Formulation development and evaluation of nasal in situ gel of promethazine hydrochloride.

OBJECTIVE: The present work aims to develop mucoadhesive thermosensitive nasal in situ gel for Promethazine hydrochloride using quality by design (QbD) approach. It can reduce nasal mucociliary clearance (MCC) and increase residence of the drug on nasal mucosa. This might increase drug absorption to improve bioavailability of the drug as compared to oral dosage form. SIGNIFICANCE: Promethazine hydrochloride is an antiemetic drug administered by oral, parenteral and rectal routes. These routes have poor patient compliance or low bioavailability. Nasal route is a better alternative as it has large surface area, high drug absorption rate and no first pass effect. Its only limitation is short drug retention time due to MCC. By formulating a mucoadhesive in situ gel, the MCC can be reduced, and drug absorption will be prolonged. Thus, improving bioavailability. METHOD: In-situ gel was prepared by cold method having material attributes as concentration of Poloxamer 407 (X1) as gelling agent and hydroxypropyl methyl cellulose K4M (X2) as mucoadhesive agent. Critical Quality Attributes (CQA) were gelation temperature, mucoadhesive force and ex-vivo diffusion. Central composite design (CCD) was adopted for optimization. RESULT: Optimized formulation satisfied all the CQA significant for nasal administration. Moreover, the formulation was found to be stable in accelerated stability studies for 3 months. CONCLUSION: It can be concluded that since the drug can easily permeate through nasal mucosa and can gain access directly in the brain without undergoing first pass metabolism along with increased residence due to mucoadhesion, mucoadhesive in situ gel has potential to increase drug bioavailability.

Ultra-low doses of the transient receptor potential vanilloid 1 agonist, resiniferatoxin, prevents vomiting evoked by diverse emetogens in the least shrew (Cryptotis parva).

Published studies have shown that the transient receptor potential vanilloid 1 (TRPV1) receptor agonist, resiniferatoxin (RTX), has pro and antiemetic effects. RTX can suppress vomiting evoked by a variety of nonselective emetogens such as copper sulfate and cisplatin in several vomit-competent species. In the least shrew, we have already demonstrated that combinations of ultra-low doses of RTX and low doses of the cannabinoid CB1/2 receptor agonist delta-9-tetrahydrocannabinol (Δ-THC) produce additive antiemetic effects against cisplatin-evoked vomiting. In the current study, we investigated the broad-spectrum antiemetic potential of very low nonemetic doses of RTX against a diverse group of specific emetogens including selective and nonselective agonists of serotonergic 5-hydroxytrptamine (5-HT3) receptor (5-HT and 2-Me-5-HT), dopaminergic D2 receptor (apomorphine and quinpirole), cholinergic M1 receptor (pilocarpine and McN-A-343), as well as the selective substance P neurokinin NK1 receptor agonist GR73632, the selective L-Type calcium channel agonist FPL64176, and the sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA) inhibitor thapsigargin. When administered subcutaneously, ultra-low (0.01 µg/kg) to low (5.0 µg/kg) doses of RTX suppressed vomiting induced by the aforementioned emetogens in a dose-dependent fashion with 50% inhibitory dose values ranging from 0.01 to 1.26 µg/kg. This study is the first to demonstrate that low nanomolar nonemetic doses of RTX have the capacity to completely abolish vomiting caused by diverse receptor specific emetogens in the least shrew model of emesis.

Formulation and evaluation of niosomal vesicles containing ondansetron HCL for trans-mucosal nasal drug delivery.

Ondansetron HCl is a (5-HT3) serotonin receptor antagonist, used as anti-emetic drug in combination with anticancer agents. Conventional dosage forms have poor bioavailability and patient compliance. These problems can be reduced by the use of nasal niosomal thermo-reversible in situ gelling system. Niosomes were formulated using various surfactants (Span 60, Span 80, Tween 20, and Tween 80) in different ratios using the thin-film hydration technique. Niosomes were evaluated for particle size, zeta potential, transmission electron microscopy (TEM) imaging, drug entrapment efficiency, and in vitro drug release. Niosomes prepared using Span 60 and cholesterol in the ratio 1:1 (F5) showed higher entrapment efficiency (76.13 ± 1.2%) and in vitro drug release (91.76%) after 12 h was optimized. The optimized niosomes were developed into thermo-reversible in situ gel, composed of Poloxamer 407 and sodium carboxymethyl cellulose, prepared by cold method technique. Compatibility study (FTIR, DSC) was made for drugs and excipients that showed no significant interaction. The gel formulation G5 showed the most suitable gelation temperature (31 °C), viscosity (1250 mpoise), bioadhesion force (5860 ± 28 dyne/cm2), and in vitro drug release (70.6%) after 12 h. Comparative in vivo pharmacokinetic study on rabbits showed a sustained release and higher relative bioavailability of the prepared nasal in situ gel compared to similar dose of oral tablets (202.4%) which make ondansetron HCl niosomal nasal thermo-sensitive in situ gel a more convenient dosage form for the administration of ondansetron HCl than oral tablets.

Determination of Ondansetron by Spectrofluorimetry: Application to Forced Degradation Study, Pharmaceuticals and Human Plasma.

The current manuscript describes a validated, responsive and rapid spectrofluorimetric method for quantifying ondansetron (OND) in authentic form, spiked human plasma and dosage forms. This is the first reported fluorescence study of Ondansetron in Triton X 100 system. Various variables affecting fluorescence response were studied precisely and optimised. The described method involved the fluorescence measurement in Triton X 100 system at λem/λex 354/317 nm. The calibration plot attained linearity over concentration range of 0.2 - 2 µg/mL. The developed method has been extensively applied to degradation studies of OND as per International Conference on Harmonisation (ICH) guidelines by exposing to oxidative, thermal, photo, acidic and alkaline conditions and also the degradation pathway has been proposed.

Transdermal Delivery of Ondansetron Hydrochloride via Bilosomal Systems: In Vitro, Ex Vivo, and In Vivo Characterization Studies.

Ondansetron hydrochloride (OND) is commonly used for management of postoperative and chemotherapeutic-induced nausea and vomiting. It suffers from low bioavailability (60%) and rapid elimination (t1/2; 3-4 h). The current work aimed to develop OND-loaded bilosomes as a promising transdermal delivery system capable of surmount drug limitations. The variables influencing the development of OND-loaded bilosomes and niosomes (18 systems) via the thin film hydration technique were investigated, including surfactant type (Span®60 or Span®80), surfactant/cholesterol molar ratio (7:0, 7:1, or 7:3), and sodium deoxycholate (SDC) concentration (0, 2.5, or 5%, w/v). The systems were characterized for particle size, polydispersity index, zeta potential, drug entrapment efficiency (EE%), and in vitro permeation. Based on factorial analysis (32·21) and calculations of desirability values, six systems were further subjected to ex vivo permeation through excised rat skin, differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), and transmission electron microscopy. Histopathological and in vivo permeation studies in rats were conducted on the best achieved system (B6) in comparison to drug solution. Higher desirability values were achieved with Span® 60-based bilosomes, surfactant/cholesterol molar ratio of 7:1, and SDC concentration of 2.5% w/v with respect to small vesicle size, polydispersity index and high zeta potential, EE%, and cumulative drug permeation. OND was dispersed in amorphous state as revealed from DSC and PXRD studies. No marked effect was observed in rat skin following application of B6 system while higher ex vivo and in vivo cumulative permeation profiles were revealed. Bilosomal systems were considered as safe and efficient carriers for the transdermal delivery for OND.

Development of Domperidone Solid Lipid Nanoparticles: In Vitro and In Vivo Characterization.

Domperidone (DOP) is extensively applied orally in the management of nausea and vomiting. Upon oral administration, its bioavailability is very poor due to its poor solubility in alkaline media. Therefore, the aim of this work was to investigate DOP-loaded solid lipid nanoparticles (DOP-SLNs) in order to sustain its release pattern and to enhance oral bioavailability. DOP-SLNs were prepared using four different lipids. Prepared DOP-SLNs were characterized for "polydispersity index (PDI), particle size, zeta potential, % entrapment efficiency (% EE), and drug release behavior." Differential scanning calorimetry (DSC) study was carried out to illustrate the physical form of DOP and excipients. The morphology of DOP-SLNs was confirmed by scanning electron microscopy (SEM). Pharmacokinetic study on optimized DOP-SLN in comparison to tablet was performed in rats. The "particle size, PDI, zeta potential, and % EE" of optimized formulation (F5) were recorded as 201.4 nm, 0.071, - 6.2 mV, and 66.3%, respectively. DSC thermograms suggested amorphous state of DOP in various SLNs. Surface morphology of SLNs using SEM suggested spherical shape of the nanoparticles within nanometer size range. In vitro release studies confirmed that all SLN formulations possessed a sustained release over a period of 12 h (51.3% from optimized formulation) in comparison with immediate release from conventional tablets (100% after 90 min). Pharmacokinetic study showed significant enhancement in oral absorption of DOP from optimized SLN in comparison with DOP tablet. The enhancement in relative bioavailability of DOP from optimized SLN was 2.62-fold in comparison with DOP tablet.

Structural basis of ligand recognition in 5-HT3 receptors.

The 5-HT(3) receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT(3) receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT(3) receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT(3) receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT(3) receptor.

Investigation of figopitant and its metabolites in rat tissue by combining whole-body autoradiography with liquid extraction surface analysis mass spectrometry.

This article describes the combination of whole-body autoradiography with liquid extraction surface analysis (LESA) and mass spectrometry (MS) to study the distribution of the tachykinin neurokinin-1 antagonist figopitant and its metabolites in tissue sections of rats after intravenous administration of 5.0 mg/kg figopitant. An overview of autoradiography results is presented together with mass spectrometry identification and semiquantification of parent drug and its metabolites based on LESA-MS. The quality and accuracy of data generated by LESA-MS were assessed in comparison with classic tissue extraction, sample cleanup, and high-performance liquid chromatography analysis. The parent drug and the N-dealkylated metabolite M474(1) (BIIF 1148) in varying ratios were the predominant compounds in all tissues investigated. In addition, several metabolites formed by oxygenation, dealkylation, and a combination of oxygenation and dealkylation were identified. In summary, the LESA-MS technique was shown to be a powerful tool for identification and semiquantification of figopitant and its metabolites in different tissues and was complementary to quantitative whole-body autoradiography for studying the distribution.

Chrysin abrogates cisplatin-induced oxidative stress, p53 expression, goblet cell disintegration and apoptotic responses in the jejunum of Wistar rats.

Cisplatin (cis-diamminedichloroplatinum (II) (CDDP)) is a commonly used chemotherapeutic drug for the treatment of numerous forms of cancer, but it has pronounced adverse effects, namely nephrotoxicity, ototoxicity, neurotoxicity, hepatotoxicity, diarrhoea and nausea. CDDP-induced emesis and diarrhoea are also marked toxicities that may be due to intestinal injury. Chrysin (5,7-dihydroxyflavone), a natural flavone commonly found in many plants, possesses multiple biological activities, such as antioxidant and anti-inflammatory properties. In the present study, we investigated the protective effect of chrysin against CDDP-induced jejunal toxicity. The plausible mechanism of CDDP-induced jejunal toxicity includes oxidative stress, p53 and apoptosis via up-regulating the expression of caspase-6 and -3. Chrysin was administered to Wistar rats orally in maize oil. A single intraperitoneal injection of CDDP was given and the animals were killed after 24 h of CDDP injection. Chrysin ameliorated CDDP-induced lipid peroxidation, increase in xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, glutathione peroxidase and glucose-6-phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin attenuated CDDP-induced goblet cell disintegration, enhanced expression of p53 and apoptotic tissue damage. Histological findings further substantiated the protective effects of chrysin against CDDP-induced damage in the jejunum. The results of the present study demonstrate that oxidative stress and apoptosis are closely associated with CDDP-induced toxicity and chrysin shows the protective efficacy against CDDP-induced jejunum toxicity possibly via attenuating the oxidative stress and apoptotic tissue damage.

Gum Ghatti--a pharmaceutical excipient: development, evaluation and optimization of sustained release mucoadhesive matrix tablets of domperidone.

The objective of this study was to extend the GI residence time of the dosage form and to control the release of domperidone using directly compressible sustained release mucoadhesive matrix (SRMM) tablets. A 2-factor centre composite design (CCD) was employed to study the influence of independent variables like gum ghatti (GG) (X1) and hydroxylpropylmethyl cellulose K 15M (HPMC K 15M) (X2) on dependent variable like mucoadhesive strength, tensile strength, release exponent (n), t50 (time for 50% drug release), rel(10 h) (release after 10 h) and rel(18 h) (release after 18 h). Tablets were prepared by direct compression technology and evaluated for tablet parametric test (drug assay, diameter, thickness, hardness and tensile strength), mucoadhesive strength (using texture analyzer) and in vitro drug release studies. The tensile strength and mucoadhesive strength were found to be increased from 0.665 +/- 0.1 to 1.591 +/- 0.1 MN/cm2 (Z1 to Z9) and 10.789 +/- 0.985 to 50.924 +/- 1.150 N (Z1 to Z9), respectively. The release kinetics follows first order and Hixson Crowell equation indicating drug release following combination of diffusion and erosion. The n varies between 0.834 and 1.273, indicating release mechanism shifts from non fickian (anomalous release) to super case II, which depict that drug follows multiple drug release mechanism. The t50 time was found to increase from 5 +/- 0.12 to 11.4 +/- 0.14 h (Z1 to Z9) and release after 10 and 18 h decreases with increasing concentration of both polymers concluding with release controlling potential of polymers. The accelerated stability studies were performed on optimized formulation as per ICH guideline and the result showed that there was no significant change in tensile strength, mucoadhesive strength and drug assay.

Metopimazine is primarily metabolized by a liver amidase in humans.

Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist used for four decades to treat acute nausea and vomiting. MPZ is currently under clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes high first-pass metabolism that produces metopimazine acid (MPZA), the major circulating metabolite in humans. Despite a long history of use, the enzymes involved in the metabolism of MPZ have not been identified. Here we report a series of studies designed to identify potential MPZ metabolites in vitro, determine their clinical relevance in humans, and elucidate the enzymes responsible for their formation. The findings demonstrated that the formation of MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor flavin-monooxygenases (FMO) were involved in the formation MPZA, although two minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative pathways are very minor and that CYP enzyme involvement was negligible compared to microsomal amidase/hydrolase in overall MPZ metabolism in humans. The metabolism by liver amidase, an enzyme family not well defined in small molecule drug metabolism, with minimal metabolism by CYPs, differentiates this drug from current D2 antagonists used or in development for the treatment of GP.

Incidence of delayed nausea and vomiting in patients with colorectal cancer receiving irinotecan-based chemotherapy.

PURPOSE: This study sought to prospectively determine the frequency of delayed nausea and vomiting with irinotecan-based chemotherapy following day 1 prophylaxis with a 5-HT3 receptor antagonist and dexamethasone. METHODS: Patients with colorectal cancer aged ≥ 18 years with ECOG performance status ≤ 2 receiving irinotecan alone, combined with cetuximab or as part of a standard folinic acid, 5- fluorouracil, irinotecan (FOLFIRI) regimen for the first time were eligible. All patients received a 5-HT3 receptor antagonist and dexamethasone 8 mg on day 1 prior to irinotecan. No routine prophylaxis for delayed emesis was given. Antiemetic outcome was recorded in patient-completed diaries for the 120-h study period after irinotecan administration. Primary endpoint was frequency of delayed (24-120 h) emesis. RESULTS: Forty-four patients were enrolled, and all are evaluable. The median age was 61 (39-79) years; the male-female ratio was 37:7. Four patients (9%) experienced vomiting or retching during the delayed period. Three patients (7%) vomited during the first 24 h after irinotecan. The overall no emesis rate was 89% (39/44). Fifteen patients (34%) experienced delayed nausea (mildin 11 patients, moderate in four patients). Six patients (14%) took rescue antiemetics during the delayed period. Delayed and overall complete response (no emesis or use of rescue antiemetics) rates were 82% and 77% respectively. CONCLUSIONS: The use of a 5-HT3 antagonist and dexamethasone prior to irinotecan results in excellent control of nausea and vomiting (CR 86%) during the 24 h after chemotherapy. Without further antiemetic treatment, most patients (82%) will not experience delayed emesis or require rescue antiemetics. Routine prophylaxis for delayed emesis following irinotecan does not appear to be warranted.

Potential for drug-drug interactions in treating cancer-related nausea and distress.

PURPOSE: To determine the extent and severity of drug-drug interactions between anti-emetics and antipsychotics or antidepressants. SUMMARY: Oncology patients are often required to deal with chemotherapy-induced nausea and vomiting at the same time as psychosocial distress. A review of primary literature, as well as several drug interaction databases, was performed with anti-emetics used in The NCCN® 1.2010 Anti-emesis Guidelines (n = 11) and all currently US-marketed antidepressants or antipsychotics (n = 40).(1) The results from these databases were compiled into a single easy-to-use chart that portrays the severity of the interaction and brief recommendation.(2,3,4) In total, 197 drug-drug interactions out of a total of 440 possible combinations (44.8%) were discovered during the analysis. CONCLUSIONS: Although most anti-emetics had several serious interactions with antidepressants or antipsychotics, palonosetron, and granisetron were found to have no significant interactions. The results can be used to avoid or limit drug interactions in the prescribing of new medications for the oncology patient.(1,2,3,4).

Identifying metabolites of diphenidol by liquid chromatography-quadrupole/orbitrap mass spectrometry using rat liver microsomes, human blood, and urine samples.

In recent years, diphenidol [1,1-diphenyl-4-piperidino-1-butanol] has been one of the drugs that appears in suicide cases, but there are few research data on its metabolic pathways and main metabolites. Metabolite identification plays a key role in drug safety assessment and clinical application. In this study, in vivo and in vitro samples were analyzed with ultra-high-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry. Structural elucidation of the metabolites was performed by comparing their molecular weights and product ions with those of the parent drug. As a result, 10 Phase I metabolites and 5 glucuronated Phase II metabolites were found in a blood sample and a urine sample from authentic cases. Three other Phase I metabolites were identified in the rat liver microsomes incubation solution. The results showed that the main metabolic pathways of diphenidol in the human body include hydroxylation, oxidation, dehydration, N-dealkylation, methylation, and conjugation with glucuronic acid. This study preliminarily clarified the metabolic pathways and main metabolites of diphenidol. For the development of new methods for the identification of diphenidol consumption, we recommend using M2-2 as a marker of diphenidol entering the body. The results of this study provide a theoretical basis for the pharmacokinetics and forensic scientific research of diphenidol.

Identification of novel metoclopramide metabolites in humans: in vitro and in vivo studies.

Metoclopramide (MCP) is frequently used to treat gastroparesis. Previous studies have documented MCP metabolism, but systematic structural identification of metabolites has not been performed. The aim of this study was to better understand MCP metabolism in humans. For examination of in vivo metabolism, a single oral 20-mg MCP dose was administered to eight healthy male volunteers, followed by complete urine collection over 24 h. In vitro incubations were performed in human liver microsomes (HLM) to characterize metabolism via cytochromes P450 and UDP-glucuronosyltransferases and in human liver cytosol for metabolism via sulfotransferases. Urine and subcellular incubations were analyzed for MCP metabolites on a mass spectrometer with accurate mass measurement capability. Five MCP metabolites were detected in vivo, and five additional metabolites were detected in vitro. The five metabolites of MCP identified both in vitro and in vivo were an N-O-glucuronide (M1), an N-sulfate (M2), a des-ethyl metabolite (M3), a hydroxylated metabolite (M4), and an oxidative deaminated metabolite (M5). To our knowledge, metabolites M1 and M4 have not been reported previously. M2 urinary levels varied 22-fold and M3 levels varied 16-fold among eight subjects. In vitro studies in HLM revealed the following additional metabolites: two ether glucuronides (M6 and M8), possibly on the phenyl ring after oxidation, an N-glucuronide (M7), a carbamic acid (M9), and a nitro metabolite (M10). Metabolites M6 to M10 have not been reported previously. In conclusion, this study describes the identification of MCP metabolites in vivo and in vitro in humans.

Rapidly disintegrating tablets containing taste masked metoclopramide hydrochloride prepared by extrusion-precipitation method.

The purpose of this study was to mask the intensely bitter taste of metoclopramide HCl and to formulate a rapid disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by complexing metoclopramide HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratio by the extrusion-precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.8, taste evaluation in oral cavity and molecular property. The complex having drug-polymer ratio of 1 : 2 shows significant taste masking, confirmed by drug release in SSF and in-vivo taste evaluation; therefore, it was selected for further study. Taste evaluation of DPCs in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) within 10 s, whereas, metoclopramide HCl was rated intensely bitter with a score of +3 for 10 s. Tablets were evaluated for various parameters like tensile strength, wetting time, water absorption ratio, in-vitro disintegration time, and disintegration in oral cavity. The effect of diluents, lubricants and sweetening agent (Xylisorb) on the disintegration time was also evaluated. Tablets of batch F3 containing mannitol and microcrystalline cellulose in the ratio 1 : 1 and 8% w/w crosspovidone showed faster disintegration (within 20 s) than the marketed formulation (180 s). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Tablets of batch F3 also revealed rapid drug release (t(90), 90 s) in SGF compared with marketed formulation (t(90), 600 s).

Pharmacogenomics in pregnancy.

Pregnant women frequently take prescription and over the counter medications. The efficacy of medications is affected by the many physiological changes during pregnancy, and these events may be further impacted by genetic factors. Research on pharmacogenomic and pharmacokinetic influences on drug disposition during pregnancy has lagged behind other fields. Clinical investigators have demonstrated altered activity of several drug metabolizing enzymes during pregnancy. Emerging evidence also supports the influence of pharmacogenomic variability in drug response for many important classes of drugs commonly used in pregnancy. Prescribing medications during pregnancy requires an understanding of the substantial dynamic physiologic and metabolic changes that occur during gestation. Pharmacogenomics also contributes to the inter-individual variability in response to many medications, and more research is needed to understand how best to manage drug therapy in pregnant women.

The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor.

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

Risk of domperidone induced severe ventricular arrhythmia.

There has been controversy over the cardiovascular safety of domperidone, attributable to the lack of a well-designed study as well as inconsistent results. This study aimed to examine the risk of severe domperidone-induced ventricular arrhythmia (VA), compared to mosapride, itopride, or non-use of all three prokinetics, in the general population. We conducted a population-based, self-controlled case series analysis. Enrolled subjects were individuals who were diagnosed with severe VA and were prescribed domperidone, mosapride, or itopride from 2003 to 2013 in the National Health Insurance Service-National Sample Cohort. The incidence rate ratio for severe VA was measured during exposure to prokinetics and compared with unexposed periods and itopride (no-proarrhythmic effect)-exposure periods, as control. A total of 2,817 subjects were included. Domperidone, mosapride, or itopride use was associated with increased risk of severe VA, compared with non-use (adjusted incidence rate ratios (IRR) of 1.342 (95% CI 1.096-1.642), 1.350 (95% CI 1.105-1.650), and 1.486 (95% CI 1.196-1.845), respectively). The risk of severe domperidone-induced VA was lower, compared to that of itopride [adjusted IRR of 0.548 (95% CI 0.345-0.870)]. Of the subjects who had been prescribed all three prokinetics, domperidone-exposure was associated with a lower risk of severe VA, compared to itopride-exposure (crude IRR, 0.571; 0.358-0.912). Mosapride-exposure did not show IRR difference for severe VA, compared to itopride-exposure. Domperidone, mosapride, or itopride use is associated with an increased risk of severe VA. However, the magnitude of association was modest and domperidone use does not increase further the risk, compared with other prokinetics.

Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor.

BACKGROUND: Palonosetron is a 5-HT(3)-receptor antagonist (5-HT(3)-RA) that has been shown to be superior to other 5-HT(3)-RAs in phase III clinical trials for the prevention of acute, delayed, and overall chemotherapy-induced nausea and vomiting. The improved clinical efficacy of palonosetron may be due, in part, to its more potent binding and longer half-life. However, these attributes alone are not sufficient to explain the results with palonosetron. We sought to elucidate additional differences among 5-HT(3)-RAs that could help explain the observations in the clinic. METHODS: Receptor site saturation binding experiments were performed with [3H] palonosetron, [3H] granisetron, and [3H] ondansetron to obtain the corresponding Scatchard analyses and Hill coefficients. Diagnostic equilibrium binding experiments and kinetic dissociation experiments were conducted to examine competitive versus potential allosteric interactions between ondansetron, granisetron and palonosetron and the 5-HT(3) receptor. Finally, the long-term effect of the three antagonists on receptor function as measured by Ca2+ influx in HEK 293 cells expressing the 5-HT(3)-receptor was compared. RESULTS: Analyses of binding isotherms using both Scatchard and Hill plots suggested positive cooperativity for palonosetron and simple bimolecular binding for both granisetron and ondansetron. Equilibrium diagnostic tests discriminated differential effects of palonosetron on [3H] ligand binding indicating that palonosetron was an allosteric antagonist whereas granisetron and ondansetron were competitive antagonists. Using dissociation rate strategies, palonosetron was shown to be an allosteric modifier that accelerated the rate of dissociation from the receptor of both granisetron and ondansetron. Differences in the binding mode of palonosetron to the 5-HT(3) receptor were shown to have an impact on receptor function. In these experiments, cells were incubated with each antagonist, followed by infinite dilutions and dissociation for 2.5 h; cells previously incubated with either granisetron or ondansetron showed calcium-ion influx similar to control cells that had not been exposed to a 5-HT(3) receptor antagonist. In contrast, substantial inhibition of calcium-ion influx was observed in cells that had been incubated with palonosetron. CONCLUSIONS: Palonosetron exhibited allosteric binding and positive cooperativity when binding to the 5-HT(3) receptor. Palonosetron also triggered functional effects that persisted beyond its binding to the 5-HT(3) receptor at the cell surface. Differences in binding and effects on receptor function may be relevant to the unique beneficial actions of palonosetron. To our knowledge, this is the first report showing palonosetron's interaction with the 5-HT(3) receptor at the molecular level, clearly differentiating it from other 5-HT(3)-RAs.