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Experimental Brain Research Aug 2014Current therapy for chemotherapy-induced nausea and vomiting includes the use of both 5-HT3 and NK1 receptor antagonists. Acute emesis has largely been alleviated with...
Current therapy for chemotherapy-induced nausea and vomiting includes the use of both 5-HT3 and NK1 receptor antagonists. Acute emesis has largely been alleviated with the use of 5-HT3 receptor antagonists, while an improvement in preventing delayed emesis has been achieved with NK1 receptor antagonists. Delayed emesis, however, remains a problem with a significant portion of cancer patients receiving highly emetogenic chemotherapy. Like other drugs in its class, palonosetron, a 5-HT3 receptor antagonist, has shown efficacy against acute emesis. However, palonosetron has also shown consistent improvement in the suppression of delayed emesis. Since both 5-HT3 and NK1 receptor antagonists are often simultaneously administered to patients, the question remains if palonosetron's effect on delayed emesis would remain distinct when co-administered with an NK1 receptor antagonist. Recent mechanistic studies using NG108-15 cells have shown that palonosetron and netupitant, an NK1 receptor antagonist currently in phase 3 clinical trials, exhibited synergistic effects when inhibiting the substance P response. The present studies showed that both netupitant and palonosetron-induced NK1 receptor internalization in NG108-15 cells and that when used together receptor internalization was additive. Palonosetron-induced NK1 receptor internalization was dependent on the presence of the 5-HT3 receptor. Results provide a possible explanation for palonosetron's enhancement of the inhibition of the SP response and suggest that the effect of palonosetron and NK1 receptor antagonists on prevention of delayed emesis could be additive.
Topics: Acids; Animals; Cell Line; Dose-Response Relationship, Drug; Drug Administration Schedule; HEK293 Cells; Humans; Isoquinolines; Mice; Neuroblastoma; Neurokinin-1 Receptor Antagonists; Palonosetron; Peptide Hydrolases; Protein Binding; Protein Transport; Pyridines; Quinuclidines; Rats; Receptors, Neurokinin-1; Serotonin Antagonists; Time Factors; Tritium
PubMed: 24969614
DOI: 10.1007/s00221-014-4017-7 -
ACS Chemical Neuroscience Dec 2016Palonosetron is a potent 5-HT receptor antagonist and an effective therapeutic agent against emesis. Here we identify the molecular determinants of compound recognition...
Palonosetron is a potent 5-HT receptor antagonist and an effective therapeutic agent against emesis. Here we identify the molecular determinants of compound recognition in the receptor binding site by obtaining a high resolution structure of palonosetron bound to an engineered acetylcholine binding protein that mimics the 5-HT receptor binding site, termed 5-HTBP, and by examining the potency of palonosetron in a range of 5-HT receptors with mutated binding site residues. The structural data indicate that palonosetron forms a tight and effective wedge in the binding pocket, made possible by its rigid tricyclic ring structure and its interactions with binding site residues; it adopts a binding pose that is distinct from the related antiemetics granisetron and tropisetron. The functional data show many residues previously shown to interact with agonists and antagonists in the binding site are important for palonosetron binding, and indicate those of particular importance are W183 (a cation-π interaction and a hydrogen bond) and Y153 (a hydrogen bond). This information, and the availability of the structure of palonosetron bound to 5-HTBP, should aid the development of novel and more efficacious drugs that act via 5-HT receptors.
Topics: Animals; Aplysia; Binding Sites; Carrier Proteins; Crystallography, X-Ray; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Isoquinolines; Membrane Potentials; Models, Molecular; Molecular Structure; Mutation; Palonosetron; Protein Engineering; Quinuclidines; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists
PubMed: 27656911
DOI: 10.1021/acschemneuro.6b00132 -
Medicine Nov 2018Microvascular decompression (MVD) is associated with a particularly high risk of postoperative nausea and vomiting (PONV) among craniotomy patients. However, there is no... (Observational Study)
Observational Study
Effect of prophylactic palonosetron and sugammadex on postoperative nausea and vomiting in patients undergoing microvascular decompression under propofol-maintained anesthesia: A retrospective observational study.
Microvascular decompression (MVD) is associated with a particularly high risk of postoperative nausea and vomiting (PONV) among craniotomy patients. However, there is no information regarding the effect of prophylactic palonosetron and sugammadex on PONV in patients undergoing MVD under propofol-maintained anesthesia.Medical records of 274 adults who had undergone MVD under propofol-maintained anesthesia were reviewed. Patients were classified into 4 groups, based on the reversal agent used (sugammadex/pyridostigmine) and whether or not prophylactic palonosetron was used. The PONV incidence and risk factors were analyzed according to the use of these agents.The overall incidence of PONV was 30.7% during the first 24 hours postoperatively. The incidence of PONV was lower in the group using combination of prophylactic palonosetron and sugammadex (19.3%) compared with the group not using both agents (37.2%). The combined use of the prophylactic palonosetron and sugammadex was identified as a factor affecting the occurrence of PONV in both univariable (OR = 0.40, 95% CI: 0.21-0.77, P = .006) and multivariable (OR = 0.38, 95% CI: 0.20-0.75, P = .005) logistic regression analyses. In multivariable logistic regression analysis, female sex was also significant independent risk factor in PONV (OR = 2.62, 95% CI: 1.35-5.08, P = .004).In this retrospective observational study, the combined use of prophylactic palonosetron before anesthetic induction and sugammadex as a reversal of neuromuscular blockade are associated with a reduction in the incidence of PONV in patients undergoing MVD under propofol-maintained anesthesia.
Topics: Aged; Anesthesia; Anesthetics, Intravenous; Antiemetics; Decompressive Craniectomy; Drug Therapy, Combination; Female; Humans; Incidence; Isoquinolines; Logistic Models; Male; Microvascular Decompression Surgery; Middle Aged; Palonosetron; Postoperative Nausea and Vomiting; Preoperative Period; Propofol; Quinuclidines; Retrospective Studies; Risk Factors; Sugammadex; Treatment Outcome; gamma-Cyclodextrins
PubMed: 30431604
DOI: 10.1097/MD.0000000000013237 -
Journal of Pharmaceutical Health Care... 2018Antiemetic effects and safety of granisetron or palonosetron alone and in combination with a corticosteroid against chemotherapy-induced nausea and vomiting (CINV) were...
BACKGROUND
Antiemetic effects and safety of granisetron or palonosetron alone and in combination with a corticosteroid against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with Hodgkin lymphoma receiving adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy.
METHODS
A total of 39 patients were eligible for this study. Before ABVD therapy, granisetron or palonosetron was intravenously administered with or without a corticosteroid (dexamethasone or hydrocortisone) and aprepitant. The proportions of patients with complete control (CC) during the overall (0-120 h after the start of ABVD therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CC was defined as no vomiting and no use of antiemetic rescue medication with only grade 0-1 nausea.
RESULTS
Granisetron and palonosetron were administered in 21 and 18 patients, respectively. The CC rate during the acute, delayed and overall phases was not statistically different between the two groups. The CINV was completely controlled during overall phase in 58.3% of patients receiving granisetron or palonosetron in combination with a corticosteroid, whereas in 11.1% of those without co-treatment of a corticosteroid ( < 0.05). There were significantly higher frequencies of anorexia, leucopenia and neutropenia in the palonosetron group. There is a statistically significant difference in the frequency of febrile neutropenia between presence and absence of a corticosteroid ( = 0.024).
CONCLUSION
These findings suggested that a combination use of a corticosteroid with a 5-HT receptor antagonist was preferable for CINV control in patients with Hodgkin lymphoma receiving ABVD therapy, although the careful management of febrile neutropenia is required.
TRIAL REGISTRATION
The study approval numbers in the institution; 24-12 and 24-359. Registered April 17, 2012 and June 21, 2012.
PubMed: 29345696
DOI: 10.1186/s40780-017-0097-4 -
Journal of Pharmaceutical Health Care... Jun 2021Recently, aprepitant has been recommended in carboplatin-based regimens, but there are limited reports on the efficacy of administering aprepitant, palonosetron, and...
BACKGROUND
Recently, aprepitant has been recommended in carboplatin-based regimens, but there are limited reports on the efficacy of administering aprepitant, palonosetron, and dexamethasone (DEX) in carboplatin-containing regimens. Moreover, because aprepitant is an expensive drug, confirming its effectiveness is very important from the medical cost perspective. In this study, we examined the efficacy of prophylactically administered aprepitant, palonosetron and DEX, in paclitaxel and carboplatin (TC) combination chemotherapy.
METHODS
Patients with gynecologic cancer who were treated with paclitaxel (175 mg/m) and carboplatin (area under the curve, AUC = 5-6) combination chemotherapy were retrospectively evaluated. The complete response (CR) rate, severity of nausea, and incidence of anorexia in the first course were compared between patients who did not receive aprepitant (control group) and those who received (aprepitant group).
RESULTS
The 106 patients were divided into two groups, consisting of 52 and 54 the control and aprepitant groups, respectively, and the patient background showed no significant difference between both groups. The CR rate of the overall phase between the control and aprepitant groups was 73.1 vs. 74.1%, that in the acute phase was 98.1 vs. 100%, and in the delayed phase was 75.0 vs. 74.1%, respectively, without any significant difference. The severity of nausea and incidence of anorexia were also not significantly different between both groups.
CONCLUSIONS
The results of the study suggest that adding aprepitant to palonosetron and DEX does not prevent carboplatin-induced nausea and vomiting in gynecologic cancer patients. Therefore, adding aprepitant to palonosetron does not decrease carboplatin-induced nausea and vomiting in patients with gynecologic cancer.
PubMed: 34059157
DOI: 10.1186/s40780-021-00204-z -
BMC Anesthesiology 2014Postoperative nausea and vomiting (PONV) is one of the most common postsurgical complications. Palonosetron, a 5-hydroxytryptamine receptor antagonist, is effective for... (Randomized Controlled Trial)
Randomized Controlled Trial
Palonosetron and aprepitant for the prevention of postoperative nausea and vomiting in patients indicated for laparoscopic gynaecologic surgery: a double-blind randomised trial.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
Topics: Adult; Analgesia, Patient-Controlled; Antiemetics; Aprepitant; Double-Blind Method; Female; Gynecologic Surgical Procedures; Humans; Isoquinolines; Laparoscopy; Middle Aged; Morpholines; Pain Measurement; Pain, Postoperative; Palonosetron; Postoperative Nausea and Vomiting; Quinuclidines; Young Adult
PubMed: 25165427
DOI: 10.1186/1471-2253-14-68 -
Clinical Journal of Oncology Nursing Apr 2018Prevention of chemotherapy-induced nausea and vomiting (CINV) can be improved with guideline-consistent use of antiemetics. However, adherence to antiemetic guidelines... (Review)
Review
BACKGROUND
Prevention of chemotherapy-induced nausea and vomiting (CINV) can be improved with guideline-consistent use of antiemetics. However, adherence to antiemetic guidelines remains often insufficient. Therefore, new strategies that improve adherence are needed.
OBJECTIVES
To review the latest antiemetic guideline recommendations and provide an update on the use of NEPA, a fixed combination antiemetic composed of the neurokinin-1 receptor antagonist (RA) netupitant and the 5-hydroxytryptamine-3 RA palonosetron (Akynzeo®).
METHODS
Analysis of the literature was performed, including guidelines, published literature, congress data on NEPA, and relevant articles on CINV.
FINDINGS
Nurses are in a unique position to promote guideline-consistent antiemetic prophylaxis and are central in the education of patients and caregivers. Thus, nurses’ continuous education on antiemetic treatments is key for the prevention and management of CINV. NEPA offers a simplified antiemetic therapy with the potential to increase guideline adherence.
Topics: Adult; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Middle Aged; Nausea; Oncology Nursing; Palonosetron; Practice Guidelines as Topic; Pyridines; Vomiting
PubMed: 29547597
DOI: 10.1188/18.CJON.E52-E63 -
Biomedicine & Pharmacotherapy =... Apr 20195-HTR antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current... (Review)
Review
5-HTR antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current study and research revealed novel potentials of these ligands in other diseases like inflammation, Alzheimer's, and drug abuse. Towards utilising these drugs as anti-smoking agents to treat nicotine dependence problem, there are conflicting reports regarding the potential of these ligands in modulating the effects of nicotine in both human and animal behavioural studies. This is complicated by the heterogeneity of 5-HTR itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HTR antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HTR antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HTR antagonists mediate the effects of nicotine could be attributed by both direct at 5-HTR and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HTR antagonist could be through α7 nAChR, 5-HT receptor (5-HTR), 5-HT receptor (5-HTR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κβ. Our review suggested that future studies should focus on newer 5-HTR antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.
Topics: Humans; Palonosetron; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Tobacco Use Disorder
PubMed: 30797147
DOI: 10.1016/j.biopha.2019.108630 -
Biomedical Journal Feb 2016The purpose of this study was to evaluate the efficacy of combined treatment with the long-acting 5-hydroxytryptamine receptor-3 antagonist, palonosetron, the...
BACKGROUND
The purpose of this study was to evaluate the efficacy of combined treatment with the long-acting 5-hydroxytryptamine receptor-3 antagonist, palonosetron, the neurokinin-1 receptor antagonist, oral aprepitant, and dexamethasone as primary antiemetic prophylaxis for cancer patients receiving highly emetogenic cisplatin-based chemotherapy.
METHODS
Chemotherapy-naïve patients received the triple combination of palonosetron (0.25 mg), aprepitant (125 mg on day 1 and 80 mg on days 2 and 3), and dexamethasone (20 mg) from the beginning of highly emetogenic chemotherapy with cisplatin-based (≥50 mg/m(2)) regimens. The primary endpoint was a complete response (no emetic episodes and no rescue antiemetics) during the days 1-6.
RESULTS
Sixty-nine hospitalized patients receiving chemotherapy from September 2012 to October 2014 were analyzed. Complete response of vomiting and nausea-free was achieved in 97.1% and 85.5% of patients in the first cycle, respectively, and 96.7% and 83.6% of patients in the second cycle, respectively. Common adverse events in all 69 patients included constipation (43%), hiccup (26%), and headache (4%).
CONCLUSION
The combination of palonosetron, aprepitant, and dexamethasone as primary antiemetic prophylaxis for cancer patients with highly emetogenic cisplatin-based chemotherapy is effective.
Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Dexamethasone; Drug Therapy, Combination; Female; Humans; Isoquinolines; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Palonosetron; Quinuclidines; Treatment Outcome; Vomiting
PubMed: 27105599
DOI: 10.1016/j.bj.2015.08.006 -
Future Oncology (London, England) Aug 2021In the absence of comparative studies, guidelines consider neurokinin 1 receptor antagonists (RAs) as interchangeable. We evaluated the pooled efficacy from... (Comparative Study)
Comparative Study
In the absence of comparative studies, guidelines consider neurokinin 1 receptor antagonists (RAs) as interchangeable. We evaluated the pooled efficacy from three cisplatin registration trials, each with arms containing netupitant/palonosetron (NEPA), a fixed neurokinin 1 RA (netupitant)/serotonin Type 3 (5-HT3) RA (palonosetron) combination, and an aprepitant (APR) regimen. Efficacy data were pooled for rates of complete response (CR: no emesis/no rescue medication), complete protection (CR + no significant nausea), total control (CR + no nausea) and no significant nausea during acute (0-24 h), delayed (>24-120 h) and overall (0-120 h) phases post chemotherapy. Among 621 NEPA and 576 APR patients, response rates were similar for the acute phase, and generally favored NEPA during delayed and overall phases. CR rates for NEPA versus APR were 88.4 versus 89.2%, 81.8 versus 76.9% (p < 0.05) and 78.4 versus 75.0% during the acute, delayed and overall phases, respectively. Oral NEPA administered on day 1 was more effective than a 3-day APR regimen in preventing delayed nausea and vomiting associated with cisplatin.
Topics: Administration, Oral; Adult; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Drug Combinations; Female; Humans; Isoquinolines; Male; Middle Aged; Multicenter Studies as Topic; Nausea; Neoplasms; Pyridines; Quinuclidines; Randomized Controlled Trials as Topic; Vomiting
PubMed: 33878896
DOI: 10.2217/fon-2021-0023