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Chemotherapy-induced emesis is the most severe side effect in term of patient's perception. Current anti-emetic regimen as high dose metoclopramide can achieve a complete response in less than 60% of patients. The HT3 receptors appear to be the principal mediator of the emetic effect and their blockade have a clear activity in the prevention of acute drug-induced emesis, superior to reference regimens.
Three antiemetic compounds (zacopride, batanopride, granisetron [BRL43694]) were evaluated for the production of gastrointestinal side effects in the conscious ferret after i.v. or p.o. administration. Zacopride evoked multiple emetic and defecatory responses at clinically relevant doses (0.003-0.3 mg/kg) and in a dose-dependent manner. The oral route was the more potent one for eliciting emesis (ED50 0.033 mg/kg). At 0.3 mg/kg p.o., zacopride reliably evoked an 80 to 100% incidence of emesis and a 40 to 80% incidence of defecation. In contrast, batanopride and BRL43694 i.v. evoked a small (10%) incidence of these side effects, but only at 0.1 to 10 mg/kg doses. When given p.o. (0.00003-10 mg/kg), these latter compounds never evoked emesis and significantly reduced (P less than .05) the incidence of defecation below that of vehicle. Responses to zacopride (0.3 mg/kg p.o.) were challenged by i.p. pretreatment with the 5-hydroxytryptamine receptor agonist 2-methyl serotonin, the 5-hydroxytryptamine receptor antagonist BRL43694, the quaternary atropine derivative glycopyrrolate, the dopamine receptor antagonist domperidone or selective abdominal vagotomies. All compounds and either bilateral or dorsal vagotomy significantly reduced the incidence of emesis, but did not abolish it. Latency to first emesis was delayed by BRL43694, domperidone or dorsal vagotomy. The data suggest that the emetic response to p.o. zacopride is mediated in part by 5-hydroxytryptamine receptors residing on either enteric neurons or vagal afferents. However, the underlying pharmacology of the response may also include activation of cholinergic and dopaminergic pathways.
In this double-blind study, the efficacy and safety of a novel anti-emetic, granisetron, was assessed at two dose levels (40 micrograms/kg; n = 149 and 160 micrograms/kg; n = 147) in 296 patients undergoing high-dose cisplatin chemotherapy. In the first 24 h, 57% and 60% of patients, respectively, experienced no vomiting and no more than mild nausea. Two further doses of granisetron (40 micrograms/kg) were permitted in the first 24 h to treat breakthrough nausea and vomiting. This resulted in resolution or improvement of symptoms in 68-89% of patients. Over the 7-day study period, 53% of patients in the lower-dose group and 51% in the higher received no conventional anti-emetic therapy. No difference in efficacy or safety between the two doses of granisetron was established. Granisetron was well tolerated throughout the dose range of the study (40-240 micrograms/kg). The commonest adverse event was headache, seen in 13-16% of patients. In all cases this resolved spontaneously or responded to simple treatment.
The efficacy and safety of granisetron, a novel anti-emetic, were compared with those of high-dose metoclopramide plus dexamethasone in 234 patients undergoing treatment with high-dose cisplatin (greater than or equal to 49 mg/m2). In this single-blind study, granisetron (40 micrograms/kg; n = 114) was administered as a 5 min infusion, with two additional 40 micrograms/kg doses allowed to control any subsequent nausea and vomiting. In 120 patients, dexamethasone 12 mg was administered intravenously over 30 min, followed by a loading dose of 3 mg/kg metoclopramide. Metoclopramide maintenance dose of 4 mg/kg was then administered over 8 h. The single 5 min infusion of granisetron was at least as effective an anti-emetic as the standard regimen. Approximately 70% of patients in each treatment group were free from vomiting and had no, or only mild nausea in the first 24 h. Granisetron administration was more convenient than the combination dosing schedule for the comparator which was up to 9 h. Only one adverse event, headache, occurred in more than five patients in the granisetron group. However, 13 extrapyramidal reactions (five of them serious) were reported in the metoclopramide plus dexamethasone group.
The clinical research programme with granisetron has involved a total of 1,229 patients, 982 receiving granisetron, 233 receiving currently available combination regimens and 14 receiving placebo. The true efficacy of granisetron was evaluated in a placebo-controlled trial with granisetron given prophylactically and being available as rescue medication in the placebo group. Granisetron produced a complete anti-emetic response in 92.9% of patients and was effective as intervention for the emesis experienced by the patients in the placebo group. Dose-finding studies have confirmed the wide therapeutic margin with four-fold increases in dose producing comparable results. In patients receiving high-dose cisplatin chemotherapy, two out of every three patients responded to a single prophylactic dose; which demonstrates granisetron's long duration of action (greater than 24 h). Additional granisetron also demonstrated benefit if the initial dose failed or delayed-onset emesis occurred. These results are also seen with other emetogenic regimens. Granisetron produces a greater degree of control than the anti-emetic combinations of metoclopramide/dexamethasone or dexamethasone/chlorpromazine. The side-effect profile in volunteers was favourable. The profile in patients is more difficult to define due to the range of potent drugs which cancer chemotherapy patients receive. Headache and constipation were the most common effects with granisetron, although the former was treatable with simple analgesics and the latter thought to be related to higher doses and subsided spontaneously. The future is promising, with the possible introduction of a fixed 3 mg i.v. dose administered over 5 min followed by oral maintenance therapy if and when required.
Work on the pharmacological effects of high-dose metoclopramide led Beecham scientists to identify the role of 5-HT3 receptors in the emetic response to cytostatic drugs and X-irradiation in animals. Further studies have confirmed and extended knowledge of the novel 5-HT3 antagonist granisetron. Dose-dependent inhibition of the 5-HT-induced Bezold-Jarisch reflex in anaesthetized rats was shown by doses of 0.1-10 micrograms/kg i.v. granisetron. Radioligand binding studies in rat brain revealed a high affinity (Ki 0.26 nM) for 5-HT3 sites and much lower affinities (Ki 1000 - greater than 10,000 nM) for 5-HT1, 5-HT2, 5-HT1A, 5-HT1B/C, 5-HT1C, alpha 1, alpha 2, dopamine D2, benzodiazepine, picrotoxin, beta, histamine H1 or opioid mu, kappa or delta binding sites. Granisetron was effective prophylactically after oral or i.v. doses or by intervention after i.v. doses (0.005-0.5 mg/kg) against cisplatin, cyclophosphamide and doxorubicin or X-irradiation-induced emesis in the conscious ferret in the absence of any side effects. It was concluded therefore, that granisetron is a selective and potent anti-emetic worthy of clinical investigation.
Despite improvements in anesthetic techniques postoperative vomiting still remains a problem, particularly in ambulant outpatients, and when an opioid is given before or during anesthesia. Anti-emetic are of limited value and often cause drowsiness or other side effects. We report a study in which a simple acupuncture procedure was used in patients undergoing fraction D & C under standard intravenous anesthesia. Sixty-four patients were included and allocated randomly into one of the two groups: control group receiving standard fentanyl-valium-thiopentone anesthesia alone, and the other group receiving injection of 3 mL normal saline into the P6 acupuncture point after the anesthesia. Ten out of the 32 control patients experienced nausea or vomiting compared with only 2 out of 32 patients receiving acupoint injection. The reduction in nausea was significant. These findings cannot be well explained, but it is recommended that the use of acupuncture as an anti-emetic should be explored further.
Comparative study was performed for assessing the postoperative anti-emetic and emesis preventive effect of domperidone. It has been found that the emesis preventive effect of Motilium tablet is identical with the effect of the well known Daedalon (Dramamin) and Torecan. From the therapeutic aspect it is of value especially in controlling nausea and in the prevention of subsequent vomiting following the use of rectal anti-emetics. This difference is attributable to the oral route of administration. Considering the lack of toxic effects domperidone is the most favourable.
The antiemetic and locomotor effects of two substituted benzamides, zacopride and batanopride (BMY25801), were compared in ferrets after bilateral 60Co irradiation at 2, 4 or 6 Gy. Both zacopride and BMY25801 were effective against emesis and related signs. Zacopride, tested at several doses (0.003, 0.03 and 0.3 mg/kg), appeared to be more potent because it abolished emesis at 100-fold lower doses than did BMY25801 (3 mg/kg). The ED50 value for the antiemetic effect of zacopride was 0.026 mg/kg (confidence levels = 0.0095, 0.072 mg/kg). However, analysis of emetic parameters recorded from vomiting animals (e.g., latency to first emesis) demonstrated that BMY25801 provided greater antiemetic protection in this population than zacopride without any apparent side effects. Locomotor activity was significantly depressed by both radiation (all doses) and zacopride alone (0.03 mg/kg and 0.3 mg/kg). BMY25801 alone did not affect locomotor activity, and protected against the radiation-induced locomotor decrement. Although zacopride potentiated the locomotor decrement to radiation, no clear dose-response relationship was evident. Bilateral abdominal vagotomy significantly increased the latency to the first emetic episode and significantly reduced the number of retches, but did not alter the duration of the prodromal response to 4-Gy irradiation. Unilateral vagotomies had no effect. Zacopride (at 0.03 mg/kg and 0.3 mg/kg) remained an effective antiemetic in animals that received a bilateral vagotomy, abolishing emesis in four of eight and two of eight ferrets, respectively. These data suggest that the antiemetic action of zacopride does not fully depend on intact vagal innervation and also acts via other pathways.
A male patient with hyperemesis as a result of hyperthyroidism was presented. Investigations for causes were negative except for hyperthyroxinaemia. Treatment with antithyroid drug relieved the symptom. Hyperemesis associated with hyperthyroidism occurs predominantly in females. A likely emetic factor oestrogen. Hyperthyroidism could have potentiated this effect. Levels of oestrogens are raised in thyrotoxicosis. The hyperthyroidism, the raised oestrogens and a low emetic threshold conspired to hyperemesis in this patient, a situation not unlike hyperemesis gravidarum. Thyrotoxic vomiting once recognised is readily by antithyroid treatment.
Amelioration of cisplatin (CDDP)-induced vomiting and anorexia by methylprednisolone (MP) was studied using conscious dogs. The incidence of vomiting was 88.9% and the mean number of emetic episodes was 8.22 +/- 1.25/dog during 5 hours after i.v. administration of 1.5 mg/kg CDDP in 9 dogs. In control dogs, food intake on the day after administration of CDDP was markedly reduced to 60 +/- 22.4 g/day from 461 +/- 23 g. Continuous high-dose infusion of MP (10 mg/kg, 10 min before the start of CDDP infusion and 50 mg/kg/h for 5 h) markedly reduced the incidence (33%) and mean number of vomiting episodes (2.00 +/- 1.51/dog) and also mitigated the reduction of food intake (350 +/- 30.6 g/day). However, continuous low-dose infusion of MP (5 mg/kg, 10 min before CDDP infusion and 16.6 mg/kg/h for 5 h) showed a little effect on CDDP-induced vomiting. Plasma MP levels after the high-dose and the low-dose regimens were 6.20 +/- 0.628 micrograms/ml and 4.66 +/- 1.72 micrograms/ml, respectively, 30 min after CDDP infusion. In both cases, MP levels gradually increased and reached to those more than twice 5 hours after CDDP infusion. Bolus administrations of MP (30 mg/kg, each time) 2 hr and 30 min before CDDP infusion also significantly reduced the mean number of emetic episodes (3.22 +/- 1.33/dog) and mitigated the reduction of food intake (325 +/- 37.3 g/day). No significant changes in catecholamines, prostaglandins, vasopressin, plasma renin activity, Na+, K+, Mg++ and osmolality in peripheral blood were noted after administration of CDDP and/or MP. The results suggest that administration of MP was effective against CDDP-induced vomiting and anorexia in dogs.
A controlled prospective study to evaluate the efficacy of expired ipecac syrup was conducted at two regional poison control centers in New England. During a 6-month period, 200 study patients treated with expired ipecac syrup and 200 control patients treated with unexpired ipecac syrup were evaluated. There were no statistical differences between the control and study groups in patient characteristics (age and sex) and product characteristics (general class, emetic potential, pretreatment, previously opened bottles, and manufacturer). In both control and study groups, emesis occurred in 100% of cases with 90% of patients vomiting with the first dose. The mean time to emesis was 24.7 minutes and 24.8 minutes in the study and control groups, respectively. Expired preparations ranged from 1 month to greater than 4 years postexpiration, with the duration of expiration not altering the mean time to emesis. Mean time to emesis between the two groups was also not affected by manufacturer, pretreatment with milk, or whether the ipecac syrup bottle was previously opened. We conclude that expired ipecac syrup (up to 4 years postexpiration date) is an effective emetic.
Forty-two patients with advanced lung cancer undergoing chemotherapy containing cisplatin (80 mg/m2) were submitted to a randomized controlled trial to evaluate the effect of the combination of metoclopramide and dexamethasone for the treatment of delayed cisplatin-induced emesis occurring more than 24 hours after cisplatin administration. All patients received intravenously (i.v.) high-dose metoclopramide and dexamethasone on the day of cisplatin treatment. Excellent emetic control (no emesis during the 24 hours following cisplatin administration) was achieved in 30 out of 41 patients (73%) with this combination. Patients treated i.v. with metoclopramide and dexamethasone on days 2-7 experienced less delayed emesis, nausea and anorexia compared to those treated with a placebo (delayed emesis, 25 vs 50%, respectively, P = 0.105; more than four days of nausea, 10 vs 35%, respectively, P = 0.059; less than three days of anorexia, 80 vs 50%, respectively, P = 0.048). Although the results of the study showed no statistically significant advantage with the combination of i.v. metoclopramide and dexamethasone for patients treated with cisplatin, in view of the short duration of anorexia and the marginal reduction in nausea. Female patients tended to have more emetic episodes and extrapyramidal side effects (except akathisia) than male patients, but the differences were not statistically significant except for acute emesis (P less than 0.005).
The possible role of the alpha-2 adrenoceptors in xylazine-induced vomiting and in motion sickness was investigated. Cats were divided into two groups according to motion sickness susceptibility and were observed after s.c. injections of xylazine. The incidence of vomiting increased with the dose, and at each dose, the high susceptibility group had a greater emetic incidence than the low susceptibility group. In another experiment with cats divided into two groups according to motion sickness susceptibility, s.c. administration of yohimbine effectively antagonized the xylazine-induced emesis in both susceptibility groups. The cats in the latter experiment were then challenged with a motion sickness stimulus, after s.c. pretreatment with yohimbine. Yohimbine failed to prevent motion sickness but did occasion an unexplained variability in the incidence of vomiting. These findings suggest that the emetic effect of xylazine results from stimulation of alpha-2 adrenoceptors but that these receptors are not fundamental to feline motion sickness. The fact that susceptibilities to xylazine-induced emesis and to motion sickness are correlated suggests a point of interaction other than the area postrema, which is known to be essential for xylazine-induced vomiting but not for motion sickness in the cat.
Scopolamine, applicable without severe side effects as a transdermal therapeutic system (TTS), has a pronounced postoperative antiemetic effect. In one publication there was found even a 50% reduction of emetic symptoms compared with placebo. In this study TTS-Scopolamine was compared with a single dose of 7.5 mg Droperidol in a group of 40 Patients undergoing cholecystectomy under standardised balanced anesthesia. After cholecystectomy patients are very much inclined for postoperative nausea and vomiting since it is an abdominal operation and it is more often necessary in women than in men. In this randomized, one-side-blind study the antinausea and antiemetic effect of transdermal Scopolamine was insufficient and significantly less than with Droperidol. In the Droperidol-group there were 45% of patients without emetic symptoms, in the Scopolamine-group only 15%. Vomiting occurred in 25% of patients in the Droperidol-group and in 50% of patients in the Scopolamine-group. Unfavourable CNS-side-effects could not be found either with transdermal scopolamine or with Droperidol. As favourable side-effects there was found a more even postoperative blood-pressure-curve in the Droperidol-group and a better scoring of preoperative sleep in the Scopolamine-group. Overall there is need for an exact indication for transdermal Scopolamine as a postoperative antiemetic. In this study Droperidol turned out to be a much stronger antiemetic for patients undergoing cholecystectomy.
The antiemetic efficacy of a combination of high-dose metoclopramide, methylprednisolone and flunitrazepam was tested in an open pilot study in 30 tumor patients undergoing strongly emetic chemotherapy. 26 of 30 patients (87%) were partially or completely protected from nausea and vomiting. In 11 of 12 patients receiving the strongly emetogenic cytostatic agent cisplatin in a dose of greater than or equal to 50 mg/m2, the gastrointestinal side effects were partially or completely abolished. The antiemetic efficacy of the combination was maintained during subsequent courses of chemotherapy. All patients experienced somnolence after administration of flunitrazepam. Only 2 of 30 patients had a shortlived extrapyramidal reaction. The combination of high-dose metoclopramide, methylprednisolone and flunitrazepam is an effective antiemetic treatment and should be considered as first-line antiemetic treatment in patients receiving strongly emetic cancer chemotherapy.
Nonrestrained adult squirrel monkeys were found to be prolific vomiters when rotated in the horizontal plane for at least 1 h with visual cues available. When multiple daily spins were given, monkeys who vomited early during the first session tended to habituate during subsequent rotations. Subjects who vomited late during the first spin tended to vomit increasingly earlier for several days before the trend reverted to habituation. When a single rotation was continued for up to 8 h, emetic waves occurred with a high probability density for about 2 h, then ceased for many hours with an occasional animal exhibiting isolated emetic episodes. Adaptation effects were transient; when retested beyond a week, most subjects vomited in less time than did inexperienced monkeys on their first exposure to rotation. Attempts to confirm the findings using sinusoidal vertical acceleration were unsuccessful because of failure to induce vomiting using this type of motion.
Methodological issues encountered in reviewing the antiemetic literature are discussed. Variables affecting antiemetic assessment include those relating to the patient, the emetic stimulus, and the differences in action of the antiemetic drugs. Study design questions including the desirability of randomization, double blinding, use of controls, and stratifications for factors such as previous exposure to chemotherapy and strength of the emetic stimulus are discussed. From a statistical viewpoint a parallel subject design with adequate sample size is recommended. The problems of standardizing the evaluation of nausea and vomiting are considered and simple ordinal scales grading severity are suggested. The patient's overall assessment of tolerance of therapy is of primary importance.