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High-dose alizapride versus high-dose domperidone: a double-blind comparative study in the management of cis-platinum-induced emesis.

A double-blind, randomized crossover trial was carried out in 44 cancer patients receiving chemotherapy with cis-platinum to compare the anti-emetic effectiveness and tolerance of alizapride and domperidone given in high dosage. Patients received 5 administrations of either 4 mg alizapride/kg body weight or 0.6 mg domperidone/kg during a chemotherapy session and then the alternative anti-emetic during the next session. Treatment order was randomized. Patients were followed-up for 12 hours and details recorded of the total time during which there was some nausea, the duration of mild and severe nausea, and the number of episodes of mild and severe vomiting. A note was also made of the duration of mild and moderate sedation, and the incidence and severity of any other side-effects either probably or possibly related to anti-emetic medication. The investigator gave an overall assessment of the severity of nausea and vomiting experienced during each chemotherapy session and an opinion on the comparative effectiveness of the two anti-emetics. At the end of the two sessions, patients were asked to state a preference, if any, for one or other treatment and to select which they would like to have for their next chemotherapy session. The results showed that whilst both alizapride and domperidone appeared to be equally effective in limiting mild nausea, alizapride was significantly better in preventing severe nausea and episodes of vomiting. In those cases where a positive choice between treatments was made, alizapride was considered to be significantly better than domperidone by the investigator and more patients preferred alizapride and would select it for their next session.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiemetics↗

Assuring the optimal use of serotonin antagonist antiemetics: the process for development and implementation of institutional antiemetic guidelines at Memorial Sloan-Kettering Cancer Center.

PURPOSE: The need to foster the appropriate and cost-effective use of serotonin-antagonist antiemetic drugs spurred the creation of guidelines. The process by which institution-wide guidelines at Sloan-Kettering were developed, implemented, assessed, and modified is described. METHODS: A multidisciplinary group working with disease-specific management teams assigned the emetic potential of chemotherapy programs to one of five categories. Antiemetic regimens, including a specified dose and schedule of a serotonin-antagonist and dexamethasone, were assigned to each emetic category. The information was collated by disease site and chemotherapy program into hospital-wide antiemetic regimen recommendations. Quality assessment was conducted initially and repeated each time the guidelines were modified. RESULTS: Patient surveys demonstrated a high level of satisfaction with emetic control, which was similar to reported results. Data from the latest survey showed zero emetic episodes in 93% and 87% of participants given moderate and highly emetogenic chemotherapy, respectively. Compliance with the guidelines, initially in 73%, has been improved using a standardized chemotherapy order "check box" labeled, "Antiemetics as per Guidelines." Antiemetic drug expenditures decreased from a projected $2.8 million to $1.3 million annually. CONCLUSION: The guidelines became an educational tool that ensured the delivery of optimal antiemetic therapy chosen by professionals with the greatest knowledge of both the particular chemotherapy regimen and cancer site. Implementation of the guidelines resulted in substantial savings while treating more patients. The guidelines were easily modified as new chemotherapeutic agents and antiemetic drugs became available.

Antiemetics↗

[Pharmacological review of tropisetron].

Tropisetron is used as an anti-emetic agent against chemotherapy-induced nausea and vomiting. Tropisetron shows strong 5-HT3 antagonist and weak 5-HT4 antagonist activities in vitro. In the various animal models of vomiting including chemotherapy- or radiotherapy-induced emesis in the dog and ferret, tropisetron is reported to inhibit the emetic episodes. The potent anti-emetic activity of oral tropisetron rather than the i.p. administered drug suggests that it can act directly from the intestinal lumen as well as from the blood stream after its absorption. Moreover, the anti-emetic activity of tropisetron may involve the 5-HT4-receptor mechanism in addition to the 5-HT3-receptor mechanism. Tropisetron has several pharmacological activities other than anti-emesis such as the stimulation of the gastric emptying and the inhibition of the diarrhea, visceral pain and anxiety. These effects of tropisetron may contribute to the high clinical efficacy of tropisetron against chemotherapy-induced emesis.

Administration, Oral↗

Comparison of various motion stimuli on motion sickness and acquisition of adaptation in Suncus Murinus.

Effects of various types of motion stimuli were compared to investigate optimum method to elicit motion sickness and adaptation in Suncus murinus (suncus). Three different direction of shaking in the horizontal plane, back and forth, right and left and revolving, induced emetic response to the similar extent. However, vertical shaking was far less effective in inducing motion sickness. Mild and severe horizontal shaking (15 min per day) was continued for 14 days and emetic response to standard motion stimulus was compared before and after the training. The severe daily acceleration strongly depressed the susceptibility to motion stimulus. The mild acceleration which was not emetic stimulus in itself also remarkably attenuated the vomiting response to standard motion stimulus. These results indicate that 1) the emetic responsiveness of the suncus does not depend on the modes of shaking as long as the direction is in the horizontal plane, 2) the suncus is relatively refractory to the vertical linear acceleration and 3) the adaptation to motion stimulus does not develop on the latest peripheral steps of the vomiting reflex pathways.

Adaptation, Physiological↗

Neuropharmacology of motion sickness and emesis. A review.

Histamine H1-receptors are involved in the development of the symptoms and signs of motion sickness, including emesis. On provocative motion stimulus, a signal for sensory conflict activates the histaminergic neuron system, and the histaminergic descending impulse stimulates H1-receptors in the emetic center of the brain stem. The histaminergic input to the emetic center through H1-receptors is independent of dopamine D2-receptors in the chemoreceptor trigger zone and serotonin 5HT3-receptors in the visceral afferent, which are also involved in the emetic reflex. Antihistamines block emetic H1-receptors to prevent motion sickness. Acetylcholine muscarinic receptors are involved in the generation of signals for sensory conflict. Anti-cholinergic drugs prevent motion sickness by modifying the neural store to facilitate the acquisition of habituation to provocative motion.

Animals↗

Serum lipids and lipoproteins in pregnancies associated with emesis gravidarum.

Nausea and/or vomiting in pregnancy (emesis gravidarum) is a very common event. The specific etiology of this disorder is still unknown. In this study we examined serum lipid and lipoprotein concentrations in 98 healthy pregnant women in early and late pregnancy. Sixty of these women complained of emesis gravidarum. Compared to non-pregnant controls the pregnancy values of serum cholesterol, triglycerides and phospholipids were elevated in all subjects due to an increase in all lipoprotein classes. In addition, low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were enriched in triglycerides relative to other components. Differences in serum lipids and lipoproteins between the emetic and non-emetic subjects were found. The lipid contents of LDL and HDL were significantly higher and lower, respectively, in the emetic women in early pregnancy. During late pregnancy the total lipid content in all fractions was higher in previously emetic subjects. Thus, a metabolic difference between the groups persisted throughout pregnancy. It is suggested that an altered influence of estrogen on the liver might be responsible for these dissimilarities.

Adult↗

Neural mechanisms of motion sickness.

Three kinds of neurotransmitters: histamine, acetylcholine and noradrenaline, play important roles in the neural processes of motion sickness, because antihistamines, scopolamine and amphetamine are effective in preventing motion sickness. Histamine H1-receptors are involved in the development of the symptoms and signs of motion sickness, including emesis. On provocative motion stimuli, a neural mismatch signal activates the histaminergic neuron system in the hypothalamus, and the histaminergic descending impulse stimulates H1-receptors in the emetic center of the brainstem. The histaminergic input to the emetic center through H1-receptors is independent of dopamine D2-receptors in the chemoreceptor trigger zone in the area postrema and serotonin 5HT3-receptors in the visceral afferent, which are also involved in the emetic reflex. Antihistamines block emetic H1-receptors to prevent motion sickness. Scopolamine prevents motion sickness by modifying the neural store to reduce the neural mismatch signal and by facilitating the adaptation/habituation processes. The noradrenergic neuron system in the locus coeruleus is suppressed by the neural mismatch signal. Amphetamine antagonizes mismatch-induced suppression of noradrenergic neural transmission, resulting in preventing motion sickness.

Animals↗

[Incidence of emesis in outpatients on chemotherapy for breast cancer and the clinical efficacy of ondansetron hydrochloride tablets].

The incidence of nausea and vomiting was investigated for a maximum of 7 days in 32 breast cancer patients receiving CAF (cyclophosphamide, adriamycin, 5-fluorouracil) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) therapies. For those patients who experienced nausea and vomiting, 4 mg/day of ondansetron hydrochloride (OND) in tablet form was given in the next course of the chemotherapy, and the anti-emetic effect of the drug was examined. During the observation period, nausea was seen in 17.2-50.0% of the patients and vomiting in 3.1-15.6%. The number of patients who had nausea and vomiting was 22. The anti-emetic effect was examined in 18 out of 22 cases with nausea and vomiting. An anti-emetic effect based on the judgement criterion (efficacy rate) was seen in 94.4% or more of patients for all the days of observation. A marked effect was seen in higher proportion of patients. In conclusion, nausea and vomiting occurred in 17.2-50.0% of the breast cancer patients on chemotherapy (CAF and CMF therapies). To improve the QOL of those patients, anti-emetic treatment using OND tablets as necessary is considered to be effective.

Ambulatory Care↗

[Risk Factors associated with post-chemotherapy vomiting in patients with breast cancer (II): analysis of the duration of emesis]

OBJECTIVE: To identify the risk factors associated with the duration of emesis after high-dose chemotherapy in high risk breast cancer patients and to assess the predictive performance of a mathematical model. METHODS: Cox regression model was developed to predict the duration of emesis, and different prognostic factors were evaluated: anthropometric characteristics, cyclophosphamide and carboplatin clearance, administration of ondansetron or tropisetron, and emesis intensity classified as a function of emetic protection degree. RESULTS: The emetic episodes started and finished, 3 and 8 days, from the beginning of chemotherapy, respectively. The probability of finishing the emesis episodes is 2 times higher in patients receiving ondansetron treatment with than in those receiving tropisetron and, 8 times higher in patient with major or complete emetic protection than in those with minor emetic protection or treatment failure. CONCLUSION: The antiemetic protection with ondansetron after high dose of chemotherapy in high risk breast cancer patients is more effective option than tropisetron because the duration of emesis is lower.

Journal Article↗

Mechanisms by which cancer chemotherapeutic drugs induce emesis.

Because the area postrema seems essential for chemotherapy-induced vomiting, both circulating and/or neurally mediated stimuli in this area could trigger the emetic response. In our laboratories results of cross-circulation and direct intracerebroventricular infusion experiments in dogs do not support a role for circulating substances. The large increases in serum vasopressin induced by cisplatin were not blocked by inhibitors of the angiotensin-converting enzyme. In the ferret inhibition of serotonin synthesis with p-chloro-phenylalanine, administration of selective antagonists of 5-hydroxy-tryptamine3 (5-HT3) receptors, or visceral deafferentation inhibited the emetic response evoked by cisplatin or high-dose cyclophosphamide. The results suggest that serotonin plays an important role and that peripheral neural mechanisms are involved in the emetic response. The strong antiemetic efficacy of selective 5-HT3 antagonists also has been confirmed in humans. In cancer patients high-dose cisplatin increased the plasma and urinary levels of 5-hydroxy-indoleacetic acid (5-HIAA), but did not affect platelet and free plasma serotonin. The changes in 5-HIAA levels paralleled the onset and development of vomiting. No evidence of serotonin depletion has been obtained after high-dose cisplatin. Dacarbazine, another strongly emetogenic agent, increased urinary 5-HIAA; however, only small increases in 5-HIAA were produced with low-dose cisplatin or cyclophosphamide-containing regimens. Thus, emetogenicity appears to be directly related to the ability of the cytotoxic agent to release serotonin. In humans, antiemetics such as ondansetron, metoclopramide, and dexamethasone did not effect high-dose cisplatin-induced increases in serotonin metabolism. Therefore, these antiemetics seem not to affect the amount of serotonin released. The mechanism by which chemotherapeutic drugs induce serotonin release is unknown; however, release may occur by direct cytotoxicity on the gastrointestinal mucosa, including the enterochromaffin cells. Delayed emesis appears to be mediated by 5-HT3-independent mechanisms. It is proposed that emesis that develops despite high-dose ondansetron (residual emesis) should be considered delayed emesis. Residual and delayed episodes of emesis have similar time courses, are characterized by very mild emetic episodes and poor response to 5-HT3 antagonists, and are not associated with increases in serotonin metabolism.

Animals↗

[Effect of Rhizoma pinelliae on vomiting in minks].

OBJECTIVE: To study emetic and anti-emetic effects of Rhizoma pinelliae in minks. METHOD: The emetic effect of raw pinellia 2 g kg(-1) (i.g.) was investigated. Three preparations of Rhizoma pinelliae (processed with ginger) were made by ethanol extraction, water extraction and water decoction respectively and their effects on emesis model induced by cisplatin (7.5 mg kg(-1), i.p.) or apomorphine (1.6 mg kg(-1), s.c.) were then studied; the effect of the decoction of ginger-processed Rhizoma pinelliae on rotation-induced emesis model in minks was also observed. RESULT: The emesis was induced by raw pinellia in minks (P < 0.01); ginger-processed Rhizoma pinelliae, metoclopramide and ondansetron significantly inhibit the emesis induced by cisplatin and apomorphine (P < 0.05). CONCLUSION: Ginger-processed Rhizoma pinelliae exhibits a anti-emetic effect in minks, which may be mediated by inhibiting the function of the vomiting center in central nervous system.

Animals↗

The efficacy of granisetron for cancer patients undergoing platinum-based chemotherapy: comparison of 1 miligram versus 3 miligram doses in preventing nausea and vomiting.

AIM: To compare the efficacy of anti-emetic and prophylactic effects of 1 milligram (mg) versus 3 mg granisetron in cancer patients. METHODS: In this double blind, randomized, parallel study, 2-dose regimens of intra venous (IV) granisetron were evaluated in 39 cancer patients who were treated with platinum-based chemotherapy. Patients who met the inclusion criteria were randomized to receive granisetron 1 mg IV plus dexamethasone 20 mg (group A) or granisetron 3 mg iv plus dexamethasone 20 mg (group B). A questionnaire was used to evaluate the anti-emetic effects of granisetron. RESULTS: Subjects consisted of 31 men and 8 women. In group A (19 patients) 57.9% showed complete response from vomiting, 10.5% of major response, and 31.6% of failure to anti-emetic therapy. There were 47.4% of patients free from nausea and 52.6% complained of nausea (mild, moderate, and severe nausea). Among group B (20 patients), 90% showed complete response from vomiting, 5% of major response, and 5% of failure to anti-emetic therapy. Eighty percent of patients were free from nausea, while 15% complained of mild nausea and 5% of moderate nausea. The differences were statistically significant for vomiting (p = 0.02) as well as for nausea (p = 0.03). CONCLUSION: Intravenous granisetron 3 mg has better efficacy than granisetron 1 mg in preventing cisplatin- induced acute emesis.

Adult↗

The symptomatic control of cytostatic drug-induced emesis. A recent history and review.

This article outlines the historical development of anti-emetic therapies and reviews the pathophysiology and clinical aspects of cytostatic drug-induced vomiting. The methodology and the factors affecting the results of clinical trials with anti-emetics are discussed. Advances in knowledge of the role of 5-hydroxytryptamine in cytostatic drug-induced vomiting have improved current anti-emetic therapy with the development of 5-HT3 receptor antagonists such as granisetron. Early trials show granisetron to be a very effective anti-emetic and suggest useful advantages over the regimens currently considered to be standard therapy for prophylaxis and treatment of cytostatic drug-induced emesis.

Antiemetics↗

Nausea and vomiting after general anaesthesia with isoflurane, enflurane or fentanyl in combination with nitrous oxide and oxygen.

One-hundred and eighty patients undergoing elective abdominal hysterectomy were anaesthetized in random order with isoflurane, enflurane or fentanyl in combination with nitrous oxide and oxygen. Incidence and severity of emetic sequelae (none, nausea, retching or vomiting) were studied during the first 24 h after the operation. Patients who received isoflurane had significantly (P less than 0.01) less emetic sequelae (27%) during the first 2 h in the recovery room compared with patients who received enflurane (45%) or fentanyl (48%). There was no difference between the groups in the overall incidence of emetic sequelae during the time period of 2-24 h post-operatively (isoflurane 65%, enflurane 77% and fentanyl 77%). Significantly (P less than 0.02) more patients had emetic sequelae if they had experienced nausea or had vomited after previous anaesthetics.

Adult↗

Antagonism of cisplatin induced emesis in the dog.

Cisplatin (cis-diammine-dichloro-platinum) administered at a dose of 3 mg/kg iv induced a reproducible and characteristic emetic response in the dog. It was characterized by a latency period (90-120 min) and multiple emetic episodes occuring within 5 hours following drug administration with sporadic delayed emesis later within the first 24 hours. There was a qualitative similarity between the emetic response of Cisplatin seen in dogs and cancer patients. Metoclopramide (1, 3 mg/kg sc) was found to be the most effective antagonsit of Cisplatin emesis in the dog while haloperidol (1 mg/kg sc) and chlorpromazine (0.3, 1, 3 mg/kg sc) offered a less complete protection. Nabilone (0.1 mg/kg iv) and AL-1612 (1 mg/kg sc) failed to to demonstrate any significant activity. A relationship between antagonism patterns of emetic responses induced by Cisplatin and apomorphine was discussed.

Animals↗

Laboratory studies on the joint effects of certain tris (p-aminophenyl) carbonium salts and antimonials as antischistosomal drugs.

Tris (p-aminophenyl) carbonium (TAC) pamoate and antimonials, such as tartar emetic and stibophen, have broad antischistosomal activity in animals and man, but both groups have important limitations. Thus the slow-acting TAC pamoate must be given for several weeks to obtain a high degree of effect and the fast-acting antimonials have a narrow therapeutic index.This study deals with whether TAC pamoate and antimonials together have a useful degree of joint action against Schistosoma mansoni without commensurate joint toxicity for the host.A marked degree of synergism in antischistosomal activity occurred with relatively low amounts of TAC pamoate and tartar emetic or stibophen in vitro and in infected mice, particularly when TAC pamoate was started ahead of the antimonial. Moreover, neither TAC pamoate nor tartar emetic affected appreciably the gross toxicity of the other for normal mice. An encouraging degree of joint antischistosomal action by TAC pamoate and tartar emetic also occurred in infected rhesus monkeys.The results suggest that the use of TAC pamoate and antimonials together may avoid some of their main limitations when used alone.

Animals↗

Antiemetic efficacy of prochlorperazine, haloperidol, and droperidol in cisplatin-induced emesis.

The antiemetic efficacy of haloperidol, droperidol, and prochlorperazine in preventing cisplatin-induced emesis was evaluated. Twenty-seven patients receiving 51 courses of cisplatin chemotherapy randomly received antiemetic treatment with prochlorperazine (6 mg/sq m), droperidol (1 mg/sq m), or haloperidol (1 mg/sq m) in a double-blind crossover study. Antiemetics were given by intramuscular injection one hour before beginning cisplatin and every three hours thereafter for a total of six doses. The number of emetic episodes, volume of emesis, and duration of the emetic episodes were monitored by oncology nurses. There were no significant differences in the median number of emetic episodes among antiemetic treatments: 3.5 for prochlorperazine, 4.0 for haloperidol, and 3.0 for droperidol. There were also no significant differences among the antiemetics in the median volume of emesis or the median duration of the emetic episodes. At the doses used in this study, the antiemetic efficacy of prochlorperazine, droperidol, and haloperidol appear to be comparable for patients receiving cisplatin chemotherapy.

Aged↗

[Chemotherapy of malignant tumors, vomiting and nausea--what to do?].

Very marked nausea and vomiting are the most frequently observed side effects of modern cytostatic agents, and make it necessary to include powerful anti-emetic drugs in any oncological chemotherapeutic concept. The selection of suitable anti-emetics, however, often proves difficult. The reasons for this are discussed. A number of important basic rules that should be observed with any anti-emetic treatment are proposed. Finally, a standardised stepwise anti-emetic plan is suggested for discussion.

Antiemetics↗