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Benign esophageal strictures are uncommon and their management remains challenging. Herein, we present a rare both functional and organic esophageal stricture in a patient with Parkinson’s disease and reflux esophagitis. The patient was diagnosed with severe complex stricture in the distal part of the esophagus, requiring surgical treatment. We performed subtotal esophageal resection and Ivor-Lewis gastroesophagoplasty. The successful management of antiparkinsonian drug therapy with adequate parenteral substitution in the early postoperative period is of great importance to avoid any further complications.

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

Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms in individuals with advanced Parkinson's disease (PD) and enables physicians to reduce doses of antiparkinsonian drugs. We investigated possible predictive factors for the successful reduction of antiparkinsonian drug dosage after STN-DBS. We evaluated 33 PD patients who underwent bilateral STN-DBS. We assessed rates of reduction of the levodopa-equivalent daily dose (LEDD) and levodopa daily dose (LDD) by comparing drug doses before vs. 6-months post-surgery. We used correlation coefficients to measure the strength of the relationships between LEDD and LDD reduction rates and preoperative factors including age, disease duration, preoperative LEDD and LDD, unified Parkinson's Disease Rating Scale part-II and -III, levodopa response rate, Mini-Mental State Examination score, dyskinesia score, Hamilton Rating Scale for depression, and the number of non-motor symptoms. The average LEDD and LDD reduction rates were 61.0% and 70.4%, respectively. Of the variables assessed, only the number of psychiatric/cognitive symptoms was significantly correlated with the LEDD reduction rate. No other preoperative factors were correlated with the LEDD or LDD reduction rate. A wide range of preoperative psychiatric and cognitive symptoms may predict the successful reduction of antiparkinsonian drugs after STN-DBS.

Hemantane is an antiparkinsonian drug with pronounced analgesic and anti-inflammatory properties. The present work evaluated topical gel dosage forms based on it for analgesic activity. It was found that gel batches 070916, 080916, and 090916 exhibited analgesic activity using the formalin test in rats and diminished behavior characteristic of pain in the inflammation-mediated tonic phase of formalin-induced pain. 5% hemantane gel batch 080916 exhibited the most distinct analgesic activity because this dosage form decreased pain indicators even in the acute phase related to the effect of formalin on primary pain afferents.

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.

Objective To investigate trends in the incidence of Parkinson’s disease (PD) between 2006 and 2016. Design Cohort study in The Health Improvement Network (THIN): a large UK primary care database. Study participants Individuals actively registered with a practice within THIN aged 50 years and over. Measures of outcome The incidence of Parkinson’s disease between 2006 and 2016 using different case definitions: 1) PD diagnostic Read code; 2) PD diagnostic Read code OR symptom Read code; 3) PD diagnostic Read code OR symptom Read code and OR at least 1 antiparkinsonian drug prescription; 4) PD diagnostic Read code OR symptom Read code plus at least 2 antiparkinsonian drug prescription. The effect of age and sex on these measures were investigated. Results The overall crude incidence of PD for people over 50 years has increased in recent years. The rates increased with increasing age and as expected, higher in men. Using the broadest case definition (3), incidence rate of PD between 2006 and 2016 in men was 190 per 100,000 person years (95% CI 187–193) and in women was 176 per 100,000 person years (95% CI 173–178). Incidence of PD was highest at age 90 (496 per 100,000 95% CI 471–522). Conclusion There is increasing diagnosis of PD in primary care setting.

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 is the most common neurodegenerative disorder after Alzheimer's disease. The aim of this study was to investigate the pharmacokinetic parameters of the mGluR4 receptor blocker Rapitalam on rabbits. There was developed the method of the quantitative determination of Rapitalam in the blood plasma of rabbits using high performance liquid chromatography with tandem mass spectrometric detection. The study was performed on 12 rabbits (males, weighing between 3,300 to 3,500 g). In intragastric dosing of the substance was administered using a gastric tube in the form of suspension in water 0.9 mg/ml, 9 mg/ml, and 90 mg/ml at a dose of 0.3 mg/kg, 3 mg/kg and 30 mg/kg. After the administration of the substance blood was sampled through a catheter in a volume of 0.5 ml in polypropylene tubes containing 20 µl of 5% EDTA before and 10, 15, 30, 60, 120, 240, 480, 1440 minutes after administration. The mean absorption time (MAT) of Rapitalam was 268.1 minutes or 4.5 hours. The half-life is longtime and it was 176.4 minutes (2.9 hours) for intravenous and 362.2 minutes (6.0 hours) for intragastric administration. The absolute bioavailability of the intragastric dosing was 26.8%. The main pharmacokinetic parameters of the substance was established on rabbits that allow you to optimize the future use of it's as a potential drug for the treatment of Parkinson's disease.

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.

A prospective study carried out in the Netherlands showed that the most important risk factor for motor function deterioration in Parkinson's disease (PD) during hospital admission was medication error, including both incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs.1 Indeed, one of the reported reasons for omitting or delaying levodopa administration has been medication unavailability on time where needed, that is, in medical wards where the patient is admitted. Skelly et al in a recent study carried out in Derby Hospital (National Parkinson Foundation Centre of Excellence for Parkinson’s Disease) report that even in a ward specially designed to treat patients with PD, with an enhanced stock of anti-PD medications, 2.5% of all doses were not administered because the drug was not available on time.2 It is likely this problem is compounded in other nonspecialized wards and especially in smaller hospitals. To counteract this problem, Parkinson's United Kingdom “Get it on time campaign,”3 among others, has suggested that all commercially available antiparkinsonian drugs should be available in all hospital wards and on time. Given the data described previously, this seems unfeasible, especially in small hospitals where having available all the anti-PD drugs would certainly result in the expiration of many of these drugs before they are used. We think a possible solution can be found in Skelly et al’s reflections: “The available stock was not used as flexibly as we had hoped: e.g. doses of modified release medications were omitted rather than a temporary switch to available standard release drugs.”2 (p. 1246) We agree and propose a therapeutic interchange protocol (Figure 1) where the unavailable PD drug is first converted to the equivalent levodopa dose according to published dose equivalency.4 Then an immediate release levodopa dose could be administered until the original drug is available. Immediate release levodopa is cheap. Thus, having it in each hospital ward is a realistic approach. Figure 1. An example of applying the proposed protocol to prevent Parkinson’s disease (PD) drug omissions. It has to be kept in mind that dose equivalencies proposed by Tomlinson et al were developed to compare dose intensities of antiparkinsonian drugs in clinical trials rather than to use them in clinical practice and were catalogued by the authors as mere approximations. Paraphrasing Magdalinou et al5: “PD medications should be regarded as important as insulin is for diabetics.” (p. 540) Using short-acting insulin instead of the patient’s chronic insulin treatment is now routine clinical practice in hospitals. Although there may be some limitations to this approach, we think changing to an equivalent dose of immediate release levodopa could help to prevent PD drug omissions and delays.