Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg. 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of non-specific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (-)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205,930, methiothepin, trimethobenzamide or BMY 7378. An indirect argument is presented that implicates a role for 5-HT1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.
 ...
PMID:RU 24969-induced emesis in the cat: 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1C implicated. 214 95

Sumatriptan is a potent and selective agonist at a vascular serotonin1 (5-hydroxytryptamine1; 5-HT1) receptor subtype (similar to 5-HT1D) and is used in acute treatment of migraine and cluster headache. Following administration of sumatriptan 100mg orally, relief of migraine headache (at 2 hours) was achieved in 50 to 67% of patients compared with 10 to 31% with placebo in controlled clinical trials. In a comparative study, oral administration of sumatriptan 100mg consistently achieved significantly greater response rates than a fixed combination of ergotamine 2mg plus caffeine 200mg during 3 consecutive migraine attacks (66 vs 48% for first attack). Oral sumatriptan 100mg was also more effective than aspirin 900mg plus metoclopramide 10mg orally in a similar study. In the majority of controlled clinical trials, headache relief (at 1 hour after administration) was achieved in 70 to 80% of patients with migraine receiving sumatriptan 6mg subcutaneously compared with 18 to 26% of placebo recipients. Approximately 40% of patients who initially responded to oral or subcutaneous sumatriptan experienced recurrence of their headache, usually within 24 hours, but the majority of these patients responded well to a further dose of sumatriptan. Patients with cluster headache were treated for acute attacks with sumatriptan 6mg subcutaneously or placebo in 2 crossover trials. Headache relief was achieved within 15 minutes in 74 and 75% of patients receiving sumatriptan in these studies compared with 26 and 35%, respectively, with placebo. Patients receiving sumatriptan 12mg had a similar response rate as those receiving 6mg, but the higher dose was associated with an increased incidence of adverse events. Based on extensive safety data pooled from controlled clinical trials, sumatriptan is generally well tolerated and most adverse events are transient. The most frequently reported adverse events following oral administration include nausea, vomiting, malaise, fatigue and dizziness. Injection site reactions (minor pain and redness of brief duration) occur in approximately 40% of patients receiving subcutaneous sumatriptan, although the incidence appears to be markedly reduced when patients self-administer the drug with an auto-injector. Chest symptoms (mainly tightness and pressure) occur in 3 to 5% of sumatriptan recipients, but have not been associated with myocardial ischaemia except in a few isolated cases. Sumatriptan is contraindicated in patients with ischaemic heart disease, angina pectoris including Prinzmetal (variant) angina, previous myocardial infarction and uncontrolled hypertension, but is not contraindicated in patients with migraine and asthma. Data from long term studies in acute treatment of migraine and cluster headache suggest that sumatriptan remains effective and well tolerated over several months.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Sumatriptan. A reappraisal of its pharmacology and therapeutic efficacy in the acute treatment of migraine and cluster headache. 751 61

Serotonin (5-HT) is a central neurotransmitter and a neuromodulator. This amine is involved in many physiological functions and pathological disorders. Most of its effects are mediated by specific 5-HT receptors. In the first part of this paper, the present knowledge of 5-HT receptors is reviewed in terms of both pharmacology and molecular biology. In the second part, the functional properties of 5-HT receptors are analyzed and their involvement in pathophysiological processes is discussed. Most 5-HT receptors belong to the G-protein-coupled receptor family (5-HT1, 5-HT2 and 5-HT4 receptors), whereas one is a member of the ligand-gated ion-channel receptor family (5-HT3 receptor). 5-HT1 receptors are characterized by their high affinity for 5-HT and comprise several subclasses. Most are negatively coupled to adenylate cyclase but the 5-HT1C subtype is linked to phospholipase C activation and resembles the 5-HT2 receptor. By contrast, the newly identified 5-HT4 receptor is positively coupled to adenylate cyclase. Most 5-HT receptors have now been cloned, but their physiological roles are not completely understood. Better knowledge of 5-HT receptors has already led to the development of new drugs, such as buspirone, a 5-HT1A partial agonist devoid of benzodiazepine-like properties for the treatment of generalized anxiety. Anxiolytic properties have also been reported for 5-HT2 and 5-HT3 receptor antagonists. A new and potent anti-migrainous drug, sumatriptan, has recently been selected among compounds obtained by research on the 5-HT1D receptor. This key receptor controls the release of monoamines, amino acids and peptides, and new drugs are expected in the near future. The therapeutic potential of 5-HT3 antagonists is impressive, as these compounds have potent antiemetic, promnesic and antipsychotic properties in various animal models. Two such drugs have already been marketed for the prevention of radiation-induced emesis (ondansetron and granisetron) and are more potent than the antidopaminergic drugs. Many other data suggest that 5-HT receptors might be involved in other illnesses. Some drugs are in the development phase but identification of the relevant receptor is often difficult. Furthermore, the lak of specific ligands for some receptors clearly hinders functional correlations.
 ...
PMID:[Central serotonin receptors. Principal fundamental and functional aspects. Therapeutic applications]. 780 Oct 37

Zolmitriptan is a new serotonergic agonist with excellent oral bioavailability exhibiting a potent symptomatic antimigraine effect. Zolmitriptan is a selective agonist of 5-HT1B/D receptors. 5-HT1B receptors are concentrated in the wall of the cranial extracerebral arteries. 5-HT1D receptors are located on the trigeminal terminals which receive pain from the leptomeningeal vessels. Migraine pain has its origin on cranial vessels. In fact, during a migraine attack the trigeminovascular system, which is composed by the cranial vessels and its trigeminal terminals, is activated. The activation of this system induces both dilatation and aseptic inflammation of cranial vessels. Zolmitriptan blocks both vascular phenomena. Its agonist action upon the 5-HT1D receptor ends the aseptic inflammation by inhibiting the release of vasoactive peptides. The dilatation of meningeal vessels disappears due to the stimulation of zolmitriptan of 5-HT1B receptors. As this drug crosses the blood brain barrier, zolmitriptan has both peripheral and central actions over the espinal trigeminal nucleus, which is rich in 5-HT1B/D receptors. Thus, the mechanism of action of zolmitriptan is double. On the one hand, zolmitriptan acts peripherally inhibiting dilatation and inflammation of cranial vessels. On the other, zolmitriptan exhibits a central nociceptive action in the brainstem nuclei. This dual action of zolmitriptan on migraine pain is completed with its beneficial effects on nausea and vomiting, due to its binding to the nucleus of the tractus solitarius, the center for control of vomiting.
 ...
PMID:[Mechanism of action of zolmitriptan]. 985 90

Several serotonin (5-HT) receptor subtypes have been defined by pharmacological responses to selective agonists and antagonists and by pathways of receptor-effector coupling. Using molecular techniques, additional receptor subtypes have been described. 5-HT receptors are prevalent in the central nervous system and gut and participate in induction of emesis. 5-HT3 antagonists are used to prevent emesis from cancer chemotherapy and also demonstrate efficacy in radiation-induced nausea, postoperative nausea, hyperemesis gravidarum, and nausea and vomiting with the acquired immunodeficiency syndrome. 5-HT4 agonists exhibit prokinetic properties in nauseated patients with gastroparesis and functional dyspepsia. Conversely, 5-HT4 antagonists have antiemetic activity in some experimental models. The 5-HT1D receptor agonist sumatriptan reduces emesis with migraine headaches and in cyclic vomiting syndrome, most likely via action on central nervous system sites. In other models, 5-HT1A and 5-HT2A/5-HT2C agonists exhibit antiemetic properties. The utility of 5-HT receptor ligands in treating emesis is the subject of active investigation.
 ...
PMID:Serotonin receptor physiology: relation to emesis. 1049 49

Nausea and vomiting are debilitating symptoms complicating many clinical conditions. Conventional antiemetic agents act as muscarinic, histamine, and dopamine receptor antagonists in the central nervous system. In a retrospective analysis, tricyclic antidepressant drugs demonstrated efficacy in long-term treatment of functional nausea. Some cases of vomiting result from impaired gastrointestinal motor activity. Agents which act on gastric serotonin (5-HT4), dopamine, and motilin receptors accelerate gastric emptying and relieve symptoms in gastroparesis. Recent investigations suggest that some patients with refractory gastroparesis may benefit from gastric electrical pacing. The treatment of acute chemotherapy-induced emesis was revolutionized by 5-HT3 receptor antagonists; however, these agents are less efficacious in delayed vomiting. Neurokinin (NK-1) receptor antagonists show promise in treating delayed chemotherapy-evoked emesis. Furthermore, animal studies indicate a broad spectrum of action for NK-1 antagonists in treating diverse causes of nausea and vomiting. The cyclic vomiting syndrome is characterized by discrete episodes of relentless vomiting separated by asymptomatic intervals and is associated with migraine headaches. Antimigraine therapies including the 5-HT1D receptor agonists sumatriptan reduce the severity of cyclic vomiting attacks. Investigations into these and other novel treatments may provide important advances in the care of difficult cases of nausea and vomiting resulting from disparate illnesses.
 ...
PMID:Novel approaches to the treatment of nausea and vomiting. 1069 61

Ergotamine and dihydroergotamine share structural similarities with the adrenergic, dopaminergic, and serotonergic neurotransmitters. As a result, they have wide-ranging effects on the physiologic processes that they mediate. Ergotamine and dihydroergotamine are highly potent at the 5-HT1B and 5-HT1D antimigraine receptors and, as a consequence, the plasma concentrations that are necessary to produce the appropriate therapeutic and physiologic effects are very low. The broad spectrum of activity at other monoamine receptors is responsible for their side effect profile (dysphoria, nausea, emesis, unnecessary vascular effects). Both ergotamine and dihydroergotamine have sustained vasoconstrictor actions. In acute migraine treatment, their mechanisms of action involve constricting the pain-producing intracranial extracerebral blood vessels at the 5-HT1B receptors and inhibiting the trigeminal neurotransmission at the peripheral and central 5-HT1D receptors. The scientific evidence for efficacy is stronger for dihydroergotamine than for ergotamine. Their wide use is based on long-term experience.
 ...
PMID:Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. 1255 71

Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, alpha-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT2C, 5-HT6) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.
 ...
PMID:Innovative approaches for the development of antidepressant drugs: current and future strategies. 1648 68

Twin studies suggest that genetic factors play a substantial role in anorexia nervosa (AN) and self-induced vomiting (SV), a key symptom that is shared among different types of eating disorders (EDs). We investigated the association of 25 single nucleotide polymorphisms (SNPs), capturing 71-91% of the common variance in candidate genes, stathmin (STMN1), serotonin receptor 1D (HTR1D), tryptophan hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF), with AN and EDs characterized by regular SV. The first allele frequencies of all the SNPs were compared between a Dutch case group (182 AN, 149 EDs characterized by SV) and 607 controls. Associations rendering P-values < 0.05 from this initial study were then tested for replication in a meta-analysis with two additional independent ED case-control samples, together providing 887 AN cases, 306 cases with an ED characterized by SV and 1914 controls. A significant effect for the minor C-allele of tryptophan hydroxylase 2 rs1473473 was observed for both AN [odds ratio (OR) = 1.30, 95% CI 1.08-1.57, P < 0.003] and EDs characterized by SV (OR = 1.52, 95% CI 1.28-2.04, P < 0.006). In the combined case group, a dominant effect was observed for rs1473473 (OR = 1.38, 95% CI 1.16-1.64, P < 0.0003). The meta-analysis revealed that the tryptophan hydroxylase 2 polymorphism rs1473473 was associated with a higher risk for AN, EDs characterized by SV and for the combined group.
 ...
PMID:Association study in eating disorders: TPH2 associates with anorexia nervosa and self-induced vomiting. 2094 55

Migraine is the most common neurovascular disorder that imparts a considerable burden to health care system around the world. However, currently there are still no effective and widely applicable pharmacotherapies for migraine patients. Herbal formulae, characterized as multiple herbs, constituents and targets, have been acknowledged with clinical effects in treating migraine, which attract more and more researchers' attention although their exact molecular mechanisms are still unclear. In this work, a novel systems pharmacology-based method which integrates pharmacokinetic filtering, target fishing and network analysis was developed and exemplified by a probe, i.e. Tianshu formula, a widely clinically used anti-migraine herbal formula in China which comprises of Rhizoma chuanxiong and Gastrodia elata. The results exhibit that 20 active ingredients of Tianshu formula possess favorable pharmacokinetic profiles, which have interactions with 48 migraine-related targets to provide potential synergistic therapeutic effects. Additionally, from systematic analysis, we speculate that R. chuanxiong as the monarch herb mediates the major targets like PTGS2, ESR1, NOS2, HTR1B and NOS3 to regulate the vascular and nervous systems, as well as the inflammation and pain-related pathways to benefit migraine patients. Meanwhile, as an adjuvant herb, G. elata may not only assist the monarch herb to improve the outcome of migraine patients, but also regulate multiple targets like ABAT, HTR1D, ALOX15 and KCND3 to modify migraine accompanying symptoms like vomiting, vertigo and gastrointestinal disorders.
...
PMID:Systems pharmacology to decipher the combinational anti-migraine effects of Tianshu formula. 2623 49


1