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- 5-Hydroxytryptamine3 receptor antagonists and cardiac side effects. [JOURNAL ARTICLE]
- Expert Opin Drug Saf 2014 Sep 6.:1-16.
Introduction: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. Areas covered: The purpose of this article is to outline the risk of cardiac adverse events (AEs) from 5-HT3-RAs, with focus on the three most commonly used, ondansetron, granisetron and palonosetron. Expert opinion: Most of the studies analyze electrocardiogram (ECG) changes after 5-HT3-RA administrations in healthy, young adults, or in noncancer patients to treat postoperative nausea and vomiting (PONV). Only a few studies have addressed ECG changes in cancer patients treated for chemotherapy-induced nausea and vomiting (CINV). Investigations in cancer patients are essential, because these patients are older and have a higher incidence of comorbidity, than those usually included in clinical trials. Furthermore, polypharmacy is frequent and drug-drug interactions between chemotherapy and other QTc-prolonging drugs may influence the pharmacokinetics and pharmacodynamics of the 5-HT3-RAs. During the next 10 - 15 years a huge increase in the number of cancer patients is expected, primarily in the group of 65-plus-year old. Therefore it will be crucial to address the incidence of cardiac AEs in cancer patients with known heart disease receiving chemotherapy and a 5-HT3 RA for the prophylaxis of CINV.
- Comparison of an extended-release formulation of granisetron (APF530) versus palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately or highly emetogenic chemotherapy: results of a prospective, randomized, double-blind, noninferiority phase 3 trial. [JOURNAL ARTICLE]
- Support Care Cancer 2014 Sep 2.
Subcutaneous APF530 provides controlled sustained release of granisetron to prevent acute (0-24 h) and delayed (24-120 h) chemotherapy-induced nausea and vomiting (CINV). This randomized, double-blind phase 3 trial compared APF530 and palonosetron in preventing acute and delayed CINV after moderately (MEC) or highly emetogenic chemotherapy (HEC).Patients receiving single-day MEC or HEC received single-dose APF530 250 or 500 mg subcutaneously (SC) (granisetron 5 or 10 mg) or intravenous palonosetron 0.25 mg. Primary objectives were to establish APF530 noninferiority to palonosetron for preventing acute CINV following MEC or HEC and delayed CINV following MEC and to determine APF530 superiority to palonosetron for preventing delayed CINV following HEC. The primary efficacy end point was complete response (CR [using CI difference for APF530 - palonosetron]). A lower confidence bound greater than -15 % indicated noninferiority.In the modified intent-to-treat population (MEC = 634; HEC = 707), both APF530 doses were noninferior to palonosetron in preventing acute CINV after MEC (CRs 74.8 % [-9.8, 9.3] and 76.9 % [-7.5, 11.4], respectively, vs. 75.0 % palonosetron) and after HEC (CRs 77.7 % [-11.5, 5.5] and 81.3 % [-7.7, 8.7], respectively, vs. 80.7 % palonosetron). APF530 500 mg was noninferior to palonosetron in preventing delayed CINV after MEC (CR 58.5 % [-9.5, 12.1] vs. 57.2 % palonosetron) but not superior in preventing delayed CINV after HEC. Adverse events were generally mild and unrelated to treatment, the most common (excluding injection-site reactions) being constipation.A single subcutaneous APF530 injection offers a convenient alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC.
- Palonosetron and aprepitant for the prevention of postoperative nausea and vomiting in patients indicated for laparoscopic gynaecologic surgery: a double-blind randomised trial. [Journal Article]
- BMC Anesthesiol 2014.:68.
Postoperative nausea and vomiting (PONV) is one of the most common postsurgical complications. Palonosetron, a 5-hydroxytryptamine receptor antagonist, is effective for PONV prevention. Herein, we compared palonosetron and aprepitant (a neurokinin-1 receptor antagonist) for PONV prevention in patients indicated for laparoscopic gynaecologic surgery.Ninety-three patients who were scheduled to undergo laparoscopic gynaecologic surgery under general anaesthesia were assigned to receive either a single intravenous injection of 0.075-mg palonosetron or 40-mg oral aprepitant in a double-blind randomised trial. The primary efficacy end points included complete response (visual analogue scale [VAS] nausea score <4 and no use of rescue therapy) 0-48 h after surgery. Nausea severity (0-10) and use of rescue therapy were monitored for 0-48 h. The secondary efficacy end points were the effect of aprepitant quantified using a 10-point VAS for pain, consumption of intravenous patient-controlled analgesia, and use of rescue analgesics.Aprepitant was non-inferior to palonosetron in terms of complete response 0-48 hours after surgery (74% vs. 77%). At 0 and 2 h after administration, the nausea severity with 40-mg aprepitant was significantly lesser than that with 0.075-mg palonosetron (P < 0.05). At 6 and 24 h after administration, fentanyl consumption with 40-mg aprepitant was significantly lower than that with 0.075-mg palonosetron. Greater amounts of rescue analgesics were required in the aprepitant group.Palonosetron and aprepitant were both effective for PONV prevention in the patients indicated for laparoscopic gynaecologic surgery. The drugs can be used in combination for multimodal therapy because they bind to different receptors. More research is needed to evaluate the effects of aprepitant on pain management in humans.
- The Efficacy of Palonosetron Plus Dexamethasone in Preventing Chemoradiotherapy-induced Nausea and Emesis in Patients Receiving Daily Low-dose Cisplatin-based Concurrent Chemoradiotherapy for Uterine Cervical Cancer: A Phase II Study. [JOURNAL ARTICLE]
- Am J Clin Oncol 2014 Aug 20.
The prevention of chemotherapy-induced and radiotherapy-induced emesis is recommended by several guidelines; however, there are no evidence-based recommendations for the use of antiemetics in concurrent chemoradiotherapy (CCRT). The aim of the present study was to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during CCRT.This is a nonrandomized, prospective, single-center, open phase II study.Twenty-six consecutive patients with cervical carcinoma were treated with daily low-dose cisplatin (8 mg/m/d)-based CCRT (2 Gy/d, 25 fractions, 5 times a week). All patients received 0.75 mg of palonosetron on day 1 of each week and 4 mg of oral dexamethasone daily. The primary endpoint was the percentage of patients achieving a complete response, which was defined as no emetic episodes and no antiemetic rescue medication during treatment.Planned daily low-dose cisplatin-based CCRT was successful without delay or interruption in 46% (12/26) of the patients. The mean dose of total cisplatin was 184 (range, 136 to 200) mg/m.No patient vomited during the treatment period. The complete response rate during CCRT was 100%. A total of 81% patients were completely free from nausea. All patients tolerated the combination of palonosetron and dexamethasone and completed the scheduled regimen. Five patients exhibited grade 1 Cushingoid features that resolved after treatment.Antiemetic therapy comprising palonosetron and dexamethasone provided complete protection from nausea and vomiting in patients with cervical cancer receiving daily low-dose cisplatin-based CCRT.
- Palonosetron versus ondansetron as rescue medication for postoperative nausea and vomiting: a randomized, multicenter, open-label study. [JOURNAL ARTICLE]
- BMC Pharmacol Toxicol 2014 Aug 16; 15(1):45.
This study compared palonosetron and ondansetron as rescue medications for postoperative nausea and vomiting (PONV) in patients who received prophylactic ondansetron. Although guidelines recommend use of an agent from a different class when prophylaxis has failed, palonosetron has unique properties relative to other serotonin 5-HT3 receptor antagonists. Prior trials assessing its use for rescue have had conflicting results. Although palonosetron has compared favorably with ondansetron for PONV prevention, the drugs have not been compared in the rescue setting of failure of 5-HT3 receptor antagonist prophylaxis.This was a randomized, open-label, multicenter trial comparing the efficacy and safety of intravenous palonosetron 0.075 mg and intravenous ondansetron 4 mg in patients experiencing PONV following laparoscopic abdominal or gynecological surgery despite prophylactic ondansetron.Of 239 patients screened, 220 were enrolled and 98 were treated for PONV: 48 and 50 in the palonosetron and ondansetron arms, respectively. Complete control during 72 hours after study drug administration was achieved in 25.0% of palonosetron recipients and 18.0% of ondansetron recipients (95% confidence interval [CI], -9.2, 23.3; p = 0.40). Corresponding incidences of vomiting were 29.2% for palonosetron and 48.0% for ondansetron (95% CI, -0.06, 37.7; p = 0.057), and 62.5% and 56.0% required additional rescue treatment, respectively (95% CI, -25.9, 12.9; p = 0.52). Other than a similar incidence of procedural pain in the 2 groups, the most common treatment-emergent adverse events, which were generally mild, were headache (14.6% vs 12.0%), constipation (8.3% vs 10.0%), and dizziness (6.3% vs 8.0%), for the palonosetron and ondansetron groups, respectively.Palonosetron and ondansetron did not show differences in the primary efficacy endpoint of CC during the 72 hours after study drug administration. There was a trend toward less emesis in the 0-72 h time period favoring palonosetron. While larger studies are needed to fully assess any clinical benefits of palonosetron to rescue patients who have failed ondansetron prophylaxis for PONV, the benefit, if any, would be limited based on this study.Trial registration: ClinicalTrials.gov, NCT00967499 (Registered August 27, 2009).
- Serotonin 5-HT3 Receptor-Mediated Vomiting Occurs via the Activation of Ca2+/CaMKII-Dependent ERK1/2 Signaling in the Least Shrew (Cryptotis parva). [JOURNAL ARTICLE]
- PLoS One 2014; 9(8):e104718.
Stimulation of 5-HT3 receptors (5-HT3Rs) by 2-methylserotonin (2-Me-5-HT), a selective 5-HT3 receptor agonist, can induce vomiting. However, downstream signaling pathways for the induced emesis remain unknown. The 5-HT3R channel has high permeability to extracellular calcium (Ca2+) and upon stimulation allows increased Ca2+ influx. We examined the contribution of Ca2+/calmodulin-dependent protein kinase IIα (Ca2+/CaMKIIα), interaction of 5-HT3R with calmodulin, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling to 2-Me-5-HT-induced emesis in the least shrew. Using fluo-4 AM dye, we found that 2-Me-5-HT augments intracellular Ca2+ levels in brainstem slices and that the selective 5-HT3R antagonist palonosetron, can abolish the induced Ca2+ signaling. Pre-treatment of shrews with either: i) amlodipine, an antagonist of L-type Ca2+ channels present on the cell membrane; ii) dantrolene, an inhibitor of ryanodine receptors (RyRs) Ca2+-release channels located on the endoplasmic reticulum (ER); iii) a combination of their less-effective doses; or iv) inhibitors of CaMKII (KN93) and ERK1/2 (PD98059); dose-dependently suppressed emesis caused by 2-Me-5-HT. Administration of 2-Me-5-HT also significantly: i) enhanced the interaction of 5-HT3R with calmodulin in the brainstem as revealed by immunoprecipitation, as well as their colocalization in the area postrema (brainstem) and small intestine by immunohistochemistry; and ii) activated CaMKIIα in brainstem and in isolated enterochromaffin cells of the small intestine as shown by Western blot and immunocytochemistry. These effects were suppressed by palonosetron. 2-Me-5-HT also activated ERK1/2 in brainstem, which was abrogated by palonosetron, KN93, PD98059, amlodipine, dantrolene, or a combination of amlodipine plus dantrolene. However, blockade of ER inositol-1, 4, 5-triphosphate receptors by 2-APB, had no significant effect on the discussed behavioral and biochemical parameters. This study demonstrates that Ca2+ mobilization via extracellular Ca2+ influx through 5-HT3Rs/L-type Ca2+ channels, and intracellular Ca2+ release via RyRs on ER, initiate Ca2+-dependent sequential activation of CaMKIIα and ERK1/2, which contribute to the 5-HT3R-mediated, 2-Me-5-HT-evoked emesis.
- ERRATUM: Correction for affiliation of the 8(th) author-corresponding author. Multicenter nonrandomized trial of ramosetron versus palonosetron in controlling chemotherapy-induced nausea and vomiting for colorectal cancer. [PUBLISHED ERRATUM]
- Ann Surg Treat Res 2014 Aug; 87(2):112.
[This corrects the article on p. 9 in vol. 87, PMID: 25025021.].
- [Incidence and Treatment of Chemotherapy-Induced Nausea and Emesis in Gastrointestinal Cancer.] [JOURNAL ARTICLE]
- Z Gastroenterol 2014 Aug; 52(8):821-830.
The incidence of gastrointestinal (GI) cancer is increasing, with approximately 2 million new cases diagnosed worldwide and about 1.2 million patients dying per year. In Europe, about 500 000 people per year are newly diagnosed with GI cancer. The most frequent cancer types that undergo chemotherapy include cancer of the oesophagus, stomach, pancreas, biliary tract and colorectum. In the last years, various new agents and combinations have been demonstrated to improve the prognosis of patients with GI cancer. However, with the introduction of new and more effective systemic treatments, the need for supportive treatment has become more complex. There has been significant improvement in the management of nausea and vomiting arising from highly and moderately emetogenic chemotherapy. Nevertheless, vomiting and especially nausea continue to be two of the most distressing side effects of antineoplastic treatment. For the prevention of chemotherapy-induced nausea and vomiting in highly emetogenic therapy, a triple therapy including a 5-HT3-receptor antagonist (RA), dexamethasone and an NK1-RA, aprepitant or fosaprepitant are recommended. In moderately emetogenic regimens, updated guidelines recommend the combination of the second-generation 5-HT3-RA palonosetron with dexamethasone, providing improved protection against acute nausea and vomiting, and demonstrating superior prevention in the delayed phase. This review provides an update of the revised clinical guidelines for antiemetic treatment and prophylaxis in GI cancer patients receiving chemotherapy.
- Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial. [Journal Article]
- Springerplus 2014.:389.
Chemotherapy-induced nausea and vomiting is ranked among the worst side effects of chemotherapy. NEPA is an oral fixed-dose combination antiemetic under development, consisting of netupitant 300 mg, a highly selective NK1 receptor antagonist (RA), and palonosetron 0.5 mg, a pharmacologically and clinically distinct 5-HT3 RA. Although palonosetron is not associated with relevant ECG effects, this study evaluated cardiovascular safety of netupitant in combination with palonosetron, as well as its tolerability. This randomised, placebo- and positively controlled study in 197 subjects included 4 treatment groups: placebo, 200 mg netupitant + 0.5 mg palonosetron (NEPA200/0.5), 600 mg netupitant + 1.5 mg palonosetron (NEPA600/1.5, a supratherapeutic dose), and 400 mg moxifloxacin. Assessments included a 24-h baseline ECG recording, followed by a single dose of treatment and ECG measurements for 2 days. Mean placebo-corrected time-averaged changes from baseline were similar in NEPA200/0.5 and NEPA600/1.5 groups primarily for individually heart rate-corrected QT interval (QTcI: +4.7 and +3.6 ms, respectively) and for heart rate (HR: -3.3 bpm and -3.0 bpm), PR interval (-0.4 ms and 0.2 ms), and QRS interval (1 ms and 0.5 ms). The time-matched analysis showed no upper confidence interval >10 ms, with no suggestion of a QTc effect by pharmacokinetic-pharmacodynamic modeling for parent/metabolites. Moxifloxacin showed the expected placebo-corrected change from baseline (+8.4 ms time average) and the expected profile to establish assay sensitivity. No new morphologic changes of clinical relevance were observed. Treatment-related adverse events were comparable among groups. This study showed that NEPA treatments produced no significant effects on QTcI, HR, PR interval, QRS interval, and cardiac morphology relative to placebo, even at supratherapeutic doses.
- Effects of pretreatment with intravenous palonosetron for propofol-remifentanil-based anesthesia in breast and thyroid cancer surgery: a double-blind, randomized, controlled study. [Journal Article]
- Korean J Anesthesiol 2014 Jul; 67(1):13-9.
We postulated that palonosetron, a novel antiemetic agent, might have the effect of alleviating injection pain from propofol and rocuronium. A double-blind, controlled study was undertaken to evaluate the effect of palonosetron on injection pain during total intravenous anesthesia and postoperative nausea and vomiting (PONV) using propofol-remifentanil in breast and thyroid cancer surgery.Sixty patients were randomly allocated to one of two groups. Before injection of propofol and rocuronium, patients in group S (n = 30) received 4 ml of saline and patients in group P (n = 30) received 75 µg (1.5 ml) of palonosetron mixed with 2.5 ml of saline (n = 30). Patients were evaluated by a blinded anesthesiologist with regard to the scoring of injection pain of propofol, withdrawal response by rocuronium, PONV, shivering, postoperative pain, recall of pain, and overall satisfaction.The differences between groups in the incidence of injection pain due to propofol and rocuronium were insignificant. However, in group P, the severity of propofol-induced injection pain (3% vs. 33%, P = 0.003) and postoperative pain (P = 0.038) was significantly lower during the first 12 h after surgery. No differences were observed between the groups with respect to PONV, shivering, recall of pain, and overall satisfaction.We concluded that pretreatment of palonosetron was effective to reduce the severity of propofol-induced injection pain and early postoperative pain, although it did not reduce the incidence of injection pain from propofol and rocuronium.