tesofensine and Parkinson-Disease

Tesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitor. We conducted a meta-analysis of TE's effect on body weight in trials investigating its potential for treatment of Parkinson's or Alzheimer's disease.. Four randomized, double-blind, multicenter trials compared TE (n = 740) and placebo (n = 228), two in each disease. Patients received oral TE or placebo once daily for 14 weeks without any weight loss program. Results were adjusted for baseline values, age, and study.. In the placebo group, 14% were obese and 21% were in the TE group. In the total cohort, weight change after 14 weeks was +0.5, -0.5, -0.9, -1.8, -2.8% in the placebo, 0.125, 0.25, 0.5 and 1.0 mg in the TE groups, respectively (P = 0.015 for dose effect). In the obese subgroup, weight changes were -0.2, -1.7, -1.6, -1.5, -3.7%, and 2.1, 8.2, 14.1, 20.9, 32.1% of the obese patients achieved > or = 5% weight loss (P < 0.001 for 0.25, 0.5, and 1.0 mg vs. placebo for both end points). Changes in heart rate were -0.4, 2.1, 4.2, 6.0, and 6.8 bpm after 14 weeks (TE vs. placebo: P < 0.001 from 0.25 mg), but no effect on blood pressure was observed.. TE produced a placebo-subtracted weight loss of approximately 4% for >14 weeks without any diet and lifestyle therapy, which is similar to that of sibutramine, but with no effect on blood pressure. On the basis of these results, TE is now being developed for obesity management.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Biogenic Monoamines; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Rate; Humans; Male; Middle Aged; Multicenter Studies as Topic; Obesity; Parkinson Disease; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Weight Loss

To assess the safety and efficacy of tesofensine, a triple monoamine reuptake inhibitor, in patients with advanced Parkinson disease (PD).. A pilot phase 2, randomized, double-blind, placebo-controlled, parallel-group trial. The study occurred in hospital-based outpatient clinics and in clinical trial units. Patients with advanced PD and levodopa-related motor fluctuations were enrolled. Tesofensine (0.125, 0.25, 0.5, or 1 mg) or placebo tablets were administered once daily for 14 weeks.. Coprimary end points were the changes from baseline in Unified Parkinson Disease Rating Scale (UPDRS) subscale II (activities of daily living) plus subscale III (motor function) total score and in percentage of waking hours spent in "off" time noted in self-scoring diaries. Secondary end points were safety, pharmacokinetics, responder analysis (> or =20% reduction in UPDRS score and in off time), and changes in percentage of waking hours spent in "on" time with and without troublesome dyskinesia.. The adjusted mean differences (relative to placebo) were -4.7 points in UPDRS subscale II plus subscale III total score (P =.005) with tesofensine, 0.5 mg, and -7.1% in off time (-68 minutes, P =.02) with tesofensine, 0.25 mg. Other dosages did not induce statistically significant effects. The plasma concentration increased with the dosage, but no clear dose-response relationship was observed. Gastrointestinal tract and neuropsychiatric adverse events were more frequent with tesofensine than with placebo, especially at the higher dosages.. Patients with PD in advanced stages showed modest improvements in UPDRS subscale II plus subscale III total score and in off time when treated with tesofensine, but a dose-response relationship could not be established for efficacy, while adverse drug reactions tended to be more frequent at higher dosages.. clinicaltrials.gov Identifier: NCT00148512.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Biogenic Monoamines; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Diseases; Humans; Male; Mental Disorders; Middle Aged; Neurotransmitter Uptake Inhibitors; Parkinson Disease; Pilot Projects; Placebos; Treatment Outcome

The objective of this study was to evaluate the efficacy and safety of three daily dosages of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) compared to placebo as monotherapy in early Parkinson's disease (PD). In MPTP (1-methyl 4-phenyl-tetrahydropyridine 1,2,3,6)-lesioned marmosets, dopamine reuptake inhibitors have been demonstrated to reverse parkinsonian signs without evoking established dyskinesia. NS 2330 inhibits reuptake of dopamine, serotonin, and norepinephrine. We performed a proof-of-concept, randomized, double-blind trial of NS 2330. Two hundred sixty-one subjects with PD < 5 years and not receiving dopaminergic treatment were randomly assigned to daily treatment with NS 2330 at 0.25 mg, 0.5 mg, 1.0 mg, or placebo. Adjusted mean difference in total Unified Parkinson's Disease Rating Scale (UPDRS) scores from baseline to week 14 was -0.7 (P = 0.64) in the 0.25-mg group, -1.3 (P = 0.41) in the 0.5-mg group, and -1.7 (P = 0.27) in the 1.0-mg group. The adjusted mean difference in total UPDRS score for the highest dose group (1.0 mg/day) was superior to placebo at week 6 (-3.1; P = 0.02), but this effect was not sustained. NS 2330 was generally well tolerated and the most commonly reported adverse events were constipation, insomnia, and dry mouth. Decreased body weight and elevated heart rate were common in the 1.0-mg dosage group. At the dosages tested, NS 2330 did not provide significantly greater benefit than placebo. It is possible that inhibition of dopamine reuptake alone does not provide clinical benefit in early PD, adequate inhibition of dopamine reuptake was not achieved in this study, or countervailing physiologic mechanisms offset the potential benefit.

Topics: Aged; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurotransmitter Uptake Inhibitors; Parkinson Disease; Retrospective Studies