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Jing Huang - One of the best experts on this subject based on the ideXlab platform.
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Palonosetron for prevention of acute and delayed nausea and vomiting in non-small-cell lung carcinoma patients
Medical Oncology, 2010Co-Authors: Xiaorong Dong, Jing HuangAbstract:Lung cancer is the leading cause of cancer-related death for both men and women worldwide, and lung cancer also has the highest morbidity and mortality rate among all cancers in China. Chemotherapy (CT) is the most effective and most widely used treatment for lung cancer. Nausea and vomiting are still among the most unpleasant side effects of chemotherapy, especially during highly emetogenic chemotherapy. The standard therapy for preventing chemotherapy-induced nausea and vomiting (CINV) is 5-hydroxytryptamine 3 (5-HT3) receptor antagonists. Palonosetron is a highly potent second-generation selective 5-HT3 receptor antagonist with stronger binding affinity for the 5-HT3 receptor. Palonosetron showed a high antiemetic activity in preclinical study and pivotal trails enrolling patients treated with moderately or high antiemetic activity drugs. Aim of the study was to verify the activity and safety of Palonosetron in patients affected by non-small-cell lung carcinoma (NSCLC) and treated with chemotherapy. Patients with stage II–IV NSCLC and receiving chemotherapy entered into the trial. Informed written consent was required. Patients were randomized to received Palonosetron or ondasetron. A single pretreatment dose of Palonosetron 0.25 mg intravenous followed was administered. Nausea and vomiting were evaluated over 7-day period. Also the adverse effects were reported. Adverse events were evaluated according to the NCI-CTC criteria. Eighty-nine patients were enrolled into the study. The complete responses during the acute phase were 95.4 and 93.3%, respectively. The main side effects were headache 4.5%, constipation 15.7%, anxiety 2.3%. Palonosetron is a very active antiemetic drug for the prevention of nausea and vomiting in NSCLC patients received chemotherapy.
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Palonosetron for prevention of acute and delayed nausea and vomiting in non-small-cell lung carcinoma patients
Medical Oncology, 2010Co-Authors: Xiaorong Dong, Jing HuangAbstract:Lung cancer is the leading cause of cancer-related death for both men and women worldwide, and lung cancer also has the highest morbidity and mortality rate among all cancers in China. Chemotherapy (CT) is the most effective and most widely used treatment for lung cancer. Nausea and vomiting are still among the most unpleasant side effects of chemotherapy, especially during highly emetogenic chemotherapy. The standard therapy for preventing chemotherapy-induced nausea and vomiting (CINV) is 5-hydroxytryptamine 3 (5-HT3) receptor antagonists. Palonosetron is a highly potent second-generation selective 5-HT3 receptor antagonist with stronger binding affinity for the 5-HT3 receptor. Palonosetron showed a high antiemetic activity in preclinical study and pivotal trails enrolling patients treated with moderately or high antiemetic activity drugs. Aim of the study was to verify the activity and safety of Palonosetron in patients affected by non-small-cell lung carcinoma (NSCLC) and treated with chemotherapy. Patients with stage II–IV NSCLC and receiving chemotherapy entered into the trial. Informed written consent was required. Patients were randomized to received Palonosetron or ondasetron. A single pretreatment dose of Palonosetron 0.25 mg intravenous followed was administered. Nausea and vomiting were evaluated over 7-day period. Also the adverse effects were reported. Adverse events were evaluated according to the NCI-CTC criteria. Eighty-nine patients were enrolled into the study. The complete responses during the acute phase were 95.4 and 93.3%, respectively. The main side effects were headache 4.5%, constipation 15.7%, anxiety 2.3%. Palonosetron is a very active antiemetic drug for the prevention of nausea and vomiting in NSCLC patients received chemotherapy.
Rudolph M. Navari - One of the best experts on this subject based on the ideXlab platform.
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Should Palonosetron be a preferred 5-HT_3 receptor antagonist for chemotherapy-induced nausea and vomiting? An updated systematic review and meta-analysis
Supportive Care in Cancer, 2018Co-Authors: Ronald Chow, Rudolph M. Navari, Marko Popovic, May Tsao, David G. Warr, Leonard Chiu, Milica Milakovic, Carlo DeangelisAbstract:Purpose Chemotherapy-induced nausea and vomiting (CINV) continues to be a common side effect of systemic anticancer therapy, decreasing quality of life and increasing resource utilization. The aim of this meta-analysis was to investigate the comparative efficacy and safety of Palonosetron relative to other 5-HT_3RAs. Methods A literature search was carried out in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Full-text references were then screened and included in this meta-analysis if they were an RCT and had adequate data regarding one of the five primary endpoints—complete response (CR), complete control (CC), no emesis, no nausea, or no rescue medications. Results A total of 24 RCTs were included in this review. Palonosetron was statistically superior to other 5-HT_3RAs for 10 of the 19 assessed endpoints. Only one endpoint—emesis in the overall phase—had noticeable more favorable data for Palonosetron to the point that it approached the 10% risk difference (RD) threshold as specified by the MASCC/ESMO antiemetic panel; another two endpoints (CR in the overall phase and nausea in the delayed phase) approached the 10% threshold. Conclusions Palonosetron seems to be more efficacious and safe than other 5-HT_3RAs—statistically superior in 10 of 19 endpoints. It is, however, only clinically significant in one endpoint and approached clinically significant difference in another two endpoints. Within the limits of this meta-analysis, our results indicate that Palonosetron may not be as superior in efficacy and safety as reported in a previous meta-analysis, and supports the recent MASCC/ESMO, ASCO, and NCCN guidelines in not generally indicating Palonosetron as the 5-HT_3RA of choice.
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should Palonosetron be a preferred 5 ht 3 receptor antagonist for chemotherapy induced nausea and vomiting an updated systematic review and meta analysis
Supportive Care in Cancer, 2018Co-Authors: Ronald Chow, Rudolph M. Navari, Marko Popovic, David Warr, May Tsao, Henry Lam, Leonard Chiu, Milica Milakovic, Carlo DeangelisAbstract:Chemotherapy-induced nausea and vomiting (CINV) continues to be a common side effect of systemic anticancer therapy, decreasing quality of life and increasing resource utilization. The aim of this meta-analysis was to investigate the comparative efficacy and safety of Palonosetron relative to other 5-HT3RAs. A literature search was carried out in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Full-text references were then screened and included in this meta-analysis if they were an RCT and had adequate data regarding one of the five primary endpoints—complete response (CR), complete control (CC), no emesis, no nausea, or no rescue medications. A total of 24 RCTs were included in this review. Palonosetron was statistically superior to other 5-HT3RAs for 10 of the 19 assessed endpoints. Only one endpoint—emesis in the overall phase—had noticeable more favorable data for Palonosetron to the point that it approached the 10% risk difference (RD) threshold as specified by the MASCC/ESMO antiemetic panel; another two endpoints (CR in the overall phase and nausea in the delayed phase) approached the 10% threshold. Palonosetron seems to be more efficacious and safe than other 5-HT3RAs—statistically superior in 10 of 19 endpoints. It is, however, only clinically significant in one endpoint and approached clinically significant difference in another two endpoints. Within the limits of this meta-analysis, our results indicate that Palonosetron may not be as superior in efficacy and safety as reported in a previous meta-analysis, and supports the recent MASCC/ESMO, ASCO, and NCCN guidelines in not generally indicating Palonosetron as the 5-HT3RA of choice.
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the current status of the use of Palonosetron
Expert Opinion on Pharmacotherapy, 2013Co-Authors: Rudolph M. NavariAbstract:Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in the quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has antiemetic activity at both central and gastrointestinal sites. In comparison to the first-generation 5-HT3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT3 receptors. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Compared to the first-generation 5-HT3 receptor antagonists, Palonosetron in combination with dexamethasone has demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy and had a similar safety profile. Due to its efficacy in controlling both acute and delayed CINV, Palonosetron may be very effective in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.
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The current status of the use of Palonosetron.
Expert Opinion on Pharmacotherapy, 2013Co-Authors: Rudolph M. NavariAbstract:Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in the quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has antiemetic activity at both central and gastrointestinal sites. In comparison to the first-generation 5-HT3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT3 receptors. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Compared to the first-generation 5-HT3 receptor antagonists, Palonosetron in combination with dexamet...
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Palonosetron a second generation 5 hydroxytryptamine 3 receptor antagonist
Expert Opinion on Drug Metabolism & Toxicology, 2009Co-Authors: Rudolph M. NavariAbstract:Background 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 characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Objective This review provides a detailed description of Palonosetron, a second generation 5-HT3 receptor antagonist. Methods The chemistry and pharmacology of Palonosetron are described, as well as the initial and recent clinical trials. Results/conclusion Palonosetron has a longer half-life and a higher binding affinity than the first generation 5-HT3 receptor antagonists. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. In recent studies, compared to the first generation 5-HT3 receptor antagonists, Palonosetron in combination with dexamethasone demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy. There were no clinically relevant adverse reactions reported in the Palonosetron clinical trials that were different from the common reactions reported for the 5-HT3 receptor antagonist class. Due to its efficacy in controlling both acute and delayed CINV, Palonosetron may be very effective in the clinical setting of multiple-day chemotherapy and bone marrow transplantation.
Carlo Deangelis - One of the best experts on this subject based on the ideXlab platform.
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Should Palonosetron be a preferred 5-HT_3 receptor antagonist for chemotherapy-induced nausea and vomiting? An updated systematic review and meta-analysis
Supportive Care in Cancer, 2018Co-Authors: Ronald Chow, Rudolph M. Navari, Marko Popovic, May Tsao, David G. Warr, Leonard Chiu, Milica Milakovic, Carlo DeangelisAbstract:Purpose Chemotherapy-induced nausea and vomiting (CINV) continues to be a common side effect of systemic anticancer therapy, decreasing quality of life and increasing resource utilization. The aim of this meta-analysis was to investigate the comparative efficacy and safety of Palonosetron relative to other 5-HT_3RAs. Methods A literature search was carried out in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Full-text references were then screened and included in this meta-analysis if they were an RCT and had adequate data regarding one of the five primary endpoints—complete response (CR), complete control (CC), no emesis, no nausea, or no rescue medications. Results A total of 24 RCTs were included in this review. Palonosetron was statistically superior to other 5-HT_3RAs for 10 of the 19 assessed endpoints. Only one endpoint—emesis in the overall phase—had noticeable more favorable data for Palonosetron to the point that it approached the 10% risk difference (RD) threshold as specified by the MASCC/ESMO antiemetic panel; another two endpoints (CR in the overall phase and nausea in the delayed phase) approached the 10% threshold. Conclusions Palonosetron seems to be more efficacious and safe than other 5-HT_3RAs—statistically superior in 10 of 19 endpoints. It is, however, only clinically significant in one endpoint and approached clinically significant difference in another two endpoints. Within the limits of this meta-analysis, our results indicate that Palonosetron may not be as superior in efficacy and safety as reported in a previous meta-analysis, and supports the recent MASCC/ESMO, ASCO, and NCCN guidelines in not generally indicating Palonosetron as the 5-HT_3RA of choice.
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should Palonosetron be a preferred 5 ht 3 receptor antagonist for chemotherapy induced nausea and vomiting an updated systematic review and meta analysis
Supportive Care in Cancer, 2018Co-Authors: Ronald Chow, Rudolph M. Navari, Marko Popovic, David Warr, May Tsao, Henry Lam, Leonard Chiu, Milica Milakovic, Carlo DeangelisAbstract:Chemotherapy-induced nausea and vomiting (CINV) continues to be a common side effect of systemic anticancer therapy, decreasing quality of life and increasing resource utilization. The aim of this meta-analysis was to investigate the comparative efficacy and safety of Palonosetron relative to other 5-HT3RAs. A literature search was carried out in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Full-text references were then screened and included in this meta-analysis if they were an RCT and had adequate data regarding one of the five primary endpoints—complete response (CR), complete control (CC), no emesis, no nausea, or no rescue medications. A total of 24 RCTs were included in this review. Palonosetron was statistically superior to other 5-HT3RAs for 10 of the 19 assessed endpoints. Only one endpoint—emesis in the overall phase—had noticeable more favorable data for Palonosetron to the point that it approached the 10% risk difference (RD) threshold as specified by the MASCC/ESMO antiemetic panel; another two endpoints (CR in the overall phase and nausea in the delayed phase) approached the 10% threshold. Palonosetron seems to be more efficacious and safe than other 5-HT3RAs—statistically superior in 10 of 19 endpoints. It is, however, only clinically significant in one endpoint and approached clinically significant difference in another two endpoints. Within the limits of this meta-analysis, our results indicate that Palonosetron may not be as superior in efficacy and safety as reported in a previous meta-analysis, and supports the recent MASCC/ESMO, ASCO, and NCCN guidelines in not generally indicating Palonosetron as the 5-HT3RA of choice.
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efficacy and safety of Palonosetron for the prophylaxis of chemotherapy induced nausea and vomiting cinv a systematic review and meta analysis of randomized controlled trials
Supportive Care in Cancer, 2014Co-Authors: Marko Popovic, David Warr, Carlo Deangelis, May Tsao, Kelvin K W Chan, Michael Poon, Cheryl Yip, Natalie Pulenzas, Henry Lam, Liying ZhangAbstract:Palonosetron, a 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) with a strong binding affinity and long half-life, has been used in numerous trials for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). We systematically reviewed the efficacy and safety of Palonosetron compared to other 5-HT3RAs in CINV prophylaxis. A literature search of Ovid MEDLINE, EMBASE, and CENTRAL was conducted to identify randomized controlled trials (RCTs) comparing Palonosetron to other 5-HT3RAs in CINV prophylaxis. Primary endpoints were the percentage of patients achieving a complete response (CR), complete control (CC), no emesis, no nausea, or taking no rescue medications. Secondary endpoints were the percentage of patients suffering from 5-HT3RA-related adverse events. Sixteen RCTs were identified with 2,896 patients randomized to Palonosetron and 3,187 patients randomized to other 5-HT3RAs. Palonosetron was consistently statistically superior in CR, CC, no emesis, or no nausea and was sometimes superior in no rescue medication. Subgroup analyses demonstrated similarity in efficacy between highly and moderately emetogenic chemotherapy cohorts. In the acute phase, statistical superiority of Palonosetron was found for trials that did not allow dexamethasone; conversely, RCTs that administered dexamethasone to all patients were nonsignificant. Palonosetron was statistically significantly safer in dizziness and mean QTc interval change and similar in constipation, headache, and diarrhea. Clinical superiority of Palonosetron was reached in 3 of 19 analyzed efficacy and safety endpoints. Palonosetron is safer and more efficacious than other 5-HT3RAs. Future antiemetic guidelines should discuss the merits of including Palonosetron as a first-line treatment.
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efficacy and safety of Palonosetron for the prophylaxis of chemotherapy induced nausea and vomiting cinv a systematic review and meta analysis of randomized controlled trials
Supportive Care in Cancer, 2014Co-Authors: Marko Popovic, David Warr, Carlo Deangelis, May Tsao, Kelvin K W Chan, Michael Poon, Natalie Pulenzas, Liying Zhang, Edward ChowAbstract:Purpose Palonosetron, a 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) with a strong binding affinity and long half-life, has been used in numerous trials for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). We systematically reviewed the efficacy and safety of Palonosetron compared to other 5-HT3RAs in CINV prophylaxis.
Barbara S Slusher - One of the best experts on this subject based on the ideXlab platform.
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The antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P-mediated responses
2016Co-Authors: Camilo Rojas, Jie Zhang, Marigo Stathis, Jesse Alt, Ajit G Thomas, Sergio Cantoreggi, Silvia Sebastiani, Claudio Pietra, Barbara S SlusherAbstract:Palonosetron is the only 5-HT3 receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, Palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT3 receptor signaling pathways; we postulated that if Palonosetron differentially inhibited NK-1/5-HT3 cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of Palonosetron, gran-isetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with Palonosetron
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netupitant and Palonosetron trigger nk1 receptor internalization in ng108 15 cells
Experimental Brain Research, 2014Co-Authors: Ajit G Thomas, Camilo Rojas, Marigo Stathis, Barbara S SlusherAbstract: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.
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inhibition of substance p mediated responses in ng108 15 cells by netupitant and Palonosetron exhibit synergistic effects
European Journal of Pharmacology, 2012Co-Authors: Marigo Stathis, Camilo Rojas, Claudio Pietra, Barbara S SlusherAbstract:Abstract Netupitant is a potent and selective NK 1 receptor antagonist under development in combination with a fixed dose of Palonosetron for the prevention of chemotherapy induced nausea and vomiting. Palonosetron is a 5-HT 3 receptor antagonist approved for both the prevention of acute and delayed chemotherapy induced nausea and vomiting after moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), a ligand acting largely on tachykinin (NK 1 ) receptors, is the dominant mediator of delayed emesis. Interestingly, Palonosetron does not bind to the NK 1 receptor so that the mechanism behind Palonosetron's unique efficacy against delayed emesis is not clear. Palonosetron exhibits a distinct ability among 5-HT 3 receptor antagonists to inhibit crosstalk between NK 1 and 5-HT 3 receptor signaling pathways. The objective of the current work was to determine if Palonosetron's ability to inhibit receptor signaling crosstalk would influence netupitant's inhibition of the SP-mediated response when the two drugs are dosed together. We first studied the inhibition of SP-induced Ca 2+ mobilization in NG108-15 cells by Palonosetron, ondansetron and granisetron. Unexpectedly, in the absence of serotonin, Palonosetron inhibited the SP-mediated dose response 15-fold; ondansetron and granisetron had no effect. Netupitant also dose-dependently inhibited the SP response as expected from an NK1 receptor antagonist. Importantly, when both Palonosetron and netupitant were present, they exhibited an enhanced inhibition of the SP response compared to either of the two antagonists alone. The results further confirm Palonosetron's unique pharmacology among 5-HT 3 receptor antagonists and suggest that it can enhance the prevention of delayed emesis provided by NK 1 receptor antagonists.
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the antiemetic 5 ht3 receptor antagonist Palonosetron inhibits substance p mediated responses in vitro and in vivo
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Camilo Rojas, Jie Zhang, Marigo Stathis, Jesse Alt, Ajit G Thomas, Sergio Cantoreggi, Silvia Sebastiani, Claudio Pietra, Barbara S SlusherAbstract:Palonosetron is the only 5-HT3 receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, Palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT3 receptor signaling pathways; we postulated that if Palonosetron differentially inhibited NK-1/5-HT3 cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of Palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with Palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with Palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either Palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that Palonosetron exhibits distinct pharmacology versus the older 5-HT3 receptor antagonists and provide a rationale for the efficacy observed with Palonosetron in delayed CINV in the clinic.
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Palonosetron triggers 5 ht3 receptor internalization and causes prolonged inhibition of receptor function
European Journal of Pharmacology, 2010Co-Authors: Camilo Rojas, Jie Zhang, Marigo Stathis, Jesse Alt, Ajit G Thomas, Sergio Cantoreggi, Silvia Sebastiani, Edward B Rubenstein, Barbara S SlusherAbstract:Abstract Palonosetron is a 5-HT 3 receptor antagonist that has demonstrated superiority in preventing both acute and delayed emesis when compared to older first generation 5-HT 3 receptor antagonists. The objective of this work was to determine if Palonosetron exhibits unique molecular interactions with the 5-HT 3 receptor that could provide a scientific rationale for observed clinical efficacy differences. Previously, we showed that Palonosetron exhibits allosteric binding and positive cooperativity to the 5-HT 3 receptor in contrast to ondansetron and granisetron which exhibit simple bimolecular binding. The present work shows, through several independent experiments, that Palonosetron uniquely triggers 5-HT 3 receptor internalization and induces prolonged inhibition of receptor function. After 24 h incubation followed by dissociation conditions, [ 3 H]Palonosetron remained associated with whole cells but not to cell-free membranes ( P 3 H]Palonosetron's binding to cells was resistant to both protease and acid treatments designed to denature cell surface proteins suggesting that the receptor complex was inside the cells rather than at the surface. Cells pretreated with unlabeled Palonosetron subsequently exhibited reduced cell surface 5-HT 3 receptor binding. Palonosetron-triggered receptor internalization was visualized by confocal fluorescence microscopy using cells transfected with 5-HT 3 receptor fused to enhanced cyan fluorescent protein. In contrast, granisetron and ondansetron showed minimal to no effect on receptor internalization or prolonged inhibition of receptor function. These experiments may provide a pharmacological basis for differences noted in published clinical trials comparing Palonosetron to other 5-HT 3 receptor antagonists.
Xiaorong Dong - One of the best experts on this subject based on the ideXlab platform.
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Palonosetron for prevention of acute and delayed nausea and vomiting in non-small-cell lung carcinoma patients
Medical Oncology, 2010Co-Authors: Xiaorong Dong, Jing HuangAbstract:Lung cancer is the leading cause of cancer-related death for both men and women worldwide, and lung cancer also has the highest morbidity and mortality rate among all cancers in China. Chemotherapy (CT) is the most effective and most widely used treatment for lung cancer. Nausea and vomiting are still among the most unpleasant side effects of chemotherapy, especially during highly emetogenic chemotherapy. The standard therapy for preventing chemotherapy-induced nausea and vomiting (CINV) is 5-hydroxytryptamine 3 (5-HT3) receptor antagonists. Palonosetron is a highly potent second-generation selective 5-HT3 receptor antagonist with stronger binding affinity for the 5-HT3 receptor. Palonosetron showed a high antiemetic activity in preclinical study and pivotal trails enrolling patients treated with moderately or high antiemetic activity drugs. Aim of the study was to verify the activity and safety of Palonosetron in patients affected by non-small-cell lung carcinoma (NSCLC) and treated with chemotherapy. Patients with stage II–IV NSCLC and receiving chemotherapy entered into the trial. Informed written consent was required. Patients were randomized to received Palonosetron or ondasetron. A single pretreatment dose of Palonosetron 0.25 mg intravenous followed was administered. Nausea and vomiting were evaluated over 7-day period. Also the adverse effects were reported. Adverse events were evaluated according to the NCI-CTC criteria. Eighty-nine patients were enrolled into the study. The complete responses during the acute phase were 95.4 and 93.3%, respectively. The main side effects were headache 4.5%, constipation 15.7%, anxiety 2.3%. Palonosetron is a very active antiemetic drug for the prevention of nausea and vomiting in NSCLC patients received chemotherapy.
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Palonosetron for prevention of acute and delayed nausea and vomiting in non-small-cell lung carcinoma patients
Medical Oncology, 2010Co-Authors: Xiaorong Dong, Jing HuangAbstract:Lung cancer is the leading cause of cancer-related death for both men and women worldwide, and lung cancer also has the highest morbidity and mortality rate among all cancers in China. Chemotherapy (CT) is the most effective and most widely used treatment for lung cancer. Nausea and vomiting are still among the most unpleasant side effects of chemotherapy, especially during highly emetogenic chemotherapy. The standard therapy for preventing chemotherapy-induced nausea and vomiting (CINV) is 5-hydroxytryptamine 3 (5-HT3) receptor antagonists. Palonosetron is a highly potent second-generation selective 5-HT3 receptor antagonist with stronger binding affinity for the 5-HT3 receptor. Palonosetron showed a high antiemetic activity in preclinical study and pivotal trails enrolling patients treated with moderately or high antiemetic activity drugs. Aim of the study was to verify the activity and safety of Palonosetron in patients affected by non-small-cell lung carcinoma (NSCLC) and treated with chemotherapy. Patients with stage II–IV NSCLC and receiving chemotherapy entered into the trial. Informed written consent was required. Patients were randomized to received Palonosetron or ondasetron. A single pretreatment dose of Palonosetron 0.25 mg intravenous followed was administered. Nausea and vomiting were evaluated over 7-day period. Also the adverse effects were reported. Adverse events were evaluated according to the NCI-CTC criteria. Eighty-nine patients were enrolled into the study. The complete responses during the acute phase were 95.4 and 93.3%, respectively. The main side effects were headache 4.5%, constipation 15.7%, anxiety 2.3%. Palonosetron is a very active antiemetic drug for the prevention of nausea and vomiting in NSCLC patients received chemotherapy.
