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Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and daily “OFF” time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25–50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily “OFF” time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive–compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa–dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.

In this work, structural, electronic, topological, and electronic and vibrational spectra of antiepileptic and antiparkinsonian drug safinamide (two enantiomers and their mesylate salt) were investigated with the DFT/TD-DFT methodology in gas phase and PCM solvent model. The absorbance maximum of safinamide was found at 227 nm, and the computed maximum transition occurred at 226 nm, which was assigned to π → π* transitions due to the chromophores C=C, C=O and C=N bonds. Electrostatic potential maps of all studied molecules revealed that the C=O group of (S)-enantiomer was more nucleophilic than the remaining molecules. Topological analysis suggested that an N–H intramolecular hydrogen bond especially in solution, and the NBO study showed a clear instability and strong ionic character of the salt. The lower electrophilicity and nucleophilicity indexes for the (S)-enantiomer than for the (R)-enantiomer, the higher reactivity it shows. At the same time, it shows higher activity as inhibitor of monoamine oxidase B. The force fields and the complete assignment of the 117 vibration normal modes of the enantiomers and 144 vibration normal modes of the mesylate salt are reported. The predicted infrared, Raman, 1H-NMR, UV–visible, and ECD spectra were in reasonable agreement with the corresponding experimental ones. In addition, the interaction with monoamine oxidase was evaluated. This study provides a structural, vibrational, and electronic characterization of the drug through theoretical insights that will contribute to further research of the biological interaction mechanism. Fil: Ledesma, Ana Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Centro de Investigación en Biofísica Aplicada y Alimentos. - Universidad Nacional de Santiago del Estero. Centro de Investigación en Biofísica Aplicada y Alimentos; Argentina Fil: Catalan, Cesar Atilio Nazareno. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Orgánica; Argentina Fil: Brandan, Silvia Antonia. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Inorgánica. Cátedra de Química General; Argentina

Aim/Introduction: Drugs interacting with multiple targets are under study for the treatment of disorders of the central nervous system. AG-00291 combines very potent agonist affinity (0.08 nM) to the dopamine D2 receptor with moderate antagonist affinity (111 nM) to the histamine H3 receptor. These receptor interactions of AG-0029 were proven by measurement of extracellular dopamine levels in rat striatum and histamine levels in rat prefrontal cortex by microdialysis. AG-0029 showed anti-Parkinson action (contralateral rotation), and a cognition-enhancing effect in the novel object recognition test of 6-OHDA-lesioned rats. This drug may improve both the motor and cognitive symptoms of Parkinson disease. The present study aims to quantify the target engagement of AG-0029. Materials and Methods: Healthy male Wistar rats were scanned in a small animal PET camera (μPET Focus 220), using the dopamine D2/D3 receptor ligand [11C]raclopride or the histamine H3 receptor ligand [11C]GSK189254, before and after treatment with an intravenous, acute, single dose of AG-0029 (0.1 or 1 mg/kg for [11C]raclopride, 1 mg/kg for [11C]GSK189254). Dynamic [11C]raclopride scans (60 min duration) were made without arterial blood sampling, and were analysed using the simplified reference tissue model with cerebellum as reference tissue. Dynamic [11C]GSK189254 scans (90 min duration) were made with arterial blood sampling. Results: Binding potential values of [11C]raclopride in the striatum were dose-dependently reduced after administration of AG-0029 (10 min before tracer injection), from 1.45±0.10 (n=9) to 1.04±0.17 (after a 0.1 mg/kg dose, n=4) and to 0.33±0.18 (after a 1 mg/kg dose, n=5), corresponding to D2/D3 receptor occupancy values of 27±12 and 78±4%. These data (0, 0.1, 1 mg/kg dose) are well-fitted by a one-site model for receptor binding (r2>0.99), half-maximal receptor occupancy being reached at a dose of 0.27 mg/kg and maximal occupancy being 99.3%. Data acquisition and analysis for the [11C] GSK189254 scans is still in progress. Frontal/occipital cortex ratios of radioactivity were reduced from 3.04±0.74 (n=4) at baseline to 2.58±0.13 (n=3) after administration of 1 mg/kg AG-0029, which may correspond to a H3 receptor occupancy of 23%. However, due to high variability of [11C]GSK189254 binding at baseline, the decline of binding potential at this dose was not statistically significant. Conclusion: Dopamine D2/D3 receptor occupancy by the agonist AG-0029 could be reliably measured with [11C]raclopride and small animal PET. Histamine H3 receptor occupancy by AG-0029 may be detectable in PET scans with [11C]GSK189254, but may require a higher dose than 1 mg/kg. References: 1 7-(4-(3-(4-(morpholinomethyl)phenoxy)propyl)piperazin-1- yl)benzo[d]oxazol-2(3H)-one.

Aim/Introduction: Drugs interacting with multiple targets are under study for the treatment of disorders of the central nervous system. AG-00291 combines very potent agonist affinity (0.08 nM) to the dopamine D2 receptor with moderate antagonist affinity (111 nM) to the histamine H3 receptor. These receptor interactions of AG-0029 were proven by measurement of extracellular dopamine levels in rat striatum and histamine levels in rat prefrontal cortex by microdialysis. AG-0029 showed anti-Parkinson action (contralateral rotation), and a cognition-enhancing effect in the novel object recognition test of 6-OHDA-lesioned rats. This drug may improve both the motor and cognitive symptoms of Parkinson disease. The present study aims to quantify the target engagement of AG-0029. Materials and Methods: Healthy male Wistar rats were scanned in a small animal PET camera (μPET Focus 220), using the dopamine D2/D3 receptor ligand [11C]raclopride or the histamine H3 receptor ligand [11C]GSK189254, before and after treatment with an intravenous, acute, single dose of AG-0029 (0.1 or 1 mg/kg for [11C]raclopride, 1 mg/kg for [11C]GSK189254). Dynamic [11C]raclopride scans (60 min duration) were made without arterial blood sampling, and were analysed using the simplified reference tissue model with cerebellum as reference tissue. Dynamic [11C]GSK189254 scans (90 min duration) were made with arterial blood sampling. Results: Binding potential values of [11C]raclopride in the striatum were dose-dependently reduced after administration of AG-0029 (10 min before tracer injection), from 1.45±0.10 (n=9) to 1.04±0.17 (after a 0.1 mg/kg dose, n=4) and to 0.33±0.18 (after a 1 mg/kg dose, n=5), corresponding to D2/D3 receptor occupancy values of 27±12 and 78±4%. These data (0, 0.1, 1 mg/kg dose) are well-fitted by a one-site model for receptor binding (r2>0.99), half-maximal receptor occupancy being reached at a dose of 0.27 mg/kg and maximal occupancy being 99.3%. Data acquisition and analysis for the [11C] GSK189254 scans is still in progress. Frontal/occipital cortex ratios of radioactivity were reduced from 3.04±0.74 (n=4) at baseline to 2.58±0.13 (n=3) after administration of 1 mg/kg AG-0029, which may correspond to a H3 receptor occupancy of 23%. However, due to high variability of [11C]GSK189254 binding at baseline, the decline of binding potential at this dose was not statistically significant. Conclusion: Dopamine D2/D3 receptor occupancy by the agonist AG-0029 could be reliably measured with [11C]raclopride and small animal PET. Histamine H3 receptor occupancy by AG-0029 may be detectable in PET scans with [11C]GSK189254, but may require a higher dose than 1 mg/kg. References: 1 7-(4-(3-(4-(morpholinomethyl)phenoxy)propyl)piperazin-1- yl)benzo[d]oxazol-2(3H)-one.

Complex I (NADH dehydrogenase) and complex IV (cytochrome-c-oxidase) of the mitochondrial electron transport chain are reported to be affected by drugs used to treat psychiatric or neurodegenerative diseases, including antidepressants, antipsychotics, anxiolytics, mood stabilizers, stimulants, antidementia and antiparkinsonian drugs. We conducted meta-analyses examining the effects of each drug category on complex I and IV. The electronic databases Pubmed, EMBASE, CENTRAL and Google Scholar were searched for studies published between 1970 and 2018. Of 3105 screened studies, 68 articles covering 53 drugs were included in the meta-analyses. All studies assessed complex I and IV in rodent brain at the level of enzyme activity. Meta-analyses revealed that selected antidepressants increase or decrease complex I and IV, antipsychotics and stimulants primarily decrease complex I but increase complex IV, whereas anxiolytics, mood stabilizers, antidementia and antiparkinsonian drugs preserve or even enhance both complex I and IV. To determine potential contributors to the drug effects, we meta-analyzed the drugs' neurotransmitter receptor profiles and found that affinity to adrenergic, dopaminergic (D1/2), glutaminergic (NMDA1,3), histaminergic (H1), muscarinic (M1,3), opioid (OP1-3), serotonergic (5-HT2A, 5-HT2C, 5-HT3A) and sigma receptors contributed most to the effects. We discuss the drug effects in relation to pharmacological mechanisms of action that might have relevance for clinical and research applications. Funding: No specific funding. Declaration of Interest: J.J.M. receives royalties for commercial use of the C-SSRS from the Research Foundation of Mental Hygiene. The remaining authors declare no competing interests. Keywords: meta-analysis; psychotropic drugs; NADH dehydrogenase; cytochrome-c-oxidase

International audience; Apomorphine is now recognized as the oldest antiparkinsonian drug on the market. Though still underused, it is increasingly prescribed in Europe for patients with advanced Parkinson's disease (PD) with motor fluctuations. However, its history is far from being limited to movement disorders. This paper traces the history of apomorphine, from its earliest empirical use, to its synthesis, pharmacological development, and numerous indications in human and veterinary medicine, in light of its most recent uses and newest challenges. From shamanic rituals in ancient Egypt and Mesoamerica, to the treatment of erectile dysfunction, from being discarded as a pharmacological tool to becoming an essential antiparkinsonian drug, the path of apomorphine in the therapeutic armamentarium has been tortuous and punctuated by setbacks and groundbreaking discoveries. Throughout history, three main clinical indications stood out: emetic (gastric emptying, respiratory disorders, aversive conditioning), sedative (mental disorders, clinical anesthesia, alcoholism), and antiparkinsonian (fluctuations). New indications may arise in the future, both in PD (palliative care, nonmotor symptoms, withdrawal of oral dopaminergic medication), and outside PD, with promising work in neuroprotection or addiction.

Aim/Introduction: Drugs interacting with multiple targets are under study for the treatment of disorders of the central nervous system. AG-00291 combines very potent agonist affinity (0.08 nM) to the dopamine D2 receptor with moderate antagonist affinity (111 nM) to the histamine H3 receptor. These receptor interactions of AG-0029 were proven by measurement of extracellular dopamine levels in rat striatum and histamine levels in rat prefrontal cortex by microdialysis. AG-0029 showed anti-Parkinson action (contralateral rotation), and a cognition-enhancing effect in the novel object recognition test of 6-OHDA-lesioned rats. This drug may improve both the motor and cognitive symptoms of Parkinson disease. The present study aims to quantify the target engagement of AG-0029. Materials and Methods: Healthy male Wistar rats were scanned in a small animal PET camera (μPET Focus 220), using the dopamine D2/D3 receptor ligand [11C]raclopride or the histamine H3 receptor ligand [11C]GSK189254, before and after treatment with an intravenous, acute, single dose of AG-0029 (0.1 or 1 mg/kg for [11C]raclopride, 1 mg/kg for [11C]GSK189254). Dynamic [11C]raclopride scans (60 min duration) were made without arterial blood sampling, and were analysed using the simplified reference tissue model with cerebellum as reference tissue. Dynamic [11C]GSK189254 scans (90 min duration) were made with arterial blood sampling. Results: Binding potential values of [11C]raclopride in the striatum were dose-dependently reduced after administration of AG-0029 (10 min before tracer injection), from 1.45±0.10 (n=9) to 1.04±0.17 (after a 0.1 mg/kg dose, n=4) and to 0.33±0.18 (after a 1 mg/kg dose, n=5), corresponding to D2/D3 receptor occupancy values of 27±12 and 78±4%. These data (0, 0.1, 1 mg/kg dose) are well-fitted by a one-site model for receptor binding (r2>0.99), half-maximal receptor occupancy being reached at a dose of 0.27 mg/kg and maximal occupancy being 99.3%. Data acquisition and analysis for the [11C] GSK189254 scans is still in progress. Frontal/occipital cortex ratios of radioactivity were reduced from 3.04±0.74 (n=4) at baseline to 2.58±0.13 (n=3) after administration of 1 mg/kg AG-0029, which may correspond to a H3 receptor occupancy of 23%. However, due to high variability of [11C]GSK189254 binding at baseline, the decline of binding potential at this dose was not statistically significant. Conclusion: Dopamine D2/D3 receptor occupancy by the agonist AG-0029 could be reliably measured with [11C]raclopride and small animal PET. Histamine H3 receptor occupancy by AG-0029 may be detectable in PET scans with [11C]GSK189254, but may require a higher dose than 1 mg/kg. References: 1 7-(4-(3-(4-(morpholinomethyl)phenoxy)propyl)piperazin-1- yl)benzo[d]oxazol-2(3H)-one.

Parkinson’s disease (PD) is a major worldwide public health problem with a prevalence that is expected to increase dramatically in the coming decades. Because administrative data are useful for epidemiologic and health service studies, we aimed to define procedural algorithms to identify PD patients (on a regional basis) using these data. We built two a priori algorithms, respecting privacy laws, with increasing theoretical specificity for PD including: (1) a hospital discharge diagnosis of PD; (2) PD-specific exemption; (3) a minimum of two separate prescriptions of an antiparkinsonian drug. The two algorithms differed for drugs included. Sensitivities were tested on an opportunistic sample of 319 PD patients from the databases of 5 regional movement disorders clinics. The estimated prevalence of PD in the sample population from Tuscany was 0.49 % for algorithm 1 and 0.28 % for algorithm 2. Algorithm 1 correctly identified 291 PD patients (sensitivity 91.2 %), and algorithm 2 identified 242 PD patients (sensitivity 75.9 %). We developed two reproducible algorithms demonstrating increasing theoretical specificity with good sensitivity in identifying PD patients based on an evaluation of administrative data. This may represent a low-cost strategy to reliably follow up a large number of PD patients as a whole for evaluating the effects of therapies, disease progression and prevalence.

International audience; Drug claims databases are increasingly available and provide opportunities to investigate epidemiologic questions. The authors used computerized drug claims databases from a social security system in 5 French districts to predict the probability that a person had Parkinson's disease (PD) based on patterns of antiparkinsonian drug (APD) use. Clinical information for a population-based sample of persons using APDs in 2007 was collected. The authors built a prediction model using demographic variables and APDs as predictors and investigated the additional predictive benefit of including information on dose and regularity of use. Among 1,114 APD users, 320 (29%) had PD and 794 (71%) had another diagnosis as determined by study neurologists. A logistic model including information on cumulative APD dose and regularity of use showed good performance (c statistic = 0.953, sensitivity = 92.5%, specificity = 86.4%). Predicted PD prevalence (among persons aged ≥18 years) was 6.66/1,000; correcting this estimate using sensitivity/specificity led to a similar figure (6.04/1,000). These data demonstrate that drug claims databases can be used to estimate the probability that a person is being treated for PD and that information on APD dose and regularity of use improves models' performances. Similar approaches could be developed for other conditions.

Background The prevalence of smoking in patients with schizophrenia is higher than that in the general population and is an important medical issue. Short-term smoking cessation tends to worsen psychiatric symptoms in patients with schizophrenia but decreases sympathetic nervous system activity and improves plasma cholesterol levels in healthy people. Few studies have assessed the long-term effects of smoking cessation in patients with schizophrenia. Methods Subjects were 70 Japanese patients with schizophrenia (38 smokers, 32 non-smokers). We compared the following clinical parameters between the two groups at baseline (before smoking cessation) and in each group separately between baseline and at three years after smoking cessation: autonomic nervous system activity, plasma cholesterol levels, body weight, drug therapy, and Global Assessment of Functioning scores. We also compared the mean changes in clinical parameters throughout this study between the groups at both time points. Autonomic nervous system activity was assessed by power spectral analysis of heart rate variability. Results Parasympathetic nervous system activity and the doses of antiparkinsonian drugs in smokers were significantly higher than those in non-smokers at baseline. Smoking cessation was associated with significantly decreased sympathetic nervous system activity and decreased doses of antipsychotics and antiparkinsonian drugs at three years after smoking cessation. However, there was no significant difference in the mean change in clinical factors scores, except for Global Assessment of Functioning scores, between smokers and non-smokers at three years after smoking cessation. Conclusions Our results suggest that smoking reduces both autonomic nervous system activity and the effectiveness of drug therapy with antipsychotics and antiparkinsonian drugs in patients with schizophrenia, but that both factors could be ameliorated over the long term by smoking cessation. Taken together with the findings of previous studies, smoking cessation in patients with schizophrenia has many long-term positive physiological effects.