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- Effect of Palonosetron on Postoperative Nausea and Vomiting in Children Following Dental Rehabilitation under General Anesthesia. [Journal Article]
- Pediatr Dent 2014; 36(1):7-11.
The purpose of this study was to evaluate the safety and efficacy of three different intravenous (IV) doses of palonosetron compared with placebo for the prevention of postoperative nausea and vomiting (PONV) in children undergoing dental rehabilitation under general anesthesia (DRGA) in the first 24 hours after discharge.A total of 286 children who were classified with an American Society of Anes- thesiologists physical status of I and II, between three and 13 years old (mean=6.13 years old), and undergoing DRGA were enrolled in this study. The children were randomized to receive one of the three doses of palonosetron (0.0025 mg, 0.0050 mg, or 0.0075 mg) or placebo immediately before induction of anesthesia.Compared with placebo, the incidence of PONV was significantly lower in the palonosetron groups (P<.05). However, there were no statistically significant differences among the palonosetron groups regarding the number of children with PONV during all time periods after anesthesia (P<.05).A single 0.0025 mg intravenous dose of palonosetron is recommended for further evalua- tion, as it appears to be an effective dose for prevention of postoperative nausea and vomiting in children undergoing dental rehabilitation under general anesthesia.
- Effect of low concentration sodium dodecyl sulfate on the electromigration of palonosetron hydrochloride stereoisomers in micellar electrokinetic chromatography. [Journal Article]
- J Chromatogr A 2014 May 16.:86-91.
The effect of low concentrations of sodium dodecyl sulfate (SDS) on the separation of palonosetron hydrochloride (PALO) stereoisomers by micellar electrokinetic chromatography (MEKC) has been investigated. It was found that the addition of SDS prolongs the migration time and the migration order of four stereoisomers changes regularly with the SDS concentration. Good separations for all the four stereoisomers were achieved at appropriate SDS concentration. The effect of SDS on the electromigration (mobilities) of PALO stereoisomers has been studied, in order to explain its effect on the separation by MEKC. It was found that low concentrations of SDS added into the separation media forms negatively charged complexes with PALO stereoisomers and hence reverses their electromigration direction. Furthermore, the migration order between two enantiomeric pairs is also reversed because the enantiomeric pair with a bigger positive mobility than that of another pair turns to have a bigger negative mobility when bound with SDS. Based on these results, the effect of SDS on the MEKC separation of PALO stereoisomers was elucidated reasonably. The performance of the developed chiral MEKC method was validated by the analysis of a real sample.
- Antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor receiving 5-day cisplatin-based combination chemotherapy. [JOURNAL ARTICLE]
- Support Care Cancer 2014 Mar 21.
This study aimed to determine the antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor (TGCT) receiving 5-day cisplatin-based combination chemotherapy.An open-label, single-arm, multicenter study was performed in patients with TGCT who were scheduled to receive 5-day cisplatin-based combination chemotherapy. The antiemetic therapy consisted of palonosetron 0.75 mg on day 1, aprepitant 125 mg on day 1 and 80 mg on days 2 to 5, and dexamethasone 9.9 mg on day 1 and 6.6 mg on days 2 to 8. The primary endpoint was complete response (CR) rate, which was defined as no vomiting and no rescue medication, in the overall period (0 to 216 h) in the first chemotherapy course. Incidence and severity of nausea were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) and a subjective rating scale completed by patients.Thirty patients were included in the analysis. CR was achieved in 90.0 % of the patients in the first chemotherapy course, and high CR rates were also observed in the second and third courses (82.1 and 78.3 %, respectively). The incidence of nausea peaked on days 4 to 6 in about 50 % of the patients. The reported adverse drug reactions were hiccups (13.3 %), anorexia (3.3 %), and stomach pain (3.3 %). None of these were unexpected and none were grade 3 or 4.The combination antiemetic therapy examined in this study was highly effective and well-tolerated in patients with TGCT receiving 5-day cisplatin-based combination chemotherapy.
- A Phase 3 study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. [JOURNAL ARTICLE]
- Ann Oncol 2014 Mar 14.
Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO) a distinct 5-HT3 RA was shown to be superior to PALO in preventing CINV after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC.This multinational, double-blind, randomized Phase 3 study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg+PALO 0.50 mg) given on Day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen+PALO+DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on Days 1-4 and in MEC on Day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue).Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/ type of adverse events were comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and ECGs. The overall (0-120 hr) CR rates in cycle 1 were 81% and 76% for NEPA and APR+PALO, respectively, and antiemetic efficacy was maintained over repeated cycles.NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.
- Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva). [Journal Article]
- Pharmacol Biochem Behav 2014 May.:124-32.
The dihydropyridine l-type calcium (Ca(2+)) channel blockers nifedipine and amlodipine reduce extracellular Ca(2+) entry into cells. They are widely used for the treatment of hypertensive disorders. We have recently demonstrated that extracellular Ca(2+) entry via l-type Ca(2+) channels is involved in emesis and that nifedipine has broad-spectrum antiemetic activity. The aim of this study was to evaluate the antiemetic efficacy of the longer-acting l-type Ca(2+) channel blocker, amlodipine. Fully effective emetic doses of diverse emetogens such as the l-type Ca(2+) channel agonist (FPL 64176) as well as selective and/or nonselective agonists of serotonergic 5-HT3 (e.g. 5-HT or 2-Me-5-HT)-, dopamine D2 (e.g. apomorphine or quinpirole)-, cholinergic M1 (e.g. pilocarpine or McN-A343)- and tachykininergic NK1 (e.g. GR73632)-receptors, were administered intraperitoneally (i.p.) in the least shrew to induce vomiting. The broad-spectrum antiemetic potential of amlodipine was evaluated against these emetogens. Subcutaneous (s.c.) administration of amlodipine (0.5-10mg/kg) attenuated in a dose-dependent and potent manner both the frequency and percentage of shrews vomiting in response to intraperitoneal (i.p.) administration of FPL 64176 (10mg/kg), 5-HT (5mg/kg), 2-Me-5-HT (5mg/kg), apomorphine (2mg/kg), quinpirole (2mg/kg), pilocarpine (2mg/kg), McN-A343 (2mg/kg), or GR73632 (5mg/kg). A combination of non-effective doses of amlodipine (0.5mg/kg, s.c.) and the 5-HT3 receptor antagonist palonosetron (0.05mg/kg, s.c.) was more effective against FPL 64176-induced vomiting than their corresponding doses tested alone. Amlodipine by itself suppressed the frequency of acute cisplatin (10mg/kg, i.p)-induced vomiting in a dose-dependent manner. Moreover, a combination of a non-effective dose of amlodipine (1mg/kg) potentiated the antiemetic efficacy of a semi-effective dose of palonosetron (0.5mg/kg, s.c.) against acute vomiting caused by cisplatin. We confirm that influx of extracellular Ca(2±) ion underlies vomiting due to diverse causes and demonstrate that l-type Ca(2+) channel blockers are a new class of broad-spectrum antiemetics.
- Analgesic effects of palonosetron in the intravenous propofol injection. [Journal Article]
- Korean J Anesthesiol 2014 Feb; 66(2):99-104.
Propofol is a good induction agent, but it has the disadvantage of causing pain on intravenous injection. The incidence of propofol-induced pain is approximately 70%. Palonosetron is a novel second-generation 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist. We presumed that palonosetron would be effective in reducing the occurrence of propofol-induced pain based on similar mechanisms to other 5-HT3 receptor antagonists.Eighty patients were randomized to either Group N (0.9% sodium chloride [normal saline] 2 ml, n = 40) or Group P (palonosetron 0.075 mg, 2 ml, n = 40). Patients were intravenously given a 2 ml pretreatment solution, containing either palonosetron 0.075 mg or normal saline. Following pretreatment with 2 ml of palonosetron 0.075 mg or normal saline, we manually occluded venous drainage midarm with the help of an assistant. One minute later, we released the occlusion of venous drainage. This was followed by a 5-second propofol injection at 25% of the total calculated doses. Patients were then interviewed about whether or not they experienced propofol-induced pain.Overall, the incidence of propofol-induced pain was 60% in the normal saline group and 27.5% in the palonosetron group. No patients in the palonosetron group experienced severe pain. The incidence of propofol-induced pain was significantly lower in the palonosetron group compared to the normal saline group (P < 0.01).Following pretreatment with palonosetron, 72.5% of patients experienced a decrease in the occurrence of propofol-induced pain.
- Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: A randomized dose-ranging pivotal study. [JOURNAL ARTICLE]
- Ann Oncol 2014 Mar 7.
NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective NK1 receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the Phase 3 NEPA program.This randomized, double-blind, parallel group study in 694 chemotherapynaïve patients undergoing cisplatin-based chemotherapy for solid tumors compared 3 different oral doses of NETU (100, 200, and 300 mg)+PALO 0.50 mg with oral PALO 0.50 mg, all given on Day 1. A standard 3-day aprepitant (APR)+IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on Days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 hr) phase.All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, 89.6% for NEPA100, NEPA200, and NEPA300, respectively vs 76.5% PALO; P<0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR+OND for all secondary efficacy endpoints of no emesis, no significant nausea and complete protection (CR plus no significant nausea) rates during the acute (0-24 hr), delayed (25-120 hr) and overall phases.Adverse events were comparable across groups with no dose-response. The percent of patients developing ECG changes was also comparable.Each NEPA dose provided superior prevention of CINV compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR+OND.
- Palonosetron versus first-generation 5-hydroxytryptamine type 3 receptor antagonists for emesis prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation. [JOURNAL ARTICLE]
- Ann Hematol 2014 Mar 7.
First-generation 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists (RAs) are currently the standard of care for prophylaxis against allo-HSCT-induced emesis. However, the efficacy of this combination in allo-HSCT recipients is not entirely satisfying. We sought to compare the efficacy of first-generation 5-HT3 RAs with that of second-generation 5-HT3 RAs in emesis prevention in allo-HSCT recipients. A total of 51 consecutive patients undergoing allo-HSCT for various hematological diseases in our institution were retrospectively reviewed. Patients who received daily first-generation 5-HT3 RAs, and 60-h palonosetron for emesis prophylaxis were stratified into the standard (n = 23) and palonosetron (n = 28) groups, respectively. Emesis severity and rescue therapy requirements in patients between these two groups were compared. Our results showed patients in standard and palonosetron groups had comparable severity of both acute and delayed emesis. However, 52.2 % of the patients in the standard group required rescue therapy, compared to only 21.4 % of the patients in the palonosetron group (p = 0.046). Subgroup analysis showed rescue therapy for acute emesis was required by 26.1 % of the patients in the standard group and by only 3.6 % of the patients in the palonosetron group (p = 0.037). In conclusion, palonosetron and first-generation 5-HT3 RAs were at least equally effective in emesis prophylaxis for allo-HSCT recipients. Patients receiving palonosetron, especially for acute emesis, required rescue therapy less frequently than those receiving first-generation 5-HT3 RAs.
- A randomized Phase 3 study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. [JOURNAL ARTICLE]
- Ann Oncol 2014 Mar 5.
Antiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). NEPA is a new oral fixed-dose combination of 300 mg netupitant, a highly-selective NK1 receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA, that targets dual antiemetic pathways.This multinational, randomized, double-blind, parallel group Phase 3 study (NCT01339260) in 1455 chemotherapy-naïve patients receiving moderately emetogenic (anthracycline-cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of NEPA versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on Day 1 only (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the delayed (25-120 hr) phase in cycle 1.The percentage of patients with CR during the delayed phase was significantly higher in the NEPA group compared with the PALO group (76.9% vs. 69.5%; P=0.001), as were the percentages in the overall (0-120 hr) (74.3% vs. 66.6%; P=0.001) and acute (0-24 hr) (88.4% vs. 85.0; P=0.047) phases. NEPA was also superior to PALO during the delayed and overall phases for all secondary efficacy endpoints of no emesis, no significant nausea and complete protection (CR plus no significant nausea). NEPA was well tolerated with a similar safety profile as PALO.NEPA plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, NEPA along with a single dose of dexamethasone on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.
- Safety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapy. [JOURNAL ARTICLE]
- Support Care Cancer 2014 Mar 4.
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.