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Background Identifying determinants of cost of illness and health-related quality of life (HRQoL) is critical for doctors, health policy decision makers and payers to make appropriate decisions. Aims To evaluate patient health status, patient and caregiver (HRQoL), cost of illness, and drivers of costs and HRQoL in Huntington's disease (HD). Methods Euro-HDB is a comprehensive, European observational study being conducted in eight European countries (including Italy and France) to assess the cost of illness of HD. Two validated self-reported questionnaires are used: one for patients and one for their caregiver. The patient questionnaire includes the Huntington Self-Assessment Instrument, a comprehensive and specific tool that assesses clinical characteristics, HRQoL and healthcare resource utilization. The 5-dimension EuroQol questionnaire and 36-item Short Form Health Survey are also included to allow for HRQoL comparisons with other disorders. Results The study is ongoing. To date, 201 patients and their caregivers have been enrolled in France and 124 in Italy. About half of patients are male (51% and 47%, respectively); average age is 57 and 54 years. All levels of disease severity are represented. Over half of patients have no occupational activity (58% and 80%). The main drivers of costs are productivity loss and patient absence from work. In France, hospitalization and nursing home costs are the main sources of medical costs. For more severely affected patients, medical resource utilization diminishes while caregiver involvement increases significantly (the shift is greater in Italy than France). In both countries, patient and caregiver HRQoL are affected greatly and to the same extent, regardless of the instrument used. For patients, physical, mental and social HRQoL domains are all seriously affected. Conclusions Euro-HDB is the first study to comprehensively asses the cost of illness of HD and shows that it is associated with significant costs. [ABSTRACT FROM PUBLISHER]

Background The UHDRS motor section is composed of 31 items related to different aspects of the motor symptoms. These are heterogeneous in terms of functional impact, course of progression, and relation to pathological changes. Aims The present study is aimed at investigating the correlational structure between UHDRS motor items and functional measures, cross-sectionally and longitudinally, as well as estimating the rate of progression of different UHDRS motor subdomains. Methods Longitudinal data including UHDRS motor scores, functional scores (tfc, fa, independence scale), CAG repeat length, age, sex, on 889 HD patients, collected in the REGISTRY project over around 5 years, were provided by EHDN. Cross-sectional relationships were analysed by principal component analysis (PCA). Longitudinal analysis was performed by PCA, and PLS regression analysis, modelling the influence of change in motor scores, as well as basic demographic data, on the decline of functional scores. Results Cross-sectional analysis shows that UHDRS motor items form four major clusters, that is chorea, dystonia, eye movements, and voluntary motor scores, the voluntary scores being most strongly, negatively correlated to the functional measures analysed (tfc, fa, is). Similarly, longitudinal analysis shows that voluntary motor impairment is most strongly correlated to the decline in functional outcomes, whereas in particular the time-course of chorea does not follow the functional decline. CAG repeat length and disease burden (CAG * age construct) were associated with a faster rate of decline in motor performance and functional outcomes. Conclusions These preliminary results support the division of UHDRS motor items into voluntary and involuntary motor symptoms, and show that the impairment of voluntary movements is strongly linked to the decline in functional outcomes, both as viewed cross-sectionally and over time. The longitudinal analysis further indicates that the CAG repeat length, as well as the disease burden, are significant determinants of the rate of progression of clinical disability in HD. [ABSTRACT FROM PUBLISHER]

Background Health-related QoL (HRQoL) instruments are critical for assessing disease burden. Generic tools allow comparison between diseases but are insensitive and do not discriminate between disease severities. Specific tools tend to be more sensitive and discriminative. No specific tool is available to assess HRQoL in patients with Huntington's disease (HD). In the context of the large and comprehensive European study on HD burden (Euro-HDB), a specific HRQoL tool was needed. Aims To assess patient HRQoL, and to capture changes related to intervention in early and intermediate stages of HD. Methods After a semi-structured interview with patients, caregivers and HD specialists, we ran a patient focus group. A self-reported questionnaire was then devised in French (42 items, 11 dimensions) and translated into English, Spanish, German, Italian, Swedish, Portuguese and Polish. In France, 178 patients were recruited to answer the questionnaire—face validity was tested according to item response rate; internal and external validity were examined using a variety of methods. Results Face validity and internal validity were acceptable. A high correlation of several items within the same dimension suggests item number can be reduced. As expected, there was a significant ceiling effect, suggesting high sensitivity at early and intermediate HD stages but low sensitivity later on. External validity supports scale robustness. HRQoL is worst in the most severe patients; depression dramatically affects HRQoL. Patient and caregiver HRQoL do not overlap completely. Voluntary motor symptoms contribute significantly to HRQoL, but chorea does not. Conclusions These data support the validity of the HQOLI in patients with HD. Sensitivity analyses, test–retest reliability and cross-cultural validation will be performed/are underway. The ceiling effect limits the use of the HQOLI in late stages of HD. [ABSTRACT FROM PUBLISHER]

Purpose: The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians. Methods: Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg). Results: The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively ( p = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p = 0.11). The mean plasma area under the time-concentration curve between time zero and 32 h (AUC) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p < 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete. Conclusions: Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine. [ABSTRACT FROM AUTHOR]

PNU-96391A is a weak dopamine (DA) D2 receptor antagonist with behavioral stabilizing properties. Previous experiments revealed that PNU-96391A antagonizes the expression of L-DOPA induced behavioral sensitization (dyskinesias) in lesioned primates without inducing akinesia or reducing the anti-Parkinsonian efficacy of L-DOPA. This study evaluated the ability of PNU-96391A to block the development of DA agonist-induced behavioral sensitization in rats with unilateral 6-OH-DA lesions of the median forebrain bundle. Repeated twice daily treatment with L-DOPA and the decarboxylase inhibitor benserazide (15 and 5 mg/kg, IP, respectively), or quinpirole (D2/D3 agonist, 0.1 mg/kg, SC) increased the contralateral rotations measured on day 7 and 14 as compared to day 1. PNU-96391A (10–60 mg/kg, SC, bid.) antagonized the development of behavioral sensitization induced by both agonists. The basal activity of L-DOPA was not affected while a reduction of quinpirole-induced rotations was observed after 30–60 mg/kg, SC of PNU-96391A. Neurochemical analyses confirmed >99 % reductions of striatal DA levels, unilaterally. Concomitant treatment with PNU-96391A and L-DOPA did not affect plasma levels of PNU-96391A indicating that the effects observed are not related to pharmacokinetic interactions. These results suggest that PNU-96391A could be therapeutically useful to prevent the development of behavioral sensitization induced by DA agonists. [Copyright &y& Elsevier]

Background Pridopidine is a dopaminergic stabiliser, a new class of compound that stabilises the dopamine system and has the potential to treat neurological and psychiatric disorders characterised by altered dopamine transmission. Aims To investigate the efficacy and safety of pridopidine in patients with Huntington's disease (HD). Methods MermaiHD was a 6 month randomised, double blind, placebo controlled European study. Eligible patients were aged ≥30 years with a score of ≥10 points in the modified motor score (mMS) at screening. The mMS is a validated subscale of the UHDRS total motor score (UHDRS-TMS) equal to the UHDRS-TMS excluding eye movements, dystonia and chorea. Patients were randomised 1:1:1 to pridopidine 45 mg once or twice daily or placebo. The primary outcome was effect of treatment on voluntary motor function (mMS). Results After 26 weeks pridopidine 45 mg twice daily improved the mMS by 0.99 points (full analysis set (FAS), n=437; p=0.042 vs placebo; NS after adjustment for multiplicity). After adjusting for CAG repeats, the mMS change from baseline with pridopidine 45 mg twice daily was −1.20 points vs placebo (FAS, n=393; p=0.019). Pridopidine 45 mg twice daily significantly improved the UHDRS-TMS (change from baseline −2.96 points; FAS, n=437; p=0.004 vs placebo) with improvements in eye movements and dystonia subdomains (not chorea). With placebo, the regression coefficients for CAG repeats versus rate of motor symptom progression was significant (p=0.0051; 0.3 points on the mMS per CAG repeat after 26 weeks). The regression coefficients were not significant with pridopidine. Effects were similar regardless of whether patients were taking neuroleptics. Pridopidine was well tolerated and had an AE profile similar to placebo. Conclusions This study suggests a beneficial effect of pridopidine 45 mg twice daily on motor function in patients with HD. A possible effect on motor symptom progression as suggested by changes in the mMS per CAG should be studied further. [ABSTRACT FROM PUBLISHER]