td-5108 and Parkinson-Disease

Constipation is common in patients with Parkinson's disease (PD). Due to the considerable negative outcomes of constipation, significant efforts have been made to prevent and manage chronic constipation in these patients.. Herein, the authors review some of the known pathophysiological causes for slow gastrointestinal (GI) transit in PD patients and the different pharmacological options. All relevant clinical and experimental data found through online databases were included. Bulking agents, osmotic and stimulant laxatives, chloride channel activators, ghrelin agonists, 5-HT4 receptor agonists, and probiotics are some of the proposed medicinal agents. of the authors further review the evidence on alpha-synuclein and botulinum neurotoxin in these patients. It should be noted, however, that some of these interventions are required to be further validated.. Reduction of GI transit and dysfunction of the anorectum is obvious in PD, affecting the incidence of constipation and thus, quality of life (QOL). Furthermore, due to an inadequate and delayed absorption of oral anti PD medications, dose adjustments and changes in the route of administration are recommended.

Topics: Chronic Disease; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Transit; Humans; Laxatives; Parkinson Disease; Probiotics; Quality of Life; Serotonin 5-HT4 Receptor Agonists

Parkinson's disease (PD) affects the nerves of the entire gastrointestinal (GI) tract and may result in profound gastrointestinal (GI) dysfunction leading to poor patient outcomes. Common GI disturbances in patients with PD include gastroparesis (GP), constipation and small intestinal bacterial overgrowth syndrome (SIBO). In particular, GP is difficult to treat due to the limited options available and precautions, contraindications and adverse effects associated with the approved treatments. Moreover, some commonly used medications can worsen pre-existing PD.. Our review will focus on treatment options for GP and SIBO with motilin agonists, dopamine receptor antagonists, Ghrelin agonists muscarinic agonists, 5-HT4 receptor agonists, antibiotics, probiotics and herbal formulation such as iberogast. Constipation occurs in the majority of patients with PD and fortunately many treatments are now available. Our review is based on original papers or reviews selected from PUBMED search and Cochrane reviews.. Motility disorders of the GI tract are found frequently in patients with PD and treating the underlying GI disorders caused by PD with various prokinetics and laxatives is paramount in achieving improvements in patient's motor function. Various prokinetics and laxatives are now available to provide some relief of the GI morbidity caused by PD leading even to better absorption of even the PD treatments.

Topics: Anti-Bacterial Agents; Blind Loop Syndrome; Constipation; Dopamine Antagonists; Gastroparesis; Humans; Laxatives; Muscarinic Agonists; Parkinson Disease; Plant Extracts; Probiotics; Serotonin 5-HT4 Receptor Agonists

We performed a double-blind randomized placebo-controlled pilot study to determine the efficacy of tegaserod (Zelnorm) in treating constipation in 15 patients with Parkinson's disease (PD). There was a trend for improvement in the Subject's Global Assessment (SGA) of satisfaction with bowel habits (NS) and the total SGA (including abdominal discomfort, bothersome constipation, and satisfaction; NS).

Topics: Aged; Constipation; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Male; Middle Aged; Parkinson Disease; Patient Satisfaction; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Mosapride citrate is a novel selective 5-HT4 receptor agonist. It facilitates acetylcholine release from the enteric cholinergic neurons. In contrast to cisapride, mosapride does not block K(+) channels or D2 dopaminergic receptors. The objective of this study is to perform an open study of mosapride citrate's effects on constipation, a prominent lower gastrointestinal tract disorder in parkinsonian patients. A total of 14 parkinsonian patients (7 with Parkinson's disease, 7 with multiple system atrophy; 10 men, 4 women; mean age, 67 years) with constipation (10 with bowel movement < 3 times/week; 14 with difficulty in defecation) were treated with 15 mg/day of mosapride citrate for 3 months. Pre- and posttreatment objective parameters in colonic transit time (CTT) and rectoanal videomanometry were obtained. Statistical analysis was made by Student's t test. Mosapride was well tolerated by all patients except for 1, who discontinued use of the drug because of epigastric discomfort. None had a worsening of parkinsonism or other adverse events. Thirteen patients reported subjective improvements in bowel frequency (>3 times/week, 13) and difficult defecation (13). Mosapride shortened CTT of the left colon (P < 0.01) and the total colon (P < 0.05). During rectal filling, mosapride lessened the first sensation (P < 0.05) and augmented the amplitude in phasic rectal contraction. During defecation, mosapride augmented the amplitude in rectal contraction (P < 0.05) and lessened the volume of postdefecation residuals. The present study showed for the first time that mosapride citrate augmented lower gastrointestinal tract motility, as shown in CTT and videomanometry, and thereby ameliorated constipation in parkinsonian patients without serious adverse effects.

Topics: Aged; Benzamides; Colon; Constipation; Female; Functional Laterality; Gastrointestinal Transit; Humans; Male; Middle Aged; Morpholines; Parkinson Disease; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Video Recording

The 5-hydroxytryptamine (5-HT) neurotransmitter system and lateral habenula (LHb) are involved in the regulation of depression, while the mechanisms remain to be clarified.. The effects and possible mecha-nism underlying activation or blockade of 5-HT4 receptors (5-HT4Rs) in the LHb in depression were investigated by behavioral and neurochemical methods based on a Parkinson's disease (PD) rat model.. 6-Hydroxydopamine (6-OHDA) was injected unilaterally into the substantia nigra pars compacta to establish the PD rat model. The depressive-like behaviors were measured by the forced swimming test (FST) and sucrose preference test (SPT). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by a neurochemical method.. The 6-OHDA lesions increased the immobility time in the FST and decreased the sucrose consumption in the SPT, suggesting the induction of depressive-like behaviors. Intra-LHb injection of BIMU-8 (5-HT4R agonist) or GR113808 (5-HT4R antagonist) produced antidepressant effects in the lesioned rats. Intra-LHb injection of BIMU-8 significantly increased the DA levels in the medial prefrontal cortex (mPFC) and ventral hippocampus (vHip), increased the 5-HT level in the mPFC and decreased the NA level in the vHip only in the lesioned rats, while intra-LHb injection of GR113808 changed DA, NA and 5-HT levels in the mPFC, LHb and vHip in both sham and the lesioned rats.. All these results suggest that activation or blockade of the LHb 5-HT4Rs produce antidepressant effects in the 6-OHDA-lesioned rats, which are related to the changes of monoamines in the limbic and limbic-related regions.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Disease Models, Animal; Dopamine; Habenula; Hippocampus; Norepinephrine; Parkinson Disease; Prefrontal Cortex; Rats; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists

Topics: Animals; CREB-Binding Protein; Cyclic AMP; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Fear; Hippocampus; Male; Memory; Mice; Mice, Inbred C57BL; Parkinson Disease; Raphe Nuclei; Receptors, Serotonin, 5-HT4; Serotonergic Neurons; Serotonin 5-HT4 Receptor Agonists; Substantia Nigra