Alosetron

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.     

Alosetron and irritable bowel syndrome

Alosetron (Lotronex^®, GlaxoSmithKline) is a potent and selective 5-HT₃-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT₃ receptors on intrinsic primary afferent neurons in the mediation of the effect of alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to alosetron is currently under investigation. The most frequent adverse event associated with the use of alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of alosetron on QOL in IBS patients and the safety of treatment with alosetron, will also be covered.     

盐酸阿洛司琼的合成

2,4-二氧代-3-哌啶甲酸甲酯钠盐脱羧后与N-甲摹苯肼缩合、环合、与4-羟甲基-5-甲基咪唑缩合，最后成盐制得盐酸阿洛司琼，总收率约40％。     

Alosetron and irritable bowel syndrome

Alosetron (Lotronex, GlaxoSmithKline) is a potent and selective 5-HT(3)-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT(3) receptors on intrinsic primary afferent neurons in the mediation of the effect of alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to alosetron is currently under investigation. The most frequent adverse event associated with the use of alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of alosetron on QOL in IBS patients and the safety of treatment with alosetron, will also be covered.     

盐酸阿洛司琼的合成

以β－氨基丙到为原料,经酯化、酰胺化、环合、水解、缩合、环合、缩合并成盐制得盐酸阿洛司酮,总收率15．6％,并且改进了中间体8和11的提取分离及纯化工艺。操作简便,产品质量得到改善。     

盐酸阿洛司琼合成工艺改进

目的：改进盐酸阿洛司琼的合成工艺，以利于工业生产。方法：以２，４—哌啶二酮－３—羧酸甲酯与Ｎ—甲基苯肼缩合后在硫酸和醋酸存在下环合得制２，３，４，５—四氢—５—甲基—１Ｈ—吡淀并［４、３—ｂ］吲哚—１—酮，然后甲基化，再与４—羟甲基—５—甲基咪唑在对甲苯磺酸催化下缩合。结果：制得合格的盐酸阿洛司琼，总收率３８％。结论：经改进的工艺操作简便，比原工艺更易于工业化生产。     

盐酸阿洛司琼片剂的研制

研制盐酸阿洛司琼片剂,建立了紫外分光光度法测定片剂的含量,在0.1mol/L盐酸溶液中测定波长为295nm,标准曲线A=0.0279C-0.0012,相关系数r=0.9999。加样回收率分别为99.01%,99.48%,100.63%,RSD均小于1%,三批片剂的含量分别为99.32%,100.04%,99.70%。含量均匀度分别为6.612,6.97,5.05。日间和日内误差分别为0.88%,0.63%。三批片剂30min的溶出度高于90%。     

盐酸阿洛司琼片剂的研制

研制盐酸阿洛司琼片剂,建立了紫外分光光度法测定片剂的含量.在0.1 mol/L盐酸溶液中测定波长为295 nm,标准曲线A=0.0279C-0.0012,相关系数r=0.9999.加样回收率分别为99.01%、99.48%、100.63%,RSD均小于1%.三批片剂的含量分别为99.32%、100.04%、99.70%,含量均匀度分别为6.61、6.97、5.05,日间和日内误差分别为0.88%、0.63%.三批片剂30min的溶出度高于90%.     

盐酸阿洛司琼合成工艺改进

目的 :改进盐酸阿洛司琼的合成工艺 ,以利于工业生产。方法 :以 2 ,4 -哌啶二酮 - 3-羧酸甲酯与 N -甲基苯肼缩合后在硫酸和醋酸存在下环合得制 2 ,3,4 ,5 -四氢 - 5 -甲基 - 1H-吡啶并 [4、3- b]吲哚 - 1-酮 ,然后甲基化 ,再与 4 -羟甲基 - 5 -甲基咪唑在对甲苯磺酸催化下缩合。结果 :制得合格的盐酸阿洛司琼 ,总收率 38%。结论 :经改进的工艺操作简便 ,比原工艺更易于工业化生产     

Alosetron for severe diarrhea-predominant irritable bowel syndrome: improving patient outcomes

Abstract

Background:

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder often diagnosed and managed by primary care physicians (PCPs). Despite the high prevalence of IBS, symptom severity is often underappreciated and inadequately managed. The goal of this review is to discern IBS treatment gaps and identify opportunities for improving its management in the primary care setting, as well as describe the most current clinical experience with alosetron, a targeted treatment for severe diarrhea-predominant IBS (IBS-D) in women.     

Alosetron does not affect the visceral perception of gastric distension in healthy subjects

Background: The effect of alosetron, a new specific 5-HT₃, receptor antagonist, on the visceral perception in response to gastric distension was assessed in 12 healthy male subjects in a randomized, double-blind, placebo controlled crossover trial Methods: Each subject was given orally either alosetron 1 mg b.d. or placebo b.d. for 6 days (wash-out period 7–28 days). At the end of each dosing period, both isobarometric and isovolumetric gastric distensions were performed using an electronic barostat. Results: Alosetron did not modify the gastric wall compliance (pressure-volume relationship). Alosetron had an effect similar to placebo on the visceral perception scores in both isobarometric and isovolumetric distensions. The mean (± SEM) thresholds for abdominal discomfort were, respectively, 16.8 ±0.7 mmHg and 825 ± 61 mL with alosetron, 16.7±0.6 mmHg and 883±45 mL with Placebo (P = NS). Conclusions: 5-HT₃ receptors do not appear to be involved in the visceral perception of gastric distension in healthy subjects.     

Alosetron,cilansetron and tegaserod modify mesenteric but not colonic blood flow in rats

Background and purpose:

As the use of the 5-HT₃ receptor antagonist alosetron (GlaxoSmithKline) and the 5-HT₄ receptor agonist tegaserod (Novartis) in patients with irritable bowel syndrome has been associated with cases of ischaemic colitis, the effects of alosetron, cilansetron (Solvay) and tegaserod on the rat splanchnic circulation were evaluated.

Experimental approach:

Phenobarbital-anaesthetised rats were instrumented to record blood flow in the superior mesenteric artery and transverse colon and to calculate mesenteric and colonic vascular conductance.

Key results:

Intravenous alosetron (0.03–0.3 mg·kg⁻¹) did not alter blood pressure or heart rate but reduced mesenteric blood flow and vascular conductance by 15–20%. This activity profile was also seen after intraduodenal alosetron and shared by the 5-HT₃ receptor antagonist cilansetron. In contrast, blood flow, vascular conductance and intraluminal pressure in the colon were not modified by alosetron and cilansetron. Intravenous or intraduodenal tegaserod (0.3–1.0 mg·kg⁻¹) had no inhibitory effect on mesenteric and colonic blood flow. Peroral treatment of rats with alosetron or tegaserod for 7 days did not modify mesenteric haemodynamics at baseline and after blockade of nitric oxide synthesis. Mild inflammation induced by dextran sulphate sodium failed to provoke a vasoconstrictor effect of cilansetron in the colon.

Conclusions and implications:

Alosetron and cilansetron, not tegaserod, caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered. The relevance of these findings to the treatment-associated occurrence of ischaemic colitis in patients with irritable bowel syndrome remains open.     

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Aim : To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing. Methods : Thirty healthy men and women received 1 mg oral alosetron twice‐daily for 29.5 days and a single oral dose of a metabolic probe cocktail before and on the last day of alosetron dosing. Serum alosetron concentrations were measured on days 1, 8, 15, 22 and 29. Probe‐substrate and metabolite concentrations were measured after each cocktail dose. Results : Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probe‐metabolite/substrate ratios associated with CYP2C19, 2E1, 2C9, or 3A4 activity, but modestly decreased those associated with CYP1A2 and N‐acetyltransferase activity. Systemic exposure to alosetron was higher in women, positively correlated with age and body mass index, and negatively correlated with CYP1A2 activity. Incidence of constipation was higher in women, but not associated with alosetron concentration. Conclusions : Single dose data can reliably predict the pharmacokinetics of alosetron after repeated doses. Alosetron exhibits limited potential for inhibition of cytochrome P450‐mediated metabolism. Interindividual differences in alosetron pharmacokinetics associated with demographic factors may be related to strong dependence on metabolism by CYP1A2.     

Alosetron in irritable bowel syndrome: strategies for its use in a common gastrointestinal disorder

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterised by recurrent abdominal pain and altered bowel habits in the absence of any discernible structural, biochemical and physiological abnormalities. Although there is no specific biological marker for the diagnosis of this disorder, recently developed symptom-based criteria provide the tools necessary to make a diagnosis. The precise underlying pathophysiology of IBS remains unknown. However, disturbances in the brain-gut axis involving the central nervous system and the enteric nervous system have emerged as an underlying concept for IBS. In this regard, conventional treatment has been recognised as unsatisfactory for many patients with IBS and novel, neuroenteric modulatory compounds have been introduced for use by clinicians. Specifically, compounds interacting with the 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT3 and 5-HT4 subtype have been demonstrated of benefit in some patients for the treatment of IBS. In this leading article, we present the current data on the pharmacology, clinical trials, indications and adverse effects of alosetron, a potent and selective 5-HT3 antagonist. As a result of the recognition of serious adverse effects, the indication for alosetron has been restricted and it is now indicated only for women with severe diarrhoea-predominant IBS who have symptoms for at least 6 months and who have failed to respond to conventional therapy. Prescribing restrictions and the risk-management programme implemented as required by the US FDA is reviewed along with a summary of the studies to be performed after reintroduction of alosetron to monitor safety.     

Alosetron relieves pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome patients

BACKGROUND: Irritable bowel syndrome is one of the most common gastrointestinal disorders, yet no therapy convincingly controls the multiple symptoms of this syndrome. AIM: To compare the efficacy and tolerability of the new 5-HT3-receptor antagonist alosetron and the smooth muscle relaxant mebeverine in a double-blind, multicentre, randomized trial. METHODS: Six hundred and twenty-three nonconstipated females with irritable bowel syndrome were randomized to receive alosetron 1 mg twice daily (n=319) or mebeverine 135 mg three times daily (n=304) for 12 weeks, followed by a 4-week post-treatment period. The primary efficacy end-point was monthly responders for adequate relief of irritable bowel syndrome related abdominal pain and discomfort (defined as patients reporting adequate relief on at least 2 out of 4 weeks). Secondary end-points included assessments of bowel function, including urgency, stool frequency and stool consistency. RESULTS: There were significantly more responders in the alosetron group compared with mebeverine at months 2 and 3 (P < 0.01). Compared with mebeverine, the alosetron group experienced significant decreases in proportion of days with urgency and mean stool frequency, and had firmer stools within 1 week of starting treatment. A similar proportion of patients reported adverse events in the two treatment groups. CONCLUSIONS: In nonconstipated female irritable bowel syndrome patients, alosetron is significantly more effective than mebeverine in improving symptoms.