Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the latter part of the 20th century, significant advances have been made in the understanding of the emetic reflex. As a result, there have been major improvements in the treatment of vomiting, particularly that associated with chemo- and radiotherapeutic treatments for neoplastic disease. The 5-HT3 receptor antagonists (ondansetron and granisetron) have been demonstrated to be of benefit in treating the profound emesis observed during cancer treatment. This observation, together with results from pharmacologic and physiologic investigations in both animals and humans, have identified 5-hydroxy-tryptamine (5-HT or serotonin) to be of fundamental importance in the pathogenesis of emesis. 5-HT appears to be released by radiation and chemotherapeutic agents from enterochromaffin cells within the wall of the intestine, and possibly from neurons within the brainstem. Stimulation of 5-HT3 receptors, located centrally in the dorsal medulla of the brainstem and peripherally on vagal afferent terminals in the gastrointestinal tract, appears to play a pivotal role in eliciting emesis. The interaction of 5-HT with non-5-HT3 receptors, particularly 5-HT1A and 5-HT4 receptors, may be important in the emetic reflex. The development of agents that interact with these receptors may offer alternative approaches to the treatment of nausea and vomiting.
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PMID:Serotonergic mediation of vomiting. 870 63

Though antiemetic therapy has improved markedly in the past 15 years, patients still regard nausea and vomiting as two of the most distressing adverse events during chemotherapy. A major progress was the development of the serotonin3 (5-HT3) receptor antagonists. A possible antiemetic effect, achieved by interference with the "serotonergic system", is not restricted to antagonism at 5-HT3 receptors, however, but also includes agonism at 5-HT1A and 5-HT2 receptors, and serotonin synthesis inhibitors. The number of receptors thought to be involved in the emetic reflex has been augmented by neurokinin1 receptors with substance P as the preferred ligand. Animal studies have demonstrated a broad antiemetic profile of substance P antagonists. The somatostatin analogue octreotide has an antiemetic effect in patients with gastrointestinal obstruction, but has not been investigated against chemotherapy-induced emesis. The next few years will disclose, whether the efficacy and safety profiles of one or more of these drugs will make it clinically useful in the treatment of chemotherapy-induced nausea and vomiting.
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PMID:New perspectives in antiemetic treatment. 896 71

Motion sickness can occur when sensory inputs regarding body position in space are contradictory or are different from those predicted from experience. Signals from the vestibular system are essential for triggering motion sickness. The evolutionary significance of this malady is unclear, although it may simply represent the aberrant activation of vestibuloautonomic pathways that typically subserve homeostasis. The neural pathways that produce nausea and vomiting during motion sickness are presumed to be similar to those that generate illness after ingestion of toxins. The neural substrate of nausea is unknown but may include neurons in the hypothalamus and inferior frontal gyrus of the cerebral cortex. The principal motor act of vomiting is accomplished through the simultaneous contractions of inspiratory and expiratory respiratory muscles and is mediated by neurons in the lateral medullary reticular formation and perhaps by cells near the medullary midline. Cocontraction of the diaphragm and abdominal muscles increases pressure on the stomach, which causes gastric contents to be ejected through the mouth. Effective drugs for combating motion sickness include antihistamines, antimuscarinics, 5-HT1A (serotonergic) receptor agonists and neurokinin type 1 receptor antagonists. However, considerable information concerning the physiological basis and pharmacology of motion sickness is unknown; future research using animal models will be required to understand this condition.
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PMID:Physiological basis and pharmacology of motion sickness: an update. 1005 67

Nausea and vomiting (emesis) occur under a variety of conditions in response to activation of one or more emetic triggers. The act of vomiting is coordinated by neuronal circuitry located in the brain stem between the obex and the retrofacial nucleus, including the region extending from the nucleus of the solitary tract through the lateral tegmental field of the reticular formation to the ventrolateral medulla. The area postrema, medullary midline, and certain higher brain centers are also important for vomiting. The sensation of nausea is thought to involve the cerebral cortex. The most effective near-term treatment for combating nausea and vomiting associated with cyclic vomiting syndrome may come from experimental drugs (NK-1 receptor antagonists, 5-HT1A receptor agonists) or P6 acustimulation, which have been shown to combat nausea and vomiting in response to a broad spectrum of emetic challenges and thus presumably act on central emetic mechanisms.
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PMID:Central mechanisms of vomiting. 1049 38

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.
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PMID:Serotonin receptor physiology: relation to emesis. 1049 49

Significant progress has been made in recent years in developing more effective means of preventing nausea and vomiting induced by cancer chemotherapy. With appropriate application of currently available antiemetic regimens, the majority of patients with cancer who are receiving chemotherapy can anticipate experiencing no emesis during their treatment. Nevertheless, incompletely controlled emesis remains a problem for a significant percentage of patients. Persistent challenges include delayed emesis and emesis following high-dose chemotherapy regimens. The goal of complete prevention of emesis in all patients remains elusive. Therefore, there is a strong rationale for investigating new antiemetic approaches. New antiemetic agents currently under development target the neurotransmitters serotonin (5-hydroxytryptamine; 5-HT) and substance P. A number of new selective antagonists of serotonin 5-HT3 receptors are in clinical trials. Given the lack of clinically significant differences between the available 5-HT3 receptor antagonists, it appears unlikely that any of these new agents will have substantial advantages over currently approved agents. Several other serotonin receptors have been targeted including the 5-HT4, 5-HT1A and 5-HT2A receptors. Of these approaches, only agonism of the 5-HT1A receptor has produced an agent that has proceeded into clinical testing. The most exciting new class of antiemetics currently under development focuses on antagonism of the effects of the neurotransmitter substance P. Results of early clinical trials with tachykinin neurokinin NK1 receptor antagonists demonstrate enhanced control of acute emesis with their addition to currently available agents and promising activity in controlling delayed emesis. Available evidence would strongly suggest that this class of agents will represent the next important advance in efforts to control nausea and vomiting induced by chemotherapy.
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PMID:Antiemetics for cancer chemotherapy-induced nausea and vomiting. A review of agents in development. 1065 96

The novel atypical antipsychotic ziprasidone has a pharmacologic profile notable for potent agonism of serotonin (5-HT)1A receptors, antagonism at 5-HT1D receptors, and reuptake inhibition of norepinephrine. 5-HT1A receptor agonism, in particular, suggests anxiolytic activity, and ziprasidone has shown preliminary efficacy in treating the symptoms of anxiety associated with psychotic disorders. In this study, the anxiolytic efficacy of ziprasidone was evaluated in nonpsychotic subjects who were anxious before undergoing minor dental surgery. We compared a single oral dose of 20 mg ziprasidone (N = 30) with that of 10 mg diazepam (N = 30) and placebo (N = 30) in a randomized, parallel-group, double-blind study. The peak anxiolytic effect of ziprasidone compared with that of placebo was similar to that of diazepam but had a later onset. At 3 hours postdose, the anxiolytic effect of ziprasidone was significantly greater than that of placebo (p < 0.05) and somewhat greater than that of diazepam. Diazepam showed a significantly greater anxiolytic effect than placebo at 1 hour (p < 0.05) but not at 3 hours. The sedative effect of ziprasidone was never greater than that of placebo, whereas that of diazepam was significantly greater than that of placebo 1 to 1.5 hours postdose. Ziprasidone was generally well tolerated. Only one patient reported treatment-related adverse events (nausea and vomiting) and, unlike diazepam, ziprasidone did not cause reductions in blood pressure. Dystonia, extrapyramidal syndrome, akathisia, and postural hypotension were not seen with ziprasidone. Thus, ziprasidone may possess anxiolytic effects in addition to its antipsychotic properties.
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PMID:The anxiolytic effect of the novel antipsychotic ziprasidone compared with diazepam in subjects anxious before dental surgery. 1191 Feb 68

Serotonin agonists can reduce glutamate-induced excitotoxicity in cerebral ischemia. The potent 5-HT1A agonist BAY x 3702, or repinotan, has reduced cortical infarct volume in pre-clinical models even when given 5 hours after injury. Early clinical trials showed that the drug was safe, and displayed primarily serotonergic side effects such as nausea and vomiting. A phase IIb trial in moderate to moderately severe strokes completed enrollment in June 2004.
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PMID:Repinotan, A 5-HT1A agonist, in the treatment of acute ischemic stroke. 1585 96