Control Of Vomiting Research Articles

Arvanil, anandamide and N‐arachidonoyl‐dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret

Cannabinoid (CB) agonists suppress nausea and vomiting (emesis). Similarly, transient receptor potential vanilloid-1 (TRPV1) receptor agonists are anti-emetic. Arvanil, N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide, is a synthetic 'hybrid' agonist of CB1 and TRPV1 receptors. Anandamide and N-arachidonoyl-dopamine (NADA) are endogenous agonists at both these receptors. We investigated if arvanil, NADA and anandamide were anti-emetic in the ferret and their mechanism of action. All compounds reduced the episodes of emesis in response to morphine 6 glucuronide. These effects were attenuated by AM251, a CB1 antagonist that was pro-emetic per se, and TRPV1 antagonists iodoresiniferatoxin and AMG 9810, which were without pro-emetic effects. Similar sensitivity to arvanil and NADA was found for prodromal signs of emesis. We analysed the distribution of TRPV1 receptors in the ferret brainstem and, for comparison, the co-localization of CB1 and TRPV1 receptors in the mouse brainstem. TRPV1 immunoreactivity was largely restricted to the nucleus of the solitary tract of the ferret, with faint labeling in the dorsal motor nucleus of the vagus and sparse distribution in the area postrema. A similar distribution of TRPV1, and its extensive co-localization with CB1, was observed in the mouse. Our findings suggest that CB1 and TRPV1 receptors in the brainstem play a major role in the control of emesis by agonists of these two receptors. While there appears to be an endogenous 'tone' of CB1 receptors inhibiting emesis, this does not seem to be the case for TRPV1 receptors, indicating that endogenously released endocannabinoids/endovanilloids inhibit emesis preferentially via CB1 receptors.

Tropisetron, Ondansetron, and Granisetron for Control of Chemotherapy-Induced Emesis in Turkish Cancer Patients: A Comparison of Efficacy, Side-Effect Profile, and Cost

Background: Tropisetron, ondansetron, and granisetron are considered equally efficacious, supported by several international studies. However, there are interindividual variations in their metabolism that could affect efficacy. The clustering of such variations may change from one to another nation. Therefore, their equality must be validated in Turkish patients. The aim of this study was to compare their efficacies, side-effect profiles, and costs in the prophylaxis of emesis induced by moderate to high emetogenic chemotherapies. Methods: A total of 158 patients with a median age of 48 years, 115 (72.8 percent) female and 43 (27.2 percent) male, were included, respectively. Fifty-one, 61, and 46 patients were allocated to tropisetron (5 mg), ondansetron (8 mg), and granisetron (3 mg IV) in combination with 8 mg dexamethasone, which were continued 5 mg once a day, 8 mg b.i.d. and 1 mg b.i.d. PO for 5 days, respectively. Results: The complete response (CR) rates in the control of acute emesis were 80.4 percent with tropisetron, 72.1 percent with ondansetron, and 71.7 percent granisetron (p = 0.877). CR rates in delayed emesis (Days 2–5) were 68.6 percent, 68.9 percent, and 76.1 percent, respectively (p = 0.527). Rates of freedom from nausea in the same period were 37.3 percent, 35.9 percent, and 33.9 percent (p = 0.949). Nausea control rates, side-effect profile did not differ. However, headache seemed to be encountered higher (45.6 percent) in Turkish patients than others (3.9–9 percent). Tropisetron is the least expensive one ($95.3 per cycle) according to current prices in Turkey. Conclusions: There were no differences among the 3 serotonin antagonists with respect to efficacy and frequency of side-effects in our patients. Tropisetron is the least expensive at current prices. The choice may be based on other parameters, such as ease of administration and patient preference.

Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat

The endogenous cannabinoid system plays a vital role in the control of nausea and emesis. Because of the rapid breakdown and hydrolysis of endocannabinoids, such as anandamide, the therapeutic effects may be enhanced by prolonging their duration of action. The present experiment evaluated the potential of various doses of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, alone and in combination with systemic administration of anandamide to modulate the establishment of lithium-induced conditioned taste reactivity responses in rats. In experiment 1, on the conditioning day, rats first received an injection of 0.3 mg/kg URB597, 0.15 mg/kg URB597, or vehicle and then received a second injection of anandamide (5 mg/kg) or vehicle, before a 3-min exposure of 0.1% saccharin by intraoral infusion. Immediately after the saccharin exposure, the rats were injected with lithium chloride. On each of three test days, rats received a 3-min intraoral infusion of saccharin solution, and the taste reactivity responses were videotaped and monitored. In experiment 2, the effects of pretreatment with the CB(1) antagonist, AM-251, on URB597 and anandamide-induced suppressed aversion was evaluated. Administration of URB597 alone and in combination with anandamide reduced active rejection reactions elicited by a LiCl-paired saccharin solution; both effects were reversed by pretreatment with AM-251, suggesting that they were CB(1) receptor mediated. The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat.

Morphine/ondansetron PCA for postoperative pain, nausea, and vomiting after skull base surgery

Patients who underwent skull base procedures have been noted to experience appreciable pain. This study examines pain after surgery and the effectiveness of patient controlled analgesia (PCA) with combination morphine ondansetron for analgesia and control of emesis. A total of 120 skull base surgery patients were randomized to receive placebo, morphine, or morphine ondansetron. Demographic and intraoperative variables were recorded along with pain, nausea, vomiting, and rescue analgesics. Total PCA use, hospital stay, satisfaction, and cost were also compared. Demographically the groups were similar. Pain was elevated with placebo PCA, and this group averaged twice as many analgesic rescues. Total usage time was lower with placebo PCA. Morphine ondansetron PCA had the lowest pain score with highest satisfaction. Nausea and vomiting was similar but female patients had more vomiting regardless of PCA group. The use of morphine PCA reduced pain and did not appreciably increase nausea or vomiting. The addition of ondansetron produced no real benefit and its PCA use cannot be justified. A-1b.

5-Hydroxytryptamine-3 Receptor Antagonist With or Without Short-Course Dexamethasone in the Prophylaxis of Radiation Induced Emesis: A Placebo-Controlled Randomized Trial of the National Cancer Institute of Canada Clinical Trials Group (SC19)

To evaluate the effectiveness of prophylactic dexamethasone for the control of radiation induced emesis (RIE) when added to ondansetron during days 1 to 5 of fractionated radiotherapy. The study had two hypotheses: ondansetron and dexamethasone could provide superior control of RIE over ondansetron alone during the prophylactic period and; the combination could provide sustained control of RIE during subsequent fractions of radiotherapy. Between May 2001 to Jan 2004, 211 patients receiving radiotherapy (> or = 15 fractions) to the upper abdomen were randomly assigned to receive ondansetron 8 mg bid with either dexamethasone 4 mg daily or placebo during fractions 1 to 5. Rescue antiemetics were provided. During the prophylactic period there was a trend for improved complete control of nausea in the dexamethasone arm (50% v 38%; P = .06) while complete and partial control of emesis, average nausea score, and use of rescue medications were similar in the two groups. During the overall study period patients receiving dexamethasone had better complete control of emesis (23% v 12%; P = .02) and a lower average nausea score (0.28 v 0.39; P = .03); there was a trend towards less use of rescue medications with dexamethasone (70% v 80%; P = .09); other outcomes were similar on the two arms. Quality of life analysis showed a significant difference in appetite. The addition of dexamethasone to ondansetron as prophylaxis provides a modest improvement in protection against RIE during moderately emetogenic fractionated radiotherapy. It is a potentially useful addition to 5-hydroxytryptamine-3 receptor antagonists in this setting.

Aprepitant as salvage antiemetic therapy in breast cancer patients receiving doxorubicin and cyclophosphamide (AC)

8618 Background: Aprepitant (APR), a neurokinin-1 receptor antagonist, has efficacy in the prevention of nausea and vomiting (NV) in breast cancer (BC) patients (pts) receiving doxorubicin (A) and cyclophosphamide (C) (JCO 2005, 23:2822). Nevertheless, many pts continue to receive only 5-hydroxytryptamine antagonists and dexamethasone (doublet therapy) during cycle 1 of AC. APR is often used as a salvage treatment, with anecdotal reports of improved outcome. We sought to prospectively evaluate this issue in a phase II trial. Methods: Design: multicenter study funded by an unrestricted grant from Merck. Eligibility: BC pts receiving their first cycle of A (≤ 60 mg/m2) and C (≥ 500 mg/m2) on day (d) 1. Antiemetics: ondansetron 8mg IV/PO, or dolasetron 100 mg IV/PO, or granisetron 1 mg IV or 2 mg PO on d 1; and dexamethasone (dex) 8–10 mg IV/PO d 1 and 4 mg PO bid d 2–3. Pts without complete control (no emesis, nausea, or rescue antiemetics) during cycle 1 could continue to cycle 2.During cycle 2, pts again received AC and identical antiemetics (except dex only 4 mg qd d 2–3) plus APR 125 mg PO d 1 and 80 mg PO d 2–3. Data on nausea (4-point scale), emesis and rescue was collected with a pt-report diary. Primary end point: proportion of pts with complete control (CC) during the 120-hours after chemotherapy. Secondary endpoints included acute (< 24 hrs), delayed (24–120 hrs) CC and complete response (no emesis or rescue) Results: Pts: total (47), female (47), eligible (46), analyzed (42), still on study (4). Median age: 49 yrs. CC during cycle 1: 8 pts (19%). Thirty-four pts continued to cycle 2. During cycle 2, 7 pts (21%)(95% CI 9–38%) achieved CC and 13 pts (38 %) complete response (CR) for the 120-hour study period. Acute CR and delayed CR rates for cycles 1 and 2 were 32%(11 pts) vs 68% (23 pts) (p=0.01) and 12%(4 pts) vs 44% (15 pts) (p=0.02) respectively. No emesis rates were 38 vs 79 % during cycles 1 and 2 respectively(p=0.02). The proportion of pts with no nausea or severe nausea for cycles 1 and 2 were 0 vs 21% and 12 vs 3 % respectively. Conclusions: The addition of APR to standard doublet therapy improves antiemetic outcome in BC pts receiving AC who failed to achieve CC during cycle 1 with standard doublet therapy alone. Improvement is seen in the control of emesis and nausea. APR was well tolerated. [Table: see text]

Acute and delayed nausea and emesis control in pediatric oncology patients

To the authors' knowledge there is little information available regarding the effectiveness of standard antiemetic therapy among cancer patients who receive emetogenic chemotherapy in clinical practice, especially in the pediatric population. The current study was undertaken to determine the effectiveness of standard antiemetic interventions among children receiving emetogenic chemotherapy. The authors conducted a retrospective review of antiemetic surveys for children who received emetogenic chemotherapy. Patients and/or their parents were surveyed for acute and delayed nausea and emesis after each course of emetogenic chemotherapy. The survey consisted of validated measures of the severity of nausea and emesis. Complete protection (CP) rates were calculated for each chemotherapy regimen during both the acute and delayed phases and also by gender and age group (ages birth-3 yrs, 4-11 yrs, and 12-20 yrs). Antiemetic therapy consisted of intravenous ondansetron administered once daily during chemotherapy either alone (for moderately emetogenic chemotherapy) or in combination with dexamethasone (for severely emetogenic chemotherapy). In total, 224 different patients completed 1256 surveys. CP from both acute and delayed nausea and emesis was more likely in the children ages birth-3 years than in older children. For moderately emetogenic regimens, nausea and emesis in the acute and delayed phases were controlled well. Among severely emetogenic chemotherapy regimens, 7 of 12 different regimen types had CP rates < 50% in either the acute phase or the delayed phase. CP rates were particularly low for cisplatin-based and cyclophosphamide-based regimens. Nausea and emesis remain significant problems among children who receive emetogenic chemotherapy. CP rates were associated significantly with patient age, and higher rates were observed among very young children.

Effects of General Anesthesia on Anandamide Blood Levels in Humans

The endocannabinoid system includes G-protein-coupled cannabinoid receptors, the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and multiple enzymes involved in the biosynthesis and degradation of endocannabinoids, including the anandamide metabolizing enzyme fatty acid amide hydrolase. Endocannabinoids play an important role in the physiologic control of sleep, pain processing, and emesis. The authors therefore investigated the effects of general anesthesia on the endocannabinoid system in humans. The authors measured whole blood levels of anandamide in 12 patients after induction of general anesthesia with etomidate (an agent shown to have no effect on anandamide levels) and maintenance of anesthesia with the volatile agent sevoflurane as well as in 12 patients undergoing total intravenous anesthesia with propofol, a known inhibitor of fatty acid amide hydrolase in the mouse brain. Anandamide levels were measured using high-performance liquid chromatography-tandem mass spectrometry at four time points (before and at 10, 20, 30, and 40 min after induction of anesthesia). Patients of the sevoflurane group showed a significant decline in anandamide levels from induction of anesthesia to 40 min after induction, whereas anandamide levels in patients of the propofol group remained unchanged (type III sum of squares = 1725.66, F = 162.60, P < 0.001, repeated-measures analysis of variance). General anesthesia influences the endocannabinoid system in a drug-dependent way, which may explain side effects of general anesthetics such as psychomimetic and antiemetic properties of propofol and the high incidence of postoperative nausea and vomiting after volatile anesthetics. These findings suggest new targets for anesthetic drug development.

Update on anti‐emetics for chemotherapy‐induced emesis

The need to control chemotherapy-induced emesis has stimulated research into anti-emetics. Emesis is not only unpleasant, but negatively impacts on global quality of life. The development of two new classes of drugs has been responsible for the major advances in anti-emesis. The 5 hydroxytryptamine3 (5HT3) antagonists in combination with dexamethasone significantly improved the control of acute post chemotherapy emesis, but delayed emesis which can last for several days was still problematic, yet its incidence was underestimated by clinicians. Both the control of acute and delayed emesis was improved when the neurokinin1 (NK1) receptor antagonists were added to 5HT3 antagonists and steroids. The complete control of delayed emesis was improved by 21% with little toxicity. The triple drug combination has become the standard of care for preventing the emesis associated with cytotoxic drugs of high emetic potential.

5‐hydroxytryptamine type‐3 receptor antagonists for chemotherapy‐induced and radiotherapy‐induced nausea and emesis

Nausea and emesis as a consequence of chemotherapy or radiotherapy can have an adverse effect on patients' quality of life during cancer treatment and may last for > 5 days after administration. Guidelines suggest that, used at appropriate doses, the 5-hydroxytryptamine type-3 (5-HT3) receptor antagonists--which are considered the antiemetic "gold standard" when they are administered in combination with corticosteroids--demonstrate equivalent efficacy and safety. However, due to financial considerations, these agents often are used at lower doses than recommended. A literature review of relevant publications pertaining to the control of chemotherapy-induced nausea and emesis and dosing issues of the 5-HT3 receptor antagonists was undertaken to provide a comprehensive review of dosing issues relevant to the 5-HT3 receptor antagonists. The issue of "down dosing" was particularly pertinent because of the nature of the 5-HT3 receptor antagonist dose-response curve: A steep dose-response profile within a narrow dose range suggests that antiemetic control will be lost suddenly after dose deescalation. However, the array of predisposing and confounding patient factors indicates that it is unlikely that a loss of antiemetic control will be apparent across a population; rather, individuals will experience loss of control as the dose is reduced below threshold. Of the 4 5-HT3 receptor antagonists currently licensed in the United States (granisetron, ondansetron, dolasetron, and palonosetron), ondansetron is used sometimes at lower than optimal doses, and there is evidence to suggest that even the approved oral dose of dolasetron may be suboptimal. Suboptimal dosing not only will be detrimental to patients' quality of life but, ultimately, will prove counterproductive in terms of hospital resources, and it will add to the already significant socioeconomic burden associated with cancer therapy. Therefore, the dose of antiemetic agent administered should be sufficiently high to ensure good emesis control across the whole patient population.

The development of a prediciton index for patients at high risk of severe chemotherapy induced nausea and vomiting

8156 Background: Despite modern antiemetic therapy, 20% to 40% of cancer patients receiving chemotherapy fail to achieve complete control of emesis. Several risk factors for acute and delayed nause...

Tropisetron: Optimal dosage for children in prevention of chemotherapy‐induced vomiting

The antiemetic efficacy and tolerability of Tropisetron (Navoban, Novartis Pharma Switzerland AG, Bern), a selective 5-hydroxytriptamine receptor antagonist, has been assessed in the prevention of acute vomiting in children receiving chemotherapy for solid tumors. Tropisetron iv was given 30 min before administration of chemotherapy at a dose of 5 mg in children <20 kg body weight and at a dose of 10 mg in those >20 kg. A total of 50 children were studied in 189 courses of chemotherapy. Control of emesis was defined as total in absence of acute vomiting, as major if 1 or 2 events of acute vomiting occurred, and as not controlled if >2 events of acute vomiting occurred. Response was studied, taking into account Tropisetron dosage, degree of emetogenicity of the chemotherapeutic agents in pretreated and non-pretreated patients, and according to age groups. Tropisetron, administered in a single daily dose of 8-12 mg/m(2), was found to be very effective in completely controlling acute emesis in 92% of the courses of moderately and highly emetogenic chemotherapy administered to pediatric patients with solid tumors. Moreover, Tropisetron, at this dosage, did not lead to any adverse effects.

Antiemetic Activity of FK1052, a 5-HT3- and 5-HT4-Receptor Antagonist, in Suncus murinus and Ferrets

We investigated the effect of FK1052 [(+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride], a 5-HT3- and 5-HT4-receptor antagonist, on the emesis induced by motion stimuli, copper sulfate, or cisplatin in either Suncus murinus or ferrets and also clarified the role of the 5-HT3 and 5-HT4 receptors in these models. In Suncus murinus, oral administration of FK1052 (100 µg/kg) completely prevented emesis induced by cisplatin (18 mg/kg, i.p.). Intraperitoneal injection of scopolamine (10 mg/kg) and promethazine (32 mg/kg), but not FK1052 (1 mg/kg), significantly reduced the emetic responses by motion stimuli. In ferrets, copper sulfate (40 mg/kg, p.o.)-induced emesis was moderately prevented by FK1052 (3.2 mg/kg), but not by granisetron (3.2 mg/kg). Cisplatin-induced acute (10 mg/kg, i.v.) and delayed (5 mg/kg, i.p.) emesis were significantly reduced by single and multiple intravenous injection of both FK1052 (3.2 mg/kg) and granisetron (3.2 mg/kg), respectively. The present study suggests that FK1052 may be useful against both acute and delayed emesis induced by cancer chemotherapy. Moreover, it is suggested that blockades of 5-HT3 and 5-HT4 receptors are not relevant to the control of motion sickness; and furthermore, it suggested that blocking 5-HT4 receptors in addition to 5-HT3 receptors does not have an additional effect on the control of cisplatin-induced emesis, but that 5-HT4 receptors are at least partly involved in the mechanism of emesis induced by copper sulfate.

A PROSPECTIVE RANDOMIZED TRIAL OF THE ANTIEMETIC EFFICACY AND COST-EFFECTIVENESS OF INTRAVENOUS AND ORALLY DISINTEGRATING TABLET OF ONDANSETRON IN CHILDREN WITH CANCER

Orally disintegrating tablet (ODT) of ondansetron is a new formulation, which instantaneously disintegrates and disperses in the saliva without need for ingestion a liquid. This makes the formulation suitable for administration in children. The objective of this study was to compare the relative efficacy and cost of ODT and intravenous (IV) formulation of ondansetron in controlling nausea and vomiting in children receiving chemotherapy regimens without cisplatin. This prospective randomized trial was performed in a single institution to compare ODT and IV formulation of ondansetron for the prevention of acute emesis in a group of 22 children. Study agents were administered 30 min before chemotherapy and 12 hourly after chemotherapy (5 mg/m2 IV or 4–8 mg oral according to body surface area in 56 and 39 courses, respectively). After randomization, IV formulation was administered to some children instead of ODT due to unavaibility of this formulation. Complete and major control of emesis was obtained in 92% of patients in the IV group and 93% of patients in the ODT group. In 56 courses with grade III–IV emetogenicity, complete response rates were not different between the two treatment arms. In the courses without corticosteroids complete response rates were not also different between the two arms. The mean costs per successfully controlled courses were 121.3 USD for the IV formulation whereas 63.2 USD for the ODT formulation. The results of this study confirmed that ODT formulation of ondansetron is a safe, well-tolerated, and cost-effective antiemetic for children during non-cisplatin-containing moderately and highly emetogenic chemotherapy.

Using decision modeling to determine pricing of new pharmaceuticals: the case of neurokinin-1 receptor antagonist antiemetics for cancer chemotherapy.

Decision analysis is commonly used to perform economic evaluations of new pharmaceuticals. The outcomes of such studies are often reported as an incremental cost per quality-adjusted life year (QALY) gained with the new agent. Decision analysis can also be used in the context of estimating drug cost before market entry. The current study used neurokinin-1 (NK-1) receptor antagonists, a new class of antiemetics for cancer patients, as an example to illustrate the process using an incremental cost of dollars Can20,000 per QALY gained as the target threshold. A decision model was developed to simulate the control of acute and delayed emesis after cisplatin-based chemotherapy. The model compared standard therapy with granisetron and dexamethasone to the same protocol with the addition of an NK-1 before chemotherapy and continued twice daily for five days. The rates of complete emesis control were abstracted from a double-blind randomized trial. Costs of standard antiemetics and therapy for breakthrough vomiting were obtained from hospital sources. Utility estimates characterized as quality-adjusted emesis-free days were determined by interviewing twenty-five oncology nurses and pharmacists by using the Time Trade-Off technique. These data were then used to estimate the unit cost of the new antiemetic using a target threshold of dollars Can20,000 per QALY gained. A cost of dollars Can6.60 per NK-1 dose would generate an incremental cost of dollars Can20,000 per QALY. The sensitivity analysis on the unit cost identified a range from dollars Can4.80 to dollars Can10.00 per dose. For the recommended five days of therapy, the total cost should be dollars Can66.00 (dollars Can48.00-dollars Can100.00) for optimal economic efficiency relative to Canada's publicly funded health-care system. The use of decision modeling for estimating drug cost before product launch is a powerful technique to ensure value for money. Such information can be of value to both drug manufacturers and formulary committees, because it would facilitate negotiations for optimal pricing in a given jurisdiction.

Granisetron plus alprazolam versus granisetron alone in the control of emesis in patients with operable breast cancer receiving anthracycline containing chemotherapy: A phase III trial

Granisetron plus alprazolam versus granisetron alone in the control of emesis in patients with operable breast cancer receiving anthracycline containing chemotherapy: A phase III trial

Granisetron plus alprazolam versus granisetron alone in the control of emesis in patients with operable breast cancer receiving anthracycline containing chemotherapy: A phase III trial

8081 Background: Even with optimal antiemetic treatment, about only 20% of patients are completely free from nausea and vomiting (NV). Benzodiazepines have been previously shown to be useful in the prophylaxis of NV. Alprazolam, a newer benzodiazepine, has antidepressant effect and may be useful in NV control. Methods: Nineteen operable breast cancer patients were included in this randomized prospective crossover open label trial. All of them received 4–6 cycles of single day anthracycline containing chemotherapy. Patients received either granisetron (G) alone 3 mg intravenously 15 minute before chemotherapy and then 2×1 mg per os for 5 days, or in combination with alprazolam (A) 0.5 mg per os starting a night and 15 minutes before chemotherapy and continued 2×0.5 mg per os for 5 days. Group A patients received G+A first and then crossed over G alone after the 2nd or 3rd cycle. Group B patients received the reverse order. Eithy four cycles were evaluated. Results: In Group A, Complete Remission (CR) plus Major Response (MR) rate was higher significantly (93.9%) with G+A than G alone (83.3%) (p=.0001) in the first 24 hour period. In Group B, CR plus MR ratio in G+A cycles (100%) was significantly higher than (85.7%) in G alone cycles (p=0.035) in 24 hour period and in 25–129 hour period (92% v.s. 90.5%, p=0.022). When the data were analyzed independently, CR plus MR ratio was signficantly better in G+A cycles (97%) than in G alone (79%) in 24 hour period (p=0.044). Conclusions: Alprazolam increases the efficacy of granisetron in patients with breast cancer who received anthracycline containing regimen. No significant financial relationships to disclose.

Nausea: the neglected symptom?

Advances in antiemetic therapy over the past decade have undoubtedly eased the burden of radiotherapy- and chemotherapy-induced nausea and vomiting. Despite this, these distressing side-effects of cancer therapy are still experienced by some patients. Moreover, nausea has both a higher incidence and a greater effect on patient quality of life than vomiting. The impact of nausea may therefore warrant more attention than perhaps it has received previously, and there is undoubtedly room for improvement regarding its treatment. Recognizing and treating nausea is complicated by the fact that it can only be measured subjectively by the patient rather than objectively by clinical staff. However, various patient-centred strategies may be employed by nurses to ensure self-reporting of the occurrence and impact of nausea. Nurses may also be best placed to identify patient-related prognostic factors in order to determine the risk of nausea. Antiemetic guidelines recommend the use of a 5-HT 3-receptor antagonist for the control of emesis with moderate and highly emetogenic cancer therapy. Although guidelines do not distinguish between the available agents, pharmacological differences do exist, and it is necessary to consider this when tailoring regimens to individual patients. As with any therapy, less complicated dosing regimens are likely to improve compliance, an issue that may be particularly pertinent in nauseated patients who are unable to ingest multiple doses. Furthermore, the focus of antiemetic therapy should be on prevention, as the presence and severity of acute symptoms have been linked to occurrence of symptoms in the delayed phase and the likelihood of anticipatory nausea and vomiting with further treatment cycles. This review aims to assess the potentially neglected symptom of nausea and focuses on recognizing and controlling this side-effect of cancer therapy.

Control of Chemotherapy-Induced Emesis with 5-Hydroxytryptamine-3 Antagonists

The paper presents a probabilistic study aimed at investigating the role of the soil hydraulic response on the stability of existing river embankments, for which the uncertainty and the inherent variability of geotechnical and hydraulic properties are typically greater when compared to new flood defence structures. The study has been carried out with reference to a specific, thoroughly investigated 20 m-long segment of the river Secchia banks (northern Italy), which experienced a catastrophic sudden failure after a period of intense rainfall, in January 2014. By taking such well-documented case as a base, the proposed probabilistic analyses consider three key aspects, typically disregarded in routine risk assessment procedures: i) transient seepage flow through earth structures due to time dependent hydraulic loads, ii) unsaturated conditions of soils forming the river embankment, iii) uncertainty of the soil model parameters, with special emphasis placed on the impact of intrinsic variability of unsaturated soil parameters. The numerical results, obtained from the application of the Point Estimate Method, allow identifying the crucial role of suction distribution on the probability of failure of the riverbank slopes and clearly show that such probability can be significantly underestimated when the variability of hydraulic parameters is neglected.

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.