Cytotoxic Drug-induced Emesis Research Articles

5-HT3 receptor blocking activity of arylalkanes isolated from the rhizome of Zingiber officinale.

Different extracts (ethanolic, hexane, aqueous) of ginger (rhizomes of Zingiber officinale) and the essential oil were tested using [14C]guanidinium influx into N1E-115 cells and the isolated rat ileum in order to identify their activity in inhibiting 5-HT3 receptor function. The hexane extract proved to be the most active and yielded upon bioassay-guided fractionation nine constituents: [6]-, [8]-, [10]-gingerols, [6]- and [8]-shogaols which were previously shown as active in vivo against cytotoxic drug-induced emesis; [4]-gingerol, [6]-gingerdiol, diacetyl-[6]-gingerdiol and [6]-dehydrogingerdione have not been previously tested for anti-emetic or 5-HT3 receptor antagonistic effects. Even though the latter four compounds are only minor constituents, their identification contributed towards the characterisation of a structure-activity relationship of this class of compounds. The order of potency for the nine constituents in the N1E-115 cell system was [6]-gingerdiol approximately diacetyl-[6]-gingerdiol approximately [6]-dehydrogingerdione approximately [6]-shogaol > or = [8]-shogaol approximately [8]-gingerol > [10]-gingerol > or = [6]-gingerol > [4]-gingerol.

The ferret: a cytotoxic drug-induced emesis model

The ferret (Mustela putorius furo), a carnivore weighting 1–1.5 kg, is highly valued as a small animal model for determining the emetic activity of cytotoxic drugs. Because of its sensitivity to emetic stimuli, the ferret is now being used routinely for testing novel cytotoxic drugs and antiemetic agents. In our laboratory, ferrets were evaluated on their behavioral changes, pathological changes and pharmacological responses to cytotoxic drug-induced emesis. Cisplatin-induced emesis in ferrets was inhibited by 5-HT3 receptor antagonists in a dose dependent manner. 5-HT levels in the area postrema and in the ileum were increased by cytotoxic agents. Both abdominal vagotomy and ondansetron, a 5-HT3 receptor antagonist, remarkably inhibited cisplatin-induced emesis and cisplatin-induced increase in 5-HT levels in the area postrema. The cisplatin-induced increase of the ileal 5-HT levels, however, was not inhibited by vagotomy or ondansetron. Furthermore, compared with intraperitoneal administration, oral administration of ondansetron blocked cyclophosphamide-induced emesis more effectively and significantly. These results suggest that cytotoxic drugs induce emesis mainly through actions on the gastrointestinal tract. Cytotoxic drugs may cause 5-HT release from the enterochromaffin (EC) cells of the intestinal mucosa to stimulate 5-HT3 receptors on the afferent vagal fibers. Stimulation from the afferent vagal nerves appear to produce an increase in 5-HT levels in the area postrema. The increased 5-HT levels in the area postrema might trigger the emetic response induced by cytotoxic agents. In this review, we also discuss abdominal afferent vagus nerve activity and 5-HT release from EC cells using data from our laboratory.

1218 Ondansetron (OND) suppository (SUP): An effective treatment in the prevention of chemotherapy-induced emesis

OND is currently available in oral (po) and intravenous (iv) formulations for chemotherapy and radiotherapy-induced emesis, sup's will provide a useful alternative. Two multicentre, randomised, double-blind, parallel group studies compared the efficacy and safety of a 16 mg once a day (od) OND sup with (i) 8 mg OND iv followed by 8 mg twice daily (bd) OND po in cisplatin chemotherapy and (ii) 8 mg bd OND po in non–cisplatin chemotherapy. Four hundred and twenty-one patients were recruited into the cisplatin study and 406 into the non–cisplatin study. In the CISPLATIN study, 92% of patients experienced complete or major control of emesis (0 to 2 emetic episodes) on day 1 in the OND iv and po combined regimen compared with 87% of patients in the OND sup regimen. In the non-cisplatin study, 81% of patients experienced complete or major control of emesis on the worst day of days 1–3 in the 8 mg bd OND po regimen compared with 73% of patients in the 16 mg od OND sup regimen. The 90% confidence interval for the difference between the treatments for complete or major control in both studies showed that the sup regimen was equivalent to the other two OND regimens. The most frequently reported drug-related event was headache. In conclusion, these two studies showed that the ondansetron sup was effective and safe in the prevention of cytotoxic drug-induced emesis. OND is currently available in oral (po) and intravenous (iv) formulations for chemotherapy and radiotherapy-induced emesis, sup's will provide a useful alternative. Two multicentre, randomised, double-blind, parallel group studies compared the efficacy and safety of a 16 mg once a day (od) OND sup with (i) 8 mg OND iv followed by 8 mg twice daily (bd) OND po in cisplatin chemotherapy and (ii) 8 mg bd OND po in non–cisplatin chemotherapy. Four hundred and twenty-one patients were recruited into the cisplatin study and 406 into the non–cisplatin study. In the CISPLATIN study, 92% of patients experienced complete or major control of emesis (0 to 2 emetic episodes) on day 1 in the OND iv and po combined regimen compared with 87% of patients in the OND sup regimen. In the non-cisplatin study, 81% of patients experienced complete or major control of emesis on the worst day of days 1–3 in the 8 mg bd OND po regimen compared with 73% of patients in the 16 mg od OND sup regimen. The 90% confidence interval for the difference between the treatments for complete or major control in both studies showed that the sup regimen was equivalent to the other two OND regimens. The most frequently reported drug-related event was headache. In conclusion, these two studies showed that the ondansetron sup was effective and safe in the prevention of cytotoxic drug-induced emesis.

Simultaneous determination of granisetron and its 7-hydroxy metabolite in human plasma by reversed-phase high-performance liquid chromatography utilizing fluorescence and electrochemical detection

A highly sensitive and selective high-performance liquid chromatographic method was developed for the determination of granisetron and its active metabolite, 7-hydroxygranisetron (7OH-G) in human plasma. Granisetron is a selective 5-hydroxtryptamine receptor antagonist used in the treatment of cytotoxic drug-induced emesis. The method involves isolation of granisetron, 7OH-G and the internal standards from plasma by solid-phase extraction prior to reversed-phase ion-pair chromatographic separation on an octyl silica column with subsequent quantification of analytes simultaneously either with electrochemical (7OH-G) or fluorescence (granisetron) detectors which are placed in series. The recovery of granisetron and 7OH-G from human plasma was quantitative. Using 1 ml of plasma, the limits of quantification for granisetron and 7OH-G were 0.1 and 0.25 ng/ml, respectively. Linear responses in analyte/internal standard peak-area ratios were observed for analyte concentrations ranging from 0.1 to 50 ng/ml plasma. Precision and accuracy were within 13% across the calibration range for both granisetron and 7OH-G. The method was sufficiently sensitive, accurate and precise to support pharmacokinetic studies for granisetron and 7OH-G, in both normal and patient populations.

Pancopride, a potent and long-acting 5-HT 3 receptor antagonist, is orally effective against anticancer drug-evoked emesis

Pancopride ((±)N-(1-azabicyclo-[2,2,2]-oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide) is a new potent and selective 5-HT 3 receptor antagonist, orally and parenterally effective against cytotoxic drug-induced emesis. In vitro, pancopride displayed high affinity (K i = 0.40 nM) for [ 3H]GR65630-labelled 5-HT 3 recognition sites in membranes from the cortex of rat brains. In vivo, pancopride antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v. 5 min (ID 50 = 0.56 μg/kg) or p.o. 60 min (ID 50 = 8.7 μg/kg) before 5-HT challenge. A single oral dose (10 μg/kg) of pancopride produced a significant inhibition of the bradycardic reflex over an 8-h period. Pancopride dose dependcntly inhibited the number of vomiting episodes and delayed the onset of vomiting induced by cisplatin in dogs (ID 50 = 3.6 μg/kg i.v. and 7.1 μg/kg p.o.). Pancopride was also effective in blocking mechlorcthamine- and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopamincrgic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.

Antiemetic used for schizophrenia.

Ondansetron, marketed for the treatment of cytotoxic drug-induced emesis, might be useful in the treatment of schizophrenia, researchers say.

5-HT3 receptor antagonists and migraine therapy

Neuronal 5-hydroxytryptamine3 (5-HT3) receptors mediate the excitatory effects of 5-HT. They are located in pain- and nausea-modulating areas in the central nervous system and on C-fibre primary afferents in the peripheral nervous system. Consequently, these receptors mediate the painful and emetic effects of 5-HT. Selective and potent 5-HT3 receptor antagonists have been shown to block inflammatory and 5-HT induced and potentiated "vascular pain". Based on the hypothesis that 5-HT3 receptor antagonists may block neurogenic dural inflammation in the distribution area of the trigeminal nerve and, thus, could potentially prevent migraine (pain), four highly selective and potent 5-HT3 receptor antagonists have been tested in both the acute and prophylactic treatment of migraine. Unfortunately, except for a clear anti-emetic effect, none of these drugs has shown unequivocal efficacy in the treatment of migraine. This may be partly due to the complex (bell-shaped) dose-response relationship of these compounds, making exact titration of the correct dose difficult. Moreover, most 5-HT3 receptor antagonists have proved to be toxic in man on chronic administration thereby preventing further trials in migraine with adjusted doses. Short-term treatment for cytotoxic drug-induced emesis so far appears to be the only proven indication for 5-HT3 receptor antagonists.

Pathophysiology of cytotoxic drug-induced emesis: far from crystal-clear

Both radiotherapy and chemotherapy for cancer are capable of causing severe nausea and vomiting, which formerly often interfered with the patient's compliance to treatment. The basic pathway and pharmacological mechanisms involved in this are still poorly understood. The recent discovery, however, that 5-HT3 receptor antagonists can prevent or greatly reduce chemotherapy-induced emesis led to a re-evaluation of the sequence of events occurring in the protective emetic reflex, which are reviewed in this paper. The vomiting centre co-ordinates the incoming and outgoing information, and is thought to be represented by complex interactions between different adjacent areas in the brainstem. Whether the main role in the emetic reflex arch is accomplished by either the central part (chemoreceptor trigger zone) or the peripheral part (gastro-intestinal tract) needs further confirmation A more important role, however, of the vagal nerve and the gastro-intestinal tract is generally accepted. The neurotransmitter serotonin (5-HT) appears to play a major role in chemotherapy-induced emesis via the 5-HT receptor. These indications could form the basis for further investigations into the involvement of other neurotransmitters, and the character of their interactions.

P-486 - Inhibitory effects of YM060, a new serotonin 5HT3 receptor antagonist, on cytotoxic drug-induced emesis in ferrets.

P-486 - Inhibitory effects of YM060, a new serotonin 5HT3 receptor antagonist, on cytotoxic drug-induced emesis in ferrets.

Selective blockade of cytotoxic drug-induced emesis by 5-HT3 receptor antagonists in Suncus murinus.

Antiemetic effects of serotonin 5-HT3 receptor antagonists (ICS205-930, zacopride, BRL43694, GR38032F) were investigated in Suncus murinus. Veratrine, nicotine, copper sulfate, cisplatin, cyclophosphamide and motion sickness were used as emetic stimuli. Serotonin 5-HT3 receptor antagonists did not inhibit emetic responses to veratrine, nicotine, copper sulfate and motion sickness. However, cisplatin- and cyclophosphamide-induced emesis was strongly blocked by them. Both subcutaneous and intravenous injections of 5-HT3 antagonists were effective. Serotonin 5-HT1 and 5-HT2 receptor antagonists were less effective. These results clearly indicate that a 5-HT3 receptor-mediated mechanism(s) is involved in the emesis caused by cancer chemotherapeutic agents and that 5-HT3 receptor antagonists are very effective as prophylactic drugs.

Selective Blockade of Cytotoxic Drug-Induced Emesis by 5-HT3 Receptor Antagonists in Suncus Murinas

Antiemetic effects of serotonin 5-HT3 receptor antagonists (ICS205-930, zacopride, BRL43694, GR38032F) were investigated in Suncus murinus. Veratrine, nicotine, copper sulfate, cisplatin, cyclophosphamide and motion sickness were used as emetic stimuli. Serotonin 5-HT3 receptor antagonists did not inhibit emetic responses to veratrine, nicotine, copper sulfate and motion sickness. However, cisplatin- and cyclophosphamide-induced emesis was strongly blocked by them. Both subcutaneous and intravenous injections of 5-HT3 antagonists were effective. Serotonin 5-HT1 and 5-HT2 receptor antagonists were less effective. These results clearly indicate that a 5-HT3 receptor-mediated mechanism(s) is involved in the emesis caused by cancer chemotherapeutic agents and that 5-HT3 receptor antagonists are very effective as prophylactic drugs.

The classification of 5-hydroxytryptamine receptors.

1. The current classification of receptors for 5-hydroxytryptamine (5-HT) is based on functional studies, and encompasses three main receptor types. 2. 5-HT1-like receptors mediate inhibition of release of various neurotransmitters from central and peripheral sites, smooth muscle contraction and relaxation (and release of endothelium-derived relaxing factor), tachycardia, a variety of behavioural actions (for example, forepaw treading, hypothermia, hyperphagia, drug discriminative stimulus properties, nociceptive pathway modulation, and anxiolytic, anti-aggressive and prosexual effects), and central neuronal excitatory and inhibitory activity. Selective antagonists for this receptor are not yet available, but the 5-HT2 receptor antagonists methysergide and methiothepin have appreciable affinity for 5-HT1-like receptors, and 5-carboxamidotryptamine is a selective agonist. 3. 5-HT2 receptors mediate smooth muscle contraction, platelet aggregation, increased capillary permeability, some behavioural syndromes (for example, head twitch and wet-dog shakes) and drug discriminative stimulus properties, central neuroexcitatory effects, and some neuroendocrine functions. Ketanserin and cyproheptadine are selective antagonists. 4. 5-HT3 receptors mediate peripheral afferent and efferent neuroexcitatory actions, anxiogenic effects, and modulation of cytotoxic drug-induced emesis, gastric emptying, and dopamine-related mesolimbic hyperactivity. Selective antagonists include cocaine, MDL 72222 and ICS 205-930; 2-methyl-5-HT is a selective agonist.

Querying the Control of Cytotoxic Drug-induced Emesis

Querying the Control of Cytotoxic Drug-induced Emesis

Cytotoxic Drug-induced Emesis

Cytotoxic Drug-induced Emesis