Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine.

Previous studies suggest that aminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. Although the mechanism underlying the beneficial effect on fatigue remains unclear, it has been proposed that aminopyridines may help to improve conduction in demyelinated central pathways, implicating both axonal and synaptic mechanisms. The objective of the present study is to determine whether 4-AP decreases daily-living fatigue in progressive multiple sclerosis. The effect of 4-AP on other neurophysiological and neuropsychological parameters was also considered. A 'double-blind', randomized, 'placebo-controlled', crossover trial was conducted on 54 patients with progressive multiple sclerosis. All patients received treatment with placebo and 32 mg per day of 4-AP, each for 6 months. The main outcome measure was the Fatigue Severity Scale. Secondary measures were EDSS, cognitive functions and neurophysiological parameters. Forty-nine patients (91%) completed the study. Changes in fatigue scores, EDSS and cognitive functions were not significantly different between 4-AP and placebo. However, when patients treated with 4-AP were divided into two groups according to the serum level of 4-AP, a significant effect on fatigue compared with placebo was observed in the 'high level' (>30 ng/ml) group (P=0.05). Synchronization of motor evoked potentials improved during 4-AP with respect to placebo (P=0.019) and this correlated positively with fatigue reduction (P=0.010). No relevant side effects were observed.     

Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study

OBJECTIVE: To determine the safety of sustained-release 4-aminopyridine in subjects with mutiple sclerosis (MS) and to examine dose-related efficacy up to 40 mg twice daily. METHOD: Multicenter, randomized, double-blind, placebo-controlled, study. Following a 4-week baseline peroid, subjects were randomly assigned to receive Fampridine-SR (n=25, doses from 10 to 40 mg twice daily, increasing in 5 mg increments weekly) or placebo (n=11). A battery of assessments was performed weekly, including the MS Functional Composite (MSFC), fatigue questionnaires, and lower extremity manual muscle testing. RESULTS: The most common adverse events were dizziness, insomnia, paresthesia, asthenia, nausea, headache, and tremor. Five subjects were discontinued from Fampridine-SR because of adverse events at doses greater than 25 mg, and these included convulsions in two subjects at doses of 30 and 35 mg twice daily. Improvement were seen in lower extremity muscle strength (prospective analysis) and walking speed (post-hoc analysis) in the Fampridine-SR group compared to placebo (unadjusted p-values of 0.01 and 0.03, respectively). There were no significant differences in other MSFC measure or fatigue scores. CONCLUSIONS: Future studies should employ doses up to 20 mg twice daily with lower extremity strength and walking speed as potential outcome measures.     

Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis

4-Aminopyridine (4-AP), a potassium channel blocker, restores conduction in blocked, demyelinated animal nerve. Its administration to multiple sclerosis (MS) patients produces transient neurological improvements. Vision improves after either oral or intravenous administration, whereas motor function improvement has been reported only with the latter. To assess further its potential as a practical symptomatic treatment, we studied the efficacy of single, oral doses of 4-AP on both visual and motor signs in MS. Twenty temperature-sensitive male MS patients were given either 10 to 25 mg of 4-AP or identically appearing lactose placebo capsules. Static quantitative perimetry, critical flicker-fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations were monitored. All of 15 MS patients given 4-AP mildly to markedly improved. Motor functions (power, coordination, gait) improved in 9 of 13 involved, vision in 11 of 13, and oculomotor functions in 1 of 2. Improvements developed gradually at doses as low as 10 mg, usually beginning within 60 minutes after drug administration, and reversed gradually over 4 to 7 hours. No serious adverse effects occurred. No significant changes were observed in 5 MS patients given placebo. We conclude that orally administered 4-AP produces clinically important improvements in multiple, chronic deficits in MS. Further studies are warranted to assess efficacy and safety of prolonged administration.     

Cyclandelate in diabetic neuropathy. A double-blind, placebo-controlled, randomized, cross-over study

Cyclandelate has the ability to improve the rheological properties of the blood and therefore may improve blood supply of peripheral nerves. Previous studies in diabetic neuropathy have shown beneficial effects of the drug. We performed a double-blind, placebo-controlled, cross-over study in 40 diabetic patients with cyclandelate in a dose of 1600 mg daily. Motor and sensory nerve conduction velocities, late responses, thermal discrimination thresholds, vibration perception thresholds and pain scores were studied. We were not able to show any positive effect of the drug and therefore conclude that cyclandelate is not effective in the treatment of diabetic neuropathy.     

A randomized, double-blind, placebo-controlled study of oral hydrolytic enzymes in relapsing multiple sclerosis

Oral administration of hydrolytic enzymes (HE), such as bromelain, trypsin and rutosid, may have beneficial effects on the clinical course of neurological symptoms related to multiple sclerosis (MS). This is supported by a complete protection by HE from experimental allergic encephalomyelitis, an animal model related to MS. Three hundred and one patients with relapsing MS were enrolled in a double-blind, placebo-controlled trial. No treatment effect between the placebo and the HE groups was found either for clinical or MRI parameters.     

Lithium addition to neuroleptic treatment in chronic schizophrenia: a randomized,double-blind,placebo-controlled,cross-over study

We studied the effect of lithium addition to neuroleptic treatment in chronic schizophrenia, for which contradictory results have been produced in previous studies. Twenty-one chronic schizophrenic inpatients received lithium in a study with randomized, double-blind, placebo-controlled, cross-over design consisting of 8 weeks each of treatment with lithium capsules and identical placebo capsules. The total Brief Psychiatric Rating Scale (BPRS) scores at week 8 of the lithium treatment were improved significantly compared with those at week 8 of the placebo treatment. Of the BPRS subscales, however, only anxiety-depression improved, whereas none of the subscales for anergia, thought disturbance, activation and hostile-suspiciousness improved. There was no significant difference between the total Scale for the Assessment of Negative Symptoms (SANS) scores at any time during lithium and placebo treatment. These results suggest that the addition of lithium to neuroleptic treatment improves anxiety-depression in chronic schizophrenia.     

High dose Vitamin D intake and quality of life in relapsing-remitting multiple sclerosis: a randomized,double-blind,placebo-controlled clinical trial

Background: Low level of vitamin D is associated with a more severe course and low quality of life in relapsing-remitting multiple sclerosis (RRMS). Low dose vitamin D intake has improved quality of life in RRMS patients.

Objective: This study explored the effect of high dose vitamin D intake on quality of life in RRMS patients in a double blind randomized clinical trial.

Methods: 94 RRMS patients were randomized to two groups. One group received 50,000 IU vitamin D3 every five days for 3 months. The other group received placebo. Interferon-β (IFN-β) continued as the main treatment in both groups. Quality of life was assessed using MSQOL-54 Persian version at the beginning and at the end of the study.

Results: After 3 months, the vitamin D group had a significant difference in mental health composite with placebo group, 62.41 ± 13.99 vs. 60.99 ± 17.99 (p-value = 0.041). Change in health was 75.74 ± 25.73 and 70.59 ± 26.45 in vitamin D and placebo group, respectively (p-value = 0.036).

Conclusions: Mental QOL improved significantly after taking high dose vitamin D for 3 months in vitamin D group relative to placebo.     

Levosulpiride in somatoform disorders: A double-blind,placebo-controlled cross-over study

BACKGROUND: Suicide notes may provide valuable information about suicide victims' final thoughts, and thus may be considered as markers of the severity of the suicide attempt. However, very few studies have described the characteristics of elderly suicide note-writers and their final thoughts. INTRODUCTION: To explore whether there is a difference between those who do and do not leave a note among the elderly victims of Fatal Self Harm (FSH). Also to examine the content of suicide notes and their clinical significance. METHODS: We carried out a retrospective review of suicide notes obtained from coroners' records of FSH in all over 60 years of age in Cheshire over a period of 13 years (1989-2001). The term 'Fatal Self Harm' was applied to all those who were subjects of coroner's inquests and attracted verdicts of suicide, misadventure and open verdicts. RESULTS: In 71 cases (33%) (43 males, 28 females) (61% M, 39% F) suicide notes were reported in the coroner's records. The variables that appeared to differ significantly between the note-leavers and non-note-leavers were: a suicide verdict, not known to psychiatric services, and method of FSH ( P < 0.05). Gender, marital status, history of DSH, social isolation, mental or physical morbidity did not appear to differ between the two groups. More of those who took an overdose, used plastic bags, electrocuted themselves or used car exhaust fumes left suicide notes. Those who died by hanging, jumping from a height, immolation or wounding appeared equally likely to leave or not to leave a suicide note. Significantly fewer cases who died by drowning left suicide notes ( P < 0.01). No statistically significant difference in the content of suicide notes was observed in relation to gender or age. CONCLUSION: The failure to identify consistent parameters that could differentiate between note-leavers and non-note-leavers only leads to the conclusion that a minority of suicide victims leave suicide notes. Suicide note-writers may not be typical of the average suicide case and information elicited from the study of suicide notes may only apply to note-writers and not to suicide in general. However, the absence of a suicide note must not be considered an indicator of a less serious attempt. (Int J Psych Clin in Pract 2002; 6: 155-161)     

4-Aminopyridine improves clinical signs in multiple sclerosis

Twelve temperature-sensitive male patients with multiple sclerosis and 5 normal men were monitored before, during, and after the intravenous injection of 7 to 35 mg of 4-aminopyridine (4-AP) in 1- to 5-mg doses, every 10 to 60 minutes. Static quantitative perimetry, flicker-fusion frequency, visual acuity, and videotaped neurological examinations were performed. Ten of the 12 patients showed mild to marked improvement. Vision improved in 7 patients, oculomotor function in 5, and motor function (power, coordination, gait) in 5. Improvements developed gradually within minutes of drug injection at doses as low as 2 mg, and gradually reversed around 2 to 4 hours after the peak drug effect. No effects were observed in 5 patients given saline injections. No serious side effects occurred in either the normal subjects or the patients receiving 4-AP. It is concluded that 4-AP lessens multiple neurological deficits in multiple sclerosis and, furthermore, that the K+ channel is functional in demyelinated central nervous system axons in humans. The improvements with 4-AP are substantial enough to be of transient therapeutic benefit in selected patients.     

American ginseng does not improve fatigue in multiple sclerosis: a single center randomized double-blind placebo-controlled crossover pilot study

This study examined the safety and efficacy of an escalating dose (100?mg, 200?mg, 400?mg/day) of American ginseng over 6 weeks in a single-center, randomized, double-blind, placebo-controlled, crossover trial with 56 subjects with multiple sclerosis and fatigue. There were no serious adverse events but fatigue on ginseng, as assessed by the Fatigue Severity Scale, was not significantly different from fatigue on placebo.     

Hyperbaric oxygen and multiple sclerosis: final results of a placebo-controlled, double-blind trial.

The long term results are reported of a trial involving 120 patients with chronic multiple sclerosis who were randomised to receive either 100% oxygen at 2 atmospheres absolute (ATA) for 90 minutes daily for 20 sessions or placebo therapy with air using a simulated compression procedure. The previous finding of subjective improvement in bowel/bladder function at the end of treatment was not confirmed by objective urodynamic assessment. The treatment did not alter disease progression as measured by the Kurtzke disability status scale nor did it alter the rate of acute relapse. There was less deterioration in cerebellar function at one year in the treated patients as measured by the Kurtzke functional systems scale. No other differences were found between the two groups. Psychometric tests and measurements of lymphocyte sub-populations showed no treatment related effects. Evoked potential studies showed no improvements but there was a significant reduction in amplitude of the visual evoked potential in the treated patients at the end of therapy. This might indicate a reversible degree of retinal damage induced by oxygen toxicity.     

The effect of levetiracetam on focal nocturnal epileptiform activity during sleep--a placebo-controlled double-blind cross-over study

Electric Status Epilepticus during Sleep (ESES) occurs in children with and without epilepsy. It may be related to disturbances as autism spectrum disorder, attention-deficit hyperactivity disorder and acquired aphasia (Landau-Kleffner syndrome). Antiepileptic drug (AED) treatment has been reported in small studies without placebo control. This study was designed to assess AED effect in a placebo-controlled double-blind cross-over study. Levetiracetam (LEV) was chosen based on clinical evidence. Eighteen patients fulfilled the inclusion criteria. The mean spike index at baseline was 56, falling to a mean of 37 at the end of the LEV treatment period. Assessed with a 2-way ANOVA, there is a significant treatment effect (p<0.0002). To the best of our knowledge, this is the first placebo-controlled double-blind cross-over study for any AED in patients with ESES. The effect of LEV is comparable with its effect in treatment of epileptic seizures.     

Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study

BACKGROUND: An inverse association between cigarette smoking and the risk of idiopathic PD has been found in many epidemiologic studies. The therapeutic and possible neuroprotective effects of nicotine formulations on parkinsonian symptoms are controversial. METHODS: In a 12-week, randomized, double-blind, placebo-controlled trial, the efficacy and tolerability of transdermal nicotine patches as an add-on treatment for cardinal symptoms were evaluated in 32 nonsmoking patients with PD. After a 1-week run-in phase, patients were randomized to receive nicotine patches (containing 17.5 mg nicotine in the first and 35.0 mg nicotine in the second and third weeks) or identically appearing placebo patches. After this treatment, 3 weeks without patch application followed. The same blinded examiner assessed the patients with the Columbia University Rating Scale, the Webster scale, the Schwab-England scale, a timed walking test, with an instrumental test for fine motor skills and hand tremor, and with the Hamilton Depression Scale. RESULTS: No significant drug effects between both groups were observed in any of the scores and quantitative tests. Side effects were mild and comparable in frequency between both groups. CONCLUSIONS: With the dosage and the period of treatment chosen, transdermal nicotine patches are not effective as an add-on treatment for symptoms of PD.     

Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind,randomized, placebo-controlled clinical trials

Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of GA efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of GA on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of GA on accumulated disability and the potential role of baseline clinical variables as predictors of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo-treated subjects and 0.82 in the pooled GA group (P = 0.004), indicating an average reduction in annualized relapse rate of 28%. About a one third reduction of the total number of on-trial relapses was also observed in patients receiving GA (P < 0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P = 0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; CI = 0.4-0.9; P = 0.02). The drug assignment (P = 0.004), baseline EDSS score (P = 0.02) and number of relapses during the two years prior to study entry (P = 0.002) were significant predictors of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of GA in reducing relapse rate and disability accumulation in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that GA efficacy is not significantly influenced by the patients' clinical characteristics at the time of treatment initiation.     

Oral interferon beta-1a in relapsing-remitting multiple sclerosis: a double-blind randomized study

BACKGROUND: Interferon beta (IFNB) is available in parenteral formulations for treatment of multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability and effects on MRI lesions of three different doses of oral IFNB-1a compared with placebo over six months in relapsing-remitting (RR) MS patients. METHODS: In this multicenter; double-blind randomized trial, RR-MS patients received 0.06, 0.6 or 6 million international units (MIU) IFNB-1a or placebo every other day for up to six months. Gadolinium DTPA-enhanced brain MRI scans were performed at screening and monthly during treatment. The primary variable was the cumulative number of newly active lesions. Secondary variables included volume of enhancing lesions on T1-weighted images each month and lesion volume on T2-weighted images at months three and six. Safety measures included adverse events, laboratory variables, vital signs, ECG, physical examination, EDSS and number of relapses. Neopterin was measured in 21 patients and neutralizing antibodies in 24 patients. RESULTS: Of 194 screened patients, 173 were randomized (42-44 patients per group) in 15 centers. Median cumulative numbers of newly active lesions over six months were 4.0 in the placebo and 0.6 MIU groups, compared with 7.5 and 9.0 in the 0.06 and 6 MIU groups (no significant differences). Secondary efficacy endpoints showed small and inconsistent differences between groups. Adverse events showed no notable group differences. Approximately two-thirds of patients in each group remained relapse free. No patients showed neutralizing antibodies. Neopterin levels were comparable between groups. CONCLUSION: Oral IFNB-1a showed neither beneficial effects in RRMS nor any systemic biological effects. Treatment was safe and well tolerated.