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- Olanzapine for preventing nausea and vomiting induced by moderately and highly emetogenic chemotherapy. [Journal Article]
- Asian Pac J Cancer Prev 2014; 15(22):9587-92.
Nausea and vomiting are common adverse events in chemotherapy. In spite of the serious effects on the quality of life and further treatment, they remain overlooked by physicians, and no standard treatment has been developed. Neurokinin-1 (NK-1) receptor antagonists and palonosetron are the major agents in the standard regimen for treating moderately and highly emetogenic chemotherapy-induced nausea and vomiting (CINV). However, NK-1 receptor antagonists first became commercially available at the end of 2013 and palonosetron has not been extensively applied in China. Olanzapine was recommended as a therapy for moderate and severe CINV in antiemesis-clinical practice guidelines in oncology in 2014 for the first time. It is an atypical antipsychotic agent, which can block multiple receptors on neurotransmitters. During more than 10 years, olanzapine has demonstrated significant effects in preventing CINV and treating breakthrough and refractor CINV, which was observed in case reports, precise retrospective studies, and phase I, II and III clinical trials, with no grade 3 to 4 adverse events. In particular, it is superior to aprepitant and dexamethasone in delayed nausea and vomiting. Therefore, this compound is worthy of further investigation.
- Pharmaceutical approval update. [Journal Article]
- P T 2014 Dec; 39(12):823-45.
Ledipasvir/sofosbuvir (Harvoni) for hepatitis C virus genotype 1 infection; dulaglutide (Trulicity) for glycemic control in type-2 diabetes; netupitant/palonosetron (Akynzeo) for prevention of nausea and vomiting related to chemotherapy; and naloxegol (Movantik) for opioid-induced constipation in patients with chronic noncancer pain.
- Characterizing new fluorescent tools for studying 5-HT3 receptor pharmacology. [JOURNAL ARTICLE]
- Neuropharmacology 2014 Nov 22.:63-73.
The pharmacological characterization of ligands depends upon the ability to accurately measure their binding properties. Fluorescence provides an alternative to more traditional approaches such as radioligand binding. Here we describe the binding and spectroscopic properties of eight fluorescent 5-HT3 receptor ligands. These were tested on purified receptors, expressed receptors on live cells, or in vivo. All compounds had nanomolar affinities with fluorescent properties extending from blue to near infra-red emission. A fluorescein-derivative had the highest affinity as measured by fluorescence polarization (FP; 1.14 nM), flow cytometry (FC; 3.23 nM) and radioligand binding (RB; 1.90 nM). Competition binding with unlabeled 5-HT3 receptor agonists (5-HT, mCPBG, quipazine) and antagonists (granisetron, palonosetron, tropisetron) yielded similar affinities in all three assays. When cysteine substitutions were introduced into the 5-HT3 receptor binding site the same changes in binding affinity were seen for both granisetron and the fluorescein-derivative, suggesting that they both adopt orientations that are consistent with co-crystal structures of granisetron with a homologous protein (5HTBP). As expected, in vivo live imaging in anaesthetized mice revealed staining in the abdominal cavity in intestines, but also in salivary glands. The unexpected presence of 5-HT3 receptors in mouse salivary glands was confirmed by Western blots. Overall, these results demonstrate the wide utility of our new high-affinity fluorescently-labeled 5-HT3 receptor probes, ranging from in vitro receptor pharmacology, including FC and FP ligand competition, to live imaging of 5-HT3 expressing tissues.
- Comparison between the antiemetic effects of palonosetron and granisetron in breast cancer patients treated with anthracycline-based regimens. [JOURNAL ARTICLE]
- Oncol Lett 2015 Jan; 9(1):119-124.
Chemotherapy-induced nausea and vomiting is a serious adverse side-effect of anthracycline-based chemotherapy regimens, in patients with breast cancer. A combination of three drugs, 5-hydroxytryptamine (5-HT3) receptor antagonist, aprepitant and dexamethasone, is recommended for antiemetic therapy. Palonosetron (PALO), a novel 5-HT3 receptor antagonist has been identified to be effective against delayed nausea and vomiting. In this study, the results of PALO for patients who received anthracycline-based chemotherapy were compared with that of granisetron (GRA) using a crossover study design. This study evaluated the efficacy of antiemetics in the first cycle of chemotherapy, as well as the second and third cycles. A total of 21 patients and 19 patients were assigned to PALO and GRA treatment groups during the first cycle of chemotherapy, respectively. The patients switched to the other antiemetic drug for the second chemotherapy cycle (PALO followed by GRA or GRA followed by PALO). The patients could select PALO or GRA antiemetics for the third cycle, according to their preference. A total of 21 patients selected PALO and 18 patients selected GRA in the third cycle, and one patient was withdrawn from the study as their third cycle questionnaire was not obtained. No significant differences between PALO and GRA were identified in first and second cycles. However, during the third cycle, a significant difference was observed in acute-phase complete control of emetic events between the PALO and GRA groups, which was defined as no emetic episode, no additional antiemetic treatment and no more than mild nausea, between PALO and GRA. These results demonstrated that changing antiemetics may affect the efficacy of antiemetics. This study indicates that alteration of antiemetic regimens, including drug combination and order, may improve the efficacy of antiemetic treatment.
- Netupitant-palonosetron combination approved by FDA. [Journal Article]
- Am J Health Syst Pharm 2014 Dec 1; 71(23):2000.
- Separation mechanisms for palonosetron stereoisomers at different chiral selector concentrations in MEKC. [JOURNAL ARTICLE]
- Electrophoresis 2014 Nov 18.
The separation mechanisms for palonosetron (PALO) stereoisomers in MEKC using sodium cholate (SC) as surfactant and chiral selector have been studied, in a wide range of concentrations below and above the CMC. It was found that SC micelles only provide chirally selective recognition for 3a carbon chiral center in PALO molecules. The resolution of the configurations of 2 carbon chiral center is achieved by the difference of mobility in continuous phase. A schematic diagram depicting the separation mechanisms and the corresponding migration orders among all of four stereoisomers was proposed based on the measured separation parameters. A MEKC method to achieve the complete separation of four stereoisomers in very short time using a very low chiral selector concentration, instead of high concentrations generally considered, was developed based on the understanding of the mechanisms. This article is protected by copyright. All rights reserved.
- Therapeutic action of 5-HT3 receptor antagonists targeting peritoneal macrophages in postoperative ileus. [JOURNAL ARTICLE]
- Br J Pharmacol 2014 Nov 6.
Postoperative ileus (POI) is induced by intestinal muscularis inflammation. The present study aimed to clarify the therapeutic action of 5-hydroxytryptamine 3 receptor (5-HT3 R) antagonists against POI.We administered three 5-HT3 R antagonists subcutaneously (s.q.) (ondansetron, tropisetron and palonosetron) to a mouse model of POI induced by surgical intestinal manipulation (IM). Immunohistochemistry, intestinal transit, inflammatory mediators mRNA expression and 5-HT content measurement were performed. In some experiments, 5-HT3aR null mice were used.Three 5-HT3 antagonists significantly reduced the IM-induced infiltration of inflammatory CD68-positive macrophages and MPO-stained neutrophils, indicating anti-inflammatory actions against POI. Ondansetron-induced anti-inflammatory action was disappeared in 5-HT3aR KO mice. Ondansetron inhibited the expression of MCP-1, IL-1β, IL-6, TNF-α and iNOS mRNAs upregulated by IM, and also ameliorated gastrointestinal transit that was delayed by IM. Peritoneal macrophages expressed 5-HT3 R, whereas most infiltrative monocyte-derived macrophages did not. IM stimulation increased the 5-HT content of peritoneal lavage fluid, which in turn upregulated the mRNA expression of proinflammatory cytokines in peritoneal macrophages. 5-HT3 R immunohistochemical localization suggests that ondansetron suppressed the expression of these mRNAs in activated peritoneal macrophages that adhered to the serosal region of the inflamed intestinal wall.5-HT3 R antagonists had anti-inflammatory effects and recovered the delayed gastrointestinal transit by IM. 5-HT3 R antagonists are a useful therapeutic agent against POI. Anti-inflammatory actions were induced by 5-HT3 R antagonists that mainly targeted peritoneal macrophages expressing 5-HT3 R.
- Review of oral fixed-dose combination netupitant and palonosetron (NEPA) for the treatment of chemotherapy-induced nausea and vomiting. [JOURNAL ARTICLE]
- Future Oncol 2014 Oct 31.:1-13.
ABSTRACTCurrent guidelines recommend the combination of a neurokinin-1 (NK1) receptor antagonist (RA) and a 5-hydroxytryptamine-3 (5-HT3) RA, together with corticosteroids, in order to prevent chemotherapy-induced nausea and vomiting with anthracycline-cyclophosphamide and highly emetogenic chemotherapy, and it is to be considered with moderately emetogenic chemotherapy. Netupitant and palonosetron (NEPA) is a fixed-dose combination of netupitant, a novel, highly selective NK1 RA, and palonosetron, a new-generation 5-HT3 RA, targeting two major emetic pathways in a single oral capsule. In clinical trials, NEPA administered on day 1 together with dexamethasone was highly effective and well tolerated in the prevention of chemotherapy-induced nausea and vomiting in patients with solid tumors undergoing moderately emetogenic chemotherapy or highly emetogenic chemotherapy. NEPA offers maximal convenience, and as a simple guideline-based regimen, has the potential to improve adherence to guidelines.
- Palonosetron for the treatment of chemotherapy-induced nausea and vomiting. [Journal Article]
- Expert Opin Pharmacother 2014 Dec; 15(17):2599-608.
Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The introduction of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists has been a major factor in the improvement of the prevention of chemotherapy-induced acute and delayed emesis. Palonosetron , a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in this drug class.Palonosetron's chemistry, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, including comparison with other antiemetics, role in controlling nausea, potential role in multi-day chemotherapy and bone marrow transplantation, and overall safety are discussed.The clinical data in the literature have established palonosetron as the 5-HT3 receptor antagonist of choice in terms of efficacy and safety for the prevention of CINV for patients receiving moderately or highly emetogenic chemotherapy. Three international guidelines have listed palonosetron as the preferred 5-HT3 receptor antagonist. Due to its higher efficacy, the use of palonosetron may be more cost effective compared to the generic first-generation 5-HT3 receptor antagonists. Clinical organizations' pharmacy and formulary committees should consider efficacy when making recommendations for agents for the prevention of CINV.
- Antiemetic therapy of fosaprepitant, palonosetron, and dexamethasone combined with cisplatin-based chemotherapy for head and neck carcinomas. [Journal Article]
- Acta Otolaryngol 2014 Nov; 134(11):1198-204.
Concomitant antiemetic therapy comprising fosaprepitant, palonosetron, and dexamethasone is effective for head and neck carcinoma.A patient diary was constructed to determine the effectiveness of concomitant antiemetic therapy with a neurokinin-1 receptor antagonist (fosaprepitant), 5-hydroxytryptamine receptor antagonist (palonosetron), and dexamethasone in accordance with guidelines.Subjects comprised 41 patients who received 71 courses of chemotherapy, along with fosaprepitant, palonosetron, and dexamethasone. A patient diary was compiled concerning the presence/absence of vomiting, vomiting episodes, presence/absence of rescue therapy, food intake, presence/absence of nausea, and general condition.The frequency of the primary end point of complete response in the overall phase was 69.0%. The proportion of patients with no vomiting in the overall phase was 90.1%. In the acute phase, the proportion of no nausea and slight nausea together was 91.5%, no change in and slightly reduced food intake together was 87.3%, and the proportion of good general condition and relatively good general condition was 85.9%. In the delayed phase, the proportion of no nausea and slight nausea together was 56.3%, no change in and slightly reduced food intake together was 43.7%, and the proportion of good general condition and relatively good general condition together was 53.5%.