ABSTRACT
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.
Subject(s)
Administration, Cutaneous , Antineoplastic Combined Chemotherapy Protocols , Capecitabine , Granisetron , Nausea , Oxaliplatin , Vomiting , Humans , Male , Female , Granisetron/administration & dosage , Granisetron/therapeutic use , Middle Aged , Capecitabine/administration & dosage , Capecitabine/adverse effects , Oxaliplatin/administration & dosage , Oxaliplatin/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Nausea/chemically induced , Nausea/prevention & control , Vomiting/chemically induced , Vomiting/prevention & control , Vomiting/drug therapy , Aged , Prospective Studies , Adult , Antiemetics/administration & dosage , Antiemetics/therapeutic use , Quality of Life , Dexamethasone/administration & dosage , Dexamethasone/therapeutic useABSTRACT
BACKGROUND: Mirtazapine blocks 5-hydroxytryptamine type (5-HT)2A, 5-HT2C, 5-HT3 and histamine H1 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.
Subject(s)
Antiemetics , Carboplatin , Dexamethasone , Granisetron , Mirtazapine , Nausea , Vomiting , Humans , Granisetron/administration & dosage , Granisetron/therapeutic use , Male , Mirtazapine/therapeutic use , Mirtazapine/administration & dosage , Female , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Middle Aged , Aged , Nausea/chemically induced , Nausea/drug therapy , Vomiting/chemically induced , Vomiting/drug therapy , Prospective Studies , Carboplatin/adverse effects , Carboplatin/administration & dosage , Antiemetics/therapeutic use , Antiemetics/administration & dosage , Thoracic Neoplasms/drug therapy , Thoracic Neoplasms/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged, 80 and over , Japan , Drug Therapy, CombinationABSTRACT
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.
Subject(s)
Antiemetics/administration & dosage , Antineoplastic Agents/adverse effects , Nausea/epidemiology , Neoplasms/drug therapy , Vomiting/epidemiology , Aged , Aprepitant/administration & dosage , Drug Therapy, Combination/methods , Female , Granisetron/administration & dosage , Humans , Incidence , Male , Middle Aged , Nausea/chemically induced , Nausea/prevention & control , Palonosetron/administration & dosage , Retrospective Studies , Treatment Outcome , Vomiting/chemically induced , Vomiting/prevention & controlABSTRACT
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-HT3 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-HT3 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-HT3 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-HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT3 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.
Subject(s)
Acute Kidney Injury/pathology , Cisplatin/adverse effects , Nausea/drug therapy , Serotonin 5-HT3 Receptor Antagonists/administration & dosage , Vomiting/drug therapy , Acute Kidney Injury/chemically induced , Aged , Animals , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Cisplatin/administration & dosage , Disease Models, Animal , Female , Granisetron/administration & dosage , Granisetron/adverse effects , Humans , Kidney/drug effects , Kidney/pathology , Kidney/physiopathology , Male , Mice , Middle Aged , Nausea/chemically induced , Ondansetron/administration & dosage , Ondansetron/adverse effects , Organic Cation Transport Proteins/metabolism , Palonosetron/administration & dosage , Palonosetron/adverse effects , Renal Elimination/physiology , Retrospective Studies , Serotonin 5-HT3 Receptor Antagonists/adverse effects , Vomiting/chemically inducedABSTRACT
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-HT3 RAs) and second-generation 5-HT3 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-HT3 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-HT3 RAs in controlling multiple-day chemotherapy-induced nausea and vomiting.
Subject(s)
Antiemetics/administration & dosage , Benzimidazoles/administration & dosage , Granisetron/administration & dosage , Nausea/drug therapy , Palonosetron/administration & dosage , Serotonin 5-HT3 Receptor Antagonists/administration & dosage , Vomiting/drug therapy , Adult , Antineoplastic Agents/adverse effects , Bleomycin/adverse effects , Drug Therapy, Combination , Etoposide/adverse effects , Female , Humans , Male , Middle Aged , Nausea/chemically induced , Neoplasms, Germ Cell and Embryonal/drug therapy , Ovarian Neoplasms/drug therapy , Platinum Compounds/adverse effects , Retrospective Studies , Testicular Neoplasms/drug therapy , Vomiting/chemically inducedABSTRACT
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.
Subject(s)
Dyskinesia, Drug-Induced/drug therapy , Granisetron/pharmacology , Levodopa/toxicity , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Animals , Antiparkinson Agents/pharmacology , Antiparkinson Agents/toxicity , Dose-Response Relationship, Drug , Dyskinesia, Drug-Induced/etiology , Female , Granisetron/administration & dosage , Levodopa/pharmacology , Oxidopamine/toxicity , Parkinsonian Disorders/drug therapy , Rats , Rats, Sprague-Dawley , Serotonin 5-HT3 Receptor Antagonists/administration & dosageABSTRACT
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.
Subject(s)
Antiemetics/therapeutic use , Antineoplastic Agents/adverse effects , Granisetron/therapeutic use , Nausea/prevention & control , Ondansetron/therapeutic use , Vomiting/prevention & control , Administration, Cutaneous , Adult , Antineoplastic Agents/therapeutic use , Cancer Survivors/statistics & numerical data , Endometrial Neoplasms/drug therapy , Female , Granisetron/administration & dosage , Humans , Male , Middle Aged , Nausea/chemically induced , Nausea/drug therapy , Ondansetron/administration & dosage , Quality of Life/psychology , Remission Induction , Uterine Cervical Neoplasms/drug therapy , Vaginal Neoplasms/drug therapy , Vomiting/chemically induced , Vomiting/drug therapyABSTRACT
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.
Subject(s)
Antiemetics/administration & dosage , Antineoplastic Agents/adverse effects , Granisetron/administration & dosage , Nausea/drug therapy , Neoplasms/drug therapy , Vomiting/drug therapy , Administration, Cutaneous , Administration, Oral , Antineoplastic Agents/therapeutic use , Humans , Nausea/chemically induced , Nausea/prevention & control , Randomized Controlled Trials as Topic , Vomiting/chemically induced , Vomiting/prevention & controlABSTRACT
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.
Subject(s)
Antiemetics/therapeutic use , Antineoplastic Agents/adverse effects , Nausea/prevention & control , Vomiting/prevention & control , Academic Medical Centers , Administration, Intravenous , Adult , Aged , Aged, 80 and over , Female , Granisetron/administration & dosage , Humans , Male , Middle Aged , Nausea/chemically induced , Neoplasms/drug therapy , Palonosetron/administration & dosage , Retrospective Studies , Serotonin 5-HT3 Receptor Antagonists/administration & dosage , Vomiting/chemically induced , Young AdultABSTRACT
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.
Subject(s)
Antiemetics/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Granisetron/administration & dosage , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Morpholines/administration & dosage , Adolescent , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Child , Child, Preschool , Female , Hematologic Neoplasms/drug therapy , Humans , Infant , Male , Nausea/chemically induced , Nausea/prevention & control , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Vomiting/chemically induced , Vomiting/prevention & controlABSTRACT
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.
Subject(s)
Antiemetics/pharmacokinetics , Aprepitant/pharmacokinetics , Granisetron/pharmacokinetics , Nausea/prevention & control , Ondansetron/pharmacokinetics , Palonosetron/pharmacokinetics , Vomiting/prevention & control , Adolescent , Adult , Aged , Aged, 80 and over , Antiemetics/administration & dosage , Antineoplastic Agents/adverse effects , Aprepitant/administration & dosage , Child , Child, Preschool , Clinical Trials as Topic , Data Interpretation, Statistical , Dose-Response Relationship, Drug , Drug Dosage Calculations , Female , Granisetron/administration & dosage , Humans , Infant , Male , Middle Aged , Nausea/chemically induced , Neurokinin-1 Receptor Antagonists/administration & dosage , Neurokinin-1 Receptor Antagonists/pharmacokinetics , Ondansetron/administration & dosage , Palonosetron/administration & dosage , Treatment Outcome , United States , United States Food and Drug Administration , Vomiting/chemically induced , Young AdultABSTRACT
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.
Subject(s)
Chromatography, Liquid/methods , Intestinal Mucosa/metabolism , Lab-On-A-Chip Devices , Models, Biological , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods , Administration, Oral , Biological Availability , Biotransformation , Caco-2 Cells , Ergotamine/administration & dosage , Ergotamine/pharmacokinetics , Granisetron/administration & dosage , Granisetron/pharmacokinetics , HT29 Cells , Humans , In Vitro Techniques , Limit of Detection , Permeability , Verapamil/administration & dosage , Verapamil/pharmacokineticsABSTRACT
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-HT3R-antagonists and NK1R-antagonists. The NK1R-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.
Subject(s)
Antiemetics/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/therapeutic use , Granisetron/therapeutic use , Morpholines/therapeutic use , Nausea/drug therapy , Vomiting/drug therapy , Adolescent , Antiemetics/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Cohort Studies , Dexamethasone/administration & dosage , Drug Therapy, Combination , Female , Granisetron/administration & dosage , Humans , Male , Morpholines/administration & dosage , Nausea/chemically induced , Vomiting/chemically inducedABSTRACT
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 3âmg every 8âhours (nâ=â77) or an equal volume of normal saline (nâ=â77) 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.
Subject(s)
Granisetron/administration & dosage , Sepsis/drug therapy , Serotonin Antagonists/administration & dosage , Shock, Septic/drug therapy , Administration, Intravenous , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/analysis , Female , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Sepsis/mortality , Shock, Septic/mortality , Single-Blind Method , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Antiemetics/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Nausea/prevention & control , Vomiting/prevention & control , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Aprepitant/administration & dosage , Cyclophosphamide/administration & dosage , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Drug Therapy, Combination , Epirubicin/administration & dosage , Female , Granisetron/administration & dosage , Humans , Middle Aged , Nausea/chemically induced , Palonosetron/administration & dosage , Prospective Studies , Vomiting/chemically inducedABSTRACT
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.
Subject(s)
Antineoplastic Agents/administration & dosage , Granisetron/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Nausea/prevention & control , Vomiting/prevention & control , Ambulatory Care , Antiemetics/administration & dosage , Antineoplastic Agents/adverse effects , Delayed-Action Preparations , Female , Humans , Middle Aged , Nausea/chemically induced , Quality of Life , Vomiting/chemically inducedABSTRACT
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).
Subject(s)
Anesthesia, Spinal/adverse effects , Antiemetics/administration & dosage , Cesarean Section/adverse effects , Granisetron/administration & dosage , Adult , Case-Control Studies , Drug Combinations , Female , Germany , Heart Rate , Hemodynamics , Humans , Oxytocin/administration & dosage , Pregnancy , Retrospective Studies , Sympathomimetics/administration & dosage , Theophylline/administration & dosage , Theophylline/analogs & derivativesABSTRACT
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.
Subject(s)
Nausea/drug therapy , Neoplasms, Germ Cell and Embryonal/drug therapy , Palonosetron/administration & dosage , Vomiting/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/adverse effects , Cisplatin/adverse effects , Drug Administration Schedule , Etoposide/adverse effects , Female , Granisetron/administration & dosage , Humans , Male , Middle Aged , Nausea/chemically induced , Nausea/pathology , Neoplasms, Germ Cell and Embryonal/complications , Neoplasms, Germ Cell and Embryonal/pathology , Vomiting/chemically induced , Vomiting/pathology , Young AdultABSTRACT
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.
Subject(s)
Anesthesia, General/adverse effects , Antiemetics/administration & dosage , Cholecystectomy, Laparoscopic/adverse effects , Granisetron/administration & dosage , Ondansetron/administration & dosage , Palonosetron/administration & dosage , Postoperative Complications/prevention & control , Postoperative Nausea and Vomiting/prevention & control , Serotonin 5-HT3 Receptor Antagonists/administration & dosage , Administration, Intravenous , Adult , Antiemetics/therapeutic use , Bangladesh , Double-Blind Method , Granisetron/therapeutic use , Humans , Middle Aged , Ondansetron/therapeutic use , Prospective Studies , Serotonin 5-HT3 Receptor Antagonists/therapeutic useABSTRACT
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 cm2 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: Cavg [AUC0-24,ss (day 5)/24 for OA and AUC24-144/120 for TD], Cmax, tmax, AUC, and T1/2. RESULTS: All of the subjects completed the TD phase, and 1 subject withdrew from the study due to increased alanine aminotransferase. The Cavg values for OA and TD were 2.95 ± 1.60 ng/mL and 2.83 ± 1.43 ng/mL, respectively. The Cmax 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 Cavg 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.â©.