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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.

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.

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.

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.

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.

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.

Using molecular simulations, we study the adsorption and diffusion of an antiparkinsonian drug known as amantadine (or 1-aminoadamantane) in different single-walled carbon nanotubes (SWCNs) with di...

Hemantane is a novel antiparkinsonian drug that is undergoing clinical trials. Hemantane in the dosage range 10 – 40 mg/kg demonstrated anti-inflammatory activity and decreased statistically significantly the intensity of the exudative reaction in an acetic-acid peritonitis model in mice. Hemantane (10 mg/kg) in a neuro-inflammation model induced by lipopolysaccharide injection in rats prevented loss of body mass, development of forepaw akinesia contralateral to the operation, and smell disturbance.

The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine.

Ethopropazine (EP) or profenamine is a phenothiazine derivative, N 10 -(2-diethylaminopropyl)phenothiazine (Figure.1), used as an antiparkinsonian drug that has anticholinergic, antihistamine, and antiadrenergic actions. Transition metal complexes of ZnBr2, CdBr2, CdI2, and HgBr2 have been synthesized using EP as the main ligand and purified by recrystallization in MeOH. These products have been characterized based on their elemental analysis, molar conductance, magnetic susceptibility, IR and 1 H-NMR data. The molecular formulations of the new mononuclear complexes have been found to be(Zn(C19H24N2S.HCl)2)Br2,(Cd(C19H24N2S.HCl)2)Br2,(Cd(C19H24N2S.HCl)2)I2 and(Hg(C19H24N2S.HCl) (C19H24N2S.HBr) (OH2)) Br2, where the ligand, EP = C19H24N2S. All the complexes show an ionic ratio of 1:2 in acetonitrile solutions. Molecular structures have been proposed. The four-coordinate complex cations of(Zn(C19H24N2S.HCl)2) Br2,(Cd(C19H24N2S.HCl)2)Br2, and(Cd(C19H24N2S.HCl)2)I2 contain an sp

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.

The physico-chemical properties and in vivo efficacies of two nanoparticulate systems delivering the antiparkinsonian drug bromocriptine (BC) were compared in the present study. Monoolein Aqueous Dispersions (MADs) and Nanostructured Lipid Carriers (NLCs) were produced and characterized. Cryogenic transmission electron microscopy (cryo-TEM) and X-ray diffraction revealed the morphology of MAD and NLC. Dimensional distribution was determined by Photon Correlation Spectroscopy (PCS) and Sedimentation Field Flow Fractionation (SdFFF). In particular, BC was shown to be encapsulated with high entrapment efficiency both in MAD and in NLC, according to SdFFF combined with HPLC. Two behavioral tests specific for akinesia (bar test) or akinesia/bradykinesia (drag test) were used to compare the effects of the different BC formulations on motor disabilities in 6-hydroxydopamine hemilesioned rats in vivo, a model of Parkinson's disease. Both free BC and BC-NLC reduced the immobility time in the bar test and enhanced the number of steps in the drag test, although the effects of encapsulated BC were longer lasting (5h). Conversely, BC-MAD was ineffective in the bar test and improved stepping activity in the drag test to a much lower degree than those achieved with the other preparations. We conclude that MAD and NLC can encapsulate BC, although only NLC provide long-lasting therapeutic effects possibly extending BC half-life in vivo.