Incidence and predictors of anticipatory nausea and vomiting in Asia Pacific clinical practice--a longitudinal analysis.

PURPOSE: Some patients experience nausea and/or vomiting (NV) before receipt of chemotherapy. Our objective was to evaluate the impact of prior chemotherapy-induced NV (CINV) on the incidence of anticipatory NV in later cycles. METHODS: This multicenter, prospective non-interventional study enrolled chemotherapy-naïve adults scheduled to receive highly or moderately emetogenic chemotherapy (HEC/MEC) for cancer in six Asia Pacific countries, excluding those with emesis within 24 h before cycle 1 chemotherapy. On day 1 before chemotherapy, patients answered four questions regarding emesis in the past 24 h, nausea, expectation of post-chemotherapy nausea, and anxiety in the past 24 h, the latter three scored from 0-10 (none-maximum). Multivariate logistic regression was used to assess the impact of prior CINV on anticipatory NV in cycles 2 and 3. RESULTS: Five hundred ninety-eight patients (59% female) were evaluable in cycle 2 (49% HEC, 51% MEC). The incidence of anticipatory emesis was low before cycles 2 and 3 (1.5-2.3%). The incidence of clinically significant anticipatory nausea (score of ≥3) was 4.8, 7.9, and 8.3% before cycles 1, 2, and 3, respectively, with adjusted odds ratio (OR), 3.95 (95% confidence interval (CI), 2.23-7.00; p < 0.001) for patients with clinically significant nausea in prior cycles, compared with none. The adjusted ORs for other anticipatory NV endpoints ranged from 4.54-4.74 for patients with prior CINV. The occurrence of clinically significant anxiety in the prior cycle also resulted in a significantly increased likelihood of anticipatory nausea. CONCLUSIONS: These findings highlight the importance of preventing CINV in cycle 1 to reduce anticipatory NV in subsequent cycles.

The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat.

RATIONALE: Anticipatory nausea (AN) experienced by chemotherapy patients is resistant to current anti-nausea treatments. In this study, the effect of manipulation of the endocannabinoid (EC) system on a rat model of nausea (conditioned gaping) was determined. OBJECTIVE: The potential of cannabidiol (CBD) and the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (URB) to reduce conditioned gaping in rats were evaluated. MATERIALS AND METHODS: In each experiment, rats received four conditioning trials in which they were injected with lithium chloride immediately before placement in a distinctive odor-laced context. During testing, in experiment 1, rats were injected with vehicle (VEH), 1, 5 or 10 mg/kg CBD 30 min before placement in the context previously paired with nausea and in experiment 2, rats were injected with VEH, 0.1 or 0.3 mg/kg URB 2 h before placement in the context. Additional groups evaluated the ability of the CB(1) antagonist/inverse agonist, SR141716A, to reverse the suppressive effects of URB. Experiment 3 measured the potential of URB to interfere with the establishment of conditioned gaping. RESULTS: When administered before testing, CBD (1 and 5, but not 10 mg/kg) and URB (0.3, but not 0.1 mg/kg) suppressed conditioned gaping. The effect of URB was reversed by pre-treatment with the CB(1) antagonist/inverse agonist, SR141716A. When administered before conditioning, URB also interfered with the establishment of conditioned gaping. CONCLUSIONS: Manipulations of the EC system may have therapeutic potential in the treatment of AN.

Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: An animal model of anticipatory nausea and vomiting.

Chemotherapy patients report not only acute nausea and vomiting during the treatment itself, but also report anticipatory nausea and vomiting upon re-exposure to the cues associated with the treatment. We present a model of anticipatory nausea based on the emetic reactions of the Suncus murinus (musk shrew). Following three pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit conditioned retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with each of the principal cannabinoids found in marijuana, Delta(9)-tetrahydrocannabinol or cannabidiol, at a dose that did not suppress general activity. On the other hand, pretreatment with a dose of ondansetron (a 5-HT(3) antagonist) that interferes with acute vomiting in this species, did not suppress the expression of conditioned retching during re-exposure to the lithium-paired context. These results support anecdotal claims that marijuana, but not ondansetron, may suppress the expression of anticipatory nausea.

[Olanzapine use in cancer patients for refractory vomiting].

Recent investigations suggest the efficacy of olanzapine in cancer patients with intractable vomiting or chemotherapy-induced nausea. Olanzapine,indicated for schizophrenia in Japan, has an affinity for multiple neurotransmitter receptors including dopaminergic, serotonergic, histaminergic, adrenergic and muscarinic receptors. This pharmacological activity thus has a potential role in the treatment of nausea and vomiting. In the present study, olanzapine was given to five cancer patients with refractory vomiting to standard medications. In 3 cases, olanzapine resolved vomiting completely and also improved anorexia, In 2 cases, vomiting was controlled for a limited period. No adverse effect was observed. These results suggest olanzapine is a useful agent for the management of both vomiting and anorexia.

A comparison of novel, selective fatty acid amide hydrolase (FAAH), monoacyglycerol lipase (MAGL) or dual FAAH/MAGL inhibitors to suppress acute and anticipatory nausea in rat models.

RATIONALE: Drugs that block fatty acid amide hydrolase (FAAH, which elevates anandamide [AEA]) and drugs which block monoacylglycerol (MAGL, which elevates 2-arachidonyl glycerol [2-AG]) have promise in treating both acute and anticipatory nausea in human patients. OBJECTIVE: This study aims to evaluate the relative effectiveness of dual MAGL/FAAH inhibition with either alone to reduce acute and anticipatory nausea in rat models. MATERIALS AND METHODS: AM4302, a new dual MAGL/FAAH inhibitor, was compared with a new selective MAGL inhibitor, AM4301, and new selective FAAH inhibitor, AM4303, for their potential to reduce acute nausea (gaping in taste reactivity) and anticipatory nausea (contextually elicited conditioned gaping) in two rat models. RESULTS: Our in vitro studies indicate that AM4302 blocks human and rat FAAH: IC50 60 and 31 nM, respectively, with comparable potencies against human MAGL (IC50 41 nM) and rat MAGL (IC50 200 nM). AM4301 selectively blocks human and rat MAGL (IC50 8.9 and 36 nM, respectively), while AM4303 selectively inhibits human and rat FAAH (IC50 2 and 1.9 nM), respectively. Our in vivo studies show that the MAGL inhibitor, AM4301, suppressed acute nausea in a CB1-mediated manner, when delivered systemically or into the interoceptive insular cortex. Although the dual FAAH/MAGL inhibitor, AM4302, was equally effective as the FAAH inhibitor or MAGL inhibitor in reducing acute nausea, it was more effective than both in suppressing anticipatory nausea. CONCLUSIONS: Dual FAAH and MAGL inhibition with AM4302 may be an especially effective treatment for the very difficult to treat symptom of anticipatory nausea.

[A patient care experience of the psychologically impaired cancer patient against chemotherapy--the successful outpatient case report using a sedative agent to reduce vomiting].

We would like to present a case report on how we managed to reduce an adverse effect of chemotherapy, specifically vomiting and nausea with a sedative agent diazepam, when a patient was intravenously injected with chemotherapeutic agents at the outpatient department. The patient was a 39-year-old female who experienced total hysterectomy and bilateral oophorectomy due to ovarian ca. (stage III) on May 29, 2002. She used to have complained of severe vomiting whenever undergoing 4-day inpatient chemotherapies every month from June 2002 to April 2003. In the last chemotherapy, she suffered vomiting prior to a day before the infusion and after 5 days of the infusion. Because of her experience, the patient refused to undergo the following chemotherapy. Based on discussions with her, use of sedatives was chosen to relieve vomiting. Due to relief of stress, the patient slept and relaxed by means of a sedative effect during and after administration of chemotherapy. Since the reduction of vomiting, she has been accepting further chemotherapies.

Optimum management of nausea and vomiting in cancer chemotherapy.

Nausea and vomiting continue to be critical problems in cancer chemotherapy, although considerable progress has been made toward understanding the neuropharmacological mechanisms of vomiting and how chemotherapeutic agents and antiemetics affect these mechanisms. The principles of behavioural psychology have also been applied in an effort to understand and effectively manage these complications which have potentially serious consequences. For example, there is now some degree of rationality to our use of metoclopramide for cisplatin-induced nausea and vomiting, the use of combination antiemetic regimens, and use of lorazepam for the prevention (albeit unproven) of anticipatory nausea and vomiting. It must be admitted, however, that our approach is for the most part still empirical. Selecting an antiemetic programme is not a simple task. The emetogenic potential of the chemotherapy being used, the presence of coexisting diseases, the potential toxicity of the antiemetic drug and whether antiemetic therapy is to take place in the hospital or in an outpatient setting, the familiarity of the clinician with the various antiemetic therapies, and cost are all factors which need to be considered. Although phenothiazines remain the standard treatment, they are of little value against chemotherapy programmes that produce moderate or severe problems. Newer pharmacological approaches including butyrophenones, cannabinoids, metoclopramide, high-dose corticosteroids, and benzodiazepines have shown increased antiemetic efficacy, as have combinations of these agents which are directed against multiple sites of emetogenic activity. The role of behavioural therapies, which have been shown to be effective particularly in children and in anticipatory nausea and vomiting, needs to be more firmly established. Rather than recommending a given antiemetic programme for any particular chemotherapy, it is preferable to think in terms of initial approaches and how they can be modified. No one antiemetic programme is effective or safe in all situations.

Quality of life issues in lung cancer. New symptom management strategies.

Diagnosis and treatment of lung cancer can significantly affect a patient's quality of life. Survival rates are dismal, but improvements have been made in dealing with common symptoms and side effects. This article reviews the nature of the problem, pertinent risk factors, and symptoms associated with nausea and vomiting, cachexia, hypercalcemia, and pain. Physicians, nurses, and other health care professionals can play a vital role in the identification and management of these complications, and thereby help to improve quality of life.

Tetrahydrocannabinol (THC) interferes with conditioned retching in Suncus murinus: an animal model of anticipatory nausea and vomiting (ANV).

Little is understood about effective countermeasures to the expression of anticipatory nausea and vomiting (ANV) in chemotherapy patients. We present a model of ANV based on the emetic reactions of the Suncus murinus (musk shrew). Following two pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with THC at a dose that did not suppress general activity. This provides the first experimental evidence in support of anecdotal reports that THC suppresses ANV.

[Antiemetic effect of ondansetron in recurrent chemotherapy with cisplatin]. / Effet antiémétique de l'ondansétron au cours de cures répétées de chimiothérapies contenant du cisplatine.

Six hundred and twenty-eight courses of cisplatin containing chemotherapy were recorded in patients receiving up to three courses of cytotoxic drugs with ondansetron (OND) given as an antiemetic agent (32 mg as a single iv dose or as a continuous infusion). The sample size of patients decreases from one course to another due to phenomena which may or may not be related to the chemotherapy and the anti-emetic treatment or to the evolution of the cancer disease. For patients with incomplete response to ondansetron, withdrawals could be related to an insufficient antiemetic effect as is known with other antiemetic drugs. Conversely, it is not the case for patients who had a complete response. Therefore, to avoid any bias due to patient selection, the analysis is based on the probability of changes from complete to incomplete response or from complete to complete response between two subsequent courses (i and i + 1). The response to OND treatment for the course i + 1 depends not only on the efficacy during this course (i + 1) but also on the response during the prior course (i). A discrete time-dependent statistical model (Markov chain) was used to test the evolution of the probability of remaining in complete response. This probability was equal to 66% between the first and the second course, and to 88% between the second and the third one. The probability of remaining in complete response significantly increased during repeated courses (P = 0.001). These results show that in patients for whom OND treatment allows a complete antiemetic control during the first course of chemotherapy, the probability of remaining with no emetic episodes at all increases during the two subsequent courses.

5-HT3 receptors and the therapeutic potential of 5-HT3 receptor antagonists.

5-HT3 receptors have been the focus of much research during the last decade. They are characterised by being located on neurones both peripherally and centrally; 5-HT3 agonists cause a rapid depolarisation of the membrane potential which results from the opening of cation channels; the 5-HT3 response rapidly desensitizes. 5-HT3 receptors appear to have a modulatory role on other neurotransmitters. The identification of selective agonists and antagonists for this receptor type has allowed the discovery of several important new therapeutic applications. The use of 5-HT3 receptor antagonists in psychoactive illnesses is being explored clinically. In addition, ondansetron, a selective 5-HT3 receptor antagonist, is already being used to prevent the severe nausea and vomiting caused by cancer chemotherapy and radiotherapy. The pharmacological properties of 5-HT3 antagonists are discussed in this chapter.

[Antiemetic treatment with metoclopramide and high-dose lorazepam and additional long-term treatment with lorazepam during CDDP administration].

We studied the antiemetic effects of a combination therapy consisting of metoclopramide (MCP) and high-dose lorazepam (HiLor; 3-4.5 mg/day) in patients with lung cancer who were being treated with cis-diamminedichloroplatinum (CDDP). This study was designed in order to compare the antiemetic efficacy of two different-term treatments. In the short-term treatment, MCP and HiLor were given for three days after the beginning of the CDDP regimen (group 1). In the long-term treatment (group 2), the same dose of MCP and a decreased dose of HiLor (1.5-3 mg/day) were administered for another three days (eventually for 6 days). Thirty-one trials were evaluated in eighteen patients for 8 days after the CDDP treatments initiated. The frequency of episodes of vomiting was less than two times in 70% and 82% of trails, in group 1 and group 2, respectively. This finding indicates that the combination therapy of MCP and HiLor for a long period would be the same or more effective than that of MCP and steroid agents. Furthermore, in group 2, the frequency and severity of late emesis were significantly less than in group 1, and appetite recovery was observed significantly earlier than in group 1. There was no side effect related to the administration of MCP and HiLor during this study. These findings suggested that the combination treatment of MCP and HiLor with a decreased dose of HiLor for a long period was markedly effective for antiemesis in patients treated with CDDP, especially for the prophylaxis of CDDP-induced late emesis.

[Examination on efficacy and safety of concurrent use of ondansetron hydrochloride and steroid in gynecological cancer patients on cisplatin].

The anti-emetic effect and safety in patients receiving ondansetron hydrochloride (OND group) and ondansetron and dexamethasone (DEX group) concurrently in cases of acute and delayed onset emesis induced by a single high dose of cisplatin, given as a chemotherapy to gynecological cancer patients, were comparatively studied. The study subjects were 139 gynecological cancer patients. The OND group received 4 mg of ondansetron via slow intravenous injection on Day 1, 30 minutes prior to cisplatin, and for Days 2 to 5, the subjects orally received 4 mg ondansetron tablet each day. The DEX group received the same dose regimen of ondansetron as the OND group for Days 1-5, but in addition the subjects received dexamethasone injection in doses of 8 mg twice daily on Day 1 and 4 mg (1 mg QID) daily for Days 2-5. An anti-emetic effect against acute nausea and vomiting was achieved in 47.9% of the OND group and in a higher rate of 84.2% of the DEX group. Significantly better efficacy was seen in the DEX group also in the complete suppression rate of nausea and vomiting and the improvement of food intake. The group also achieved better efficacy in delayed onset of emesis. Adverse reactions were observed in 2 cases (2 reports of headache) in the OND group and 5 cases (2 reports of hiccups, 2 headache, 2 diarrhea, one constipation, one hot facial flushes and one elevation of gamma-GTP) in the DEX group; however, since the symptoms were all mild, we did not consider there was any problem in safety. We conclude from the above findings that concurrent administration of ondansetron hydrochloride and dexamethasone is a clinically useful treatment for acute and delayed onset emesis induced by a single high dose of cisplatin given to gynecological cancer patients.

[Clinical evaluation of granisetron hydrochloride for nausea and vomiting induced by oral anticancer drugs].

We investigated the antiemetic effect, safety and usefulness of granisetron hydrochloride tablets on nausea and vomiting induced by oral anticancer drugs used in chemotherapy for gastric cancer and colorectal cancer. In the present trial, oral administration of granisetron hydrochloride was performed during 5 days after nausea or vomiting. 1) Clinically, the effective rate of granisetron hydrochloride (the percentage of cases in which the drug was assessed as "Remarkably effective" or "Effective") was more than 75% on each day of administration. There were no adverse events or abnormal laboratory tests. 2) In terms of usefulness, granisetron hydrochloride was rated "Extremely useful" or "Useful" in 17 out of 23 cases (78.2%). The above results have shown that granisetron hydrochloride tablets, administrated orally once daily at a dose of 2 mg, have an excellent antiemetic effect, and that this is a safe and useful drug.

[Anti-emetic treatment for patients with lung cancer after chemotherapy, and usefulness of prochlorperazine for psychiatric emesis].

Clinical study of cisplatin 80 mg/m2 and other agents was undertaken to determine whether they could prevent psychiatric emesis during chemotherapy in 50 patients with lung cancer. YG character tests revealed that 9 patients had a coupled rightward shift in N (nervous) and I (inferior complex) components, and were classified as emotionally unstable. In these 9 cases, addition of 15 mg prochlorperazine to the preventive combined administration of 3 mg granisetoron, 500 mg methylpredonisolon, and 40 mg metoclopramide decreased the post-chemotherapy psychiatric emesis from 100% in 3 control cases to 16.7% in 6 added cases. In the remaining 41 cases, the preventive combined administration alone was effective. The good control of acute emesis is the first priority in emotionally unstable patients. The addition of prochlorperazine might be a useful therapy for psychiatric emesis induced by anticancer agents in emotionally unstable patients.

[Chronological observation of nausea and vomiting in outpatients given oral antimetabolites as chemotherapy--two patients receiving ondansetron hydrochloride tablets].

The incidence of nausea and vomiting or anorexia was investigated in 16 outpatients receiving oral antimetabolites such as 5-FU (fluorouracil) as chemotherapy, during a maximum observation period of 28 days. In those patients who experienced the above symptoms which meet the standard defined in the study protocol, ondansetron hydrochloride tablets in a 4 mg/day dose were given based on the decision of the physician in charge, and its efficacy in those patients was examined. Nausea and emesis or anorexia was observed in six cases (37.5%) during the period of observation. Anorexia appeared in a majority of the above cases, with an incidence rate was 31.3% (5/16 cases). In two of the cases, anorexia improved after ondansetron tablets were administered. No adverse drug reaction was reported with ondansetron tablets. We conclude that although antimetabolites have low emetogenicity, as anorexia appeared in approximately 30% of the patients, the use of ondansetron tablets or other antiemetics should be considered in order to maintain patients' QOL and drug compliance.

[Pharmacokinetics of azasetron (Serotone), a selective 5-HT3 receptor antagonist].

5-HT3 receptor antagonists have been established in a number of clinical trials as effective agents in the management of nausea and vomiting induced by cancer chemotherapy including cisplatin. Azasetron (Serotone) is a potent and selective 5-HT3 receptor antagonist, and classified as benzamide derivative. It has a different chemical structure from indole-type 5-HT3 receptor antagonists such as granisetron, ondansetron, ramosetron and tropisetron. The major difference is found in the pharmacokinetic profiles. Approximately 60-70% of azasetron administered i.v. and orally is excreted in urine as the unmetabolized form. Also, orally-administered azasetron has shown to be absorbed and/or secreted by the saturable transport mechanism in the small intestine, resulting in good bioavailability as approximately 90%. In this report, the relationship between the structure of 5-HT3 receptor antagonists (especially azasetron) and their pharmacokinetics were described.

[Clinical evaluation of granisetron (BRL43694) in nausea and vomiting induced by anticancer drugs--pediatrics].

Granisetron has been used widely for the prevention and treatment of nausea and vomiting associated with anticancer drugs in adult patients with cancer. This multi-center open study was conducted to study the efficacy, safety and usefulness of granisetron in children with cancer. Among 166 evaluable patients, the efficacy rate (percentage of "remarkably effective" or "effective") was 84.9% and the usefulness rate (percentage of "extremely useful" or "useful") was 87.3%. No serious adverse effects were observed. As granisetron 40 micrograms/kg had an excellent antiemetic effect and a high degree of safety against nausea and vomiting associated with anticancer drugs, it was shown to be useful for children with cancer.

[Effect of ondansetron hydrochloride injection and tablet against nausea and vomiting in lung cancer patients receiving carboplatin].

We investigated the efficacy of combination of ondansetron hydrochloride injection and tablet against nausea and vomiting in 22 lung cancer patients (total number of chemotherapy courses: 23) receiving chemotherapy of single-dose carboplatin (CBDCA) at a dose of 302.2 +/- 31.9 mg/m2. For suppressing emesis, the patients were given 4 mg of ondansetron injection on the day of CBDCA injection (Day 1), and 4 mg/day of ondansetron tablet for Days 2 to 5. The following results were obtained 5 days after the administration of carboplatin. 1) Control of nausea graded 'Good' or better counted for 95% or higher of all cases for each day of the chemotherapy. A complete nausea suppression rate was seen in 91.3%, 81.0%, 71.4%, 63.6% and 71.4% from Day 1 to Day 5, respectively. 2) Control of vomiting graded 'Major' control or better was achieved in 95% or more of all cases, for each day. The complete vomiting suppression rate observed from Day 1 to Day 5 was 91.3%, 78.3%, 65.2%, 69.6% and 91.3%, respectively. 3) Inhibitory effect on nausea and vomiting for each day of Days 1 to 5 graded as 'Effective' or better was shown in 90% or higher of all cases; based on overall judgement for Days 1 to 5, all cases were graded as 'Effective' or better. 4) The proportion of cases which was evaluated as 'Can eat most of the meal' was 88.0%, 73.9%, 50.7%, 50.7% and 65.2% from Days 1 to 5, respectively, against 95.7% prior to the start of chemotherapy. 5) No adverse drug reaction or abnormal clinical laboratory values were seen along with ondansetron. 6) In conclusion, combined treatment with ondansetron injection and tablet was considered clinically useful in control of nausea and vomiting during administration of carboplatin, and may also be useful for out-patient chemotherapy.