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Viruses Aug 2021Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation....
Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.
Topics: Adenosine Triphosphatases; Adrenergic Antagonists; Antiviral Agents; Brain; Computer Simulation; Dengue; Drug Discovery; Drug Evaluation, Preclinical; Drug Repositioning; Humans; Liver; Metabolic Networks and Pathways; NF-kappa B; Serotonin Antagonists; Severe Dengue; Spleen; Transcriptome
PubMed: 34452405
DOI: 10.3390/v13081540 -
Molecules (Basel, Switzerland) Aug 2021Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β...
Since westernized diet-induced insulin resistance is a risk factor in Alzheimer's disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.
Topics: Aconitine; Alzheimer Disease; Amyloid beta-Peptides; Animals; CARD Signaling Adaptor Proteins; Cognition; Diet, Western; Disease Models, Animal; Hippocampus; Humans; Inflammasomes; Inflammation; Insulin Resistance; Interleukin-18; Lipopolysaccharides; Microglia; Palonosetron; Peptide Fragments; Pyroptosis; Rats; Receptors, Serotonin, 5-HT3; Risk Factors; Spatial Memory
PubMed: 34443654
DOI: 10.3390/molecules26165068 -
Medicine Aug 2021Postoperative nausea and vomiting (PONV) is an undesirable complication in patients undergoing general anesthesia. Combination therapy via different mechanisms of action...
BACKGROUND
Postoperative nausea and vomiting (PONV) is an undesirable complication in patients undergoing general anesthesia. Combination therapy via different mechanisms of action for antiemetic prophylaxis has been warranted for effective treatment of PONV. This study was designed to compare the prophylactic antiemetic effect between midazolam combined with palonosetron (group MP) and palonosetron alone (group P) after laparoscopic cholecystectomy surgeries.
METHODS
A prospective randomized controlled trial was investigated in non-smoking female. Eighty-eight patients were randomly divided into 2 groups with 44 patients each. Group MP received 0.05 mg/kg of midazolam intravenously before induction of anesthesia whereas group P received the same volume of normal saline. Immediately after anesthetic induction, 0.075 mg of palonosetron was administered to both the groups. The incidence and severity of PONV were assessed during 2 time intervals (0-2 hours, 2-24 hours), postoperatively.
RESULTS
The incidence of PONV during 24 hours after surgery was lower in group MP as compared to group P. There was also a significant difference in the use of rescue antiemetics. The severity of nausea was significantly lower in group MP as compared to group P, in the initial 2 hours after surgery. The incidence of side effects was similar between the 2 groups.
CONCLUSION
In the prevention of PONV, midazolam combined with palonosetron, administered during induction of anesthesia was more effective as compared to palonosetron alone.
Topics: Adjuvants, Anesthesia; Adult; Antiemetics; Cholecystectomy, Laparoscopic; Female; Humans; Male; Midazolam; Middle Aged; Palonosetron; Postoperative Nausea and Vomiting; Prospective Studies; Republic of Korea
PubMed: 34414984
DOI: 10.1097/MD.0000000000026997 -
Brazilian Journal of Anesthesiology... 2024End-stage renal diseases patients have a high risk of postoperative nausea and vomiting (PONV), which is multifactorial and need acute attention after renal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
End-stage renal diseases patients have a high risk of postoperative nausea and vomiting (PONV), which is multifactorial and need acute attention after renal transplantation for a successful outcome in term of an uneventful postoperative period. The study was done to compare the efficacy of palonosetron and ondansetron in preventing early and late-onset PONV in live donor renal transplantation recipients (LDRT).
METHODS
The prospective randomized double-blinded study was done on 112 consecutive patients planned for live donor renal transplantation. Patients of both sexes in the age group of 18...60 years were randomly divided into two groups: Group O (Ondansetron) and Group P (Palonosetron) with 56 patients in each group by computer-generated randomization. The study drug was administered intravenously (IV) slowly over 30.ßseconds, one hour before extubation. Postoperatively, the patients were accessed for PONV at 6, 24, and 72.ßhours using the Visual Analogue Scale (VAS) nausea score and PONV intensity scale.
RESULTS
The incidence of PONV in the study was found to be 30.35%. There was significant difference in incidence of PONV between Group P and Group O at 6.ßhours (12.5% vs. 32.1%, p.ß=.ß0.013) and 72.ßhours (1.8% vs. 33.9%, p.ß<.ß0.001), but insignificant difference at 24.ßhours (1.8% vs. 10.7%, p.ß=.ß0.113). VAS-nausea score was significantly lower in Group P as compared to Group O at a time point of 24.ßhours (45.54.ß...ß12.64 vs. 51.96.ß...ß14.70, p.ß=.ß0.015) and 72.ßhours (39.11.ß...ß10.32 vs. 45.7.ß...ß15.12, p.ß=.ß0.015).
CONCLUSION
Palonosetron is clinically superior to ondansetron in preventing early and delayed onset postoperative nausea and vomiting in live-related renal transplant recipients.
Topics: Male; Female; Humans; Adolescent; Palonosetron; Ondansetron; Postoperative Nausea and Vomiting; Antiemetics; Kidney Transplantation; Prospective Studies; Double-Blind Method
PubMed: 34411635
DOI: 10.1016/j.bjane.2021.07.027 -
Supportive Care in Cancer : Official... Jan 2022Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent adverse events compromising quality of life (QoL) in patients undergoing autologous stem cell...
Netupitant/palonosetron without dexamethasone for preventing nausea and vomiting in patients with multiple myeloma receiving high-dose melphalan for autologous stem cell transplantation: a single-center experience.
Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent adverse events compromising quality of life (QoL) in patients undergoing autologous stem cell transplantation (ASCT). However, CINV prophylaxis is still lacking uniformity for high-dose melphalan (HDM), which is used to condition patients with multiple myeloma (MM). Netupitant/palonosetron (NEPA) is administered with dexamethasone (DEXA) for CINV prevention in several chemotherapy regimens. Our study aims to assess the efficacy of NEPA, without DEXA, in preventing CINV in 106 adult patients with MM receiving HDM and ASCT. All patients had antiemetic prophylaxis with multiple doses of NEPA 1 h before the start of conditioning and after 72 h and 120 h. A complete response (CR) was observed in 99 (93%) patients at 120 h (overall phase). The percentage of patients with complete control was 93%. The CR rate during the acute phase was 94% (n = 100). During the delayed phase, the CR rate was 95% (n = 101). Grade 1 nausea and vomiting were experienced by 82% and 12% of the patients, respectively. Grade 2 nausea was reported in 18% and vomiting in 10% of patients. Our results showed, for the first time, that NEPA, without DEXA, was a well-tolerated and effective antiemetic option for MM patients receiving HDM followed by ASCT.
Topics: Antiemetics; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Nausea; Palonosetron; Pyridines; Quality of Life; Quinuclidines; Transplantation, Autologous; Vomiting
PubMed: 34347181
DOI: 10.1007/s00520-021-06472-7 -
Drugs Jul 2021Netupitant/palonosetron (NEPA; Akynzeo), available in oral and intravenous (IV) formulations, is a fixed-dose combination of the neurokinin 1 (NK1) receptor antagonist... (Review)
Review
Netupitant/palonosetron (NEPA; Akynzeo), available in oral and intravenous (IV) formulations, is a fixed-dose combination of the neurokinin 1 (NK1) receptor antagonist netupitant (or the prodrug, fosnetupitant, in the IV formulation) and the second-generation serotonin 3 (5-HT) receptor antagonist palonosetron. Administered as a single dose, (fos)netupitant/palonosetron (in combination with dexamethasone) is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in adults. In clinical trials, (fos)netupitant/palonosetron plus dexamethasone was associated with high complete response rates (no emesis and no rescue medication) in the acute, delayed and overall phases in patients receiving highly or moderately emetogenic chemotherapy, with efficacy maintained over multiple cycles. Further, oral netupitant/palonosetron was found to be superior to palonosetron and non-inferior to aprepitant plus granisetron in preventing CINV in individual trials. Both the oral and IV formulations of the drug combination are well tolerated. The fixed-dose combination is concordant with guideline recommendations and provides a simple and convenient option for prophylaxis against acute and delayed CINV in patients receiving highly or moderately emetogenic chemotherapy.
Topics: Administration, Intravenous; Administration, Oral; Antiemetics; Antineoplastic Agents; Clinical Trials as Topic; Dexamethasone; Drug Combinations; Drug Interactions; Humans; Isoquinolines; Nausea; Pyridines; Quinuclidines; Vomiting
PubMed: 34292534
DOI: 10.1007/s40265-021-01558-2 -
Brazilian Journal of Anesthesiology... 2024We tested the hypothesis that, within the margin of 15% of risk difference, palonosetron is not inferior to ondansetron in reducing the incidence of postoperative nausea... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We tested the hypothesis that, within the margin of 15% of risk difference, palonosetron is not inferior to ondansetron in reducing the incidence of postoperative nausea and vomiting (PONV) in laparoscopic cholecystectomy.
METHODS
We conducted a double-blind, non-inferiority, randomized, controlled trial of 212 patients aged 18 to 65 years undergoing laparoscopic cholecystectomy under general anesthesia in two secondary care hospitals. Patients were randomly assigned to receive either palonosetron (0.075.ßmg) or ondansetron (8.ßmg) intravenously at induction of anesthesia. Ondansetron (8.ßmg) was also administered 8 and 16.ßhours postoperatively. All anesthetic and surgical procedures were standardized. Patients were evaluated for 24.ßhours postoperatively for the occurrence of PONV.
RESULTS
A high incidence of PONV was observed at 2...6.ßhours postoperatively, with a rate of 36.8% (95% confidence interval [CI] 28.2...46.3) in the palonosetron group, as compared to 43.4% (95% CI 34.4...52.9) in the ondansetron group. The risk difference (95% CI) between palonosetron and ondansetron for PONV was 0 (-10.9 to 10.9) at 0...2.ßhours, -6.6 (-19.4 to 6.5) at 2...6.ßhours, -0.9 (-11.0 to 9.2) at 6...12.ßhours, and -2.8 (-9.6 to 3.6) at 12...24.ßhours. There was no statistically significant difference between the palonosetron and ondansetron groups in the use of rescue medication (dimenhydrinate). There were no adverse events associated with the medications under study.
CONCLUSION
Palonosetron is not inferior to ondansetron in patients at risk of PONV undergoing laparoscopic cholecystectomy, providing a good option for PONV prophylaxis, as it can be administered in a single dose.
Topics: Humans; Ondansetron; Palonosetron; Postoperative Nausea and Vomiting; Antiemetics; Cholecystectomy, Laparoscopic; Treatment Outcome; Anesthesia, General; Double-Blind Method
PubMed: 34280455
DOI: 10.1016/j.bjane.2021.06.020 -
The Oncologist Oct 2021Neurokinin (NK) 1 receptor antagonists (RAs), administered in combination with a 5-hydroxytryptamine-3 (5-HT ) RA and dexamethasone (DEX), have demonstrated clear... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Neurokinin (NK) 1 receptor antagonists (RAs), administered in combination with a 5-hydroxytryptamine-3 (5-HT ) RA and dexamethasone (DEX), have demonstrated clear improvements in chemotherapy-induced nausea and vomiting (CINV) prevention over a 5-HT RA plus DEX. However, studies comparing the NK RAs in the class are lacking. A fixed combination of a highly selective NK RA, netupitant, and the 5-HT RA, palonosetron (NEPA), simultaneously targets two critical antiemetic pathways, thereby offering a simple convenient antiemetic with long-lasting protection from CINV. This study is the first head-to-head NK RA comparative study in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy (MEC).
MATERIALS AND METHODS
This was a pragmatic, multicenter, randomized, single-cycle, open-label, prospective study designed to demonstrate noninferiority of single-dose NEPA to a 3-day aprepitant regimen in preventing CINV in chemotherapy-naive patients receiving AC/non-AC MEC in a real-life setting. The primary efficacy endpoint was complete response (no emesis/no rescue) during the overall (0-120 hour) phase. Noninferiority was achieved if the lower limit of the 95% confidence interval (CI) of the difference between NEPA and the aprepitant group was greater than the noninferiority margin set at -10%.
RESULTS
Noninferiority of NEPA versus aprepitant was demonstrated (risk difference 9.2%; 95% CI, -2.3% to 20.7%); the overall complete response rate was numerically higher for NEPA (64.9%) than aprepitant (54.1%). Secondary endpoints also revealed numerically higher rates for NEPA than aprepitant.
CONCLUSION
This pragmatic study in patients with cancer receiving AC and non-AC MEC revealed that a single dose of oral NEPA plus DEX was at least as effective as a 3-day aprepitant regimen, with indication of a potential efficacy benefit for NEPA.
IMPLICATIONS FOR PRACTICE
In the absence of comparative neurokinin 1 (NK ) receptor antagonist (RA) studies, guideline committees and clinicians consider NK RA agents to be interchangeable and equivalent. This is the first head-to-head study comparing one NK RA (oral netupitant/palonosetron [NEPA]) versus another (aprepitant) in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy. Noninferiority of NEPA versus the aprepitant regimen was demonstrated; the overall complete response (no emesis and no rescue use) rate was numerically higher for NEPA (65%) than aprepitant (54%). As a single-dose combination antiemetic, NEPA not only simplifies dosing but may offer a potential efficacy benefit over the current standard-of-care.
Topics: Antibiotics, Antineoplastic; Antiemetics; Antineoplastic Agents; Aprepitant; Double-Blind Method; Humans; Isoquinolines; Nausea; Palonosetron; Prospective Studies; Quinuclidines; Vomiting
PubMed: 34216177
DOI: 10.1002/onco.13888 -
International Journal of Molecular... Jun 2021The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that...
The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP uptake by OCT2 listed in order of potency was palonosetron (IC: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC: 85.4 μM) and the inhibition of ASP uptake by MATE1 in order of potency was ondansetron (IC: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC: 27.4 μM). Ondansetron (0.5-20 μM) inhibited the basolateral-to-apical transcellular transport of ASP up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP. Taken together, these data suggest that 5-HT antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.
Topics: Animals; Antiemetics; Biological Transport; Cell Line; Cells, Cultured; Dogs; Gene Expression; HEK293 Cells; Humans; Kidney; Madin Darby Canine Kidney Cells; Molecular Structure; Organic Cation Transport Proteins; Organic Cation Transporter 2; Serotonin 5-HT3 Receptor Antagonists
PubMed: 34208557
DOI: 10.3390/ijms22126439