Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa/Levodopa Functionally Scored Tablet.

Levodopa/carbidopa remains the gold standard for treating Parkinson disease (PD), but chronic pulsatile administration contributes to motor complications. This Phase 1 study used a new immediate-release (IR) formulation of carbidopa/levodopa 25/100 mg that is functionally scored for easy and precise splitting to evaluate the effects on levodopa plasma variability when smaller doses are taken more frequently. These functionally scored tablets were shown to be bioequivalent to carbidopa/levodopa 25-/100-mg IR generic reference tablets. Twenty-two healthy volunteers received a whole tablet every 4 hours versus half of the tablet every 2 hours. Plasma levodopa fluctuations were significantly reduced with half-tablets dosed every 2 hours, with a 44% reduction in peaks (P < .0001). While drug exposure did not differ, parameters that underlie motor response variations, including mean peak-to-trough difference and variance, were 51% and 56% less, respectively, with more frequent dosing (both P ≤ .0024). Safety and tolerability of both regimens were similar. In conclusion, more frequent administration of half-tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity.

Donepezil Plus Solifenacin (CPC-201) Treatment for Alzheimer's Disease.

Available cholinergic drugs for treating Alzheimer's disease (AD) provide modest symptomatic benefit. We hypothesized that co-administration of a peripheral anticholinergic to reduce dose-limiting adverse effects (AEs) would enable the safe/tolerable use of higher cholinesterase inhibitor doses and thus improve their antidementia efficacy. A modified single-blind, ascending-dose, phase IIa study of donepezil plus solifenacin (CPC-201) lasting 26 weeks was conducted in 41 patients with probable AD of moderate severity. Entry criteria included the use of donepezil at a dose of 10 mg/day during the preceding 3 months. The primary outcome measure was the maximum tolerated dose (MTD) of donepezil achieved (to protocol limit of 40 mg/day) when administered with the anticholinergic solifenacin 15 mg/day. Secondary measures included assessments of cognitive and global function, as well as of AEs. The mean ± SD donepezil MTD increased to 38 ± 0.74 mg/day (median 40 mg/day; p < 0.001); 88% of the study population safely attained this dose at the end of titration. Markedly reduced donepezil AE frequency, especially gastrointestinal, allowed this dose increase. There were no drug-related serious AEs or clinically significant laboratory abnormalities. At 26 weeks, Alzheimer's Disease Assessment Scale Cognitive Component scores in the efficacy evaluable population improved by 0.35 ± 0.85 points over baseline (p < 0.05), an estimated 2.5 ± 0.84 points above 10 mg/day donepezil and 5.4 ± 0.84 points above historic placebo (both p < 0.05). Clinical Global Impression of Improvement scores improved by 0.94 ± 0.20 to 3.1 ± 0.20 points (p < 0.001). The findings suggest that limiting donepezil AEs by co-administration of solifenacin allows the safe administration of substantially higher cholinesterase inhibitors doses that may augment cognitive and global benefits in patients with AD.

Safety and Efficacy of Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment of Chorea Associated with Huntington's and Other Diseases.

BACKGROUND: Although tetrabenazine, a drug that depletes presynaptic dopamine by inhibiting vesicular monoamine transporter 2 (VMAT2), was approved by the U.S. Food and Drug Administration in 2008 for the treatment of chorea associated with Huntington's disease (HD), there is a paucity of data on its long-term efficacy and safety. METHODS: Approximately 2,000 patients with a variety of hyperkinetic movement disorders had been treated with open-label tetrabenazine at the Movement Disorders Clinic, Baylor College of Medicine, since 1979. Tetrabenazine was usually started at 12.5 mg/day, and the dosage was gradually increased (up to 300 mg/day). Responses were rated by the investigator 1-5, with 1  =  marked chorea reduction, excellent improvement in function; 2  =  moderate chorea reduction, very good improvement in function; 3  =  fair chorea improvement, only mild improvement in function; 4  =  poor or no response for chorea and function; and 5  =  worsening chorea, some functional deterioration. Efficacy and safety were analyzed retrospectively. RESULTS: By 2004, 98 HD chorea patients had received tetrabenazine for a mean of 3.1 years (range ≤1-11.4 years). Of those with valid ratings, 75% had either marked or very good responses (rating 1 or 2) at their optimal dosages. The most common adverse events occurring in ≥5% of the patients were somnolence (39%), insomnia (33%), depression (31%), accidental injury (26%), and dysphagia (19%). Efficacy and safety were comparable to results for non-HD chorea patients. DISCUSSION: Tetrabenazine treatment was associated with long-term improvement in chorea. Adverse event rates were comparable to those reported from controlled trials.

Use of Tetrabenazine in Huntington Disease Patients on Antidepressants or with Advanced Disease: Results from the TETRA-HD Study.

The safety and effectiveness of tetrabenazine in different sub-populations of Huntington disease (HD) is not known. In this study, we evaluated the safety of tetrabenazine in individuals on an antidepressant and its effectiveness in advanced HD. Tetrabenazine was not associated with an increased incidence of depressed mood among those taking antidepressants and was effective at reducing chorea in those with advanced HD.

Tetrabenazine for the treatment of chorea and other hyperkinetic movement disorders.

Tetrabenazine (TBZ; Xenazine) is a potent, selective, reversible depletor of monoamines from nerve terminals. TBZ inhibits the vesicular monoamine transporter type 2 which, in humans, is expressed nearly exclusively in the brain. TBZ is rapidly metabolized in the liver by carbonyl reductase to stereoisomers of hydrotetrabenazine, some of which are potent inhibitors of vesicular monoamine transporter type 2. Initially developed in the 1950s for schizophrenia, since the 1970s several publications have reported on the efficacy of TBZ in the treatment of various hyperkinetic movement disorders. Although quite effective in controlling the involuntary movements, there were considerable inter-individual differences in the optimal dose, defined as the dose judged by the investigator to provide the greatest efficacy with minimal or tolerable adverse events. This variability is in part owing to differences in severity and mechanism of the target symptoms and to variable activity of the enzyme carbonyl reductase that metabolizes TBZ to its active metabolites. Dose-limiting adverse events, consisting mainly of sedation, parkinsonism, akathisia and depression, are usually rapidly reversible upon dosage reduction. In addition to its established antichorea efficacy in Huntington's disease, the drug has been reported to also be effective in a variety of other hyperkinetic movement disorders, including tardive dyskinesia and tics associated with Tourette's syndrome.

Double-blind treatment of apathy in patients with poststroke depression using nefiracetam.

Nefiracetam is a novel pyrrolidone-type nootropic compound shown in preliminary trials to increase blood flow and improve patient outlook and energy following stroke. Of 137 stroke patients with major depression, 70 also met published diagnostic criteria for apathy (51.1%) and were randomly assigned either to placebo or 600 mg or 900 mg of nefiracetam per day, and received at least 4 weeks of treatment. Using the group with at least 4 weeks of treatment as the intention-to-treat sample with last observation carried forward, repeated measures analysis of variance of Apathy Scale scores demonstrated a significant time-by-treatment interaction. Patients taking 900 mg nefiracetam had a significantly greater change in Apathy Scale scores compared to 600 mg of nefiracetam or placebo. Future studies should assess whether apathy without depression may respond to this novel treatment.

Double-blind randomized treatment of poststroke depression using nefiracetam.

In preliminary trials, nefiracetam, a gamma aminobutyric compound, enhanced blood flow and improved mood following stroke. Within 3 months following stroke with major depression, 159 patients were enrolled in a double-blind trial of nefiracetam or placebo. Repeated measures analysis of covariance failed to show a significant time-by-treatment interaction. Response rates were greater than 70% and remission rates were greater than 40% for nefiracetam and placebo. The top quintile of Hamilton Depression Rating Scale scores showed significant effect after 900 mg of nefiracetam versus 600 mg or placebo. Nefiracetam was not an effective treatment for poststroke depression but produced significant improvement in the most severely depressed patients.