David Devos1, Stéphanie Lejeune2, Florence Cormier-Dequaire2, Khadija Tahiri3, Fanny Charbonnier-Beaupel4, Nathalie Rouaix5, Alain Duhamel5, Bernard Sablonnière5, Anne-Marie Bonnet6, Cecilia Bonnet7, Noel Zahr8, Jean Costentin9, Marie Vidailhet10, Jean-Christophe Corvol10. 1. INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France; Lille Nord de France University, Department of Medical Pharmacology, Lille University Medical Center, Faculty of Medicine of Lille 2, EA 4610, France. Electronic address: david.devos@chru-lille.fr. 2. INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France; INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France. 3. INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France. 4. INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France; APHP (Assistance Publique Hopitaux de Paris), Pitié-Salpêtrière Hospital, Department of Pharmacy, France; APHP, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France. 5. Lille Nord de France University, Department of Molecular Biology, Lille University Medical Center, France. 6. APHP, Pitié-Salpêtrière Hospital, Department of Neurology, France. 7. INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France. 8. APHP, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France. 9. University of Rouen, Neuropharmacology Laboratory, Rouen, France. 10. INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France; INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France; APHP, Pitié-Salpêtrière Hospital, Department of Neurology, France.
Abstract
BACKGROUND: In Parkinson's disease (PD), the response to L-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from L-dopa is decarboxylation by aromatic L-amino acid decarboxylase (AAAD, encoded by the DDC gene). OBJECTIVE: To determine the motor response to L-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDC(T/C)) and rs3837091 AGAG del (DDC(AGAG/-))). METHODS:Thirty-three Caucasian PD patients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to L-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following L-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of L-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study. RESULTS: When adjusted for the L-dopa dose, the AUCΔUPDRS was significantly lower in DDC(CC/CT) patients (n = 14) than in DDC(TT) patients (n = 19) and significantly lower in DDC(-/- or AGAG/-) patients (n = 8) than in DDC(AGAG/AGAG) patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for L-dopa and dopamine. DISCUSSION: The rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to L-dopa but do not significantly change peripheral pharmacokinetic parameters for L-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease.
RCT Entities:
BACKGROUND: In Parkinson's disease (PD), the response to L-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from L-dopa is decarboxylation by aromatic L-amino acid decarboxylase (AAAD, encoded by the DDC gene). OBJECTIVE: To determine the motor response to L-dopa in PDpatients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDC(T/C)) and rs3837091 AGAG del (DDC(AGAG/-))). METHODS: Thirty-three Caucasian PDpatients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to L-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following L-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of L-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study. RESULTS: When adjusted for the L-dopa dose, the AUCΔUPDRS was significantly lower in DDC(CC/CT) patients (n = 14) than in DDC(TT) patients (n = 19) and significantly lower in DDC(-/- or AGAG/-) patients (n = 8) than in DDC(AGAG/AGAG) patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for L-dopa and dopamine. DISCUSSION: The rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to L-dopa but do not significantly change peripheral pharmacokinetic parameters for L-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease.
Authors: Daniel P Eisenberg; Philip D Kohn; Catherine E Hegarty; Angela M Ianni; Bhaskar Kolachana; Michael D Gregory; Joseph C Masdeu; Karen F Berman Journal: Neuropsychopharmacology Date: 2016-02-29 Impact factor: 7.853
Authors: Julia Kraemmer; Kara Smith; Daniel Weintraub; Vincent Guillemot; Mike A Nalls; Florence Cormier-Dequaire; Ivan Moszer; Alexis Brice; Andrew B Singleton; Jean-Christophe Corvol Journal: J Neurol Neurosurg Psychiatry Date: 2016-04-13 Impact factor: 10.154