Network meta-analysis of triple therapy for the prevention and treatment of acute nausea and vomiting caused by emetogenic chemotherapy drugs with moderate and high risk / 中国药房

OBJECTIVE To evaluate the efficacy of the triple therapy of 5-HT3 receptor antagonists， neurokinin-1 receptor antagonists and dexamethasone （referred to as “triple therapy”） in the prevention and treatment of acute nausea and vomiting caused by moderately and highly emetogenic chemotherapy drugs. METHODS Retrieved from PubMed， Embase， the Cochrane Library， CNKI and Wanfang data， randomized controlled trials （RCTs） about triple therapy or 5-HT3 receptor antagonist combined with dexamethasone （referred to as “dual therapy”） were collected during the inception to May 2023. After literature screening， data extraction and literature evaluation， network meta-analysis was performed by using Stata 16.0 software. RESULTS A total of 59 RCTs were included， involving 23 418 patients and 15 interventions. Results of network meta-analysis showed that fosaprepitant + palonosetron + dexamethasone （FPD） was most effective in terms of acute nausea and vomiting control rate， followed by fosaprepitant + granisetron + dexamethasone （FGD） and aprepitant + ramosetron + dexamethasone （AMD）. In terms of acute nausea control rate， FPD was the most effective， followed by aprepitant + palonosetron + dexamethasone （APD） and FGD. In terms of acute vomiting control rate， FPD was the most effective， followed by FGD and APD. CONCLUSIONS Fosaprepitant + palonosetron + dexamethasone is better than other triple therapy or dual therapy in preventing acute nausea and vomiting caused by moderately and highly emetogenic chemotherapy drugs.

Network Meta-analysis of 5-HT3 Receptor Antagonists for Prevention of Acute Nausea and Vomiting Caused by High-dose Chemotherapy / 中国药学杂志

OBJECTIVE: To evaluate the efficacy of 5-HT3 antagonists in the prevention of acute nausea and vomiting caused by high-dose chemotherapy using the network Meta-analysis system. METHODS: Developing retrieval strategies, system retrieves electronic databases such as Pubmed, EMbase, Cochrane Library, VIP, Wanfang and CNKI (as of October 2018), to find a randomized controlled trial (RCT) that uses 5-HT3 receptor antagonist alone to prevent nausea and vomiting caused by high-dose chemotherapy in adults. Quality assessment and data extraction were performed on eligible RCTs, with outcomes including acute nausea and vomiting. The RESULTS of the included RCT studies were combined using traditional STA analysis and network Meta-analysis using STATA13.0 software and WINBUG software.The RESULTS of the included RCT studies were combined using traditional Meta-analysis and network Meta-analysis. RESULTS: A total of 20 studies were included, involving a total of 4 042 patients with high-dose emetogenic chemotherapy.Seven interventions were included (granstron, ondansetron, ramosetron, tropisetron, dolasetron, azasetron, and palonosetron) with a total arm count of 41.The traditional Meta RESULTS showed that palonosetron was more effective in preventing acute nausea and vomiting caused by high-dose chemotherapy than ondansetron, and the difference was statistically significant (P0.05). Ondansetron may be inferior to granisetron (OR=1.238), but the difference is not statistically significant (P>0.05).For acute nausea caused by high-dose chemotherapy, ondansetron may be inferior to granisetron (OR=1.232), but the difference was not statistically significant (P>0.05).Ramosetron may be better than granisetron (OR=0.632), but the difference was not statistically significant (P>0.05).Network Meta-analysis found that ondansetron was inferior to palonosetron in the treatment of acute vomiting due to high-dose chemotherapy (OR=0.60, 95%CI:0.39-0.88). Palonosetron was superior to ramosetron (OR=2.54, 95% CI:1.16-5.80). SCURA RESULTS showed that the best treatment for acute nausea caused by high-dose chemotherapy was palonosetron, followed by ramosetron, dolasetron, ondansetron, granisetron and tropisetron. The best treatment for acute vomiting caused by high-dose chemotherapy is palonosetron, followed by ramosetron, azasetron, dolasetron, tropisetron, granisetron and ondansetron. The RESULTS of the network Meta-analysis are basically consistent with those obtained by traditional Meta-analysis. CONCLUSION: Compared with the first-generation 5-HT3 receptor antagonist, palonosetron is more effective in preventing acute nausea and vomiting caused by high-dose chemotherapy, ramosetron is more effective than other first-generation 5-HT3 receptor antagonists. Whether the RESULTS of this study will guide the clinical practice still requires a large-scale prospective study designed specifically to verify.

Regulatory Actions of Intestines-unblocking and Turbid-purging Recipe on Colonic 5-Hydroxytryptamine and Its Receptor in Rats with Constipation-dominant Irritable Bowel Syndrome / 广州中医药大学学报

Objective To investigate the regulatory actions of Intestines-unblocking, Turbid-purging Recipe (ITR) on colonic 5-hydroxytryptamine (5-HT) and its receptor 5-hydroxytryptamine 3 (5-HT3) in rats with constipation-dominant irritable bowel syndrome (IBS-C), and to explore the therapeutic mechanism of ITR in treating IBS-C. Methods Forty-two male SD rats were randomly divided into 6 groups, namely normal group, model group, western medicine group, high-, middle- and low-dose Chinese medicine groups, 7 rats in each group. IBS-C rat model was established by intragastric administration of ice water. After establishment of the model, western medicine group was given intragastric administration of Cisapride Tablets (at the dosage of 3.6 mg·kg-1·d-1), Chinese medicine groups were given intragastric administration of various dosages of ITR granules (18.5, 9.25, 4.625 g·kg-1·d-1 respectively) , and the model group was given intragastric administration of normal saline, the treatment lasting 14 d. The rats in various groups were given normal feeding and drinking. After treatment, HE staining method was used to observe pathological changes in the intestinal tissue, immunohistochemistry method was used to observe the expression levels of intestinal 5-HT and 5-HT3 receptor. Results Compared with the normal group, the expression level of rat intestinal 5-HT was increased (P < 0.05) and that of 5-HT3 receptor was decreased (P < 0.05) in the model group and the medication groups. Compared with the model group, 5-HT expression level was decreased significantly (P<0.05) and 5-HT3 receptor expression level was increased (P < 0.05) in the medication groups, and the improvement of the middle-dose Chinese medicine group was more obvious (P < 0.05). Conclusion ITR has therapeutic efficacy for IBS-C rats through lowering 5-HT expression and increasing 5-HT3 receptor expression, which results into the improvement of intestinal sensitivity and abnormal dynamic of the rats.

Clinical analysis of aprepitant for treating vomiting caused by cis-platin regimen / 重庆医学

Objective To investigate the clinical efficacy of aprepitant in the treatment of cisplatin based chemotherapy in-duced nausea and vomiting.Methods The tumor patients treated with cisplatin(80 mg/m2)chemotherapeutic regimen in Affiliated Shantou Hospital of Sun Yat-Sen University from December 1,2014 to December 1,2016 were selected,61 cases still had vomiting after using granisetron and dexamethasone for routinely stopping vomiting,the patients with aprepitant and dexamethasone for fur-ther stopping vomiting served as the aprepitant group,while the patients with granisetron and dexamethasone as the granisetron group.Then the complete response(CR)rates within 24,24-72,>72-144 h were observed in the two groups.Results The CR rates within 24 h in the aprepitant group and granisetron group were 66.67% and 51.61% respectively,the difference was not sta-tistically significant(P=0.232),which at 24-72 h were 80.00% and 54.84% respectively,the aprepitant group was significantly better than the granisetron group(P=0.036),which at >72-144 h were 86.67% and 64.52% respectively,the aprepitant group was better than the granisetron group(P=0.045).The comparison of adverse reactions between the two antiemetic drugs found that constipation,diarrhea,urticaria,fatigue and anxiety had no significant difference(P>0.05),the occurrence rate of total adverse reactions in the aprepitant group was 23.33%,which in the granisetron group was 25.81%,the difference between the two groups was not statistically significant(P>0.05).Conclusion Aprepitant combined with dexamethasone has better effect for treating hy-peremetic chemotherapy drug cisplatin chemotherapy caused nausea and vomiting with good tolerance.

Lamotrigine, an antiepileptic drug, inhibits 5-HT₃ receptor currents in NCB-20 neuroblastoma cells

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine (5-HT)₃ receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine (1~300 µM) resulted in a concentration-dependent reduction in peak amplitude of currents induced by 3 µM of 5-HT for an IC₅₀ value of 28.2±3.6 µM with a Hill coefficient of 1.2±0.1. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, 5-HT₃-mediated currents evoked by 1 mM dopamine, a partial 5-HT₃ receptor agonist, were inhibited by lamotrigine co-application. The EC₅₀ of 5-HT for 5-HT₃ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate 5-HT₃ receptor desensitization, inhibited 5-HT₃ receptor currents in a concentration-dependent manner. The deactivation of 5-HT₃ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of 5-HT₃ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the 5-HT3 receptor currents. These results indicate that lamotrigine inhibits 5-HT₃-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

Efficacy and safety of multiple-dose 5-HT3 receptor antagonists in preventing multi-day-based and highly emetogenic chemotherapy-induced nausea and vomiting / 中国肿瘤临床

Objective:To evaluate efficacy and safety of multiple-dose tropisetron plus dexamethasone (DXM) versus palonosetron plus DXM for chemotherapy-induced nausea and vomiting. (CINV) in patients received multiple day-based highly emetogenic chemotherapy. Methods:Cancer patients who were receiving multiday-based highly emetogenic chemotherapy were randomly assigned to AB or BA groups. A randomized, cross self-control ed method was applied. Patients in AB group received palonosetron (0.25 mg) 30 min before chemotherapy on day 1 and 3 or additional day 5 in the first cycle;and with tropisetron (5 mg) 30 min before chemotherapy on day 1, 2, and 3, or sup-plementary days (day 4 and 5) in the second cycle. Patients in BA group were treated with tropisetron in the first cycle and with palonosetron in the second cycle. Tropisetron and palonosetron were administered with DXM (10 mg) on day 1, followed by additional doses (5 mg) on days 2 to 5. Palonosetron group comprised patients in the AB group in the first cycle and BA group in the second cycle, whereas tropisetron group included patients in the AB group in the second cycle and BA group in the first cycle. Efficacy and safety of tropisetron versus palonosetron in preventing CINV were evaluated. Results:Ninety-one patients were included in analyses. At day 3, 4, and 5, incidence rates of nausea in the palonosetron group reached 28.6%, 30.8%, and 24.2%, respectively, and those of the tropisetron group totaled 42.8%, 47.3%, and 39.6%, respectively (P<0.05). At day 4, 5, and 6, incidence rates of vomiting in the palonosetron group measured 28.6%, 18.7%, and 5.5%, respectively, and those of the tropisetron group reached 42.9%, 34.1%, and 14.3%, respectively (P<0.05). From day 4 to day 5, day 6 to day 7, and day 1 to day 7, the palonosetron group yielded significantly lower incidence rates of nausea and vomiting than tropisetron group (P<0.05). Rate of rescue treatment in the palonosetron group was lower than that in tropisetron group (13.2%vs. 24.2%, P=0.057). No statistical difference in toxicities was observed between the two groups. Conclusion:Palonosetron plus DXM features better efficacy than that of tropisetron plus DXM against delayed CINV induced by multiple day-based highly emetogenic chemotherapy, which was well tolerated in the two treatments.

Tropisetron for the prevention of postoperative nausea and vomiting：a Meta-analysis / 重庆医学

Objective To evaluate the efficacy and safety of tropisetron for the prevention of postoperative nausea and vomi -ting (PONV) after general anesthesia .Methods We searched the PubMed ,EBSCO ,Cochrane ,CNKI and Weipu database to identi-fy randomized controlled trials (RCT ) about tropisetron in preventing PONV after general anesthesia .The methodological quality of the included RCT was assessed and data were extracted .The meta-analyses were performed by Rev Man5 .0 software .Results A total of 18 RCT met the inclusion criteria ,involving 2 901 patients .All RCT were randomized double-blind experiments .The results of meta-analyses showed that :(1)tropisetron could significantly decrease the incidence of PONV after general anesthesia ,[OR =0 .43 ,95% CI(0 .33 - 0 .57)] ,the efficacy in later period [OR = 0 .41 ,95% CI(0 .25 - 0 .65)] was better than that in earlier period [OR = 0 .66 ,95% CI(0 .44 - 0 .98)] ;(2)compared with tropisetron ,the combination of tropisetron and dexamethasone could signifi-cantly decrease the incidence of PONV [OR = 0 .37 ,95% CI(0 .22 - 0 .64)] ;(3)compared with granisetron or ondansetron ,tropise-tron could not significantly decrease the incidence of PONV ,the OR was [OR = 1 .08 ,95% CI(0 .68 - 1 .73)] and [OR = 0 .77 ,95%CI(0 .27 - 2 .21)] respectively ;(4)compared with dexamethasone ,tropisetron could not significantly decrease the incidence of PONV [OR = 1 .06 ,95% CI(0 .49 - 2 .30)] .Conclusion Tropisetron can significantly decrease the incidence of PONV after general anesthesia .It has also the advantage of decreasing incidence of the incidence of PONV combined with other non-5 HT-3 receptor in-hibitor such as dexamethasone .

Retrospective analysis of the clinical rational drug use refer to NCCN antiemetic guideline / 中国药学杂志

OBJECTIVE: To investigate the application of antiemetics in patients with gynecological cancers during chemotherapy. METHODS: Medical records of 182 patients receiving chemotherapy lor gynecological cancer were evaluated and a descriptive a-nalysis was carried out.Logistic regression was performed to determine the predictors of compliance. RESULTS: The rate of adherence to guideline (CINV) for patients receiving one-day chemotherapy is 80%. prophylactic usage rate in patients receiving multi-days chemotherapy is 95%, with a 47% 5-HT3 receptor antagonist.The adherence to NCCN anti-emesis guideline was better in patients having paclitaxel-based chemotherapy than patients having no paclitaxel. CONCLUSION: As the biggest cancer hospital in China, antiemetics were commonly given as prevention of CINV in the form of 5-HT3 receptor antagonist, but antiemetic effect of dexametha-sone was ignored and needed to be emphasized.

Association of 5-HT3B Receptor Gene Polymorphisms with the Efficacy of Ondansetron for Postoperative Nausea and Vomiting

PURPOSE: Postoperative nausea and vomiting (PONV) is a common problem after general anesthesia. Although 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists have significantly reduced PONV, over 35% of patients treated with ondansetron can experience PONV. In this study, we investigated whether the Y129S and -100_-102AAG deletion polymorphisms of the 5-HT3B receptor gene affect the efficacy of ondansetron in preventing PONV. MATERIALS AND METHODS: Two hundred and forty-five adult patients who underwent laparoscopic cholecystectomy were enrolled. Ondansetron 0.1 mg/kg was intravenously administered 30 minutes before the end of surgery. Genomic DNA was prepared from blood samples using a nucleic acid isolation device. Both the Y129S variant and the -100_-102AAG deletion variant were screened for using a single base primer extension assay and a DNA direct sequencing method, respectively. The relationship between genetic polymorphisms and clinical outcomes of ondansetron treatment was investigated. RESULTS: Among the 5-HT3B AAG deletion genotypes, the incidence of PONV was higher in patients with the homomutant than with other genotypes during the first 2 hours after surgery (p=0.02). There were no significant differences in the incidence of PONV among genotypes at 2-24 hours after surgery. In the Y129S variants of the 5-HT3B receptor gene, there were no significant differences in the incidence of PONV among genotypes during the first 2 hours and at 2-24 hours after surgery. CONCLUSION: The response to ondansetron for PONV was significantly influenced by the -100_-102AAG deletion polymorphisms of the 5-HT3B gene. Thus, the -100_-102AAG deletion variants may be a pharmacogenetic predictor for responsiveness to ondansetron for PONV.

Palonosetron versus granisetron in combination with aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer / 부인종양

OBJECTIVE: There is no research regarding the appropriate antiemetic agents for female patients, especially those receiving moderately emetogenic chemotherapy (MEC). We evaluated the antiemetic efficacy of a combination of 5-HT3 receptor with/without aprepitant in patients with gynecological cancer treated with the TC (paclitaxel and carboplatin) regimen of MEC. METHODS: We enrolled 38 patients diagnosed with gynecologic cancer and scheduled to receive the TC regimen. The patients were randomly assigned to receive a 5-HT3 receptor antagonist, either palonosetron in the first cycle followed by granisetron in the second cycle or vice versa. In the third cycle, all patients received a combination of the 5-HT3 receptor and dexamethasone with/without aprepitant. RESULTS: When three drugs were administered, palonosetron consistently produced an equivalent complete response (CR) rate to granisetron in the acute phase (89.5% vs. 86.8%, p=0.87) and delayed phase (60.5% vs. 65.8%, p=0.79). With regard to the change in dietary intake, palonosetron exhibited similar efficacy to granisetron in the acute phase (92.1% vs. 89.4%, p=0.19) and delayed phase (65.7% vs. 68.4%, p=0.14). However, in the delayed phase, the addition of aprepitant therapy with a 5-HT3 receptor antagonist and dexamethasone produced a higher CR rate than a 5-HT3 receptor antagonist with dexamethasone (93.3% vs. 47.8%, p<0.001) and allowed the patients to maintain a higher level of dietary intake (93.3% vs. 56.5%, p<0.001). CONCLUSION: The addition of aprepitant therapy was more effective than the control therapy of a 5-HT3 receptor antagonist, and dexamethasone in gynecological cancer patients treated with the TC regimen.

Ondansetron versus Amitriptyline in the Treatment of Peripheral Neuropathy: A Randomized Double Blind Prospective Clinical Study.

Background and Objective: Clinical trials have shown the potential use of 5-HT3 receptor antagonists like Ondansetron, Tropisetron and Zacopride in a number of disorders of gastrointestinal tract and the central nervous system such as cancer chemotherapy induced vomiting, anxiety, depression, schizophrenia and migraine. Various experimental and clinical studies also point the usefulness of Ondansetron in neuropathic pain. Therefore, the present study was conducted to find out whether Ondansetron could be used as an alternative to a standard drug, Amitriptyline in the treatment of peripheral neuropathy. Methodology: A randomized double blind prospective clinical study was conducted on Original Research Article British Journal of Medicine & Medical Research, 4(26): 4444-4454, 2014 4445 thirty six patients of peripheral neuropathy divided into two groups of equal number of patients. Group 1 received Ondansetron 8 mg per day while Group 2 received Amitriptyline 25 mg per day. Patients were being evaluated on the basis of improvements (decrease) in LANSS (Leeds Assessment of Neuropathic Symptoms and Signs), VAS (Visual Analogue Scale) and NCV (Nerve Conduction Velocity) for six weeks. Student’s ttest and/or repeated measure ANOVA followed by Bonferoni correlation was used to compare sets of paired observations. The Friedman test followed by multiple comparisons was used to compare the data which was not normally distributed. Results: LANSS and VAS scores showed significant improvements in the 1st and 2nd visit in both the groups. NCV showed improvement in Ondansetron group with less number of adverse effects compared to that of Amitriptyline. NCV in Amitriptyline group demonstrated significant increase in one of the parameters, F-waves, indicating a worsening in left tibial nerve (p=0.036), whereas no such change was found in the group treated with Ondansetron. Conclusion: Ondansetron has beneficial role in peripheral neuropathy by improving its sensory component as it significantly decreased LANSS and VAS scores. Our results also demonstrated that Ondansetron was at least as efficacious as Amitriptyline in the treatment of peripheral neuropathy with lesser adverse effects.

Anxiolytic-like effect of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (6o) in experimental mouse models of anxiety.

The present research was designed to explore the anxiolytic-like activity of a novel 5-HT3 receptor antagonist (6o) in experimental mouse models of anxiety. The anxiolytic activity of '6o' at (1 and 2 mg/kg, ip) was evaluated in mice by using a battery of behavioural tests of anxiety such as elevated plus maze (EPM), light/dark aversion test, hole board (HB) and open field test (OFT) with diazepam (2 mg/kg, ip) as a standard anxiolytic. None of the tested doses of '6o' affected the base line locomotion. Compound '6o' (2 mg/kg, ip) and diazepam (2mg/kg, ip) significantly increased the percentage of both time spent and open arm entries in the EPM test. Compound '6o' in (1 mg/kg, ip) dose was only able to affect the percentage time spent in open arm significantly in the EPM test. In the light and dark test, compound '6o' (2 mg/kg, ip) and diazepam (2mg/kg, ip) significantly increased the total time spent in light compartment as well as number of transitions from one compartment to other and number of square crossed. Compound '6o' (1 and 2 mg/kg, ip) and diazepam (2 mg/kg, ip) also significantly increased number of head dips and number of squares crossed, whereas significantly decreased the head dipping latency in HB test as compared to vehicle control group. In addition, '6o' in both the doses and diazepam (2mg/kg, ip) significantly increased the ambulation scores (squares crossed) in OFT however, there was no significant effect of '6o' (1 and 2 mg/kg, ip) and diazepam (2 mg/kg, ip) on rearing scores. To conclude compound '6o' exhibited an anxiolytic-like effect in animal models of anxiety.

Anti-depressant like activity of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (6o) a 5-HT3 receptor antagonist.

The compound 6o (at 0.5, 1 and 2 mg/kg, ip) with optimum log P and pA2 value, was subjected to forced swim test (FST) and tail suspension test (TST). The compound 6o significantly reduced the duration of immobility in mice without affecting the base line locomotion in actophotometer. Moreover, 6o (2 mg/kg, ip), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and at 1 and 2 mg/kg, ip antagonized the reserpine-induced hypothermia (RIH) in rats. In interaction studies with various standard drugs/ligands using FST, 6o (1 and 2 mg/kg, ip) potentiated the anti-depressant effect fluoxetine (5 mg/kg, ip) and reversed the depressant effect of parthenolide (1 mg/kg, ip) by reducing the duration of immobility. Furthermore, 6o (1 and 2 mg/kg, ip) potentiated the effect of bupropion (10 mg/kg, ip) in TST. The behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic 6o (1 and 2 mg/kg) treatment as observed from the modified open field test (parameters: ambulation, rearing, fecal pellet). The results suggest that compound 6o exhibited anti-depressant like effect in rodent models of depression.

Effects of Ramosetron on Gastrointestinal Transit of Guinea Pig

BACKGROUND/AIMS: A selective 5-hydroxytryptamine (5-HT) type 3 receptor antagonist, ramosetron, inhibits stress-induced abnormal defecation in animals and is currently used as a therapeutic drug for irritable bowel syndrome with diarrhea. The aim of this study is to investigate the effect of ramosetron on altered gastrointestinal (GI) transit. METHODS: Male guinea pigs weighing approximately 300 g were used. The effect of ramosetron was investigated on altered GI transit induced by thyrotropin-releasing hormone (TRH), 5-HT, or mustard oil (MO). GI transit was evaluated by the migration of charcoal mixture from the pylorus to the most distal point, and expressed as a percentage (%) of charcoal migration (cm) of the total length of total small intestine (cm). RESULTS: The average charcoal transit was 51.3 +/- 20.1% in the control (vehicle) group, whereas in the ramosetron group charcoal moved 56.6 +/- 21.9%, 46.9 +/- 9.14% and 8.4 +/- 5.6% of the total small intestine at the concentrations of 10, 30 and 100 microg/kg, respectively. GI transit after administration of TRH (100 microg/kg), 5-HT (10 mg/kg) or MO (10 mg/kg) was accelerated compared to vehicle (5-HT, 94.9 +/- 9.22%; TRH, 73.4 +/- 14.7%; MO, 81.0 +/- 13.7%). Ramosetron inhibited GI transit altered by 5-HT, TRH or MO. CONCLUSIONS: Ramosetron modulated GI transit. We suggest that ramosetron may be therapeutically useful for those with accelerated upper GI transit.

Effects of Palonosetron, a 5-HT3 Receptor Antagonist, on Mechanical Allodynia in a Rat Model of Postoperative Pain

BACKGROUND: 5-hydroxytryptamine 3 (5-HT3) receptors have been known to be associated with the modulation of nociceptive transmission. However, it is uncertain whether 5-HT3 plays a role in the antinociceptive or pronociceptive pathway for incisional pain. In this study, we evaluated the effects of palonosetron, a 5-HT3 receptor antagonist, on incisional pain in rats when administered intrathecally or intraplantarly. METHODS: An intrathecal catheter was implanted through the cisterna magna and placed in the intrathecal space of rats. An incision in the plantaris muscle of the right hind paw was done under anesthesia with sevoflurane. Withdrawal thresholds were evaluated with the von Frey filament after 2 hours. Palonosetron (0.5 and 0.1 microg intrathecally; 0.5 microg intraplantarly) was administered and the thresholds were observed for 4 hours. RESULTS: Mechanical hypersensitivity developed after the incision. Intrathecal palonosetron (0.5 microg and 0.1 microg) did not alter the paw withdrawal threshold. Intraplantar palonosetron (0.5 microg) also did not change the paw withdrawal threshold. CONCLUSIONS: Intrathecal and intraplantar palonosetron (0.5 microg) had no effect on modulating the mechanical hypersensitivity in the incisional pain model of rats.

Chemotherapy induced nausea & vomiting (CINV).

Chemotherapy is the first line treatment in management of many cancers, both for cure and palliation; hence it’s crucial to minimize the unpleasant side effects of chemotherapy to increase tolerability to chemotherapy. Most of the conventional anti cancer drugs are emetogenic. Patients receiving chemotherapy experience different degrees of nausea and vomiting depending on the emetogenic potential of the anti cancer drugs given and the patient characteristics. With a better understanding of the pathophysiology, distinct phases of chemotherapy-induced nausea and vomiting (CINV) i.e., acute emesis, delayed emesis and anticipatory emesis have been identified. Identification of various mediators has led to the development of different drugs acting through different mechanisms which are useful in the prevention and treatment of CINV. Serotonin receptor three (5-HT3) antagonists, corticosteroids and neurokinin type one receptor (NK-1) antagonists are of proven usefulness and have wide therapeutic indexes in the prevention of CINV. Other drugs like dopamine receptor antagonists & benzodiazepines are not routinely used because of their narrow therapeutic index. Practice guidelines for prevention of CINV will not only improve patient’s tolerability to chemotherapy & wellbeing, but also decrease hospital stay and overall cost of treatment of the patient.

Chemotherapy induced nausea & vomiting (CINV).

Chemotherapy is the first line treatment in management of many cancers, both for cure and palliation; hence it’s crucial to minimize the unpleasant side effects of chemotherapy to increase tolerability to chemotherapy. Most of the conventional anti cancer drugs are emetogenic. Patients receiving chemotherapy experience different degrees of nausea and vomiting depending on the emetogenic potential of the anti cancer drugs given and the patient characteristics. With a better understanding of the pathophysiology, distinct phases of chemotherapy-induced nausea and vomiting (CINV) i.e., acute emesis, delayed emesis and anticipatory emesis have been identified. Identification of various mediators has led to the development of different drugs acting through different mechanisms which are useful in the prevention and treatment of CINV. Serotonin receptor three (5-HT3) antagonists, corticosteroids and neurokinin type one receptor (NK-1) antagonists are of proven usefulness and have wide therapeutic indexes in the prevention of CINV. Other drugs like dopamine receptor antagonists & benzodiazepines are not routinely used because of their narrow therapeutic index. Practice guidelines for prevention of CINV will not only improve patient’s tolerability to chemotherapy & wellbeing, but also decrease hospital stay and overall cost of treatment of the patient.

Antidepressant and anxiolytic-like effects of 4n, a novel 5-HT3 receptor antagonist using behaviour based rodent models.

The present study was designed to investigate the putative antidepressant and anxiolytic-like effects of N-n-Butylquinoxalin-2-carboxamide (4n), a novel 5-HT3 receptor antagonist, with an optimal log P (2.01) and pA2 value (7.3) greater than ondansetron (6.9) using rodent behavioural models of depression and anxiety. Acute treatment of 4n (1-4 mg/kg, ip) in mice produced antidepressant-like effect in forced swim test (FST) without affecting the baseline locomotion in actophotometer test in mice. 4n (2-4 mg/kg, ip) treatment also potentiated the 5-hydroxytryptophan (5-HTP) induced head twitch response in mice. Further, 4n (1-4 mg/kg, ip) treatment antagonized reserpine induced hypothermia in rats. Chronic treatment (14 days) with 4n (1-4 mg/kg) and paroxetine (10 mg/kg) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in modified open field paradigm. An anxiogenic-like behaviour was induced by light alone as the stimulus using light-dark aversion test. 4n (2-4 mg/kg, ip) treatment significantly increased no. of transitions between dark and lit area and the time spent in the lit area. In conclusion, these preliminary investigations confirm that 4n exhibited antidepressant and anxiolytic-like effects in rodent models of depression and anxiety.

Inhibition of 5-HT3 Receptors-activated Currents by Cannabinoids in Rat Trigeminal Ganglion Neurons / 华中科技大学学报（医学）（英德文版）

This study investigated the modulatory effect of synthetic cannbinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-Hr3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique.The results showed that:(!) The majority of examined neurons (78.70％) were sensitive to 5-HT (3-300 μmol/L).5-HT induced inward currents in a concentrationdependent manner and the currents were blocked by ICS 205-930 (1 μmol/L),a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01-1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners.The concentration-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value.The EC50values of two curves were very close (17.5±4.5) μmol/L vs.(15.2±4.5) μmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HI3 by (48.65±4.15)％; (3) Neither AM281,a selective CBI receptor antagonist,nor AM630,a selective CB2 receptor antagonist reversed the inhibition of I5-HT3by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application,inhibitory effect was gradually increased and the maximal inhibition took place at 90 s,and the inhibition remained at the same level after 90 s.We are led to concluded thatWIN55,212-2 inhibited I5-Hr3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2.Moreover,WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor.WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner.The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2,but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.

Comparison of ramosetron and ondansetron for control of post-operative nausea and vomiting following laparoscopic cholecystectomy.

Background: Post-operative nausea and vomiting (PONV) is common. 5HT 3 receptor antagonists are commonly used drugs for its prevention. A study was designed to compare the efficacy and safety of ramosetron and ondansetron in patients undergoing laparoscopic cholecystectomy (lap chole). Materials and Methods: A prospective randomized case controlled study was conducted at J. N. Medical College Hospital, Aligarh Muslim University, Aligarh, India, in patients who underwent lap chole following intravenous administration of ondansetron (4mg) or ramosetron (0.3mg) at the end of surgery, and efficacy as well as side effects of ondansetron and ramosetron was documented and compared. Results: One hundred and thirty adult females undergoing lap chole were studied - 65 patients in each of the two groups. In first 24 h after surgery, complete response (No PONV) was observed in 28 patients of the ondansetron group and in 32 patients of the ramosetron group (P>0.05). Complete response in the second 24 h after surgery was observed in 30 patients of the ondansetron group and in 45 patients of the ramosetron group (P<0.05). During the first and second 24 h, PONV requiring rescue antiemetic was significantly higher (P<0.05) in the ondansetron group as compared to the ramosetron group. Adverse drug effects in the post-operative period were observed in 11 and 8 patients in ondansetron and ramosetron groups respectively (P>0.05). Conclusion: Ramosetron was found safe and more effective antiemetic than ondansetron in patients undergoing lap chole.