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The severity of sickness in the first 5 days after cancer chemotherapy was compared in patients who had or had not received ondansetron 8 mg three times daily. Patients were divided into those having highly emetic chemotherapy, irrespective of gender and women having moderately emetic drugs. Ondansetron appeared to be more effective in the former group.
In order to investigate the putative anti-emetic effect of propofol, 53 patients undergoing gynaecological laparoscopy were given a standard anaesthetic including induction with thiopentone. At the end of surgery, the patients received either a sub-anaesthetic does of propofol or an equivalent volume of normal saline. There was no difference in the incidence of nausea and vomiting between the propofol and control group. It is concluded that low-dose propofol does not have an anti-emetic effect.
Roles of neurons in the nucleus of the solitary tract corresponding to the area subpostrema (mNST) for the retching reflex were investigated in decerebrate, paralyzed dogs. Retching was defined as rhythmic coactivation of the phrenic and abdominal muscle nerves. Retching which had been induced by stimulation of the left and right abdominal vagus nerves was impaired by cooling the left and right mNSTs, respectively. This result indicates that the mNST neurons mediate activities of emetic vagal afferents. All 40 non-respiratory neurons in the mNST, which had excitatory response to pulse train stimulation of the vagus nerve, were also activated by continuous stimulation of the vagus nerve to provoke retching. During provoked retching, however, these neurons did not exhibit any activities modulated in association with retching. The average latency of responses of these neurons to the pulse train stimulation (306.5 ms) was significantly shorter than that of the inspiratory neurons in the lateral NST and the adjacent reticular formation. Discharge frequencies of these neurons in the mNST gradually increased after administration of apomorphine (6/10) and glutamate (14/14) to the 4th ventricle. Antidromic responses to stimulation of the Bötzinger complex were observed in some (20/289) of the mNST neurons. These findings suggest that neurons in the mNST mediate the information from both the abdominal vagal afferents and the area postrema and drive the pattern generator for retching and vomiting, which is assumed to be located in the Bötzinger complex.
More than 35,000 alcoholics have received chemical aversion (emetic therapy) in at least 75 settings worldwide since the 1930s. This consummatory aversion (CA) treatment, which pairs ethanol ingestion with emetically induced nausea, incorporates the highly efficient variety of learning known as taste aversion (TA) conditioning. The CA literature indicates that emetic therapy should induce conditioned alcohol aversions in many alcoholics. Such aversions have been widely reported by clinicians and have been confirmed by recent psychophysiological evidence. Long standing evidence of treatment effectiveness is found in the results of private hospitals which have consistently produced 1-yr abstinence rates approximating 60%. Diminished alcohol craving is a frequently reported benefit. Few experimental evaluations have been completed, as is generally the case for all alcoholism treatments, but those which used methodologically sound temporal parameters during conditioning have supported the clinical efficacy of emetic therapy. The clear need for more definitive research notwithstanding, there are compelling indications that emetic therapy is a useful component of multimodal treatment within certain alcoholic populations. However, its availability is severely limited. Many alcoholics could probably benefit from expanded treatment availability. The time is ripe for a reevaluation of resistances to the clinical use of emetic therapy alcoholism treatment.
1 The ability of cyclizine (50 mg) and perphenazine (2.5 and 5.0 mg) to counteract the emetic effects of pethidine (100 mg) and morphine (10 and 15 mg) was compared in women undergoing a standard minor operation with a standard anaesthetic. 2 Perphenazine (5.0 mg) was as effective an anti-emetic as cyclizine (50 mg) and both were more effective than perphenazine (2.5 mg). 3 The reduction in vomiting and nausea by cyclizine (50 mg) and perphenazine (5 mg) was approximately the same following pethidine (100 mg) and morphine (10 mg) but much less against the larger dose of morphine. 4 Both anti-emetics had a rapid onset of action but their anti-emetic activity did not last as long as the emetic effect of morphine. 5 Perphenazine (5 mg) was accompanied by an unacceptably high incidence of restlessness. 6 In clinical practice cyclizine (50 mg) is preferred to perphenazine (5 mg) as an anti-emetic.
In order to make an objective evaluation of anti-emetic effect, safety and usefulness of ondansetron injection in nausea and vomiting associated with cancer chemotherapy, we carried out a double-blind placebo controlled comparative study in patients receiving high-single dose (50 mg/m2 or more) of cisplatin. Either 4 mg of ondansetron or saline injection was given intravenously at 15 min. before administration of cisplatin. If anti-emetic effect of the test drug was insufficient, an additional dose of 4mg of ondansetron was given intravenously, as the rescue medication. Ondansetron was significantly superior to placebo in anti-emetic effect (p < 0.001). Efficacy rates were 66.7% (22/33 cases) in ondansetron and 20.0% (6/30 cases) in placebo groups. Seven and 21 cases required rescue medication with 4 mg single intravenous dose of ondansetron due to insufficiency of anti-emetic effect, in ondansetron group and placebo group, respectively. Thus the number of patients who required rescue medication was obviously greater in placebo group than that in ondansetron group. The rates of inhibitory effect of rescue medication on nausea and emesis were 14.3% (1/7 cases) in ondansetron group and 61.9% (13/21 cases) in placebo group. Side effects were observed in 1 case (eruption) in ondansetron group and in 2 cases (headache, diarrhoea; 1 case each) in placebo group. Furthermore, fever developed in 1 case in placebo group after the rescue medication. Elevation of total bilirubin value was observed in 2 cases in ondansetron group and 1 case in placebo group, however, these changes were mild and did not pose noteworthy clinical problem. From these results, ondansetron was shown to possess an excellent anti-emetic effect on nausea and emesis induced by highly emetogenic anti-cancer drugs, such as cisplatin, and to have no problem in safety, and thus it was considered to be a useful anti-emetic agent.
There have been major clinical advances in the control of chemotherapy-induced nausea and emesis. These advances were achieved partly by the introduction of new anti-emetic agents but important improvement came from the use of existing agents in ways developed from the results of studies based on new approaches and methods in anti-emetic research. By developing basic research tools, improving methodology and applying psychometrically sound assessments better management or chemotherapy-induced nausea and vomiting has been achieved. The goals of anti-emetic assessment are discussed here along with data and examples of assessment techniques for emesis and nausea. Examination of 153 separate anti-emetic studies between the years of 1975 and 1988 showed that emesis was the most common outcome measure used and that approximately 1 out of five studies measured some other type of outcome usually in the context of nausea and emesis. The frequency of outcome events was most commonly the dimension assessed. Examination of size of the effect of an anti-emetic regimen for these anti-emetic studies showed it to be independent of the type of outcome measured, but to be quite dependent on how the outcome was quantified. For instance, differences in the frequency or incidence of either nausea or emesis were generally larger than measurements made of the duration of either of these.
The most promising anti-emetic drugs are identified during preclinical testing. Phase I and II clinical studies are used to optimize doses and schedules for the various routes of administration. Most methodological issues arise in relation to phase III studies. A prospective, randomised, double-blind, parallel-subjects design is recommended. Stratification helps balance the factors influencing emesis between the 2 arms of a randomised study. The most important of these are the strength of the emetic stimulus, prior exposure to chemotherapy, age, sex and a history of chronic alcohol consumption. The evaluation of efficacy of an anti-emetic should include its efficacy in controlling acute post-chemotherapy nausea and vomiting as well as anticipatory and delayed emesis. The side effects of an anti-emetic must also be considered since they may negate any anti-emetic advantage. Patients and observers have reported successfully evaluating these parameters using both categorical and linear-analogue scales.
The anti-emetic effect of ondansetron in cisplatin induced nausea and vomiting was studied in a randomized cross-over trial in 52 patients. The dose of cisplatin was 80-120 mg/M2 iv drip given in 1-3 days. The patients randomly received ondansetron or our routine anti-emetic regimen in the first cycle of chemotherapy. All the patients were crossed-over to the other anti-emetic regimen on the second cycle of the same cisplatin containing regimen. The results showed that ondansetron was superior to our routine anti-emetic regimen in controlling acute nausea and vomiting. 86% of patients treated with ondansetron and 20.4% treated with the routine regimen had a complete or marked response (O-2 emetic episodes). The mean frequency of vomiting were 1.3 times in ondansetron and 8.0 times in the routine regimen (P less than 0.01). Control of delayed emesis was comparable in the two arms. No patient had neurological symptoms in the ondansetron group whereas 4 patients in the routine group had extrapyramidal symptoms.
Preparation for bone marrow transplantation (BMT) uses the extremely emetogenic combination of chemotherapy and total body irradiation (TBI). Ondansetron is a selective 5-HT3 antagonist and has clear anti-emetic capabilities. The efficacy of the drug was assessed in 15 children (aged 2-17 years) who received high dose cyclophosphamide (on days -6 and -5) and TBI (days -3 to 0 inclusive). During days -6 to -4 when the emetic effect of cyclophosphamide would be most pronounced, 12 of the 15 patients (80%) had fewer than five emetic episodes during their worst 24-h period, 11 (73%) had fewer than three vomits whilst nine (60%) experienced no vomiting or retching. Eleven patients progressed to TBI and 10 (91%) had fewer than five emetic events in the worst 24-h period (days -3 to +2), six (55%) had no vomiting at all. Of 100 evaluable 'patient-days' 83 (83%) were without any vomiting or retching and a further 10 'patient-days' had only one or two emetic episodes. There were no significant side-effects noted and in particular no extrapyramidal reactions. Headaches and constipation, which have been seen in adult studies, were not reported by patient or parent on any of the study days and transient elevation of liver enzymes were noted in only two patients. Ondansetron has a major role in preparing patients for BMT.
Emetic thresholds to copper sulfate administered into the Pavlov pouch, Forrest pouch, Thiry fistulas of the jejunum and ileum, and duodenal, jejunal and ileal catheters were measured in dogs to conjecture the site of emetic action of copper sulfate. The oral emetic threshold had been measured preoperatively. In the stomach, the pyloric antrum had a high sensitivity, while the corpus had a low sensitivity to the topically applied copper sulfate. In the intestine, the sensitivity was high in the duodenum, whereas a low sensitivity was noted in the jejunum. Almost no sensitivity was observed in the ileum. Thus it would appear that the site of the emetic action of copper sulfate was the pyloric antrum and/or duodenum.
Ondansetron, a selective 5-HT3 receptor antagonist, has already been reported to have a marked effect to alleviate or prevent nausea and vomiting associated with cancer chemotherapy, after its intravenous administration. The present study was planned to examine the usefulness of its tablet form, which was prepared for the convenient use in outpatients receiving chemotherapy. In order to make an objective evaluation of anti-emetic effect and safety of ondansetron 4 mg tablet, this study was conducted in double-blind comparison versus placebo in patients receiving cisplatin at a single dose of 50mg/m2 or higher. Either 4 mg of ondansetron or placebo (lactose tablet) was administered orally once at 2 hrs prior to administration of cisplatin. If any satisfactory anti-emetic effects were not obtained, 4 mg of ondansetron injection was given once intravenously as a rescue medication. The inhibitory effect on nausea and vomiting was assessed in 4 grades as "excellent", "good", "fair" and "poor" based on severity of nausea and number of vomiting that occurred during the first 24hrs after administration of cisplatin. When rescue medication was conducted, the case was assessed as "poor". Ondansetron was significantly superior to placebo in inhibition of nausea and vomiting, in which efficacy rates (excellent+good) of ondansetron and placebo groups were 58.1% (25/43 cases) and 16.7% (7/42 cases), respectively. Number of cases requiring rescue medication with ondansetron injection was obviously greater in placebo group (31 cases) than that in ondansetron group (12 cases). In those patients given ondansetron injection as the rescue medication, satisfactory effects were obtained in 5 cases in ondansetron group and in 18 cases in placebo group. Although side effects including chest itching (ondansetron group), headache and dull headache (placebo group) were observed after the rescue medication with ondansetron injection, these symptoms were not severe and disappeared after 1-2 days. As mentioned above, ondansetron tablet was shown to possess excellent anti-emetic effect on nausea and emesis induced by high dose of cisplatin and to have no problem in safety. Hence ondansetron was proven to be clinically very useful anti-emetic.
IN THIS INVESTIGATION, the effects of the examined antibilharzial agents are as follows: Bilharcid and tartar-emetic similarly affected succinate oxidation. 50% inhibition could be obtained at a concentration of 10(-3) of both drugs. Malate oxidation was differently affected by the drugs. Bilharcid and tartar-emetic at a concentration of 10(-3) M induced 50% and 70% inhibition respectively, while tartar-emetic stimulated malate oxidation if added in a concentration of 10(-5) M. Pyruvate oxidation was affected in the same manner and to the same extent as malate oxidation. Citrate oxidation was slightly inhibited by Bilharcid and tartar-emetic. 10% and 30% inhibition could be obtained if the concentration was 10(-3) M of both drugs respectively. Bilharcid had a biphasic effect on citrate oxidation. Stimulation could be observed at low concentrations (up to 10(-8) M and inhibition at higher ones (up to 10(-3) M. Piperazine hexahydrate was nearly without effect on the rate of oxidation of the four mentioned substrates.
Under control (intact and laparotomized) conditions, arterial pressure of urethan-anesthetized ferrets rose significantly in response to intragastric copper sulfate (CuSO4; 10 ml of 5 mg/ml). CuSO4 was emetic 75-90% of the time, and a cardiovascular response always immediately preceded and accompanied emetic responses. The cardiovascular response was significantly reduced or abolished by hexamethonium (0.35 mg/kg) pretreatment combined with atropine methyl bromide (1 mg/kg). Addition of the alpha 2-receptor antagonist 2,3-dichloro-alpha-methylbenzylamine HCl (DCMB, 10 mg/kg) and the beta-receptor antagonist propranolol (3 mg/kg) to the hexamethonium and atropine combination prevented its reduction of the cardiovascular response. Given individually, these agents did not alter cardiovascular response, nor did yohimbine (0.30 mg/kg), RS(+/-)-zacopride (0.30 mg/kg), or granisetron (0.50 mg/kg). Only RS(+/-)-zacopride significantly reduced incidence of emesis. Atropine methyl bromide alone, with hexamethonium, or with hexamethonium, propranolol, and DCMB significantly delayed the first emetic episode. Conversely, bilateral abdominal vagotomy significantly reduced the number of vomiting animals without affecting cardiovascular response. These results suggest that the neural pathways mediating the two events are not identical. In another series of experiments, a significantly greater proportion of animals vomited in response to intragastric CuSO4 than to intraduodenal CuSO4, suggesting that the primary site of CuSO4 action in the ferret is the stomach.
Positive inotropic and renal vasodilatory effects of a novel dopamine prodrug, docarpamine, [N-(N-acetyl-L-methionyl)-3,4-bis(ethoxycarbonyl)dopamine; TA-870] and those of levodopa were compared in anesthetized dogs, and emetic effects of the two drugs were compared in conscious dogs. Intraduodenal administrations of docarpamine and levodopa at 20 mg/kg produced similar increases in cardiac contractility. The maximal increases in the left ventricular dP/dtmax after docarpamine and levodopa were 36.6 +/- 14.2 and 39.2 +/- 12.1%, respectively. The two drugs also produced similar decreases in renal vascular resistance (21.2 +/- 2.2 and 13.6 +/- 3.4%, respectively) and increases in renal blood flow (27.9 +/- 3.2 and 17.9 +/- 5.2%, respectively), however, the duration of renal vasodilation after docarpamine was longer than that of levodopa. Oral administration of the two drugs in conscious dogs produced vomiting. The ED50 value of the emetic effect for docarpamine was greater than 160 mg/kg, and that for levodopa was 11.0 mg/kg. The emesis was inhibited by pretreatment with a DA2 antagonist, domperidone. In conclusion, docarpamine and levodopa produced similar cardiorenal effects, but the emetic effect of docarpamine was much weaker than that of levodopa. Docarpamine can be used as a selective dopamine prodrug for the peripheral circulation.
The emetic actions of syrup of ipecacuanha have been evaluated in 105 adult patients presenting at the emergency department of the Royal Perth Hospital with a diagnosis of accidental or intentional poisoning. The australian Pharmaceutical Formulary (APF) and the United States Pharmacopeia (USP) formulations of the syrup were compared and gave similar overall emetic responses of 88% and 89% respectively at a dose level of 15 ml. A 30 ml dose regimen of the APF formulation gave a slightly but not significantly increased overall emetic response of 96%. There were no differences between the three groups of patients in the time taken to vomit, the duration of vomiting or the volume of stomach contents recovered.
In order to assess the involvement of alpha-1 and alpha-2 adrenoceptors in emesis, the emetic effect of eight alpha agonists was studied in dogs. The i.m. administration of each agonist elicited dose-dependent emesis. The order of potency in inducing emesis was: clonidine greater than oxymetazoline greater than tramazoline greater than naphazoline greater than xylazine greater than epinephrine greater than methoxamine = phenylephrine. The clonidine-induced emesis was antagonized by adrenoceptor antagonists showing alpha-2 blocking activity, yohimbine, tolazoline and phentolamine. Among these antagonists, yohimbine was the most effective. The alpha-1 and beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptor antagonists did not prevent the clonidine-induced emesis. The emesis induced by oxymetazoline, tramazoline, xylazine, naphazoline and epinephrine was also antagonized by a selective alpha-2 adrenoceptor antagonist, yohimbine, but not by a selective alpha-1 adrenoceptor antagonist, prazosin. In contrast, methoxamine and phenylephrine-induced emesis was antagonized by prazosin, but not by yohimbine. Neither yohimbine nor prazosin prevented the morphine- and histamine-induced emesis. These results indicate that alpha-2 adrenoceptors are involved in the mediation of emetic action, and that the alpha adrenoceptor-mediated emesis does not involve beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptors in the emetic pathway. This study further suggests that alpha adrenoceptors involved in the emesis are mainly of the alpha-2 type, although the involvement of alpha-1 adrenoceptors cannot be ruled out.
A total of 24 patients who were receiving combination chemotherapy (POMB) including cisplatin at a dose of 100-120 mg/m2 were treated with the 5HT3 antagonist GR38032F (GR) as an anti-emetic prophylaxis. GR was given as a 15-min loading infusion followed by a 24-h infusion at three escalating dose levels of 1, 2 and 4 mg/h. In the first 24 h after commencing treatment, six patients had complete control of nausea and vomiting (CR), two had 1-2 emetic episodes (MR) and five had 3-5 emetic episodes (mR). The major response rate (CR + MR) was thus 35%. Eight responding patients (CR or MR) went on to receive oral GR at 8 or 12 mg t.i.d. for 5 days. In this group there was one CR, one MR, two mRs and four failures (F). There was no evidence of an improved therapeutic effect with increasing dose in either the infusion or the oral section of the study, although numbers were limited in the latter part of the trial. Toxicity was mild, with low-grade headache affecting 25% of patients being the most frequent side effect. Pharmacokinetic data was obtained in six patients at each dose level. There was a progressive rise in clearance with increasing dose, indicating that the kinetics are non-linear. However, there was no evidence of an association between high plasma levels and therapeutic efficacy. GR38032F is well tolerated and has promising single-agent activity in preventing vomiting induced by high-dose cisplatin.