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PubMed1999

Gastrointestinal motor and myoelectric correlates of motion sickness.

The objectives of this study were to characterize the digestive tract motor and myoelectric responses associated with motion sickness. Twenty-two cats (1.5-3.0 kg) were chronically implanted with force transducers and electrodes on the stomach and small intestine. Motion sickness was activated by vertical oscillation (VO) at +/-0.5 g and identified as salivation, licking, or vomiting. Vomiting was initiated chemically by UK-14304 (2.5-15 microg/kg iv) or CuSO4 (10-50 mg ig). We found that VO caused vomiting (45% of trials), a decrease in gastrointestinal (GI) motility (69% of trials), salivation or licking (59% of trials), bradygastria (39% of trials), retrograde giant contraction (RGC, 43% of trials), giant migrating contraction (GMC, 5% of trials), and defecation (18% of trials). The decrease in GI motility occurred with (62% of trials) or without (69% of trials) vomiting. Motion sickness was accompanied by bradygastria (52% of trials) and decreased GI motility (70% of trials). Similar events occurred after CuSO4 and UK-14304, but the incidences of responses after CuSO4 were less frequent, except for vomiting, RGC, and GMC. UK-14304 never caused GMCs or defecation. The magnitude and velocity of the RGC were the same during all emetic stimuli, and RGCs never occurred without subsequent vomiting. Supradiaphragmatic vagotomy (n = 1) or atropine (n = 2, 10 or 50 microg/kg iv) blocked the RGC, but not vomiting, due to VO. We concluded that 1) oculovestibular stimulation causes digestive tract responses similar to other types of emetic stimuli, 2) decreased GI motility and bradygastria may be physiological correlates of the motion sickness, and 3) motion sickness may not be dependent on any specific GI motor or myoelectric response.

Animals↗
PubMed1991

Emesis, learned aversion, and chemical defense in octocorals: a central role for prostaglandins?

Prostaglandin A2 and its ester derivatives comprise as much as 8% of the wet tissue weight of some octocoral species such as Plexaura homomalla (phylum Cnidaria, class Anthozoa, subclass Octocorallia). These high levels of prostaglandins, although initially palatable to fish, may function as defensive toxins by inducing emesis and learned aversions in potential predators. As the fish Fundulus heteroclitus and Halichoeres garnoti gain experience through the course of experiments, they increasingly reject foods containing emetic prostaglandins, but do not alter their acceptance of untreated control foods. Emesis is also induced in fish by consumption of tissue or lipid extracts from the subtropical whip coral Leptogorgia virgulata (subclass Octocorallia, order Gorgonacea). The emetic properties of L. virgulata induce learned aversions in the fish Micropterus salmoides and Morone saxatilis. Extracts of L. virgulata do not contain high levels of prostaglandins but do, however, contain other metabolites that appear to mimic the effects of eicosanoids. Some nonprostanoid secondary metabolites may induce emesis by stimulating prostaglandin biosynthesis in the gastric mucosa of predators.

Animals↗
PubMed1993

Plasticity of autonomic control of emesis in irradiated ferrets.

To investigate the plasticity of the emetic response to irradiation, five groups of ferrets (with the appropriate controls) had either the vagal or the splanchnic nerves transected and either were immediately irradiated under urethan anesthesia or were irradiated in a conscious state at 0.5-4, 4-9, and 24 h and 7 days after nerve transection. All the ferrets used in this study had the left carotid artery and the right jugular vein catheterized several hours before irradiation so that blood pressures could be monitored. In ferrets that were irradiated while anesthetized, bilateral abdominal vagotomy performed immediately before 6-Gy irradiation prevented emesis. Acute bilateral abdominal splanchnicectomy markedly reduced emesis in such cases but had no statistically significant effect in conscious ferrets. The incidence of emesis in conscious controls laparotomized 0.5-4 h before irradiation was 50% after 2 Gy and 100% after 6 Gy. Intact conscious controls were tested with 10 Gy only and showed a 100% incidence of emesis after this dose. Bilateral abdominal vagotomy, performed on ferrets 4-9 h before 8-Gy irradiation of conscious animals, markedly reduced the incidence of radiation-induced emesis. When performed 24 h before irradiation, it abolished emesis. In contrast, vagotomy was ineffective when performed 7 days before irradiation. The data suggest that, after 2-8 Gy, the vagi are the major emetic pathway in conscious ferrets and the splanchnic nerves may, under certain conditions, constitute second or alternate pathways.

Animals↗
PubMed2001

Plasma hormone levels and central c-Fos expression in ferrets after systemic administration of cholecystokinin.

Posterior pituitary hormone secretion and central neural expression of the immediate-early gene product c-Fos was examined in adult ferrets after intravenous administration of CCK octapeptide. Pharmacological doses of CCK (1, 5, 10, or 50 microg/kg) did not induce emesis, but elicited behavioral signs of nausea and dose-related increases in plasma vasopressin (AVP) levels without significant increases in plasma oxytocin (OT) levels. CCK activated neuronal c-Fos expression in several brain stem viscerosensory regions, including a dose-related activation of neurons in the dorsal vagal complex (DVC). Activated brain stem neurons included catecholaminergic and glucagon-like peptide-1-positive cells in the DVC and ventrolateral medulla. In the forebrain, activated neurons were prevalent in the paraventricular and supraoptic nuclei of the hypothalamus and also were observed in the central nucleus of the amygdala and bed nucleus of the stria terminalis. Activated hypothalamic neurons included cells that were immunoreactive for AVP, OT, and corticotropin-releasing factor. Comparable patterns of brain stem and forebrain c-Fos activation were observed in ferrets after intraperitoneal injection of lithium chloride (LiCl; 86 mg/kg), a classic emetic agent. However, LiCl activated more neurons in the area postrema and fewer neurons in the nucleus of the solitary tract compared with CCK. Together with results from previous studies in rodents, our findings support the view that nauseogenic treatments activate similar central neural circuits in emetic and nonemetic species, despite differences in treatment-induced emesis and pituitary hormone secretion.

Animals↗
PubMed1988

Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides.

1. Multiple-barreled microelectrodes were used to record from neurons in the area postrema of anesthetized dogs and to test the responses of the neurons to a variety of substances in this structure, which is known to function as the chemoceptive trigger zone for emesis. 2. The neurons in area postrema were silent at rest but could be "found" by virtue of their response to ionophoretic glutamate. The glutamic response was brief and of short latency with high frequency of discharge. 3. Dog area postrema neurons were also excited by over 20 other substances, including acetylcholine, the biogenic amines, several peptides, and at least two hormones. Not all agents were excitatory, however. 4. The responses to all excitatory agents except glutamate were similar and unusual. All responses showed a relatively long latency (3-20 s), a long duration of excitation (30 s to many minutes), and a low discharge frequency (1-3 Hz). 5. There was a good correlation between substances that were excitatory on area postrema neurons and substances known to cause emesis. Because emesis due to intravenous application of these substances is known to be abolished in animals with ablation of the area postrema, it is very likely that recordings were from the neurons which trigger the response. 6. Because so many substances elicit the same type of response there is a possibility that all utilize a common second messenger. Neurons were not excited by ionophoresis of guanosine 3',5'-cyclic monophosphate (cGMP) but were excited by 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) and by forskolin, an activator of adenylate cyclase. 7. Behavioral studies were performed looking for emetic responses in awake dogs following intravenous injection of apomorphine, insulin, angiotensin II, and leucine enkephalin. For each a threshold concentration could be determined, which would consistently evoke emesis. 8. Dogs pretreated with phosphodiesterase inhibitors (theophylline, 3-isobutyl-1-methylxanthine, or RO 1724) showed a shift in the threshold concentration of the above substances that triggered emesis, such that emesis was evoked by lower concentrations than in the control. 9. These results suggest that neurons of the dog area postrema trigger the emetic reflex in response to specific receptors for a great variety of transmitters, peptides, and hormones, and that these receptors act through a common second messenger, cAMP.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Gastric electrical stimulation in intractable symptomatic gastroparesis.

BACKGROUND: The treatment of gastroparesis remains unsatisfactory despite prokinetic and anti-emetic drugs. Gastric electrical stimulation has been proposed as a therapeutic option. We have assessed the effect of gastric electrical stimulation on symptoms, medical treatment, body weight and gastric emptying in patients with intractable symptomatic gastroparesis in a non-placebo-controlled study. METHODS: In this multicenter study, 38 highly symptomatic patients with drug-refractory gastroparesis were enrolled. Patients first received temporary electrical stimulation using percutaneous electrodes. The 33 responders to temporary stimulation then underwent surgical implantation of a permanent stimulator. Severity of vomiting and nausea was assessed before and after stimulation. Patients were reassessed 3, 6, and 12 months after permanent implantation. RESULTS: With stimulation, 35/38 patients (97%) experienced >80% reduction in vomiting and nausea. This effect persisted throughout the observation period (2.9-15.6 months, 341 patient-months). Gastric emptying did not initially change, but improved in most patients at 12 months. At 1 year, the average weight gain was 5.5% and 9/14 patients initially receiving enteral or parenteral nutrition were able to discontinue it. CONCLUSION: Electrical stimulation of the stomach has an immediate and potent anti-emetic effect. It offers a safe and effective alternative for patients with intractable symptomatic gastroparesis.

Adolescent↗
PubMed1983

A 1983 neuropharmacologic perspective of space sickness.

Space sickness is generally considered a variant of motion sickness although not fully proved as such. Understanding space sickness requires objective and quantitative characterization of the disorder. Vomiting is a quantifiable physiological event performed by the respiratory muscles which generate the pressures that evacuate the gut. Vomiting from all causes is coordinated by the vomiting center in the medulla oblongata. The emetic chemoreceptor trigger zone (CTZ) in the area postrema is thought to be an indispensable element in the afferent pathway of motion sickness. About 30 potential neurotransmitters exist in the vomiting control mechanism which includes at least eight chemical transmission steps through the reflex pathway of motion sickness. Individual synaptic transmitters do not likely mediate specific functions, but particular combinations of those transmitters might well serve distinct functions. Adaptation to the cause of space sickness probably results from readjustment of a cerebellar circuit or of a humoral factor acting on the CTZ, rather than from stimulus-receptor desensitization. Space sickness must, for purposes of investigation, be treated as a unique disorder engendered by weightlessness until proved equivalent to any emetic syndrome that occurs on earth.

Adaptation, Physiological↗
PubMed1994

Further studies of the antiemetic activity of granisetron against whole body X-irradiation or cisplatin-induced emesis in the ferret.

In ferrets, the highly selective 5-HT3 receptor antagonist, granisetron, abolished or reduced emesis induced by cisplatin (10 mg/kg i.v.) or whole body X-irradiation (50 Gy in 10.4 min) in a dose-dependent manner when administered by a variety of routes (intravenous, per os, subcutaneous, intramuscular). Complete protection from vomiting and retching was achieved with 0.5 mg/kg i.v. or p.o. granisetron. Granisetron (0.5 mg/kg i.v.) was also effective when given 6 h before cisplatin, completely protecting 50% of ferrets for a total of 10 h. Following repeat dosing, for either 4 days i.v. or 10 days p.o. before emetic challenge, granisetron (0.5 mg/kg) still retained its antiemetic activity on the 5th or 11th day. Prior treatment with cyclophosphamide (80 mg/kg i.v.) resulted in a significantly shorter time to the onset of vomiting after exposure to X-irradiation. Granisetron, but not saline, abolished vomiting and nausea when given as intervention after this combined emetic regimen. These results show that granisetron has potential flexibility for administration via a variety of different routes and also a long duration of action when used as an antiemetic against a wide range of cytostatic agents.

Animals↗
PubMed1989

[Reducing the side effects of aggressive chemotherapy (cisplatin and epirubicin) with xenogenic peptides (factor AF2) in patients with hormone refractory metastatic prostate cancer. A prospective, randomized study].

The indication of a chemotherapy is advisable with patients who are suffering from a progressively metastasised, secondarily hormone refractory carcinoma of the prostate. In search of efficient chemotherapy protocols we combined cisplatin with epirubicin (PE scheme) in our clinic. Massive side effects of that aggressive chemotherapy scheme like gastro-intestinal trouble and myelotoxicity are the limiting factors of the scheme. With measures like reducing the dosage, delaying the next cycle, or breaking off the therapy the effective dosage can often not be achieved. The anti-emetics which are usually used today exclusively give anti-emetic protection. The additional administration of xenogenic peptides (Factor AF2) had additionally myeloprotective effect in former studies. In this study we examined whether, by additionally giving Factor AF2, the patients' subjective condition, and above all their hemogram, could be stabilised in order to achieve the effective dosage or dosage intensity. For that, the patients were prospectively randomised in two groups by means of a random selection board. The analysis of the data gained in the protocol showed that the additional administration of Factor AF2 improves the patients' subjective conditions significantly. Apart from that, we noticed a considerable reduction of the vomiting frequency. Concerning the objective measured parameters of the leukocytes, thrombocytes, erythrocytes, and the hemoglobin level, the significantly myeloprotective effect of Factor AF2 could be proved. Due to the fact that in the verum group there were considerably fewer cases of breaking off or delays of the treatment than in the control group, the effective dosage intensity could be achieved with a higher number of patients in that group.

Aged↗
PubMed1991

Control of refractory, chemotherapy-induced emesis with the serotonin antagonist ondansetron (GR38032F).

Twenty-four patients with severe post-chemotherapy emesis (greater than 15 emetic episodes) refractory to prior combination antiemetic therapy were treated with a selective 5-HT3 receptor antagonist ondansetron (GR38032F). Ondansetron was given as 8 mg three times daily orally for 5 days with the first dose given 1 h prior to chemotherapy. Control of emesis was evaluated over the 5-day period. All chemotherapy was administered on an outpatient basis. Worst day analysis of antiemetic response was 87.5%: complete protection in 9/24 patients (37.5%) and major protection (1-2 emetic episodes) in 12/24 patients (50%). No protection from emesis was observed in 3 patients (12.5%). No side effects and no alterations in liver function tests were observed. Ondansetron is a safe and highly effective antiemetic agent.

Adult↗
PubMed1992

Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer.

This was a multicentre, randomised, double-blind, parallel-group study which included female breast cancer patients, receiving their first of 6 scheduled courses of chemotherapy (cyclophosphamide greater than or equal to 500 mg/m2). Patients received an intravenous dose of 16 mg dexamethasone with either 8 mg ondansetron or 60 mg metoclopramide before chemotherapy, followed by oral dosing with 8 mg ondansetron or 20 mg metoclopramide 3 times daily for 5 days. A total of 93 patients were treated with ondansetron and 94 patients with metoclopramide. On day 1 of their first course of treatment 91 and 60% of patients in the ondansetron and metoclopramide groups respectively were free of emesis (p less than 0.001). Over the 5-day treatment period, the corresponding figures were 81 and 48% (p less than 0.001). The results for nausea also revealed highly statistically significant treatment differences (p less than 0.001) in favour of ondansetron for both day 1 and day 1-5 analyses of the first treatment course. Over the series of courses, 67% of patients receiving ondansetron completed all 6 courses with a maximum of 2 emetic episodes on their worst day, compared with 28% of patients receiving metoclopramide (p less than 0.001). A similar analysis for nausea revealed that 49% of patients receiving ondansetron completed all 6 courses with 'none' or 'mild' nausea compared with 27% of patients receiving metoclopramide (p less than 0.001). These differences were reflected in quality of life data (Rotterdam Symptom Checklist). After the first course of treatment, a statistically significant improvement (p = 0.002) in the psychological subscale scores was observed after ondansetron compared with metoclopramide. No differences were observed in the physical or functional activity subscales after the first course. However, the quality of life results over the series of courses revealed a more pronounced difference in favour of ondansetron in the psychological subscale scores (p less than 0.001) as well as trends in favour of ondansetron in the physical (p = 0.096) and functional activity (p = 0.056) subscales. Extrapyramidal symptoms were reported in 19% of patients in the metoclopramide group and resulted in 15% of patients withdrawing from their randomised anti-emetic schedule, either during or between treatment courses. Other adverse events were generally minor in nature and did not necessitate withdrawal from treatment. In conclusion, this study shows that ondansetron is significantly superior to metoclopramide (each with a single pre-treatment dose of dexamethasone) in the control of emesis over 6 courses of chemotherapy for breast cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMedDate not supplied

Ondansetron plus dexamethasone compared to the 'standard' metoclopramide combination.

This paper describes a multicentre, double-blind, parallel group study which compared ondansetron (0.15 mg/kg i.v. x 3) plus dexamethasone (20 mg i.v.) with metoclopramide (3 mg/kg i.v. x 2) plus dexamethasone (20 mg i.v.) and diphenhydramine (50 mg i.v.) for the prevention of cisplatin-induced emesis and nausea. Two hundred and eighty-nine consecutive patients receiving chemotherapy containing cisplatin at doses > or = 50 mg/m2 entered the study and 267 patients were evaluable for efficacy. The ondansetron regimen was significantly superior compared with the metoclopramide regimen in the control of acute emesis and nausea. Ondansetron plus dexamethasone provided complete protection against retching and vomiting in 79% of patients compared with 59% of patients given the metoclopramide combination (p < 0.002). Similarly ondansetron plus dexamethasone completely prevented nausea in 77% of patients, whereas the metoclopramide combination protected 66% of patients (p < 0.051). Success (no nausea and no emesis) was afforded to 69% of those patients given ondansetron plus dexamethasone as opposed to 50% of patients given the metoclopramide combination (p < 0.003). From day 2-4 all patients received the same anti-emetic regimen of oral metoclopramide and intramuscular dexamethasone. Significantly fewer patients who had received the ondansetron regimen on day 1 vomited on days 2 and 3 compared with those who had received the triple drug combination (84-86 and 68-71%, respectively, p < 0.006). Nausea was also better controlled in this group on day 2. On subsequent cisplatin cycles, the incidence of acute vomiting rose to 53% in those patients given the metoclopramide regimen, but remained low (26%) in the group treated with ondansetron plus dexamethasone. Patients receiving the metoclopramide regimen had significantly more sedation than patients receiving ondansetron plus dexamethasone (12 vs. 2%; p < 0.005). Extrapyramidal reactions were only observed in metoclopramide-treated patients (3%). The results of this study suggest that ondansetron plus dexamethasone is a more effective and better tolerated anti-emetic regimen compared with metoclopramide plus dexamethasone and diphenhydramine for the prevention of acute cisplatin-induced emesis.

Cisplatin↗
PubMedDate not supplied

Global experience with ondansetron and future potential.

Ondansetron was first synthesised in 1983 and it is estimated that over 4 million patient treatments have been given with ondansetron in clinical practice. Clinical trials in over 15,000 patients have demonstrated that ondansetron is effective and well tolerated in a range of clinical settings, including adults and children and over repeated courses of treatment. Ondansetron is convenient to administer, being effective as a single intravenous dose for the control of acute emesis and as oral therapy on a twice-daily schedule. Recent studies have also shown it to be a cost-effective anti-emetic when the costs of treatment failure of traditional anti-emetics are taken into account. Studies have also demonstrated an improved quality of life with ondansetron compared to treatment with metoclopramide. Ondansetron has also been found to be effective in the prevention or treatment of postoperative nausea and vomiting and other studies are underway to investigate its potential use in other clinical settings. Furthermore, appropriately designed trials are ongoing to evaluate the place of ondansetron in the control of cisplatin-induced delayed emesis. In conclusion, ondansetron has been shown to be a major advance in the control of nausea and vomiting associated with chemotherapy and radiotherapy.

Antineoplastic Agents↗
PubMed1996

Mechanisms of chemotherapy/radiotherapy-induced emesis in animal models.

Animal models of chemotherapy/radiotherapy-induced emesis successfully predicted the clinical efficacy of the 5-HT3 receptor antagonists for the control of acute emesis. Further studies in animals have provided valuable information relating to the pathophysiology of emesis and the mechanism of action of 5-HT3 receptor antagonists. These agents inhibit emesis by blocking the action of 5-HT at 5-HT3 receptors on the vagus nerve in the gastrointestinal tract and in the hindbrain vomiting system. 5-HT is hypothesized to be released from enterochromaffin cells following cytotoxic therapy or radiation. The mechanism by which 5-HT is released from enterochromaffin cells is unknown and, although various mechanisms have been proposed, none of these have provided convincing supportive evidence. In collaboration with scientists at Glaxo we have pioneered two models of cisplatin-induced acute and delayed emesis [Rudd et al., 1994]. In the first model, ferrets are given a low dose of cisplatin (5 mg/kg i.p.) and observed for 3 days. A pattern of emesis similar to that seen in the clinic has been observed with two distinct phases of emesis. Ondansetron, and particularly ondansetron plus high-dose dexamethasone, are effective in reducing the emetic response over days 1-3. The second model uses a higher dose of cisplatin (10 mg/kg i.p.) and an observation period of 24 h. Part of the emetic response over this time is resistant to 5-HT3 receptor antagonism. Studies into the mechanism of the emesis induced in both models may give an insight into cisplatin-induced emesis in man that is not controlled with 5-HT3 receptor antagonists.

Animals↗
PubMed1996

Serotonin mechanisms in chemotherapy-induced emesis in cancer patients.

Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, nitrogen mustard and dacarbazine induce increases in urinary 5-hydroxyindoleacetic acid (5-HIAA) in parallel with the development of the period of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5-HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a modest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cisplatin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which is mostly resistant to 5-HT3 receptor antagonists (also known as 'delayed emesis'). This form of emesis is not associated with increases in urinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis inhibitor) inhibited cisplatin-induced emesis and cisplatin-induced increases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemotherapy-induced emesis. Serotonin released from enterochromaffin cells seems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5-HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cells by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplatin-induced emesis resistant to 5-HT3 receptor antagonists ('delayed emesis') is not mediated by serotonin released from enterochromaffin cells.

Antineoplastic Agents↗
PubMed1996

Management of cyclophosphamide-induced emesis over repeat courses.

This paper describes the only published study to date which prospectively evaluates the efficacy of a 5-HT3 receptor antagonist over repeated courses of cyclophosphamide chemotherapy. The combination of ondansetron and dexamethasone was significantly superior to metoclopramide and dexamethasone over 6 courses of chemotherapy given for the treatment of breast cancer. Importantly, patients given ondansetron benefited from a superior quality of life over the six courses of treatment. A Markov chain statistical model has been applied to these data. This model assumes that the results over subsequent courses is dependent on the efficacy of the anti-emetic therapy and the results obtained during the previous course of chemotherapy. This model successfully predicts the actual results obtained in the clinical study. Using this model it is possible to hypothesise on the results obtained following different treatment strategies. These data emphasise that it is important to give optimal anti-emetic therapy from the first course of chemotherapy as this will facilitate good control during subsequent courses.

Adult↗
PubMed1996

Pathophysiology, severity, pattern, and risk factors for carboplatin-induced emesis.

Carboplatin has proven efficacy in the treatment of ovarian cancer and has been proven to be less toxic compared to the parent compound cisplatin. Nevertheless, emesis is still a major problem associated with carboplatin-containing chemotherapy. Several investigators have focussed on the understanding of the pathophysiology and pattern of cisplatin-induced emesis. Data describing both the pathomechanisms and pattern of carboplatin-induced emesis are still lacking. This paper combines data from the literature with our own experience with the pattern and control of carboplatin-induced emesis, and presents data contributing to the understanding of the underlying pathomechanisms. Carboplatin induces a significant increase in urinary 5-HIAA excretion, the main metabolite of serotonin. 5-HIAA excretion levels remain elevated over 3 days following chemotherapy. Carboplatin-induced emesis is observed in about 40% of patients despite anti-emetic prophylaxis with 5-HT3 antagonists. Vomiting after carboplatin extends over days 1-3 with an equal distribution regarding the severity on each day. Analysis of the pattern of emesis revealed that delayed emesis (> 24 h after chemotherapy) is a major problem associated with carboplatin therapy. Description of the pattern of emesis as 'prolonged emesis' seems to be appropriate. 5-HT3 receptor antagonists such as ondansetron seem to be efficacious both in the control of acute and prolonged emesis following carboplatin chemotherapy, but randomly controlled data comparing ondansetron with other anti-emetic regimens have not yet been published. Univariate analysis reveals gender and combination therapy containing carboplatin and cyclophosphamide and/or anthracyclines as risk factors for emesis.

Adult↗
PubMed1987

Staphylococcal enterotoxin B as a nonimmunological mast cell stimulus in primates: the role of endogenous cysteinyl leukotrienes.

The immediate-type skin reaction and the emetic response in unsensitized monkeys on challenge with staphylococcal enterotoxin B (SEB) were studied to define the role of cysteinyl leukotrienes (LTs) in the action of the toxin. LY 171883, a selective LTD4/LTE4 receptor inhibitor, antagonized SEB-induced skin reactions and emetic responses completely. Inhibition of prostanoid formation by indomethacin, however, and pretreatment with BW 755C, a dual lipoxygenase and cyclooxygenase inhibitor, did not influence these reactions. The generation of endogenous cysteinyl LTs upon intragastric SEB administration was established in vivo. There was a tenfold increase in LTE4, the major biliary cysteinyl LT, and a novel cysteinyl LT metabolite in urine occurred, indicating strongly enhanced LT generation on SEB challenge. These results provide the first evidence that cysteinyl LTs may be important mediators in the pathophysiology of SEB-induced effects, as a model for pseudo-allergic reactions.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗