Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 5-HT3A receptor, a ligand-gated ion channel, is involved in pain pathways, nausea and emesis, and irritable bowel syndrome, and may play a role in the pathogenesis of psychiatric diseases such as schizophrenia and depression. Recently, a naturally occurring variation (ProArg) in the second intracellular loop of the human (h) 5-HT3A receptor was identified in a schizophrenic patient. Because the substitution of proline, an alpha-imino acid, by arginine may affect the conformation of the whole receptor, the aim of the present study was to determine the pharmacological and functional properties of this variant compared to the wild-type receptor in stably transfected HEK293 cells. Studies of binding of [H]GR65630, a 5-HT3 receptor antagonist, to membranes (saturation and competition experiments with 5-HT3 receptor ligands) and patch-clamp studies of agonist-induced currents in outside-out patches were carried out. In comparison to the wild-type, the variant receptor exhibited no changes in the receptor density and the affinities for nine representative ligands (five agonists and four antagonists). The potencies and efficacies of three 5-HT3 receptor agonists in inducing currents through the ion channel and the potencies of two 5-HT3 receptor antagonists in blocking 5-HT-evoked currents did not differ between wild-type and variant receptors. In addition, there were no differences in the desensitization kinetics of both receptor isoforms. In conclusion, the ArgPro variation of the h5-HT3A receptor does not change ligand binding to the h5-HT3A receptor, nor does it modify current through the receptor channel.
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PMID:Pharmacological and electrophysiological properties of the naturally occurring Pro391Arg variant of the human 5-HT3A receptor. 1516 4

This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT(4) receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation. Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems. Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy. Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not effect electrocardiographic parameters. Laboratory parameters are mostly unaffected by tegaserod, although several individuals have exhibited increased eosinophil counts. In summary, tegaserod exhibits a favourable safety and tolerability profile in IBS patients based on data from clinical trials. Diarrhoea is the most common adverse event associated with tegaserod use. Continued post-US marketing surveillance will further define the safety and tolerability profile of tegaserod.
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PMID:Safety profile of tegaserod, a 5-HT4 receptor agonist, for the treatment of irritable bowel syndrome. 1523 Jun 44

Urinary continence and voiding are complex physiological processes and require the coordination of all three efferent areas of the nervous system (parasympathetic, sympathetic, somatic). The pudendal nerve contains efferent as well as afferent fibers, the former ones having their origin in Onuf's nucleus. A number of studies see a link in the central modulation of lower urinary tract activity through 5-HT and NE receptor agonists as well as antagonists. Previous information about the modulation of the lower urinary tract in humans has been obtained from animal experiments. Duloxetin, a combined serotonin/norepinephrine reuptake inhibitor may prove to be a new therapeutic agent for stress urinary incontinence. Duloxetin appears to act at the presynaptic neuron of Onuf's nucleus. A phase II and three phase III studies have shown significant and clinically relevant improvement in several parameters in comparison to placebo control. The most frequent adverse event observed was nausea.
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PMID:[Pharmaceutical treatment of stress incontinence. New approaches via a direct effect of duloxetine on Onuf's nucleus]. 1532 58

The bowel exhibits reflexes in the absence of CNS input. To do so, epithelial sensory transducers, such as enterochromaffin (EC) cells, activate the mucosal processes of intrinsic (IPANs) and extrinsic primary afferent (sensory) neurons. EC cells secrete serotonin (5-HT) in response to mucosal stimuli. Submucosal IPANs, which secrete acetylcholine and calcitonin gene-related peptide, initiate peristaltic and secretory reflexes and are activated via "5-HT1P" receptors. Release of neurotransmitters is enhanced by 5-HT4 receptors, which are presynaptic and strengthen neurotransmission in prokinetic pathways. 5-HT3 receptors mediate signaling to the CNS and thus ameliorate cancer chemotherapy-associated nausea and the visceral hypersensitivity of diarrhea-predominant irritable bowel syndrome (IBS-D); however, because 5-HT3 receptors also mediate fast ENS neurotransmission and activate myenteric IPANs, they may be constipating. 5-HT4 agonists are prokinetic and relieve discomfort and constipation in IBS-C and chronic constipation. 5-HT4 agonists do not initiate peristaltic and secretory reflexes but strengthen pathways that are naturally activated. Serotonergic signaling in the mucosa and the ENS is terminated by a transmembrane 5-HT transporter, SERT. Mucosal SERT and tryptophan hydroxylase-1 expression are decreased in experimental inflammation, IBS-C, IBS-D, and ulcerative colitis. Potentiation of 5-HT due to the SERT decrease could account for the discomfort and diarrhea of IBS-D, while receptor desensitization may cause constipation. Similar symptoms are seen in transgenic mice that lack SERT. The loss of mucosal SERT may thus contribute to IBS pathogenesis.
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PMID:Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. 1579 84

Primary headaches such as migraine and cluster headache are neurovascular disorders. Migraine is a painful, incapacitating disease that affects a large portion of the adult population with a substantial economic burden on society. The disorder is characterised by recurrent unilateral headaches, usually accompanied by nausea, vomiting, photophobia and/or phonophobia. A number of hypothesis have emerged to explain the specific causes of migraine. Current theories suggest that the initiation of a migraine attack involves a primary central nervous system (CNS) event. It has been suggested that a mutation in a calcium gene channel renders the individual more sensitive to environmental factors, resulting in a wave of cortical spreading depression when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Genom wide scans have been performed in migraine with susceptibility regions on several chromosomes some are associated with altered calcium channel function. With positron emission tomography (PET), a migraine active region has been pointed out in the brainstem. In cluster headache, PET studies have implicated a specific active locus in the posterior hypothalamus. Both migraine and cluster headache involve activation of the trigeminovascular system. In support, there is a clear association between the head pain and the release of the neuropeptide calcitonin gene-related peptide (CGRP) from the trigeminovascular system. In cluster headache there is, in addition, release of the parasympathetic neuropeptide vasoactive intestinal peptide (VIP) that is coupled to facial vasomotor symptoms. Triptan administration, activating the 5-HT(1B/1D) receptors, causes the headache to subside and the levels of neuropeptides to normalise, in part through presynaptic inhibition of the cranial sensory nerves. These data suggest a central role for sensory and parasympathetic mechanisms in the pathophysiology of primary headaches. The positive clinical trial with a CGRP receptor antagonist offers a new promising way of treatment.
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PMID:Neurobiology in primary headaches. 1591 51

Venlafaxine is a new antidepressant that inhibits the reuptake of both 5-hydroxytryptamine (serotonin; 5-HT) and noradrenaline (NA). It is somewhat more potent as an inhibitor of the reuptake of 5-HT than NA. Its potency to inhibit the reuptake of 5-HT is comparable to that of tricyclic antidepressants (TCAs) such as amitriptyline or imipramine, but it is less potent than these drugs at inhibiting the reuptake of NA. Consequently, at low doses, venlafaxine may be a more effective inhibitor of the reuptake of 5-HT than that of NA. The major metabolite of venlafaxine in humans, O-desmethylvenlafaxine, has comparable potency to the parent drug for inhibiting the reuptake of either NA or 5-HT in vitro, but it is less potent in vivo. Both venlafaxine and O-desmethylvenlafaxine are essentially devoid of activity at muscarinic cholinergic, H1 histaminergic, and 1-adrenoceptors. This probably accounts for venlafaxine having a side-effect profile similar to that of selective serotonin reuptake inhibitors (SSRIs) rather than that of TCAs. Venlafaxine is subject to extensive first-pass metabolism and is metabolised by the cytochrome P450 isoenzyme IID6 in the liver. The half-life of venlafaxine is 3-4 h and that of its principal metabolite is about 10 h. The daily dose of venlafaxine can be administered as either two or three divided doses without altering significantly the pharmacokinetics of venlafaxine. The most common side-effects of venlafaxine are nausea, sedation, dizziness, dry mouth and sweating, as well as sexual dysfunctions, primarily problems with erection and delayed ejaculation. In some patients, venlafaxine also causes sustained elevations in both systolic and diastolic blood pressure; this effect is dose-dependent. Venlafaxine is much safer in overdosage than the TCAs. Antidepressant efficacy of venlafaxine has been found both in out-patients and in-patients. In general, its efficacy is comparable to that of comparator drugs (primarily TCAs or SSRIs), and in some cases even greater, and its efficacy is greater than that measured with placebo.
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PMID:Venlafaxine:a novel antidepressant compound. 1598 62

The class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now comprises three medications: venlafaxine, milnacipran, and duloxetine. These drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity. Whereas milnacipran blocks 5-HT and norepinephrine reuptake with equal affinity, duloxetine has a 10-fold selectivity for 5-HT and venlafaxine a 30-fold selectivity for 5-HT. All three SNRIs are efficacious in treating a variety of anxiety disorders. There is no evidence for major differences between SNRIs and SSRIs in their efficacy in treating anxiety disorders. In contrast to SSRIs, which are generally ineffective in treating chronic pain, all three SNRIs seem to be helpful in relieving chronic pain associated with and independent of depression. Tolerability of an SNRI at therapeutic doses varies within the class. Although no direct comparative data are available, venlafaxine seems to be the least well-tolerated, combining serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with a dose-dependent cardiovascular phenomenon, principally hypertension. Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity.
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PMID:SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. 1614 13

Chemotherapy patients report not only acute nausea and vomiting during the treatment itself, but also report anticipatory nausea and vomiting upon re-exposure to the cues associated with the treatment. We present a model of anticipatory nausea based on the emetic reactions of the Suncus murinus (musk shrew). Following three pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit conditioned retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with each of the principal cannabinoids found in marijuana, Delta(9)-tetrahydrocannabinol or cannabidiol, at a dose that did not suppress general activity. On the other hand, pretreatment with a dose of ondansetron (a 5-HT(3) antagonist) that interferes with acute vomiting in this species, did not suppress the expression of conditioned retching during re-exposure to the lithium-paired context. These results support anecdotal claims that marijuana, but not ondansetron, may suppress the expression of anticipatory nausea.
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PMID:Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: An animal model of anticipatory nausea and vomiting. 1619 70

The basic CNS neuropharmacology of naratriptan is reviewed here. Naratriptan is a second-generation triptan antimigraine drug, developed at a time when CNS activity was thought not to be relevant to its therapeutic effect in migraine. It was, however, developed to be a more lipid-soluble, more readily absorbed and less readily metabolized variant on preexisting triptans and these variations conferred on it a higher CNS profile. Naratriptan is a 5-HT(1B/1D) receptor agonist with a highly selective action on migraine pain and nausea, without significant effect on other pain or even other trigeminal pain. Probable sites of therapeutic action of naratriptan include any or all of: the cranial vasculature; the peripheral terminations of trigeminovascular sensory nerves; the first-order synapses of the trigeminovascular sensory system; the descending pain control system; and the nuclei of the thalamus. Naratriptan may prevent painful dilatation of intracranial vessels or reverse such painful dilatation. Naratriptan can prevent the release of sensory peptides and inhibit painful neurogenic vasodilatation of intracranial blood vessels. At the first order synapse of the trigeminal sensory system, naratriptan can selectively suppress neurotransmission from sensory fibers from dural and vascular tissue, while sparing transmission from other trigeminal fibers, probably through inhibition of neuropeptide transmitter release. In the periaqueductal gray matter and in the nucleus raphe magnus, naratriptan selectively activates inhibitory neurons which project to the trigeminal nucleus and spinal cord and which exert inhibitory influences on trigeminovascular sensory input. Naratriptan has also a therapeutic effect on the nausea of migraine, possibly exerting its action at the level of the nucleus tractus solitarius via the same mechanisms by which it inhibits trigeminovascular nociceptive input. The incidence of naratriptan-induced adverse effects in the CNS is low and it is not an analgesic for pain other than that of vascular headache. In patients receiving selective serotonin uptake inhibitors (SSRIs) naratriptan may cause serotonin syndrome-like behavioral side effects. The mechanism of action involved in the production of behavioral and other CNS side effects of naratriptan is unknown.
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PMID:Preclinical neuropharmacology of naratriptan. 1638 95

We performed a retrospective study that compared the efficacy and safety of dexamethasone (DEX) 8 mg with DEX 16 mg in cases of acute and delayed emesis induced by cisplatin (CDDP) chemotherapy in patients with lung cancer. Sixty-eight lung cancer patients treated with combination cisplatin, ifosfamide, and irinotecan therapy were studied. The DEX 8 mg group and the DEX 16 mg group received DEX intravenous injection 30 min prior to CDDP. All patients then received a 5-HT(3) antagonist intravenous injection 30 min before CDDP. Protection from acute nausea (day 1) was significantly superior in the DEX 16 mg group compared with the DEX 8 mg group (DEX 8 mg, 76.5%; DEX 16 mg, 100%). Protection from delayed emesis (day 1) was significantly superior in the DEX 16 mg group compared with the DEX 8 mg group. There was no reported severe nausea (grade 3) and vomiting (grade 2) in the DEX 16 mg group. Furthermore, perphenazine hydrochloride for use as rescue medication was required by significantly fewer patients in the DEX 16 mg group than in the DEX 8 mg group (DEX 8 mg, 41.2%; DEX 16 mg, 0%). Adverse effects were observed in 10 cases (nine reports of generalized fatigability, two of headache) in the DEX 8 mg group and in 16 cases (11 reports of generalized fatigability, one of pruritus) in the DEX 16 mg group. However, because the symptoms were all mild, we did not consider that there was any safety problem. In conclusion, DEX 16 mg is a clinically useful treatment for acute and delayed emesis induced by cisplatin-induced chemotherapy in patients with lung cancer.
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PMID:[Comparison of dexamethasone 8 mg and 16 mg for the prevention of acute and delayed cisplatin-induced emesis in patients with lung cancer]. 1639 51


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