Receptor Antagonist Ondansetron Research Articles

The Role of 5-HT3 and Other Excitatory Receptors in Central Cardiorespiratory Responses to Hypoxia: Implications for Sudden Infant Death Syndrome

Although brainstem serotonergic (5-HT) systems are involved in the protective responses to hypoxia, abnormalities of 5-HT function are strongly implicated in SIDS, and the neurochemical mechanisms by which 5-HT receptors influence brainstem cardiorespiratory responses to hypoxia remains unclear. This study focuses on the role of excitatory neurotransmission, including 5-HT3 signaling, to cardiac vagal neurons (CVNs) that dominate the control of heart rate. Excitatory synaptic inputs to CVNs, located in the nucleus ambiguus (NA), were recorded simultaneously with respiratory activity in in vitro brainstem slices. During control conditions excitatory inputs to CVNs were blocked by application of NMDA and AMPA/kainate glutamatergic receptor antagonists, whereas the 5-HT3 and purinergic receptor antagonists ondansetron and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), respectively, had no effect. However, during hypoxia ondansetron inhibited excitatory neurotransmission to CVNs. In recovery from hypoxia, spontaneous and respiratory-related excitatory events were blocked by glutamatergic and purinergic receptor blockers, respectively, whereas ondancetron had no effect. These results demonstrate that hypoxia recruits a 5-HT pathway to CVNs that activates 5-HT3 receptors on CVNs to maintain parasympathetic cardiac activity during hypoxia. Exaggeration of this 5-HT neurotransmission could increase the incidence of bradycardia and risk of sudden infant death during hypoxia.

Involvement of Hypothalamic Glutamate in Cisplatin-Induced Emesis in Suncus murinus (House Musk Shrew)

We investigated the effect of cisplatin on glutamate release in the hypothalamus of Suncus murinus measured by brain microdialysis. Dialysis samples were collected every 20 min for 1 h before and 3 h after the cisplatin (30 mg/kg, i.p.) administration with the animals also being observed for the development of emesis. Cisplatin increased glutamate levels within 1 h and this was closely associated with the occurrence of emesis. Pretreatment with the 5-HT3– receptor antagonist ondansetron (2 mg/kg, i.p.) inhibited both the emesis and the increased glutamate levels. These results suggest that hypothalamic glutamate is involved in cisplatin-induced emesis in Suncus murinus.

Stimulation of basolateral amygdaloid serotonin 5-HT 2C receptors promotes the induction of long-term potentiation in the dentate gyrus of anesthetized rats

We have previously found that the induction of hippocampal long-term potentiation (LTP) is modulated by neuron activities in the basolateral amygdala (BLA). However, little is known about what neurotransmitter system in the BLA contributes to modulation of hippocampal LTP. In the present study, we investigated possible involvement of BLA serotonergic system in the induction of LTP at the perforant path (PP)-dentate gyrus (DG) granule cell synapses of anesthetized rats. The induction of PP-DG LTP was significantly inhibited by intra-BLA injection of the 5-HT 2 receptor antagonist cinanserin (25–50 nmol), but not by intra-BLA injection of the 5-HT 1,7 receptor antagonist methiothepin (50 nmol), the 5-HT 3 receptor antagonist ondansetron (50 nmol) or the 5-HT 4 receptor antagonist RS23597-190 (100 nmol). In addition, intra-BLA injection of the 5-HT 2C receptor agonist MK212 (50 nmol) facilitated the induction of PP-DG LTP. These results suggest that the induction of PP-DG LTP is promoted by activation of 5-HT 2C receptors in the BLA.

Localized Release of Serotonin (5-Hydroxytryptamine) by a Fecal Pellet Regulates Migrating Motor Complexes in Murine Colon

The colonic migrating motor complex (CMMC) is a motor pattern that regulates the movement of fecal matter through a rhythmic sequence of electrical activity and/or contractions along the large bowel. CMMCs have largely been studied in empty preparations; we investigated whether local reflexes generated by a fecal pellet modify the CMMC to initiate propulsive activity. Recordings of CMMCs were made from the isolated murine large bowel, with or without a fecal pellet. Transducers were placed along the colon to record muscle tension and propulsive force on the pellet and microelectrodes were used to record electrical activity from either side of a fecal pellet, circular muscle cells oral and anal of a pellet, and in colons without the mucosa. Spontaneous CMMCs propagated in both an oral or anal direction. When a pellet was inserted, CMMCs increased in frequency and propagated anally, exerting propulsive force on the pellet. The amplitude of slow waves increased during the CMMC. Localized mucosal stimulation/circumferential stretch evoked a CMMC, regardless of stimulus strength. The serotonin (5-hydroxytryptamine-3) receptor antagonist ondansetron reduced the amplitude of the CMMC, the propulsive force on the pellet, and the response to mucosal stroking, but increased the apparent conduction velocity of the CMMC. Removing the mucosa abolished spontaneous CMMCs, which still could be evoked by electrical stimulation. The fecal pellet activates local mucosal reflexes, which release serotonin (5-hydroxytryptamine) from enterochromaffin cells, and stretch reflexes that determine the site of origin and propagation of the CMMC, facilitating propulsion.

5‐Hydroxytryptamine selectively activates the vagal nodose C‐fibre subtype in the guinea‐pig oesophagus

The afferent neurons innervating the oesophagus originate from two embryonic sources: neurons located in vagal nodose ganglia originate from embryonic placodes and neurons located in vagal jugular and spinal dorsal root ganglia (DRG) originate from the neural crest. Here, we address the hypothesis that 5-hydroxytryptamine (5-HT) differentially stimulates afferent nerve subtypes in the oesophagus. Extracellular recordings of single unit activity originating from nerve terminals were made in the isolated innervated guinea-pig oesophagus. Whole cell patch clamp recordings (35 degrees C) were made from the primary afferent neurons retrogradely labelled from the oesophagus. 5-Hydroxytryptamine (10 micromol L(-1)) activated vagal nodose C-fibres (70%) in the oesophagus but failed to activate overtly vagal jugular nerve fibres and oesophagus-specific spinal DRG neurons. The response to 5-HT in nodose C-fibre nerve terminals was mimicked by the selective 5-HT(3) receptor agonist 2-methyl-5-HT (10 micromol L(-1)) and nearly abolished by the 5-HT(3) receptor antagonists ondansetron (10 micromol L(-1)) and Y-25130 (10 micromol L(-1)). In patch clamp studies, 2-methyl-5-HT (10 micromol L(-1)) activated a proportion of isolated oesophagus-specific nodose capsaicin-sensitive neurons (putative cell bodies of nodose C-fibres). We conclude that the responsiveness to 5-HT discriminates placode-derived (vagal nodose) C-fibres from the neural crest-derived (vagal jugular and spinal DRG) afferent nerves in the oesophagus. The response to 5-HT in nodose C-fibres is mediated by the 5-HT(3) receptor in their neuronal membrane.

Serotonergic and noradrenergic facilitation of the visceromotor reflex evoked by urinary bladder distension in rats with inflamed bladders

Bladder inflammation resulting from intravesical administration of zymosan significantly enhances the visceromotor reflex (VMR) evoked by urinary bladder distension (UBD). The present study examined whether intrathecal (i.t.) administration of receptor antagonists to either norepinephrine (NE) or serotonin (5-HT) altered this enhancement effect. I.t. administration of the non-specific 5-HT receptor antagonist methysergide (30 microg), the 5-HT(3) receptor antagonist ondansetron, or the 5-HT(1A) receptor antagonist WAY 100635 eliminated the enhancement effect produced by intravesical zymosan and also tended to reduce electromyographic (EMG) responses to UBD in non-inflamed rats. I.t. administration of either the non-specific NE receptor antagonist phentolamine (30 microg) or the alpha(1) antagonist WB 4101 also eliminated the enhancement effect, whereas i.t. administration of the alpha(2) antagonist yohimbine failed to significantly affect the enhancement effect. The effects of phentolamine and methysergide were not mediated by changes in bladder compliance. This is the first study to demonstrate that bladder hypersensitivity resulting from bladder inflammation is partly mediated by 5-HT and NE facilitatory effects. Based on these and previous findings we conclude that the net nociceptive response to bladder distension under conditions of bladder inflammation represents a complex interaction of facilitatory influences of spinal 5-HT and NE, and inhibitory influences of spinal opioids.

PRO: The Food and Drug Administration Black Box Warning on Droperidol Is Not Justified

PRO: The Food and Drug Administration Black Box Warning on Droperidol Is Not Justified

Activation of the serotonin 5-HT 3 receptor in the dorsal raphe nucleus suppresses REM sleep in the rat

The effects of the selective 5-HT 3 receptor agonist and antagonist m-chlorophenylbiguanide ( m-CPBG) and ondansetron, respectively, were studied in adult male Wistar rats implanted for chronic sleep recordings. Microinjection of m-CPBG (2.0 and 4.0 mM) into the dorsal raphe nucleus (DRN) decreased rapid-eye-movement sleep (REMS) and the number of REM periods during the first, second, and third 2-h recording period. On the other hand, direct infusion of ondansetron (0.5–1.0 mM) into the DRN induced no significant changes in sleep variables over the 6 h of recording. Pretreatment with ondansetron (0.5 mM) antagonized the m-CPBG (2.0 mM)-induced reduction of REMS and of the number of REM periods. The data are consistent with the hypothesis that the 5-HT 3 receptor is involved in the effect of DRN serotonergic neurons on brainstem structures that act to promote and induce REMS. It is suggested that the suppression of REMS after the microinjection of m-CPBG into the DRN is related, at least in part, to the stimulation of glutamatergic interneurons that express 5-HT 3 receptors. Activation of these receptors facilitates the release of glutamate, which, in turn, acts on postsynaptic N-methyl- d-aspartate and non- N-methyl- d-aspartate receptors expressed by serotonergic neurons of the DRN and increases the release of 5-HT at postsynaptic sites.

Current Prevention and Treatment of Postoperative Nausea and Vomiting after Gynecological Laparoscopic Surgery

Postoperative nausea and vomiting (PONV) are two of the commonest and most distressing complications of general anesthesia and surgery, with a remarkably high incidence after gynecological laparoscopic surgery. Numerous antiemetics have been studied for the prevention of PONV after gynecological laparoscopic surgery. Traditional antiemetics, including butyrophenones (e.g., droperidol) and benzamide (e.g., metoclopramide), are used for preventing PONV. The available non-traditional antiemetics for the prophylaxis against PONV are propofol, dexamethasone, and ephedrine. Serotonin receptor antagonists (ondansetron, granisetron, and dolasetron), compared with traditional antiemetics, are highly effective for PONV prophylaxis. None of the available antiemetics is entirely effective, perhaps because most of them act through the blockade on one type of receptor. There is a possibility that combined antiemetics with different sites of activity would be more effective than one drug alone for preventing PONV Combination antiemetic therapy with ondansetron and droperidol or dexamethasone is highly effective in the prevention of PONV. P6 acupoint injection is non-pharmacological technique and is as effective as droperidol for preventing PONV. Management of PONV after gynecological laparoscopic surgery depends on the prophylaxis. If the prophylactic therapy fails, treatment would be required. Ondansetron is effective in the treatment of established PONV. Knowledge regarding antiemetics is necessary to completely prevent and treat PONV in women undergoing gynecological laparoscopic surgery. Keywords: Butyrophenones, Droperidol, chemoreceptor trigger zone, Propofol, serotonin receptor antagonists

Antiemetics – current standards and open questions

Chemotherapy induced nausea and vomiting (CINV) is among the most feared side effects of chemotherapy for cancer patients and is associated with significant deterioration in quality of life. The major risk factors for CINV are emetogenic potential of chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (younger age, female gender, history of motion sickness, alcohol consumption). The use of first generation 5-hydroxytryptanine (5-HT3) receptor antagonists (ondansetron, tropisetron, dolasetron and granisetron) in combination with dexamethason has significantly improved the control of acute CINV. Additional improvement in the control of acute and delayed CINV for highly and moderately emetogenic chemotherapy has been demonstrated recently with two newer antiemetic agents, a second generation 5-HT3 receptor antagonist palonosetron and neurokinin-1 (NK-1) receptor antagonist aprepitant. However, the role of palonosetron with respect to old 5-HT3 antagonists remains to be verified when both are combined with dexamethason in the first 24 hours and recommended therapies for delayed emesis. Aprepitant is a current standard of care for the prevention of acute and delayed CINV in patients receiving highly emetogenic chemotherapy. The value of this agent has been demonstrated also in breast cancer patients receiving anthracycline-based chemotherapy. Despite recent progress, a significant number of patients still develop CINV. To further improve control of acute and delayed CINV many questions remain to be addressed in ongoing and future properly designed randomized clinical trials. These include use of new antiemetic combinations as are palonosetron and aprepitant with current and other agents (olanzepin, gabapentin, midazolam, gherlin); new NK1 antagonists; single day vs. multiple days dosing of antiemetics and in different clinical settings (multiple days chemotherapy, bone marrow transplantation).

Prévention et traitement des nausées et vomissements postopératoires chez l'enfant : une approche basée sur les preuves

Significant improvement towards an efficacious control of postoperative nausea and vomiting (PONV) has taken place recently. These improvements may be summarised using the « rule of three ». That rule describes a pragmatic and rational approach of PONV control. First, identify the patient at risk using predictive factors. Second, modify the anaesthesia technique to keep the baseline risk as low as possible. Third, administer antiemetics rationally, considering their degree of efficacy, their risk, and their potential additive effects. Despite considerable research efforts, identifying the patient at high risk of PONV remains a difficult task. However, today, we understand the degree of efficacy, dose-responsiveness, and adverse effects of most antiemetics. None of those molecules should be regarded as being universally efficacious, there is no gold standard, and, when used alone, their degree of efficacy is limited. Thus, they should be combined for improved efficacy. Among the most promising molecules are butyrophenones (droperidol, haloperidol), 5-HT 3 receptor antagonists (ondansetron, dolasetron, tropisetron, granisetron), and steroids (for instance, dexamethasone). The lack of relevant paediatric PONV data remains a major drawback and is highly unsatisfactory. Hopefully, future research will further improve the control of PONV not only in adults but also in children.

Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats

Enterochromaffin (EC) cells of the epithelial cells release 5-HT into the lumen, as well as basolateral border. However, the physiological role of released 5-HT into the lumen is poorly understood. Concentrations of 5-HT in the colonic mucosa, colonic lumen, and feces were measured by HPLC in rats. To investigate whether intraluminal 5-HT accelerates colonic transit, 5-HT and (51)Cr were administered into the lumen of the proximal colon, and colonic transit was measured. To investigate whether 5-HT is released into the lumen, we used an ex vivo model of isolated vascularly and luminally perfused rat proximal colon. To investigate whether luminal 5-HT is involved in regulating stress-induced colonic motility, the distal colonic motility was recorded under the stress loading, and a 5-HT(3) receptor antagonist (ondansetron, 10(-6) M, 0.5 ml) was administered intraluminally of the distal colon. Tissue content of 5-HT in the proximal colon (15.2 +/- 4.3 ng/mg wet tissue) was significantly higher than that in the distal colon (3.3 +/- 0.7 ng/mg wet tissue), while fecal content and luminal concentration of 5-HT was almost the same between the proximal and distal colon. Luminal administration of 5-HT (10(-6)-10(-5) M) significantly accelerated colonic transit. Elevation of intraluminal pressure by 10 cmH(2)O significantly increased the luminal concentration of 5-HT but not the vascular concentration of 5-HT. Stress-induced stimulation of the distal colonic motility was significantly attenuated by the luminal administration of ondansetron. These results suggest that luminally released 5-HT from EC cells plays an important role in regulating colonic motility in rats.

Reduction in methamphetamine induced sensitization and reinstatement after combined pergolide plus ondansetron treatment during withdrawal

We have previously found the 5-HT 3 receptor antagonist ondansetron to be useful in reducing cocaine self-administration and cocaine induced sensitization in rats when given during cocaine withdrawal. More recently we have found the combination of the dopamine agonist pergolide plus ondansetron, 3.5 h later, to reverse cocaine sensitization and associated changes in NMDA and AMPA receptors. Here we tested this drug combination in 1) a methamphetamine sensitization model and 2) a reinstatement model after intravenous methamphetamine self-administration using a nose-poke task. We found pergolide plus ondansetron given from days 3–7 of methamphetamine withdrawal to reverse methamphetamine induced sensitization and attenuate reinstatement. We hypothesize that pergolide may evoke a methamphetamine associated memory and that ondansetron can disrupt its reconsolidation. These data suggest that pergolide plus ondansetron treatment may be useful as a therapy to reduce relapse in methamphetamine abusers.

Risperidon vs haloperidol in treatment of schizophrenia

Previous studies suggest that the serotonin-3 (5-HT3) receptor antagonist ondansetron possesses the therapeutic potential for schizophrenia. This study was designed to determine whether ondansetron as an adjunct to haloperidol could enhance the clinical efficacy and reduce the adverse side effects in chronic treatment-resistant schizophrenia.Under double-blind, randomized conditions, 121 treatment-resistant inpatients with chronic DSM-IV-diagnosed schizophrenia received haloperidol (4–30 mg/day) combined with either placebo (N = 63) or a fixed dose of 8 mg/day of ondansetron (N = 58) for 12 weeks. Efficacy was defined as the change from baseline to endpoint in score on overall scale and subscales of the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Side effects were evaluated using the Treatment Emergent Symptom Scale and Extrapyramidal Symptom Rating Scale.Ondansetron combined with haloperidol produced a significantly greater improvement on PANSS overall scale and subscales for negative symptoms, general psychopathology, and cognition at endpoint compared to placebo with haloperidol, but no between-treatment group difference was observed on the subscale for positive symptoms and CGI-S. The ondansetron-treated group had a significantly higher proportion of patients with a 30% or greater baseline-to-endpoint reduction in PANSS total score than placebo. Patients in adjunctive ondansetron therapy also experienced significantly lower incidence and severity of parkinsonism and akathisia as well as fewer behavioral hyperactivity, cardiac, and gastrointestinal side effects.Ondansetron is an effective adjunctive agent in enhancing the effectiveness and reducing some adverse side effects of antipsychotic therapy for chronic, treatment-resistant schizophrenia, particularly for negative and cognitive symptoms.

The central amygdala regulates sodium intake in sodium-depleted rats: Role of 5-HT 3 and 5-HT 2C receptors

In the present paper, we have evaluated the participation of 5-HT 3 and 5-HT 2C receptors in the central amygdala (CeA) in the regulation of water and salt intake in sodium-depleted rats. m-CPBG-induced pharmacological activation of 5-HT 3 receptors located in the CeA resulted in a significant reduction in salt intake in sodium-depleted rats. This antinatriorexic effect of m-CPBG was reverted by pretreatment with the selective 5-HT 3 receptor antagonist ondansetron. The injection of ondansetron alone into the CeA had no effect on sodium-depleted and normonatremic rats. Conversely, pharmacological stimulation of 5-HT 2C receptors located in the central amygdala by the selective 5-HT 2C receptor agonist m-CPP failed to modify salt intake in sodium-depleted rats. Additionally, the administration of a selective 5-HT 2C receptor blocker, SDZ SER 082, failed to modify salt intake in rats submitted to sodium depletion. These results lead to the conclusion that the pharmacological activation of 5-HT 3 receptors located within the CeA inhibits salt intake in sodium-depleted rats and that 5-HT 2C receptors located within the CeA appear to be dissociated from the salt intake control mechanisms operating in the central amygdala.

Effects of ghrelin on feeding regulation and interdigestive migrating complex in rats

Objective. Ghrelin is an orexigenic peptide with remarkable prokinetic effects. However, its mechanisms in regulating feeding and gastrointestinal migrating myoelectrical complex (MMC) are not fully understood. The aim of this study was to examine the effects of ghrelin on feeding regulation and duodenal motility in rats. Material and methods. Feeding regulation was investigated at different times after intravenous injection of ghrelin and its receptor antagonist (D-Lys3)GHRP-6 in fasted rats. Rats were supplied with a pair of silver bipolar electrodes embedded in the duodenal serosa for electromyography. Ghrelin was injected intravenously into the rats during the fed state or fasted state. Some rats were pretreated with atropine, phentolamine, propranolol, L-arginine, the 5-hydroxytryptamine3 receptor antagonist ondansetron, and (D-Lys3)GHRP-6. Results. Ghrelin had little effect on food intake in the first 30 min after administration, but was found to increase feeding during the subsequent hours. (D-Lys3)GHRP-6 decreased feeding and antagonized the effect of ghrelin. Ghrelin induced duodenal MMC after administration in the fed state, and shortened the duodenal MMC cycle length and the duration of phase III during fasting. The amplitude and frequency of phase III were increased without affecting the percentage of phase III in the MMC cycle. Pretreatment with atropine, L-arginine, ondansetron, and (D-Lys3)GHRP-6 inhibited the effects of ghrelin. Propranolol and phentolamine had little influence on these effects. Conclusions. Ghrelin appears to be closely related to feeding and intestinal motility. The excitatory effects of ghrelin are dependent on the cholinergic pathway, and it has a close relationship with the NOS-NO or 5-HT pathway. The grehlin receptor is involved in its activities.

Serotonin-type 3 receptors mediate intestinal lipid-induced satiation and Fos-like immunoreactivity in the dorsal hindbrain

Several gastrointestinal stimuli, including some intestinal nutrients, have been shown to exert their satiating effect via activation of serotonin type-3 (5-HT(3)) receptors. The presence of lipids in the small intestine potently suppresses food intake; however, whether 5-HT(3) receptors play a role in this response has not been directly examined. Therefore, using the selective 5-HT(3) receptor antagonist ondansetron, we tested the hypothesis that duodenal infusion of lipid suppresses intake of both sucrose solution and chow through 5-HT(3) receptor activation. Rats duodenally infused with 72 and 130 mM Intralipid suppressed 1-h 15% sucrose intake by 33 and 67%, respectively. Suppression of sucrose intake by 72 mM Intralipid was significantly attenuated by ondansetron at all doses tested (0.5, 1.0, 2.0, and 5.0 mg/kg ip), whereas the lowest effective dose of ondansetron to attenuate suppression of intake by 130 mM Intralipid was 1.0 mg/kg. Furthermore, infusion of 130 mM Intralipid suppressed 1- and 4-h chow intake by 35 and 20%, respectively. Ondansetron administered as low as 0.5 mg/kg significantly attenuated 1-h Intralipid-induced suppression of chow intake and completely reversed the suppression by 4 h. Administration of ondansetron alone did not alter sucrose or chow intake compared with vehicle injection at any time. Finally, to test whether Intralipid-induced neuronal activation of the dorsal vagal complex is mediated by 5-HT(3) receptors, Fos-like immunoreactivity (Fos-LI) was quantified in ondansetron-pretreated rats following intestinal lipid infusion. Ondansetron (1 mg/kg) significantly attenuated duodenal intralipid-induced Fos-LI in the dorsal hindbrain. These data support the hypothesis that 5-HT(3) receptors mediate both satiation, as well as hindbrain neuronal responses evoked by intestinal lipids.

Differential effects of dexamethasone, ondansetron and a tachykinin NK 1 receptor antagonist (GR205171) on cisplatin-induced changes in behaviour, food intake, pica and gastric function in rats

This study aimed to dissect the mechanisms involved in malaise induced by the anti-cancer drug cisplatin by attempting to uncouple its effects on locomotor activity, arguably at least partly indicative of fatigue, from those effects indicative of emesis (pica, gastric stasis, reduced food intake) using pharmacological agents in the rat. Over 2 days cisplatin (6 mg/kg i.p.) reduced food intake, stimulated kaolin consumption, increased the wet weight of gastric contents and reduced locomotor activity. In animals treated with cisplatin: the 5-HT 3 receptor antagonist ondansetron (1 mg/kg s.c. bd.) had no effect on either activity or weight of gastric contents but did increase food intake on day 1 ( P < 0.05) and the total over both days (27.6 ± 1.8 vs. 19.9 ± 2.3g, P < 0.05), reducing kaolin consumption on day 2 ( P < 0.01) but not the total over both days; the NK 1 receptor antagonist GR205171 (1 mg/kg s.c. bd.) was without effect on activity, but reduced the wet weight of gastric contents ( P < 0.05), increased food intake on day 2 ( P < 0.01) and total consumption over both days (28.1 ± 1.7 g vs. 19.9 ± 2.3 g; P < 0.05) and reduced kaolin consumption on day 2 ( P < 0.05) but not over both days; dexamethasone (2 mg/kg s.c. bd.) blocked the cisplatin-induced reduction in activity on days 1 and 2 ( P < 0.01), reduced the wet weight of gastric contents by 43% ( P < 0.01), reduced kaolin consumption on both days ( P < 0.01) and arguably decreased the reduction in food intake caused by cisplatin. This study has revealed novel insights into the different spectra of activities of 5-HT 3 and NK 1 receptor antagonists and dexamethasone, which have implications for therapeutic strategies to alleviate the emetic, anorectic, dyspeptic and activity-reducing effects of anti-cancer chemotherapy.

Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: A double-blind, randomized, placebo-controlled study

Background Previous studies suggest that the serotonin-3 (5-HT 3) receptor antagonist ondansetron possesses the therapeutic potential for schizophrenia. This study was designed to determine whether ondansetron as an adjunct to haloperidol could enhance the clinical efficacy and reduce the adverse side effects in chronic treatment-resistant schizophrenia. Methods Under double-blind, randomized conditions, 121 treatment-resistant inpatients with chronic DSM-IV-diagnosed schizophrenia received haloperidol (4–30 mg/day) combined with either placebo ( N = 63) or a fixed dose of 8 mg/day of ondansetron ( N = 58) for 12 weeks. Efficacy was defined as the change from baseline to endpoint in score on overall scale and subscales of the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Side effects were evaluated using the Treatment Emergent Symptom Scale and Extrapyramidal Symptom Rating Scale. Results Ondansetron combined with haloperidol produced a significantly greater improvement on PANSS overall scale and subscales for negative symptoms, general psychopathology, and cognition at endpoint compared to placebo with haloperidol, but no between-treatment group difference was observed on the subscale for positive symptoms and CGI-S. The ondansetron-treated group had a significantly higher proportion of patients with a 30% or greater baseline-to-endpoint reduction in PANSS total score than placebo. Patients in adjunctive ondansetron therapy also experienced significantly lower incidence and severity of parkinsonism and akathisia as well as fewer behavioral hyperactivity, cardiac, and gastrointestinal side effects. Conclusions Ondansetron is an effective adjunctive agent in enhancing the effectiveness and reducing some adverse side effects of antipsychotic therapy for chronic, treatment-resistant schizophrenia, particularly for negative and cognitive symptoms.

Ondansetron for postoperative nausea and vomiting

Postoperative nausea and vomiting, both early onset and delayed, continues to be a major concern of patients and practitioners. Postoperative nausea and vomiting is recognized as a debilitating and potentially dangerous occurrence during the recovery period. Extensive studies of the serotonin subtype 5-hydroxytryptamine3 receptor antagonist ondansetron have demonstrated efficacy and safety in all age groups. Ondansetron has been shown to be most effective in preventing early postoperative vomiting in high-risk populations. Nausea and delayed postoperative nausea and vomiting are more effectively treated by combination therapies. Further understanding of patient-to-patient variability in the metabolism of ondansetron and the interaction of the different receptors in the nausea–vomiting neuroendocrine pathway may eventually greatly decrease the incidence of postoperative nausea and vomiting.