developed for use in this type of study.     

Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study

Analysis of germinal centers (GCs) in chronically inflamed human tonsils has led to the dogma that GCs contain two compartments with separate functions: a dark zone where B cells proliferate and hypermutate; and a light zone where selection and differentiation occur. However, here Stephanie Camacho and colleagues discuss immunohistological analysis of splenic GCs arising de novo that reveal a more plastic structure.     

Fluvoxamine in the treatment of binge-eating disorder: a multicenter placebo-controlled, double-blind trial

OBJECTIVE: The purpose of this study was to assess the efficacy of fluvoxamine in the treatment of binge-eating disorder. Binge-eating disorder is a newly described eating disorder characterized by recurrent episodes of binge eating but without purging behaviors. Uncontrolled reports have suggested that serotonin selective reuptake inhibitors (SSRIs) may be effective in treating this disorder. METHOD: Eighty-five outpatients with a DSM-IV diagnosis of binge-eating disorder were randomly assigned to receive either fluvoxamine (N=42) or placebo (N=43) in a 9-week, parallel-group, double-blind, flexible dose (50-300 mg) study at three centers. The primary outcome measures were frequency of binge eating, expressed as log ([binges/week]+1), and Clinical Global Impression (CGI) scale ratings. Secondary measures included the level of response (based on the percentage change in frequency of binges), body mass index, and Hamilton Rating Scale for Depression score. Except for the level of response, the outcome measures were analyzed by random regression methods; the treatment-by-time interaction was the measure of treatment effect. RESULTS: Compared with placebo, fluvoxamine was associated with a significantly greater rate of reduction in the frequency of binges, rate of reduction in CGI severity scores, rate of increase in CGI improvement scores, level of response for patients who completed the 9-week study, and rate of reduction in body mass index. There was no significant difference between placebo and fluvoxamine groups in the rate of decrease in Hamilton depression scale scores. A significantly greater proportion of patients receiving fluvoxamine than those receiving placebo discontinued treatment because of an adverse medical event. CONCLUSIONS: In this placebo-controlled trial, fluvoxamine was found to be effective according to most outcome measures in the acute treatment of binge-eating disorder.     

Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial

The efficacy and acceptability of nebivolol 5 mg and enalapril 10 mg, each given once daily, were compared in essential hypertension in a multicentre, randomised, double-blind trial over 3 months. For the index pre-declared variable, sitting diastolic pressure at trough drug level, nebivolol achieved greater falls in pressure (-12.3 vs -9.9 mmHg; P = 0.009) and a higher response rate (70% vs 55%; P = 0.002). The trough-to-peak sitting diastolic ratios also favoured nebivolol (84% vs 60%, P = 0.002). Nebivolol, but not enalapril, slightly but significantly lowered heart rate. Both drugs were well-tolerated, although enalapril was accompanied by a significantly higher incidence of coughing.     

What happens with patients after participation in a clinical trial?

107 patients with primary hypercholesterolaemia participated for five years in a clinical trial with dietary and drug treatment (a statin) at the Lipid Clinic. At the end of the study the patients were referred back to their own physicians, with written advice on diet and drug therapy. At a recall two years later we studied to what extent recommended therapy and follow-up had been implemented. 15% had no follow-up after participating in the study and 18% had not measured their cholesterol for one year or more. The majority of the patients did not follow the recommended diet and level of physical activity satisfactorily, and 20% had stopped their lipid-lowering medication. In general they had been prescribed too low doses of the lipid-lowering agent, and 70% of the patients had not reached the target of the LDL-cholesterol. In conclusion, adequate treatment and a five-year follow-up is not sufficient to keep the patient compliant when the follow-up becomes less intensive. When a clinical trial is terminated, greater efforts should be made to secure better compliance to therapy.     

A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy

In the past 4 years, cytokine flow cytometry has emerged as the premier technique for enumeration of cytokine producing T cells. The multiparameter capability of flow cytometry permits the simultaneous detection of two or more cytokines within a single cell, allowing true Th1 vs. Th2 determination. The high throughput inherent to flow cytometry has enormous advantages when applied to clinical research questions previously not amenable for study using labor intensive techniques such as ELISPOT, limiting dilution and T cell cloning. Furthermore, cytokine flow cytometry allows the study of individual T cells directly ex vivo, minimizing artifacts due to long term culture. As such, cytokine flow yields unique insights into cytokine biology heretofore not possible. We have used cytokine flow cytometry to examine coexpression of cytokines within the memory/effector CD4+, CD27- subset. Doing so, we have found distinct cytokine producing subsets that correlate with the previously described Th1, Th2 and Th0 subsets. The majority of cytokine producing cells were of these first two subsets with fewer cells coexpressing IFN-gamma and IL-4. These results validate the Th1/Th2 hypothesis and demonstrate specific subsets of cytokine producing T cells in fresh ex vivo human T cells.     

Albendazole for treatment and prophylaxis of microsporidiosis due to Encephalitozoon intestinalis in patients with AIDS: a randomized double-blind controlled trial

STUDY OBJECTIVES: To determine whether obese, apparently healthy individuals experience dyspnea at rest and, if so, whether their pulmonary function test (PFT) profile and maximal respiratory pressures are different from obese, healthy subjects without dyspnea. DESIGN: Prospective, open. SETTING: Pulmonary function test laboratory, Veterans Administration Medical Center. PATIENTS: Twenty-three obese male subjects (each with a body mass index [BMI] of > 28 kg/m2) with an FEV1 level and an FEV1/FVC ratio > or = 80% of predicted and no coexisting conditions. Fifteen complained of dyspnea, where eight denied having it, at rest. MEASUREMENTS AND RESULTS: Standard PFT parameters and maximum static inspiratory (P(Imax)) and expiratory (P(Emax)) mouth pressures were determined. Subjects with dyspnea had similar age and height but larger body weight (113.9+/-5.0 vs 97.4+/-2.6 kg, p = 0.03) and BMI (37.4+/-1.6 vs 31.8+/-0.7 kg/m2, p = 0.02) than subjects without dyspnea, and a greater number of them were current or previous smokers. Forced expiratory flow at 75% vital capacity (54.9+/-6 vs 75.5+/-7% predicted, p = 0.05), maximum voluntary ventilation (MVV; 90.2+/-3.8 vs 107.8+/-9.3% predicted, p = 0.05), and P(Emax) (77+/-2 vs 97.8% predicted, p = 0.007) were significantly reduced in the group of subjects with dyspnea. Large airway function (FVC, FEV1, and FEV1/FVC ratio), lung volumes, and gas exchange parameters were similar between the two groups. CONCLUSIONS: Some obese, but otherwise healthy, individuals experience dyspnea at rest. Reduced P(Emax) and MVV combined with greater body mass and peripheral airway disease are most likely responsible for the sensation of dyspnea in these individuals.     

Randomised double-blind clinical trial of intermediate- versus high-dose chloral hydrate for neuroimaging of children

Orally administered chloral hydrate is the most widely used sedative in children undergoing MRI. We compared intermediate- and high-dose oral chloral hydrate in 97 consecutive children undergoing MRI in a prospective, controlled, double-blind, randomised clinical trial. There were 50 girls and 47 boys, mean weight (+/- SD) 14.7 +/- 6.4 kg, and mean age 38 +/- 31. The children were randomly allocated to receive chloral hydrate syrup either 70 mg/kg (group A, n = 50) or 100 mg/kg (group B, n = 47). These two groups were not significantly different in sex, weight, age, diagnosis or ambulatory medication. The mean initial dose (+/- SEM) was 64 +/- 2 mg/kg for group A and 93 +/- 2 mg/kg for group B. Because adequate sedation was not achieved, 14 patients in group A and 6 in group B required a second dose, giving a mean total dose of 70 +/- 2 mg/kg for group A and 96 +/- 2 mg/kg for group B. The percentage of successful examinations after the initial dose (A: 64%, B: 87%; p < 0.05) and the total dose (A: 92%, B:100%; p = 0.14) was higher in group B. Significant differences were found for the time of onset of sedation (A:28 +/- 2 min, B: 21 +/- 1 min; p < 0.05), but not for the time to spontaneous awakening after the completion of the examination. The rate of adverse reactions was similar (A: 20%, B: 21%; p = 1.00). We conclude that high-dose oral chloral hydrate improves the management of children undergoing MRI.     

Clonazepam in the treatment of panic disorder: a double-blind, placebo-controlled trial investigating the correlation between clonazepam concentrations in plasma and clinical response

The aim of this study was to investigate the possibility of neuromuscular dysfunction in patients with faecal incontinence by measuring interference patterns in the external anal sphincter and puborectalis muscles with quantitative electromyography. The design was an open study including 20 patients with faecal incontinence; in 14 the aetiology was idiopathic and 6 had rupture of the external anal sphincter. Electromyographic interference patterns (turns/amplitude analysis) measured at rest and during maximum voluntary contraction in all patients were recorded together with fibre density measured by single fibre electromyography (n = 10) and anal pressure measured at rest and at maximum contraction (n = 17). A comparison was made with results of a previously published series of reference values taken from normal volunteers. The density of the interference pattern on maximum contraction of the puborectalis muscle was significantly lower among the patients with idiopathic faecal incontinence than among the reference group (137 compared with 241 turns/second, p < 0.01). There was also a significant difference on maximum contraction of the anal sphincter muscle among the group in whom it was ruptured compared with the reference group (76 compared with 165 turns/second, p < 0.05). Fibre density increased with age and was significantly higher among those with idiopathic incontinence (1.64 (0.2) compared with 1.33 (0.1) in the reference group, p < 0.01). There were no significant differences in anal manometry measurements between the groups. In conclusion, in patients with faecal incontinence the role of central activation of the perineal muscles is important, though other factors may play a part.     

Antiaggregatory effects of picotamide in long-term treatment: a 2-year, double-blind placebo-controlled trial

With faster CT scanners, asymmetric/heterogeneous enhancement (ASHE) of the internal jugular veins (IJVs) is frequently encountered in the absence of pathology. We investigated the frequency, side, pattern and significance of ASHE in 200 patients with various head and neck lesions. Non-ionic contrast medium (300 mgI/ml) was infused into a forearm vein (right, n = 100); left, n = 100). Forty seconds after contrast medium injection, contiguous 5-mm-thick sections were obtained craniocaudally from the skull base to the aortic arch. CT machines with two different scanning cycle times (3 s, n = 100; 2 s, n = 100) were used. ASHE of the IJVs was observed in 51 patients (25.5%); the patient group receiving a right-sided injection with a 2-s scan cycle machine, showing a higher frequency (44%). ASHE was divided into four patterns: homogeneous low density, focal low density, heterogenous opacification and fluid-fluid level formation. ASHE was frequently observed in routine contrast-enhanced CT of the head and neck. Frequency of ASHE increased when the scanning cycle was shorter. We should be aware of this phenomenon to avoid its misinterpretation as venous thrombosis or other pathology.     

Field trial of a locally produced, killed, oral cholera vaccine in Vietnam

BACKGROUND: Several studies have shown that orally administered killed cholera vaccines are safe and protective in populations at risk of cholera in developing countries. However, these vaccines have not been adopted for use in developing countries because of their expense and limited efficacy in young children. We have tested an inexpensive, killed whole-cell cholera vaccine developed and produced in Vietnam. METHODS: The efficacy of the vaccine was assessed in a large-scale, open field trial in people at least 1 year old residing in 22,653 households in the central coastal city of Hue. Alternate households were assigned vaccine (67,395 people; two doses per person) or no vaccine (67,058 people). Surveillance for cholera was conducted in all Ministry of Health facilities serving this population. Analysis was by intention to treat. FINDINGS: During an outbreak of El Tor cholera 8-10 months after vaccination, 37 cases of cholera requiring inpatient care occurred among age-eligible people allocated to the vaccine group, and 92 cases among age-eligible people allocated to the no-vaccine group (protective impact 60% [95% CI 40-73]). Among the 51,975 people who received the complete two-dose vaccine regimen, the protective efficacy was 66% (46-79): in this subset, the protective efficacy was similar for children aged 1-5 years (68%) and for older people (66%). INTERPRETATION: These findings suggest that oral killed whole-cell vaccines can confer substantial protection against El Tor cholera in young children, who are at highest risk of cholera in endemic settings. An inexpensive, locally produced, and effective oral cholera vaccine may be within reach of the limited health-care budgets of poor countries with endemic cholera, if our findings can be replicated in a randomised double-blind trial.