Oral immunotherapy of recurrent urinary tract infections: a double-blind placebo-controlled multicenter study

We treated 166 patients suffering from recurrent urinary tract infections under double-blind conditions for 3 months with 1 capsule daily of either the immunostimulating bacterial extract (85) or a placebo (81), followed by a 3-month observation period without the test drugs. The bacterial extract exerted a significant beneficial curative action and long-term consolidative effect on the frequency of recurrent urinary tract infections with marked improvements in the characteristic signs and symptoms. It was significantly superior to placebo for the majority of the assessed parameters: number of recurrent urinary tract infections, bacteriuria, leukocyturia, erythrocyturia, nitrituria, albuminuria and casts in urine. Consumption of antibiotics, chemotherapeutics, urinary antiseptics or disinfectants was significantly less under active drug therapy compared to placebo. Tolerance was good with only 2 side effects reported in 2 patients (2%) in the active group compared to 11 among 5 (6%) in the placebo group. Therefore, the bacterial extract can be considered an efficient and well tolerated drug for the treatment of urinary tract infections, and their accompanying signs and symptoms, as well as for decreasing the risk of recurrences and the need for antibiotics and other antibacterial drugs.     

Mianserin and chronic pain: a double-blind placebo-controlled process and outcome study

There is evidence that antidepressants may have an analgesic effect in chronic pain. To replicate this effect and to throw light on the processes involved, a 12-week cross-over double-blind trial of mianserin versus placebo was carried out in 4 diagnostic groups: A) depressive patients without pain complaints (n = 8), B) depressive patients with chronic organic pain (n = 8), C) patients with somatoform pain disorder and vital signs of depression (n = 11) and D) patients with chronic organic pain without depression (n = 8). Although a mianserin-induced antidepressant effect in group A was evident, no significant pain reduction was accomplished in any group. The reasons for this failure to replicate the antidepressant-induced analgesic effect are discussed.     

Botulinum toxin A for hyperkinetic facial lines: results of a double-blind, placebo-controlled study

Although enterotoxins have been implicated in disease states such as food poisoning and toxic shock syndrome, their role in infectious arthritis is not known. To study the arthritogenic properties of toxic shock syndrome toxin 1 (TSST-1), two pairs of S. aureus strains isogenic for TSST-1 production were injected intravenously into healthy Swiss mice. Mice injected with TSST-1-secreting staphylococcal strains developed more frequent and more severe arthritis than did mice inoculated with the isogenic TSST-1-deficient counterparts. Immunohistochemical analysis of arthritic joints revealed an equal number of infiltrating phagocytes in both groups; however, mice inoculated with TSST-1-producing staphylococci had significantly more (P < .01) interleukin-2 receptor-expressing cells in the inflamed synovium than did mice that received the isogenic counterpart. Thus, TSST-1 is a virulence determinant in S. aureus arthritis in mice. The precise mechanism by which this toxin contributes to the development and progression of arthritis needs further investigation.     

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.     

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.     

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.     

High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril

OBJECTIVES: To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. BACKGROUND: The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. METHODS: In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. RESULTS: At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses. CONCLUSIONS: Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.     

Oral glucocorticosteroid-sparing effect of budesonide administered by Turbuhaler: a double-blind, placebo-controlled study in adults with moderate-to-severe chronic asthma. Pulmicort Turbuhaler Study Group

The purpose of this study was to evaluate the correlation between alteration in telomere length and prognosis in patients with pathological stage I-II non-small cell lung cancer. We measured telomeric repeat length and telomerase activity by use of southern blot analysis of terminal restriction fragments and a non-radioactive ELISA-based assay, respectively. RESULTS: Alterations in TRF lengths were present in 17(29.8%) of 57 patients. Patients with altered TRF length had significantly shorter survival than did patients without (P = 0.0051). In multivariate analysis, only alteration in TRF length independently correlated with shortened survival (P = 0.0033).     

Clinical effects of buspirone in social phobia: a double-blind placebo-controlled study

BACKGROUND: The results of open pilot studies suggest that the serotonin-1A (5-HT1A) receptor agonist buspirone might be effective in social phobia. METHOD: In the present study, the efficacy of buspirone was investigated in patients with social phobia using a 12-week double-blind placebo-controlled design. Thirty social phobic patients (DSM-IV) were treated with either buspirone 30 mg daily or placebo. Efficacy of treatment was measured using the Social Phobia Scale (subscores anxiety and avoidance) and the Hamilton Rating Scale for Anxiety. RESULTS: Taking a reduction of 50% or more on the Social Phobia Scale as a criterion for clinically relevant improvement, only 1 patient on buspirone and 1 on placebo were classified as responder to treatment. A subjective and clinically relevant improvement was reported by 4 patients (27%) on buspirone and 2 patients (13%) on placebo. There were no statistically significant differences between buspirone and placebo on any of the outcome measures. Generally speaking, buspirone was well tolerated. CONCLUSION: The results of the study do not support the results of open studies, in which a reduction of social anxiety and social avoidance was reported in patients with social phobia treated with buspirone.     

Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-related outcome measures

BACKGROUND: To compare combined and sequential hormonal replacement therapies to each other as well as placebo in patients suffering from the postmenopausal syndrome. Clinical outcomes were measured concerning both the specific postmenopausal symptoms (using the Kupperman scale) and health or well-being dimensions (using subscales of the General Health Questionnaire and specific depression and anxiety scales). METHODS: A prospective randomized double-blind study over 12 months of 105 normal early postmenopausal women in the setting of a general hospital. RESULTS: Both hormone replacement therapies were superior to placebo on the Kupperman scale (sweating, hot flushing, myalgia and vertigo). The psychic symptoms on the Kupperman scale were psychometrically invalid. However, psychic symptoms as measured by the Beck Depression Inventory and the General Health Questionnaire were significantly improved by the hormonal replacement therapies. No differences were observed when combined therapy was compared to sequential therapy. CONCLUSION: One-year treatment with hormonal replacement therapy is superior to placebo in measuring the somatic and psychic symptoms of the menopausal syndrome. No differences were found in this respect between combined and sequential replacement therapy.     

Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study

The hypothesis was tested that 7-sulfooxymethylbenz[a]anthracene (7-SBA) is an ultimate electrophilic and carcinogenic form of 7-hydroxymethylbenz[a]anthracene. In conformity with this hypothesis, 7-SBA was more carcinogenic than 7-HBA in inducing sarcomas at the site of repeated subcutaneous injection. These metabolites were individually administered to female Sprague-Dawley rats, beginning at 30 days of age, in 0.2 mumol doses given three times each week for 20 doses. One year after the first injection of 7-SBA, seven of thirteen female Sprague-Dawley rats had developed sarcomas. 7-HBA, on the other hand, had induced sarcomas at the site of injection in only two of tweleve rats. No tumors developed either in the control group given sesame oil:DMSO only or in the untreated control group. It would appear from the results summarized here that the search for an ultimate electrophilic and carcinogenic form of 7-HBA has been successful.     

Oral dolasetron mesylate for prevention of postoperative nausea and vomiting: a multicenter, double-blind, placebo-controlled study. The Oral Dolasetron PONV Prevention Study Group

Parafunctional activities are assumed to play an important role in temporomandibular disorders (TMD), but experimental data in support of this hypothesis are lacking. This study examined the role of parafunctional clenching on various measures of TMD pain. Five subjects participated in daily 17-minute electromyogram biofeedback training sessions structured in three phases. Subjects were instructed to maintain temporalis and masseter muscle activity below 2 microV in the first (decrease) phase of training (10 sessions), above 10 microV in the second (increase) phase (1 to 8 sessions), and below 2 microV in the third (decrease) phase (10 to 15 sessions). Preliminary screening examinations showed that none of the subjects had TMD. Two subjects reported intolerable pain during increase training, and both were diagnosed with a TMD during this phase. No subject was diagnosed with TMD pain during either decrease training phase. The authors conclude that chronic, low-level parafunctional clenching may be a factor in the cause of TMD pain.     

L-ornithine vs. L-ornithine-L-aspartate as a treatment for hyperammonemia-induced encephalopathy in rats

BACKGROUND/AIMS: The effect of L-ornithine (ORN) and L-ornithine-L-aspartate (OA) therapy on "extracerebral" nitrogen metabolism, brain metabolism and neurotransmission has been investigated in portacaval shunted rats with hyperammonemia-induced encephalopathy. METHODS: One day before ammonium-acetate infusion, a portacaval shunt was performed in three experimental groups: 1-control rats, 2-ORN-treated rats and 3-OA-treated rats. Ammonium-acetate was given as an intravenous bolus injection (0.4 mmol.kg bw-1) followed by a constant infusion (1.9 mmol.kg bw-1.h-1) so that steady-state blood ammonia concentrations (500-800 microM) were obtained in the course of 5 h. After 1 h, ammonium-acetate infusion, either L-ornithine or L-ornithine-L-aspartate, was infused for the next 4 h (3.0 mmol.kg bw-1.h-1) in the treated groups. The following parameters were measured: clinical grade of encephalopathy, EEG activity (n = 10 - 20/group), amino acids in plasma (n = 10 - 20/group) and brain dialysate (n = 5 - 9/group), and brain metabolites obtained by in vivo cerebral 1H-MRS (n = 4 - 6/group). RESULTS: ORN and OA treatment resulted in significantly lower blood (34% and 39%) and brain (42% and 22%) ammonia concentrations, significantly higher urea production (39% and 86%) and significantly smaller increases in brain glutamine and lactate concentrations than in controls. These changes were associated with a significantly smaller increase in clinical grade of encephalopathy in ORN- and OA-treated rats, and a significant improvement in EEG activity in ORN-treated rats. OA-treated rats showed a significant increase in aspartate and glutamate concentrations in brain dialysate. CONCLUSIONS: The beneficial effects of both treatments on the manifestations of hyperammonemia-induced encephalopathy can be explained by a reduction in blood and brain ammonia concentrations. It is suggested that when OA is administered, the effect of ornithine is partly counteracted by aspartate, inducing high brain extracellular concentrations of the two excitatory amino acids glutamate and aspartate, and perhaps causing overstimulation of NMDA receptors.     

Bromocriptine in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled study

The objective of this study was to investigate the efficacy and safety of bromocriptine (BRC) as an adjunct to conventional treatment in systemic lupus erythematosus (SLE). A prospective, double-blind, randomized, placebo-controlled study compared BRC at a fixed daily dosage of 2.5 mg with placebo. Patients were followed for 2-17 months (mean 12.5 months). Disease activity was assessed using the SLE Disease Activity Index (SLEDAI), numbers of flares were recorded, and serum prolactin (PRL) levels were obtained at intervals during the study. Patients were allowed to take prednisone and immunosuppressive drugs. Sixty-six patients with SLE entered the study. Thirty-six were treated with BRC, and 30 controls received placebo. Sixteen patients were removed from the study during the treatment period: five in each group left the study because of adverse effects, five became pregnant, and one patient who took placebo died with central nervous system lupus. Four patients in the BRC treatment group and three patients in the placebo group moved away or stopped coming for study visits for unknown reasons, and were lost to follow-up during the course. At entry, serum PRL was (mean+/-s.d.) 24.8 ng/ml+/-18.4 in the BRC treatment group. This value fell to 5.8+/-9.0 after 12 months of treatment. Corresponding PRL values in controls were 23.7+/-22.1 pretreatment and 20.3+/-14 after 12 months. PRL levels in BRC-treated subjects were significantly lower than levels in control subjects after 3, 6, 9, and 12 months of treatment. The SLEDAI score on the fifth protocol visit was decreased significantly in the BRC group vs controls: 0.9+/-1.4 vs 2.6+/-4.5 (P < 0.05). Although the absolute number of flares in each group was similar, the mean number of flares/patient/month was decreased significantly in the BRC group compared to the control group (0.08+/-0.1 vs 0.18+/-0.2, P = 0.03). Long term treatment with a low dose of BRC appears to be a safe and effective means of decreasing SLE flares in SLE patients.     

S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study

A tubular bioassay was used to measure analytically the local production and concentration of the antifungal Trichoderma secondary metabolite 6-n-pentyl-2H-pyran-2-one (6PAP) at the Trichoderma antagonist/pathogen interface. 6PAP levels significantly increased in the presence of the pathogen Botrytis cinerea, typically 300-700%, and were highest near the pathogen source. The level of response for a particular Trichoderma isolate was found to vary with the test organism used. Two products produced by biotransformation of 6PAP by B. cinerea in response to the interaction were also detected.     

Bathing suit delivery of 8-methoxypsoralen for psoriasis: a double-blind, placebo-controlled study

Twenty-four patients, 15 men and 9 women, aged 18-70 years with stable plaque-type psoriasis involving more than 20% of the body surface were subjected to a randomized, double-blind, age- and sex-matched, placebo-controlled study. Containers containing 25 mL of either 1% 8-MOP or a color-matched placebo were randomly numbered and stored. To 2 L of water was added 0.8 mL of 1% 8-MOP to obtain a concentration of 3.75 mg/L3, into which a bathing suit was soaked for 5 min. The suits were then gently squeezed to remove excess water and the patients were advised to put on the suit covered by a raincoat for 15 min. Immediately after removal of the raincoat and the suit, patients were irradiated with an initial dose of 4 J/cm2 UVA with increments of 0.5 J/cm2 on alternate days in a whole-body phototherapy unit obtained from the National Biological Corporation, Ohio. Erythema, scaling, and thickness (EST) of the index lesions were assessed on a 3-point scale (Table 1) and photographs were taken before and after completion of the study.     

Recombinant interferon-alpha therapy for acute hepatitis B: a randomized, double-blind, placebo-controlled trial

In spite of the availability of hepatitis B vaccine, acute hepatitis B continues to be a worldwide problem for which no specific therapy is available. We investigated the safety and the effectiveness of recombinant interferon-alpha2b (rIFN-alpha2b) in the treatment of acute hepatitis B by determining overall severity and duration of symptoms, time required to clear viral antigens and hepatitis B virus (HBV) DNA, and titre of antibodies to hepatitis B surface antigen (HBsAb), 24 weeks after the onset of therapy. One hundred patients were randomly assigned to treatment with either 3 million units (MU) (n = 34) or 10 MU (n = 33) rIFN-alpha2b or to placebo (n = 33), three times weekly for 3 weeks. Follow-up was for 24 weeks. A significantly shorter duration of the symptoms and signs of acute hepatitis was observed in patients who received 3 MU rIFN-alpha2b compared with those who received 10 MU rIFN-alpha2b or placebo. Twenty-one weeks post-therapy, patients treated with 10 MU rIFN-alpha2b showed a significantly higher geometric mean HBsAb titre than those treated with placebo (85.1 vs 35.5 IU l-1, P < 0.05). rIFN-alpha2b administration was well tolerated even in jaundiced patients. No serious side-effects were observed necessitating reduction in dose or discontinuation of the drug. The effect of rIFN-alpha2b on transition of HBV infection to chronicity could not be evaluated in this trial because such an unfavourable course was not seen in any of the treated or the control patients. In conclusion, rIFN-alpha2b was safe in acute hepatitis B, and at low dose was found to ameliorate symptoms and to shorten significantly the duration of illness.     

Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial

PURPOSE: To study the efficacy and safety of various dosages of metformin as compared with placebo in patients with type II diabetes mellitus. PATIENTS AND METHODS: A 14-week, multicenter, double-blind, dose-response study was conducted. After a 3-week, single-blind, placebo-controlled washout, 451 patients with fasting plasma glucose levels of at least 180 mg/dL were randomized to receive an 11-week course of placebo or metformin given at 500, 1000, 1500, 2000, or 2500 mg daily. RESULTS: Metformin improved glucose variables as compared with placebo. The adjusted mean changes in fasting plasma glucose from baseline associated with each metformin group at week 7, 11, or at endpoint exceeded those associated with placebo by 19 to 84 mg/dL at dosages of 500 to 2000 mg daily, respectively. The corresponding between-group differences in glycated hemoglobin (HbA1c) ranged from 0.6% to 2.0% at dosages of 500 to 2000 mg daily, respectively. All between-group differences were significant (P < 0.05) for both fasting plasma glucose and HbA1c at week 7, week 11, and endpoint, except for the difference between placebo and metformin 500 mg in fasting plasma glucose at endpoint (P = 0.054). Treatment-related adverse events occurred in 15% of patients in the placebo group and in 28% in the metformin group (P = 0.02); these were primarily manifested as digestive disturbances, such as diarrhea. CONCLUSIONS: Metformin lowered fasting plasma glucose and HbA1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin; maximal benefits were observed at the upper limits of the recommended daily dosage. All dosages were well tolerated. Metformin appears to be a useful therapeutic option for physicians who wish to titrate drug therapy to achieve target glucose concentrations.     

Combination therapy with thymosin alpha1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled double-blind trial

Hepatitis C is a major cause of liver disease leading to cirrhosis. Although interferon (IFN) is the only approved therapy, treatment is characterized by low response rates and dose-limiting side effects. We evaluated the addition of thymosin alpha1 (TA1), an immunomodulatory peptide, to the standard treatment regimen for hepatitis C to determine if combination therapy shows biological activity using outcome measures including normalization of alanine aminotransferase levels, histological activity, and viral load during treatment. We performed a randomized, double-blind, placebo-controlled trial to compare the biological activity of a combination TA1 and IFN with that seen for IFN alone in patients with chronic hepatitis C infection. One hundred nine patients were randomized for intention to treat and received 1.6 mg of TA1 subcutaneously twice weekly and 3 MU of IFN three times weekly; 3 MU of IFN three times weekly and placebo TA1; or placebo for both agents. All patients had chronic HCV infection with confirmation of chronic hepatitis on liver biopsy. Biochemical responders were followed up until alanine aminotransferase (ALT) levels became abnormal or for 26 weeks, and relapsers were retreated for 26 weeks in the same treatment arm. One hundred three patients completed treatment for 26 weeks, and six patients dropped out. The groups were similar with regard to sex, gender distribution, baseline histological activity index (HAI) score, risk factors, and viral titers. End-of-treatment biochemical response was seen in 37.1% of patients treated with combination therapy, 16.2% of patients treated with IFN alone, and 2.7% of untreated controls by intent-to-treat analysis (IFN/TA1 vs. IFN, chi2 = 4.05, P = .04). HCV RNA clearance was seen in 37.1% of IFN/TA1-treated patients and 18.9% of IFN-treated subjects. Mean HCV RNA titers were significantly lower than baseline at weeks 8, 16, and 24 after drug initiation among patients treated with IFN/TA1 but not in the other treatment arms. Histological improvement, as evidenced by a decrease in HAI of more than two points, occurred in the combination therapy arm more frequently than in comparison groups. Cumulative sustained biochemical responses were 14.2% and 8.1% in the IFN/TA1 and IFN arms, respectively, based on an intention-to-treat model. The combination of TA1 and standard IFN treatment for chronic hepatitis C showed evidence of biological activity at the completion of treatment by biochemical, histological, and virological outcome measures. Further research involving longer duration and varied dosing is needed.