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Objective: To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy., Design: Open-label, prospective, multi-center phase II trial., Setting: Three institutions., Participants: Fifty-four patients scheduled to receive CapeOX chemotherapy., Interventions: Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone., Main Outcome Measures: The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life., Results: The complete control rate for delayed CINV over the entire period (25-480 h) was 72.7% (95% CI 0.57-0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69-0.95). No serious adverse events related to the antiemetic regimen were reported., Conclusion: Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX., Trial Registration: ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021., (© 2024. The Author(s).)

Background: Mirtazapine blocks 5-hydroxytryptamine type (5-HT) 2A , 5-HT 2C , 5-HT 3 and histamine H 1 receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers., Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24-120 h)., Results: Between July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24-120 h), overall (0-120 h), and acute periods (0-24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0., Conclusions: Prophylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA-based regimen at AUC ≥ 4 mg/mL per minute., Competing Interests: Declaration of competing interest Dr. Iihara has received personal fees from Taiho, Chugai, Yakult, Astellas, Eli Lilly, Daiichi Sankyo, AstraZeneca, Nippon Kayaku, Ono, and Nippon Boehringer Ingelheim and consulting fees for their institution from Taiho and Eisai outside the submitted work. Dr. Morita has received personal fees from AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Amgen, Eli Lilly, Takeda, Taiho, Thermo Fisher, Nihon Kayaku, MSD, Novartis, Pfizer outside the submitted work. Ms. Hirose has received personal fees from Eli Lilly, Eisai, Merck, Chugai, and Nippon Kayaku outside the submitted work. Dr. Kawazoe has received grants for their institution from Eli Lilly outside the submitted work. Dr. Fukunaga has received personal fees from Boehringer Ingelheim, Novartis, Sanofi, GlaxoSmithKline, AstraZeneca, and Kyorin outside the submitted work and grants for their institution from Boehringer Ingelheim and Chugai outside the submitted work. Dr. Fukunaga has received personal fees from Boehringer Ingelheim, Novartis, Sanofi, GlaxoSmithKline, AstraZeneca, and Kyorin outside the submitted work and grants for their institution from Boehringer Ingelheim and Chugai outside the submitted work. Dr. Suzuki has received personal fees from Toa Eiyo, Asahi Kasei, Daiichi Sankyo, Pfizer, Eisai, Nippon Shinyaku, Celltrion Healthcare Japan, Otsuka, Sandoz, Tsumura, Nipro, Taiho, Kyowa-Kirin, Nippon Chemiphar, Japan Blood Products Organization, Takeda, and Nippon Boehringer Ingelheim and grants for their institution from Nippon Kayaku, Asahi Kasei, Chugai, Taiho, Daiichi Sankyo, Japan Blood Products Organization, Mochida, and Sun Pharma outside the submitted work. Other authors do not have conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT 3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT 3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT 3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT 3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT 3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT 3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Administration of L-3,4-dihydroxyphenylalanine (L-DOPA) provides Parkinson's disease patients with effective symptomatic relief. However, long-term L-DOPA therapy is often marred by complications such as dyskinesia. We have previously demonstrated that serotonin type 3 (5-HT3) receptor blockade with the clinically available and highly selective antagonist ondansetron alleviates dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to explore the antidyskinetic efficacy of granisetron, another clinically available 5-HT3 receptor antagonist. Rats were rendered hemi-parkinsonian by 6-OHDA injection in the medial forebrain bundle. Following induction of stable abnormal involuntary movements (AIMs), granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or vehicle was acutely administered in combination with L-DOPA and the severity of AIMs, both duration and amplitude, was determined. We also assessed the effect of granisetron on L-DOPA antiparkinsonian action by performing the cylinder test. Adding granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) to L-DOPA resulted in a significant reduction of AIMs duration and amplitude, with certain parameters being reduced by as much as 38 and 45% (P < 0.05 and P < 0.001, respectively). The antidyskinetic effect of granisetron was not accompanied by a reduction of L-DOPA antiparkinsonian action. These results suggest that 5-HT3 blockade may reduce L-DOPA-induced dyskinesia without impairing the therapeutic efficacy of L-DOPA. However, a U-shaped dose-response curve obtained with certain parameters may limit the therapeutic potential of this strategy and require further investigation., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Patients who undergo multiple-day chemotherapy sessions experience hard-to-treat nausea and vomiting. Currently, there is no effective standard treatment for this condition. This study compared the preventive effect of first-generation 5-hydroxytryptamine 3 receptor antagonists (5-HT 3 RAs) and second-generation 5-HT 3 RAs palonosetron in multiple-day chemotherapy-induced nausea and vomiting. The design of this study was a retrospective case-control study of patients who received a five-day cisplatin-based chemotherapy and were treated with aprepitant, dexamethasone, granisetron, and ramosetron or palonosetron. The patients were divided into two groups: patients given granisetron and ramosetron (the first-generation group), and those given palonosetron (palonosetron group). The percentage of patients with a complete response or total control was assessed. They were divided into three phases: 0-216 h (overall phase), 0-120 h (remedial phase), and 120-216 h (after phase). The remedial phase was further divided into 0-24 h (early phase) and 24-120 h (later phase). Moreover, the nutritional status of each patient was assessed by noting the patients' total calorie-intake per day and total parenteral nutrition. First-generation 5-HT 3 RAs and palonosetron were used for treatment in 18 and 28 patients, respectively. The complete response rate and caloric oral intake of the later phase were higher in the palonosetron group than in the first-generation group. We conclude that palonosetron treatment was more effective than first-generation 5-HT 3 RAs in controlling multiple-day chemotherapy-induced nausea and vomiting.

The triplet antiemetic regimen is administered to prevent chemotherapy-induced nausea and vomiting (CINV) after moderately emetogenic chemotherapy (MEC). However, the superiority of palonosetron over first-generation 5-hydroxytryptamine-3 receptor antagonists in triplet antiemetic therapy remains unclear. In this study, we evaluated the efficacy of palonosetron (PALO) and granisetron (GRA) in triplet antiemetic therapy for CINV. This study included 267 patients who received MEC at our hospital between April 2017 and September 2020. Patients were pretreated with antiemetic therapy comprising PALO or GRA and dexamethasone on day 1 and aprepitant on days 1-3. We evaluated the rate of complete response (CR) (i.e., no vomiting and no use of rescue medication) in the acute phase (0-24 h), delayed phase (24-120 h), and overall phase (0-120 h) after first-cycle chemotherapy. Furthermore, multivariate analysis was conducted to identify risk factors for non-CR. The rate of CR in the overall and delayed phases was significantly higher in the PALO group (91.9 and 91.9%, respectively) than in the GRA group (74.1 and 75.5%, respectively). In the acute phase, the incidence was not different between the GRA and PALO groups (96.5 and 99.2%, respectively). Multivariate analysis revealed that female sex and the use of GRA were risk factors for non-CR. Subgroup analysis revealed the superiority of PALO over GRA in female patients, but not in male patients. In conclusion, PALO was more effective than GRA in triplet antiemetic therapy in preventing CINV during MEC, especially for female patients.

Purpose: To compare rates of complete response (no emesis, retching, or rescue antiemetics) in the late phase (days 4-7 post-chemotherapy) of cycle 1 between transdermal granisetron and oral ondansetron in cervical, endometrial, or vaginal cancer survivors undergoing chemoradiation at The University of Texas MD Anderson Cancer Center and LBJ Hospital in Houston, TX., Methods: In this non-blinded parallel design trial, eligible patients received a granisetron patch replaced every 7 days or 8 mg of ondansetron thrice daily continued for 72 h after chemotherapy completion. Data were collected on medication compliance, episodes of chemotherapy-induced nausea and vomiting (CINV), use of rescue antiemetics, and effects of CINV on quality of life., Results: Seventy-five survivors receiving chemoradiation for cervical (n = 61), endometrial (n = 12), or vaginal (n = 2) cancer were electronically randomized to transdermal granisetron (n = 41) or oral ondansetron (n = 34). In the late phase of cycle 1, the rate of complete response was 49.8% (95% CI, 35.2-64.3%) for transdermal granisetron and 39.7% (95% CI, 24.4-56.1%) for oral ondansetron. The posterior probability that transdermal granisetron achieved a higher success rate in controlling late-onset CINV compared with oral ondansetron was 82%. During the acute phase (day 1 post-chemotherapy) of cycles 2 and 3, transdermal granisetron patients used more rescue antiemetics than oral ondansetron patients (p = 0.006 and p = 0.003, respectively). Otherwise, no between-group differences in CINV events were observed. Medication compliance and the effect of CINV on quality of life were similar between groups., Conclusion: Transdermal granisetron was 82% more like to control CINV than oral ondansetron in the late phase of cycle 1 and performed similarly to oral ondansetron in all other cycles. Transdermal granisetron should be considered an option as prophylactic antiemetic therapy for gynecologic cancer survivors undergoing chemoradiation.

Purpose: To compare the efficacy of transdermal granisetron versus oral granisetron in controlling chemotherapy-induced nausea and vomiting (CINV) in patients with cancer METHODS: Data sources were CENTRAL, MEDLINE, EMBASE, Clinicaltrials.gov , and Google Scholar. Inclusion criteria included randomized controlled trials comparing transdermal versus oral granisetron in patients with CINV. For data extraction, two authors independently analyzed the methodological quality and extracted data. A random effects model was used to estimate the risk ratio (RR) or odds ratio (OR) with 95% confidence interval (CI)., Results: Three studies (1086 patients) were included. Oral granisetron is superior (OR 0.77; 95% CI 0.60 to 0.99) to its transdermal form in achieving complete control of CINV in patients receiving chemotherapy. As for the risk of constipation (RR 1.32; 95% CI 0.73 to 2.40) and QTc prolongation (RR 0.17; 95% CI 0.02 to 1.40) as adverse effects, no statistically significant difference was observed between the two routes., Conclusion: Oral granisetron is better in achieving complete control of CINV in patients receiving chemotherapy. As for the risk of constipation and QTc prolongation as adverse effects, there was no statistically significant difference between the two routes.

Introduction: Chemotherapy-induced nausea and vomiting (CINV) can be a serious and debilitating adverse effect that is highly feared by cancer patients. For patients receiving moderately emetogenic chemotherapy regimens at our institution in the ambulatory infusion center, palonosetron was selected as the preferred serotonin (5-HT3) antagonist for CINV prophylaxis per the 2016 NCCN Guidelines, when a neurokinin1 antagonist was not included in the prophylactic regimen. The purpose of this study was to evaluate the efficacy of dexamethasone and palonosetron versus granisetron for the prevention of CINV in patients receiving moderately emetogenic chemotherapy regimens., Methods: This study is an Institutional Review Board-approved, single-center retrospective review of electronic health records including patients who received moderately emetogenic chemotherapy regimens with CINV prophylaxis with dexamethasone and either palonosetron or granisetron., Results: A total of 268 eligible patients were included in the study. Eighty-eight patients received palonosetron and 180 patients received granisetron as their 5-HT3 receptor antagonist between October 31, 2014 and October 31, 2016. There were no statistically significant differences between the two antiemetic groups for the primary outcome of presence of any change in day 1 intravenous prophylactic antiemetics. Nine (10.23%) palonosetron patients and 15 (8.33%) granisetron patients required a change in their day 1 intravenous prophylactic antiemetics ( P  = 0.610)., Conclusions: Despite palonosetron's better efficacy, longer half-life, and higher binding affinity, the results of this retrospective review demonstrates that the choice of serotonin antagonist, palonosetron or granisetron, did not result in a change in day 1 intravenous prophylactic antiemetics or antiemetic outpatient medications for patients undergoing moderately emetogenic chemotherapy regimens.

Chemotherapy-induced nausea and vomiting (CINV) is a common treatment-related adverse event that negatively impacts the quality of life of cancer patients. During pediatric drug development, extrapolation of efficacy from adult to pediatric populations is a pathway that can minimize the exposure of children to unnecessary clinical trials, improve efficiency, and increase the likelihood of success in obtaining a pediatric indication. The acceptability of the use of extrapolation depends on a series of evidence-based assumptions regarding the similarity of disease, response to intervention, and exposure-response relationships between adult and pediatric patients. This study evaluated publicly available summaries of data submitted to the US Food and Drug Administration for drugs approved for CINV to assess the feasibility of extrapolation for future development programs. Extracted data included trial design, emetogenic potential of chemotherapy, primary end points, participant enrollment criteria, and antiemetic pharmacokinetics. Adult and pediatric clinical trial designs for assessment of efficacy and safety shared key design elements. Antiemetic drugs found to be efficacious in adults were also efficacious in pediatric patients. Systemic drug concentrations at approved doses were similar for ondansetron, granisetron, and aprepitant, but an exposure-response analysis of palonosetron in children suggested that higher palonosetron systemic exposure is necessary for the prevention of CINV in the pediatric population. For 5-hydroxytryptamine-3 and neurokinin-1 receptor antagonist antiemetic drugs, efficacy in adults predicts efficacy in children, supporting the extrapolation of effectiveness of an antiemetic product in children from adequate and well-controlled studies in adult patients with CINV., (© 2020, The American College of Clinical Pharmacology.)

Background: Chemotherapy-induced nausea and vomiting (CINV) is a severe and distressing complication during allogeneic hematopoietic stem cell transplantation (alloHSCT). The antiemetic fosaprepitant has shown favorable results in pediatric and adult patients receiving chemotherapy. Data on fosaprepitant in children and adolescents undergoing alloHSCT are missing., Methods: In this non-interventional observation study, 120 children and adolescents with a median age of 11.8 years undergoing alloHSCT after a moderately or highly emetogenic conditioning (MEC or HEC) were analyzed. They received an antiemetic prophylaxis with granisetron (2 × 40 µg/kg d -1 ) with or without fosaprepitant (4 mg/kg; single dose, max. 1 × 150 mg/kg BW), and were analyzed in the control (CG; n = 60) or fosaprepitant group (FG; n = 60). The efficacy and safety of the two antiemetic prophylaxis regimens were analyzed and compared with respect to the acute (0-24 h) and the delayed (> 24-120 h) CINV phase and > 120-240 h after MEC or HEC administration., Results: During MEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (58.6 vs. 25.0%; p = 0.0156) and during > 24-120 h (93.1% vs. 57.1%; p = 0.0020), compared with the FG. Likewise, significantly more vomiting events (269 vs. 136; p < 0.0001) were registered in the CG. During HEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (32.3 vs. 9.4%; p = 0.0319) compared with the FG. Significantly more vomiting events (241 vs. 99; p < 0.0001) were registered in the CG. Laboratory and clinical adverse events were not significantly different between the two groups (p > 0.05)., Conclusions: Antiemetic prophylaxis with fosaprepitant and granisetron was well tolerated, safe, and effective in pediatric patients undergoing alloHSCT. However, larger prospective trials are necessary to evaluate these findings.

In oral bioavailability studies, evaluation of the absorption and transport of drugs and food components across the intestinal barrier is crucial. Advances in the field of organ-on-a-chip technology have resulted in a dynamic gut-on-a-chip model that better mimics the in vivo microenvironment of the intestine. Despite a few recent integration attempts, ensuring a biologically relevant microenvironment while coupling with a fully online detection system still represents a major challenge. Herein, we designed an online technique to measure drug permeability and analyse unknown product formation across an intestinal epithelial layer of Caco-2 and HT29-MTX cells cultured on a flow-through Transwell system, while ensuring the quality and relevance of the biological model. Chip-based ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was coupled to the dynamic Transwell system via a series of switching valves, thus allowing alternating measurements of the apical and basolateral sides of the in vitro model. Two trap columns were integrated for online sample pre-treatment and compatibility enhancement. Temporal analysis of the intestinal permeability was successfully demonstrated using verapamil as a model drug and ergotamine epimers as a model for natural toxins present in foods. Evidence was obtained that our newly developed dynamic system provided reliable results versus classical static in vitro models, and moreover, for the first time, epimer-specific transport is shown for ergotamine. Finally, initial experiments with the drug granisetron suggest that metabolic activity can be studied as well, thus highlighting the versatility of the bio-integrated online analysis system developed. Graphical abstract.

Background: Chemotherapy-induced nausea and vomiting (CINV) are a major burden for patients undergoing emetogenic chemotherapy. International guidelines recommend an antiemetic prophylaxis with corticosteroids, 5-HT 3 R-antagonists and NK 1 R-antagonists. The NK 1 R-antagonist fosaprepitant has shown favorable results in pediatric and adult patients. There is little pediatric experience with fosaprepitant., Methods: This non-interventional observation study analyzed 303 chemotherapy courses administered to 83 pediatric patients with a median age of 9 years (2-17 years), who received antiemetic prophylaxis either with fosaprepitant and granisetron with or without dexamethasone (fosaprepitant group/FG; n=41), or granisetron with or without dexamethasone (control group/CG; n=42), during moderately (CINV risk 30-90%) or highly (CINV risk>90%) emetogenic chemotherapy. The two groups' results were compared with respect to the safety and efficacy of the antiemetic prophylaxis during the acute (0-24hrs after chemotherapy), delayed (>24-120hrs after chemotherapy) and both CINV phases. Laboratory and clinical adverse events were compared between the two cohorts., Results: Adverse events were not significantly different in the two groups (p>0.05). Significantly fewer vomiting events occurred during antiemetic prophylaxis with fosaprepitant in the acute (23 vs 142 events; p<0.0001) and the delayed (71 vs 255 events; p<0.0001) CINV phase. In the control group, the percentage of chemotherapy courses with vomiting was significantly higher during the acute (24%/FG vs 45%/CG; p<0.0001) and delayed CINV phase (28%/FG vs 47%/CG; p=0.0004). Dimenhydrinate (rescue medication) was administered significantly more often in the CG, compared to the FG (114/FG vs 320/CG doses; p<0.0001). Likewise, in the control group, dimenhydrinate was administered in significantly more (p<0.0001) chemotherapy courses during the acute and delayed CINV phases (79 of 150; 52.7%), compared to the fosaprepitant group (45 of 153; 29.4%)., Conclusion: Antiemetic prophylaxis with fosaprepitant and granisetron with or without dexamethasone was well tolerated, safe and effective in pediatric patients. However, larger prospective trials are needed to evaluate these findings., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Cabanillas Stanchi et al.)

Introduction: The incidence, mortality, and treatment costs of sepsis are high and, thus, present a major challenge for critical care medicine. Our previous studies suggest that intestinal metabolite granisetron has a potential therapeutic effect on sepsis. Granisetron is a clinically widely used antiemetic, which is safe, inexpensive, and reliable. However, its value in the treatment of sepsis remains unclear. This study aims to explore the efficacy and safety of granisetron in the treatment of sepsis., Methods and Analysis: A single-center, single-blind, randomized, controlled clinical trial will be conducted on 154 patients with sepsis. Patients who meet sepsis 3.0 diagnostic criteria, aged ≥18 and ≤80 years, with PCT ≥ 2 ng/mL will be recruited. Patients will be randomized to receive intravenous granisetron 3 mg every 8 hours (n = 77) or an equal volume of normal saline (n = 77) for a treatment period of 4 days or to ICU discharge. The primary outcome is 28-day all-cause mortality. Secondary outcome measures include requirements for organ function support, changes of organ function, changes in infection biomarkers, changes in inflammatory and immune biomarkers, and the proportion of new organ failure. Adverse events and serious adverse events also will be observed closely., Ethics and Dissemination: The study was approved by the Clinical Ethics Committee of Zhujiang Hospital of Southern Medical University (2018-ZZJHZX-009). The trial results will be disseminated at national and international conferences and through peer-reviewed journal., Trial Registration: NCT03924518.URL: www.clinicaltrials.gov., Protocol Date: 1 May 2019. version 2.1.

Objective: To assess the effect of a 5-hydroxytryptamine-3 receptor antagonist (granisetron) on the use of sympathomimetic (cafedrine/theodrenaline) and uterotonic (oxytocin) agents after spinal anesthesia during cesarean delivery., Methods: A retrospective observational analysis was conducted using intraoperative records (n=240) created at a single hospital in Germany between November 1, 2016, and July 31, 2017. The granisetron group (n=120) had received 3 mg of granisetron immediately before induction of spinal anesthesia. The control group (n=120) had not received granisetron. The primary endpoints were the intraoperative requirements for sympathomimetic and uterotonic agents. The secondary endpoints were parameters of intraprocedural maternal hemodynamic and clinical states., Results: More patients in the granisetron group than in the control group received intraoperative cafedrine/theodrenaline (P=0.045), with the cumulative intraoperative dosage also increased in the granisetron group (P=0.016). By contrast, the cumulative intraoperative dose of oxytocin was lower in the granisetron group than in the control group (P<0.001). Decreases in heart rate and mean arterial blood pressure were lower in the granisetron group versus the control group (P=0.015 and P=0.002, respectively)., Conclusion: Treatment with granisetron immediately before cesarean delivery did not reduce the perioperative requirement for sympathomimetics but did reduce the need for uterotonics. REGISTERED AT CLINICALTRIALS.GOV (NCT03318536)., (© 2019 International Federation of Gynecology and Obstetrics.)

Purpose: We aimed to investigate the efficacy of 0.25 mg dose of palonosetron and granisetron in triplet antiemetic prophylaxis in breast cancer patients receiving HEC., Methods: Patients with nonmetastatic breast cancer who received HEC [doxorubicin or epirubicin plus cyclophosphamide (AC/EC)] were enrolled in the study. The prophylactic triplet antiemetic regimens were used according to the doctor's preference during the first cycle of HEC as intravenous dexamethasone and palonosetron 0.25 mg or granisetron 3 mg on day 1 as well as oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3).The primary endpoint was complete response rate (CR) on acute and delayed chemotherapy-induced nausea and vomiting (CINV), separately., Results: A total of 118 female patients were included in the study. Patients received AC (83%), EC (3%), and dose-dense AC (14%) as adjuvant (88%) or neoadjuvant (12%). The majority of patients received palonosetron (59%) containing antiemetic treatment. The CR rate on acute and delayed vomiting was very high and not statistically different in both of the arms (acute 87% vs. 96%, p = 0.089; delayed 90% vs. 92%, p = 0.489), respectively. Nevertheless, the CR rate on either acute or delayed nausea was lower than vomiting (acute 51% vs. 51%; delayed 38% vs. 29%, p = 0.203; respectively)., Conclusions: This is the second study that compared a 0.25 mg dose of palonosetron with first-generation setron in triplet antiemetic prophylaxis in cancer patients receiving HEC. We could not find meaningful statistical differences between two arms, regarding CR rate on acute and delayed CINV.

Nausea and vomiting induced by chemotherapy (CINV) occur in 70-80% of onco-haematological patients undergoing antiblastic therapy. The anti-emetic therapy chosen according to the guidelines and characteristics of the single patient solve CINV in about 80% of cases. The concept of supportive care, which includes the treatment of CINV, has been formalized by the Multinational Association Supportive Care in Cancer (MASCC) to prevent and manage the side effects of antiblastic therapy. The evaluation of co-morbidities makes it possible to choose the most suitable antiemetic drug in compliance with multi-drug non-oncology therapies. The most immediate benefits are an improvement in the quality of life (QoL), a greater adherence of the patient to cancer therapy, and a lower interaction between drugs.

Background/aim: The control of chemotherapy-induced nausea and vomiting during bleomycin, etoposide, and cisplatin (BEP) treatment is important for maintaining treatment intensity. The effects of palonosetron and granisetron were compared in BEP chemotherapy., Patients and Methods: The administration of palonosetron on days 1 and 5 (Pal method) and granisetron daily (days 1-5, Gra method) were compared in terms of their efficacy and cost-effectiveness., Results: Additional rescue antiemetic agents were used in 15 of 32 and 30 of 30 cycles in the Pal and Gra method groups, respectively (p<0.05). The complete response rate, defined as no vomiting and no rescue agent usage, in each cycle, was 50% and 0% in the Pal and Gra method groups, respectively (p<0.05). The average cost of antiemetic agents in a cycle was 50,759 and 54,555 yen in the Pal and Gra method groups, respectively (p<0.05)., Conclusion: The Pal method may be the standard method in BEP., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims: To examine the pharmacokinetics and safety of granisetron during transdermal delivery and oral administration to healthy Chinese male subjects., Materials and Methods: A single 34.3 mg/52 cm 2 transdermal delivery patch of granisetron and the 1-mg tablet of granisetron were dosed to subjects in an open-label, randomized, crossover study. Two dosing schemes were established: scheme 1, in which the 5-day oral administration phase of the tablet (the OA phase) (twice daily every 12 hours) was conducted, followed by the 6-day transdermal delivery phase of the patch (the TD phase); and scheme 2, in which these two phases were conducted in reverse order. Plasma concentrations of granisetron were measured according to high-performance liquid chromatography, and the following pharmacokinetic parameters were determined: C avg [AUC 0-24,ss (day 5)/24 for OA and AUC 24-144 /120 for TD], C max , t max , AUC, and T 1/2 ., Results: All of the subjects completed the TD phase, and 1 subject withdrew from the study due to increased alanine aminotransferase. The C avg values for OA and TD were 2.95 ± 1.60 ng/mL and 2.83 ± 1.43 ng/mL, respectively. The C max values at steady state for OA and TD were 5.98 ± 2.27 ng/mL and 3.91 ± 2.23 ng/mL, respectively. The incidences of adverse events (AEs) possibly or definitely related to OA and TD were 45.83% and 37.5%, respectively. No serious AEs were found in the two dosing schemes., Conclusion: The C avg values determined through TD and OA were equivalent, indicating similar drug exposures. Therefore, the granisetron patch may be an alternative formulation for oral granisetron in Chinese individuals.
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Palonosetron is a new, potent and long-acting 5HT3-receptorsantagonist that had been approved by the FDA for use in postoperative nausea and vomiting (PONV) prophylaxis. The objective of this study was to investigate and compare the prophylactic effects of intravenously administered palonosetron, ondansetron and granisetron on prevention of postoperative nausea and vomiting after general anesthesia. This randomized double blind prospective clinical study was carried out in the Department of Anaesthesia, DMCH, Dhaka, Bangladesh from January 2014 to December 2015. A total of 102 patients who underwent laparoscopic cholecystectomy under general anesthesia, out of which patients who received Palonosetron were in Group A (n=34), patients who received Ondansetron were in group B (n=34) and patients who received Granisetron were in group C (n=34) and also the patients were selected randomly by lottery method. Statistical analyses of the results were obtained by using window based computer software devised with Statistical Packages for Social Sciences (SPSS-22). Nausea was found 3(8.8%) in group A, 8(23.5%) in group B and 6(17.6%) in group C. Vomiting was found 3(8.8%) in group A, 10(29.4%) in group B and 7(20.6%) in group C. Vomiting was significantly higher in group B compare with group A. For group B rescue anti-emetic injection motilon (metoclopramide hydrochloride) 5mg IV slowly was given. Palonosetron is effective prophylaxis against post operative nausea and vomiting.

Since the peripheral serotoninergic pathway is involved in the development of radiation-induced nausea and vomiting, referred to as radiation sickness, serotonin 5-HT 3 receptor antagonists are used as a preventive measure, although patients still suffer from these symptoms. Glutamate is known as the excitatory neurotransmitter and is involved in various autonomic symptoms. We investigated the effect of radiation on glutamate release in rats, as measured by in vivo brain microdialysis, and the effects of glutamate receptor antagonists on radiation-induced pica, which can be used as a behavioral assessment of radiation sickness in rats. A microdialysis probe was inserted into the hypothalamus of rats that received 4 Gy total-body irradiation (TBI) with or without pretreatment of 5-HT 3 receptor antagonist (granisetron, 0.1 mg/kg, i.p.), and dialysates were collected for 3 h after TBI and subjected to HPLC assay of glutamate. In addition, rats were intracerebroventricularly injected with NMDA receptor antagonist (MK-801: 3 μg/rat) or AMPA receptor antagonist (CNQX: 1 μg/rat) before TBI, and radiation-induced pica was determined. An increase in glutamate release was observed within 1 h postirradiation. The increased glutamate release was suppressed by granisetron. We also found that CNQX, but not MK-801, effectively inhibited radiation-induced pica. These results indicate that the hypothalamic glutamatergic system contributes to radiation-induced pica through the AMPA receptors.

In the management of cancer patients, supportive therapies play a crucial role. In patients with HNSCC in particular, swallowing may be difficult or completely prevented, therefore it is necessary to resort to alternative routes of administration instead of the oral one. The use of transdermal patches containing granisetron is thereby particularly indicated for the management of nausea and vomiting in these patients, ensuring a better quality of life and better compliance to the antineoplastic therapy.

The aim of this study was to formulate granisetron hydrochloride (GH) spanlastic in mucoadhesive gels and lyophilized inserts for intranasal administration to improve GH bioavailability and brain targeting. Carpapol 934 and HPMC were incorporated in GH spanlastic in nasal gels (GHSpNGs). Gelatin and HPMC as matrix former, glycine as a collapse protecting and mannitol as an insert filler and sweeting agent were used to prepare GH spanlastic loaded in lyophilized inserts (GHSpNIs). The prepared GHSpNGs were characterized for pH measurement, drug content, rheology, and in vitro drug release. The prepared GHSpNIs were characterized for drug content, surface pH, GH release, and mucoadhesion. Biological investigations including pharmacokinetics studies and brain drug targeting efficiency dimensions were performed on rats (LC-MS/MS). The results showed thixotropic pseudoplastic gels and white insert with pH values in a physiological range, drug content (89.9-98.6%), (82.4-98.38%) for gel and insert, respectively and rapid release rate of GH. Biological studies showed that C max and AUC 0-6 h in brain and plasma after intranasal administration of gel and insert were higher compared to IV administration of GH solution. A high brain targeting efficiency (199.3%, 230%) for gel and insert, respectively and a direct nose to brain transport (49.8%, 56.95%) for gel and insert, respectively confirmed that there is a direct nose to brain transport of GH following nasal administration of GH spanlastic loaded in nasal gel and insert. GHSpNIs can be considered as potential novel drug delivery system intended for brain targeting via the nasal rout of administration than GHSpNGs.

Purpose: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug., Methods: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course., Results: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%-83%) in the overall phase and 91% (95% CI: 78%-97%) in the acute phase and 70% (95% CI: 55%-83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed., Conclusions: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Purpose: To assess the gelation power of N-palmitoyl L-alanine derivatives in injectable oils and to use the best chosen organogel as parenteral implant of granisetron for the treatment of emesis., Methods: Twelve N-palmitoyl L-alanine derived organogels were developed and evaluated in terms of morphology, thermal properties and in vivo performance. The ability of the selected formula to form in situ gel upon subcutaneous injection in rats and its biocompatibility were monitored over 2 weeks by histopathological examination of the injection site., Results: The acid derivative (N-palmitoyl L-alanine; PA) was superior to ester derivatives. The chosen formula (PA/safflower oil 10% w/v) was successful in forming an in situ gel of granisetron when subcutaneously injected in rats, lasting for 2 weeks and proved to be biocompatible by histopathological examination. Moreover, it exerted an extended antiemetic activity by decreasing the cisplatin-induced pica for a duration of 96 h and reduced preprotachykinin A mRNA expression and Substance P level for up to 4 days (gastric tissue) or 5 days (medulla oblongata) in rats., Conclusion: Granisetron organogel could be considered as a safe, sustained-release and supportive anticancer treatment in both acute and chronic emesis as well as an accompanying treatment with chemotherapeutics in cancer cases.

Cancer chemotherapy often induces gastrointestinal symptoms such as anorexia, nausea, and vomiting. Antiemetic agents are effective in inhibiting nausea and vomiting, but patients still experience anorexia. We previously reported that chemotherapeutic agent-induced anorexia is associated with an increase of inflammatory cytokines. Other studies also reported that antagonism of the histamine H 4 receptor is anti-inflammatory. In this study, we investigated the involvement of the H 4 receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin-induced anorexia occurred within 24 h of its administration and continued for 3 days. The early phase (day 1), but not the delayed phase (days 2 and 3), of anorexia was inhibited by the daily injection of a 5-HT 3 receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H 4 receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-α mRNA expression in the hypothalamus and spleen, and the period of expression increase paralleled the onset period of anorexia. In addition, pretreatment with JNJ7777120 completely inhibited the increased expression. These results suggest that TNF-α mRNA expression via H 4 receptors may contribute to the development of cisplatin-induced anorexia, and that H 4 receptor antagonists are potentially useful treatments., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The antiemetic effects and safety of granisetron and palonosetron against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy. A total of 61 patients were eligible for this study. Before starting the bendamustine-based chemotherapy, granisetron or palonosetron were intravenously administered with or without aprepitant and/or dexamethasone. The proportions of patients with complete control (CC) during the overall (during the 6 days after the start of the chemotherapy), acute (up to 2 days), and delayed (3 to 6 days) phases were assessed. CC was defined as complete response with only grade 0-1 nausea, no vomiting, and no use of antiemetic rescue medication. Granisetron or palonosetron alone were administered to 9 and 19 patients, respectively. Aprepitant and/or dexamethasone were combined with granisetron and palonosetron in 28 and 5 patients, respectively. Acute CINV was completely controlled in all patients. Both granisetron monotherapy and palonosetron combination therapy could provide good control of delayed CINV, although the CC rates during the delayed and overall phases were not significantly different among mono- and combination therapy of the antiemetics. There was no significant difference in the frequencies of adverse drug events between the granisetron and palonosetron treatment groups. The present study showed that the antiemetic efficacy and safety of granisetron-based therapy were non-inferior to those of palonosetron-based therapy. Taken together with treatment costs, granisetron monotherapy would be adequate to prevent CINV in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy.

Swellable microneedles (SMNs) are made of hydrogels and can deliver drug with controlled delivery rate by the cross-link density of the hydrogel. In this study, an acryl resin-based SMNs was developed for poorly water-soluble drugs. The making process of the SMNs is very simple and only need 60 min. The SMNs has high mechanical strength and is not easily broken. In-vitro release of SMNs-loaded model drug, granisetron base (GRB), was investigated. The results showed that seven days controlled release of GRB was obtained when SMNs contained pore-foaming agents (1.5% dicalcium phosphate (CaHPO 4 ) and 1.5% polyvinylpyrrolidone (PVP)). The maximum amount delivered into skin was 86.158 ± 7.82% of the initial GRB (2.1 mg) loaded on SMNs preparation. Pharmacokinetics study in rats indicated a dose-dependent profile of plasma GRB concentrations and that the controlled release of 2.1 mg dose was observed for 144 hours. In conclusion, these SMNs provided a potential minimally invasive route for controlled-release systemic delivery of poorly water-soluble drugs.

Prophylaxis or therapy with a combination of a neurokinin 1 (NK-1) receptor antagonist (RA), a 5-hydroxytryptamine- 3 (5-HT3) RA, and dexamethasone is recommended by international antiemesis guidelines for the prevention of chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy and for select patients receiving moderately emetogenic chemotherapy. VARUBI (rolapitant) is a substance P/NK-1 RA that was recently approved by the U.S. Food and Drug Administration as an injectable emulsion in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Granisetron Hydrochloride Injection USP is one of the 5-HT3 RAs indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Herein, we describe the physical and chemical compatibility and stability of VARUBI (rolapitant) injectable emulsion (166.5 mg/92.5 mL [1.8 mg/mL], equivalent to 185 mg of rolapitant hydrochloride) admixed with Granisetron Hydrochloride Injection USP (1.0 mg/mL, equivalent to 1.12 mg/mL hydrochloride). Binary admixtures of VARUBI injectable emulsion and Granisetron Hydrochloride Injection USP were prepared and stored in VARUBI ready-to-use glass vials and in four types of commonly used intravenous administration (tubing) sets. Evaluation of the physical and chemical compatibility and stability of the admixtures in the VARUBI ready-to-use vials stored at room temperature (20°C to 25°C) under fluorescent light and under refrigeration (2°C to 8°C protected from light) was conducted at 0, 1, 6, 24, and 48 hours, and that of the admixtures in the intravenous tubing sets was evaluated at 0, 2, and 6 hours of storage at 20°C to 25°C. Physical stability was evaluated by visual examination of the container contents under normal room light, and measurement of turbidity, globule size, and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations (potency) and impurity levels by high-performance liquid chromatographic analysis. The pH, turbidity, globule size, and particulate matter of all samples remained within narrow and acceptable ranges at all study time points, indicating that combining the two formulations into a binary admixture is physically and chemically compatible and stable. VARUBI injectable emulsion admixed with Granisetron Hydrochloride Injection USP demonstrated compatibility and stability in a ready-to-use glass vial for at least 24 hours at room temperature and 48 hours under refrigeration, as well as in the four intravenous tubing sets for at least 6 hours at 20°C to 25°C. No decrease of drug concentration (or potency) of any admixed components occurred in the samples stored at the two conditions and time periods studied based on high-performance liquid chromatographic analysis. The levels of impurities stayed below the safety limits set by International Conference on Harmonisation during the study period., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Introduction: Chemotherapy induced nausea and vomiting (CINV) are major side effects of chemotherapy and a great burden to patients' quality of life. Serotonin and substance P are the major neurotransmitters involved in the pathophysiology of CINV, but in spite of new antiemetics no completely effective regime exists for its prevention or treatment. Areas covered: In this review the authors provide a detailed description of granisetron's chemistry pharmacokinetics, pharmacodynamics, toxicity and a brief review of clinical trials involving granisetron and the management of CINV. We searched reviews, meta-analysis and randomized controlled trials (Medline, Embase and article reference lists). Expert opinion: According to current literature, granisetron 2 mg orally or 0,01mg/kg (1 mg) intravenously per day, co-administered with dexamethasone and NK-1 antagonists is the recommended regime for highly emetogenic chemotherapy. In the future the role of transdermal and subcutaneous formulations against delayed CINV will be clarified and probably enhance patients' convenience.

Background Two pivotal Phase III trials compared the efficacy of palonosetron, ondansetron and granisetron, combined with dexamethasone, for the prevention of nausea and vomiting following highly emetogenic chemotherapy. However, an economic evaluation of these three regimens in the real-world setting of Chinese adult patients has not been determined. Objectives To estimate, from the perspective of the Chinese healthcare system, which of these frequently used strategies consisting of 0.25 mg palonosetron (0.25P), 16 mg ondansetron (Onda), and 3 mg granisetron (Gran), is the most cost-effective option in patients following highly emetogenic chemotherapy. Methods A Markov decision-analytic model was developed. The health and economic outcomes of the three strategies; 0.25P, Onda, and Gran were investigated. The clinical and utility data were taken from published studies. The cost data were calculated according to current local Chinese practices. Sensitivity analyses were performed to determine the impact of uncertainty regarding the results. Results The base-case analysis showed that the 0.25P strategy yielded maximum health benefits compared with the other two strategies. However, the probabilistic sensitivity analysis demonstrated that the Gran strategy was the most cost-effective approach when the willingness-to-pay threshold was not more than US$22,515/quality-adjusted life year. Moreover, palonosetron is not cost-effective in preventing 'overall' nausea and vomiting following highly emetogenic chemotherapy in Chinese patients. Conclusions Our analysis suggests that, compared with palonosetron and ondansetron, 3 mg granisetron may be a cost-effective treatment option in the current Chinese healthcare setting.

Albumin-bound paclitaxel (Abraxane®, nab-paclitaxel) is not recommended to be administered concurrently or sequentially with other drugs due to concern for instability. The need to administer drugs separately increases infusion time. We evaluated the compatibility and stability of solutions containing nab-paclitaxel and other drugs, including gemcitabine hydrochloride, carboplatin, dexamethasone sodium phosphate, granisetron hydrochloride, and palonosetron hydrochloride. We visually examined changes in appearance, pH, and concentration of the mixed solutions of nab-paclitaxel and other drugs for up to 24 h. Concentration was measured using high-performance liquid chromatography (HPLC). The appearance and pH of the mixed solutions did not change for up to 24 h. The change in concentration up to 24 h was within 2%. The chromatogram did not change until 8 h. The results showed that the physical compatibility and chemical stability of nab-paclitaxel were not influenced when it was combined with other drugs until 8 h. This study suggests that nab-paclitaxel could be administered in a mixture or sequentially with other drugs to reduce administration time.

Objective  The objective of this study was to observe the efficacy of antiemetic therapy (no emesis/retching episodes and no rescue medication use) when granisetron is administered via a transdermal patch system (TDS) in women who are 6 to 14 weeks pregnant when compared with oral ondansetron by evaluating the frequency of the use of rescue medications for control of nausea/vomiting of pregnancy (NVP). Methods  This was an observational case series study to observe the potential benefits of granisetron TDS compared with oral ondansetron for management of NVP in pregnant patients during the first trimester. Dates of data collection were September 1, 2014, through December 31, 2015. There was no direct contact with patient. The oral ondansetron and granisetron TDS patients were matched by age, 4:1. The proportion of patients who received rescue antiemetics was calculated from those patients who continued to experience NVP. Risk factors for NVP were identified and compared between groups. Descriptive statistics were used to describe study results. Results  Patients were prescribed rescue antiemetics in 0/3 patients in the granisetron TDS group compared with 2/12 patients in the oral ondansetron group. Conclusion  Prospective efficacy studies on the use of granisetron TDS for management of NVP are needed to confirm this clinical observation., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective This study was designed to compare the effectiveness of granisetron plus dexamethasone for preventing postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic surgery. Methods We searched the literature in the Cochrane Library, PubMed, EMBASE, and CNKI. Results In total, 11 randomized controlled trials were enrolled in this analysis. The meta-analysis showed that granisetron in combination with dexamethasone was significantly more effective than granisetron alone in preventing PONV in patients undergoing laparoscopy surgery. No significant differences in adverse reactions (dizziness and headache) were found in association with dexamethasone. Conclusion Granisetron in combination with dexamethasone was significantly more effective than granisetron alone in preventing PONV in patients undergoing laparoscopic surgery, with no difference in adverse reactions between the two groups. Granisetron alone or granisetron plus dexamethasone can be used to prevent PONV in patients undergoing laparoscopic surgery.

Background & Objective: Our research objective was to design, develop, optimize and characterize Granisetron HCl transdermal gel in order to minimize side effects associated with oral delivery., Method: A statistical design was practically applied for further optimization and preparation of transfersomal gel using Box-Behnken methodology at three levels. The selected independent and dependent variables were Lipoid, surfactant and sonication time and encapsulation efficiency, size and flux correspondingly., Result: The optimized formulation (GTV-16) morphology, shape, size, potential, encapsulation capacity and flux (using Franz-diffusion cell assembly via animal skin barricade medium) were determined. Then, GTV-16 incorporated into gel and during evaluation nano-transformal gel has good particle size of 127.7±1.08 nm, better entrapment efficiency of 83.0 ± 3.22 % and flux of 20.0 ± 1.88µgcm-2/h., Conclusion: The results demonstrated that Granisetron Hydrochloride loaded nano-gel was significantly superior with 8.5 fold enhancement in bioavailability as compared with drug solution., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: To evaluate the clinical and cost benefits of the administration of aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) during high-dose chemotherapy (HDCT)., Methods: We retrospectively reviewed the charts of patients who received HDCT at our institution between January 2009 and December 2013. Cost-effectiveness was analyzed using direct medical costs., Results: We identified a total of 38 patients (27 with non-Hodgkin lymphoma and 11 with multiple myeloma). Thirteen patients received aprepitant and granisetron (aprepitant group) for CINV prophylaxis, whereas 25 patients received granisetron only (non-aprepitant group). The incidence of severe nausea (≥grade 3) was significantly lower in the aprepitant group than in the non-aprepitant group (p = 0.039). The total mean cost per patient during hospitalization, excluding the cost of HDCT and transplantation, was USD 10,941.8 in the aprepitant group and USD 14,577.2 in the non-aprepitant group (p = 0.041). This cost benefit reflected reductions in the costs of hospitalization, transfusion, and infection treatment., Conclusions: Our data indicated that the addition of aprepitant for CINV prophylaxis during HDCT reduced the incidence of severe nausea and might also provide economic benefit in the overall management of HDCT prior to autologous peripheral blood stem cell transplantation., (© 2017 S. Karger AG, Basel.)

Background: Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large interindividual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1, and ABCB1 can alter drug metabolism., Objective: This study evaluated the influence of polymorphisms in CYP3A4, CYP3A5, CYP1A1, and ABCB1 on the pharmacokinetic properties of granisetron in pregnant women., Methods: The study enrolled 16 pregnant women (gestational age of 12-19 wks). All patients had nausea and vomiting and were treated with granisetron 1 mg. Granisetron plasma concentrations were determined using liquid chromatography tandem-mass spectrometry. The patients' genotype was determined using TaqMan SNP Genotyping Assays. The Hardy-Weinberg equilibrium was assessed by comparing observed and expected genotype frequencies, using the exact test. Intravenous granisetron clearance was used as the dependent variable for analysis of associations., Results: Of 16 patients, 25% were homozygous for the allele variant CYP3A5*3 and had a significantly lower granisetron clearance and increased area under the plasma concentration-versus-time curve (AUC) compared with nonhomozygous patients. Approximately one-third of patients (n=5) were carriers for the allele variant CYP1A1*2A and had a significantly higher granisetron clearance and decreased AUC. We did not find significant differences in the AUC or clearance for any SNPs in CYP3A4 and ABCB1 genes., Conclusions: Polymorphisms in CYP3A5 and CYP1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women., (© 2016 Pharmacotherapy Publications, Inc.)

An extended-release (ER) subcutaneously injectable formulation of the first-generation 5-HT 3 receptor antagonist granisetron is now available in the USA (Sustol ® ), where it is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide combination chemotherapy regimens in adults. Granisetron ER is administered as a single subcutaneous injection and uses an erosion-controlled drug-delivery system to allow prolonged granisetron release. Primary endpoint data from phase III studies after an initial cycle of chemotherapy indicate that, when used as part of an antiemetic regimen, granisetron ER injection is more effective than intravenous ondansetron in preventing delayed CINV following highly emetogenic chemotherapy (HEC); is noninferior to intravenous palonosetron in preventing both acute CINV following MEC or HEC and delayed CINV following MEC; and is similar, but not superior, to palonosetron in preventing delayed CINV following HEC. The benefits of granisetron ER were seen in various patient subgroups, including those receiving anthracycline plus cyclophosphamide-based HEC, and (in an extension of one of the studies) over multiple MEC or HEC cycles. Granisetron ER injection is generally well tolerated, with an adverse event profile similar to that of ondansetron or palonosetron. Thus, granisetron ER injection expands the options for preventing both acute and delayed CINV in adults with cancer receiving MEC or anthracycline plus cyclophosphamide-based HEC.

Background: The granisetron transdermal delivery system (GTDS) has been demonstrated effectiveness in the control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of GTDS in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in China., Methods: A total of 313 patients were randomized into the GTDS group (one transdermal granisetron patch, 7 days) or the oral granisetron group (granisetron oral 2 mg/day, ≥2 days). The primary endpoint was the percentage of patients achieving complete control (CC) from chemotherapy initiation until 24 h after final administration (PEEP). Chi-square test and Fisher's exact test were used for statistical analysis., Results: Two hundred eighty-one patients were included in the per protocol analysis. During PEEP, CC was achieved by 67 (47.52%) patients in the GTDS group and 83 (59.29%) patients in the oral granisetron group. There was no statistical significance between the groups (P=0.0559). However, the difference of the CC percentage mainly occurred on the first day of chemotherapy between the groups. The CC was 70.13% on day 1 in the GTDS group, which was significantly lower than that of 91.03% in the oral granisetron group in the full analysis set. In the following days of chemotherapy, the CC was similar between the groups. In terms of cisplatin-contained regimen and female, there was statistical significance between the groups. Both treatments were well tolerated and safe. The most common adverse event was constipation., Conclusions: GTDS provided effective and well-tolerated control of CINV in Chinese patients, especially to non-cisplatin-contained regimen.

Background: Sugammadex reverses neuromuscular block (NMB) through binding aminosteroid neuromuscular blocking agents. Although sugammadex appears to be highly selective, it can interact with other drugs, like corticosteroids. A prospective single-blinded randomized clinical trial was designed to explore the significance of interactions between dexamethasone and sugammadex., Methods: Sixty-five patients who were anesthetized for elective abdominal or urological surgery were included. NMB was assessed using train-of-four stimulation (TOF), with rocuronium used to maintain the desired NMB depth. NMB reversal at the end of anaesthesia was achieved using sugammadex. According to their received antiemetics, the patients were randomized to either the granisetron or dexamethasone group. Blood samples were taken before and after NMB reversal, for plasma dexamethasone and rocuronium determination. Primary endpoint was time from sugammadex administration to NMB reversal. Secondary endpoints included the ratios of the dexamethasone and rocuronium concentrations after NMB reversal versus before sugammadex administration., Results: There were no differences for time to NMB reversal between the control (mean 121 ± 61 s) and the dexamethasone group (mean 125 ± 57 s; P = 0.760). Time to NMB reversal to a TOF ratio ≥0.9 was significantly longer in patients with lower TOF prior to sugammadex administration (Beta = -0.268; P = 0.038). The ratio between the rocuronium concentrations after NMB reversal versus before sugammadex administration was significantly affected by sugammadex dose (Beta = -0.375; P = 0.004), as was rocuronium dose per hour of operation (Beta = -0.366; p = 0.007), while it was not affected by NMB depth before administration of sugammadex (Beta = -0.089; p = 0.483) and dexamethasone (Beta = -0.186; p = 0.131). There was significant drop in plasma dexamethasone after sugammadex administration and NMB reversal (p < 0.001)., Conclusions: Administration of dexamethasone to anesthetized patients did not delay NMB reversal by sugammadex., Trial Registration: The trial was retrospectively registered with The Australian New Zealand Clinical Trials Registry (ANZCTR) on February 28th 2012 (enrollment of the first patient on February 2nd 2012) and was given a trial ID number ACTRN12612000245897 and universal trial number U1111-1128-5104.

Background: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC)., Patients and Methods: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea)., Results: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369)., Conclusion: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point., Clinical Trial Registry Identifier: UMIN000004863., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Granisetron transdermal delivery system (GTDS) is the first 5-HT3 drug to be transdermally delivered and represents a convenient alternative to oral and intravenous antiemetics for the treatment of chemotherapy-induced nausea and vomiting. GTDS is effective and well tolerated in patients receiving multiple-day moderate-to-highly emetogenic chemotherapy. In this setting noninferiority studies showed similar efficacy when GTDS was compared with intravenous and oral granisetron and intravenous palonosetron. GTDS has shown good cardiovascular safety; however, special caution is needed in patients at risk for developing excessive QTc interval prolongation and arrhythmias. So far, GTDS has been investigated for intravenous prevention in comparison with granisetron and palonosetron; however, further prospects open the route to future clinical investigations.

Chemotherapy-induced nausea and vomiting is a challenging issue. Although aprepitant is sometimes used as a therapeutic option in patients receiving moderately emetogenic chemotherapy, the potential benefit of sequential addition of aprepitant to dexamethasone and a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist during the second cycle of carboplatin-based chemotherapy remains unclear. Chemo-naïve patients with advanced non-small cell lung cancer (NSCLC) who received carboplatin-based chemotherapy were treated with doublet antiemetic therapy with dexamethasone and a 5-HT3 receptor antagonist during the first cycle of chemotherapy. Aprepitant was then added during the second cycle of chemotherapy. The primary endpoint was overall complete response rate, defined as no vomiting and no rescue therapy during the 120 h after administration of chemotherapy. Sixty-seven patients were enrolled, 63 of whom were eligible after two cycles of chemotherapy. The overall complete response rate was significantly improved in the second cycle [87.3 %, 95 % confidence interval (CI) 76.5-94.4 %] compared with the first cycle (65.1 %, 95 % CI 52.0-76.7 %; p < 0.001). Improvement was observed in the delayed phase, but not in the acute phase. Subsequent addition of aprepitant significantly improved the overall complete response rate in NSCLC patients receiving a second cycle of carboplatin-based chemotherapy.

Background: Limited options exist for women with nausea and vomiting of pregnancy (NVP) who cannot tolerate oral intake. Transdermal delivery of granisetron, a 5-hydroxytryptamine-3 receptor antagonist, provides an effective alternative for such patients., Objective: The objective of this study was to evaluate the pharmacodynamics of granisetron administered intravenously (IV) and as a sustained release transdermal patch in women with NVP., Study Design: We recruited 16 women with singleton gestation between 12 0/7-18 6/7 weeks who were receiving treatment for NVP and had a Pregnancy Unique Quantification of Emesis and Nausea (PUQE) score of ≥6. All consenting subjects received 1 mg of granisetron as an IV infusion over 5 minutes and blood was obtained prior to the infusion and at 10, 20, 30, and 60 minutes and at 2, 4, 6, 8, 12, and 24 hours after the start of the infusion. After a minimum washout of 48 hours after initiation of IV granisetron, a 52-cm(2) granisetron patch (34.3 mg) was placed on the upper arm of all subjects for 7 days. Blood was drawn prior to patch placement and daily thereafter for 9 days. The subjects were evaluated daily. The PUQE score was obtained from these subjects prior to the IV infusion and daily for 2 days after and again prior to and daily for 9 days after patch placement., Results: Complete data were available in 15 women after IV administration and 13 women after patch placement. One woman stopped participation during the IV infusion while data were not available in 2 additional women after patch placement due to noncompliance. Peak plasma granisetron concentrations after IV and transdermal administration were similar (∼10 ng/mL). Prior to IV administration of granisetron, the PUQE score was 8.6 ± 1.8 (mean ± SD). The PUQE scores were significantly reduced for the ensuing 2 days (P < .01). The PUQE score prior to patch placement was 7.6 ± 2.4. Scores were significantly (P < .001) reduced within 1 day of patch placement and stayed significantly reduced during the ensuing 6 days of patch placement. The patch was removed on the seventh day and PUQE scores increased significantly on the third day after patch removal. No serious side effects were reported either during IV administration or patch placement., Conclusion: Granisetron significantly improved symptoms of nausea and vomiting as gauged by the PUQE score. After IV infusion the reduction in PUQE score was observed within 1 day. When granisetron was administered as a patch, benefit likewise was seen within 1 day suggesting rapid absorption of the medication transdermally. The beneficial effect of transdermal granisetron on the PUQE score persisted for the entire 7 days during which the patch was in place. In this small cohort, the granisetron patch appeared to be efficacious in reducing the symptoms of nausea and vomiting. The patch provides another option for treating this disorder and may be particularly useful in women who cannot tolerate oral medications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen., Methods: HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication)., Results: A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions., Conclusion: APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Objective: Rolapitant, a novel neurokinin-1 receptor antagonist (RA), was shown to protect against delayed chemotherapy-induced nausea and vomiting (CINV) during the first cycle of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in randomized, double-blind trials. This analysis explored the efficacy and safety of rolapitant in preventing CINV over multiple cycles of MEC or HEC., Patients and Methods: Patients in one phase III MEC, one phase II HEC, and two phase III HEC clinical trials were randomized to receive oral rolapitant (180 mg) or placebo in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Regardless of response in cycle 1, patients could continue the same antiemetic treatment for up to six cycles. On days 6-8 of each subsequent chemotherapy cycle, patients reported the incidence of emesis and/or nausea interfering with normal daily life. Post hoc analyses of pooled safety and efficacy data from the four trials were performed for cycles 2-6., Results: Significantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 (p = 0.006), 3 (p < 0.001), 4 (p = 0.001), and 5 (p = 0.021). Over cycles 1-6, time-to-first emesis was significantly longer with rolapitant than with control (p < 0.001). The incidence of treatment-related adverse events during cycles 2-6 was similar in rolapitant (5.5%) and control (6.8%) arms. No cumulative toxicity was observed., Conclusions: Over multiple cycles of MEC or HEC, rolapitant provided superior CINV protection and reduced emesis and nausea interfering with daily life compared with control and remained well tolerated., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Iontophoresis has been used to deliver small molecules, peptides and proteins into and across the skin. In principle, it provides a controlled, non-invasive method for poly-pharmacotherapy since it is possible to formulate and to deliver multiple therapeutic agents simultaneously from the anodal and cathodal compartments. The objective of this proof-of-principle study was to investigate the simultaneous anodal iontophoretic delivery of granisetron (GST) and metoclopramide (MCL) and cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P). In addition to validating the hypothesis, these are medications that are routinely used in combination to treat chemotherapy-induced emesis. Two preliminary in vitro studies using porcine skin were performed: Study 1 - effect of formulation composition on anodal co-iontophoresis of GST and MCL and Study 2 - combined anodal iontophoresis of GST (10mM) and MCL (110 mM) and cathodal iontophoresis of DEX-P (40 mM). The results from Study 1 demonstrated the dependence of GST/MCL transport on the respective drug concentrations when co-iontophoresed at 0.3 mA·cm(-2). Although they possess similar physicochemical properties, MCL seemed to be a more efficient charge carrier (JMCL=0.0591∗CMCLvs JGST=0.0414∗CGST). In Study 2, MCL permeation was markedly superior to that of GST (2324.83 ± 307.85 and 209.83 ± 24.84 μg·cm(-2), respectively); this was consistent with the difference in their relative concentrations; DEX-P permeation was 336.94 ± 71.91 μg·cm(-2). The in vivo studies in Wistar rats (10mM GST, 110 mM MCL and 40 mM DEX-P (0.5 mA·cm(-2) for 5h with Ag/AgCl electrodes and salt bridges) demonstrated that significant drug levels were achieved rapidly for each drug. This was most noticeable for dexamethasone (DEX) where relatively constant plasma levels were obtained from the 1 to 5h time-points; DEX-P was not detected in the plasma since it was completely hydrolyzed to the active metabolite. The calculated input rates in vivo (k01) for GST, MCL and DEX were 0.45 ± 0.05, 3.29 ± 0.48 and 1.97 ± 0.38 μg·cm(-2) · min(-1), respectively. The study confirmed that iontophoresis provided a controlled method for the simultaneous administration of multiple therapeutic agents and that it could be of use for poly-pharmacotherapy in general and more specifically that it was able to deliver different drugs used in the treatment of chemotherapy-induced emesis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: There is no research regarding the appropriate antiemetic agents for female patients, especially those receiving moderately emetogenic chemotherapy (MEC). We evaluated the antiemetic efficacy of a combination of 5-HT₃ receptor with/without aprepitant in patients with gynecological cancer treated with the TC (paclitaxel and carboplatin) regimen of MEC., Methods: We enrolled 38 patients diagnosed with gynecologic cancer and scheduled to receive the TC regimen. The patients were randomly assigned to receive a 5-HT₃ receptor antagonist, either palonosetron in the first cycle followed by granisetron in the second cycle or vice versa. In the third cycle, all patients received a combination of the 5-HT₃ receptor and dexamethasone with/without aprepitant., Results: When three drugs were administered, palonosetron consistently produced an equivalent complete response (CR) rate to granisetron in the acute phase (89.5% vs. 86.8%, p=0.87) and delayed phase (60.5% vs. 65.8%, p=0.79). With regard to the change in dietary intake, palonosetron exhibited similar efficacy to granisetron in the acute phase (92.1% vs. 89.4%, p=0.19) and delayed phase (65.7% vs. 68.4%, p=0.14). However, in the delayed phase, the addition of aprepitant therapy with a 5-HT₃ receptor antagonist and dexamethasone produced a higher CR rate than a 5-HT₃ receptor antagonist with dexamethasone (93.3% vs. 47.8%, p<0.001) and allowed the patients to maintain a higher level of dietary intake (93.3% vs. 56.5%, p<0.001)., Conclusion: The addition of aprepitant therapy was more effective than the control therapy of a 5-HT₃ receptor antagonist, and dexamethasone in gynecological cancer patients treated with the TC regimen.

Background: APF530 is a novel sustained-release formulation of granisetron. In a Phase III trial, APF530 500 mg was noninferior to palonosetron 0.25 mg in preventing acute chemotherapy-induced nausea and vomiting (CINV) after moderately (MEC) or highly emetogenic chemotherapy (HEC) and delayed CINV after MEC, but not superior in preventing delayed CINV after HEC. Emetogenicity was classified by Hesketh criteria; this reanalysis uses newer American Society of Clinical Oncology criteria., Methods: Complete responses (no emesis or rescue medication) after cycle one were reanalyzed after reclassification of MEC and HEC by American Society of Clinical Oncology criteria., Results: APF530 maintained noninferiority to palonosetron., Conclusion: Single-dose APF530 is a promising alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC. The Clinicaltrials.gov identifier for this study is NCT00343460.

Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well., (Copyright © 2015 Elsevier B.V. All rights reserved.)