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.

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.

Anticipatory nausea and vomiting due to chemotherapy.

As a specific variation of chemotherapy-induced nausea and vomiting, anticipatory nausea and vomiting (ANV) appears particularly linked to psychological processes. The three predominant factors related to ANV are classical conditioning; demographic and treatment-related factors; and anxiety or negative expectancies. Laboratory models have provided some support for these underlying mechanisms for ANV. ANV may be treated with medical or pharmacological interventions, including benzodiazepines and other psychotropic medications. However, behavioral treatments, including systematic desensitization, remain first line options for addressing ANV. Some complementary treatment approaches have shown promise in reducing ANV symptoms. Additional research into these approaches is needed. This review will address the underlying models of ANV and provide a discussion of these various treatment options.

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.

[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.

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.

[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.

[Management of nausea, vomiting and anorexia due to anticancer agents].

This report outlines measures for controlling nausea, vomiting, and anorexia caused by anticancer agents. Combination therapy with a 5-hydroxytryptamine (5-HT3) receptor antagonist and a steroid preparation is effective for controlling acute vomiting. In the chronic stage, however, the response to 5-HT3 receptor antagonists is less marked, so a steroid preparation is used as the major treatment in combination with a 5-HT3-receptor antagonist or metoclopramide. The antiemetic effect of recently developed tachykinin NK-1 (NK-1)-receptor antagonists has been shown to be additive to that of existing treatments for acute and chronic symptoms, especially chronic nausea/vomiting. Steroid preparations have been shown to improve anorexia, while medroxyprogesterone acetate (MPA: a synthetic progesterone) has been reported to improve anorexia and promote weight gain.

[Incidence of emesis in outpatients on chemotherapy for breast cancer and the clinical efficacy of ondansetron hydrochloride tablets].

The incidence of nausea and vomiting was investigated for a maximum of 7 days in 32 breast cancer patients receiving CAF (cyclophosphamide, adriamycin, 5-fluorouracil) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) therapies. For those patients who experienced nausea and vomiting, 4 mg/day of ondansetron hydrochloride (OND) in tablet form was given in the next course of the chemotherapy, and the anti-emetic effect of the drug was examined. During the observation period, nausea was seen in 17.2-50.0% of the patients and vomiting in 3.1-15.6%. The number of patients who had nausea and vomiting was 22. The anti-emetic effect was examined in 18 out of 22 cases with nausea and vomiting. An anti-emetic effect based on the judgement criterion (efficacy rate) was seen in 94.4% or more of patients for all the days of observation. A marked effect was seen in higher proportion of patients. In conclusion, nausea and vomiting occurred in 17.2-50.0% of the breast cancer patients on chemotherapy (CAF and CMF therapies). To improve the QOL of those patients, anti-emetic treatment using OND tablets as necessary is considered to be effective.

[Clinical usefulness of ondansetron hydrochloride for nausea and vomiting during repeated courses of chemotherapy for malignant lymphoma--impact of prognosis announcement on anti-emetic effect and evaluation of patient perception of chemotherapy-associated adverse events].

We evaluated the efficacy and safety of ondansetron hydrochloride (OND) on nausea and vomiting during repeated courses of CHOP or ACOMP-B therapy in patients with malignant lymphoma. The impact of the prognosis announcement on the anti-emetic effect and chemotherapy-associated adverse events was also investigated. Forty-two subjects with malignant lymphoma who underwent CHOP or ACOMP-B therapy including cyclophosphamide 600 mg/m2 and adriamycin 40 mg/m2 were investigated for a maximum of 6 courses. For acute nausea and vomiting, ondansetron was injected intravenously before the start of chemotherapy on the first day of each course of chemotherapy. For delayed emesis, ondansetron was administered orally for 4 days from the following day. The efficacy on acute nausea and vomiting was found to be 95.0% (1st course), 95.0% (2nd course), 90.9% (3rd course), 88.2% (4th course), 92.3% (5th course) and 91.7% (6th course), respectively. A high efficacy of > or = 85% was also obtained for delayed nausea and vomiting on each day. Though the adverse event of elevated GPT value developed in one subject. It was mild and resolved. No difference in efficacy was seen with or without announcement of prognosis to patients. Following the investigation on antiemetic effect, patient perception of chemotherapy-induced adverse events was evaluated. The most common event was hair loss, followed by taste abnormality and numbness and hyposthesia of the tips of the fingers. The incidence of nausea and vomiting was the 4th and 5th most common, which are less frequent than in the report of Coates in 1983. In conclusion, ondansetron is considered clinically useful with stable anti-emetic effect on both acute and delayed nausea and vomiting over repeated courses of chemotherapy, without any significant safety problem.

[Development of a Japanese version of the FLIE].

Nausea and vomiting induced by chemotherapy have an impact on cancer patients' quality of life (QOL). The Functional Living Index-Emesis (FLIE), which is designed to assess the change in QOL from the influence of nausea and vomiting is rarely used in Japan, regardless of its utility, because it is written in English. We investigated the use by cancer patients with the main object of designing a reliable and valid Japanese version of the FLIE. We also verified the validity of a Japanese translation and improved part to design a highly precise Japanese version FLIE. Consequently, we found a correlation between the FLIE Japanese version and the QOL questionnaire Quality of Life Assessment of Cancer Patients Receiving Chemotherapy (QOL-ACPRC), which was the external standard. Furthermore, we improved the questionnaire to raise the rate of patient response, and improve reliability and validity. We think that this FLIE Japanese version will become useful in assessing the change in patient QOL due to the influence of nausea and vomiting.

[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.

[Evaluation of efficacy of ramosetron orally disintegrating tablets and patient preference as to the dosage form in gynecological cancer chemotherapy].

The efficacy of an oral 5-HT3 antagonist, ramosetron orally disintegrating tablet (ODT), in the treatment of chemotherapy-induced emesis was investigated in 21 female patients with cancer. Patient preference for the dosage form was also investigated. Eighteen (85.7%) of 21 patients answered that ODT is easy to take. Eleven (68.8%) of 16 patients who had previously taken granisetron tablets preferred ramosetron ODT to conventional tablets. The complete suppression rate of nausea or vomiting was more than 90% for 6 days. No adverse drug reactions associated with ramosetron were observed. As ambulatory or home chemotherapy becomes frequent, the use of oral 5-HT3 antagonists rather than intravenous agents will be increased. Chemotherapy for elderly cancer patients is becoming frequently used. Considering these circumstances, it is suggested that ramosetron ODT is a palatable and useful treatment of chemotherapy-induced emesis.

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

The anti-emetic effect and safety in patients receiving ondansetron hydrochloride (OND group) and concurrent use of ondansetron and dexamethasone (DEX group) in cases of acute and delayed onset emesis induced by a single high dose of cisplatin, given as a chemotherapy to lung cancer patients, were comparatively studied. The study subjects were 78 lung 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 83.8% of the OND group and in a higher rate of 94.6% of the DEX group. Significantly better efficacy was seen in the DEX group as to 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. Two cases of adverse reactions (hiccups and elevation of ALT and BUN) were observed 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 lung cancer patients.

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.

[Prevention and treatment of the side effects of cancer chemotherapy].

Management of the side effects of chemotherapy in cancer patients is important because side effects can affect the tolerability and continuation of therapy, in addition to lowering the quality of life of patients. A significant efficacy of serotonin receptor antagonists against nausea and vomiting due to cancer chemotherapy, and granulocyte colony-stimulating factor against neutropenia secondary to chemotherapy, has been recently demonstrated. New chemoprotective drugs have been developed, such as amifostine for cisplatin-induced nephrotoxicity and neurotoxicity, and dexrazoxane for cardiac toxicity due to anthracyclines. Antiviral agents including lamivudine and interferons suppress virus replication, preventing the development of fulminant hepatitis during chemotherapy in cancer patients who have chronic hepatitis B infection. Various supportive therapies have resulted in the advance of cancer chemotherapy.

[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.