Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe our clinical experience in the evaluation of gastrointestinal symptoms in patients with Parkinson's disease. Dysphagia, heartburn, medication-related nausea, and constipation were the predominant symptoms. Although all of the patients localized their dysphagia to the oropharynx and although oropharyngeal dysfunction was common, evaluation revealed significant dysfunction in either the esophageal body or lower esophageal sphincter in many--gastroesophageal reflux-related disease being especially common. Studies of anorectal sphincter and pelvic floor function in those patients with constipation demonstrated a high incidence of abnormal external anal sphincter dysfunction. We conclude, first, that dysphagia in patients with Parkinson's disease should not be assumed to result solely from oropharyngeal dysfunction but deserves detailed evaluation and, second, that constipation in Parkinson's disease is commonly consequent on anorectal sphincter and pelvic floor dysfunction.
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PMID:Gastrointestinal dysfunction in Parkinson's disease. A report of clinical experience at a single center. 793 Apr 24

The radiologic characteristics of pharyngoesophageal (PE) dysfunction in Parkinson's disease (PD) are not well established, partly because most previous studies have examined only small numbers of patients. We administered a dynamic videofluoroscopic swallowing function study to 71 patients with idiopathic PD. Using the Hoehn and Yahr disease severity scale, patients were subdivided into those with mild/moderate disease, subgroup I (n = 38), and advanced PD disease, subgroup II (n = 33). From pharyngeal ingestion to gastric emptying, bolus transport was normal in only 2 patients. The most common abnormalities occurring during pharyngeal ingestion included impaired motility, vallecular and pyriform sinus stasis, supraglottic and glottic aspiration, and deficient epiglottic positioning and range of motion. Esophageal abnormalities were multiple but most commonly included delayed transport, stasis, bolus redirection, and tertiary contractions. Typical aberrations of lower esophageal sphincter (LES) function included an open or delayed opening of the LES and gastro-esophageal reflux. A pathogenesis linking PE with the pathology of PD is proposed.
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PMID:Pharyngo-esophageal dysphagia in Parkinson's disease. 899 27

Patients with gastroparesis frequently present challenging clinical, diagnostic, and therapeutic problems. Data from 146 gastroparesis patients seen over six years were analyzed. Patients were evaluated at the time of initial diagnosis and at the most recent follow-up in terms of gastric emptying and gastrointestinal symptomatology. The psychological status and physical and sexual abuse history in female idiopathic gastroparesis patients were ascertained and an association between those factors and gastrointestinal symptomatology was sought. Eighty-two percent of patients were females (mean age: 45 years old). The mean age for onset of gastroparesis was 33.7 years. The etiologies in 146 patients are: 36% idiopathic, 29% diabetic, 13% postgastric surgery, 7.5% Parkinson's disease, 4.8% collagen vascular disorders, 4.1% intestinal pseudoobstruction, and 6% miscellaneous causes. Subgroups were identified within the idiopathic group: 12 patients (23%) had a presentation consistent with a viral etiology, 48% had very prominent abdominal pain. Other subgroups were gastroesophageal reflux disease and nonulcer dyspepsia (19%), depression (23%), and onset of symptoms immediately after cholecystectomy (8%). Sixty-two percent of women with idiopathic gastroparesis reported a history of physical or sexual abuse, and physical abuse was significantly associated with abdominal pain, somatization, depression, and lifetime surgeries. At the end of the follow-up period, 74% required continuous prokinetic therapy, 22% were able to stop prokinetics, 5% had undergone gastrectomy, 6.2% went onto gastric electrical stimulation (pacing), and 7% had died. At some point 21% had required nutrition support with a feeding jejunostomy tube or periods of parenteral nutrition. A good response to pharmacological agents can be expected in the viral and dyspeptic subgroups of idiopathics, Parkinson's disease, and the majority of diabetics, whereas a poorer outcome to prokinetics can be expected in postgastrectomy patients, those with connective tissue disease, a subgroup of diabetics, and the subset of idiopathic gastroparesis dominated by abdominal pain and history of physical and sexual abuse. Appreciation of the different etiologies and psychological status of the patients may help predict response to prokinetic therapy.
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PMID:Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. 982 25

As with other neurodegenerative diseases, neurologic and nutritional elements may interact affecting each other in Parkinson's disease (PD). However, the long-term effects of such interactions on prognosis and outcome have not been given much attention and are poorly addressed by current research. Factors contributing to the clinical conditions of patients with PD are not only the basic features of PD, progression of disease, and the therapeutic approach but also fiber and nutrient intakes (in terms of both energy and protein content), fluid and micronutrient balance, and pharmaconutrient interactions (protein and levodopa). During the course of PD nutritional requirements frequently change. Accordingly, both body weight gain and loss may occur and, despite controversy, it seems that both changes in energy expenditure and food intake contribute. Nonmotor symptoms play a significant role and dysphagia may be responsible for the impairment of nutritional status and fluid balance. Constipation, gastroparesis, and gastro-oesophageal reflux significantly affect quality of life. Finally, any micronutrient deficiencies should be taken into account. Nutritional assessments should be performed routinely. Optimization of pharmacologic treatment for both motor and nonmotor symptoms is essential, but nutritional interventions and counseling could and should also be planned with regard to nutritional balance designed to prevent weight loss or gain; optimization of levodopa pharmacokinetics and avoidance of interaction with proteins; improvement in gastrointestinal dysfunction (e.g., dysphagia and constipation); prevention and treatment of nutritional deficiencies (micronutrients or vitamins). A balanced Mediterranean-like dietary regimen should be recommended before the introduction of levodopa; afterward, patients with advanced disease may benefit considerably from protein redistribution and low-protein regimens.
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PMID:Major nutritional issues in the management of Parkinson's disease. 1969 Nov 25

Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) have previously been implicated in a number of pathophysiological conditions, based on preclinical, and to some extent clinical, proof of concept for migraine, gastroesophageal reflux disease, Parkinson's disease and anxiety. In the past, the potential use of known mGlu5 antagonists for the treatment of lower urinary tract disorders was disclosed. In the patent evaluated herein, novel derivatives of 4-(prop-2-ynylidene)piperidine are described and claimed by Recordati Ireland Ltd, Ireland, as NAMs at mGlu5 for the treatment of lower urinary tract disorders. Selected compounds reported in this application were efficacious in the cystometry model of bladder dysfunction in conscious rats, and mGlu5 NAMs are, therefore, suggested to have potential for the treatment of lower urinary tract disorders.
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PMID:Novel heterocyclic compounds as mGlu5 antagonists: WO2009015897. 2018 Jun 23

Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson's disease and L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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PMID:Metabotropic glutamate receptors: from the workbench to the bedside. 2103 82

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson's disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability to enhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.
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PMID:Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders. 2136 21

An 89-year-old female resident in the assisted living section of a continuing care retirement community complained of dizziness and lightheadedness at 10 am daily and was experiencing frequent falls. The facility staff requested a consultant pharmacist perform an extensive review of her medications and medical conditions. Following a chart review and interview with the resident, the consultant pharmacist found that her past medical history consists of coronary artery disease, atrial fibrillation, congestive heart failure, hypertension, dyslipidemia, osteoporosis, gastroesophageal reflux disease, glaucoma, mild dementia, overactive bladder, and Parkinson's disease (PD). The nursing staff monitored the resident's blood pressure during these episodes and determined that the resident was experiencing orthostatic hypotension (OH). During the review, the consultant pharmacist found a recent neurology note that concluded the resident may have multiple-system atrophy (MSA) and her therapy for PD may not be beneficial. As autonomic dysfunction is a common feature of MSA, it is important to minimize the use of medications that can cause or aggravate OH. Additionally, data suggest only a modest and nonsustained response to levodopa in patients with MSA. Therefore, the pharmacist recommended multiple medication changes as well as follow-up monitoring by the patient and assisted living community staff to minimize medication-related problems such as falls.
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PMID:Multiple-system atrophy and medications: how to minimize the risk of falling. 2414 45

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu(5)) have remained attractive to researchers as potential therapies for a number of central nervous system related diseases, including anxiety, pain, gastroesophageal reflux disease (GERD), addiction, Parkinson's disease (PD), and fragile X syndrome (FXS). In addition to the many publications with supportive preclinical data with key tool molecules, recent positive reports from the clinic have bolstered the confidence in this approach. During the two year time span from 2009 through 2010, a number of new mGlu(5) NAM chemotypes have been disclosed and discussed in the primary and patent literature. A summary of several efforts representing many diverse chemotypes are presented here, along with a discussion of representative structure activity relationships (SAR) and synthetic approaches to the templates where possible.
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PMID:Recent advances in the design and development of novel negative allosteric modulators of mGlu(5). 2192 49

Glutamate is the major excitatory transmitter in the mammalian CNS, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (Group I: mGlu(1) and mGlu(5); Group II: mGlu(2) and mGlu(3); Group III: mGlu(4), mGlu(6), mGlu(7), and mGlu(8)). Non-competitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu(5) offer potential therapeutic applications in diseases such as pain, anxiety, gastroesophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of SAR in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu(5) antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu(5) NAM in this novel assay.
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PMID:(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu(5): Discovery of a new tool compound with activity in the OSS mouse model of addiction. 2192 50


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