Administration Of Palonosetron Research Articles

Effect of intravenous palonosetron on hypotension induced by spinal anesthesia for cesarean section: A randomized controlled trial.

The aim of this study was to evaluate the impact of intravenous palonosetron compared to ondansetron on hypotension induced by spinal anesthesia in women undergoing cesarean section. Fifty-four women scheduled for elective cesarean section were, randomly allocated to ondansetron group (n = 27) or palonosetron group (n = 27). Ten minutes prior to the administration of spinal anesthesia, participants received an intravenous injection of either ondansetron or palonosetron. A prophylactic phenylephrine infusion was initiated immediately following the intrathecal administration of bupivacaine and fentanyl. The infusion rate was titrated to maintain adequate blood pressure until the time of fetal delivery. The primary outcome was total dose of phenylephrine administered. The secondary outcomes were nausea or vomiting, the need for rescue antiemetics, hypotension, bradycardia, and shivering. Complete response rate, defined as the absence of postoperative nausea and vomiting and no need for additional antiemetics, were assessed for up to 24 hours post-surgery. No significant differences were observed in the total dose of phenylephrine used between the ondansetron and palonosetron groups (387.5 μg [interquartile range, 291.3-507.8 μg versus 428.0 μg [interquartile range, 305.0-507.0 μg], P = 0.42). Complete response rates also showed no significant differences between the groups both within two hours post-spinal anesthesia (88.9% in the ondansetron group versus 100% in the palonosetron group; P = 0.24) and at 24 hours post-surgery (81.5% in the ondansetron group versus 88.8% in the palonosetron group; P = 0.7). In addition, there was no difference in other secondary outcomes. Prophylactic administration of palonosetron did not demonstrate a superior effect over ondansetron in mitigating hemodynamic changes or reducing phenylephrine requirements in patients undergoing spinal anesthesia with bupivacaine and fentanyl for cesarean section.

Antiemetic Efficacy and Safety of Palonosetron on Days 1 and 5 with Aprepitant and Dexamethasone during Bleomycin, Etoposide, and Cisplatin Chemotherapy in Patients with Germ Cell Tumor: A Prospective Study

Objective. BEP (bleomycin, etoposide, and cisplatin) chemotherapy is a standard regimen for germ cell tumors (GCTs); however, their high emetogenicity is problematic. The control of chemotherapy‐induced nausea and vomiting (CINV) is crucial to complete the treatment. We conducted this study to explore the efficacy and safety of antiemetic therapy with dexamethasone and aprepitant for 5 days in combination with palonosetron 0.75 mg on days 1 and 5 in BEP. Methods. This open‐label single‐arm study was prospectively conducted in 4 hospitals. Chemotherapy‐naïve men with GCT who were scheduled to receive the BEP regimen were eligible. The primary endpoint was the complete response (CR) rate of CINV. Results. A total of 19 patients were enrolled. Overall, 16 (84.2%) patients experienced some nausea, whereas only 4 (21.1%) patients had grade 1 emetic events. Overall CR of CINV was achieved in 9 (47.4%) patients. Although 14 (73.7%) patients experienced 22 adverse events after palonosetron administration, severe adverse events (grade 3 or more) attributable to it did not occur. Conclusion. The results suggest that aprepitant, palonosetron, and dexamethasone antiemetic therapy for patients with GCT receiving BEP is safe, whereas the efficacy of additional palonosetron administration on day 5 for prevention of delayed CINV remains unclear. This trial is registered with UMIN000008110.

Ocular Administration of Palonosetron in the Prevention of Cisplatin-Induced Nausea and Vomiting.

Cancer treatments are frequently associated with nausea and vomiting despite greatly improved preventive medication. Administration of antinausea agents as eye drops might provide easy and rapid access to the systemic circulation for prevention of nausea and vomiting and for the treatment of breakthrough nausea, but the ocular administration route has rarely been evaluated. Palonosetron is a second-generation 5-hydroxytryptamine 3 receptor antagonist approved for prevention and treatment of chemotherapy-induced nausea and vomiting. We compared ocular administration of palonosetron to non-active vehicle eye drops and to intravenous palonosetron in the prevention of cisplatin-induced nausea and vomiting in beagle dogs. Palonosetron ocular drops at the dose of 30 µg/kg reduced cumulative nausea over time as measured with the area under the visual analog scale curve by 98% compared with the vehicle and reduced nausea-associated dog behavior by 95%. Vomiting was completely prevented with repeated palonosetron ocular dosing. Hydroxypropyl-β-cyclodextrin (HP-β-CD) palonosetron formulation was well tolerated locally at the palonosetron concentration of 3 mg/ml. Absorption of palonosetron from eye drops was fast. Ten minutes after ocular administration, palonosetron plasma concentrations were similar compared with intravenous administration, and remained similar for six hours. We conclude that palonosetron is rapidly absorbed into the systemic circulation from eye drops. Ocularly administered palonosetron was well tolerated in the HP-β-CD formulation and was highly effective in the prevention of cisplatin-induced nausea and vomiting. Evaluation of the safety and efficacy of ocular administration of palonosetron is warranted in the prevention and treatment of chemotherapy-induced nausea and vomiting in clinical trials. SIGNIFICANCE STATEMENT: Palonosetron, an effective and well-tolerated antiemetic drug was rapidly absorbed into the systemic blood circulation when administered as eye drops. The achieved palonosetron blood concentrations prevented cisplatin-induced nausea and vomiting in beagle dogs. Palonosetron eye drops might provide an easy and quick method for administering palonosetron when parenteral administration is desired and intravenous administration is not feasible.

Comparison of the Effectiveness of Palonosetron and Ramosetron in Preventing Postoperative Nausea and Vomiting: Updated Systematic Review and Meta-Analysis with Trial Sequential Analysis.

This updated systematic review and meta-analysis with trial sequential analysis aimed to compare the efficacy of the perioperative administration of palonosetron with that of ramosetron in preventing postoperative nausea and vomiting (PONV). A total of 17 randomized controlled trials comparing the efficacy of the perioperative administration of palonosetron to that of ramosetron for preventing PONV were included. The primary outcomes were the incidences of postoperative nausea (PON), postoperative vomiting (POV), and PONV, which were measured in early, late, and overall phases. Subgroup analysis was performed on the basis of the administration time of the 5-HT3 receptor antagonist and divided into two phases: early phase and the end of surgery. A total of 17 studies with 1823 patients were included in the final analysis. The incidence of retching (relative risk [RR] = 0.525; 95% confidence interval [CI] = 0.390 to 0.707) and late POV (RR = 0.604; 95% CI = 0.404 to 0.903) was significantly lower in the palonosetron group than in the ramosetron group. No significant differences were demonstrated in the incidence of PON, PONV, complete response, use of antiemetics, and adverse effects. Subgroup analysis showed that palonosetron was superior to ramosetron in terms of early PON, late PON, overall POV, and use of rescue antiemetics when they were administered early; in terms of retching, regardless of the timing of administration. Ramosetron was superior to palonosetron in terms of early PON when they were administered late. The prophylactic administration of palonosetron was more effective than that of ramosetron in preventing the development of retching and late POV. In this meta-analysis, no significant differences in PONV prevention between the two drugs were demonstrated. Further studies are required to validate the outcomes of our study.

SAFETY AND EFFICACY ANTIEMETIC EFFECT OF INTRAVENOUS PALONOSETRON AND ONDANSETRON FOR THE PREVENTION OF INTRA-OPERATIVE NAUSEA AND VOMITING FOLLOWING SPINAL ANAESTHESIA DURING CESEAREAN SECTION.

BACKGROUND AND OBJECTIVE Intra-operative nausea and vomiting is one of the most common complications in patients undergoing spinal anaesthesia for cesearean section . This study is done to know the efficacy and safety of administration of palonosetron and ondansetron in the prevention of intra operative nausea and vomiting in patients undergoing spinal anaesthesia for cesearean section. MATERIAL AND METHODS After obtaining the approval of institutional ethical committee a prospective observational study was conducted for one years on 60 patients belonging to American Society of anaesthesiologists grade I and II ( ASA I and II ) patients aged between 19 to 30 years scheduled for cesearean section under spinal anaesthesia, the patients who fulfil the inclusion and exclusion criteria and willing to participate in the study were included in the study.60 patients fulfilling the inclusion and exclusion criteria were divided into two groups Group A (patients receiving inj. palonosetron 75 micrograms I.V.) and Group B (patients receiving inj. ondansetron 4 milligrams I.V.) before the induction of anaesthesia. Standard anaesthetic management was done in all cases. Incidence of intra operative nausea and vomiting was recorded in all patients for the efficacy of palonosetron to ondansetron in the prevention of intra operative nausea and vomiting was evaluated. Data was evaluated statistically using MS Exel 2007 and MS Word 2007,mean,SD,and percentages generated. RESULT AND CONCLUSION Both group A and group B had comparable demographic profile [(age, weight ASA grade, duration of surgery). At the conclusion of the study it was found that the prophylactic usage of inj. Palonosetron 75 mcg I.V. is more effective than inj. ondansetron in the prevention of intra operative nausea and vomiting in patients undergoing spinal anaesthesia for cesearean section.

Efficacy of Palonosetron and Dexamethasone for Prevention of Post-operative Nausea and Vomiting in Female Patients Undergoing Laparoscopic Cholecystectomy: A Prospective Randomised Double-Blind Trial.

Post-operative nausea and vomiting is a frequent complication following anaesthesia. We compared the efficacy and safety of intravenous palonosetron and intravenous dexamethasone as prophylactic antiemetic in patients undergoing laparoscopic cholecystectomy. After obtaining institutional ethical committee approval, 100 adult female patients undergoing laparoscopic cholecystectomy were randomised to receive 4mg dexamethasone (group I, n ¼ 50) or 0.075 mg palonosetron (group II, n ¼ 50) intravenously (IV) over 2-5 minutes prior to induction of anaesthesia. Standard anaesthetic technique was followed, and the residual neuromuscular block was antagonised at theend of the procedure. A single anaesthesiologist assessed all the cases for post-operative nausea and vomiting (PONV) for 24 hours. The complete response rate and the overall patient satisfaction were noted. If patient experienced PONV, injection metoclopramide 10 mg was given as rescue antiemetic IV. A total of six patients had vomiting within 6 hours (four patients in groups I and two patients in group II), whereas none had vomiting after 6 hours (P ¼ .39). Complete response rate was 88 and 90% in both group I and group II. Three patients in both group I and group II required rescue antiemetics. Ninety-two percent patients were completely satisfied in group I, while 96% patients were fully satisfied in group II. Intravenous administration of palonosetron (0.075 mg) is as effective as dexamethasone (4 mg) as prophylactic antiemetic without any untoward side effects for female patients undergoing laparoscopic cholecystectomy.

Efficacy of ondansetron and palonosetron in prevention of shivering under spinal anesthesia: A prospective randomized double-blind study in patients undergoing elective LSCS.

Background and Aims:Postanesthesia shivering (PAS) is a common, distressing experience. Ondansetron, the classical 5HT3 antagonist has been in use for its prevention since long. Palonosetron, a newly introduced potent antiemetic drug with better pharmacodynamics is currently in use by clinicians. Hence, a study was conducted to compare the efficacy of ondansetron and palonosetron in preventing PAS in patients undergoing elective lower segment caesarean section (LSCS) under spinal anaesthesia.Material and Methods:A total of 84 patients scheduled for elective LSCS under spinal anesthesia were randomly allocated to one of the two study groups (Group O & P). Accordingly, 8 mg of ondansetron or 0.075 mg palonosetron was administered in the same volume intravenously 30 min preoperatively. Sublingual temperature was recorded regularly. All patients were observed for 90 min postspinal for PAS. Observations were analyzed statiscally.Results:No statistically significant intergroup difference was observed in the duration of surgery, and sublingual temperature. However, statistically significant difference was recorded for PAS (23.8% in ondansetron group, 9.5% in palonosetron group).Conclusion:Prophylactic administration of palonosetron significantly reduced incidence of PAS compared to ondansetron. However, further studies with larger sample size and more heterogeneous groups are suggested.

Palonosetron versus ondansetron for prophylaxis of postoperative nausea and vomiting following craniotomy: A prospective randomized controlled trial

BackgroundPostoperative nausea and vomiting (PONV) is a common adverse event that may occur in as many as 80% of high-risk patients after general anesthesia. Intracranial neurosurgery, especially infratentorial type, is considered as an additional PONV risk factor. We performed our study to compare antiemetic efficacy of ondansetron versus palonosetron for prevention of PONV in patients undergoing elective neurosurgery for intracranial tumors remove. Methods80 patients 18 to 80 years of age with ASA physical status I or II underwent elective neurosurgery for intracranial tumor removal under general anesthesia were randomized into two groups in 1:1 ratio to receive ondansetron (8 mg) or palonosetron (0.075 mg). Each group included two equal subgroups based on the type of procedure: supratentorial and infratentorial. In both subgroups we provided IV anesthesia based on propofol. Both antiemetic drugs were given intravenously before closing the dura mater. In most patients dexamethasone 8 mg for PONV prevention was also used. Incidence of PONV in 48 hours period after surgery as primary outcome was evaluated. PONV scale was used for assessment at 30 min, 1, 2, 6, 12, 24, and 48 hours after extubation postoperatively. Patient-related risk factors for PONV, intervention characteristics, visual analog scale (VAS) pain scores at 30 min, 1, 2, 6, 12, 24, and 48 hours after extubation postoperatively, rate of rescue antiemetic drug use were also recorded. ResultsThe final analysis included 78 patients (38 in palonosetron group and 40 in ondansetron group). Palonosetron significantly decreased incidence of PONV in infratentorial subgroup of patients compared to ondansetron (70% vs. 28%, respectively; RR=0.40; 95% СI: 0.18-0.89). However, the difference was not statistically significant in the general cohort of study patients (26.3% vs. 45%, respectively; RR=0.58; 95% СI: 0.31-1.10). The administration of palonosetron was not associated with decreased use of rescue antiemetics in either the palonosetron or the ondansetron group (15.8% vs. 22.5%, respectively; p=0.57) nor in the infratentorial subgroup that received palonosetron compared to which received ondansetron (16.6% vs. 40%, respectively; p=0.159). ConclusionIntraoperative palonosetron was more effective than ondansetron for prevention of PONV in patients following infratentorial craniotomy. Risk reduction of PONV after craniotomy in general was insignificant.

Abstract 593: Ocular drops of palonosetron reduce chemotherapy-induced acute nausea and vomiting in the dog

Abstract Background: Nausea and vomiting are common side effects of cancer therapies thereby seriously affecting the quality of life of patients. Therefore, the prevention or treatment of chemotherapy-induced nausea and vomiting has become an important part of the comprehensive treatment of cancer. Several 5-HT3 receptor antagonists have been developed in the treatment of nausea and vomiting using mainly the oral route of administration (which is not convenient due to vomiting) or the intravenous route. In this study we tested whether ocular administration of the 5-HT3 receptor antagonist palonosetron (eye drops) could prevent nausea and vomiting associated with intravenous cisplatin injection in dogs. Methods: Six adult male Beagle dogs (10-13 kg) were included in a randomized crossover study. This study was carried out in AAALAC facilities in strict accordance with the European and French animal welfare regulations for animal use in experimentation. Dogs were administered 18 mg/m2 cisplatin intravenously over a 20-min period, followed 45 min later by ocular administration (eye drops, 200µL/eye) of either placebo (2% povidone in saline) or palonosetron (30 or 120 µg/kg). The number of vomits and nausea associated behaviours, scored on a visual analogue scale (VAS), were recorded every 15 min for 7 h following cisplatin administration. Blood samples were collected to measure plasma levels of palonosetron. Results: The placebo treated group vomited an average number of 10.2±2.1 times (range 5-17) over the 7-h period following cisplatin infusion. Ocular administration of palonosetron at 30 μg/kg in cisplatin-treated dogs very strongly and significantly decreased vomiting episodes, with only 1 vomiting episode in 2 dogs overall (p<0.0001). After ocular administration of palonosetron at 120 μg/kg, no vomiting episodes were observed in any dog throughout the observation period (p<0.0001). With regards to the VAS, in the placebo-treated group the nausea-associated behaviour started between 2.5 and 2.75 h after the end of the cisplatin infusion and peaked between 3.75 and 4.25 h after the end of the cisplatin infusion. The area under the curve (AUC) of VAS was 7344 ± 1050 mm*min in the placebo-treated group. Ocular administration of palonosetron at 30 or 120 µg/kg in cisplatin-treated dogs decreased the VAS score strongly. The VAS AUCs were 320 ± 268 (p<0.0001) and 0 ± 0 mm*m (p<0.0001) in 30 µg/kg and 120 µg/kg palonosetron groups, respectively. Plasma palonosetron concentration reached 10.3 ± 3.9 ng/mL, 5 min after ocular administration of palonosetron at 30 µg/kg and 2.8 ± 0.5 ng/mL and 0.9 ± 0.2 ng/mL at 2 h and 6 h post dosing, respectively. Conclusions: This study demonstrates for the first time that palonosetron administered via ocular route produces a rapid clear-cut anti-emetic and anti-nausea effect in conscious dogs exposed to cisplatin. This finding points out the tremendous interest of this novel and convenient route of administration which could help improving the quality of life of patients. Citation Format: Sandra Nourry, Minja Hyttila-Hopponen, Pierre Montagne, Lasse Saloranta, Sari Pappinen, Jouko Levijoki, Christophe Drieu La Rochelle. Ocular drops of palonosetron reduce chemotherapy-induced acute nausea and vomiting in the dog [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 593.

A Retrospective Comparative Study of 3-day Granisetron and 1-day Palonosetron Administration for Nausea and Vomiting during Transcatheter Arterial Chemoembolization with Cisplatin

A Retrospective Comparative Study of 3-day Granisetron and 1-day Palonosetron Administration for Nausea and Vomiting during Transcatheter Arterial Chemoembolization with Cisplatin

Palonosetron on Days 1 and 5 Versus Granisetron Daily (Days 1-5) in Germ Cell Tumour Therapy.

The control of chemotherapy-induced nausea and vomiting during bleomycin, etoposide, and cisplatin (BEP) treatment is important for maintaining treatment intensity. The effects of palonosetron and granisetron were compared in BEP chemotherapy. The administration of palonosetron on days 1 and 5 (Pal method) and granisetron daily (days 1-5, Gra method) were compared in terms of their efficacy and cost-effectiveness. Additional rescue antiemetic agents were used in 15 of 32 and 30 of 30 cycles in the Pal and Gra method groups, respectively (p<0.05). The complete response rate, defined as no vomiting and no rescue agent usage, in each cycle, was 50% and 0% in the Pal and Gra method groups, respectively (p<0.05). The average cost of antiemetic agents in a cycle was 50,759 and 54,555 yen in the Pal and Gra method groups, respectively (p<0.05). The Pal method may be the standard method in BEP.

Single-dose palonosetron and dexamethasone in preventing nausea and vomiting induced by moderately emetogenic chemotherapy in breast and colorectal cancer patients.

Palonosetron, a unique second-generation 5-HT3 receptor antagonist, has been demonstrated to control emesis related to chemotherapy-induced nausea and vomiting (CINV). The aim of this study was to evaluate the efficacy and tolerability of palonosetron followed by a single dose of dexamethasone in patients with breast cancer (BC) or colorectal cancer (CRC) receiving moderate emetogenic chemotherapy (MEC). Chemotherapy-naive BC and CRC patients were given MEC as adjuvant or first-line treatment. Palonosetron (0.25 mg IV) and dexamethasone (8 mg IV) were administered before chemotherapy on day 1. The primary endpoint was complete response (CR; no vomiting and no use of rescue medication) during the overall study period (days 1-5). The antiemetic response was evaluated during the acute (day 1) and delayed (days 2-5) phases. Sixty-eight patients were enrolled (median age 61 years, 56 females; BC = 40, CRC = 28). CR was observed in 46 of 68 patients (67.6%), while CR during the acute and delayed phases was 75.0% in each cancer group. The antiemetic regimen was well tolerated. A single administration of palonosetron and dexamethasone on day 1 in BC and CRC patients adequately controls CINV during the entire period of emetic risk.

Implications of palonosetron in elderly patients undergoing laparoscopic cholecystectomy with respect to its anti-shivering effect.

The elderly are vulnerable to hypothermia and have a higher risk of cardiovascular events induced by marked increases in oxygen consumption due to shivering. Five-hydroxytryptamine-3 (5-HT3) receptor antagonists have been previously reported to reduce post-anesthesia shivering. In the present study, the authors investigated the effects of palonosetron, a new-generation 5-HT3 antagonist, on core hypothermia and the incidence of shivering after laparoscopic cholecystectomy in elderly patients. Forty-eight patients (65-80 years) were randomly assigned to one of two groups and administered palonosetron 0.075mg (palonosetron group, n=24) or the same volume of normal saline (control group, n=24) before anesthesia induction. Core body temperatures and hemodynamic variables were monitored during and after operation. Post-anesthetic shivering (PAS) and pain scores were obtained in a post-anesthetic care unit. Intraoperative esophageal temperature changed significantly over time (P=0.010), but significant intergroup difference in change was not observed (P=0.706). Furthermore, shivering frequencies were similar in the two groups (P=0.610). However, postoperative pain scores at 30min after entering the post-anesthesia care unit were significantly lower in the palonosetron group (P=0.002). Regardless of the previously reported anti-shivering effect of 5-HT3 receptor antagonists, pre-operative palonosetron 0.075mg did not influence perioperative hypothermia or PAS in this study. This discrepancy might be due to the dose responsiveness of palonosetron to PAS and relatively low incidence of PAS in the elderly. Pre-operative administration of palonosetron 0.075mg did not influence perioperative hypothermia or post-anesthesia shivering in elderly patients undergoing laparoscopic cholecystectomy. However, palonosetron might be beneficial for reducing early postoperative pain in elderly patients with opioid-based patient-controlled analgesia.

Effect of Palonosetron on the QTc Interval in Patients Undergoing Sevoflurane Anaesthesia

Abstract Background Palonosetron is a recently introduced 5-HT3 receptor antagonist for postoperative nausea and vomiting. Detailed standardized evaluation of corrected QT (QTc) interval change by palonosetron under sevoflurane anaesthesia is lacking. We evaluated QTc intervals in patients who are undergoing surgery with sevoflurane anaesthesia and receive palonosetron. Methods Our study included 100 patients who were undergoing elective surgery under sevoflurane anaesthesia. The patients were randomly assigned to two groups: those who received an i.v. injection of palonosetron 0.075 mg immediately before induction of anaesthesia (pre-surgery group, n=50) and those who received it after surgery in the recovery room (post-surgery group, n=50). QTc intervals were measured before operation, intraoperatively (baseline, immediately after tracheal intubation, and at 2, 10, 15, 30, 60, and 90 min after administration of palonosetron or placebo), and after operation (before and at 3, and 10 min after administration of palonosetron or placebo). QTc intervals were calculated using Fridericia's, Bazett's, or Hodges formulas. Results The perioperative QTc intervals were significantly increased from the baseline values, but were not affected by the pre- or post-surgical timing of palonosetron administration. Conclusions There was no significant difference in the QTc intervals during the perioperative period, whether 0.075 mg of palonosetron is administered before or after sevoflurane anaesthesia. Palonosetron may be safe in terms of QTc intervals during sevoflurane anaesthesia. Clinical trial registration ClinicalTrials.gov: NCT01650961.

Synergistic effect of 5-hydroxytryptamine 3 and neurokinin 1 receptor antagonism in rodent models of somatic and visceral pain.

Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT3) and tachykinergic neurokinin 1 (NK1) receptor-mediated responses. This study investigated the efficacy of a 5-HT3 antagonist, palonosetron, and a NK1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P < 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome.

Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy

The aims of this study were to evaluate the safety, efficacy, and pharmacokinetics of repeated doses of palonosetron 0.75 mg on days 1 and 3 in Japanese patients who received highly or moderately emetogenic chemotherapy. Twenty- six patients received palonosetron 0.75 mg intravenously before chemotherapy on days 1 and 3 plus dexamethasone (12-16 mg before chemotherapy on day 1 and 4-8 mg on days 2 and 3). The primary endpoints were safety and pharmacokinetics. Pharmacokinetics were evaluated in a subset of patients (n=6). Complete response and complete protection were evaluated as secondary endpoints. The accumulation ratios for C max and AUClast after the second dose on day 3 were 1.42 and 1.37, respectively. These values were consistent with the theoretical values expected from the half-life of palonosetron on day 1. Almost all of the patients had no nausea or vomiting in the acute phase (complete response (CR) rate, 96.2% [25/26]; CP rate, 92.3% [24/26]). In the delayed phase (24-192 h post-chemotherapy), the complete response and complete protection rates were 76.9% (20/26) and 61.5% (16/26), respectively. Treatment was well tolerated. This is the first study to report the pharmacokinetics of multiple doses of palonosetron 0.75 mg, given on days 1 and 3, in Japanese patients. Repeated treatment with palonosetron was safe and well tolerated by patients who received highly or moderately emetogenic anticancer chemotherapy.

Effect of palonosetron on the QTc interval in patients undergoing sevoflurane anaesthesia

BackgroundPalonosetron is a recently introduced 5-HT3 receptor antagonist for postoperative nausea and vomiting. Detailed standardized evaluation of corrected QT (QTc) interval change by palonosetron under sevoflurane anaesthesia is lacking. We evaluated QTc intervals in patients who are undergoing surgery with sevoflurane anaesthesia and receive palonosetron. MethodsOur study included 100 patients who were undergoing elective surgery under sevoflurane anaesthesia. The patients were randomly assigned to two groups: those who received an i.v. injection of palonosetron 0.075 mg immediately before induction of anaesthesia (pre-surgery group, n=50) and those who received it after surgery in the recovery room (post-surgery group, n=50). QTc intervals were measured before operation, intraoperatively (baseline, immediately after tracheal intubation, and at 2, 10, 15, 30, 60, and 90 min after administration of palonosetron or placebo), and after operation (before and at 3, and 10 min after administration of palonosetron or placebo). QTc intervals were calculated using Fridericia's, Bazett's, or Hodges formulas. ResultsThe perioperative QTc intervals were significantly increased from the baseline values, but were not affected by the pre- or post-surgical timing of palonosetron administration. ConclusionsThere was no significant difference in the QTc intervals during the perioperative period, whether 0.075 mg of palonosetron is administered before or after sevoflurane anaesthesia. Palonosetron may be safe in terms of QTc intervals during sevoflurane anaesthesia. Clinical trial registrationClinicalTrials.gov: NCT01650961.

Randomized Pharmacokinetic Study Comparing Subcutaneous and Intravenous Palonosetron in Cancer Patients Treated with Platinum Based Chemotherapy

BackgroundPalonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron.Patients and MethodsPatients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0–24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA).ResultsFrom October 2009 to July 2010, 25 evaluable patients were included. AUC0–24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p = 0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69–168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration.ConclusionsPalonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy. Trial Registration ClinicalTrials.gov NCT01046240

Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin

5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5-HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin.

Effects of palonosetron on prolongation of corrected QT intervals may be less than reliable.

Min et al. [1] investigated the effects of palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist, on corrected QT (QTc) intervals on electrocardiograms of patients undergoing laparotomies under sevoflurane anesthesia. Considering that prolongation of the QTc interval is associated with torsades de pointes, and palonosetron may at least theoretically increase QTc intervals by similar pharmacological mechanisms as ondansetron [2], clinicians will agree that an investigation into the effects of palonosetron on QTc intervals is required. Careful consideration is, however, needed, although Min et al. [1] concluded that palonosetron may induce QTc prolongation during general anesthesia with sevoflurane. In the present study [1], there was a significantly different factor, famotidine, which also can influence the QTc interval. Consequently, it is difficult to exclude its effect on the QTc intervals, in contrast to the authors' description. Additionally, underlying diseases, electrolyte abnormalities, other drugs, adrenergic tone, temperature, and circadian variation, have other effects that may also result in prolongation of QTc intervals [3]. All of these influences may result in QTc prolongation, diminishing the effects of palonosetron alone. Furthermore, a less well-defined target population, risk of selection bias, and confounding factors in retrospective studies may affect the results [4]. Finally, Min et al. [1] concluded that palonosetron could induce QTc prolongation during general anesthesia with sevoflurane, whereas the prospective, randomized, and double-blinded study by Kim et al. [5] showed that preanesthetic administration of palonosetron (0.075 mg) did not affect the QTc interval during the intraoperative period. Thus, to better understand the effects of palonosetron on QTc intervals, it is essential to consider all of the factors related to QTc intervals, the weaknesses of retrospective studies, and related research results. Further well-designed studies on this issue from various perspectives will also be helpful.