Aprepitant in antiemetic combinations to prevent chemotherapy-induced nausea and vomiting

Aprepitant is an oral neurokinin-1 receptor antagonist which acts centrally to block chemotherapy-induced emesis. Its main pathway of elimination is by the cytochrome p450 isozyme CYP3A4, which is the basis for drug interactions with dexamethasone and oral contraceptives. Aprepitant is well tolerated, and phase II trials in high-dose cisplatin-induced emesis showed that it is most effective when 125 mg orally is added to a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone for acute emesis and then an 80 mg oral dose continued with dexamethasone on days 2 and 3 to prevent delayed emesis. Two pivotal phase III trials enrolling a total of 1099 patients showed that the complete control of emesis improved by 20% in patients receiving aprepitant as compared with standard therapy, with the most impressive differences being in delayed emesis. Control was maintained over multiple cycles and occurred in both males and females and young and old adults.     

The role of serotonin as a mediator of emesis induced by different stimuli

The aim of this work was to evaluate the impact of changes in serotonin metabolism on the pathophysiology of different types of emesis: pregnancy-induced emesis, emesis associated with inner-ear dysfunction, and cisplatin-induced emesis. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, was measured in 13 women with pregnancy-induced emesis, 12 patients who had nausea and vomiting following inner-ear dysfunctions, 27 patients with cisplatin-induced emesis and a control group of 21 women. 5-HIAA was measured with a fluorescence polarization immunoassay (Abbott) and corrected for varying urine concentrations. Both patients with emesis associated with inner-ear dysfunction and patients with pregnancy-associated emesis showed a similar 5-HIAA excretion pattern compared with the control group. No correlation between intensity of nausea or vomiting and changes in 5-HIAA excretion could be detected. In patients receiving cisplatin, the 5-HIAA excretion increased rapidly within the 12 h following cisplatin administration and returned to baseline levels after 24 h. There was a parallel increase of 5-HIAA excretion and numbers of emetic episodes in the first 12 h, but delayed emesis was not associated with elevated 5-HIAA excretion. Our results provide evidence that serotonin is involved in the pathophysiology of cisplatin-induced acute emesis. Cisplatin-induced delayed emesis, pregnancy-associated emesis, and emesis due to inner-ear dysfunction are not associated with elevated levels of 5-HIAA excretion. The serotonin pathway probably represents only one of many different afferent mechanisms capable of initiating the emesis cascade.     

Medroxyprogesterone acetate for refractory emesis in Cisplatin-treated patients

Abstract Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects in systemic chemotherapies. Recently, several effective agents have been developed to prevent CINV, and CINV can be prevented in 70%-80% of patients receiving chemotherapies. Conversely, 20%-30% of patients still suffer from CINV despite recommended optimal antiemetic preventions. Refractory emesis is defined as emesis occuring despite the use of antiemetic prophylaxis during the previous cycle of chemotherapy. Salvage treatments for refractory emesis are necessary, but there are few effective treatments at present. We consider medroxyprogesterone acetate to be a potentially promising agent for refractory emesis. We encountered three cases in which medroxyprogesterone acetate was extremely effective for refractory emesis induced by cisplatin-containing chemotherapy.     

Delayed emesis: incidence, pattern, prognostic factors and optimal treatment

Delayed emesis has been arbitrarily defined as vomiting and/or nausea beginning, or persisting for, more than 24 h after chemotherapy administration. Acute emesis is the most important prognostic factor for delayed emesis. Owing to the relatively high incidence and severity all patients treated with cisplatin > or = 50 mg/m(2) should receive antiemetic prophylaxis. In these patients a combination of dexamethasone plus metoclopramide or a 5-HT3 antagonist is the most efficacious regimen. All patients submitted to moderately emetogenic chemotherapy, such as cyclophosphamide, carboplatin, doxorubicin and epirubicin, should also receive antiemetic prophylaxis with oral dexamethasone to prevent delayed emesis.     

The incidence and significance of emesis associated with out-of-hospital cardiac arrest

STUDY OBJECTIVE: Studies have suggested that emesis may occur in up to a third of cardiac arrest patients. The goal of this investigation was to characterize the frequency, timing, and outcome association of emesis in persons suffering out-of-hospital cardiac arrest in order to understand the role and care-implications of emesis better. METHODS: We conducted a cohort study of persons 18 years and over suffering non-traumatic out-of-hospital cardiac arrests who received attempted resuscitation by paramedics in the study community from January 1, 2004 through December 31, 2005 (n=1009). The presence and timing of emesis were determined by paramedics and recorded on the Emergency Medical Services report form. We used logistic regression analyses to assess whether emesis was independently associated with survival to hospital discharge. RESULTS: The presence or absence of emesis was documented in 76% (1009/1333) of cases. Emesis was present in 32% (318/1009). Two-thirds (208/312) of emesis occurred prior to EMS arrival; 28% (88/312) of episodes occurred between EMT arrival and intubation; and 4% (13/312) occurred after intubation. After adjustment for potential confounders, the presence of emesis was associated with a decreased odds of survival to hospital discharge among all-rhythm arrest (Odds ratio (OR)=0.50 [0.28-0.89]) and ventricular fibrillation arrest (OR=0.52 [0.27-0.98]). CONCLUSION: Given the frequency of emesis, the potential that some portion of emesis may be related to care, and the adverse association between emesis and survival, approaches that treat or prevent emesis better may improve the chances of survival following out-of-hospital cardiac arrest.     

How do we manage patients with refractory or breakthrough emesis?

There is evidence that, in spite of the Perugia consensus, acute and delayed emesis are treated in a suboptimal way. Thus breakthrough and refractory emesis as defined in this paper may be related to inadequate therapy. Several interventions have been used in attempts to stop breakthrough emesis, including use or repeat use of setrons, corticosteroids, D2-receptor antagonists including neuroleptics, or sedatives. It has been documented that refractory emesis responds to various modifications of the original antiemetic regimen, including the addition of a D2-receptor antagonist or a switch to another setron. In conclusion, no level I or II evidence-based guidelines can be given, as few adequate studies have been performed in this area, which therefore remains poorly documented.     

Probable involvement of the 5-hydroxytryptamine(4) receptor in methotrexate-induced delayed emesis in dogs

Delayed emesis in cancer patients undergoing chemotherapy remains a significant problem. The pathogenesis of delayed emesis is still obscure. It was recently demonstrated that methotrexate (MTX), an anticancer drug, evoked delayed emesis in dogs in a manner similar to its actions in humans. We evaluated the antiemetic activity of FK1052, a potent antagonist for both the 5-hydroxytryptamine (HT)(3) and 5-HT(4) receptors, on delayed emesis induced by MTX in beagle dogs. Animal behavior was recorded for 3 days using a video camera. Delayed emesis lasting up to 72 h was observed in dogs treated with MTX (2.5 mg/kg i.v.), but acute emesis did not occur. The following antiemetics, at the dose that prevents cisplatin-induced acute emesis in dogs, were administered i.v. as multiple injections every 12 h during days 2 to 3. FK1052 (1 and 3.2 mg/kg) significantly reduced the emetic episodes caused by MTX, whereas ondansetron (1 mg/kg), a selective 5-HT(3) receptor antagonist, was not effective. The emetic episodes induced by MTX were also inhibited by another 5-HT(3/4) receptor antagonist, tropisetron (1 mg/kg). CP-122,721 (0. 1 mg/kg), a potent selective tachykinin NK(1) receptor antagonist, significantly reduced the emetic responses to MTX. Copper sulfate-induced emesis in dogs was also prevented by FK1052, tropisetron, and CP-122,721 but not by ondansetron. FK1052, tropisetron, and ondansetron had negligible affinity for the NK(1) receptor at 1 microM. These results suggest that the 5-HT(4) receptor may be in part involved in the production of delayed emesis induced by MTX in dogs and that FK1052 may be a useful drug against both acute and delayed emesis induced by cancer chemotherapy.     

Syrup of Ipecac in Children Less Than One Year of Age

Abstract

A prospective study was conducted to determine if children less than one year of age developed any complications from syrup of ipecac-induced emesis. All patients in the study were derived from cases received by the poison center. Syrup of ipecac (10 ml) was administered with clear fluids to 24 children less than twelve months of age (mean age 8.7 months; median age 9.0 months; range 3.0-12.0). The average time for the onset of emesis was 26.10 minutes. All children vomited with a single dose of syrup of ipecac. No adverse sequelae such as aspiration or prolonged episodes of emesis were observed. Contrary to the popular belief that emesis may be contraindicated in children less than twelve months of age, we believe that emesis can be safely induced in the home setting in these young children.     

Alpha adrenoceptor subtypes involved in the emetic action in dogs.

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.     

Delayed emesis following anticancer chemotherapy

As the control of acute chemotherapy-induced emesis has improved, delayed emesis (occurring 24 h or more after treatment) has become the most bothersome vomiting problem. Delayed vomiting occurs after treatment with many anticancer drugs, but has been most often studied following cisplatin or combinations of cyclophosphamide and anthracyclines. The mechanism of this phenomenon is unknown. Empirical trials of antiemetic agents effective in controlling acute emesis identified the combination of metoclopramide and dexamethasone as useful in lessening delayed emesis after displatin in a randomized, placebocontrolled study. The specific serotonin receptor (5-HT₃) antagonist ondansetron yielded results equivalent to the prior placebo results in a phase II trial using identical methodology in similar patients given cisplatin. Following anthracycline and cyclophosphamide combination chemotherapy, the delayed vomiting prevention observed with dexamethasone alone exceeds that of ondansetron. These observations suggest that delayed emesis is primarily mediated by neurotransmitters other than serotonin. Since delayed emesis occurs more frequently in patients who experience nausea and vomiting on the day they receive chemotherapy, tested combination antiemetic regimens, employing a 5-HT₃ antagonist (either granisetron, metoclopramide, ondansetron or tropisetron), dexamethasone, and a benzodiazepine (lorazepam and alprazolam) should be routinely employed. This approach provides the best protection for acute and delayed emesis. Further research, looking beyond the specific 5-HT₃ antagonists, provides the best strategy to improve the control of delayed symptoms.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994     

Antiemetic research: a look to the future

 The classification of receptors involved in the emetic reflex has completely changed during the past 10 years. Today investigational agents acting as combined 5-HT₃ antagonists/5-HT₄ agonists, dopamine D₂/D₃ antagonists and the neurokinin₁ antagonists are in focus. Positron emission tomography (PET) is rapidly advancing as an investigational tool in the detection and staging of cancer and in the evaluation of response to treatment. It is emphasized that PET could also be useful in further investigations of the pathophysiology of emesis. Though antiemetic treatment has been optimized, delayed emesis, emesis during multiple cycles and, especially, refractory emesis after chemotherapy continue to present significant challenges requiring further clinical investigations, as does the syndrome of chronic nausea and vomiting in patients with advanced cancer.     

米氮平预防大剂量顺铂化疗的恶心和呕吐的临床研究

目的观察米氮平对大剂量顺铂化疗引起的恶心和呕吐的预防效果和安全性。方法采用自身交叉对照方法。63例大剂量顺铂（60 mg/m2或75 mg/m2）联合吉西他滨化疗者在第一周期时随机分配至对照（A）周期或米氮平（B）周期;第2周期用药互相交叉。A和B两周期化疗方案相同。d1~d5代表化疗周期的第1~5天。恶心、呕吐或食欲减退明显减少的患者比例用控制率表示;完全控制（complete response,CR）率代表无恶心、无呕吐或无食欲减退的比例。共观察d1~d5的恶心、呕吐、食欲减退的控制率。A周期采用恩丹西酮联合地塞米松二药预防恶心和呕吐;B周期在A周期用药基础上联合米氮平。药物用法：（1）恩丹西酮8 mg,iv,每天3次,于d1和d2给药;（2）地塞米松5 mg,iv,每天1次,于d1和d2给药;（3）米氮平15 mg,每天1次,于d1~d5睡前口服;（4）吉西他滨1000 mg/m2或1250 mg/m2,iv,于d1、8给药;（5）顺铂60 mg/m2或75 mg/m2,iv,分2天（于d1、d2）给药。结果米氮平（B）周期与A周期的恶心、急性呕吐、迟发性呕吐、食欲减退控制率分别为71.4%（45/63例）与65.1%（41/63例）（P〈0.01）、79.4%（50/63例）与68.3%（43/63例）（P〈0.01）、88.9%（56/63例）与61.9%（39/63例）（P〈0.01）、50.8%（32/63例）与25.4%（16/63例）（P〈0.05）。B与A周期的恶心、急性呕吐、迟发性呕吐、食欲减退控制率的CR率分别为52.4%（33/63例）与46.0%（29/63例）（P〉0.05）、74.6%（47/63例）与60.3%（38/63例）（P〈0.01）、49.2%（31/63例）与22.2%（19/63例）（P〈0.01）、47.6%（30/63例）与23.8%（15/63例）（P〈0.05）。B与A周期之间迟发性呕吐控制率差值明显高于急性呕吐控制率差值（27.0%vs.11.1%,P〈0.01）。B与A周期中均未见严重副作用。结论米氮平可有效控制大剂量顺铂化疗所致的恶心、呕吐和食欲减退;而迟发性呕吐改善相对更明显。     

RG 12915: a potent 5-hydroxytryptamine-3 antagonist that is an orally effective inhibitor of cytotoxic drug-induced emesis in the ferret and dog

RG 12915 [4-[N-(1-azabicyclo[2.2.2.]octan-3-(S)-yl)]2-chloro-cis 5a-(S)-9a-(S)-5a,6,7,8,9,9a-hexahydrobenzofurancarboxamide hydrochloride] is a potent and effective agent against cisplatin-induced emesis in the ferret after i.v. or p.o. administration. This agent (p.o.) is also highly protective against cisplatin-induced emesis in the dog, as well as cyclophosphamide/doxorubicin-induced emesis in the ferret. When administered either p.o. or i.v., RG 12915 has a lower ED50 value (0.004 mg/kg) than GR 38032F, BRL 43694 and metoclopramide for attenuating cisplatin-induced emetic episodes in the ferret. It also has a long duration of action against cisplatin-induced emesis in the ferret. In contrast to metoclopramide, RG 12915 lacks significant antidopaminergic activity both in vitro [( 3H]spiroperidol displacement), as well as in vivo (apomorphine-induced emesis). In radioligand binding assays, RG 12915 is a potent and selective displacer of binding of 5-hydroxytryptamine (5-HT)3 binding sites (IC50 value = 0.16 nM), whereas failing to displace binding of ligands for the alpha-1, alpha-2 and beta adrenergic, 5-HT1 or 5-HT2 or cholinergic-muscarinic sites with IC50 values less than 1 microM. At a p.o. dose (1 mg/kg) in which RG 12915 is highly protective against cisplatin-induced emesis in the dog, RG 12915 has no significant gastroprokinetic activity in the same species. In summary, RG 12915 is a potent and p.o. effective agent against cytotoxic drug-induced emesis in animal models. The antiemetic potency of RG 12915 against cisplatin is unrelated to antidopaminergic or gastroprokinetic activity, but may be related to its affinity for 5-HT3 binding sites.     

Does postoperative pain induce emesis?

OBJECTIVE: The aim of this prospective, controlled study was to evaluate the risk factors for postoperative emesis in patients undergoing gynecologic surgery and receiving patient-controlled analgesia for three days. METHODS: Six hundred twenty-five gynecologic patients with an American Society of Anesthesiologists physical status of I to III undergoing lower-abdominal surgeries were enrolled. A standard, general anesthetic technique was used. Postoperative pain was treated by a patient-controlled analgesia device with bolus intravenous doses of 1 mg morphine. For 3 days after surgery patients were assessed for occurrence of emesis, sedation, and pain intensity when at rest and during movement. RESULTS: The incidence of emesis was 26% on postoperative day 1, 13% on day 2, and 4% on day 3. On all 3 days, patients' pain scores when at rest and when coughing were higher for those with emesis than for those without. During the first 2 postoperative days the patients with and those without emesis consumed similar amounts of morphine daily, but on the third day the patients with emesis consumed significantly more morphine than did those without emesis ( <0.05). Further logistic regression analysis showed that incident pain was the main risk factor for postoperative emesis on all 3 days. CONCLUSIONS: The results suggested that postoperative pain was an associative risk factor to increase the incidence of emesis in these female patients.     

Using aprepitant as secondary antiemetic prophylaxis for cancer patients with cisplatin-induced emesis

Purpose

Chemotherapy-induced emesis remains a problem despite prophylaxis with 5-hydroxytryptamine (5-HT3) antagonists and dexamethasone. The purpose of the current study was to evaluate the efficacy of adding aprepitant, a neurokinin-1(NK-1) receptor antagonist, as a secondary antiemetic prophylaxis in cases failing to achieve full protection against emesis during the first cycle of a cisplatin-based regimen.

Methods

Patients receiving chemotherapy with a dose of at least 50?mg/m² of cisplatin-based regimens were eligible. If patients failed to achieve complete protection against vomiting when antiemetics (5-HT3 antagonists and dexamethasone) were given in cycle 1, aprepitant was added in subsequent cycles. The primary endpoint was complete response (no emetic episodes and no rescue antiemetics) during days 1–6.

Results

We analyzed 257 patients consecutively. Forty-nine patients (19%) had acute and/or delayed emesis during the first cycle of chemotherapy. Forty of 49 patients received aprepitant for secondary prophylaxis of emesis in the second cycle. Complete protection from vomiting and nausea was achieved in 63% and 55% of patients, respectively. Thirty-five patients received aprepitant for the third cycle. Complete protection from vomiting and nausea was achieved in 77% and 71% of patients, respectively.

Conclusions

Primary antiemetic prophylaxis with 5-HT3 antagonists plus dexamethasone provided more than 80% complete protection against cisplatin-induced emesis. Addition of aprepitant as secondary antiemetic prophylaxis in subsequent cycles provided adequate emesis protection in patients who failed primary prophylaxis. Using aprepitant as secondary antiemetic prophylaxis for cancer patients with cisplatin-induced emesis is feasible and cost-effective.     

Delayed emesis following anticancer chemotherapy

Delayed emesis is a distinct syndrome where vomiting begins or persists 24 or more hours after chemotherapy. It is more likely to occur when the stimulus for emesis is strong and/or acute vomiting is poorly controlled. The pathophysiology appears different than that which causes acute emesis. The literature reporting clinical trials to prevent delayed nausea and vomiting are presented. The best ways of preventing delayed emesis following anticancer chemotherapy are discussed.     

Progress in preventing chemotherapy-induced nausea and vomiting

Our understanding of the pathophysiology of emesis has improved over the past 2 decades, and we now have drugs that can prevent acute emesis in most patients. Prevention and treatment of the delayed and anticipatory forms of chemotherapy-induced emesis remain a challenge.     

Prevention of cisplatin-induced delayed emesis: still unsatisfactory

 The incidence of and prognostic factors in cisplatin-induced delayed emesis were evaluated in 522 naive cancer patients. They each received an intravenous combination of ondansetron and one of four different doses of dexamethasone for the prevention of acute emesis and a combination of orally administered metoclopramide plus intramuscular dexamethasone for the prevention of delayed emesis. Despite the best prophylaxis for acute and delayed emesis, 37.4% / 57.1% of patients experienced delayed vomiting / nausea. The presence of acute vomiting / nausea was the main prognostic factor in delayed vomiting / nausea; therefore, a multifactorial analysis of the results achieved during the delayed phase adjusted for those obtained during the acute phase should be carried out in every study evaluating the efficacy of different antiemetic drugs for delayed emesis. Published online: 9 September 1999     

A double-blind, crossover, randomized comparison of granisetron and ramosetron for the prevention of acute and delayed cisplatin-induced emesis in patients with gastrointestinal cancer: is patient preference a better primary endpoint?

BACKGROUND: Serotonin receptor antagonists are recommended by the American Society of Clinical Oncology for the prevention of acute and delayed chemotherapy-induced emesis. However, the most effective agent in this class of antiemetic drugs for preventing emesis has not been clearly defined. We therefore performed a double-blind, crossover, randomized, controlled trial comparing the efficacy of granisetron and ramosetron, using patient preference as the primary endpoint. METHODS: Thirty patients receiving two courses of combined chemotherapy (including > or =60 mg/m(2) cisplatin) for gastric or esophageal cancer were randomly assigned to the granisetron-ramosetron group (treatment phase 1: granisetron, 3 mg; treatment phase 2: ramosetron, 0.3 mg) or the ramosetron-granisetron group (treatment phase 1: ramosetron, 0.3 mg; treatment phase 2: granisetron, 3 mg). All patients received methylprednisolone sodium, 250 mg i.v., during each treatment phase. RESULTS: The efficacy of granisetron and ramosetron was similar in terms of the suppression of emesis and appetite status. However, the majority of patients (19/30, 63.3%) expressed a preference for granisetron, as compared with 9 patients (30.0%) who preferred ramosetron; 2 patients (6.7%) had no preference (chi(2) test: p = 0.008; Fisher's exact test: p = 0.015). CONCLUSIONS: (1) A significant proportion of patients prefer granisetron over ramosetron for the prevention of chemotherapy-induced emesis. (2) Granisetron and ramosetron possess similar effectiveness for the suppression of emesis. (3) The variable of 'patient preference' should be accepted as a primary endpoint of antiemetic drug efficacy.     

Nausea and vomiting

Nausea and vomiting are the most distressing side effects reported by patients undergoing CDDP-based cancer chemotherapy. Dopamine receptor antagonists and corticosteroids are used as anti-emetics for chemotherapy induced nausea and vomiting. Recently, a highly selective 5-HT3 receptor antagonist are proved to demonstrate antiemetic activity. 5-HT3 receptor antagonists are developed such as Granisetron, Ondansetron, Ramosetron, Azasetron. For acute emesis, complete control of vomiting was achieved in 80% of patients receiving 5-HT3 receptor antagonists. Though, it is reported to be only 20% effective for the complete control of delayed emesis. Psychiatric medications sometimes play a prominent role in the control of persisting emesis, particularly anticipatory or conditioned nausea. Nausea and vomiting are well controlled using various anti-emetics considering patient's condition and chemotherapy schedule.