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

The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure. Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibit both dopamine D2- and 5-HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that contribute to their effectiveness. The cannabinoids are effective in cytotoxic-induced vomiting, perhaps acting via endorphin receptors or by inhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral neuronal 5-HT3 receptors. Vomiting constitutes a major disadvantage to the use of many drugs; vomiting induced by aminoglycoside antibiotics appears to be due to ototoxicity and is relieved by histamine H1-receptor antagonists. The protracted vomiting associated with the use of some cytotoxics in cancer chemotherapy may involve psychic components, the chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, such as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved would appear to offer improved control. The use of dopamine receptor antagonists in controlling emesis induced by dopamine agonists used in Parkinson's disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drugs may produce some impairment of therapeutic responses to the agonists. Muscarinic and nicotinic agonists currently under investigation in Alzheimer's disease pose another therapeutic dilemma as emesis is due to a central action of these compounds. Several sites may be involved including the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or mu-receptors on dopaminergic nerves, but serotonergic mechanisms may also be involved in the action of some opiates.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Pharmacological agents affecting emesis. A review (Part I). 137 16

The influence of memantine on several properties of a neuronal cell line was tested. The aim was to get some insight into possible mechanisms of action of this drug which is therapeutically applicable in treatment of spasticity, Parkinson's disease, and cerebral coma. In neuroblastoma X glioma hybrid cells, memantine, at micromolar concentrations, blocked the depolarization induced by iontophoretically applied serotonin (5-hydroxytryptamine, 5-HT). In the hybrid cells, receptors of the 5-HT3 type mediated the depolarization, which was frequently accompanied by a series of action potentials. The inhibition by memantine of the serotonin response occurred fast and was completely reversible, irrespective of whether the cell showed a stable membrane potential or spontaneous action potentials. However, memantine did not alter spontaneous or electrically evoked action potential activity in the hybrid cells, and apparently did not block the underlying ionic conductances. Furthermore memantine did not affect either the cation permeability activated by substance P in the hybrid cells or the K+ channel triggered by bradykinin in a glioma cell line. Thus, memantine appears specifically to suppress the ion channel opened by serotonin in the hybrid cells. The interaction of memantine with serotonin receptors and the associated ion channels reported here, might give an important clue, as to a site of action of memantine in the nervous system.
 ...
PMID:Memantine (1-amino-3,5-dimethyladamantane) blocks the serotonin-induced depolarization response in a neuronal cell line. 335 74

The present study assessed 5-HT3 receptor recognition site levels in homogenates of putamen derived from patients with clinically and neurochemically diagnosed Huntington's disease or Parkinson's disease and those from age-, sex- and post-mortem delay-matched neurologically and psychiatrically normal patients to investigate the cellular location of 5-HT3 receptors in the human putamen. Specific [3H]granisetron (0.91 nM) binding (defined by ondansetron, 10 microM) was significantly reduced in putamen homogenates from eight out of ten patients with Huntington's disease compared to similar homogenates from 'control' patients (72 +/- 6 and 39 +/- 8 fmol/g wet weight, mean +/- S.E.M., n = 10 and 8, tissue from 'control' and Huntington's disease patients, respectively, P = 0.004). In contrast, specific [3H]granisetron (1.04 nM) binding levels were similar in putamen homogenates from patients with Parkinson's disease when compared to homogenates from 'control' patients. The present results indicate that at least a proportion of the 5-HT3 receptor population in the human putamen is located on neurones that have their cell bodies within this brain region and that these receptors are not primarily located on dopamine neurone terminals in the human putamen.
 ...
PMID:Reduced levels of 5-HT3 receptor recognition sites in the putamen of patients with Huntington's disease. 825 10

Serotonergic mechanisms have been implicated in pathophysiology of Parkinson's disease, an illness where the dopamine deficiency represents the prime biochemical deficit. Present interest centres on the possible involvement of serotonergic receptors in modulating dopamine transmission. In this paper the binding of the selective 5-HT3 antagonist [3H]GR 65630 was studied in rats with a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. The maximal density of specific [3H]GR 65630 binding was reduced in homogenates of entorhinal (17.1%, P < 0.05) and prefrontal cortex (27.5%, P < 0.05) on the lesioned side of the rat brain compared to the control tissues. An increase in affinity for [3H]GR 65630 binding was also found in homogenates of prefrontal cortex (33.8%, P < 0.05). No changes in the characteristics of [3H]GR 65630 binding to homogenates from the amygdala and hippocampus were observed. These data suggest that altered dopamine function may affect serotonergic mechanisms in the cortex in Parkinson's disease.
 ...
PMID:Reduction in cortical 5-HT3 binding sites following a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle in rats. 846 85

The involvement of abdominal afferent vagal activity and serotonergic mechanisms were examined following intravenous administration of talipexole, a dopamine D2 receptor agonist used for treatment of Parkinson's disease, in anesthetized rats. Intravenous administration of dopamine receptor agonists including D1/D2 components increased the spontaneous firing of afferent vagal neurons as did 2-methyl-5-hydroxytryptamine. Both talipexole (0.25-1.0 mg/kg) and bromocriptine (1.0-10.0 mg/kg) increased vagal nerve activity in a dose-dependent manner, and the effect of 10 mg/kg of bromocriptine was significantly greater than that noted with 1.0 mg/kg of talipexole. Increasing vagal firing induced by talipexole was prevented by pretreatment with granisetron, but not with metoclopramide or by spinal section, indicating that afferent vagal firing was mediated via stimulation of the 5-HT3 receptors on the neurons and secondarily caused by stimulation of dopamine receptors. On the other hand, bromocriptine at 5 mg/kg increased 5-HIAA concentration in the ileum, and serotonin turnover (5-HIAA/5-HT) was increased approximately 4-fold when compared to the vehicle group. Bromocriptine also increased the activities of tryptophan hydroxylase and monoamine oxidase. Talipexole at 0.5 mg/kg did not affect ileal 5-HT metabolism and the enzymatic activities. These findings suggest that dopamine receptor agonists may induce changes in abdominal afferent vagal activity and ileal 5-HT metabolism similar to those observed with emetic compounds, and that talipexole has a much smaller influence on serotonin-mediated responses than does bromocriptine with equipotent antiparkinsonian doses. One of the possible reason why talipexole showed fewer emetic side effects in patients with Parkinson's disease may be that the emetic responses triggered by D2 receptor stimulation may secondarily cause an increase of abdominal afferent vagal activity, which may be weakened by the 5-HT3 receptor antagonistic property of talipexole.
 ...
PMID:Effects of talipexole on emesis-related changes in abdominal afferent vagal activity and ileal serotonin metabolism in rats. 905 50

The use of ondansetron, a selective serotonin 5-HT3 receptor antagonist, is well established in patients with nausea and vomiting associated with cancer chemotherapy, radiotherapy or anaesthesia and surgery. The wide distribution of 5-HT3 receptors in the body and the role of these receptors in disease have provided the rationale for investigation of ondansetron in novel applications. Preliminary data have shown ondansetron to have clinical benefit in patients with nausea and vomiting associated with drug overdosage or poisoning, anti-infective or antidepressant therapies, uraemia or neurological trauma, and in patients with pruritus. Patients with gastrointestinal motility disorders (e.g. carcinoid syndrome, irritable bowel syndrome, diarrhoea associated with cryptosporidiosis or diabetes, and chronic refractory diarrhoea) have also shown some improvement when treated with ondansetron, as have patients with certain pain or CNS-related disorders [e.g. alcohol (ethanol) dependence, opiate withdrawal, vertigo, cerebellar tremor and Parkinson's disease treatment-related psychosis]. In contrast to conventional antiemetics, ondansetron is generally well tolerated with a lower incidence of sedation and only isolated case reports of extrapyramidal reactions. Furthermore, unlike dopamine receptor-blocking neuroleptics, ondansetron does not appear to worsen the symptoms of Parkinson's disease. Thus, in addition to its established indications, preliminary results suggest that ondansetron may be beneficial in a number of novel applications. This drug may represent a treatment alternative in patients with refractory disease, or an effective treatment of conditions for which current therapies are either poorly tolerated or not available. Further investigation of ondansetron in a range of potential new applications appears to be warranted.
 ...
PMID:Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications. 911 22

Several 5-HT3 receptor antagonists are available (tropisetron, ondansetron, granisetron, dolasetron, and palonsetron), and further compounds are in clinical development. These substances show only minor differences in the activity profile regarding their affinity for particular receptors. 5-HT3 receptor antagonists are primarily used and found effective in the prevention and treatment of chemotherapy-induced nausea and emesis, and in postoperative nausea and vomiting (PONV). Antagonism of the 5-HT3 receptors in the peripheral and central nervous system is a probable mechanism of action. The substances are suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting. 5-HT3 receptor antagonists are an important constituent in the prevention and treatment of emesis and nausea caused by radiation therapy, especially in patients receiving whole body or upper abdominal treatment. Alosetron was found clinically effective in diarrhoea-predominant irritable bowel syndrome, whereas tropisetron in fibromyalgia and related pain disorders. Further indications for such treatment include anxiety disorders, alcohol dependence, drug withdrawal, and psychosis related to treatment of Parkinson's disease. 5-HT3 receptor antagonists are well tolerated with the most frequently reported adverse effects being headache, constipation, dizziness, tiredness, and gastrointestinal disturbances such as abdominal pain or constipation. Intravenous administration of serotonin induces the Bezold-Jarisch reflex and causes small reversible changes in electrocardiogram (ECG) parameters.
 ...
PMID:Spectrum of use and tolerability of 5-HT3 receptor antagonists. 1551 6

Clozapine is efficacious for treating dopaminergic psychosis in Parkinson's disease and ameliorates l-DOPA-induced motor complications. Based on its pharmacology and reported enhancing effects on dopamine metabolism and tyrosine hydroxylase activity, we investigated whether it could modulate the activity of aromatic l-amino acid decarboxylase (AAAD), the second enzyme for the biosynthesis of catecholamines and indoleamines. A single dose of clozapine increased AAAD activity of striatum in a dose- and time-dependent manner. At 1 h, enhanced enzyme activity was characterized by an increased V(max) for substrate and cofactor and was accompanied by elevated levels of protein in striatum and mRNA in substantia nigra, ventral tegmental area, locus coeruleus, and raphe nuclei. Acute clozapine increased tyrosine hydroxylase activity in striatum but with differing temporal patterns from AAAD and heightened dopamine metabolism. Interestingly, the response of the dopaminergic markers to clozapine was greater following a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion. Chronically administered clozapine increased AAAD activity and protein and dopamine metabolism in striatum without affecting tyrosine hydroxylase. Exogenous l-DOPA decarboxylation was accelerated in the striatum of intact and MPTP-lesioned mice following acute clozapine, and the effect was exaggerated in the MPTP mice. To identify receptors involved, antagonists of receptors occupied by clozapine were employed. D4, 5-HT1(A), and 5-HT2(A), in addition to D1, D2, and D3, antagonists, augmented AAAD activity in striatum, whereas 5-HT2(C), 5-HT3, muscarinic, and alpha-1 and alpha-2 adrenergic antagonists were ineffective. For the first time, these studies provide evidence that clozapine modulates AAAD activity in the brain and suggests that dopamine and serotonin receptors are involved.
 ...
PMID:Clozapine modulates aromatic L-amino acid decarboxylase activity in mouse striatum. 1641 89

The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.
 ...
PMID:Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. 1704 11

For 10 years, we have used intravenous and oral perphenazine as part of a multimodal antiemetic prophylaxis care plan for at least 10,000 outpatients. We have never encountered an adverse event, to our knowledge, when the intravenous dose was less than or equal to 2 mg, or when the single preoperative oral dose did not exceed 8 mg (with no repeated dosing). As a single-dose component of multimodal antiemetic prophylaxis therapy, we believe that this track record of anecdotal safety in adults who meet certain criteria (age 14-70, no less than 45 kg, no history of extrapyramidal reactions or of Parkinson disease, and no Class III antidysrhythmic coadministered for coexisting disease) constitutes a sufficient patient safety basis for formal prospective study. We believe that future perphenazine studies should include routine coadministration with prospectively established multimodal antiemetics (i.e., dexamethasone and a 5-HT3 antagonist). In settings where droperidol is still routinely used and deemed acceptable by local scientific ethics committees, we believe that oral perphenazine 8 mg should be compared head to head with droperidol 0.625-1.25 mg in patients receiving coadministered dexamethasone and 5-HT3 antagonists in order to determine differences in synergistic efficacy, if any. Similar trials should be performed, individually evaluating cyclizine, transdermal scopolamine, and aprepitant in combination with coadministered dexamethasone and a 5-HT3 antagonist. Such studies should also quantify efficacy in preventing nausea and vomiting after discharge home, and also quantify the extent to which the prophylaxis plans reduce postanesthesia care unit (PACU) requirements (i.e., increase PACU bypass), reduce the need for any nursing interventions for postoperative nausea and/or vomiting (PONV), and influence the extent to which any variable costs of postoperative nursing care are reduced.
 ...
PMID:Routine multimodal antiemesis including low-dose perphenazine in an ambulatory surgery unit of a university hospital: a 10-year history. Supplement to: Eliminating postoperative nausea and vomiting in outpatient surgery with multimodal strategies including low doses of nonsedating, off-patent antiemetics: is "zero tolerance" achievable? 1761 79


1 2 Next >>