Olivier Rascol - Academia.edu (original) (raw)
Papers by Olivier Rascol
Movement Disorders
There are no effective treatments for multiple system atrophy (MSA).
Neurologie.com
L’efficacite et la tolerance des agonistes dopaminergiques ont ete validees par des essais cliniq... more L’efficacite et la tolerance des agonistes dopaminergiques ont ete validees par des essais cliniques randomises et controles. Cependant, la place exacte des agonistes dopaminergiques dans le traitement de la maladie de Parkinson reste encore debattue. En effet, il n’existe pas, a ce jour, de strategie consensuelle et d’etudes avec un niveau de preuve suffisant pour permettre d’elaborer un arbre decisionnel definitif de la strategie therapeutique dans cette pathologie. Une approche pragmatique tend a privilegier chez le patient jeune les agonistes dopaminergiques par rapport a la L-Dopa afin d’en retarder l’introduction du fait des complications motrices. Les agonistes non ergotes sont desormais privilegies en raison du risque de complications a type de fibrose lie a l’usage des agonistes ergotes.
Journal of Neural Transmission
Abstractl-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson’s disease (PD) and im... more Abstractl-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson’s disease (PD) and impact negatively health-related quality of life. Amantadine has demonstrated significant antidyskinetic effects in animal PD models and in randomized double-blind placebo-controlled trials (RCTs) in patients with PD. These effects are thought to be related to the blockade of NMDA receptors modulating cortico-striatal glutamatergic–dopaminergic interactions involved in the genesis of LIDs. There are three pharmaceutical forms of amantadine currently available in the market: an oral immediate-release (IR) formulation, which is widely available; an extended-release (ER) formulation (ADS-5102) which has been recently developed and approved by the FDA; and an intravenous infusion (IV) solution, which is not commonly used in clinical practice. RCTs with amantadine IR or ER, involving more than 650 patients have shown consistent and long-lasting reductions in LIDs. Interestingly, ADS-5102 not only reduced LIDs, but also reduced significantly at the same time the duration of daily OFF-time, a unique finding compared with other antiparkinsonian medications that usually reduce time spent OFF at the cost of worsening of LIDs. Amantadine IR might also have possible effects on other PD symptoms such as apathy or fatigue. The most common adverse reactions with amantadine are constipation, cardiovascular dysfunction including QT prolongation, orthostatic hypotension and edema, neuropsychiatric symptoms such as hallucinations, confusion and delirium, nausea and livedo reticularis. Corneal degeneration is rare but critical. In summary, amantadine immediate and extended-release are effective and safe for the treatment of LIDs.
European journal of clinical pharmacology, 2018
Three studies have suggested a potential positive association between the use of tamoxifen in bre... more Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure. To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018. Among women ≥ 55 years, we measured the risk of reporting "Parkinsonism" compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors. During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71-0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33-0.46). This study did not find evidence for Parkinsonism associated with tamoxifen.
Movement disorders : official journal of the Movement Disorder Society, 2018
Neurology, Jan 25, 2018
To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching fro... more To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching from entacapone over 1 year of treatment in patients with fluctuating Parkinson disease. After completion of a placebo- and entacapone-controlled double-blind study of opicapone (5, 25, or 50 mg), 495 patients continued to a 1-year extension phase in which patients were treated with opicapone. Patients began with once-daily opicapone 25 mg for 1 week, followed by individually tailored levodopa and/or opicapone dose adjustments. The primary efficacy variable was the change from baseline in absolute "off" time based on patient diaries. Other outcomes included proportion of responders, scale-based assessments, and standard safety assessments. One year of treatment with opicapone reduced "off" time by a half-hour (33.8 minutes) vs the open-label baseline and >2 hours (126.9 minutes) vs the double-blind baseline. Whereas patients who were originally treated with opicapone ...
Movement disorders : official journal of the Movement Disorder Society, 2018
Multimodal MRI approach is based on a combination of MRI parameters sensitive to different tissue... more Multimodal MRI approach is based on a combination of MRI parameters sensitive to different tissue characteristics (eg, volume atrophy, iron deposition, and microstructural damage). The main objective of the present study was to use a multimodal MRI approach to identify brain differences that could discriminate between matched groups of patients with multiple system atrophy, Parkinson's disease, and healthy controls. We assessed the 2 different MSA variants, namely, MSA-P, with predominant parkinsonism, and MSA-C, with more prominent cerebellar symptoms. Twenty-six PD patients, 29 MSA patients (16 MSA-P, 13 MSA-C), and 26 controls underwent 3-T MRI comprising T2*-weighted, T1-weighted, and diffusion tensor imaging scans. Using whole-brain voxel-based MRI, we combined gray-matter density, T2* relaxation rates, and diffusion tensor imaging scalars to compare and discriminate PD, MSA-P, MSA-C, and healthy controls. Our main results showed that this approach reveals multiparametric m...
Neurology, Jan 13, 2017
Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gap... more Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided.
CNS Drugs
Dopamine agonists are well-established symptomatic medications for treating early and advanced Pa... more Dopamine agonists are well-established symptomatic medications for treating early and advanced Parkinson disease (PD). Piribedil was one of the first agonists to be marketed (1969) and is widely used as an extended-release oral formulation in European, Latin-American, and Asian countries. Piribedil acts as a non-ergot partial dopamine D2/D3-selective agonist, blocks alpha2-adrenoreceptors and has minimal effects on serotoninergic, cholinergic, and histaminergic receptors. Animal models support the efficacy of piribedil to improve parkinsonian motor symptoms with a lower propensity than levodopa to induce dyskinesia. In PD patients, randomized double-blind studies show that piribedil (150–300 mg/day, three times daily) is superior to placebo in improving motor disability in early PD patients. Based on such evidence, piribedil was considered in the last Movement Disorder Society Evidence-Based Medicine review as “efficacious” and “clinically useful” for the symptomatic treatment of PD, either as monotherapy or in conjunction with levodopa, in non-fluctuating early PD patients. This effect appears comparable to what is known from other D2 agonists. However, randomized controlled trials are not available to assess the effect of piribedil in managing levodopa-induced motor complications. Pilot clinical studies suggest that piribedil may improve non-motor symptoms, such as apathy, but confirmatory trials are needed. The tolerability and safety profile of piribedil fits with that of the class of dopaminergic agonists. As for other non-ergot agonists, pneumo-pulmonary, retroperitoneal, and valvular fibrotic side effects are not a concern with piribedil. The original combination of piribedil D2 dopaminergic and alpha-2 adrenergic properties deserve further investigations to better understand its antiparkinsonian profile.
Movement Disorders
Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although... more Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although many clinical trials have been conducted, there is still no treatment that cures the disease or slows its progression. We sought to assess the clinical trials, methodology, and quality of reporting of clinical trails conducted in MSA patients. We conducted a systematic review of all trials with at least 1 MSA patient subject to any pharmacological/nonpharmacological interventions. Two independent reviewers evaluated the methodological characteristics and quality of reporting of trials. A total of 60 clinical trials were identified, including 1375 MSA patients. Of the trials, 51% (n = 31) were single-arm studies. A total of 28% (n = 17) had a parallel design, half of which (n = 13) were placebo controlled. Of the studies, 8 (13.3%) were conducted in a multicenter setting, 3 of which were responsible for 49.3% (n = 678) of the total included MSA patients. The description of primary outcomes was unclear in 60% (n = 40) of trials. Only 10 (16.7%) clinical trials clearly described the randomization process. Blinding of the participants, personnel, and outcome assessments were at high risk of bias in the majority of studies. The number of dropouts/withdrawals was high (n = 326, 23.4% among the included patients). Overall, the design and quality of reporting of the reviewed studies is unsatisfactory. The most frequent clinical trials were small and single centered. Inadequate reporting was related to the information on the randomization process, sequence generation, allocation concealment, blinding of participants, and sample size calculations. Although improved during the recent years, methodological quality and trial design need to be optimized to generate more informative results. © 2017 International Parkinson and Movement Disorder Society.
Journal of the American Medical Directors Association, Jan 13, 2017
To evaluate mortality rate in elderly and very elderly (≥85 years) residents with Parkinson disea... more To evaluate mortality rate in elderly and very elderly (≥85 years) residents with Parkinson disease (PD) in nursing homes (NHs) with and without antipsychotic drugs. Cross-sectional study. All residents with PD from the 6275 NH residents participating in the Impact d'une démarche QUAlité sur l'évolution des pratiques et le déclin fonctionnel des Résidents en Etablissement d'hébergement pour personnes âgées dépendantes (IQUARE) study. A total of 175 NHs in Midi-Pyrénées region, South-Western France. Patients with PD taking antipsychotic drugs. All-cause mortality between baseline and 18 months. Logistic regression was used to explore baseline characteristics associated with mortality rate and with antipsychotic use at 18 months. At baseline, among 452 residents with PD, 72 (15.9%) received at least 1 antipsychotic drug. Mortality rates at 18 months in residents with PD with and without antipsychotic use were similar (34.3% and 38.2%, respectively, P = .58). Among factors ...
Expert review of neurotherapeutics, 2017
Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) ... more Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy. Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy. Expert commentary: With its convenient once-daily regimen, adjunct opicapone should be considered as an effective option for use in L-DOPA treated PD patients experiencing motor fluctuations.
Neurology, Jan 10, 2017
To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the tr... more To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy. This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3). The number of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 weeks. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a negative difference in...
JAMA neurology, Jan 27, 2016
Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor... more Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of...
British journal of clinical pharmacology, Mar 30, 2016
Pharmacovigilance databases are usually used to detect new potential signals relevant for drug sa... more Pharmacovigilance databases are usually used to detect new potential signals relevant for drug safety. They are seldom used for explanatory purposes, e.g. to understand the mechanisms of adverse drug reactions (ADRs). The aim of the present study was to combine pharmacovigilance and pharmacodynamic data to investigate the association between D2, 5HT2A, and M1 receptor occupancy and the risks of antipsychotic (AP)-induced movement disorders. First, we performed a case non-case analysis using spontaneous reports from the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database, VigiBase®. We thus measured the risk of movement disorder reporting compared to all other ADRs (expressed as a Reporting Odds Ratio) for antipsychotics (APs). Second, we performed a linear regression analysis to explore the association between the estimated risk of reporting for individual drugs and their receptor occupancy properties for D2, 5HT2A, and M1 receptors. FGAPs were found...
Neurology, Jan 14, 2016
To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA... more To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10(-6), including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem t...
Movement disorders : official journal of the Movement Disorder Society, Jan 19, 2016
Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to resp... more Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to respond well to levodopa (or other forms of dopaminergic medication) or appear to become resistant to levodopa treatment with disease progression and longer disease duration. In this narrative review, we elaborate on this issue of levodopa resistance in PD. First, we discuss the possibility of pseudoresistance, which refers to dopamine-sensitive symptoms or signs that falsely appear to be (or have become) resistant to levodopa, when in fact other mechanisms are at play, resulting in suboptimal dopaminergic efficacy. Examples include interindividual differences in pharmacodynamics and pharmacokinetics and underdosing because of dose-limiting side effects or because of levodopa phobia. Moreover, pseudoresistance can emerge as not all features of PD respond adequately to the same dosage of levodopa. Second, we address that for several motor features (eg, freezing of gait or tremor) and several ...
Movement Disorders
There are no effective treatments for multiple system atrophy (MSA).
Neurologie.com
L’efficacite et la tolerance des agonistes dopaminergiques ont ete validees par des essais cliniq... more L’efficacite et la tolerance des agonistes dopaminergiques ont ete validees par des essais cliniques randomises et controles. Cependant, la place exacte des agonistes dopaminergiques dans le traitement de la maladie de Parkinson reste encore debattue. En effet, il n’existe pas, a ce jour, de strategie consensuelle et d’etudes avec un niveau de preuve suffisant pour permettre d’elaborer un arbre decisionnel definitif de la strategie therapeutique dans cette pathologie. Une approche pragmatique tend a privilegier chez le patient jeune les agonistes dopaminergiques par rapport a la L-Dopa afin d’en retarder l’introduction du fait des complications motrices. Les agonistes non ergotes sont desormais privilegies en raison du risque de complications a type de fibrose lie a l’usage des agonistes ergotes.
Journal of Neural Transmission
Abstractl-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson’s disease (PD) and im... more Abstractl-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson’s disease (PD) and impact negatively health-related quality of life. Amantadine has demonstrated significant antidyskinetic effects in animal PD models and in randomized double-blind placebo-controlled trials (RCTs) in patients with PD. These effects are thought to be related to the blockade of NMDA receptors modulating cortico-striatal glutamatergic–dopaminergic interactions involved in the genesis of LIDs. There are three pharmaceutical forms of amantadine currently available in the market: an oral immediate-release (IR) formulation, which is widely available; an extended-release (ER) formulation (ADS-5102) which has been recently developed and approved by the FDA; and an intravenous infusion (IV) solution, which is not commonly used in clinical practice. RCTs with amantadine IR or ER, involving more than 650 patients have shown consistent and long-lasting reductions in LIDs. Interestingly, ADS-5102 not only reduced LIDs, but also reduced significantly at the same time the duration of daily OFF-time, a unique finding compared with other antiparkinsonian medications that usually reduce time spent OFF at the cost of worsening of LIDs. Amantadine IR might also have possible effects on other PD symptoms such as apathy or fatigue. The most common adverse reactions with amantadine are constipation, cardiovascular dysfunction including QT prolongation, orthostatic hypotension and edema, neuropsychiatric symptoms such as hallucinations, confusion and delirium, nausea and livedo reticularis. Corneal degeneration is rare but critical. In summary, amantadine immediate and extended-release are effective and safe for the treatment of LIDs.
European journal of clinical pharmacology, 2018
Three studies have suggested a potential positive association between the use of tamoxifen in bre... more Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure. To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018. Among women ≥ 55 years, we measured the risk of reporting "Parkinsonism" compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors. During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71-0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33-0.46). This study did not find evidence for Parkinsonism associated with tamoxifen.
Movement disorders : official journal of the Movement Disorder Society, 2018
Neurology, Jan 25, 2018
To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching fro... more To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching from entacapone over 1 year of treatment in patients with fluctuating Parkinson disease. After completion of a placebo- and entacapone-controlled double-blind study of opicapone (5, 25, or 50 mg), 495 patients continued to a 1-year extension phase in which patients were treated with opicapone. Patients began with once-daily opicapone 25 mg for 1 week, followed by individually tailored levodopa and/or opicapone dose adjustments. The primary efficacy variable was the change from baseline in absolute "off" time based on patient diaries. Other outcomes included proportion of responders, scale-based assessments, and standard safety assessments. One year of treatment with opicapone reduced "off" time by a half-hour (33.8 minutes) vs the open-label baseline and >2 hours (126.9 minutes) vs the double-blind baseline. Whereas patients who were originally treated with opicapone ...
Movement disorders : official journal of the Movement Disorder Society, 2018
Multimodal MRI approach is based on a combination of MRI parameters sensitive to different tissue... more Multimodal MRI approach is based on a combination of MRI parameters sensitive to different tissue characteristics (eg, volume atrophy, iron deposition, and microstructural damage). The main objective of the present study was to use a multimodal MRI approach to identify brain differences that could discriminate between matched groups of patients with multiple system atrophy, Parkinson's disease, and healthy controls. We assessed the 2 different MSA variants, namely, MSA-P, with predominant parkinsonism, and MSA-C, with more prominent cerebellar symptoms. Twenty-six PD patients, 29 MSA patients (16 MSA-P, 13 MSA-C), and 26 controls underwent 3-T MRI comprising T2*-weighted, T1-weighted, and diffusion tensor imaging scans. Using whole-brain voxel-based MRI, we combined gray-matter density, T2* relaxation rates, and diffusion tensor imaging scalars to compare and discriminate PD, MSA-P, MSA-C, and healthy controls. Our main results showed that this approach reveals multiparametric m...
Neurology, Jan 13, 2017
Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gap... more Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided.
CNS Drugs
Dopamine agonists are well-established symptomatic medications for treating early and advanced Pa... more Dopamine agonists are well-established symptomatic medications for treating early and advanced Parkinson disease (PD). Piribedil was one of the first agonists to be marketed (1969) and is widely used as an extended-release oral formulation in European, Latin-American, and Asian countries. Piribedil acts as a non-ergot partial dopamine D2/D3-selective agonist, blocks alpha2-adrenoreceptors and has minimal effects on serotoninergic, cholinergic, and histaminergic receptors. Animal models support the efficacy of piribedil to improve parkinsonian motor symptoms with a lower propensity than levodopa to induce dyskinesia. In PD patients, randomized double-blind studies show that piribedil (150–300 mg/day, three times daily) is superior to placebo in improving motor disability in early PD patients. Based on such evidence, piribedil was considered in the last Movement Disorder Society Evidence-Based Medicine review as “efficacious” and “clinically useful” for the symptomatic treatment of PD, either as monotherapy or in conjunction with levodopa, in non-fluctuating early PD patients. This effect appears comparable to what is known from other D2 agonists. However, randomized controlled trials are not available to assess the effect of piribedil in managing levodopa-induced motor complications. Pilot clinical studies suggest that piribedil may improve non-motor symptoms, such as apathy, but confirmatory trials are needed. The tolerability and safety profile of piribedil fits with that of the class of dopaminergic agonists. As for other non-ergot agonists, pneumo-pulmonary, retroperitoneal, and valvular fibrotic side effects are not a concern with piribedil. The original combination of piribedil D2 dopaminergic and alpha-2 adrenergic properties deserve further investigations to better understand its antiparkinsonian profile.
Movement Disorders
Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although... more Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although many clinical trials have been conducted, there is still no treatment that cures the disease or slows its progression. We sought to assess the clinical trials, methodology, and quality of reporting of clinical trails conducted in MSA patients. We conducted a systematic review of all trials with at least 1 MSA patient subject to any pharmacological/nonpharmacological interventions. Two independent reviewers evaluated the methodological characteristics and quality of reporting of trials. A total of 60 clinical trials were identified, including 1375 MSA patients. Of the trials, 51% (n = 31) were single-arm studies. A total of 28% (n = 17) had a parallel design, half of which (n = 13) were placebo controlled. Of the studies, 8 (13.3%) were conducted in a multicenter setting, 3 of which were responsible for 49.3% (n = 678) of the total included MSA patients. The description of primary outcomes was unclear in 60% (n = 40) of trials. Only 10 (16.7%) clinical trials clearly described the randomization process. Blinding of the participants, personnel, and outcome assessments were at high risk of bias in the majority of studies. The number of dropouts/withdrawals was high (n = 326, 23.4% among the included patients). Overall, the design and quality of reporting of the reviewed studies is unsatisfactory. The most frequent clinical trials were small and single centered. Inadequate reporting was related to the information on the randomization process, sequence generation, allocation concealment, blinding of participants, and sample size calculations. Although improved during the recent years, methodological quality and trial design need to be optimized to generate more informative results. © 2017 International Parkinson and Movement Disorder Society.
Journal of the American Medical Directors Association, Jan 13, 2017
To evaluate mortality rate in elderly and very elderly (≥85 years) residents with Parkinson disea... more To evaluate mortality rate in elderly and very elderly (≥85 years) residents with Parkinson disease (PD) in nursing homes (NHs) with and without antipsychotic drugs. Cross-sectional study. All residents with PD from the 6275 NH residents participating in the Impact d'une démarche QUAlité sur l'évolution des pratiques et le déclin fonctionnel des Résidents en Etablissement d'hébergement pour personnes âgées dépendantes (IQUARE) study. A total of 175 NHs in Midi-Pyrénées region, South-Western France. Patients with PD taking antipsychotic drugs. All-cause mortality between baseline and 18 months. Logistic regression was used to explore baseline characteristics associated with mortality rate and with antipsychotic use at 18 months. At baseline, among 452 residents with PD, 72 (15.9%) received at least 1 antipsychotic drug. Mortality rates at 18 months in residents with PD with and without antipsychotic use were similar (34.3% and 38.2%, respectively, P = .58). Among factors ...
Expert review of neurotherapeutics, 2017
Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) ... more Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy. Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy. Expert commentary: With its convenient once-daily regimen, adjunct opicapone should be considered as an effective option for use in L-DOPA treated PD patients experiencing motor fluctuations.
Neurology, Jan 10, 2017
To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the tr... more To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy. This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3). The number of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 weeks. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a negative difference in...
JAMA neurology, Jan 27, 2016
Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor... more Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of...
British journal of clinical pharmacology, Mar 30, 2016
Pharmacovigilance databases are usually used to detect new potential signals relevant for drug sa... more Pharmacovigilance databases are usually used to detect new potential signals relevant for drug safety. They are seldom used for explanatory purposes, e.g. to understand the mechanisms of adverse drug reactions (ADRs). The aim of the present study was to combine pharmacovigilance and pharmacodynamic data to investigate the association between D2, 5HT2A, and M1 receptor occupancy and the risks of antipsychotic (AP)-induced movement disorders. First, we performed a case non-case analysis using spontaneous reports from the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database, VigiBase®. We thus measured the risk of movement disorder reporting compared to all other ADRs (expressed as a Reporting Odds Ratio) for antipsychotics (APs). Second, we performed a linear regression analysis to explore the association between the estimated risk of reporting for individual drugs and their receptor occupancy properties for D2, 5HT2A, and M1 receptors. FGAPs were found...
Neurology, Jan 14, 2016
To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA... more To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10(-6), including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem t...
Movement disorders : official journal of the Movement Disorder Society, Jan 19, 2016
Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to resp... more Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to respond well to levodopa (or other forms of dopaminergic medication) or appear to become resistant to levodopa treatment with disease progression and longer disease duration. In this narrative review, we elaborate on this issue of levodopa resistance in PD. First, we discuss the possibility of pseudoresistance, which refers to dopamine-sensitive symptoms or signs that falsely appear to be (or have become) resistant to levodopa, when in fact other mechanisms are at play, resulting in suboptimal dopaminergic efficacy. Examples include interindividual differences in pharmacodynamics and pharmacokinetics and underdosing because of dose-limiting side effects or because of levodopa phobia. Moreover, pseudoresistance can emerge as not all features of PD respond adequately to the same dosage of levodopa. Second, we address that for several motor features (eg, freezing of gait or tremor) and several ...