Select serotonin receptor (5-HT3) antagonists block serotonin both peripherally, on gastrointestinal (GI) vagal nerve terminals, and centrally in the chemoreceptor trigger zone. This results in powerful antiemetic effects. Currently, there are four 5-HT3 receptor antagonists on the market, which are FDA-approved for the prevention of nausea and vomiting in children and adults related to chemotherapy use, radiation therapy, and the effects of postoperative anesthesia. Dolasetron is also FDA-approved for the treatment of postoperative nausea and vomiting in adults and children. There are a number of formulations providing clinicians and patients many options for effective dose administration. The most common adverse effects include headaches, fatigue, and constipation. Rarely, 5-HT3 receptor antagonists can cause QT prolongation if administered concomitantly with other QT-prolonging medications or in patients with a history of congenital, long-QT syndrome. There are also documented cases of serotonin syndrome in susceptible patient populations. There is also the concern for masking symptoms of bowel obstruction in the elderly or postoperative patient. An overdose of 5-HT3 receptor antagonists is rare and no fatal dose has been established. Treatment is largely supportive in these cases. Overall, select serotonin receptor antagonists are an effective antiemetic class with a wide therapeutic index and mild side effect profile.

Objectives The objectives were to evaluate the pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PDs) of SC dolasetron in healthy cats. Methods Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.8 mg/kg SC and IV dolasetron in a crossover format. Serum samples were obtained via a jugular catheter at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the administration of dolasetron. Dolasetron and the active metabolite hydrodolasetron were measured using liquid chromatography/tandem mass spectrometry. Non-compartmental PK analysis was performed. In the PD study, SC dolasetron (0.8 mg/kg and 1.0 mg/kg) and saline were administered 30 mins prior to administration of 0.44 mg/kg intramuscular xylazine in a randomized three-way crossover. Number of emetic events, lip licks, time to onset of emesis and visual nausea score were scored by a blinded observer. Results In the PK study, dolasetron was quickly metabolized to the active metabolite hydrodolasetron, limiting assessment of dolasetron PK parameters. Median (range) PK parameters for IV hydrodolasetron were as follows: maximum serum concentration (Cmax) 116 ng/ml (69-316 ng/ml), time to maximum concentration (Tmax) 0.5 h (0.3-0.5 h), half-life 3.3 h (2.9-7.2 h) and area under the curve until the last measurable concentration (AUClast) 323 h/ng/ml (138-454 h/ng/ml). Median (range) PK parameters for SC hydrodolasetron were as follows: Cmax 67.9 ng/ml (60.4-117 ng/ml), Tmax 0.5 h (0.5-1.0 h), half-life 3.8 h (2.9-5.3 h) and AUClast 437 h/ng/ml (221.5-621.8 h/ng/ml). There was no significant difference in exposure to hydrodolasetron between the routes of administration. With regard to PD, when dolasetron was administered prior to xylazine, there was no significant difference in the mean number of emetic events, lip licks, time to onset of emesis or visual nausea score when compared with saline. Conclusions and relevance Administration of 0.8 mg/kg dolasetron does not maintain serum concentrations of active metabolite for 24 h. Administration of dolasetron at 0.8 mg/kg and 1 mg/kg did not prevent xylazine-induced vomiting. Additional feline dose studies are needed to determine if a higher dose is efficacious.

Deoxynivalenol (DON), one of trichothecene mycotoxins produced by the fungus Fusarium, is commonly detected in cereal foods and in secondary food production across the world. Lower concentrations of DON induce a dose-related feed refusal (anorexia), whereas it acts as a potent emetic agent at higher levels. DON-induced emesis in humans and livestock can be observed and recorded in both undeveloped and developed regions such as Lixian, Guide and Huangzhong in China and Illinois in the USA. Some studies with different animal models (pigs and minks) suggested that DON could change expressions of 5-hydroxytryptamine, peptide YY, neuropeptide Y2 receptor and nucleobindin-2/nesfatin-1 in plasma and different areas of the brain. Some selective antagonist of 5-hydroxytryptamine 3 receptors can inhibit DON-induced emetic response. Otherwise, the Ca2+homeostasis and MAPK pathway could be potential directions in future studies. Dolasetron, dantrolene and JNJ-31020028 can be used in clinical treatment but they have potential toxic effects. (-)Epicatechin, ginger phytochemicals and isoflavone can be tested in in vitro and in vivo for their usage as food additives for reducing the emesis. The present review summarizes and discusses some information from previous and recent prominent publications with the aim to provide some comprehensive and helpful data for understanding the mechanism of DON-induced emesis. Copyright © 2017 John Wiley & Sons, Ltd.

A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of 3-Mercaptopropionic acid (MPA) capped CdS quantum dots (QDs). The structure, morphology, and optical properties of synthesized QDs were characterized by using UV-Vis absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. Under the optimum conditions, the MPA-CdS QDs fluorescence probe offered good sensitivity and selectivity for detecting DM. The probe provided a highly specific selectivity and a linear detection of DM in the range of 2-40 µg/mL with detection limit (LOD) 1.512 µg/mL. The common excipients did not interfere in the proposed method. The fluorescence quenching mechanism of CdS QDs is also discussed. The developed sensor was applied to the quantification of DM in urine and human serum sample with satisfactory results.

5-hydroxytryptamine 3 receptor (5-HT3 receptor) antagonists are administered for prevention and therapy of nausea and vomiting. Although regarded as safe therapeutics, they can also provoke arrhythmias by prolonging the QRS interval. However, the mechanisms mediating this cardiotoxicity are poorly understood. Here we investigated effects of 5-HT3 receptor antagonists on the cardiac Na(+) channel Nav1.5. We explored the interaction of dolasetron, tropisetron, granisetron and ondansetron on the human α-subunit Nav1.5 heterologously expressed in HEK293 cells. Sodium currents were explored by means of whole-cell patch clamp recordings. All four substances inhibited the Nav1.5 in a concentration and state-dependent manner. Dolasetron displayed the lowest blocking efficacy, and tropisetron was the most potent blocker with a half maximum blocking concentration of 18µM for tonic block of inactivated channels. Tropisetron was also the most potent use-dependent inhibitor, and it also induced a strong open -channel block. Both tonic and use-dependent block by tropisetron were abbreviated on the local-anesthetic insensitive mutant Nav1.5-F1760A. Co-administration of tropisetron and the local anesthetic bupivacaine or the hypnotic propofol augmented inhibition of Nav1.5. Our data demonstrate that 5-HT3 receptor antagonists induce a local-anesthetic like inhibition of Nav1.5, and that they display different blocking efficacies. Reports on a relevant cardiotoxicity of dolasetron as opposed to other 5-HT3 receptor antagonists do not seem to correlate with a block of Nav1.5. As inhibition of Nav1.5 was enhanced by propofol and bupivacaine however, it is possible that a combined administration of Na(+) channel blockers and 5-HT3 receptor antagonists can provoke arrhythmias.

[This corrects the article on p. 67 in vol. 4, PMID: 22427733.].