Ramosetron as an add-on therapy for refractory fibromyalgia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: This study aimed to assess the efficacy and safety of intravenous ramosetron for pain relief in patients with fibromyalgia (FM) unresponsive to conventional treatments. METHODS: In this prospective, double-blind, placebo-controlled trial, 80 FM patients were randomly allocated to receive either placebo (n = 40) or ramosetron (n = 40) at a dosage of 0.3 mg/day intravenously for five consecutive days. The primary outcome was the reduction in pain intensity at the end of the treatment period, evaluated using a visual analogue scale (VAS). Secondary outcome measures included the FM Impact Questionnaire, Beck Depression Inventory (BDI), Multi-Dimensional Health Assessment Questionnaire (MDHAQ), EQ-5D and State-Trait Anxiety Inventory on days 5 (end of treatment), 7, 10 and 28. Safety was continuously monitored throughout the study. RESULTS: At the end of the treatment phase, the ramosetron group demonstrated a significantly greater reduction in VAS pain scores compared with the placebo group (1.18 ± 1.60 vs 0.54 ± 1.59, P < 0.05). Additionally, the ramosetron group exhibited significant improvements in BDI (4.42 ± 5.18 vs 1.33 ± 4.87, P < 0.05) and MDHAQ pain scale (0.37 ± 0.74 vs 0.04 ± 0.52, P < 0.05) scores. However, these improvements in pain VAS and BDI scores were not sustained through day 28. The safety profile of ramosetron was favorable, with gastrointestinal symptoms, particularly constipation, being the most commonly reported adverse events. CONCLUSIONS: Intravenous administration of ramosetron provided safe and effective short-term relief of pain intensity in FM patients with inadequate response to standard treatments.

Efficacy and safety of SENS-401 in sudden sensorineural hearing loss: The AUDIBLE-S randomized placebo-controlled phase IIb trial.

PURPOSE: Safety and efficacy of SENS-401, a serotonin type 3 (5-HT3) receptor antagonist and calcineurin inhibitor, in patients with acute sudden sensorineural hearing loss (SSNHL). METHODS: Multicentre randomized, double blind, placebo-controlled trial enrolled adult subjects with sudden sensorineural hearing loss (SSNHL) or unilateral/bilateral acute acoustic trauma leading to SSNHL within 96 h of disease onset. Subjects were randomly assigned to one of the three oral dose groups: 29 mg, 43.5 mg or placebo given twice daily for 28 days. The primary endpoint was the change from baseline in Pure Tone Average (PTA) in the affected ear to the end of treatment visit (day 28). Subjects were further followed up 8 weeks after the end of the treatment period (day 84). RESULTS: A total of 115 subjects were randomized. SENS-401 was well tolerated. Although the primary efficacy endpoint was not met at day 28, post-hoc analyses revealed clinically significant and meaningful efficacy outcomes with SENS-401 when compared to placebo in a substantial group of participants diagnosed with idiopathic SSNHL and who had received corticosteroid treatment. Notable improvements were observed in the PTA change from baseline, the complete hearing recovery rate, and the Word Recognition Score (WRS), particularly at day 84. The responder rate consistently favored treated subjects over those who received the placebo. CONCLUSION: While the primary endpoint was not achieved at the end of the treatment period, the study revealed consistently positive efficacy results of clinical relevance in patients with idiopathic SSNHL who received SENS-401, particularly in the 8-weeks follow-up phase after the completion of the treatment.

Isopropyl alcohol inhalation versus 5-HT3 antagonists for treatment of nausea: a meta-analysis of randomised controlled trials.

PURPOSE: Nausea is a common and unpleasant sensation for which current therapies such as serotonin (5-HT3) antagonists are often ineffective, while also conferring a risk of potential adverse events. Isopropyl alcohol (IPA) has been proposed as a treatment for nausea. We aimed to compare IPA with 5-HT3 antagonists for the treatment of nausea across all clinical settings. METHODS: MEDLINE, EMBASE, PubMed, CENTRAL and CINAHL were searched from inception to 17 July 2023 for randomised controlled trials (RCTs) comparing inhaled IPA and a 5-HT3 antagonist for treatment of nausea. Severity and duration of nausea, rescue antiemetic use, adverse events and patient satisfaction were the outcomes sought. Risk of bias (RoB) was assessed using Cochrane RoB 2. Random-effects model was used for meta-analysis. Combination of meta-analyses and narrative review was used to synthesise findings. The evidence was appraised using GRADE. RESULTS: From 1242 records, 4 RCTs were included with 382 participants. Participants receiving IPA had a significantly lower mean time to 50% reduction in nausea (MD - 20.06; 95% CI - 26.26, - 13.85). Nausea score reduction at 30 min was significantly greater in the IPA group (MD 21.47; 95% CI 15.47, 27.47). IPA led to significantly reduced requirement for rescue antiemetics (OR 0.60; 95% CI 0.37, 0.95; p = 0.03). IPA led to no significant difference in patient satisfaction when compared with a 5-HT3 antagonist. The overall GRADE assessment of evidence quality ranged from very low to low. CONCLUSION: IPA may provide rapid, effective relief of nausea when compared with 5-HT3 antagonists.

Palonosetron as prophylaxis for post-discharge nausea and vomiting: a prospective, randomised, double-blind, placebo-controlled trial in ambulatory surgery.

BACKGROUND: Approximately 25% of ambulatory surgery patients experience post-discharge nausea and vomiting (PDNV). We aimed to investigate whether palonosetron, a long-acting anti-emetic, decreases the incidence of PDNV in high-risk patients. METHODS: In this prospective, randomised, double-blind, placebo-controlled trial, 170 male and female patients undergoing ambulatory surgery under general anaesthesia, with a high predicted risk for PDNV, were randomised to receive either palonosetron 75 µg i.v. (n=84) or normal saline (n=86) before discharge. During the first 3 postoperative days (PODs), we measured outcomes using a patient questionnaire. The primary outcome was the incidence of a complete response (no nausea, vomiting, or use of rescue medication) until POD 2. Secondary outcomes included the incidence of PDNV each day until POD 3. RESULTS: The incidence of a complete response until POD 2 was 48% (n=32) in the palonosetron group and 36% (n=25) in the placebo group (odds ratio 1.69 [95% confidence interval: 0.85-3.37]; P=0.131). No significant difference in the incidence of PDNV was observed between the two groups on the day of surgery (47% vs 56%; P=0.31). Significant differences in the incidence of PDNV were found on POD 1 (18% vs 34%; P=0.033) and POD 2 (9% vs 27%; P=0.007). No differences were observed on POD 3 (15% vs 13%; P=0.700). CONCLUSIONS: Compared with placebo, palonosetron did not reduce the overall incidence of post-discharge nausea and vomiting up to postoperative day 2. The lower incidence of post-discharge nausea and vomiting on poatoperative days 1 and 2 in the palonosetron group requires further investigation. CLINICAL TRIAL REGISTRATION: EudraCT 2015-003956-32.

In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs.

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 µM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 µM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 µM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 µM). Ondansetron (0.5-20 µM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 µM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 µM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

Effect of palonosetron and dexamethasone administration on the prevention of gastrointestinal symptoms in hepatic arterial chemoembolization with epirubicin.

PURPOSE: There are several studies on premedication to prevent postembolization syndromes which occurs after transcatheter arterial chemoembolization (TACE), but the medication to be used is still not established. This study aimed to examine the effect of palonosetron and dexamethasone on the prevention of gastrointestinal symptoms induced by TACE. METHODS: Patients with hepatocellular carcinoma who were treated with TACE with epirubicin were retrospectively evaluated. The complete response rate of antiemetic drugs and incidence and severity of gastrointestinal symptoms were compared between the antiemetic group (AE group), which includes 51 patients prophylactically administered with palonosetron 0.75 mg and dexamethasone 9.9 mg intravenously before TACE on day 1 and dexamethasone 6.6 mg intravenously on days 2 and 3, and control group with 101 patients without antiemetic premedication. RESULTS: Complete response rate in the entire evaluation period was significantly higher in the AE group compared with that in the control group. In the acute phase, the incidence and severity of nausea, vomiting, and anorexia significantly decreased in the AE group, but only anorexia improved in the delay phase. Additionally, postembolization syndromes, such as abdominal pain and fever, were significantly attenuated in the AE group; however, constipation worsened in this group. CONCLUSIONS: Premedication of palonosetron and dexamethasone significantly prevents the incidence and reduces the severity of gastrointestinal symptoms especially in the acute phase. Further studies will be needed to determine the most recommended 5-HT3 antagonist or dosage of dexamethasone in establishing the optimal antiemetic regimen.

Pharmacokinetics/pharmacodynamics, safety, and tolerability of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients.

BACKGROUND: Current antiemetic regimens are less effective in children than in adults. Fosaprepitant was recently approved for prevention of chemotherapy-induced nausea and vomiting (CINV) in children aged six months and older. PROCEDURE: The pharmacokinetic (PK)/pharmacodynamic (PD) profile, safety, and tolerability of a single intravenous dose of fosaprepitant administered concomitantly with ondansetron with/without dexamethasone were evaluated in pediatric patients with cancer receiving emetogenic chemotherapy. PK/PD from three doses of fosaprepitant (3.0, 1.2, and 0.4 mg/kg, up to 150, 60, and 20 mg, respectively) were compared with placebo in 2- to 17-year-old subjects; an open-label amendment evaluated a fourth dose (5.0 mg/kg, up to 150 mg) in those under 12 years old. Historical adult PK data were used for comparison. Efficacy was measured as an exploratory endpoint. RESULTS: PK data were evaluable for 167/234 subjects who completed cycle one. Aprepitant exposures were dose proportional; adolescents (12 to 17 years) receiving fosaprepitant 150 mg had exposures similar to adults at the same dose. Higher weight-normalized doses (5 mg/kg) were necessary for children aged < 12 years to achieve comparable adult exposures. The adverse event profile was typical of cancer patients receiving emetogenic chemotherapy. Drug-related adverse events were reported in 16 (6.8%) subjects, with hiccups being most common (n = 5; 2.1%). CONCLUSIONS: Intravenous fosaprepitant was well tolerated by pediatric subjects with cancer, and dose-proportional exposures were observed. Subjects < 12 years old required higher doses to achieve comparable adult exposures.

Blockade of 5-HT3 receptors with granisetron does not affect trigeminothalamic nociceptive transmission in rats: Implication for migraine.

One way to expand the existing range of anti-migraine drugs seems to be the search for pharmacological agents with anti-cephalalgic properties among medicines approved for clinical indications other than migraine. Numerous experimental and clinical data imply that selective serotonin 5-HT3 receptor antagonists can be considered as potential anti-migraine agents. Therefore, the objective of our work was to examine the impact of selective 5-HT3 receptor blockade with granisetron on migraine-related nociceptive transmission within the spinal trigeminal nucleus (STN) and the ventroposteromedial nucleus of the thalamus (VPM). Using an electrophysiological model of trigemino-durovascular nociception in anaesthetised male Wistar rats, we evaluated the effects of intravenous administration of granisetron on ongoing firing and dural electrical stimulation-evoked responses of the spinal trigeminal and thalamic cells. Granisetron did not substantially affect responses of the STN and VPM neurons to electrical stimulation of the dura mater as well as did not cause steady changes in ongoing firing of the spinal trigeminal cells. The results obtained argue against the use of 5-HT3 receptor antagonists for treating migraine. These data also lead to the conclusion that in the absence of sustained sensitisation of neurons along the trigemino-thalamo-cortical pathway the role of 5-HT3 receptor-dependent mechanisms in serotonergic modulation of trigeminovascular nociceptive transmission can hardly be considered crucial.

Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study.

BACKGROUND: Treatments for reducing opioid withdrawal are limited and prone to problematic side effects. Laboratory studies, clinical observations, and limited human trial data suggest 5-HT3-receptor antagonists and antihistamines may be effective. OBJECTIVES: This double-blind, crossover, placebo-controlled study employing an acute physical dependence model evaluated whether (i) treatment with a 5-HT3-receptor antagonist (palonosetron) would reduce opioid withdrawal symptoms, and (ii) co-administration of an antihistamine (hydroxyzine) would enhance any treatment effect. METHODS: At timepoint T = 0, healthy (non-opioid dependent, non-substance abuser) male volunteers (N = 10) were pre-treated with either a) placebo, b) palonosetron IV (0.75 mg), or c) palonosetron IV (0.75 mg) and hydroxyzine PO (100 mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10 mg/70kg). At T = 165, 10 mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15. RESULTS: Comparison of average baseline OOWS scores with OOWS scores obtained 15 minutes after naloxone was significant (p = 0.0001). Scores from 15 minutes post-naloxone infusion showed significant differences in OOWS scores between treatment groups: placebo, 3.7 ± 2.4; palonosetron, 1.5 ± 0.97; and palonosetron with hydroxyzine, 0.2 ± 0.1333. CONCLUSIONS: Pretreatment with palonosetron significantly reduced many signs of experimentally-induced opioid withdrawal. Co-administration with hydroxyzine further reduced opioid withdrawal severity. These results suggest that 5-HT3 receptor antagonists, alone or in combination with an antihistamine, may be useful in the treatment of opioid withdrawal.

A suspected case of serotonin syndrome induced by palonosetron and ramosetron administration.

Serotonin syndrome occurs when serotonin (5-hydroxytryptamine, 5-HT) levels increase and is accompanied by symptoms of mental status changes, neuromuscular abnormalities, and autonomic hyperactivity. Serotonin receptor 3 antagonists, such as palonosetron or ramosetron, are commonly used for their antiemetic effects during general anesthesia. However, overdosage of these drugs carries a risk of serotonergic toxicity as they increase serum serotonin levels due to inhibition of serotonin reuptake. Serotonin syndrome caused by 5-HT3 antagonists is thought to be caused by the synergistic effects of high doses of serotonergic drugs or the combination of two or more serotonergic drugs with different mechanisms of action. The incidence of serotonin syndrome is unknown because it is a rare condition that cannot be selected for in randomized clinical trials. Therefore, physicians must focus on the clinical manifestations of the syndrome and manage patients before the condition becomes life-threatening.

Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control.

OBJECTIVES: In this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain. METHODS: A total of 48 chronic back pain patients (N = 48) participated in this double-blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS). RESULTS: We observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (ΔOOWS = 4.3 ±â€¯2.4, p < 0.0001; ΔSOWS = 14.1 ±â€¯11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups. CONCLUSION: We hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co-administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT3 receptor antagonists are useful in preventing opioid physical dependence.

Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test.

Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1µg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001µg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation.

Efficacy, safety and effectiveness of ondansetron compared to other serotonin-3 receptor antagonists (5-HT3RAs) used to control chemotherapy-induced nausea and vomiting: systematic review and meta-analysis.

INTRODUCTION: Chemotherapy-induced nausea and vomiting are adverse effects responsible for worsening quality of life in cancer patients. To assess the efficacy, safety and effectiveness of serotonin receptor antagonist in cancer patients undergoing chemotherapy, comparing ondansetron with granisetron, dolasetron, tropisetron and palonosetron. AREAS COVERED: Systematic review and meta-analysis. The data were collected using CINAHL; CENTRAL; MEDLINE/PubMed; and LILACS databases; grey literature; and manual search. The methodological quality was assessed using the modified Jadad scale; Cochrane Collaboration's tool for assessing risk of bias in randomized clinical trials and the Newcastle-Ottawa Scale for observational studies. The search was completed in November, 2015. 26 studies were included in the meta-analysis. Ondansetron exhibited similar efficacy than granisetron and tropisetron, as well as greater efficacy than dolasetron for acute vomiting. Palonosetron exhibited greater efficacy than ondansetron for delayed nausea and acute and delayed vomiting. The comparison of granisetron with ondansetron in the cohort studies showed no difference. Expert commentary: In this review, palonosetron had increased efficiency compared with ondansetron, except in the subgroup analysis and acute nausea. Few cohort studies have been published addressing this topic.

QCM-4 a novel 5-HT3 antagonist attenuates the behavioral and biochemical alterations on chronic unpredictable mild stress model of depression in Swiss albino mice.

OBJECTIVES: The inconsistent therapeutic outcome necessitates identifying novel compounds for the treatment of depression. Therefore, the present study is aimed at evaluating the antidepressant-like effects of a novel 5-HT3 receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alterations in mice. METHODS: Animals were subjected to different stressors for a period of 28 days. Thereafter, battery tests like locomotor score, sucrose preference test, forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM) and open field test (OFT) were performed. Biochemical assays like lipid peroxidation, nitrite levels, reduced glutathione (GSH), catalase and superoxide dismutase (SOD) were assessed in brain homogenate. KEY FINDINGS: QCM-4 dose dependently reversed the CUMS induced behavioral and biochemical alterations by increasing the sucrose consumption, reducing the immobility time in FST and TST, increasing the percent time in open arm in EPM and increasing the ambulation along with the rearings and decreased number of fecal pellets in OFT. Further, biochemical alterations were attenuated by QCM-4 as indicated by reduced lipid peroxidation and nitrite levels and elevated antioxidant enzyme levels like GSH, catalase and SOD. CONCLUSIONS: QCM-4 attenuated the behavioral and biochemical derangements induced by CUMS in mice, indicating antidepressant behavior of the novel compound.

Anti-anxiety effect of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide (6k) using battery tests for anxiety in mice.

OBJECTIVE: To investigate the anti-anxiety activity of "6k", a novel 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist in in mice. MATERIALS AND METHODS: Anti-anxiety activity of "6k" (1, 2, and 4 mg/kg, intraperitoneally (i.p.)) was evaluated in mice by behavioral tests such as elevated plus maze (EPM), open field test (OFT), light-dark box (L&D), and hole board test (HBT). Diazepam (2 mg/kg, i.p.) served as reference standard. RESULTS: "6k" significantly (P < 0.05) increased the time and entries in open arm in EPM as compared to vehicle control group. Further, "6k" significantly (P < 0.05) increased the central and peripheral ambulation along with rearings and time in central area; whereas, reduced the fecal pellets in OFT as compared to vehicle control group. There was significant (P < 0.05) reduction in the latency to enter dark chamber; whereas, increased number of crossings and time in light chamber in L&D aversion test by treatment with "6k" as compared to vehicle control group. In HBT, "6k" significantly (P < 0.05) increased the number of head dipping and squares crossed; whereas, reduced the latency for first head dip and number of fecal pellets as compared to vehicle control group. CONCLUSION: A novel 5-HT3 receptor antagonist has anti-anxiety action.

Integration of modeling and simulation to support changes to ondansetron dosing following a randomized, double-blind, placebo-, and active-controlled thorough QT study.

Prolongation of the QT interval has been observed with ondansetron and other members of the 5-HT3 antagonist class. This is the first thorough QTc study of ondansetron conducted in accordance with ICH E14 guidelines, designed to investigate the effect of single intravenous (IV) doses of ondansetron on cardiac conduction compared to placebo and a positive control, moxifloxacin, in healthy subjects. Statistical analysis of dose-response showed the maximum mean difference in QTcF, compared to placebo and corrected for baseline (ddQTcF), was less than 10 milliseconds (ms) after an 8 mg IV dose and approximately 20 ms after the 32 mg dose, each infused over 15 minutes. The concentration-response (Cp-ddQTcF) model resulted in similar predictions for the 8 and 32 mg and was used to predict the maximum mean ddQTcF (upper 90% CI bound) of 9.2 (11.2) ms for 16 mg IV. As a result, single IV doses of ondansetron greater than 16 mg should no longer be used. Adult cancer patients, under 75 years, may receive up to a maximum initial 15-minute IV dose of 16 mg, prior to chemotherapy, followed by 2 additional IV or IM doses of 8 mg for the management of chemotherapy-induced nausea and vomiting (CINV).

Optimizing outcomes with alosetron hydrochloride in severe diarrhea-predominant irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder that causes a range of symptoms. Currently, alosetron hydrochloride (Lotronex®), a selective serotonin type 3 receptor antagonist, is the only medication approved for the treatment of severe diarrhea-predominant irritable bowel syndrome (IBS-D) in women who have inadequately responded to conventional therapy. Alosetron has demonstrated efficacy compared with placebo in clinical trials and has been shown to improve overall health-related quality of life (HRQoL). However, rare instances of ischemic colitis and severe complications of constipation have been reported. As a result, in 2000 alosetron was voluntarily withdrawn from the market but was reintroduced in 2002 with a more restricted indication and a requirement that clinicians and patients follow a prescribing program. Although the efficacy and benefit of alosetron has been clearly demonstrated, it has been used sparingly since its reintroduction. This brief review describes the history of alosetron, efficacy of alosetron in the treatment of IBS, the impact of severe IBS on HRQoL, safety considerations, the risk evaluation and mitigation strategy program under which alosetron is now prescribed, and an update on postmarketing surveillance data.