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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.

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.

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.

methyltransferase (COMT) offers a novel possibility for treating Parkinson’s disease. Bisubstrate inhibitors ofCOMT containing the adenine of S-adenosylmethionine (SAM) and a catechol moiety are a new class of potentand selective inhibitor. In the present study, we used receptor-oriented pharmacophore-based

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.

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: L-dopa is an important antiparkinsonian drug. It is a precursor of dopamine and the other catecholamines. Potentially, administration of L-dopa could lead to increased urinary excretion of catecholamines and their metabolites to abnormal amounts. The current study aimed to determine these excretions in patients with Parkinson's disease (PD) receiving L-dopa compared with suitable controls. This is the first assessment of the effect of exogenous administration of L-dopa on urinary free metadrenalines. Methods: Using one-way analysis of variance (ANOVA), urine catecholamines and metabolites, expressed as mmol per mole creatinine, were compared in: patients with PD who were receiving L-dopa; patients with PD but not receiving L-dopa; and patients without PD who were being investigated for the presence of phaechromocytoma but were found not to have the disease. Results: Significantly higher values for urinary dopamine, homovanillic acid, free normetadrenaline and free metadrenaline were found in patients with PD receiving L-dopa compared with the other two control groups. In all the patients with PD, these four analytes were significantly correlated with daily dose of L-dopa. Conclusion: L-dopa therapy can result in production of false positives for urinary excretion of dopamine, homovanillic acid, free normetadrenaline or free metadrenaline and thereby decrease the diagnostic value of these measurements in identifying phaeochromocytoma and related tumours.

The authors review management issues in Parkinson’s disease (PD) and provide an overview of the current pharmacological management strategies, with a specific focus on safinamide. Current therapeutic management of PD largely involves strategies to optimize the replacement of deficient dopamine, using levodopa, dopamine agonists, and inhibitors of dopamine-metabolizing enzymes. Currently under investigation for use in the treatment of PD, safinamide has multiple modes of action including monoamine oxidase B inhibition. It is well absorbed orally, has a long plasma half-life, and does not have liver enzyme-inducing or liver enzyme-inhibiting activity. Peak plasma concentration occurs 2–4 hours after single oral doses. Safinamide as monotherapy and as an adjunct to dopamine agonists improves Unified Parkinson’s Disease Rating Scale motor scores. One randomized, placebo-controlled trial involving 168 patients given a median safinamide dose of 70 mg/day (range 40–90 mg/day) significantly increased the proportion of responders – defined as patients improving their Unified Parkinson’s Disease Rating Scale motor scores by 30% or more from baseline – after 3 months (37.5% for safinamide versus 21.4% for placebo; P < 0.05). Safinamide increased “on” time with no or minor dyskinesia compared with the placebo in another trial, but dyskinesia severity was not reduced. Safinamide was well tolerated, with an adverse effect profile similar to that of the placebo. Further Phase III trial data for safinamide efficacy is awaited, and will be of interest in a comparison with other developments in PD therapeutics: modified formulations of available compounds, new drug classes such as adenosine receptor antagonists, and gene-based therapies.

Many investigators have recently reported marked beneficial effects of L-DOPA in the treatment of Parkinsonism.This author has already reported clinical ex periences with L-DOPA in the treatment of 145 cases of Parkinsonism at St. Barnabas Hospital in N. Y. C., published in the Japanese Journal of Brain and Nerve on December 1970.In this report, following results were stressed. Namely, 80.7% of the patients showed some improvement of symptoms and especially such symptoms as rigidity, bradykinesia, difficulty of speech and ambulation showed moderate or significant improvement, while tremor was unable to get significant relief.This time, the author is reporting clinical experiences with APD-512 (L-DOPA) in the treatment of 14 cases of Parkinsonism, treated at Sapporo District Hospital, Ground Self Defense Force, Japan.The results are summarized as follows: —1. APD-512 was given orally in every case.Initial daily doses started at 500 mg and were increased gradually every couple of days.2. Initial effective daily doses were proved to be 1.5 or 2.0 gm and an average daily maintenance dosage between 2.0 gm and 4.0 gm was sufflcient.3. All 14 cases were responsive to the drug, with apparent improvement of Parkinsonian symptoms.4. Side effects were almost the same as experienced in previous cases, including nausea, vomiting, anorexia, psychic reaction, etc. However, the severity of these complaints was lighter in Japanese cases.5. Marked improvement was noted in such symptoms as rigidity, akinesia, gait and balance and A. D. L., while there was a minimal improvement in tremor.6. The relationship between the severity of the disease and the beneficial effect of APD-512 was very hard to assess in this small series. However, it appears that far advanced cases of the disease show very little marked improvement from the drug so far.These results are almost coincident with other investigators' reports that APD-512 (L-DOPA) is the most useful antiparkinsonian drug ever used.

The clinical potency of 3 drugs, apomorphine, N-propylnorapomorphine, and bromocryptine, have been found to be closely correlated to their potencies in competing for 3H-haloperidol and 3H-spiroperidol both of which label the dopamine receptor. This correlation indicates that the direct binding assay may be used to predict clinical potencies of anti-parkinsonian drugs, and indicates that agonists as well as antagonists compete potently for 3H-neuroleptic binding.

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.