Effects of aerosolized surfactant in patients with stable chronic bronchitis: a prospective randomized controlled trial

BACKGROUND/AIMS: Fulminant hepatic failure (FHF) is usually fatal without liver transplantation. Auxiliary heterotopic partial liver transplantation (AHPLT) may offer advantages over orthotopic liver transplantation (OLT) or any other heterotopic procedure for the treatment of patients with fulminant liver failure. We studied AHPLT in a severe acute hepatic failure model in pigs. METHODOLOGY: Group A (control: n = 5) underwent portal vein and hepatic artery ligation and side-to-side portocaval shunting. Group B (AHPLT: n = 15) underwent host portal vein and hepatic artery ligation and AHPLT. RESULTS: All of the pigs in group A died within 48 hours from massive liver necrosis. Ten of the 15 pigs (67%) in group B had well-functioning grafts. Five of these ten died between 8 and 17 days postoperatively due to various complications. The remaining five survived for sixty days postoperatively in healthy condition. At the time of sacrifice, four of these five had well-functioning grafts weighing 739 +/- 52 g (mean +/- SEM) and regenerated, but still atrophied, host livers weighing 262 +/- 23 g (p < 0.0002). On the other hand, the one remaining pig had an atrophied graft weighing 310 g and a well-regenerated host liver weighing 470 g, probably due to a late, poorly functioning graft associated with severe rejection. CONCLUSION: AHPLT may result in survival despite host hepatic failure, and the host liver may recover within two months, despite total interruption of blood inflow.     

Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy

OBJECTIVE: This study compares the antihypertensive efficacy and tolerability of valsartan, a novel angiotensin II antagonist, given with hydrochlorothiazide (HCTZ) vs placebo or vs valsartan or HCTZ alone. DESIGN: 871 adult out-patients with essential hypertension participated in this double-blind study. Patients were randomised in equal number to receive either combination therapy of valsartan (80 mg or 160 mg) and HCTZ (12.5 mg or 25 mg), or valsartan (80 mg or 160 mg) or HCTZ (12.5 mg or 25 mg) alone, or placebo. Patients were treated once daily for 8 weeks and assessed at 2, 4 and 8 weeks after randomisation. MAIN OUTCOME MEASURES: The primary efficacy variable was change from baseline in mean sitting diastolic blood pressure (MSDBP) at end-point. The secondary variable was change in mean sitting systolic blood pressure (MSSBP) from baseline to end-point. RESULTS: All active treatments produced a statistically significant difference in MSDBP (P < 0.001) from baseline to end-point compared with placebo. Similar results were obtained for MSSBP. All combination regimens produced a statistically significantly greater reduction in MSDPB and MSSBP than the corresponding monotherapies. Dizziness and headache were the most common treatment-related adverse experiences reported. Hypokalaemia, associated with the use of thiazide diuretics, was more commonly reported in the higher dose HCTZ 25 mg groups. CONCLUSIONS: Valsartan 80 mg and 160 mg act additively with HCTZ 12.5 mg or 25 mg to lower MSDBP and MSSBP in patients with essential hypertension. The addition of HCTZ to valsartan 80 mg or 160 mg was well tolerated.     

Effect of gallopamil on myocardial microperfusion in patients with stable effort angina: a randomized, cross-over, double-blind, placebo-controlled trial

We evaluated the efficacy and safety of daily administration of gallopamil 150 mg/day and its effects on myocardial perfusion in a medium-term, randomized, double-blind, cross-over, placebo-controlled trial. We studied 19 patients (17 males and 2 females; mean age 57 +/- 6.8 years) with stable effort angina, angiographically documented coronary artery disease and reversible perfusion defects during exercise thallium-201 myocardial scintigraphy of at least one segment of the left ventricle. After 2 weeks of a single-blind placebo run-in period, during which each patient underwent at least 2 exercise tests and a 48-hour Holter ECG recording, all patients were treated with either placebo or gallopamil 50 mg t.i.d. for 28 days. At the end of this period, patients crossed over to the alternate regimen. This phase was double blind. After treatment with placebo or gallopamil, patients underwent exercise tests, 24-hour Holter ECG recording and thallium-201 myocardial scintigraphy. Weekly angina frequency and trinitroglycerin (TNT) consumption and safety were also evaluated. No patients dropped out of the study because of major side effects. The number of total ischemic and symptomatic events recorded at 24-hour ECG monitoring, weekly angina frequency and TNT consumption were significantly reduced during gallopamil treatment. After gallopamil administration, exercise duration significantly increased (run-in: 419 +/- 116 s, placebo: 420 +/- 118 s, gallopamil: 511 +/- 144 s; p < 0.05), and ST segment depression was significantly reduced (run-in: -1.3 +/- 0.3 mm, placebo: -1.3 +/- 0.3 mm, gallopamil: -0.94 +/- 0.68 mm; p < 0.01), while heart rate, systolic blood pressure and rate-pressure product were unchanged at rest, at submaximal and at peak exercise. Qualitative and quantitative evaluation of myocardial perfusion and the myocardial uptake percentage of thallium-201 in ischemic zones were significantly improved by gallopamil treatment. These findings demonstrate that gallopamil can improve myocardial perfusion and reduce myocardial oxygen consumption.     

The efficacy of intravesical Tice strain bacillus Calmette-Guerin in the treatment of interstitial cystitis: a double-blind, prospective, placebo controlled trial

PURPOSE: Interstitial cystitis is a debilitating bladder disease of unknown etiology with no cure. A recent report suggested that bacillus Calmette-Guerin (BCG) may be effective in the treatment of interstitial cystitis. A randomized, prospective, double-blind, placebo controlled trial to evaluate the safety and efficacy of intravesical BCG in treating interstitial cystitis was done. MATERIALS AND METHODS: Patients meeting the National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases criteria for interstitial cystitis received 6 weekly instillations of Tice strain BCG or placebo. Periodic questionnaires, voiding diaries and cystometrograms were obtained. A total of 30 evaluable subjects was enrolled in the study with a mean followup of 8 months (range 6 to 13). Based on an exit questionnaire a responder was defined as one who rated the interstitial cystitis symptoms as moderately improved or better. RESULTS: A 60% BCG response rate was noted, compared to a 27% placebo response rate. Minimum voided volume and quality of life improved in the BCG group compared to placebo. Adverse events were similar in each group, mostly irritative in nature, and no significant systemic events were noted. CONCLUSIONS: Intravesical Tice strain BCG appears to be safe and efficacious in the treatment of interstitial cystitis. Additional studies must be performed to confirm the results of this pilot study.     

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.     

Whole blood platelet aggregation and coagulation factors in patients with systemic sclerosis

It is unclear whether the changes in platelet function which are observed in systemic sclerosis are a primary characteristic of this disease or whether they occur secondary to vascular changes. Whole blood platelet aggregation was studied in 26 patients with systemic sclerosis, normal subjects matched for age, sex and secondary characteristics, 19 patients with Raynaud's disease and 19 patients with systemic lupus erythematosus. Plasma levels of fibrinogen, von Willebrand factor antigen and factor VIII:C were also measured. Systemic sclerosis was associated with a significant (P > 0.001) enhancement of the sensitivity of platelets to collagen. In contrast, significant enhancement of the response to either ADP or adrenaline was not observed. Enhanced sensitivity to collagen was not associated with the presence of either Raynaud's disease or systemic lupus erythematosus. Systemic sclerosis was associated with significantly raised levels of von Willebrand factor antigen and fibrinogen. On an individual patient basis, von Willebrand factor antigen was related to the severity of the disease whereas platelet sensitivity to collagen was not. In conclusion, this study suggests that the enhanced sensitivity to collagen which occurs in systemic sclerosis is due to a primary change in the platelet and that this change can combine with elevated levels of adhesive proteins.     

A randomized, double-blind, controlled trial of natural interferon-beta therapy for e-antigen-negative chronic hepatitis B patients with abnormal transaminase levels

Intermittent interferon (IFN) therapy appears to be effective for patients with e-antigen-negative chronic hepatitis B who exhibit abnormal fluctuations of alanine aminotransferase (ALT) levels and histological evidence of disease progression. To determine the optimal dose of IFN in such patients, we studied the effects of natural IFN-beta in a prospective, randomized, double-blind, controlled trial in 36 patients with e-antigen-negative chronic hepatitis B who repeatedly demonstrated abnormal fluctuations in ALT levels. Thirty-six patients were randomly assigned to three groups, receiving doses of: 0.3 MIU IFN (group 1; n = 12), 1 MIU (group 2; n = 12), or 3 MIU (group 3; n = 12), administered twice per week for 24 weeks. Patients were regarded as responders if ALT levels remained within the normal range and HBV-DNA tested negative for 6 months after the initiation of the therapy. According to this criterion, treatment was effective in 16.7% of the patients (2/12) in group 1, 33.3% (4/12) in group 2, and 75% (9/12) in group 3, the efficacy rate in group 3 being significantly higher than that in the other two groups. However, in 12 of the 15 responders, (80%) ALT levels were frequently elevated again within 3 years of the termination of IFN therapy. Although IFN was effective in controlling the manifestations of hepatitis in terms of e-antigen-negative patients who exhibited abnormal fluctuations in ALT, it appears that continuous treatment with intermittent high-dose IFN is necessary to maintain ALT levels within the normal range.     

Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group

BACKGROUND: Phase II trials of leflunomide, an inhibitor of de-novo pyrimidine synthesis, have shown efficacy in rheumatoid arthritis. This double-blind randomised trial compared leflunomide with placebo and sulphasalazine in active rheumatoid arthritis. METHODS: 358 patients were randomly assigned leflunomide (100 mg daily on days 1-3, then 20 mg daily), placebo, or sulphasalazine (0.5 g daily, titrated progressively to 2.0 g daily at week 4). The primary endpoints were tender and swollen joint counts and investigator's and patient's overall assessments. Analyses were by intention to treat. FINDINGS: The mean changes in the leflunomide, placebo, and sulphasalazine groups were -9.7, -4.3, and -8.1 for tender joint count; -7.2, -3.4, and -6.2 for swollen joint count; -1.1, -0.3, and -1.0 for physician's overall assessment; and -1.1, -0.4, and -1.1 for patient's overall assessment. Leflunomide and sulphasalazine were significantly superior to placebo (p=0.0001 for joint counts; p<0.001 for assessments). Radiographic disease progression was significantly slower with leflunomide and sulphasalazine than with placebo (p<0.01). Most common adverse events with leflunomide were diarrhoea (17%), nausea (10%), alopecia (8%), and rash (10%). Transiently abnormal liver function was seen in three leflunomide-group patients and five sulphasalazine-group patients. There were two cases of reversible agranulocytosis in the sulphasalazine group. INTERPRETATION: Leflunomide was more effective than placebo in treatment of rheumatoid arthritis and showed similar efficacy to sulphasalazine. Leflunomide was well tolerated. This drug may be a useful option as a disease-modifying antirheumatic drug.     

Effects of mental and physical stress on platelet function in patients with stable angina pectoris and healthy controls

The effects of mental and physical stress on platelet function in patients with stable angina pectoris and healthy controls were investigated. Platelet function was studied at rest, and during mental stress (colour word test), or after exercise (bicycle ergometry), in 113 angina patients (21 on aspirin) and 50 matched controls. Platelet function was assessed by filtragometry ex vivo (reflecting platelet aggregability), by measuring platelet secretion (beta-thromboglobulin and platelet factor 4 levels in plasma), and by Born aggregometry in vitro. At rest, platelet function did not differ between patients and controls. Exercise increased platelet aggregability and secretion similarly in both groups. Aspirin did not attenuate the platelet activating effect of exercise despite inhibition at rest. Mental stress increased heart rate, blood pressure and plasma catecholamines, but platelet responses were highly variable. However, mental stress tended to shorten filtragometry readings in patients but not in controls (P < 0.05 between the groups); plasma beta-thromboglobulin showed a similar difference between patients and controls (P < 0.05 between the groups; aspirin-treated patients included). Physical exercise activates platelets in patients with stable angina pectoris and healthy controls. Aspirin is not an effective inhibitor of exercise-induced platelet aggregation. Platelet responses to mental stress are variable, but more pronounced in angina patients.     

Dose-dependent effect of betahistine on the vestibulo-ocular reflex: a double-blind, placebo controlled study in patients with paroxysmal vertigo

Behavioral adaptations exhibited by two African fossorial mammals for the reception of vibrational signals are discussed. The Namib Desert golden mole (Eremitalpa granti namibensis) is a functionally blind, nocturnal insectivore in the family Chrysochloridae that surface forages nightly in the Namib desert. Both geophone and microphone recordings in the substrate suggest that the golden mole is able to detect termite colonies and other prey items solely using seismic cues. This animal exhibits a hypertrophied malleus, an adaptation favoring detection of low-frequency signals. In a field study of the Cape mole-rat (Georychus capensis), a subterranean rodent in the family Bathyergidae, both seismic and auditory signals were tested for their propagation characteristics. This solitary animal is entirely fossorial and apparently communicates with its conspecifics by drumming its hind legs on the burrow floor. Auditory signals attenuate rapidly in the substrate, whereas vibratory signals generated in one burrow are easily detectable in neighboring burrows. The sensitivity to substrate vibrations in two orders of burrowing mammals suggests that this sense is likely to be widespread within this taxon and may serve as a neuroethological model for understanding the evolution of vibrational communication. Neuroethological implications of these findings are discussed.     

Effects of amlodipine and isosorbide dinitrate on exercise-induced and ambulatory ischemia in patients with chronic stable angina pectoris

This study was designed to compare once-daily administration of 5-10 mg amlodipine with two daily doses of 40 mg sustained-release isosorbide dinitrate in 59 patients with stable angina using a randomized, double-blind, crossover study design. Anginal episodes, nitroglycerin consumption, and possible adverse events were recorded in a diary. A maximal symptom-limited bicycle exercise test and 48-hour ambulatory ECG monitoring were performed at baseline and at the end of each 5-week period of therapy. Exercise time, time to angina, time to ST depression, and maximal ST depression were measured during exercise. During ambulatory monitoring, the number of ischemic episodes and the duration per hour of ST depression were assessed. Amlodipine significantly reduced anginal episodes (P < 0.001) when compared with isosorbide dinitrate. Furthermore, amlodipine prolonged time to ST depression (P < 0.001) and time to angina (P < 0.05) when compared with isosorbide dinitrate. The number and duration of ischemic episodes during ambulatory monitoring were significantly reduced with amlodipine when compared with baseline values (P < 0.05), whereas no differences were found between isosorbide dinitrate and baseline. Adverse events were reported more frequently with isosorbide dinitrate than with amlodipine (P < 0.02). Amlodipine appears to be more effective and tolerable than sustained-release isosorbide dinitrate as monotherapy for chronic stable angina.     

Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial

Amphotericin B, despite its intrinsic servere toxicity, is the most commonly used empirical antifungal therapy in cancer patients with unexplained fever not responding to empirical antibacterial therapy. The aim of this study was to show whether fluconazole was as effective as, and less toxic than, amphotericin, with no effort made to compare the antifungal activity of the two drugs. A group of 112 persistently febrile (> 38 degrees C) and granulocytopenic (< 1000 cells/mm3) cancer patients, not receiving any absorbable antifungal antibiotic for prophylaxis, with a mean age of 27 years (range 1-73 years), undergoing chemotherapy for a variety of malignancies and with a diagnosis of unexplained fever after at least 96 h of empirical antibacterial therapy, were randomised to receive either fluconazole (6 mg/kg/day up to 400 mg/day) or amphotericin B (0.8 mg/kg/day) as empirical antifungal treatment. Patients were required to have normal chest X-rays at randomisation, no previous history of aspergillosis and negative surveillance cultures for Aspergillus. The intention-to-treat analysis showed defervescence and survival without treatment modification in 42 of 56 patients (75%) in the fluconazole group and in 37 of 56 (66%) in the amphotericin B group (P = 0.4). Duration of therapy was 6 days (95% CI = 4-8 days) in both groups. Death occurred in 3 patients (5%) in the fluconazole and in 2 (4%) in the amphotericin B group. No fungal death was documented in either group. Adverse events developed in 18 of 56 patients (32%) in the fluconazole group and in 46 of 56 (82%) in the amphotericin B group (P < 0.001). In the amphotericin B group, 5 patients had treatment discontinued because of toxicity, versus none in the fluconazole group, a difference which approached statistical significance (P = 0.06). This study shows that fluconazole is by far less toxic than amphotericin B and suggests that it might be as effective as amphotericin B, in pragmatical terms and for this specific indication. However, numbers are too small to allow definitive conclusions about efficacy, and the use of fluconazole for this indication remains experimental. Future studies should try to identify patients more at risk of fungal infections, with the aim of individualising antifungal approaches.     

Recombinant human erythropoietin reduces the need for erythrocyte and platelet transfusions in pediatric patients with sarcoma: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the effect of recombinant human erythropoietin (EPO) and iron supplementation on transfusion requirements in pediatric patients with sarcoma who were receiving chemotherapy, we performed a double-blind, placebo-controlled, randomized trial. METHODS: Twenty-four pediatric patients with malignant solid tumors were randomly assigned to receive either placebo (saline solution) or EPO for a 16-week study period. The starting dose was 150 IU/kg per dose three times a week and was escalated by 50 IU/kg per dose increments monthly until packed red blood cell (PRBC) transfusion independence was achieved or a dosage of 300 IU/kg per dose was reached. Iron supplementation was prescribed at a dose of 6 mg of elemental iron per kilogram daily. The primary study end point was the comparison of PRBC transfusion requirements in the two groups. RESULTS: Of 24 patients, 20 were evaluable for response. The median PRBC transfusion requirement during the 16-week period was 23 ml/kg in EPO-treated patients versus 80 ml/kg in placebo patients (p = 0.02). The median number of single-donor platelet units transfused was zero in the EPO-treated patients compared with four in the placebo group (p = 0.005). No statistical difference in the intensity of bone marrow suppression was seen, as measured by the median number of complete blood cell counts with an absolute neutrophil count of < 1000 cells/microliter. CONCLUSIONS: Treatment with EPO and iron significantly reduces PRBC transfusions in pediatric patients receiving concomitant chemotherapy for malignant sarcomas. A decrease in the number of platelet transfusions was also seen and deserves further study.     

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 ralationship between changes in 5-HT induced platelet aggregation and clinical state in patients treated with fluphenazine

Platelet aggregation responses to 5-HT and adenosine diphosphate were examined in a population of eighteen patients treated with fluphenazine decanoate for longer than one year. 5-HT induced aggregation was enhanced in ten subjects. This enhancement was similar to that previously described in patients receiving chlorpromazine. Patients who showed enhanced 5-HT induced aggregation showed less rateable psychopathology and less extrapyramidal side-effects than patients who did not show enhancement. These findings suggest that platelet aggregation responses could be used to identify patients who could be safely withdrawn from long-term neuroleptic therapy.     

Short-term effects of captopril on exercise tolerance in patients with chronic stable angina pectoris and normal left ventricular function

A double-blind, placebo-controlled, crossover study was carried out to evaluate the short-term effects of captopril on exercise tolerance in 18 normotensive patients with chronic stable angina pectoris and normal left ventricular function. Captopril 25 mg (or placebo) was given twice, i.e. in the evening (10 p.m.) and the following morning (8 a.m.), prior to a maximal symptom-limited bicycle exercise test (11 a.m.). Captopril reduced the systolic and diastolic blood pressures at rest (p < 0.01) without causing any reflex tachycardia. The time to onset of S-T depression was prolonged (p < 0.05), and the maximal S-T depression was reduced (p < 0.02). No differences were found between captopril and placebo in total exercise duration or time to onset of angina. The effects of captopril on exercise-induced ischemia were demonstrated most clearly in patients who responded with a greater than 10 mm Hg fall in the resting systolic blood pressure. In conclusion, this study suggests that captopril has anti-ischemic properties, which may be of importance in the treatment of patients with chronic stable angina and normal left ventricular function. These beneficial effects probably relate to a reduction in afterload and myocardial wall stress and therefore a reduction in myocardial oxygen demand.     

Oral thymic extract for chronic hepatitis C in patients previously treated with interferon. A randomized, double-blind, placebo-controlled trial

Stress echocardiography and perfusion scintigraphy are both useful techniques in the assessment of myocardial viability. The use of one technique or the other as the first choice test depends mainly on each hospital's experience. Perfusion scintigraphy should be chosen as the first technique in the following situations: a) hospitals with little experience in stress echocardiography and a good Nuclear Medicine department; b) patients with a bad acoustic window in rest echocardiography; c) contraindication of a high dobutamine dose, and d) need of quantification of viable area. When having chosen echocardiography as the first technique, perfusion scintigraphy is indicated when the response to dobutamine of the asynergic area does not allow the confirmation or the rejection of the presence of viability.     

Molsidomine and isosorbide dinitrate: a comparative trial of tolerance in long-term intake by IHD patients with stable angina of effort

Potential tolerance to isosorbide dinitrate (ID) and molsidomine (M) was studied in 18 ischemic heart disease (IHD) patients with stable angina of effort entered in a double blind cross-over trial. Each drug was administered for 3 weeks 4 times a day in individual effective dose. Single doses of ID and M were similar by effectiveness, but after 3 weeks of regular intake their efficacy fell, ID becoming less potent than M. For ID, tolerance after long-term intake manifested in 7 out of 18 patients, for M--in 5 out of 18. Complete tolerance was registered in 3 of 18 and 1 of 18 patients, respectively. Thus, tolerance is possible for the two drugs, but for M it is less pronounced.