Control Of Vomiting Research Articles

Use of granisetron transdermal system in the prevention of chemotherapy-induced nausea and vomiting: a review

Until now only intravenous and oral formulations of 5HT(3) receptor antagonists have been available. Recently a new formulation of a 5HT(3) receptor antagonist, transdermal granisetron, has been developed, and approved by the FDA. Three phase I studies to evaluate its pharmacokinetic profile have shown that granisetron administered by a transdermal delivery system is absorbed by passive diffusion and maximal concentration is reached 48 hours after patch application. The patch of 52 cm(2), which contains 34.3 mg of granisetron, releases 3.3 mg of the drug every day and maintains a stable average plasma concentration of 2.2 ng/mL over 6 days, similar to levels obtained with 2 mg of oral granisetron, administered every day during the same period of time. Two randomized as yet unpublished clinical trials (phase II/III) have been conducted to evaluate the antiemetic efficacy of transdermal granisetron in chemotherapy-induced nausea and vomiting, in patients receiving moderately and highly emetogenic chemotherapy, compared with 2 mg of oral granisetron. More than 800 cancer patients were included in the trials. The rate of complete control of acute emesis was 49% for the phase II trial and 60% for the phase III trial. Neither trial showed a statistically significant difference between transdermal and oral granisetron. The control of delayed emesis was observed in 46% of patients, and there were no statistically significant differences between transdermal and oral granisetron. The most common adverse effects in both trials were constipation (<7%) and headache (<1%); there were no statistically significant differences between transdermal and oral granisetron. These data show that transdermal granisetron is effective and safe in controlling acute emesis induced by chemotherapy with both moderate and high emetogenic potential. Efficacy and safety of transdermal granisetron are fully comparable with that of oral granisetron. More clinical trials using regimens of 2 or 3 drugs, including dexamethasone and/or aprepitant, are needed to confirm the place of transdermal granisetron in the control of chemotherapy-induced nausea and vomiting.

3080 A double-blind randomized controlled trial comparing 3 mg and 1 mg of Granisetron for the control of chemotherapy-induced acute emesis

3080 A double-blind randomized controlled trial comparing 3 mg and 1 mg of Granisetron for the control of chemotherapy-induced acute emesis

5193 Can adjuvant homeopathy improve the control of post-chemotherapy emesis in breast cancer patients? Results of a randomized placebo-controlled trial

Con el presente artículo, se intenta esquematizar una serie de puntos básicos a tener en cuenta en el tratamiento del cáncer para que sirva como plan de actuación base sobre el que situar a nuestro paciente aquejado de enfermedad cancerosa y en función de ello elegir los remedios más indicados en cada momento.No se pretende dar pautas de tratamiento, simplemente establecer un esquema que sirva de guía durante el proceso y nos ayude a familiarizarnos con éste.In the present article an attempt is made to schematize a series of basic points to take into account in the treatment of cancer so that it may serve as basic action plan on which to place our patient suffering from cancer and depending on this to choose the remedies most suitable at each moment.It is not intended to give treatment guidelines, simply to establish a scheme that may serve as a guide during the process and may help to familiarise ourselves with this.

3029 The dosing frequency of sustained-release opioids and the prevalence of end-of-dose failure in cancer pain control: a Korean multicenter study

Little information exists on the functional impact of effective antiemetic protection. In the present study, the Functional Living Index—Emesis (FLIE), was used to assess patient-reported impact of chemotherapy-induced nausea and vomiting (CINV) after administration of a new NK-1 receptor antagonist (aprepitant). Cisplatin-treated patients in a double-blind randomised trial received either aprepitant+dexamethasone+ondansetron on day 1 and aprepitant+dexamethasone on days 2–5 or standard antiemetic therapy (dexamethasone and ondansetron on day 1 and dexamethasone on days 2–5). Emetic events, nausea ratings and rescue medications were recorded in a 5-day diary and the FLIE was completed on day 6. Compared with standard therapy, significantly more patients treated with the high dose aprepitant regimen achieved a Complete Response (71 vs 44%, P<0.001) and also reported no impact on daily life as indicated by the FLIE total score (84 vs 66%, P<0.01). Use of the FLIE demonstrated that improved control of emesis was highly effective in reducing the impact of CINV on patients’ daily lives.

The efficacy of oral ondansetron and dexamethasone for the prevention of acute chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy - a retrospective audit

The optimal dose of oral ondansetron for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) resulting from moderately emetogenic chemotherapy (MEC) is unknown. This retrospective audit was conducted to determine the efficacy of 8 mg oral ondansetron plus 8 mg oral dexamethasone as pre-chemotherapy anti-emetic regimen for patients receiving MEC. The efficacy outcomes analysed were the proportion of patients with no acute vomiting, proportion of patients with no acute nausea and the incidence of grade 3 or 4 CINV. A total of 81 patients were identified. The most frequent chemotherapy regimens received in the study population were anthracycline- (48%) and carboplatin-based (28%). No acute vomiting and nausea rates in the study population were 75% and 44% respectively. The incidence of grade 3 CINV was 1%. Patients who received anthracycline-based regimens had a significantly higher incidence of acute emesis (P= 0.001) and nausea (P < 0.0001) when compared with patients who received non-anthracycline-based regimens. In this study, the use of 8 mg oral ondansetron plus 8 mg oral dexamethasone achieved control of acute emesis in 75% of all patients receiving MEC which is comparable to previously reported rates of 70-80%. The benefits of using oral pre-chemotherapy anti-emetics include reduction in the costs of drugs and nursing administration time.

Can adjuvant homeopathy improve the control of post-chemotherapy emesis in breast cancer patients? Results of a randomized placebo-controlled trial

e20566 Background: Homeopathy used as an adjunct in the treatment of chemotherapy (CT)-induced emesis has rarely been evaluated. Methods: Patients with non-metastatic breast cancer treated with 6 courses of FAC 50, FEC 100 or TAC chemotherapy were randomized to Cocculus/nux vomica/tabacum/petroleum extract (Cocculine, C) or Placebo (P) in a multicentric comparative double-blind phase III study. Anti-emetic treatment was standardized (corticoids + ondansetron). Patients were evaluated after each course. The primary endpoint was nausea measured after the 1st CT course using the FLIE (Functional Living Index for Emesis) with 5-day recall. The planned sample size was 396 evaluable patients based on a minimum expected difference in mean of 0.5 ± 1.6 on a scale from 1 (a lot) to 7 (not at all) with 5% two-sided α error and 85% power. An intent-to-treat analysis was planned. Secondary evaluation criteria were: vomiting measured by the FLIE score, patient self-evaluation (EVA) and investigator recording (NCI-CTC) of nausea and vomiting intensities, and compliance. Results: From September 05 to January 08, 431 patients were randomized (217 to P and 214 to C). Patient characteristics were well balanced between groups. Median age was 53 years, 35% of the patients experienced nausea or vomiting. In total, 403 patients (93.5%) were assessable for the primary endpoint, with few nausea episodes (FLIE nausea scores after the 1st CT course were 6.02 and 6.07 for P and C, respectively) and very good compliance (81% patients complied with the protocol). Adverse events related to nausea occurred in 51% vs. 47% of the patients treated with P and C, respectively (p = 0.48). FLIE and NCI-CTC vomiting scores were similar between the 2 arms (6.91 vs. 6.88, p = 0.47, and 20% vs. 21%, p = 0.73, for P and C, respectively). Grade II-III nausea occurred in 17.6% and 15.7% of patients receiving P and C (p = 0.62). Conclusions: No benefit of homeopathy over standard treatment was noted in this study. But surprisingly we observed lower rates of nausea and vomiting measured by patients and by investigators, than in other studies using identical chemotherapy regimens. The observation and management of emesis could modify the perception and rate of such adverse events. No significant financial relationships to disclose.

Differential time course of action of 5-HT3 and NK1 antagonists when used with highly and moderately emetogenic chemotherapy (HEC and MEC)

9629 Background: Cisplatin-based HEC displays a biphasic pattern of emesis with both an early and delayed period. In contrast, MEC has a monophasic pattern. The objective of this analysis was to investigate the time course of action of the 5-HT3antagonist ondansetron (OND) and the NK1 antagonist aprepitant (APR) in trials with HEC and MEC. Methods: Phase III HEC and MEC trials of APR were included. In 2 HEC studies, patients (pts) scheduled to receive cisplatin- based chemotherapy were randomized to an active-control group (OND + dexamethasone [DEX] Day 1, DEX bid Days 2–4) or an APR group (APR + OND + DEX Day 1; APR + DEX qd Days 2–3; and DEX Day 4). In a third HEC study, control pts also received OND on Days 2- 3. For the MEC study, breast cancer pts receiving anthracycline + cyclophosphamide-based chemotherapy were randomized to an active- control group (OND + DEX pre chemotherapy and OND 8 hours (h) later; OND bid Days 2–3) or an APR group (APR + OND + DEX pre chemotherapy and OND 8 h later; APR qd Days 2–3). In a post-hoc analysis, multivariate logistic regression models were used to assess the impact on emesis at different time intervals using a modified intent-to-treat approach. No multiplicity adjustment was planned, so nominal p-values are reported. Results: 1,527 pts and 856 pts were randomized and assessed for efficacy in the HEC and MEC trials respectively. For HEC, APR reduced risk of emesis beginning 15–18 h after cisplatin and extending to 48 h by 45–77% compared to control and by 45–67% compared to the OND control. For MEC, APR markedly reduced emesis from 6–9 h by 61% compared to control (p=0.0012). Conclusions: Time of onset (15 h vs. 6 h) and time course (15–48 h vs. 6–9 h) for the enhanced control of emesis with the addition of APR differs between HEC and MEC respectively. With HEC these results suggest that 5-HT3 dependent mechanisms are most important in the first 12 h after HEC with NK1-dependent mechanisms having a key role later. With MEC both 5-HT3 and NK1 mechanisms appear to be important early and the greatest impact of the NK1 antagonist occurs in the first 9 h. These results provide a rationale for maximizing NK1-antagonist exposure early on with MEC as a means to improve emesis control. [Table: see text]

Can prognostic factors identify women receiving anthracycline plus cyclophosphamide-based chemotherapy (MEC) who do not require an NK1 receptor antagonist?

e20502 Background: Age, alcohol use, and history of sickness associated with pregnancy or motion have been identified as risk factors for chemotherapy-induced emesis. This post hoc analysis addressed two questions: 1) Can prognostic factors identify a low risk group for whom ondansetron (OND) plus dexamethasone [D] alone provide a high level of protection (≥80% no emesis)? 2) Does the NK1 receptor antagonist aprepitant improve antiemetic outcome regardless of emetic risk? Methods: The analysis was based upon outcomes in patients with breast cancer enrolled in a Phase III double-blind, placebo-controlled trial randomized to Day 1 OND 8 mg and D 20 mg before chemotherapy and OND 8 hours later and OND 8 mg bid Days 2–3 vs. Day 1 aprepitant 125 mg PO, OND 8 mg, and D 12 mg before chemotherapy and OND 8 mg 8 hours later and aprepitant 80 mg PO qd Days 2–3. Multivariate logistic regression models were used to assess the impact on emesis of the regimen with aprepitant, and previously reported risk factors, including age (&lt;55 and ≥55 years), ethanol use (0–4 or ≥5 drinks/week), history of pregnancy-related morning sickness, and history of motion sickness, using a modified intent-to-treat approach. Results: 856 patients were assessed for efficacy. Treatment with aprepitant (p&lt;0.0001), older age (p=0.006), ethanol use (p=0.0048), and no history of morning sickness (p=0.0007) were all significantly associated with reduced likelihood of emesis; motion sickness was not a risk factor. The Table below shows the probability of no emesis associated with the presence of 0, 1, 2, or all of these factors in the aprepitant and active control arms. Conclusions: 1) The low-risk group identified by this analysis is of questionable utility because it comprised less than 3% of patients. 2) We could not confirm that motion sickness was a significant risk factor. 3) Aprepitant improved the control of emesis irrespective of the number of risk factors for emesis. [Table: see text] [Table: see text]

Progress in the Control of Chemotherapy-Induced Emesis: New Agents and New Studies.

New agents and studies have demonstrated benefit in improving antiemetic therapy. Incorporating evidence-based guideline recommendations and appropriate emesis assessments are key components to achieving the best practice.

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

To assess the efficacy of adding aprepitant to a 5-HT(3) antagonist and dexamethasone as salvage antiemetic therapy for breast cancer patients receiving their initial cycle of an anthracycline and cyclophosphamide (AC) and failing to achieve complete control of emesis. Eligibility: breast cancer patients receiving their first cycle of AC. standard dose of a 5-HT(3) antagonist and dexamethasone 8-10 mg IV/PO on day 1 prior to cycle 1 of AC and dexamethasone 4 mg bid on days 2 and 3. Patients without complete control (no emesis, no nausea, or rescue antiemetics) during cycle 1 could proceed to cycle 2. During cycle 2, patients received AC and identical antiemetics (except dexamethasone 4 mg qd on days 2 and 3) plus aprepitant 125 mg PO day 1 and 80 mg PO days 2 and 3. Primary endpoint: complete control, 0-120 h after chemotherapy. Sixty-two patients received cycle 1 of AC. Complete control cycle 1: 13 patients (21%; 95%CI, 12-33%). Of the 49 patients eligible for cycle 2, four elected not to continue on study. Of the 45 patients receiving cycle 2, 44 were evaluable. Complete control and complete response (no emesis, no rescue) for the 5-day study period improved from 0% to 18% (p = 0.14) and 7% to 36% (p = 0.02) on cycles 1 and 2, respectively. In breast cancer patients receiving AC, the addition of aprepitant to a 5-HT(3) antagonist and dexamethasone during cycle 2 of treatment improved antiemetic outcome. Although the improvement in the primary endpoint of complete control during cycle 2 was not significant, all secondary endpoints such as complete response and no emesis rates were significantly better during cycle 2. The extent of antiemetic control during cycle 2 was numerically inferior to the results achieved in a phase III trial employing aprepitant with cycle 1 of AC chemotherapy, suggesting that the preferred approach is to include aprepitant with the initial cycle of AC chemotherapy.

Efficacy of Granisetron in the Antiemetic Control of Nonsurgical Intestinal Obstruction in Advanced Cancer: A Phase II Clinical Trial

The objective of this study was to assess antiemetic efficacy of granisetron in inoperable intestinal obstruction caused by advanced cancer. The study was open, prospective, and multi-centered. We assessed 24 patients (mean age: 61.3 years; 10 males, 14 females) with intestinal obstruction who were refractory to previous antiemetics. Obstruction involved the upper intestine in six patients, the lower intestine in three, and was at multiple levels in 15. Daily treatment included intravenous granisetron (3 mg) and dexamethasone (8 mg); nasogastric drainage was not allowed. Subcutaneous haloperidol was available as rescue therapy. A numeric scale was used to evaluate nausea, pain, asthenia, and anorexia at baseline visit and every 24 hours up to the completion of four days of treatment (final visit). Treatment failure was defined as nausea >4 on the numeric scale, vomiting 2/day or more, and rescue therapy with haloperidol at 5 mg/day or more. Of the 24 patients, 23 were evaluable for efficacy. Evaluation pre- vs. post-treatment indicated a significant decrease in the severity of nausea (score 6.9 vs. 0.8; P < 0.001), number of episodes of vomiting (5.3 vs. 1.0; P < 0.001), and abdominal pain (score 4.4 vs. 1.2; P < 0.001). Nausea and vomiting control was achieved in 86.9% of patients. Although there was a trend toward greater efficacy in the lower and multiple levels of obstruction, the differences were not statistically significant owing, probably, to small sample size. We conclude that granisetron may be highly efficacious in the control of emesis resulting from intestinal obstruction caused by metastatic cancer, and can be used effectively in patients refractory to other antiemetics.

Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy

9645 Background: Oxaliplatin (OX) is a platinum compound commonly used in colorectal cancer. The emetogenic potential of OX has not been well characterized despite reports of frequent nausea (N) and vomiting/retching (V) in phase I and II studies. Platinum compounds such as cisplatin and carboplatin have a well defined ability to cause delayed (> 24 hours post chemotherapy) NV in the absence of antiemetic prophylaxis. There is no information available on the potential for OX to produce delayed NV.This trial sought to prospectively determine the frequency of delayed N and V with OX-based chemotherapy following day 1 prophylaxis with a 5-HT3 antagonist (5-HT3A) and dexamethasone (DEX). Methods: Eligibility: Pts ≥ age 18 with colon cancer receiving OX (85–100mg/m2) as part of a standard FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) regimen for the first time. Performance status: 0–2. Antiemetic treatment: 5-HT3A (ondansetron, dolasetron, or granisetron but not palonosetron) at an approved dose and DEX 20mg PO/IV on day 1 prior to OX infusion. No routine prophylaxis for delayed N/V was given. Episodes of V, N, and use of rescue antiemetics were recorded in patient-completed diaries. Four point (none, mild, moderate, severe) categorical scales were used to assess N. Study period: 120 hours after OX administration. Definitions: complete response (CR) - no V and no use of rescue antiemetics (RA); complete control (CC) - no V, no N and no RA. Results: Pts: 36; evaluable 35; median age: 68 (48–85); M/F 46%/54%. History of moderate - heavy ethanol use: 8 pts (23%). Acute CR: 91% (32/35); Delayed CR: 51% (18/35); Delayed CC: 40% (14/35); Overall CR (0–120 hrs): 51% (18/35); Overall CC: 37% (13/35). Median time to first emesis/first rescue: 57 hrs/47 hrs. Conclusions: The use of a single dose of a 5-HT3A and DEX prior to OX results in excellent control of emesis (CR - 91%) during the 24 hours after chemotherapy. However, without further antiemetic treatment, complete response rate in the delayed period (hours 24 - 120) decreased to 51%. In addition, a majority of pts (57%) noted delayed N, with N of moderate to severe intensity in 9 (26%) pts. This study supports the need for routine antiemetic prophylaxis for delayed N and V following OX-based chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis

High incidence of Antiemetic treatment failure to standard chemotherapy in women with breast cancer – A prospective QOL study in clinical practice setting in Spain – EME-Q Study

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 significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. The first generation 5-HT3 receptor antagonists have been very effective in the control of chemotherapy induced emesis in the first 24 h postchemotherapy (acute emesis), but have not been as effective against delayed emesis (24–120 h postchemotherapy). Palonosetron, a second generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors, has emerged in recent trials as an effective preventative agent for chemotherapy–induced emesis and nausea, as well as a very effective agent for the treatment of breakthrough emesis and nausea. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant

Fosaprepitant is a prodrug of aprepitant, a neurokinin(1) (NK(1)) receptor antagonist used in prophylactic antiemetic regimens used prior to cytotoxic chemotherapy. Fosaprepitant is being developed to provide a parenterally administered alternative to the orally administered aprepitant. Fosaprepitant is rapidly converted to aprepitant and an intravenous dose of 115 mg is bioequivalent to 125 mg orally, with similar plasma concentrations at 24 hours. In phase I and II trials fosaprepitant shows efficacy, but the large randomized efficacy studies have utilized aprepitant. When it is added to dexamethasone and a 5HT(3) receptor antagonist on day 1 prior to chemotherapy aprepitant improves the control of acute post chemotherapy emesis and when continued on days 2 and 3 with dexamethasone it demonstrated even greater improvement in the control of delayed emesis. This has been shown with both cisplatin-containing regimens and those based upon cyclophosphamide and an anthracycline. Fosaprepitant is well tolerated with mild to moderate venous irritation being the only additional toxicity to those seen with oral aprepitant, and that is a function of dose, concentration, and infusion rate. Headaches are the other toxicity most commonly reported. Fosaprepitant can be used as a parenteral alternative to aprepitant in regimens to control chemotherapy-induced emesis.

Aprepitant for the prevention of nausea and vomiting associated with chemotherapy and postoperative recovery

Chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) can negatively impact patient quality of life, functional performance and activities of daily living. Although the development of serotonin receptor antagonists has greatly improved the control of acute emesis, delayed CINV remains a significant clinical issue. Aprepitant (Emend®) is the first commercially available drug from a new class of agents, the neurokinin-1 receptor antagonists. Elucidation of its mechanism of action has produced a greater understanding of the pathophysiology of nausea and vomiting. Oral aprepitant, in combination with a selective serotonin (5-HT3) receptor antagonist and corticosteroids, is indicated for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy in adults. Aprepitant alone or in combination only with dexamethasone does not optimally control acute emesis compared with triple combination therapy. By contrast, aprepitant as monotherapy is indicated for the prevention of PONV. Aprepitant represents an emerging class of agents and its addition to standard therapy provides an advanced benefit in the prevention and treatment of CINV and PONV. Investigations of aprepitant for other indications are ongoing.

Chemotherapy- and Cancer-Related Nausea and Vomiting

Approximately one half of cancer patients will experience nausea or vomiting during the course of their disease either because of the cancer itself or because of their treatment. Emesis attributable to cancer warrants a careful investigation to determine whether a treatable underlying cause is responsible. Interventions using dexamethasone and octreotide may reduce vomiting attributable to bowel obstruction. In the absence of a bowel obstruction or a correctable cause, the usual approach is a sequential trial of antiemetics guided by considerations of cost and side effects.Major progress in managing chemotherapy-induced emesis followed from the use of a combination of a corticosteroid and 5-hydroxytryptamine(3) (5-HT(3)) receptor antagonist for moderately to highly emetogenic chemotherapy. Nevertheless, vomiting still occurred in approximately 40% of women receiving chemotherapy containing an anthracycline plus cyclophosphamide and in approximately 50% of patients receiving high-dose cisplatin. The addition of aprepitant, a neurokinin 1 receptor antagonist, improved control of emesis by a further 15%-20%, and that agent is now recommended as part of standard antiemetic therapy for patients at high risk of emesis. Based largely on anecdotal experience, cannabinoids and olanzapine are sometimes also recommended in patients with refractory emesis. Phase III trials are required to confirm their efficacy as add-ons to a corticosteroid, a 5-HT(3) receptor antagonist, and possibly aprepitant.

Anandamide Inhibition of 5-HT3A Receptors Varies with Receptor Density and Desensitization

Converging evidence has suggested that anandamide (AEA), an endogenous agonist of cannabinoid (CB) receptors, can directly interact with certain types of ligand-gated ion channels (LGICs). However, little is known about the molecular and cellular mechanisms of AEA-induced direct effects on LGICs. Here, we report that AEA inhibited the function of serotoningated ion channels (5-HT(3A)) expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells in a manner that was dependent on the steady-state receptor density at the cell surface. The magnitude of AEA inhibition was inversely correlated with the expression levels of receptor protein and function. With increasing surface receptor expression, the magnitude of AEA inhibition decreased. Consistent with this idea, pretreatment with actinomycin D, which inhibits transcription, decreased the amplitude of current activated by maximal concentrations of 5-hydroxytryptamine (5-HT) and increased the magnitude of AEA inhibition. AEA did not significantly alter 5-HT(3A) receptor trafficking. However, AEA accelerated 5-HT(3A) receptor desensitization time in a concentration-dependent manner without significantly changing receptor activation and deactivation time. The desensitization time was correlated with the AEA-induced inhibiting effect and mean 5-HT current density. Applications of 5-hydroxyindole and nocodazole, a microtubule disruptor, significantly slowed 5-HT(3A) receptor desensitization and reduced the magnitude of AEA inhibition. These observations suggest that 5-HT(3) receptor density at the steady state regulates receptor desensitization kinetics and the potency of AEA-induced inhibiting effect on the receptors. The inhibition of 5-HT(3) receptors by AEA may contribute to its physiological roles in control of pain and emesis.

The endocannabinoid system and gut–brain signalling

The endocannabinoid system (ECS) consists of cannabinoid receptors, endogenous ligands and the biosynthetic and metabolic enzymes for their formation and degradation. Within the gastrointestinal (GI) tract, the ECS is involved in the regulation of motility, secretion, sensation, emesis, satiety and inflammation. Recent studies examining the ECS in the gut-brain axis have shed new light on this system and reveal many facets of regulation that are amenable to targeting by pharmacological interventions that may prove valuable for the treatment of GI disorders. In particular, it has been shown that endocannabinoid levels in the brain and gut vary according to states of satiety, and in conditions of diarrhea, emesis and inflammation. The expression of cannabinoid (CB)(1) receptors on vagal afferents is controlled by the states of satiety and by gut peptides such as cholecystokinin and ghrelin. Vagal control of gut motor function and emesis is regulated by endocannabinoids in the brainstem acting on CB(1), CB(2) and transient receptor potential vanilloid (TRPV)-1 receptors. The ECS is involved in the modulation of visceral sensation and likely contributes to effects of stress on GI function. This review examines recent developments in our understanding of the ECS in gut-brain signalling.

Differential Subcellular Localization of RIC-3 Isoforms and Their Role in Determining 5-HT3 Receptor Composition

RIC-3 has been identified as a chaperone molecule involved in promoting the functional expression of nicotinic acetylcholine and 5-HT(3) receptors in mammalian cells. In this study, we examined the effects of RIC-3a (isoform a) and a truncated isoform (isoform d) on RIC-3 localization, mobility, and aggregation and its effect on 5-HT3 receptor composition in mammalian cells. Human RIC-3a possesses an amino-terminal signal sequence that targets it to the endoplasmic reticulum where it is distributed within the reticular network, often forming large diffuse "slicks" and bright "halo" structures. RIC-3a is highly mobile within and between these compartments. Despite the propensity for RIC-3a to aggregate, its expression enhances the level of surface 5-HT3A (homomeric) receptors. In contrast, RIC-3a exerts an inhibitory action on the surface expression of heteromeric 5-HT3A/B receptors. RIC-3d exhibits an altered subcellular distribution, being localized to the endoplasmic reticulum, large diffuse slicks, tubulo-vesicular structures, and the Golgi. Bidirectional trafficking between the endoplasmic reticulum and Golgi suggests that RIC-3d constitutively cycles between these two compartments. In support of the large coiled-coil domain of RIC-3a being responsible for protein aggregation, RIC-3d, lacking this cytoplasmic domain, does not aggregate or induce the formation of bright aggregates. Regardless of these differences, isoform d is still capable of enhancing homomeric, and inhibiting heteromeric, 5-HT3 receptor expression. Thus, both isoforms of RIC-3 play a role in determining 5-HT3 receptor composition.

A randomized, double-blinded, pilot trial of aprepitant added to standard antiemetics during conditioning therapy for hematopoietic stem cell transplant (HSCT)

9112 Background: Antiemetic prophylaxis for standard dose chemotherapy has improved while that for high dose chemotherapy ± total body irradiation (TBI) has not. Aprepitant (A), a neurokinin-1 antagonist, was added to standard antiemetic therapy for planned conventional HSCT to test for improved emesis control. Methods: During cyclophosphamide (Cy)-based conditioning therapy patients were randomized to receive ondansetron (O) ± dexamethasone plus A or a placebo (P) on days of chemo/radiotherapy. The primary aim was to reduce N/V during and after HSCT conditioning. Nausea, emesis, and nutritional intake were evaluated from the onset of therapy through day +7. Busulfan doses were targeted to disease appropriate AUCs and pharmacokinetic (PK) analysis was performed on Cy, Cy- metabolites (HCY &amp; CEPM), and A. Responses were defined as Complete (CR) - no emesis, mild-moderate nausea, and Major (MR) - 1–2 emesis on only 1 day with any level nausea or no emesis with severe nausea. Results: Fifteen patients have been randomized per arm. Eleven patients received TBI (1,200 cGy) CY (120 mg/kg) and 19 received Bu (16 mg/kg) CY (120 mg/kg). A/P was begun on Day -7 (125 mg) with the first O dose and given daily (80 mg) through day +4 (alone on days +1 through +4). Overall responses (CR + MR) were seen in 14/15 A patients and 7/15 P patients. (p=0.014) No emesis occurred in 10/15 A patients and 5/15 P patients (p=0.143). Preliminary PK show the observed AUCs of CY, HCY and CEPM, for both regimens and PK differences between the 2 regimens, were consistent with previously published data. Most busulfan patients, 87%, required dose adjustments (primarily reductions) to stay within target AUCs. Anti-seizure prophylaxis with phenytoin may significantly decrease A levels, but this didn't appear to be clinically relevant. Adverse effects were similar between arms. One case of sinusoidal obstruction syndrome occurred in the P arm. Conclusions: In this interim analysis, aprepitant added to standard antiemetics improved emesis prevention during Cy-containing conditioning therapy prior to HSCT, without significant changes in Cy pharmacokinetics or increased toxicity. Data on the target accrual of 40 patients will be presented. [Table: see text]