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PubMed1993

Sigma receptor-mediated emetic response in pigeons: agonists, antagonists and modifiers.

In order to more fully characterize sigma ligand-induced emesis in the pigeon, the effects of a number of compounds were tested alone or in combination with ditolyguanidine (DTG). The drugs tested could be categorized into three types: agonists, which produced the emetic response (DTG > amitriptyline > BD 737 > thioridazine), antagonists, which effectively antagonized the effects of DTG (haloperidol > BMY 14802 > BD 1139 > chlorpromazine), and agents which did not produce the emetic response on their own, but potently enhanced the emetic effect of DTG (BD-1008 > or = phencyclidine > (+)-n-allylnormetazocine > or = propranolol). Chronic haloperidol resulted in a markedly diminished emetic response to DTG, which returned to control levels by 24.5 days. Haloperidol, but not BMY 14802, was effective in antagonizing the lethal effects of DTG. These data suggest further in vivo evidence for a functional mediation by sigma sites of the emetic response to DTG in the pigeon, and may provide in vivo evidence for potential allosteric modification of sigma ligands.

Animals↗
PubMed1982

Assessment of emetic and antiemetic activity.

Compounds having acute emetic or antiemetic activities have been quantitatively evaluated and compared with the reference standards, apomorphine and chlorpromazine, respectively. The bioassay for an emetic required the establishment of mean threshold emetic doses in groups of dogs for both the reference standard apomorphine and the test compound. The bioassay for antiemetics was based upon the degree to which the test drug elevated the threshold emetic dose for apomorphine. That effect was contrasted with the change in emetic threshold produced by equimolar concentrations of chlorpromaine.

Animals↗
PubMed2001

The anti-emetic action of the neurokinin(1) receptor antagonist CP-99,994 does not require the presence of the area postrema in the dog.

Microinjection and ligand binding studies have implicated NK(1) receptors in the area postrema (AP) in the emetic response to intragastric copper sulphate that is mediated by abdominal vagal afferents. Because these afferents terminate in the brainstem in the nucleus tractus solitarius in close proximity to the AP or in the AP itself, the results of such studies may be difficult to interpret. The present study has demonstrated in the dog that the emetic response to intragastric copper sulphate is unaffected by AP ablation, demonstrated functionally by absence of an emetic response to apomorphine (100 microg kg(-1) i.v.). In AP ablated animals the selective NK(1) receptor antagonist CP-99, 994 (1 mg kg(-1) i.v.) blocked the emetic response to copper sulphate as it did in intact animals. The results demonstrate that the AP is not involved in the blockade of the emetic response to intragastric copper sulphate by an NK(1) receptor antagonist and hence provides further support for other sites proposed such as the nucleus tractus solitarius and central pattern generator.

Animals↗
PubMed2005

Emetic toxin formation of Bacillus cereus is restricted to a single evolutionary lineage of closely related strains.

An in-depth polyphasic approach was applied to study the population structure of the human pathogen Bacillus cereus. To assess the intraspecific biodiversity of this species, which is the causative agent of gastrointestinal diseases, a total of 90 isolates from diverse geographical origin were studied by genetic [M13-PCR, random amplification of polymorphic DNA (RAPD), multilocus sequence typing (MLST)] and phenetic [Fourier transform Infrared (FTIR), protein profiling, biochemical assays] methods. The strain set included clinical strains, isolates from food remnants connected to outbreaks, as well as isolates from diverse food environments with a well documented strain history. The phenotypic and genotypic analysis of the compiled panel of strains illustrated a considerable diversity among B. cereus connected to diarrhoeal syndrome and other non-emetic food strains, but a very low diversity among emetic isolates. Using all typing methods, cluster analysis revealed a single, distinct cluster of emetic B. cereus strains. The isolates belonging to this cluster were neither able to degrade starch nor could they ferment salicin; they did not possess the genes encoding haemolysin BL (Hbl) and showed only weak or no haemolysis. In contrast, haemolytic-enterotoxin-producing B. cereus strains showed a high degree of heterogeneity and were scattered over different clusters when different typing methods were applied. These data provide evidence for a clonal population structure of cereulide-producing emetic B. cereus and indicate that emetic strains represent a highly clonal complex within a potentially panmictic or weakly clonal background population structure of the species. It may have originated only recently through acquisition of specific virulence factors such as the cereulide synthetase gene.

Bacillus cereus↗
PubMed1971

Cat assay for the emetic action of digitalis and related glycosides (digitoxin, digoxin, lanatoside C, ouabain and calactin).

1. A titration assay with two end points is described for comparison of the emetic and lethal potencies of digitalis-like drugs.2. A drug was infused at constant rate to a conscious, unrestrained cat, through an indwelling venous cannula. At the moment of vomiting the cat was rapidly anaesthetized and infusion continued at the same rate until the moment of cardiac arrest.3. With very slow and very fast infusions, the emetic and lethal doses tended to rise. In the range between these extremes (which varied from drug to drug) they were independent of time.4. The observations could be accounted for by analogue computation, assuming that the drugs entered an initial pool and were distributed at finite rates to receptors in the CNS (vomiting centre) and heart.5. Half times of metabolic loss derived from this computation for digitoxin, digoxin and ouabain (17, 9.9 and 1.8 h, respectively) were in the same ratio as the threefold longer half times reported for these drugs in man.6. When measured with infusion rates in the time independent range, the ratio of lethal to emetic doses did not vary between the drugs studied. All caused vomiting at 40% of the lethal dose.7. From a review of the literature, the emetic and cardiotoxic actions of digitalis-like drugs appear inseparable and probably share a common biochemical mechanism.8. It is concluded that foreseeable improvements in digitalis-like drugs are small and would depend on the elimination of any local emetic effect on gut receptors which they may have.

Animals↗
PubMed1996

Effect of vagal and splanchnic nerve section on Fos expression in ferret brain stem after emetic stimuli.

Previous studies have demonstrated that intraduodenal hypertonic saline (IHS) induces dense Fos expression within two regions of the ferret dorsal vagal complex (DVC): the area postrema (AP) and the medial subnucleus of the nucleus of the solitary tract (mn). The aims of the present experiments were to determine the peripheral pathways involved in excitation of DVC neurons after IHS and the relative importance of mn and AP excitation in the emetic response to this stimulus. The emetic response and the distribution of Fos were examined after IHS in animals that had received either vagotomy alone, vagotomy and splanchnic nerve section, or sham operation. The emetic response was studied in both awake and anesthetized animals, and Fos induction was studied in anesthetized animals. Vagotomy alone or combined with splanchnic nerve section abolished the emetic response and the area of dense labeling within the mn and reduced but did not abolish the labeling in the AP. It was concluded that both the emetic reflex and the dense expression of Fos within the mn after IHS are dependent on an intact vagus nerve. The excitation of neurons in the AP after IHS is partially dependent on vagal afferents, and the residual labeling that is present in the AP of neurectomized animals may be mediated via a blood-borne route.

Amidines↗
PubMed1982

Cytogenetic effect of two antimonial antibilharzial drugs: tartar emetic and bilharcid.

The effects of tartar emetic and bilharcid, two antimonial antibilharzial drugs, on the chromosomes of laboratory rats are studied. The drugs were administered intraperitoneally in three doses--clinical, intermediate, and maximum tolerated--both acutely (6, 24, and 48 hours) and subacutely. The two drugs produced the same types of chromosomal aberrations with tartar emetic, inducing a higher rate of incidence. No significant differences in the number of cells with chromosomal aberrations were generally observed among the 6, 24, and 48 hours of the acute treatment with both tartar emetic and bilharcid. The dose-response relationship was examined for both the acute and the subacute treatments. Whereas the acute treatment of tartar emetic showed a dose-dependent linear increase in the number of cells with chromosomal aberrations, the subacute treatment of tartar emetic and the acute and subacute treatments of bilharcid displayed their maximum effects at an intermediate dose.

Animals↗
PubMed2004

Bacillus cereus, the causative agent of an emetic type of food-borne illness.

Bacillus cereus is the causative agent of two distinct forms of gastroenteritic disease connected to food-poisoning. It produces one emesis-causing toxin and three enterotoxins that elicit diarrhea. Due to changing lifestyles and eating habits, B. cereus is responsible for an increasing number of food-borne diseases in the industrial world. In the past, most studies concentrated on the diarrhoeal type of food-borne disease, while less attention has been given to the emetic type of the disease. The toxins involved in the diarrhoeal syndrome are well-known and detection methods are commercially available, whereas diagnostic methods for the emetic type of disease have been limited. Only recently, progress has been made in developing identification methods for emetic B. cereus and its corresponding toxin. We will summarize the data available for the emetic type of the disease and discuss some new insights in emetic strain characteristics, diagnosis, and toxin synthesis.

Bacillus cereus↗
PubMed1993

The efficacy of various classes of anti-emetics in preventing deoxynivalenol-induced vomiting in swine.

The Fusarium mycotoxin deoxynivalenol (DON) is a potent emetic agent. While the basic mechanisms which invoke and mediate emesis are still poorly understood, various neurotransmitters appear to be involved. The action of these transmitters can be blocked by various receptor-specific antagonists. The current study investigated the efficacy of several classes of receptor antagonists to block the emetic effect of DON. Following anti-emetic pretreatment, pigs were administered the toxin (i.v., 80 micrograms/kg, or oral, 300 micrograms/kg) and the onset of emesis was monitored. Certain specific serotonin (5HT3)-receptor antagonists (ICS 205-930, BRL 43694 A) were found to efficaciously prevent DON-induced vomiting. These observations support the hypothesis that serotonin plays an important role in chemically induced emesis. Also moderately effective, but requiring high doses, were the 5HT2-receptor antagonists, cyproheptadine and sulpiride. A variety of compounds possessing strong anticholinergic activity were also efficacious. These, however, apparently act directly at the emetic center and thus are capable of preventing emesis regardless of the cause, including chemically induced vomiting. Non-effective were the antihistaminic and antidopaminergic anti-emetics; except, those which also possessed considerable anticholinergic activity, and i.v. administered chlorpromazine which has been speculated to block specific receptors found in the brain's chemoreceptor trigger zone (CTZ) reportedly involved in initiating emesis.

Animals↗
PubMed1995

The anti-emetic activity of GK-128 in Suncus murinus.

In Suncus murinus, various emetic responses and the anti-emetic activity of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128 (2-[(2-methylimidazol-1-yl) methyl benzo[f]thiochromen-1-one monohydrochloride hemihydrate), were investigated. Cancer chemotherapeutic agents, cisplatin and cyclophosphamide, dose-dependently induced emesis of long-lasting duration. The 5-HT3 receptor agonist, 2-methyl-5-HT, and copper sulfate also induced emesis of short duration. However, another 5-HT3 receptor agonist, m-chlorophenylbiguanide, was not consistently emetic. GK-128 inhibited the emetic responses induced by chemotherapeutic agents and 2-methyl-5-HT with similar potency. The anti-emetic action of GK-128 was more potent than that of ondansetron, Y-25130, granisetron and metoclopramide. The order of potency of these drugs, except granisetron, was consistent with that of their 5-HT3 receptor binding affinity in rat cortex. GK-128 failed to inhibit copper sulfate-induced emesis. These data suggest that GK-128 has a potent inhibitory effect on emesis via the 5-HT3 receptor, and that the 5-HT3 receptor involved in emesis in Suncus murinus may be different from the classically defined 5-HT3 receptor in other animals such as rats, dogs and ferrets.

Animals↗
PubMed1983

A randomised multicentre single blind comparison of a cannabinoid anti-emetic (levonantradol) with chlorpromazine in patients receiving their first cytotoxic chemotherapy.

One hundred and eight patients selected to receive combinations of highly emetic cytotoxic chemotherapy for malignant disease were included in a study of anti-emetic therapy. The patients were randomly allocated to receive levonantradol (0.5, 0.75 or 1 mg) or chlorpromazine (25 mg) prior to receiving their first course of cytotoxic therapy. The appropriate anti-emetic was administered 2 hr prior to the start of chemotherapy, 2 hr after chemotherapy and subsequently at 4-hourly intervals for a further 8 hr. The extent of anorexia, nausea and vomiting along with other side-effects were assessed at regular intervals by physicians and nursing staff during the 24 hr following chemotherapy. In addition, a self-assessment questionnaire was completed by the patients. Levonantradol (0.5 mg) was superior to chlorpromazine (25 mg) as an anti-emetic. Both were reasonably well tolerated, although at this dose of levonantradol 22% of patients experienced dysphoric reactions. At higher doses of levonantradol the proportion of patients experiencing these reactions rose to 50%, but without a concomitant increase in antiemetic activity. Neither drug achieved satisfactory control of vomiting in patients receiving combinations containing cis-platinum. We conclude that levonantradol (0.5 mg) is a more effective anti-emetic than chlorpromazine (25 mg) in patients receiving cytotoxic chemotherapy. However, its use cannot be recommended due to its high incidence of unacceptable central nervous system side-effects.

Adolescent↗
PubMed1984

Advances in anti-emetic therapy.

Evaluation of the activity of anti-emetic drugs in randomized controlled trials has, in most cases, demonstrated the superiority of treatment over placebo administration for the control of chemotherapy-induced emesis (see Table 15). The degree of control of emesis relates both to the intensity of the emetogenic stimulus and to the effectiveness of the anti-emetic agent employed. Prochlorperazine is a relatively weak anti-emetic. The drug exhibits modest activity in the treatment of emesis produced by mild emetogenic stimuli, but is relatively ineffective in the treatment of patients on moderate to severely emetogenic drugs. Domperidone has demonstrated activity against moderately emetogenic stimuli but has not been evaluated in cisplatin-treated patients. The cannabinoids have proved efficacious in the treatment of emesis induced by more severe emetogenic stimuli. THC therapy, however, has been limited in some studies by toxicity. High-dose metoclopramide has demonstrated efficacy in small series of patients in the treatment of cisplatin-induced vomiting. Dexamethasone activity as a single agent is in doubt but the drug may improve the efficacy of metoclopramide when used in combination. For the future, the use of combinations of anti-emetics with differing sites of action and non-overlapping toxicities, may lead to further improvement in efficacy. Combinations of centrally-acting drugs such as the cannabinoids plus dopamine antagonists such as metoclopramide or domperidone, are worth evaluating. The control of anticipatory nausea and vomiting is another major area of interest which has, as yet, not been studied in any depth. A single comparative trial has been reported in the literature (50) and in this study, behavioural therapy rather than drug therapy was evaluated. There may be a place for the evaluation of behavioural therapy in combination with drugs exhibiting anxiolytic properties such as the benzodiazepines and the cannabinoids. Finally, new anti-emetic drugs with an improved therapeutic index will be welcomed by the patient.

Antiemetics↗
PubMed2000

The development of the emetic reflex in the house musk shrew, Suncus murinus.

The emetic (retching and vomiting) reflex is an important component of the body's defence system against accidentally ingested toxins and emesis is also a common symptom of disease and a side-effect of a number of pharmacological therapies. The development of the reflex has been the subject of few systematic studies. The aim of this study was to characterise the development of the emetic reflex in Suncus murinus (the house musk shrew) using emetic stimuli acting via three different afferent pathways: motion via the vestibular system, pyrogallol via abdominal vagal afferents and resiniferatoxin (a capsaicin analog) via the brainstem. The emetic reflex was not present to any stimulus prior to postnatal day 10 but the onset of the response to motion lagged behind that to the other stimuli in not being present until postnatal day 15. Body weight was not a determinant of the presence of the reflex. It is proposed that the delayed presence of the emetic reflex in Suncus makes it an ideal species in which to investigate factors regulating its development.

Age Factors↗
PubMed1999

Guidelines for anti-emetic therapy: acute emesis.

Anti-emetic therapy has become integral to the management of patients with cancer. Goals related to complete emesis control include providing treatment that reduces hospitalisation and time in the ambulatory setting, care that is convenient for the patient and therapy that enhances patients' quality of life. A panel of clinical, health economic and basic scientists with expertise in various oncology disciplines reviewed published literature to develop evidence-based consensus guidelines for the prevention and treatment of chemotherapy-induced emesis. Currently, serotonin receptor antagonists and corticosteroids are the two categories of anti-emetics that are most effective, have the fewest side-effects and are convenient to use. These agents are recommended in combination for highly emetogenic chemotherapy regimens and as single agents or in combination for moderately to highly emetogenic chemotherapy. When possible, these agents may be given orally in single doses; current evidence does not support dose escalation for either category of anti-emetics. In special situations, such as the use of high-dose chemotherapy combination regimens, the most emetogenic component of the regimen should dictate the choice of anti-emetic. Appropriate anti-emetic use described in these guidelines represents both good medical practice and a sensible economic approach to care.

Acute Disease↗
PubMed1990

Dexamethasone can potentiate the anti-emetic action of a 5HT3 receptor antagonist on cyclophosphamide induced vomiting in the ferret.

A new group of selective 5HT3 antagonists are proving to be effective anti-emetics for cytotoxic and radiation induced vomiting in both animal models and man. Current anti-emetic regimens often benefit from combination therapy, in particular the efficacy of metoclopramide (which can be a weak 5HT3 antagonist), can be improved by combination with dexamethasone, another anti-emetic. Hence it was of interest to evaluate whether a 5HT3 receptor antagonist GR38032F could be improved by combination with dexamethasone. Vomiting induced by cyclophosphamide in the ferret was observed after pre-treatment with dexamethasone alone or in combination with GR38032F. Animals were also observed for signs of 'nausea'. Dexamethasone alone proved a weak anti-emetic in this system but did have significant effects on 'nausea'. GR38032F has previously been shown to be capable of totally controlling emesis due to cyclophosphamide in the ferret. Here a dose of GR38032F that is not 100% effective was employed; this was shown to have effects on 'nausea' but most interestingly its anti-emetic action was increased by combination with dexamethasone. This may be important for the minority of patients whose vomiting is not completely controlled by GR38032F alone.

Animals↗
PubMed1998

Initial high anti-emetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles.

We have reported previously that the anti-emetic efficacy of single agent 5HT3 antagonists is not maintained when analysed with the measurement of cumulative probabilities. Presently, the most effective anti-emetic regimen is a combination of a 5HT3 antagonist plus dexamethasone. We, therefore, assessed the sustainment of efficacy of such a combination in 125 patients, scheduled to receive cisplatin > or = 70 mg m(-2) either alone or in combination with other cytotoxic drugs. Anti-emetic therapy was initiated with 10 mg of dexamethasone and 3 mg of granisetron intravenously, before cisplatin. On days 1-6, patients received 8 mg of dexamethasone and 1 mg of granisetron twice daily by oral administration. Protection was assessed during all cycles and calculated based on cumulative probability analyses using the method of Kaplan-Meier and a model for transitional probabilities. Irrespective of the type of analysis used, the anti-emetic efficacy of granisetron/dexamethasone decreased over cycles. The initial complete acute emesis protection rate of 66% decreased to 30% according to the method of Kaplan-Meier and to 39% using the model for transitional probabilities. For delayed emesis, the initial complete protection rate of 52% decreased to 21% (Kaplan-Meier) and to 43% (transitional probabilities). In addition, we observed that protection failure in the delayed emesis period adversely influenced the acute emesis protection in the next cycle. We conclude that the anti-emetic efficacy of a 5HT3 antagonist plus dexamethasone is not maintained over multiple cycles of highly emetogenic chemotherapy, and that the acute emesis protection is adversely influenced by protection failure in the delayed emesis phase.

Adolescent↗
PubMed2002

Impact of a multimodal anti-emetic prophylaxis on patient satisfaction in high-risk patients for postoperative nausea and vomiting.

Postoperative nausea and vomiting (PONV) are frequent and unpleasant symptoms. This prospective study aimed to assess the efficacy of a multimodal approach to prevent PONV, and patient satisfaction using the willingness-to-pay method. Two validated risk scores were applied to forecast the individual risk for PONV in 900 consecutive patients of whom 108 were identified as high-risk patients (predicted risk: 79-87%). High-risk patients received multimodal anti-emetic prophylaxis: total intravenous anaesthesia with propofol, high fractional inspired oxygen (80%), omission of nitrous oxide, dexamethasone 8 mg, haloperidol 10 microg.kg(-1), and tropisetron 2 mg. Of the remaining patients with low or moderate risk for PONV, a random sample of 71 females received balanced propofol-desflurane anaesthesia without prophylactic anti-emetics. All patients were interviewed 2 and 24 h after surgery for occurrence of nausea and vomiting. Patient satisfaction was measured using the willingness-to-pay method. The incidence of PONV (95%-confidence interval) in the control-group was 41% (29-51%), slightly lower than predicted by the risk scores (53-57%). The multimodal anti-emetic approach reduced the predicted risk (79-87%) in the high risk-group to 7% (3-14%). This was associated with a high willingness-to-pay median (25th/75th percentile) of 84 UK pounds (33-184 UK pounds) in the multimodal anti-emetic group compared to 14 UK pounds (4-30 UK pounds) in the control group. A multimodal anti-emetic approach can considerably reduce the incidence of PONV in high-risk patients and is associated with a high patient satisfaction as measured by the willingness-to-pay method.

Adult↗
PubMed1982

Emetic action of staphylococcal enterotoxin A on weanling pigs.

Peroral and intraduodenal administration of staphylococcal enterotoxin A (SEA) to weanling pigs elicited an emetic response. Peroral administration of an emetic dose of SEA resulted in a single emetic episode occurring 90 to 180 min after dosing. Intraduodenal administration via a surgically implanted catheter of 100 or 150 micrograms of SEA resulted in multiple emetic episodes occurring 150 to 210 min after dosing, suggesting an intestinal site of action for SEA. The 50% emetic dose for perorally administered SEA was between 40 and 50 micrograms for 4.1- to 9.1-kg weanling pigs and 20 micrograms in 0.9- to 2.3-kg weanling pigs. Neurobehavioral responses, including alternating periods of drowsiness and restlessness, staggering, temporary loss of the righting reflex, and refusal to feed were also observed in pigs given an oral dose of SEA. Based on the demonstrated responsiveness of pigs to SEA, pigs should be considered suitable animal models for studies on the sites and mode of action of the toxin.

Administration, Oral↗