Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, placebo-controlled, crossover trial

To examine the efficacy and toxicity of oral 3,4 diaminopyridine (DAP) in dosages up to 100 mg/day, 36 patients with multiple sclerosis (MS) enrolled in a randomized, double-blind, placebo-controlled, crossover trial. The primary outcome measure was improvement of a prospectively defined neurologic deficit, which was leg weakness in 34 patients. Secondary outcome measures included the patient's subjective response, scored manual motor testing (MMT) of leg strength, scored leg strength from videotaped motor testing (VMT), quadriceps and hamstrings strength (QMT) measured by isometric dynamometry, neuropsychological testing (NPT), ambulation index (AI), and Expanded Disability Status Scale (EDSS) score. Paresthesias and abdominal pain were common and were dose limiting in eight patients. Three patients had episodes of confusion, and one patient had a seizure while on DAP. Eight patients withdrew from the study, leaving 28 evaluable patients for the efficacy analysis. The prospectively defined neurologic deficit improved in 24 patients-22 on DAP and 2 on placebo (p = 0.0005). All improvements were in leg weakness. Subjective response and measures of leg strength and function (MMT, VMT, QMT, and AI) improved on DAP compared with placebo. Neither NPT nor EDSS scores improved. DAP treatment can induce improvements in leg strength in MS patients, but toxicity is limiting in many patients.     

Desmopressin in the treatment of daytime urinary frequency in patients with multiple sclerosis

Necrotizing fasciitis is a rare but serious condition with a poor prognosis both in adults and in children. Retroperitoneal localization is mostly associated with fatal outcome. Early diagnosis, extensive and repeated surgical debridement, and use of antibiotics are necessary. Herein the authors report on a 4-year-old girl in whom retroperitoneal necrotizing fasciitis developed after she suffered from pyelonephritis. In this case, the outcome was favorable because of early surgical intervention, confirming the diagnosis.     

A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia

OBJECTIVE: To study the effect of fluoxetine (FL) and amitriptyline (AM), alone and in combination, in patients with fibromyalgia (FM). METHODS: Nineteen patients with FM completed a randomized, double-blind crossover study, which consisted of 4 6-week trials of FL (20 mg), AM (25 mg), a combination of FL and AM, or placebo. Patients were evaluated on the first and last day of each trial period. Outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) scale, and visual analog scales (VAS) for global well-being (1 completed by the physician and 1 by the patient), pain, sleep trouble, fatigue, and feeling refreshed upon awakening. RESULTS: Both FL and AM were associated with significantly improved scores on the FIQ and on the VAS for pain, global well-being, and sleep disturbances. When combined, the 2 treatments worked better than either medication alone. Similar, but nonsignificant, improvement occurred in the BDI scale, the physician global VAS, and the VAS for fatigue and feeling refreshed upon awakening. Trends were less clear for the tender point score. CONCLUSION: Both FL and AM are effective treatments for FM, and they work better in combination than either medication alone.     

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.     

Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial

BACKGROUND: The pharmacological effects of infusion of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure have not been characterized previously. METHODS AND RESULTS: Twenty patients with severe congestive heart failure were randomized in a double-blind, placebo-controlled, crossover trial to receive incremental 90-minute infusions of hBNP (0.003, 0.01, 0.03, and 0.1 microgram/kg per minute) or placebo on 2 consecutive days. At the highest completed dose of the hBNP, mean pulmonary artery pressure decreased from 38.3 +/- 1.6 to 25.9 +/- 1.7 mm Hg; mean pulmonary capillary wedge pressure decreased from 25.1 +/- 1.1 to 13.2 +/- 1.3 mm Hg; mean right atrial pressure decreased from 10.9 +/- 1 to 4.8 +/- 1.0 mm Hg; mean arterial pressure decreased from 85.2 +/- 2.0 to 74.9 +/- 1.7 mm Hg; and cardiac index increased from 2.0 +/- 0.1 to 2.5 +/- 0.1 L/min per square meter (all P < .01 versus placebo). Urine volume and urine sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90 +/- 38 versus 67 +/- 27 mL/h and 2.6 +/- 2.4 versus 1.4 +/- 1.2 mEq/h, respectively, both P < .05 versus placebo), whereas creatinine clearance and urinary potassium excretion did not change. CONCLUSIONS: Infusion of incremental doses of hBNP is associated with favorable hemodynamic and natriuretic effects in patients with severe congestive heart failure.     

Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial

A T-cell receptor (TCR) peptide vaccine from the V beta 5.2 sequence expressed in multiple sclerosis (MS) plaques and on myelin basic protein (MBP)-specific T cells boosted peptide-reactive T cells in patients with progressive MS. Vaccine responders had a reduced MBP response and remained clinically stable without side effects during one year of therapy, whereas nonresponders had an increased MBP response and progressed clinically. Peptide-specific T helper 2 cells directly inhibited MBP-specific T helper 1 cells in vitro through the release of interleukin-10, implicating a bystander suppression mechanism that holds promise for treatment of MS and other autoimmune diseases.     

Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial

BACKGROUND: The selective serotonergic medication fluoxetine has demonstrated efficacy in the treatment of major depression and has suggested efficacy in the treatment of alcoholism. However, no completed trials with any selective serotonergic medication have been reported in patients who display both major depression and alcoholism, despite previous observations that both depression and alcoholism are associated with low serotonergic functioning. METHODS: Fifty-one patients diagnosed as having comorbid major depressive disorder and alcohol dependence were randomized to receive fluoxetine (n = 25) or placebo (n = 26) in a 12-week, double-blind, parallel-group trial. Weekly ratings of depression and alcohol consumption were obtained throughout the 12-week course of the study. RESULTS: The improvement in depressive symptoms during the medication trial was significantly greater in the fluoxetine group than in the placebo group. Total alcohol consumption during the trial was significantly lower in the fluoxetine group than in the placebo group. CONCLUSIONS: Fluoxetine is effective in reducing the depressive symptoms and the alcohol consumption of patients with comorbid major depressive disorder and alcohol dependence. It is unknown whether these results generalize to the treatment of less depressed and less suicidal alcoholics.     

Lipid peroxidation in patients with multiple sclerosis

Questions of lipid metabolism in patients with multiple sclerosis are considered in the light of biomembrane (myelin) pathology. The results of of the study of the lipids fatty acids spectrum in the blood plasma and the secondary product of their spontaneous and NADPhH-dependent peroxidation, malonic dialdehyde, are stated. The dependence of changes in saturation of fatty acids spectrum and dialdehyde concentrations on the stage and heaviness of the multiple sclerosis is shown. Certain dynamics of lipid metabolism indices as a result of treatment was found. The authors also give some recommendations as to the use of drugs at various stages of the disease.     

Influenza vaccination in patients with multiple sclerosis

Vaccination was well tolerated by 93 patients with multiple sclerosis who received a total of 209 doses of influenza vaccine. In one patient, evidence of a new lesion developed after vaccination; the relapse rate was less than would be expected in the natural course of the illness. Toxic and allergic reactions appeared with 7% and 0.5% of the vaccinations, respectively--a rate no higher than that observed in the general population.     

A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression

BACKGROUND: Case reports and open studies have reported beneficial therapeutic effects of adding buspirone to a selective serotonin reuptake inhibitor (SSRI) in the management of treatment-refractory depression. This is the first placebo-controlled study to evaluate the efficacy and safety of this combination. METHOD: One hundred nineteen patients (82 women, 37 men) who fulfilled criteria for a major depressive episode according to DSM-IV and who had failed to respond to a minimum of 4 weeks (mean = 211 days) of treatment with citalopram or paroxetine were randomly assigned to 4 weeks of treatment with an SSRI plus buspirone (N = 58) or an SSRI plus placebo (N = 61). In addition, 97 patients participated in an optional open-label poststudy treatment phase with the SSRI plus buspirone for 2 weeks. The primary outcome measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale. RESULTS: A total of 50.9% of patients in the buspirone group and 46.7% in the placebo group responded after 4 weeks of treatment. The difference in response rate was not statistically significant. No statistically significant differences were found in the frequency of adverse events. At the follow-up of the open SSRI plus buspirone treatment, 69.4% of patients had responded. CONCLUSION: Adding buspirone to an SSRI is a safe and well-tolerated drug regimen. This study failed to demonstrate any difference in efficacy between buspirone or placebo augmentation of an SSRI. It could be argued, however, that the study was inconclusive due to the unusually high placebo response.     

A trial of antilymphocyte globulin in the treatment of chronic progressive multiple sclerosis

Twenty-three patients with chronic progressive multiple sclerosis (MS), resistant to steroid therapy, were treated with antilymphocyte globulin (ALG) and prednisone (30 mg by mouth daily). Twelve patients completed a full course of therapy (2 ml ALG i.m. daily for 2 weeks and 2 ml i.m. on alternate days for 2 weeks) and 6 others completed at least 2 weeks of daily injections. Six patients experienced an overall improvement of at least 15% using a comprehensive neurological scoring system. Three other patients had limited, but functionally useful improvement in specific neurologic functions. Six months after the completion of therapy, no patient had deteriorated to a level of function below that noted prior to treatment. Adverse reactions, which often necessitated stopping treatment, included fever, local inflammatory reactions, local rash, general malaise, mild anaphylactoid reactions, and enlargement and tenderness of regional lymph nodes. Because of the short duration of immunosuppression and the toxic side effects of ALG, we do not feel that ALG treatment yet deserves to be intorduced as a standard treatment in clinical practice. However, the improvement or arrest of progression seen in these patients who were deteriorating progressively despite steroid therapy would seem to justify a continued search for a safer method of suppressing immunity in MS patients.     

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.     

New therapeutic agents in the management of multiple sclerosis

THERAPEUTIC ADVANCES: Several effective therapies for multiple sclerosis capable of modifying the disease course in certain patients are now available in France. INTERFERONS: Interferon beta-1b and interferon beta-1a have been given specific marketing approval in France for ambulatory patients with active relapsing-remitting multiple sclerosis. Interferon beta-1b has been shown to have a beneficial effect in progressive multiple sclerosis. COPAXONE: This drug has a temporary authorization in France for ambulatory patients with relapsing-remitting multiple sclerosis who cannot tolerate interferon. PERSPECTIVES: Other promising therapeutic options (mitoxantrone, intravenous immunoglobulins, drug associations) are under evaluation.     

Bladder dysfunction and management in multiple sclerosis

Symptomatic bladder dysfunction occurs at some time in most patients with multiple sclerosis. The relapsing-remitting course and progressive loss of mobility associated with multiple sclerosis make management of urinary urgency and incontinence difficult. Urodynamic evaluation serves as a guideline for appropriate treatment. After accurate diagnosis of bladder dysfunction, a management program is developed with use of fluid schedules, voiding techniques, neuropharmacologic manipulation, intermittent catheterization, surgical treatment, and other adjunctive measures as indicated. The goals of treatment are to protect and preserve renal function, relieve symptomatic voiding dysfunction, and avoid subsequent urinary complications. A management program should be individualized, dynamic, and monitored with periodic, systematic urologic review to maintain these goals.     

Influenza virus vaccination of patients with multiple sclerosis

Our previous data showed that at least five PKC isoforms (alpha, delta, zeta, lambda and tau) were present in the decidualization. In this study, we then localized the PKC alpha and zeta by immunohistochemistry in the decidualized uterine tissues. The decidualized uterine tissues were induced by trauma-stimulation and fixed in formalin. The immunofluorescence were photographed by confocal microscope. The data revealed that the fluorescence of PKC alpha was present in the deciduomata and myometrium. In the deciduomata, PKC alpha was mainly located in the surrounding nuclear. This phenomenon of localization was especially performed on day 2 and 3 of the decidualization, just on the time of higher frequence of cell mitosis. Since the myometrium with hypertrophy did not display the phenomenon of perinuclear localization, these suggested that the expression and localization of PKC alpha may be associated with the cell proliferation. On the other hand, the PKC zeta was also present and distributed broadly in the deciduomata and myometrium. This expression was increased and similar to the previous Western blot studies. Thus, the data confirmed that the various expression and localization of PKC isoforms may be correlated with the development of deciduomata.     

The metabolic characteristics of patients with multiple sclerosis

A comprehensive clinical and biochemical evaluation has been carried out in patients with multiple sclerosis (MS). Measured in the patients' blood were levels of cholesterol, triglycerides, malonic dialdehyde, and superoxidedysmutase activity. The interrelationship revealed between the above measures provides a deeper insight into the mechanisms of pathometabolism in MS.     

Treatment of acute cortical infarct with intravenous glycerol. A double-blind, placebo-controlled randomized trial

BACKGROUND AND PURPOSE: This clinical trial investigates the effectiveness of intravenous glycerol therapy in patients with acute cortical infarction in whom intracerebral hemorrhage was rigorously excluded. METHODS: Within 48 hours of symptoms from their first ischemic stroke, 113 hospital inpatients were randomized into the trial, provided that hemorrhage was excluded by computed tomography and informed consent was obtained. Patients were stratified into alert, semicoma, and coma groups using the Glasgow Coma Scale. Treatment was allocated according to a double-blind, randomized protocol; 56 patients received 500 mL of 10% glycerol in saline over 4 hours on 6 consecutive days, and 57 patients received corresponding placebo treatment with saline. Using a variety of objective scoring systems, patient follow-up was up to 6 months. RESULTS: Corresponding measures of outcome in the glycerol and placebo groups were similar. At 6 months, respective mortality rates were 17 of 56 and 16 of 57, and mean +/- SD improvements in scores were 9.98 +/- 14.40 vs 10.51 +/- 12.68 (long-term), 1.12 +/- 7.20 vs 1.57 +/- 6.30 (prognostic), -1.94 +/- 5.53 vs -2.06 +/- 5.34 (Glasgow Coma Scale), and 21.72 +/- 23.40 vs 11.94 +/- 18.10 (Barthel Index rating in survivors). Hemolysis (generally subclinical) was the only adverse effect. CONCLUSIONS: There was no clinically or statistically significant difference in outcome between the groups; a trend toward greater functional recovery among survivors was evident after treatment with glycerol.