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The objective of this randomised, double blinded clinical trial was to evaluate the efficacy of prophylactic administration of 4 mg ondansetron as monotherapy versus combination therapy of 4 mg ondansetron plus 8 mg dexamethasone for the prevention of intrathecal morphine-associated pruritus in caesarean section within 24 h. A total of 194 patients were included, 96 patients in the monotherapy group and 98 in the combination group. One hour after the operation, 11.5% of patients in ondansetron group had failure of prophylaxis for pruritus compared to 13.5% of patients in the combination group ( p  = .66). This decreased throughout the follow-up to reach 0.0% and 1.0% at 24 h in the ondansetron vs. the combination groups respectively. There was no superiority of combining ondansetron with dexamethasone over the use of ondansetron as prophylactic antipruritic in parturients receiving intrathecal morphine for caesarean section.IMPACT STATEMENT What is already known on this subject? The incidence of pruritus has been reported to be between 36% and 60% in patients undergoing caesarean section with intrathecal morphine. Ondansetron has been identified as possible antipruritic agent while the antipruritic effect of dexamethasone is inconclusive. What do the results of this study add? The study demonstrated that there was no superiority of combining ondansetron with dexamethasone over the use of ondansetron as prophylactic antipruritic in parturients receiving intrathecal morphine for caesarean section. Moreover, it seems that there is no effect of combining ondansetron with dexamethasone over ondansetron alone on antiemetic consequences. What are the implications of these findings for clinical practice and/or further research? Ondansetron could be an effective antipruritic if used solely for patients undergoing caesarean section.

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/cm 2 ), 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.

Ondansetron HCl (OSH) is a 5-HT3 receptor antagonist indicated for the prevention of nausea and vomiting associated with radiotherapy (adults: 8 mg, t.i.d) and/or chemotherapy (adults: 8 mg, b.i.d to t.i.d) and prevention of postoperative nausea and/or vomiting (adults: 8 mg, b.i.d). In elderly subjects, bioavailability may be somewhat higher (65%) and lower clearance, presumably due to reduced hepatic first-pass metabolism. OSH is extensively distributed in the body; about 70-75% of the drug in plasma is protein-bound and terminal elimination half-life is about 3 h after oral administration. The study was aimed to develop Push-pull Osmotic Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets. The granulation was carried out using non-aqeous solvents followed by compression, seal coating, semi permeable coating, laser drilling (0.6 mm), and drug film coating with loading dose. The drug release was controlled by swelleable osmotic polymers of pull layer and push layer and orifice on the surface of tablet. The formulations were optimized for its core composition, extended release coating (Semipermeable membrane) polymer as to plasticizer ratio and orifice diameter. Optimized formulations were evaluated for micromeritic properties and in vitro drug release. The analytical methods were developed and validated to estimate in vitro drug potency, drug release, and in vivo pharmacokinetic parameters. Stability studies were done as per the ICH guidelines. The results of in vivo study concludes that the once OSH ER dose consistently maintains plasma concentration of drug within the therapeutic window over a period of 24 h.

Context: Disintegrants are the key excipients administered in tablet formulations to boost the decomposition of the tablet into smaller pieces in the gastrointestinal environment, thereby increasing the available surface area and enhancing a more rapid release of the active ingredient., Objective: Polysuccinimide (PSI), a biodegradable polymer synthesized from aspartic acid, was reacted with starch and fully assessed by CHN, 1 H-NMR, and FTIR., Methods: PSI-grafted starch (PSI-St) was synthesized and applied as a disintegrant in the formulation of a rapidly disintegrating tablet of Ondansetron, a nausea and vomiting medicine. The tablet formulated with the newly developed superdisintegrant was evaluated for hardness, friability, disintegration time, and dissolution rate, and the results were compared with tablets formulated with an identical composition of test formulation differing only in type of disintegrant., Results: Tablets prepared with starch and tablets prepared with sodium starch glycolate (SSG) were used as negative and positive controls, respectively. Dissolution study results indicated that although the onset of disintegration action was faster for SSG than PSI-St, higher amounts of drug were released from tablets formulated from PSI-St than from those formulated from SSG during 10 min., Conclusion: It was concluded that the novel synthesized superdisintegrant has an appropriate potential for the application in the formulation of fast dissolving tablets.

Nausea and vomiting are some of the major side effects caused by certain drug therapies, e.g. chemotherapy, radiotherapy and general anesthesia. Because of the nature of the symptoms, oral delivery is inappropriate, while intravenous administration may be unpractical. The aim of the present study was to develop a transdermal gel (2% Klucel®) for ondansetron, a first line 5-HT3-receptor-antagonist antiemetic. The effects of the penetration enhancer camphor and isopropyl-myristate (IPM) were first investigated in-vitro using modified Franz diffusion-cells and then tested in-vivo in a rabbit model by measuring skin and plasma concentrations. Since a disadvantage of transdermal delivery is a prolonged lag-time, the effect of skin treatment with a micro-needle roller was tested. The in-vitro permeation studies through excised porcine ear skin showed that the presence of 2.5% camphor or IPM increased steady state flux by 1.2- and 2.5-fold, respectively, compared to the control gel. Ondansetron was not detectable in either skin or plasma following in-vivo application of the base-gel, whereas the camphor gel and IPM gel delivered 20 and 81 µg/cm(2) of ondansetron, respectively. Microporation led to an increase in plasma Cmax and AUC by 10.47 ± 1.68-fold and 9.31 ± 4.91-fold, respectively, for the camphor gel, and by 2.31 ± 0.53-fold and 1.59 ± 0.38-fold, respectively for the IPM gel. In conclusion, the 2.5% IPM gel demonstrated optimal in-vivo transdermal flux. Skin pretreatment with a micro-needle roller slightly improved the delivery of the IPM gel, whereas dramatically increased the transdermal delivery of the camphor gel.

Context: Masking the bitter taste of Ondansetron hydrochloride (ONS) may improve palatability, acceptance and compliance of ONS products., Objective: ONS-loaded, taste-masked microspheres were prepared with a polycationic pH-sensitive polymer and 3(2) full factorial design (FFD) was applied to optimize microsphere batches., Materials and Methods: Solvent evaporation, in acetone--methanol/liquid paraffin system, was used to prepare taste-masked ONS microspheres. The effect of varying drug/polymer (D/P) ratios on microspheres characteristics were studied by 3(2) FFD. Desirability function was used to search the optimum formulation. Microspheres were evaluated by FTIR, XRD and DSC to examine interaction and effect of microencapsulation process. In vitro taste assessment approach based on bitterness threshold and drug release was used to assess bitterness scores., Results: Prepared ONS microspheres were spherical and surface was wrinkled. ONS was molecularly dispersed in microspheres without any incompatibility with EE100. In hydrochloric acid buffer pH 1.2, ONS released completely from microsphere in just 10 min. Contrary to this, ONS release at initial 5 min from taste-masked microspheres was less than the bitterness threshold., Conclusion: Full factorial design and in vitro taste assessment approach, coupled together, was successfully applied to develop and optimize batches of ONS incorporated taste-masked microspheres.

Introduction: Postoperative nausea and vomiting (PONV) is associated with poor patient satisfaction and delayed recovery after general anesthesia. Multiple neurotransmitters are involved in the mediation of PONV but despite the introduction of new antiemetics, no completely effective drug exists for its prevention or treatment., Areas Covered: This review provides a detailed description of ondansetron's chemistry, pharmacokinetics, pharmacodynamics, toxicity and a brief review of clinical trials involving ondansetron and the management of PONV. We searched reviews, meta-analysis and randomized controlled trials (Medline, Embase and article reference lists)., Expert Opinion: According to current literature, administering ondansetron 4 mg i.v. near the end of surgery provides sufficient protection against PONV in low- and moderate-risk patients, comparable to traditional antiemetics such as antihistamines and droperidol. High-risk patients require a multimodal approach since one quarter of them will not respond to monotherapy. In the future, transdermal formulation or formulations for nasal or buccal delivery will be available. The development of non-racemic mixture consisting of R-ondansetron would enhance the safety profile and probably the efficacy too.

Background: Antiemetics have been shown to be effective in multiple hospital settings, but few studies have been done in the prehospital environment., Objectives: Our hypotheses were 1) that the amount of normal saline administered during an emergency medical services (EMS) transport was not related to a change in nausea and vomiting and 2) that the addition of the ondansetron orally disintegrating tablet (ODT) would decrease the degree of nausea., Methods: This was a pre-post study of two cohorts of consecutive patients with nausea in the prehospital setting. During phase 1 of the study, our local EMS agency adopted a protocol form to complete whenever a patient with nausea and/or vomiting was assessed and transported to one of the area hospitals. Patients were asked to rate their nausea on a visual analog scale (VAS) and a Likert scale, and saline administration and active vomiting were documented. During phase 2, our EMS system adopted the use of ondansetron ODT for nausea and continued to complete the same forms. The nausea forms completed by EMS during phase 1 (saline only) and phase 2 (ondansetron ODT) were evaluated and compared. For both phases, the primary outcome measures were the change in VAS nausea rating (0 = no nausea, 100 = most nausea imaginable) from beginning to end of the transport and the results on the Likert scale completed at the end of the transport. Relationships were considered significant if p < 0.01., Results: Data were collected from 274 transports in phase 1 and 372 transports in phase 2. The average patient age was 50 ± 12 years. In phase 1 of the study, 178 of 274 patients (65%) received normal saline (mean volume ± standard deviation = 265 ± 192 mL). There was no significant correlation between the VAS change and the amount of fluid administration in either phase of the study. Conversely, during phase 2, patients receiving ondansetron ODT showed significant improvement in both measures of nausea. The difference in nausea improvement between phase 1 and phase 2 was significant (difference in VAS change: 24.6; 95% confidence interval 20.9, 28.3)., Conclusion: There was no improvement in patient nausea related to quantity of saline alone during an EMS transport. The addition of ondansetron ODT resulted in a significant improvement in degree of nausea.

Background: For the buccal drug delivery, chitosan (CS) can be used to improve drug absorption and reduce application frequency and drug amount. The aim of this study is to develop and evaluate mucoadhesive ondansetron buccal films for the treatment of emesis using CS as a mucoadhesive polymer., Methods: The film prepared by solvent casting method was comprised of ondansetron (approximately 65 μg)-loaded mucoadhesive gels containing 1, 2 or 3% CS and impermeable backing layer. Rheological property of the gels, physiochemical properties of the films (weight, thickness, drug content, swelling ratio, adhesion time and mucoadhesive force) and in vitro ondansetron release profile from the films were determined to evaluate the formulation. The films containing 3% CS (diameter: 0.5 cm; thickness: 170 μm) was selected as the novel formulation, and were used for the in vivo study. Comparative pharmacokinetic studies of ondansetron with this film and oral solution were performed at the same dose in hamsters., Results: The mean values of T(max) and C(max) of the film and oral solution were similar. However, the half-life, mean residence time and AUC(0-24 h) of the film were about 1.7, 1.4 and 2.0-fold higher than those of the oral solution, respectively. The film showed enhanced bioavailability and prolonged efficacy compared to the oral solution., Conclusions: The mucoadhesive ondansetron buccal film may be a potential alternative to the marketed oral formulation, parenterals and solid suppositories with better patient compliance and higher bioavailability for the treatment of emesis.

The objective of the study was to develop a mathematical model for predicting the disintegration time of fast disintegrating tablets (FDTs) by estimating the powder characteristics of powder blend prior to compression. A combination of chitosan-alginate complex and glycine in the ratio of 50:50 was used for preparing FDTs. The developed mathematical model allowed water sorption time (WST), effective pore radius (R(eff.p)) and swelling Index (SI) of powder mixture as well as tablet crushing strength to be successfully correlated with disintegration time (DT) of FDTs. The predicted model showed that disintegration time of FDTs to be directly correlated with powder characteristics and inversely correlated with tablet crushing strength. Furthermore, a correlation of 0.97 was obtained when DT of FDTs was compared with SI/(WST * R(eff.p)). This correlation was not affected by inclusion of water soluble (ondansetron hydrochloride or metaclopramide hydrochloride) or water insoluble (domperidone) drugs in the powder blend or FDTs. These observations indicated the versatility of the mathematical model in predicting the disintegration time of FDTs by evaluating the selected characteristics of the powder blends without actually preparing the FDTs.

Unlabelled: OBJCTIVE: The objectives were to evaluate the safety and efficacy of ondansetron in the out-of-hospital treatment of undifferentiated nausea or vomiting., Methods: Patients with severe nausea or intractable vomiting who were transported by paramedic-staffed ambulances in eight California counties were treated with intravenous (IV), intramuscular (IM), or oral dissolving tablet (ODT) administration of ondansetron. Data were collected prospectively for a six-month period using an online database. Prospectively defined outcome measures were 1) efficacy as measured by a quantitative visual analog nausea scale and 2) incidence of adverse effects. There were no control or placebo groups., Results: Data was collected for 2072 patients, but one patient did not receive the medication. Therefore, Ondansetron was administered to 2,071 patients (3.7% of transported patients). Most patients were adult, with only 66 patients less than 18 years old. Of the 2,071 patients, 1,320 (64%) received IV administration, 77 (4%) received IM administration, and 674 (33%) received ODT administration of ondansetron. Intravenous administration resulted in the largest improvements in nausea scores (mean 4.4; 95% confidence interval [CI] 4.2, 4.5), followed by IM (mean 3.6; 95% CI 3.0, 4.3) and ODT (mean 3.3; 95% CI 3.1, 3.5). Overall, the mean decrease in nausea score was 4.0 (95% CI 3.9, 4.1; p < 0.001) on a 10-point scale. After medication administration, four patients had mild hypotension, one had hypertension, two had itching or rash, and one had a brief episode of supraventricular tachycardia that resolved spontaneously., Conclusions: Ondansetron is safe and effective for out-of-hospital treatment of nausea and vomiting when administered by paramedics via the IV, IM, or oral route. When available to paramedics, ondansetron is used frequently.

Gellan gum-based mucoadhesive microspheres of ondansetron hydrochloride for intranasal systemic delivery were prepared to avoid first pass effect, an alternative route of administration to injection and to enhance systemic bioavailability of ondansetron hydrochloride. The microspheres were prepared using spray method. The evaluation results of microspheres were reported in our previous study. The aim of this work was to study the in vivo performance of mucoadhesive microspheres in comparison with oral and intravenous preparations of ondansetron hydrochloride. The nasal delivery system gave increased AUC(0-240) and C(max) as compared to those of oral delivery. In conclusion, the gellan gum-based microsphere formulation of ondansetron hydrochloride with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.

Background: The aim of this study was to develop chitosan microspheres for nasal delivery of ondansetron hydrochloride (OND)., Method: Microspheres were prepared with spray-drying method using glutaraldehyde as the crosslinking agent. Microspheres were characterized in terms of morphology, particle size, zeta potential, production yield, drug content, encapsulation efficiency, and in vitro drug release., Results: All microspheres were spherical in shape with smooth surface and positively charged. Microspheres had also high encapsulation efficiency and the suitable particle size for nasal administration. In vitro studies indicated that all crosslinked microspheres had a significant burst effect, and sustained drug release pattern was observed until 24 hours following burst drug release. Nasal absorption of OND from crosslinked chitosan microspheres was evaluated in rats, and pharmacokinetic parameters of OND calculated from nasal microsphere administration were compared with those of both nasal and parenteral administration of aqueous solutions of OND. In vivo data also supported that OND-loaded microspheres were also able to attain a sustained plasma profile and significantly larger area under the curve values with respect to nasal aqueous solution of OND., Conclusion: Based on in vitro and in vivo data, it could be concluded that crosslinked chitosan microspheres are considered as a nasal delivery system of OND.

The aim of this study was to prepare ondansetron-loaded biodegradable microspheres as a nasal delivery system. Microspheres were prepared with emulsification/spray-drying technique using poly(d,l-lactide) (PLA) and two different types of poly(d,l-lactide-co-glycolide) (PLGA). The effect of the type of organic solvent (dichloromethane (DCM) or a mixture of DCM and ethyl acetate) on the microsphere characteristics was also examined. The prepared microspheres were evaluated with respect to the morphological properties, particle size, zeta potential, drug loading efficiency, and in vitro drug release. The mean particle size (d(50)) of microsphere formulations was ranged from 11.67-25.54 μm, indicating suitable particle size for nasal administration. All microspheres had low drug loading efficiency in the range of 12.28-21.04%. The results indicated that particle size of microspheres were affected by both type of polymer and organic solvent, however drug loading efficiency of microspheres were affected by only the type of organic solvent used. All microspheres were negatively charged due to the polymers (PLA or PLGA) used. A prolonged in vitro drug release profile was observed for 96 h. Based on in vitro data, the selected microsphere formulation has been applied via nasal route to rats in vivo. Following nasal administration of ondansetron-loaded microsphere to rats, ondansetron plasma levels were within a range of 30-48 ng/mL during 96 h, indicating a sustained drug delivery pattern and relatively a constant plasma drug concentration level. The results suggested that biodegradable microspheres prepared with emulsification/spray-drying technique could be considered to deliver ondansetron via nasal route to obtain a prolonged release.

The present investigation aims at development of pressure sensitive adhesive (PSA) based drug in adhesive type transdermal systems of ondansetron hydrochloride with higher permeation flux. The effect of mixture of two chemical permeation enhancers (oleic acid and lauric acid diethanolamide); and drug loading dose on the ex vivo human cadaver skin permeation from the transdermal patches has been investigated using a d-optimal combined mixture design. Incorporation of chemical permeation enhancers significantly improved the permeability parameters and it was also found that blend of permeation enhancers is more effective than either permeation enhancer. Criterion of desirability was employed to numerically optimize the transdermal system. Optimized formulation was achieved with 67.5% lauric acid diethanolamide, 32.5% oleic acid and 10% drug loading in an acrylate based PSA matrix. Optimized formulation was found to be nonirritating and safe for dermatological application.

The objective of the present investigation was to formulate and evaluate orodispersible tablets (ODTs) of ondansetron HCl possessing sufficient mechanical strength by wet granulation or direct compression method. A combination of glycine and chitosan was employed for providing a sweet tasting disintegrating system. The evaluation of ODTs prepared by a wet granulation method revealed that in vitro disintegration time (DT) as well as wetting time (WT) increased and water absorption ratio (WAR) decreased with an increase in concentration of chitosan (as binder). However, an opposite relationship was obtained when ODTs were prepared by direct compression method. The FTIR spectra and DSC analysis indicated that the -NH3+ moieties of chitosan interacted with COO- moieties of glycine in ODTs prepared by the wet granulation method. However, chitosan was found to be present in the unionized state in ODTs prepared by direct compression method. Furthermore, in vitro as well as in vivo disintegration tests revealed that ODTs containing the chitosan-glycine mixture were superior to those containing well known superdisintegrants. The results suggested that the chitosan-glycine system not only improved disintegration time but also made it possible to prepare ODTs with higher crushing strength as compared to tablets containing superdisintegrants.

Gellan gum microspheres of ondansetron hydrochloride, for intranasal delivery, were prepared to avoid the first pass metabolism as an alternative therapy to parentral, and to improve therapeutic efficiency in treatment of nausea and vomiting. The microspheres were prepared using conventional spray-drying method. The microspheres were evaluated for characteristics like particle size, incorporation efficiency, swelling ability, zeta potential, in-vitro mucoadhesion, thermal analysis, XRD study and in-vitro drug release. Treatment of in-vitro data to different kinetic equations indicated diffusion controlled drug delivery from gellan gum microspheres. The results of DSC and XRD studies revealed molecular amorphous dispersion of ondansetron into the gellan gum microspheres.

The objective was to evaluate ethylene vinyl acetate (EVA) copolymer membranes with vinyl acetate content of 18% w/w (EVA1802) for transdermal delivery of ondansetron hydrochloride. The EVA1802 membranes containing selected concentrations (0, 5, 10 and 15% w/w) of PEG6000 were prepared, and subjected to in vitro permeation studies from a nerodilol-based drug reservoir. Flux of ondansetron from EVA1802 membranes without PEG6000 was 64.1 +/- 0.6 microg/cm(2.)h, and with 10%w/w of PEG6000 (EVA1802-PEG6000-10) it increased to 194.9 +/- 4.6 microg/cm(2.)h. However, with 15%w/w of PEG6000, EVA1802 membranes produced a burst release of drug which in turn decreased drug flux. The EVA1802-PEG6000-10 membrane was coated with an adhesive emulsion, applied to rat epidermis and subjected to in vitro permeation studies against controls. Flux of ondansetron from transdermal patch across rat epidermis was 111.7 +/- 1.3 microg/cm(2.)h, which is about 1.3 times the required flux. A TTS was fabricated using adhesive-coated EVA1802-PEG6000-10 membrane and other TTS components, and subjected to in vivo delivery in human volunteers against a control. It was concluded from the comparative pharmacokinetic study that TTS of ondansetron, prepared with EVA1802-PEG6000-10 membrane, provided average steady-state plasma concentration on par with multiple-dosed oral tablets, but with a low percent of peak-to-trough fluctuation.

The present investigation was carried out to formulate a terpene-based hydroxypropyl cellulose (HPC) gel drug reservoir system for its optimal transdermal permeation of ondansetron hydrochloride. The HPC gel formulations containing ondansetron hydrochloride (3% w/w) and selected concentrations of either nerodilol (0% w/w, 1% w/w, 2% w/w, 3% w/w, and 4% w/w), carvone (0% w/w, 2% w/w, 4% w/w, 8% w/w, and 10% w/w), or limonene (0% w/w, 2% w/w, 3% w/w, and 4% w/w) were prepared and subjected to in vitro permeation of the drug across rat epidermis. All the 3 terpene enhancers increased the transdermal permeation of ondansetron hydrochloride. The optimal transdermal permeation was observed with 3% w/w of nerodilol (175.3 +/- 3.1 microg/cm(2.)h), 8% w/w of carvone (87.4 +/- 1.6 microg/cm(2.)h), or 3% w/w of limonene (181.9 +/- 0.9 microg/cm(2.)h). The enhancement ratio (ER) in drug permeability with 3% w/w nerodilol, 8% w/w carvone, and 3% w/w limonene were 21.6, 10.8, and 22.5, respectively, when compared with that obtained without a terpene enhancer (control). However, there was 1.04-, 2.09-, and 2.17-fold increase in the optimal drug flux obtained with carvone, nerodilol, and limonene, respectively, when compared with the desired drug flux (84 microg/cm(2.)h). It was concluded that the HPC gel drug reservoir systems containing either 3% w/w nerodilol or 3% w/w limonene act as optimal formulations for use in the design of membrane-controlled transdermal therapeutic system (TTS) of ondansetron hydrochloride.

Objective: To compare the efficacy and tolerability of dronabinol, ondansetron, or the combination for delayed chemotherapy-induced nausea and vomiting (CINV) in a 5-day, double-blind, placebo-controlled study., Research Design and Methods: Patients receiving moderately to highly emetogenic chemotherapy received dexamethasone (20 mg PO), ondansetron (16 mg IV) and either placebo or dronabinol (2.5 mg) prechemotherapy on day 1. Patients randomized to active treatment (dronabinol and/or ondansetron) also received dronabinol (2.5 mg) after chemotherapy on day 1. On day 2, fixed doses of placebo, dronabinol (10 mg), ondansetron (16 mg), or combination therapy were administered. On days 3-5, patients received placebo, flexible doses of dronabinol (10-20 mg), ondansetron (8-16 mg), or dronabinol and ondansetron (10-20 mg dronabinol, 8-16 mg ondansetron)., Main Outcome Measures: Total response (TR = nausea intensity <5 mm on visual analog scale, no vomiting/retching, no rescue antiemetic), nausea (occurrence and intensity) and vomiting/retching episodes., Results: Sixty-four patients were randomized; 61 analyzed for efficacy. TR was similar with dronabinol (54%), ondansetron (58%), and combination therapy (47%) versus placebo (20%). Nausea absence was significantly greater in active treatment groups (dronabinol, 71%; ondansetron, 64%; combination therapy, 53%) versus placebo (15%; p < 0.05 vs. placebo for all). Nausea intensity and vomiting/retching were lowest in patients treated with dronabinol. Active treatments were well tolerated. The low number of patients due to slow enrollment limits the interpretation of these data., Conclusions: Dronabinol or ondansetron was similarly effective for the treatment of CINV. Combination therapy with dronabinol and ondansetron was not more effective than either agent alone. Active treatments were well tolerated.

Orally disintegrating tablet (ODT) of ondansetron is a new formulation, which instantaneously disintegrates and disperses in the saliva without need for ingestion of a liquid. This makes the formulation suitable for administration in children. The objective of this study was to compare the relative efficacy and cost of ODT and intravenous (IV) formulation of ondansetron in controlling nausea and vomiting in children receiving chemotherapy regimens without cisplatin. This prospective randomized trial was performed in a single institution to compare ODT and IV formulation of ondansetron for the prevention of acute emesis in a group of 22 children. Study agents were administered 30 min before chemotherapy and 12 hourly after chemotherapy (5 mg/m2 IV or 4-8 mg oral according to body surface area in 56 and 39 courses, respectively). After randomization, IV formulation was administered to some children instead of ODT due to unavailability of this formulation. Complete and major control of emesis was obtained in 92% of patients in the IV group and 93% of patients in the ODT group. In 56 courses with grade III-IV emetogenicity, complete response rates were not different between the two treatment arms. In the courses without corticosteroids complete response rates were not also different between the two arms. The mean costs per successfully controlled courses were 121.3 USD for the IV formulation whereas 63.2 USD for the ODT formulation. The results of this study confirmed that ODT formulation of ondansetron is a safe, well-tolerated, and cost-effective antiemetic for children during non-cisplatin-containing moderately and highly emetogenic chemotherapy.

The influence of drug concentration, pH in donor chamber, and 1-octanol/buffer partition coefficient on transbuccal permeation of ondansetron hydrochloride (pKa, 7.4) across porcine buccal mucosa was studied by using an in-line Franz type diffusion cell at 37 degrees C. The pH was adjusted to several values and the solubility of the drug in different pH was measured. Solubility of ondansetron hydrochloride decreases with increasing pH. The permeability of the drug was evaluated at different donor pH and drug concentrations. Permeability of un-ionized (Pu) and ionized (Pi) species of drug was calculated by fitting the data to a mathematical model. The steady state flux increased linearly with the donor concentration (r2 = 0.9843) at pH 7.4. The permeability coefficient and the partition coefficient of the drug increased with increasing pH. The values of Pu and Pi were 4.86 x 10(-6) cm/sec and 7.18 x 10(-7) (c)m/sec, respectively. The observed permeability coefficients and the permeability coefficients calculated from the mathematical model at various pH showed good linearity (r2 = 0.9799). The total permeability coefficient increased with increasing the fraction of un-ionized form of the drug. The drug permeated through buccal mucosa by a passive diffusion process. The non-ionized species of drug penetrated well through buccal mucosa and the permeation was a function of pH. Transbuccal delivery is a potential route for the administration of ondansetron hydrochloride.

Transdermal application can be an alternative drug delivery route for ondansetron, an antiemetic drug. Previous studies found that fatty acids, namely oleic and lauric, were the most effective penetration enhancers. The aim of this study was to investigate the formation of an ion pair between ondansetron and lauric acid as a possible mechanism of its enhancing action. Several techniques were used to reveal the formation of an ion pair complex. Partitioning experiments, where the n-octanol/water coefficient was measured, showed an increase in the distribution coefficient in the presence of the acid, possibly as a result of the formation of more lipophilic ion pairs between the charged molecules of ondansetron and lauric acid. Further evidence of complex formation between ondansetron and lauric acid, was gained from the 13C-nuclear magnetic resonance (13C-NMR) spectra of ondansetron, lauric acid, and their mixture (molar ratio 1:1). The NMR spectra revealed alterations to the magnetic environment of the carbon atoms adjacent to the ionized group, which are the carbonyl group of the acid and the nitrogen of the imidazole ring of ondansetron. This evidence substantiates the theory of ion pair formation. Finally, thermal analysis of the binary mixtures of ondansetron and lauric acid revealed the formation of an additional compound, with different melting point from pure ondansetron and lauric acid, which is thermodynamically favored.

Nausea and vomiting of pregnancy (NVP) affects 80% of pregnancies. Its severe form, hyperemesis gravidarum (HG), results in dehydration, electrolyte imbalance, the need for hospitalisation and can, rarely, be fatal. This was a prospective, open-labelled, controlled, interventional study to evaluate the effectiveness of pre-emptive treatment of NVP symptoms in women who experienced severe NVP or HG in their previous pregnancy. Twenty-five women who reported severe symptoms of NVP with or without HG in their previous pregnancy were recruited and counselled to commence the use of antiemetics as soon as they became aware of the present pregnancy, and no later than the beginning of symptoms. They were followed-up prospectively through the index pregnancy for symptoms of NVP, and were counselled continuously as to how to modify antiemetic doses based on symptoms. A comparison group consisted of randomly selected women also counselled by us for NVP, who had also had severe NVP in the previous pregnancy, but who did not call before a planned pregnancy and thus could not be offered pre-emptive therapy. The recruited women commenced pre-emptive drug therapy for NVP before conception or up to 7 weeks' gestation, before the appearance of NVP symptoms in all cases. In comparison to the previous pregnancy, only eight of these 18 women experienced a HG again in the index pregnancy (P = 0.01). The majority of study the women had an improvement in severity of NVP symptoms compared to the previous pregnancy. In the comparison group (n = 35), symptoms in the index pregnancy remained severe in 28 cases (80%), decreased to moderate in six (16.6%) and decreased to mild in five cases (13.9%). There were five cases of HG in the previous pregnancy and three in the index pregnancy. The pre-emptive group was improved significantly compared to the control group (P = 0.01). Pre-emptive symptom management appears to be effective in preventing severe NVP in general, and HG in particular. Women who have experienced severe NVP in a previous pregnancy may benefit from taking antiemetics before, or immediately at the start of symptoms in a subsequent pregnancy.

This prospective study was designed to compare the efficacy of ondansetron with granisetron in terms of complete emesis control and time spent in an ambulatory care setting in children with acute lymphoblastic leukemia (ALL) undergoing moderately emetogenic cyclophosphamide-based chemotherapy. The costs for both treatments are also examined. A total of 33 children (mean age: 7.8 +/- 4.9 year) were studied during 66 chemotherapy cycles. Analysis was based on 33 courses of a single oral dose of granisetron and 33 courses of ondansetron incorporating 2 intravenous doses of ondansetron 0.15 mg/kg followed by 1 dose of the same dosage orally. There was no significant difference between the 2 treatments in terms of overall efficacy (McNemar's chi-square test). Twenty of 33 patients (60.6%) receiving granisetron and 15 of 33 patients (45.5%) receiving ondansetron experienced no emesis 24 h after chemotherapy (p = .227). Boys experienced greater rates of vomiting than did girls despite antiemetic treatment; however, no apparent reason for the gender discrepancy was noted. Both antiemetic regimens have similar antiemetic efficacy for treating the moderately emetogenic effects associated with cyclophosphamide-based chemotherapy. It is possible that the granisetron regimen may be preferable because it is simpler to administer and more cost-effective.

The effects of vehicles and penetration enhancers on the in vitro permeation of ondansetron hydrochloride (OS) across dorsal hairless mouse skins were investigated. Various types of vehicles, including ester, alcohol, and ether and their mixtures were used, and then a series of fatty acids and fatty alcohols were employed as enhancers. Among pure vehicles used, water and ethanol showed high permeation fluxes, which were 48.2+/-23.7 and 41.9+/-17.9 microg/cm2 per h, respectively. Even though propylene glycol monocaprylate (PGMC) alone did not show a high permeation rate, the skin permeability of OS was increased by the addition of diethylene glycol monoethyl ether (DGME); the highest flux was achieved at 40% of DGME. Also, the combination of PGMC and ethanol (80:20) or PGMC and propylene glycol (PG) (60:40) increased the permeation flux by six- and two-fold, respectively, compared to PGMC alone. The synergistic enhancement was also obtained by using PG-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. The enhancement factors with the addition of oleic acid or linoleic acid to PG were about 1250 and 450, respectively. But saturated fatty acids failed to show a significant enhancing effect. When the PGMC-DGME (60:40) cosolvent system was used as a vehicle, all fatty acids, including unsaturated fatty acids, failed to show significant enhancing effects. The results indicate that the combinations of oleic acid, linoleic acid, or oleyl alcohol with PG, or PGMC-DGME (60:40) cosolvent could be used for the design of the OS transdermal system.

Granisetron (Kytril, Roche) is a 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin. Its indication expanded in August 2002, with approval from the FDA for the prevention and treatment of postoperative nausea and vomiting. Granisetron strongly and selectively binds to the 5-HT(3) receptor with a binding constant of 0.26 nM and exhibits a 4000 - 40,000 times greater binding affinity for the 5-HT(3) receptor than other binding sites, including other 5HT subtypes and adrenergic, histaminergic and opioid receptors. Its selectivity to the 5-HT(3) receptor over other receptor types is > 1000:1. Granisetron noncompetitively binds to the 5-HT(3) receptor and is associated with a long duration of action as shown by the inhibition of a 5-HT axonal response flare for up to 24 h. Granisetron is unique among the 5-HT(3)-receptor antagonists because it is not metabolised via the cytochrome P450 (CYP) 2D6 pathway and is, therefore, less susceptible to variation in patient response because of factors such as pharmacogenomic differences. Granisetron and other 5-HT(3)-receptor antagonists are first-line agents for acute chemotherapy-induced nausea and vomiting (CINV), whereas combination therapy with 5-HT(3)-receptor antagonists, dexamethasone and neurokinin (NK)-1 receptor antagonism (i.e., with the recently approved aprepitant) is an effective approach to prevent delayed CINV. Granisetron has been shown to be an effective within-class rescue antiemetic for prophylactic failures, which may be linked to its pharmacological properties including non-competitive, insurmountable binding to the 5-HT(3) receptor. As with other 5-HT(3)-receptor antagonists, granisetron is well-tolerated with adverse events of mild severity including headache, asthenia and constipation. Overall, data demonstrate that granisetron is an efficacious, safe and cost-effective member of the 5HT(3)-receptor antagonist class for the prevention of CINV.

We examined whether the clock time of cisplatin plus antiemetic and diuretic administration affects the amount of cisplatin-associated emesis and severity of renal toxicity. We treated 22 patients with urogenital cancer with two courses of chemotherapy containing 70 mg/m2 of cisplatin. Cisplatin together with furosemide was administered in the morning (05:00) or evening (17:00) during two courses 1 month apart in a crossover fashion. Ondansetron was given either before or after cisplatin to control nausea and vomiting. The number of vomiting episodes, serum creatinine, serum urea nitrogen (BUN), creatinine clearance, and urinary beta-N-acetyl glucosamidase (NAG) concentration were evaluated before and after each treatment course. Regardless of the timing of ondansetron, morning compared to evening cisplatin was always associated with greater vomiting in the first treatment course. However, prophylactic administration of ondansetron markedly diminished the impact of the clock time of cisplatin administration. Serum creatinine transiently decreased rather than increased 14 days after cisplatin and furosemide administration, while NAG excretion increased 3 days after cisplatin and furosemide administration. In the first course, serum creatinine levels were similar regardless of the clock time of cisplatin and furosemide administration. However, in the second course, serum creatinine rose in patients given evening cisplatin and furosemide, while it remained unchanged in those given morning cisplatin and furosemide. Moreover, the first course morning cisplatin and furosemide treatment was associated with less change in NAG excretion (less kidney toxicity) than the first course of evening cisplatin and furosemide treatment. The second course evening cisplatin and furosemide treatment was associated with an increase in NAG excretion compared to the first course of treatment, while morning cisplatin and furosemide treatment in the second course showed less change in NAG excretion compared to the first course. The clock time of cisplatin administration had an impact on the frequency of emesis. Prophylactic ondansetron, however, diminished the time-of-day dependency of cisplatin-induced vomiting. Administration of cisplatin and furosemide in the morning rather than evening appears to cause less renal damage, and this damage may be further reduced with aggressive hydration and routine administration of furosemide.

This double-blind, parallel-group, multicenter study compared the efficacy and safety of intravenous (i.v.) ondansetron with oral syrup ondansetron plus oral dexamethasone in the prevention of nausea and emesis in pediatric patients receiving moderately/highly emetogenic chemotherapy. On each day of chemotherapy, patients were administered ondansetron 5 mg/m2 i.v. and placebo syrup orally (n = 215) or ondansetron 8 mg syrup orally and placebo i.v. (n = 223) plus dexamethasone 2-4 mg p.o. Ondansetron 4 mg syrup p.o. was administered twice daily for 2 days following the cessation of chemotherapy. Complete or major control of emesis was obtained in 89% patients in the i.v. group and 88% patients in the oral syrup group during the worst day of chemotherapy treatment (90% CI: -6, 4) and in 85% and 82% patients, respectively, during the worst day of the study period (90% CI: -8, 3). Intravenous or oral syrup ondansetron plus dexamethasone was well tolerated and effective in preventing chemotherapy-induced emesis in pediatric patients.

The 5-HT3 receptor antagonists are the most potent antiemetics known at present. Lerisetron is a new 5-HT3 receptor antagonist chemically unrelated to other antagonists like Ondansetron. An emesis model in the dog induced by irradiation with 60Co was used, and 8 Gy were administered over the total body surface. An irradiated control group was established and received no medication, and two irradiated groups received treatment with either Ondansetron or Lerisetron. The 'up-down' technique was employed to determine the effective dose (ED50). A logarithmic-scale was used to increase or decrease the doses in each case. The initial doses were 300 microg/kg for Ondansetron and 100 microg/kg for Lerisetron. All animals in the control group vomited. The ED50 of Ondansetron was 178+/-151 microg/kg body wt and that of Lerisetron was 63+/-18 microg/kg. Lerisetron is more potent and presented less individual variability than Ondansetron, but its antiemetic effects were equally effective.

Ondansetron, a highly selective 5-HT3 receptor antagonist, is available in an intravenous (IV) formulation and tables, but syrup would be particularly useful in children. As chemotherapy can affect taste perceptions, this study was undertaken to determine the preference between two flavors of ondansetron syrup in children undergoing chemotherapy. Fifty-nine children, randomized into a multicenter, double-blind, crossover study, each received 5 mg/m2 of IV ondansetron daily before chemotherapy. The syrup was then randomly given in two doses, one of each flavor, strawberry and grape, 30 minutes apart. The preference was assessed 30 minutes after the second dose of syrup had been administered. Taste was assessed by the child against a panel of five faces. Of those children expressing any preference, 70% preferred the strawberry flavor. Overall, 59% of children preferred the strawberry flavor, whilst 25% preferred grape (P = 0.005) and 15% expressed no preference. The only adverse event assessed as drug related by the investigator was constipation, which occurred in one patient. In conclusion, a strong preference was found for the strawberry formulation. The ondansetron syrup was safe and well tolerated.

Background: The role of serotonergic type-3 receptors in proximal human colon is unclear. Our aims were to assess the postprandial volume and emptying of the ascending colon and to explore the role of 5-hydroxytryptamine-3 (5HT3) mechanisms., Methods: In healthy subjects with unprepared colons we evaluated in a randomized trial the effects of the 5HT3 antagonist ondansetron (n = 5) or placebo (n = 5) on ascending colon volume and emptying, using a scintigraphic method., Results: Base-line ascending colon volumes were similar and were unaltered by ondansetron. After a 1000-kcal liquid meal the placebo group showed a variable change in volume (P = NS versus base line) during the first 25 min (median, -4%; range, -13% to 135%). Increases in volume during this period coincided with ileal emptying of chyme. During a second phase (30-105 min) there was a significant decrease of ascending colon volume (P = 0.02) relative to the early postprandial volume, but the volume was not significantly different from base line. This second phase was associated with transfer of chyme towards the transverse colon. In the ondansetron group there was an initial modest increase in volume (median, 5%; range, -15% to 14%; P = NS versus base line), and the second phase of contraction was inhibited., Conclusions: The ascending colon response to a meal in health is characterized by a variable initial change in volume, accommodating ileal chyme in some individuals, and a more consistent reduction in volume from 30 to 105 min postprandially. The latter response is inhibited by ondansetron, suggesting partial control of postprandial colonic motor function by 5HT3 mechanisms.

One hundred children with non-central nervous system malignancies received ondansetron at initiation of chemotherapy and every 8 hours for 5 days after cisplatin-containing therapy and for 3 days after other chemotherapy. Ondansetron was administered orally except with the intravenous chemotherapy. For the chemotherapy days, 72 of 93 children (76%) had complete or major control of vomiting on their worst day, 25% with cisplatin-containing protocols, 60% with ifosfamide-containing protocols, and 82% with other protocols. For the overall period, 71 of 93 children (76%) reported complete or major control of vomiting on the worst day, 14% with cisplatin, 60% with ifosfamide, and 83% with other chemotherapy. All had mild or no nausea. Of the 355 chemotherapy days, 228 children (64%) were emesis free, 40% with cisplatin, 60% with ifosfamide, and 68% with other regimens. Of the overall period (541 days), 393 days were emesis free, 45% with cisplatin, 71% with ifosfamide, and 86% with other regimes. Sixty-nine patients were not hospitalized, and oral ondansetron was given when chemotherapy was completed. Of the 241 ambulatory chemotherapy days, 178 (74%) were emesis free. No significant toxicity was encountered. Oral ondansetron reduced hospitalization without reducing antiemetic efficiency in children.

A phase II study using a combination of Ondansetron and Lorazepam to treat patients receiving either highly or moderately emetogenic chemotherapy regimens has recently been completed. A total of 56 patients were enrolled and data from 53 is amenable to analysis. The overall response rates were 100% and 91% for the highly and moderately emetogenic regimens respectively, with 16 out of 20 patients (80%) and 18 out of 33 patients (54.5%) achieving a complete or major response respectively. Toxicity was mild and no dose modifications were necessary.

Forty-seven patients receiving non-cisplatin-containing chemotherapy were entered in a prospective study in which the efficacy of ondansetron plus dexamethasone and tropisetron plus dexamethasone in the prophylaxis of acute vomiting was evaluated. Thirty-nine patients were evaluable for cross-over analysis. During the 24 hours following the start of chemotherapy, 97% of patients on ondansetron plus dexamethasone reported total control of vomiting compared with 82% of those on tropisetron plus dexamethasone (p = 0.026). Thus, both 5-HT3- receptor antagonists combined with dexamethasone were highly effective in controlling acute vomiting induced by non-cisplatin-containing chemotherapy. The observed difference between the treatments may be caused by different dose schedules of ondansetron and tropisetron. A double-blind design with equal number of placebo-controlled administrations is needed to ascertain whether there is a significant pharmacological difference between ondansetron and tropisetron.