Ondansetron: a pharmacoeconomic and quality-of-life evaluation of its antiemetic activity in patients receiving cancer chemotherapy

Ondansetron is more effective than high-dose metoclopramide in the prevention of acute nausea and vomiting due to highly emetogenic chemotherapy, and, unlike metoclopramide, is rarely associated with extrapyramidal effects. Pharmacoeconomic analyses have demonstrated that, in specified clinical settings, ondansetron (8mg 4-hourly for 3 doses or 8mg followed by 1 mg/h for 24 hours) is equally cost-effective as high-dose metoclopramide (3 mg/kg followed by 0.5 mg/kg/h for 8 hours) in the prophylaxis of emesis in patients receiving highly emetogenic chemotherapy, at an acquisition cost 4- or 5-fold higher than that of the metoclopramide regimen. Furthermore, the combination of dexamethasone plus ondansetron has been shown to be more effective than ondansetron monotherapy in controlling emesis. In patients receiving high-dose ( greater than 50 mg/m2) cisplatin-based chemotherapy, antiemetic therapy with ondansetron (8mg intravenously as a single dose) plus dexamethasone (16mg total intravenous dose) was shown to be more cost-effective than the combination of high-dose metoclopramide (11 mg/kg total intravenous dose), dexamethasone (8mg intravenously as a single dose) plus lorazepam (1 to 1.5mg intravenously as a single dose). In a limited number of studies, quality-of-life scores, as assessed using the Rotterdam Symptom Checklist or the Functional Living Index--Emesis instrument, were significantly higher with ondansetron than with other antiemetic agents, including metoclopramide. Together, these results suggest that ondansetron, as an alternative to antiemetic regimens including high-dose metoclopramide, is appropriate cost-effective therapy for the prevention of acute nausea and vomiting in patients receiving highly emetogenic chemotherapy. Ondansetron is effective in controlling acute emesis associated with moderately emetogenic chemotherapy, and its use in this clinical setting may best be reserved for patients who have not responded well to previous antiemetic therapy with more traditional agents. However, poorly controlled emesis can lead to anticipatory nausea and vomiting in subsequent courses of chemotherapy, thus, consideration should also be given to the use of ondansetron in patients receiving moderately emetogenic chemotherapy, although further pharmacoeconomic investigations are required to clarify its use in this clinical setting.     

Granisetron. A pharmacoeconomic evaluation of its use in the prophylaxis of chemotherapy-induced nausea and vomiting

The efficacy of granisetron in preventing acute nausea and vomiting during the 24 hours following chemotherapy in patients with cancer is equivalent to that of other serotonin 5-HT3 receptor antagonists (ondansetron and tropisetron) and similar to or greater than that of conventional antiemetic regimens such as metoclopramide plus dexamethasone. Like other 5-HT3 receptor antagonists, granisetron is generally well tolerated by most patients and its antiemetic efficacy is enhanced when used concomitantly with dexamethasone. To date, pharmacoeconomic evaluations of granisetron have involved intravenous administration of the drug to adult patients with cancer receiving single-dose or fractionated chemotherapy of moderate to high emetogenic potential. In economic analyses conducted in France, a single dose of granisetron 3mg was associated with a mean direct treatment cost per patient (or per well-controlled patient) approximately 50% lower than that for ondansetron 8mg intravenously followed by 8mg orally every 8 hours for 3 days, in patients receiving single-dose chemotherapy. Direct costs per patient were approximately 20 to 30% lower with granisetron (usually 3 mg/day) than ondansetron (usually 24 to 32 mg/day intravenously) in patients receiving chemotherapy fractionated over several days. Sensitivity analysis showed that the results, were robust to variations in the acquisition costs of the antiemetics. Granisetron also remained more cost effective than ondansetron with variations in the antiemetic dosage regimens, except when the granisetron dosage remained unchanged while the ondansetron dosage was reduced to a single 8mg intravenous dose on each day prior to chemotherapy (and no change in efficacy was assumed). Other economic evaluations suggest that granisetron may be more cost effective than a combined antiemetic regimen of high dose metoclopramide plus dexamethasone, and selected use of granisetron or ondansetron in patients receiving emetogenic chemotherapy can be implemented with relatively small incremental increases to the total cancer treatment budget, albeit with a marked increase in antiemetic acquisition costs. In conclusion, granisetron is an effective and well tolerated agent for the prophylaxis of acute chemotherapy-induced nausea and vomiting, and its selective use in this clinical setting can provide cost-effective antiemetic therapy.     

Cancer chemotherapy-induced nausea and vomiting: role of mediators, development of drugs and treatment methods

The development of serotonin 5-HT3 receptor antagonists dramatically improved the treatment of chemotherapy-induced nausea and vomiting. Ondansetron, a serotonin 5-HT3 receptor antagonist in combination with dexamethasone is widely used to treat chemotherapy-induced nausea and vomiting. This treatment regimen is effective against acute nausea and vomiting, but fails to control delayed nausea and vomiting. Metoclopramide along with other antiemetics are used to treat delayed nausea and vomiting. The high doses of metoclopramide needed may produce extra pyramidal side effects. The recent developments of 5-HT3 and dopamine D2 dual receptor antagonists have been found to exhibit a broad spectrum of activity against peripherally and centrally acting stimuli, but are not much effective against delayed emesis associated with chemotherapy. In various animal models, neurokinin NK1 receptor antagonists showed promising results against acute and delayed emesis, but the clinical trials revealed that triple therapy (NK1 receptor antagonist, 5-HT3 receptor antagonist and dexamethasone) is superior than standard therapy (5-HT3 receptor antagonist & dexamethasone) or NK1 receptor antagonist alone, in controlling acute as well as delayed nausea and vomiting. Ginger, which is used traditionally for controlling emesis induced by various stimuli, also showed good activity against chemotherapy-induced nausea and vomiting in animal models. Non-pharmacological methods such as acupressure and acustimulation are good adjunct methods in treating nausea and vomiting. Since many mediators are involved in emesis induced by chemotherapy, cocktail treatment is proven to be more efficacious than a single drug, but increases treatment costs. So there is a need of further research in this field to get economically useful methods for the treatment of acute and delayed chemotherapy-induced nausea and vomiting.     

Palonosetron

Palonosetron is a potent and highly selective serotonin 5-HT(3) receptor antagonist that has been evaluated for the prevention of chemotherapy-induced nausea and vomiting. black triangle Intravenously administered palonosetron has a linear pharmacokinetic profile, with a long terminal elimination half-life ( approximate, equals 40 hours) and moderate (62%) plasma protein binding. In two randomised, double-blind trials in 1132 cancer patients receiving moderately emetogenic chemotherapy, intravenous palonosetron 0.25 mg was more effective than intravenous ondansetron 32 mg in producing a complete response (no emesis, no use of rescue medication) during acute (0-24 hours) or delayed (24-120 hours) phases, and similar to intravenous dolasetron 100 mg in acute, but more effective in delayed phase. Palonosetron 0.75 mg was similar to ondansetron (acute and delayed phase) or dolasetron (acute phase), but more effective than dolasetron in delayed phase. In patients receiving highly emetogenic chemotherapy (n = 667), the complete response rates during acute and delayed phases with intravenous palonosetron (0.25 or 0.75 mg) were similar to those seen in intravenous ondansetron 32 mg recipients in a randomised, double-blind trial. Intravenous palonosetron was generally well tolerated in clinical trials, with few adverse events being treatment related. Palonosetron had no significant effect on the corrected QT interval or laboratory parameters.     

The utility of antiemetics in the prevention and treatment of postoperative nausea and vomiting in patients scheduled for laparoscopic cholecystectomy

Postoperative nausea and vomiting (PONV) are distressing and frequent adverse events of anesthesia and surgery, with a relatively high incidence after laparoscopic cholecystectomy. Numerous antiemetics have been studied for the prevention and treatment of PONV in patients scheduled for laparoscopic cholecystectomy. Traditional antiemetics, including anticholinergics (e.g., scopolamine), antihistamines (e.g., dimenhydrinate), phenothiazines (e.g., promethazine), butyrophenones (e.g., droperidol), and benzamide (e.g., metoclopramide), are used for the control of PONV. The available nontraditional antiemetics for the prophylaxis against PONV are dexamethasone and propofol. Serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, and ramosetron), compared with traditional antiemetics, are highly efficacious for PONV. The prophylactic ondansetron, granisetron, tropisetron, and dolasetron in antiemetic efficacy are comparable. Ramosetron is effective for the long-term prevention of PONV. None of the available antiemetics is entirely effective, perhaps because most of them act through the blockade on one type of receptor. There is a possibility that combined antiemetics with different sites of activity would be more effective than one drug alone for the prophylaxis against PONV. Combination antiemetic therapy is often effective for the prevention of PONV following laparoscopic cholecystectomy. The efficacy of a combination of serotonin receptor antagonists (ondansetron and granisetron) and droperidol is superior to monotherapy with a serotonin receptor antagonist or droperidol. Similarly, adding dexamethasone to ondansetron or granisetron improves antiemetic efficacy in PONV. Knowledge regarding antiemetics is necessary to completely prevent and treatment of PONV in patients scheduled for laparoscopic cholecystectomy.     

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.     

Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis

Palonosetron (Aloxi) is a 5-HT(3)-receptor antagonist antiemetic indicated for the prevention of acute and delayed nausea and vomiting following moderately emetogenic chemotherapy and for acute nausea and vomiting following highly emetogenic chemotherapy. Although it is the fourth member of this class to enter the US market, palonosetron is distinguished by distinct pharmacological characteristics. It has a higher binding affinity for the 5-HT(3 )receptor and a terminal serum half-life at least four times greater than any other available agent of this class (approximately 40 h). The high affinity and long half-life may explain the persistence of antiemetic effect throughout the delayed emesis risk period. The indications for palonosetron are supported by one dose-ranging study and three large, randomised, Phase III studies that all demonstrated at least equivalent activity (and in some cases, superior activity) compared to other 5-HT(3)-receptor antagonists. In spite of the pharmacological differences, the side effect profile of palonosetron is comparable to that of other 5-HT(3)-receptor antagonists. Palonosetron may prove valuable in combination therapy for delayed emesis and may be an appropriate agent for clinical settings, such as multiple-day chemotherapy, where acute emesis is repeatedly induced. Palonosetron provides a convenience advantage if multiple-day 5-HT(3)-receptor antagonist therapy is anticipated and is a unique addition to the antiemetic armamentarium.     

观察昂丹司琼防治肿瘤化疗引起呕吐的临床疗效分析

目的：观察新一代止吐药昂丹司琼对防治肿瘤患者化疗引起的恶心呕吐胃肠道反应的疗效,以保证化疗顺利进行。方法：60例患者采用自身交叉对照法随机分为A、B两组,化疗第一周期,A组应用昂丹司琼8mg静滴,化疗前20分钟应用,每日一次,d1～d5天,B组应用胃复安20mg肌注,每日二次,并加用吗叮啉片10mg,每日三次口服,d1～d5天。第二周期化疗,A、B两组止吐药物交换,两组止吐药均与化疗日期同步。采用1990年欧洲临床肿瘤会议推荐的恶心呕吐标准,对两组止吐药物的疗效进行对比和评价。结果：两组药物的有效率有显著的统计学差异（P〈0.005）。在控制化疗引起的恶心呕吐方面,昂丹司琼的疗效明显优于胃复安加吗叮啉。结论：新一代止吐剂昂丹司琼能够有效控制以顺铂为主的不同联合化疗方案引起的恶心呕吐胃肠道反应,其疗效明显优于传统的常规止吐药物,并且副作用小,使用安全,有效作用时间长,这对提高肿瘤化疗的疗效,延长患者的生存期,提高患者的生活质量有重要作用。因此,昂丹司琼应作为化疗辅助用药的首选药物之一。     

Prevention and treatment of postoperative nausea and vomiting

Pain, nausea and vomiting are frequently listed by patients as their most important perioperative concerns. With the change in emphasis from an inpatient to outpatient hospital and office-based medical/surgical environment, there has been increased interest in the 'big little problem' of postoperative nausea and vomiting (PONV). Currently, the overall incidence of PONV is estimated to be 25 to 30%, with severe, intractable PONV estimated to occur in approximately 0.18% of all patients undergoing surgery. PONV can lead to delayed postanaesthesia care unit (PACU) recovery room discharge and unanticipated hospital admission, thereby increasing medical costs. The aetiology and consequences of PONV are complex and multifactorial, with patient-, medical- and surgery-related factors. A thorough understanding of these factors, as well as the neuropharmacology of multiple emetic receptors [dopaminergic, muscarinic, cholinergic, opioid, histamine, serotonin (5-hydroxy-tryptamine; 5-HT)] and physiology [cranial nerves VIII (acoustic-vestibular), IX (glossopharyngeal) and X (vagus), gastrointestinal reflex] relating to PONV are necessary to most effectively manage PONV. Commonly used older, traditional antiemetics for PONV include the anticholinergics (scopolamine), phenothiazines (promethazine), antihistamines (diphenhydramine), butyrophenones (droperidol) and benzamides (metoclopramide). These antiemetics have adverse effects such as dry mouth, sedation, hypotension, extrapyramidal symptoms, dystonic effects and restlessness. The newest class of antiemetics used for the prevention and treatment of PONV are the serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron). These antiemetics do not have the adverse effects of the older, traditional antiemetics. Headache and dizziness are the main adverse effects of the serotonin receptor antagonists in the dosages used for PONV. The serotonin receptor antagonists have improved antiemetic effectiveness but are not as completely efficacious for PONV as they are for chemotherapy-induced nausea and vomiting. Older, traditional antiemetics (such as droperidol) compare favourably with the serotonin receptor antagonists regarding efficacy for PONV prevention. Combination antiemetic therapy improves efficacy for PONV prevention and treatment. In the difficult-to-treat PONV patient (as in the chemotherapy patient), suppression of numerous emetogenic peripheral stimuli and central neuroemetic receptors may be necessary. This multimodal PONV management approach includes use of: (i) multiple different antiemetic medications (double or triple combination antiemetic therapy acting at different neuroreceptor sites); (ii) less emetogenic anaesthesia techniques; (iii) adequate intravenous hydration; and (iv) adequate pain control.     

Emerging drugs for chemotherapy-induced emesis

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, no alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a significant clinical problem. Two new agents, palonosetron and aprepitant, have recently been approved for the prevention of both acute and delayed CINV. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. Aprepitant is the first agent available in the new drug class of neurokinin-1 receptor (NK-1) antagonists. There are a number of 5-HT3 receptor antagonists and NK-1 receptor antagonists currently in Phase II and III clinical trials. Revised antiemetic guidelines for the prevention of CINV are reviewed. Future studies may consider the use of palonosetron and aprepitant with current and other new agents (olanzapine, gabapentin) in moderately and highly emetogenic chemotherapy, as well as in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.     

Ondansetron. Therapeutic use as an antiemetic.

Ondansetron (GR 38032F) is a highly selective 5-HT3 receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron reduces the 24-hour incidence and severity of nausea and vomiting induced by cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the 'moderate' doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatin-treated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available. Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics.     

3种5-HT3受体拮抗剂预防肝癌患者介入治疗后恶心呕吐的疗效比较

目的:通过测定中药制剂参芪扶正注射液中Cu、Zn、Mn、Se、Mo、Fe、Cr、Ni、V、Sn、Pb、Cd、Hg、As等14种微量元素的含量,探讨该中药注射液中元素的分布是否存在某种规律性.方法:微波消解法制备供试品,电感耦合等离子体-质谱(ICP-MS)法测定.结果:参芪扶正注射液中Cu、Fe、Zn、Cr、Se的相对含量较高,有毒元素Pb、Cd、Hg、As中As含量接近美国FAD药品与功能性食品要求标准,Pb、Cd、Hg含量均明显低于最高限量.结论:测定结果为探讨中药制剂中微量元素与抗肿瘤作用的关系提供有用的数据.     

Ondansetron antiemetic therapy for chemotherapy and radiotherapy induced vomiting in children.

AIM: To evaluate ondansetron as the sole antiemetic in children treated with emetogenic chemotherapy and irradiation. METHODS: Fifteen children aged 3-11 years were studied. Seven had acute lymphoblastic leukaemia, two acute myeloid leukaemia, two lymphoma and four had other tumours. Ondansetron 5 mg/m2 IV or 4 mg by mouth was given immediately before chemotherapy or radiation treatment and continued eight hourly for 24 hours. Nausea and vomiting was assessed during treatment and for the next 48 hours, and graded using WHO criteria. RESULTS: Thirty-eight courses of chemotherapy were assessed, 27 severely emetogenic and 11 moderately emetogenic. Two included total body irradiation. The most severe nausea and vomiting was grade 2 (transient vomiting) reported in six children. Nausea and vomiting was abolished on subsequent courses in four of these children by increasing the ondansetron dose frequency to six hourly. The remaining children experienced no nausea or vomiting (n = 7) or only nausea (n = 2). Nausea and vomiting were each completely controlled in 27 courses. CONCLUSIONS: Ondansetron is a cost effective and safe antiemetic in children receiving chemotherapy and total body irradiation, minimises weight loss on treatment and enables outpatient chemotherapy in some cases.     

The benefits and risks of different therapies in preventing postoperative nausea and vomiting in patients undergoing thyroid surgery

Postoperative nausea and vomiting (PONV) are distressing and frequent adverse events of anesthesia and surgery, with a relatively high incidence following thyroidectomy. These symptoms predispose to aspiration of gastric contents, increased intraocular pressure, psychological distress, and delayed recovery and discharge times. Numerous antiemetics have been studied for the prevention and treatment of PONV following thyroidectomy. These drugs include butyrophenones (e.g., droperidol), benzamides (e.g., metoclopramide), antihistamines (e.g., dimenhydrinate), corticosteroids (e.g., dexamethasone), propofol, oxygen, and serotonon receptor antagonists (e.g., ondansetron). Most of published trials indicate improved prophylaxis against PONV by avoiding risk factors and/or by using effective antiemetic therapy in patients scheduled for thyroid surgery. Traditional antiemetics (droperidol, metoclopramide, and alizapride), non-traditional antiemetics (propofol and dexamethasone), and serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, and ramosetron) have been studied for the prevention of PONV. Serotonin receptor antagonists are more effective than traditional antiemetics. Combination antiemetic therapy with granisetron plus droperidol or granisetron plus dexamethasone is highly effective in preventing PONV. The benefits and risks of different therapies are needed to prevent PONV following thyroid surgery.     

The current status of the use of palonosetron

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in the quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist, has antiemetic activity at both central and gastrointestinal sites. In comparison to the first-generation 5-HT₃ receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT₃ receptors. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Compared to the first-generation 5-HT₃ receptor antagonists, palonosetron in combination with dexamethasone has demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy and had a similar safety profile. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.     

Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting

Granisetron (Kytril, Roche) is a 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin. Its indication expanded in August 2002, with approval from the FDA for the prevention and treatment of postoperative nausea and vomiting. Granisetron strongly and selectively binds to the 5-HT(3) receptor with a binding constant of 0.26 nM and exhibits a 4000 - 40,000 times greater binding affinity for the 5-HT(3) receptor than other binding sites, including other 5HT subtypes and adrenergic, histaminergic and opioid receptors. Its selectivity to the 5-HT(3) receptor over other receptor types is > 1000:1. Granisetron noncompetitively binds to the 5-HT(3) receptor and is associated with a long duration of action as shown by the inhibition of a 5-HT axonal response flare for up to 24 h. Granisetron is unique among the 5-HT(3)-receptor antagonists because it is not metabolised via the cytochrome P450 (CYP) 2D6 pathway and is, therefore, less susceptible to variation in patient response because of factors such as pharmacogenomic differences. Granisetron and other 5-HT(3)-receptor antagonists are first-line agents for acute chemotherapy-induced nausea and vomiting (CINV), whereas combination therapy with 5-HT(3)-receptor antagonists, dexamethasone and neurokinin (NK)-1 receptor antagonism (i.e., with the recently approved aprepitant) is an effective approach to prevent delayed CINV. Granisetron has been shown to be an effective within-class rescue antiemetic for prophylactic failures, which may be linked to its pharmacological properties including non-competitive, insurmountable binding to the 5-HT(3) receptor. As with other 5-HT(3)-receptor antagonists, granisetron is well-tolerated with adverse events of mild severity including headache, asthenia and constipation. Overall, data demonstrate that granisetron is an efficacious, safe and cost-effective member of the 5HT(3)-receptor antagonist class for the prevention of CINV.     

Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting

Aprepitant (Emend) is the first commercially available drug from a new class of agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults.In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2 and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63-73% versus 43-52%, p < 0.01 for all comparisons).Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase.The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy.Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis.Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used.In conclusion, when added to standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer.     

Randomized, multicenter comparison of oral granisetron and oral ondansetron for emetogenic chemotherapy

Study Objectives. To compare the antiemetic effectiveness and safety of oral granisetron plus dexamethasone with those of oral ondansetron plus dexamethasone administered before emetogenic chemotherapy. Design. Randomized, prospective, multicenter, open-label study. Settings. University-teaching hospital and veterans health care system. Patients. Sixty-one chemotherapy-naïve patients scheduled to receive emetogenic antineoplastic agents. Intervention. A single-dose oral granisetron 1 mg and dexamethasone 12 mg or single-dose oral ondansetron 16 mg and dexamethasone 12 mg was administered before chemotherapy. Measurements and Results. Twenty-four hours after administration patients were contacted to assess nausea, emesis, and adverse events. There were no statistical differences in frequency of nausea or emesis between groups. Seventy-six percent and 82% of patients receiving ondansetron and granisetron, respectively, experienced no emesis 24 hours after chemotherapy. Complete protection from nausea occurred in 58% and 46% of patients receiving the drugs, respectively. Adverse events were similar between groups. Conclusion. Oral granisetron 1 mg and ondansetron 16 mg plus dexamethasone are safe and effective in preventing nausea and vomiting related to emetogenic chemotherapy.     

The antiemetic efficacy of tropisetron plus dexamethasone as compared with conventional metoclopramide-dexamethasone combination in Orientals receiving cisplatin chemotherapy: a randomized crossover trial

1We report a single-blind randomized crossover trial comparing the efficacy of tropisetron plus dexamethasone (TROPDEX) vs conventional combination of metoclopramide, dexamethasone and diphenhydramine (METDEX) in prevention of acute and delayed vomiting in Chinese patients receiving high dose cisplatin. 2Thirty-six consecutive patients with nasopharyngeal carcinoma were entered into the study, all received cisplatin at a dose range of 60–100 mg/m². Patients were randomized in the sequence of antiemetic regimens used in two consecutive cycles. 3The TROPDEX regimen consisting of tropisetron 5 mg i.v. and dexamethasone 20 mg i.v. given on day 1 of chemotherapy, followed by oral maintenance with tropisetron 5 mg daily and dexamethasone 4 mg twice daily from day 2 to 6. The METDEX regimen consisting of metoclopramide 1 mg kg⁻¹ i.v., dexamethasone 20 mg i.v. and diphenhydramine 25 mg i.v. given before chemotherapy and then 2 hourly for two more doses on day 1, followed by oral metoclopramide 20 mg 6 hourly from day 2 to 6. 4Complete control of acute vomiting was observed in 64% of patients with TROPDEX as compared with 14% with METDEX (P<0.01). While complete plus major control of acute vomiting was observed in 84% with TROPDEX as compared with 58% with METDEX. The mean vomiting episodes on day 1 were 1.4 with TROPDEX as compared with 3.5 with METDEX (P<0.01). There was, however, no significant difference between the two regimens in the control of delayed vomiting. 5When patients randomized to TROPDEX in the second cycle were compared with those with TROPDEX in the first cycle, the antiemetic efficacy was reduced, with mean acute vomiting episodes of 2 in the former compared with 0.8 in the latter (P<0.01). 6The most common adverse effect observed was headache in TROPDEX (27%) and dizziness in METDEX (40%). 7In conclusion, the antiemetic regimen TROPDEX is effective in Chinese patients receiving high dose cisplatin chemotherapy and is well tolerated. It is better than conventional METDEX regimen in the control of acute vomiting, but not in the control of delayed vomiting.     

Granisetron. A review of its pharmacological properties and therapeutic use as an antiemetic.

Granisetron (BRL 43694) is a highly selective 5-HT3 receptor antagonist which possesses significant antiemetic activity, likely mediated through antagonism of 5-HT3 receptors on abdominal vagal afferents and possibly in or near the chemoreceptor trigger zone. Clinical trials in cancer patients demonstrate that, compared with placebo, granisetron significantly reduces the incidence of nausea and vomiting for 24 hours after administration of high-dose cisplatin. In large comparative trials, 70% of patients who received granisetron prior to cisplatin or other chemotherapy experienced complete inhibition of vomiting with little or no nausea for 24 hours after antineoplastic administration; these results were similar to those obtained with high-dose metoclopramide plus dexamethasone, and superior to a combination of chlorpromazine plus dexamethasone, or prochlorperazine plus dexamethasone, or methylprednisolone monotherapy. The most frequently reported adverse event associated with granisetron administration is headache which occurs in about 10 to 15% of patients while constipation, somnolence, diarrhoea and minor transient changes in blood pressure have been reported less frequently. Extrapyramidal effects, which can occur with high-dose metoclopramide and may be a limiting factor in its use, have not been noted with granisetron administration. Thus, granisetron is an effective, well tolerated and easily administered agent for the prophylaxis of nausea and vomiting induced by cancer chemotherapy which appears to be devoid of extrapyramidal side effects associated with metoclopramide. As a member of a new class of drugs, the selective 5-HT3 receptor antagonists, granisetron provides the medical oncologist with a new, potentially more acceptable antiemetic therapy.