Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double-blind, placebo-controlled study. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/L-carnitine for the treatment of cocaine dependence. Effects of doxorubicin-containing chemotherapy and a combination with L-carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma.
Treatment with acetyl L-carnitine (ALCAR) has been shown to improve fatigue in patients with chronic fatigue syndrome, but there have been no trials on the effect of ALCAR for treating fatigue in multiple sclerosis (MS). To compare the efficacy of ALCAR with that of amantadine, one of the drugs most widely used to treat MS-related fatigue, 36 MS patients presenting fatigue were enrolled in a randomised, double-blind, crossover study. Patients were treated for 3 months with either amantadine (100 mg twice daily) or ALCAR (1 g twice daily). After a 3-month washout period, they crossed over to the alternative treatment for 3 months. Patients were rated at baseline and every 3 months according to the Fatigue Severity Scale (FSS), the primary endpoint of the study. Secondary outcome variables were: Fatigue Impact Scale (FIS), Beck Depression Inventory (BDI) and Social Experience Checklist (SEC). Six patients withdrew from the study because of adverse reactions (five on amantadine and one on ALCAR). Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale (p = 0.039). There were no significant effects for any of the secondary outcome variables. The results of this study show that ALCAR is better tolerated and more effective than amantadine for the treatment of MS-related fatigue. Carnitine deficiency is prevalent in populations with chronic illness, including cancer. In a recent open-label study, L-carnitine supplementation was well tolerated and appeared to improve fatigue and other outcomes in cancer patients. To further evaluate this finding, adult patients with advanced cancer, carnitine deficiency (free carnitine more than 35 micromol/L for males or less than 25 micromol/L for females, or acyl/free carnitine ratio of more than 0.4), moderate to severe fatigue, and a Karnofsky Performance Status (KPS) score of 50 or more, were randomly assigned to receive either L-carnitine (0.5 g/day for two days, followed by 1g/day for two days, and then 2g/day for 10 days) or placebo. This double-blind phase was followed by an open-label phase, during which all patients received L-carnitine supplementation for two weeks. Outcomes included the fatigue subscale of the Functional Assessment of Cancer Therapy-Anemia (FACT-An), the Linear Analog Scale Assessments (LASA), the Mini-Mental State Exam (MMSE), and the KPS. Twenty-nine patients (12 placebo, 17 L-carnitine) were included in the intent-to-treat (ITT) analysis. From baseline to the end of the double-blind phase, serum total and free L-carnitine increased from 32.9+/-3.8 to 56.6+/-20.5 (P=0.004), and from 22.9+/-19.4 to 45.3+/-17.2 (P=0.004), respectively, in the L-carnitine-treated group, and from 28.2+/-10.2 to 36.2+/-8.7 (P=ns), and from 22.6+/-7.9 to 28.7+/-8.6 (P=ns) in the placebo group, respectively. The planned ITT analysis revealed no significant improvement in any of the study's endpoints, and these negative findings were not different when data from two patients who did not adhere to the protocol were eliminated. However, an exploratory covariate analysis that excluded these two protocol violators and included outcome data from both the double-blind and open-label phases demonstrated significantly improved fatigue on the FACT-An fatigue subscale (P<0.03), and significantly improved FACT-An functional well-being subscale (P<0.03), and KPS (P<0.003), in the group that started with L-carnitine during the double-blind phase. These data do not support the conclusion that L-carnitine in the doses tested reverses cancer-related fatigue in carnitine-deficient patients. However, L-carnitine supplementation does increase L-carnitine serum levels, and the positive findings in an exploratory analysis justify a larger study to determine if this strategy could be of benefit for a subpopulation of cancer patients. To determine the relative efficacy of amantadine, pemoline, and placebo in treatment of multiple sclerosis (MS)-related fatigue.
                Fatigue is a complication of MS. Both pemoline and amantadine have been used to treat MS fatigue, but their relative efficacy is not known.
                Amantadine, pemoline, and placebo were compared in a randomized, double-blind, placebo-controlled study using a parallel-group design. Ninety-three ambulatory MS patients completed the study. Primary outcome measures were the fatigue severity scale (FSS); the MS-specific fatigue scale (MS-FS); and subjective response determined by verbal self-report. Secondary outcome measures consisted of assessments of sleep, depression, and vitality. Repeated-measures analysis of variance with planned post-hoc contrasts and Fisher's exact test were used to compare treatment response.
                Amantadine-treated patients showed a significantly greater reduction in fatigue, as measured by the MS-FS, than did patients treated with placebo (p = 0.04). By verbal report at the end of the study, 79% of patients treated with amantadine versus 52% treated with placebo and 32% treated with pemoline preferred drug therapy compared with no treatment (p = 0.03). No significant differences in any primary outcome measures were noted between pemoline and placebo. Neither amantadine nor pemoline affected sleep or depression relative to placebo.
                Amantadine was significantly better than placebo in treating fatigue in MS patients, whereas pemoline was not. The benefit of amantadine was not due to changes in sleep, depression, or neurologic disability. A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with 1 g acetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratory tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory. 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. Fatigue occurs in a majority of patients with MS and is generally independent of measurable neurologic disability. Few options for treatment are available. We conducted a double-blind, placebo-controlled, crossover trial for each of two 4-week treatment periods. Forty-six eligible patients entered and five dropped out due to concurrent exacerbations. Nineteen patients (46.3%) experienced excellent or good relief of fatigue with pemoline, and eight patients (19.5%) with placebo (p = 0.06, Fisher's exact test). One-fourth of patients did not tolerate the drug well, and 7% had to discontinue pemoline during the study due to side effects. The most common side effects were anorexia, irritability, and insomnia. Pemoline may be an effective short-term treatment for fatigue associated with MS, but its adverse effects are not well tolerated by many patients. Fatigue is a commonly encountered symptom of human immunodeficiency virus (HIV) disease, associated with significant psychological and functional morbidity and poor quality of life. Preliminary studies on the treatment of fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants may be effective in reducing fatigue.
                To compare the efficacy of 2 psychostimulant medications, methylphenidate hydrochloride (Ritalin) and pemoline (Cylert), with a placebo intervention for the treatment of fatigue in patients with HIV disease.
                In this double-blind trial, 144 ambulatory patients with HIV disease and persistent and severe fatigue were randomized to treatment with methylphenidate, pemoline, or placebo. Medications were titrated up to a maximum dose of 60 mg of methlyphenidate hydrochloride, 150 mg of pemoline, or 8 capsules of placebo daily. Fatigue was measured using 2 self-reported rating scales, the Piper Fatigue Scale (PFS) and the Visual Analogue Scale for Fatigue (VAS-F). We also used the timed isometric unilateral straight leg-raising task, a measure of muscular endurance. Quality-of-life and psychological well-being measures included the Beck Depression Inventory, the Brief Symptom Inventory, and the 36-Item Short-Form Medical Outcomes Study Health Status Survey. Side effects were monitored using the Systematic Assessment for Treatment Emergent Events and the Extra-pyramidal Symptom Rating Scale. All measures were rated weekly.
                One hundred nine subjects completed the 6-week trial; 15 patients (41%) receiving methylphenidate and 12 patients (36%) receiving pemoline demonstrated clinically significant improvement compared with 6 patients (15%) receiving placebo. Patients receiving methylphenidate or pemoline demonstrated significantly more improvement in fatigue on several self-reported rating scales (PFS total score, P=.04; affective subscale, P=.008; sensory subscale, P=.04; and VAS-F energy subscale, P=.02). Analysis of the regression slopes by means of hierarchical linear modeling demonstrated a significantly greater rate of improvement in PFS total scores among patients receiving psychostimulants compared with the placebo group (P=.02). There were no significant differences in the efficacy between methlyphenidate and pemoline on any outcome measure studied. Improvement in fatigue was also significantly correlated with improvement in measures of depression, psychological distress, and overall quality of life. Severe side effects were relatively uncommon among this sample, and only hyperactivity or jitteriness occurred significantly more often among subjects receiving active medication.
                Many patients with HIV- and acquired immunodeficiency syndrome-unrelated fatigue respond favorably to treatment with methylphenidate or pemoline. Both psychostimulants appear to be equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects. Moreover, improvement of fatigue was significantly associated with improved quality of life and decreased levels of depression and psychological distress. To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L-carnitine combination versus placebo for the treatment of cocaine dependence.
                A four-arm, modified blinded, parallel group study in an out-patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design.
                The study was performed at the New York Medications Development Research Unit (MDRU).
                All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Sixty-eight participants were enrolled with 39 completing the study.
                After a 2-week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L-carnitine (500 mg/day) combination or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment.
                Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side-effects tests.
                Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self-report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed.
                This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/L-carnitine combination for the treatment of cocaine dependence. Chemotherapy regimens based on anthracycline (doxorubicin) are well established in lymphoma therapy. The purpose of this study was to examine the effects of L-carnitine with a view to reducing cytotoxic side-effects.
                20 patients were scheduled to receive 3 g L-carnitine before each chemotherapy cycle, followed by 1 g L-carnitine/day during the following 21 days, while 20 patients received a placebo (randomized controlled trial). The plasma lipid profile and relative mRNA levels of key enzymes of oxidative metabolism (carnitine acyltransferases) were measured at three points of time. In addition to the clinical parameters we used the mRNA of white blood cells to evaluate the toxic effects on cardiomyocytes.
                In the present study no cardiotoxicity of anthracycline therapy was detected. Carnitine treated patients showed a rise in plasma carnitine which led to an increase of relative mRNA levels from CPT1A (liver isoform of carnitine palmitoyltransferase) and OCTN2 (carnitine transporter). Following chemotherapy, an activation of carnitine acyltransferases was associated with a stimulation of OCTN2 in both groups.
                Biochemical and molecular analyses indicated a stimulation of oxidative metabolism in white blood cells through carnitine uptake.
There is insufficient evidence that carnitine for the treatment of MS-related fatigue offers a therapeutic advantage over placebo or active comparators. Results of the ongoing trial are eagerly anticipated in order to provide clarity.