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

The discovery of SP and its potent biological activities have lead to the discovery of other tachykinins and to receptors for them, including the NK1 receptor. Blockade of the NK1 receptor has a number of potentially beneficial effects in medical care including the management of drug-induced emesis and the treatment of depression. The analgesic potential of NK1 receptor antagonists that, in theory, seemed so promising has not met early expectations. However, there is still reason to predict valuable clinical uses for more potent NK1 receptor antagonists in a variety of medical conditions, including FMS.
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PMID:The promise of substance P inhibitors in fibromyalgia. 1212 21

Vagal afferents are extensively distributed in the digestive tract from the oesophagus to the colon. They are involved in the reflex control of normal gastrointestinal (GI) tract function (e.g. secretion and motility) as well as reflexes more characteristic of diseases such as functional dyspepsia and gastroesophageal reflux disease (e.g. vomiting, disordered lower esophageal sphincter relaxation and gastric accommodation). They are also implicated in signalling non-painful sensations (e.g. nausea and early satiety) associated with disease. A variety of receptors has been identified on vagal afferents, which can either enhance (e.g. 5-HT3, CCK1, VR1 and NK1 receptors) or reduce (e.g. ghrelin, leptin, k-opioid and GABAB receptors) activity, offering a range of potential therapeutic targets. Commonly used laboratory species (e.g. rat and mouse) lack an emetic reflex, and the implications of this for models of upper GI disorders have been explored in the light of expanding knowledge of the neuropharmacology of the emetic reflex implicating glutamate, prostanoids, cannabinoids and substance P. Additional pathophysiological roles for vagal afferents (e.g. in thermoregulation, arousal and fatigue) are being investigated, raising the intriguing possibility of the vagus as a target in non-GI disorders.
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PMID:Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. 1248 26

Substance P belongs to a group of neurokinins (NKs), small peptides that are broadly distributed in the central nervous system (CNS) and peripheral nervous system (PNS). The biological effects of substance P in the CNS, namely regulation of affective behavior and emesis in the brain and nociception in the spinal cord, are mediated by its binding to the NK1 receptor. The substance P-NK1 (SP-NK1) receptor system is the most extensively studied NK pathway, and in contrast to receptors for other neurotransmitters, such as glutamate, which have high expression throughout the CNS, only a minority of neurons (5% to 7%) in certain CNS areas express the NK1 receptor. The NK1 receptor is distributed in the plasma membrane of cell bodies and dendrites of unstimulated neurons, but upon substance P binding, the NK1 receptor undergoes rapid internalization, followed by rapid recycling to the plasma membrane. Release of substance P is induced by stressful stimuli, and the magnitude of its release is proportional to the intensity and frequency of stimulation. More potent and more frequent stimuli allow diffusion of substance P farther from the site of release, allowing activation of an approximately 3- to 5-times greater number of NK1 receptor-expressing neurons. Recent studies employing pharmacologic or genetic inactivation of NK1 receptors demonstrate the important role of the SP-NK1 receptor system in the regulation of affective behavior and suggest that inhibition of this pathway may be a useful approach to treatment of depression and associated anxiety.
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PMID:Neurobiology of substance P and the NK1 receptor. 1256 37

The study of tachykinin NK1 (substance P) receptor antagonists has emerged as a field of great promise due to accumulating evidence that NK1 antagonists offer possible new treatment options in therapeutic areas ranging from pain, emesis, and pulmonary disorders to depression and anxiety. It is hoped that the unique mechanism of action of these agents, which involves modulation of effects mediated by the interaction of the neuropeptide substance P with it's G-protein coupled receptor, will provide improvements over existing therapies. For this reason many pharmaceutical companies are engaged in intense research programs with the goal of bringing safe and effective new drugs to the market. To date a wealth of diverse NK1 antagonists have been discovered, several of which have been evaluated in clinical trials. Despite rich structural diversity in this area of medicinal chemistry a number of structural features are commonly shared amongst otherwise unrelated antagonists. This theme and others are covered with the aim of conveying recent successful approaches to the discovery of potent and selective nonpeptide NK1 antagonists. This review focuses mainly on reports appearing in the year 2001 and the first half of 2002.
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PMID:Medicinal chemistry of selective neurokinin-1 antagonists. 1287 Nov 73

Neurokinin receptors in the central nervous system are involved in the neural circuitry of anxiety, depression and emesis. This has led to the development of nonpeptidic NK1 receptor antagonists as therapeutic agents. Clinical trials have shown that NK1 receptor antagonists have efficacy in chemotherapy-induced emesis and depression. Sequence polymorphisms can potentially influence the efficacy of drugs in patient populations and are an important consideration in the drug development process. To identify DNA sequence variants in the NK1 receptor, comparative DNA sequencing was performed on a population of 93 individuals. In total, 19 single-nucleotide polymorphisms (SNPs) were identified with one SNP (g.78351T>C) resulting in a tyrosine to histidine substitution at residue 192 (Y192H). The Y192H variant was expressed using site-directed mutagenesis and was characterized with respect to affinity, receptor kinetics, functional calcium response and receptor internalization. In all cases the Y192H variant was found to display properties similar to those of the wild-type receptor.
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PMID:Identification of single-nucleotide polymorphisms of the human neurokinin 1 receptor gene and pharmacological characterization of a Y192H variant. 1545 52

The incidence of cancer is highest among individuals > or =65 years of age. Physiological changes associated with aging, such as cognitive decline, renal and hepatic dysfunction, can often complicate treatment options, and the elderly represent a particular challenge to the oncologist because of the high incidence of comorbidity and polypharmacy. Effective supportive care is of particular importance in elderly cancer patients as they may recover less satisfactorily if adverse events are poorly controlled. Nevertheless, evidence suggests that supportive care agents, for example, antiemetics, are underutilised in this patient population. Chemotherapy and radiotherapy regimens are frequently associated with nausea and vomiting--symptoms that can have deleterious effects on vulnerable patients if not adequately managed. The serotonin 5-HT3-receptor antagonists represent a class of antiemetics that are currently regarded as the gold standard treatment for chemotherapy- and radiotherapy-induced nausea and vomiting. They are recommended as first-line treatment for patients at moderate-to-high risk of emesis. However, antiemetic guidelines do not differentiate between these agents and, more importantly, do not contain specific recommendations for the elderly. Pharmacological differences exist between the commonly available 5-HT3-receptor antagonists (dolasetron, granisetron, ondansetron, tropisetron and palonosetron), namely receptor sensitivity, duration of action, metabolism and tolerability profile. Of particular concern with prescriptions to elderly cancer patients is the convenience of once-daily administration, the low potential for drug-drug interactions and cardiovascular adverse effect profile. Moreover, the addition of the newly approved neurokinin NK1-receptor antagonist aprepitant to the choice of antiemetic regimen may complicate therapy and exacerbate the drug-drug interaction risk in elderly patients. Therefore, the use of antiemetics that are well tolerated and with the lowest risk of drug-drug interactions is imperative in this patient population and will enable even those patients with several comorbidities and a high level of polypharmacy to receive effective antiemetic therapy.
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PMID:Same old story? Do we need to modify our supportive care treatment of elderly cancer patients? Focus on antiemetics. 1549 48

Previous studies showed that diphenidol was effective on emetogens-induced pica, eating of non-nutritive substances, in rats, a model analogous to emesis in other species. We evaluated the actual antiemetic activity of diphenidol against four emetic stimuli in the dog and ferret, animals that possess an emetic reflex. In dogs, emetic responses to apomorphine were significantly prevented by diphenidol (3.2 mg/kg, i.v.), whereas diphenidol (3.2 mg/kg, i.v. x 2) showed a weak inhibition to the vomiting evoked by cisplatin. In ferrets, diphenidol (10 mg/kg, i.p.) exhibited a weak antiemetic activity on the emesis induced by copper sulfate and had no activity on emesis by loperamide. On the other hand, CP-122,721, a NK1-receptor antagonist, significantly reduced the emetic episodes to all four stimuli. These results suggest that the prediction of antiemetic activity of compounds in animals lacking an emetic reflex does not always correspond with actual antiemetic activity.
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PMID:Diphenidol has no actual broad antiemetic activity in dogs and ferrets. 1552 40

Nausea and vomiting are considered as two of the most distressing side-effects of chemotherapy. Chemotherapy-induced nausea and vomiting have been classified into acute, delayed and anticipatory based on the time of onset. The frequency of nausea and vomiting depends primarily on the emetogenic potential of the chemotherapeutic agents used. With the introduction of the 5-HT3 receptor-antagonists in combination with dexamethasone in the early 1990s approximately 70% of patients receiving highly emetogenic chemotherapy were protected from acute emesis. However, 40% of patients have symptoms in the delayed phase. Another group of antiemetics, the neurokinin-1-receptor-antagonists, have recently been introduced. The addition of neurokinin receptor (NK1 receptor)-antagonists to standard therapy significantly improves emesis protection in the acute and in particular in the delayed phase by approximately 20%. Due to these new developments, revised antiemetic guidelines have been set. Here, the most recent developments in antiemetic therapy, including these guidelines, are reviewed.
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PMID:Chemotherapy-induced nausea and vomiting: current and new standards in the antiemetic prophylaxis and treatment. 1566 43

The development of serotonin 5-HT3 receptor antagonists dramatically improved the treatment of chemotherapy-induced nausea and vomiting. Ondansetron, a serotonin 5-HT3 receptor antagonist in combination with dexamethasone is widely used to treat chemotherapy-induced nausea and vomiting. This treatment regimen is effective against acute nausea and vomiting, but fails to control delayed nausea and vomiting. Metoclopramide along with other antiemetics are used to treat delayed nausea and vomiting. The high doses of metoclopramide needed may produce extra pyramidal side effects. The recent developments of 5-HT3 and dopamine D2 dual receptor antagonists have been found to exhibit a broad spectrum of activity against peripherally and centrally acting stimuli, but are not much effective against delayed emesis associated with chemotherapy. In various animal models, neurokinin NK1 receptor antagonists showed promising results against acute and delayed emesis, but the clinical trials revealed that triple therapy (NK1 receptor antagonist, 5-HT3 receptor antagonist and dexamethasone) is superior than standard therapy (5-HT3 receptor antagonist & dexamethasone) or NK1 receptor antagonist alone, in controlling acute as well as delayed nausea and vomiting. Ginger, which is used traditionally for controlling emesis induced by various stimuli, also showed good activity against chemotherapy-induced nausea and vomiting in animal models. Non-pharmacological methods such as acupressure and acustimulation are good adjunct methods in treating nausea and vomiting. Since many mediators are involved in emesis induced by chemotherapy, cocktail treatment is proven to be more efficacious than a single drug, but increases treatment costs. So there is a need of further research in this field to get economically useful methods for the treatment of acute and delayed chemotherapy-induced nausea and vomiting.
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PMID:Cancer chemotherapy-induced nausea and vomiting: role of mediators, development of drugs and treatment methods. 1573 95

In the present studies we investigated the mechanism of action of prostaglandin E2 (1 mg/kg, i.p.) to induce emesis and defecation and/or tenesmus in the ferret. The emesis was antagonized significantly (P<0.05) by ondansetron (0.3 and 1 mg/kg, i.p.) and (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenlypiperidine hydrochloride (CP-99,994; 10 mg/kg, i.p.), but neither compound reduced defecations and/or tenesmus, with ondansetron (0.3 mg/kg) actually producing a slight increase (P<0.05). Droperidol (1 and 3 mg/kg), metoclopramide (0.3 and 3 mg/kg), domperidone (0.3 and 3 mg/kg), promethazine (0.3 and 3 mg/kg) and scopolamine (0.3 and 3 mg/kg) failed to reduce prostaglandin E2 induced emesis. However, droperidol (1 and 3 mg/kg) and scopolamine (0.3 and 3 mg/kg) reduced significantly the defecatory and/or tenesmus response (P<0.05). Bilateral abdominal vagotomy was ineffective to reduce emesis and defecations and/or tenesmus. The data suggests that 5-HT3 receptor and NK1 tachykinin receptor antagonists could be useful in the clinic to prevent emesis but not defecations induced by prostaglandin E2.
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PMID:Differential action of anti-emetic drugs on defecation and emesis induced by prostaglandin E2 in the ferret. 1684 11


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