Serotonergic modulation and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT₃ receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac?, a 5-HT₄ receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.     

RU 24969-induced emesis in the cat: 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1c implicated

RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg. 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of non-specific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (−)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205 930, methiothepin, trimethobenzamide or BMY 7378. An indirect arguments is presented that implicates a role for 5-HT_1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.     

抗血小板药物研究进展

近年来心脑血管疾病对人类健康已造成严重威胁,因而开发安全有效、价格低廉的抗血栓、抗血小板及抗凝血药已成当务之急。阿司匹林与氯吡格雷是目前抗血小板治疗的标准组合。但两药合用导致的出血发生率增加、以及日益受到关注的阿司匹林和氯吡格雷抵抗等问题,使得现有抗血小板治疗难以满足临床需要。本文从ADP受体抑制剂、凝血酶受体抑制剂、5-羟色胺受体抑制剂这四方面综述了近年来新的抗血小板药物的研究进展。     

Endothelium-dependent relaxation of porcine pulmonary arteries via 5-HT1C-like receptors

Summary In PGF₂-precontracted pulmonary arteries with intact endothelium, 5-hydroxytryptamine (5-HT, 1.0-100 nmol/l) caused a concentration-dependent reversible relaxation, at higher concentrations the contractile response prevailed. In endothelium-denuded vessels relaxation was absent. 5-HT-induced relaxation of precontracted pulmonary arteries was probably mediated by release of an endothelium-derived relaxing factor (EDRF). Preincubation of the arteries with methylene blue or N^G-nitro-Lrarginine (200 mol/l) attenuated the relaxant effect. The 5-HT-induced relaxation was accompanied by an increase in cGMP. Indomethacin (3 mol/l) did not influence the 5-HT-induced relaxation indicating that eicosanoids are not involved in the relaxant response to 5-HT.The 5-HT_1C and 5-HT₂ receptor agonist -methyl-5HT was as potent as 5-HT in inducing relaxation. The rank order of relaxant potency of the agonists investigated was -methyl-5-HT > 5-HT > 5-methoxytryptamine > tryptamine > -methyl-5-HT > 5-carboxamidotryptamine >2-methyl-5-HT > 5,6-dihydroxytryptamine > m-chlorophenylpiperazine >sumatriptan > 8-OH-DPAT.Phentolamine, pindolol and ICS 205-930 did not interfere with the relaxant effect. The 5-HT₂ receptor antagonist ketanserin (1 mol/l) inhibited the contractile response but did not alter vasodilatation. Apart from the blockade of the contractile effects, mesulergine, cyproheptadine and mianserin (0.1-3.0 mol/l, each) induced a parallel shift to the right of the concentration-response curve for the relaxation induced by a-methyl-5-HT or 5-HT. Spiperone (0.3 mol/l) exerted weak inhibitory effects on relaxation and contraction. The most potent (noncompetitive) antagonist against relaxant responses was metitepine (0.1-1.0 mol/l) which markedly depressed the relaxant maximum effect of the agonists.The failure of ketanserin and ICS 205-930 to inhibit the relaxant effect of 5-HT receptor agonists suggests that classical 5-HT₂ and 5-HT₃ receptors are not involved in the endothelium-dependent relaxation. Comparison of the rank order of potencies of agonists and antagonists with their affinities for brain binding sites revealed that the endothelial 5-HT receptors are similar to the 5-HT_1C receptor subtype. Furthermore, the endothelial receptors exhibit marked similarity to the recently cloned 5-HT receptor mediating contraction of the rat stomach fundus. Correspondence to E. Glusa at the above address     

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.     

The role of 5-HT on the cardiovascular and renal systems and the clinical potential of 5-HT modulation

The main peripheral sources of 5-hydroxytryptamine (5-HT) are as a neurotransmitter and local hormone in the gastrointestinal tract, and stored in circulating platelets and pulmonary neuroepithelial bodies. 5-HT has been shown to have many possible physiological and pathophysiological roles on the cardiovascular and renal systems. Thus, 5-HT may contribute to valvular heart disease, coronary artery disease, pulmonary hypertension, pulmonary embolism, pre-eclampsia, peripheral vascular disease and diabetic nephropathy. Consequently, modulators of the 5-HT system have diverse clinical potential. For instance, selective 5-HT subtype 3 receptor (5-HT₃) antagonists may have potential in the treatment of the pain associated with myocardial infarction. MCI-9042 (sarpogrelate) or other 5-HT_2A antagonists may have clinical potential for the treatment of vasospastic angina, ischaemic heart disease, reperfusion injury and hindlimb ischaemia. Several modulators of 5-HT (5-HT transporter inhibitors, 5-HT_1B and _2B antagonists) may have potential alone or in combination in the treatment of pulmonary hypertension. In hypertension, agonists at the 5-HT₇ and antagonists at the 5-HT_2B may reduce blood pressure, and in diabetes, sarpogrelate may protect against nephropathy.     

Inhibition of the 5-HT-induced cardiogenic hypertensive chemoreflex by the selective 5-HT3 receptor antagonist ICS 205-930

Summary We investigated the effect of ICS 205-930 [(3-tropanyl)-1H-indole-3-carboxylic acid ester], a selective antagonist at 5-HT₃ receptors, on the cardiogenic hypertensive chemoreflex in the anaesthetized dog. The reflex was elicited by injection of 5-HT (12.5–1600 g) into the left cardiac ventricle and consisted of a dose-dependent systemic hypertension associated with a decrease in heart rate. ICS 205-930 (10, 30, and 100 g/kg i.v.) caused a displacement to the right of both the dose-response curves of 5-HT-induced blood pressure increase and heart rate reduction. Its blocking effects upon the action of 5-HT could be surmounted by increasing the dose of the agonist. The selective 5-HT₂ receptor antagonist, ketanserin (0.1 mg/kg i.v.) and the combined 5-HT₁ and 5-HT₂ receptor antagonist, methiothepin (0.1 mg/kg i.v.) had no influence on the hypertensive reflex. When the reflex was elicited by the ganglionic stimulant, 1,1-dimethyl-4-phenyl-piperazinium (DMPP; 100–1600 g), ICS 205-930 had no blocking effect. The results suggest that the 5-HT-induced cardiogenic hypertensive chemoreflex is mediated by 5-HT₃ receptors. Send offprint requests to H. Berthold at the above address     

Potential serotonergic agents for the treatment of schizophrenia

Introduction: For the last 30 years, drugs targeting serotonin receptors (5-HTR) have been intensively investigated in schizophrenia. New drugs targeting 5-HTRs are under development in patients with schizophrenia.

Areas covered: In this review, the authors describe the recent clinical trials for schizophrenia with selective serotonergic agents and provide an opinion on how the investigated drugs can help to fulfil current treatment needs. Clinical trials were found in US and EU clinical trial registries and in the medical literature. Relevant 5-HTR antagonists active in animal models of schizophrenia were also analysed.

Expert opinion: Antipsychotics reduce positive symptoms of schizophrenia (delusions, hallucinations and disordered thought), but have undesirable side effects. Moreover, satisfactory treatment of negative symptoms (apathy, poverty of speech, lack of interest in social interactions) and cognitive dysfunction is currently not available. The selective 5-HT2CR full agonist vabicaserin showed antipsychotic efficacy with fewer side effects than olanzapine. Adjunctive pimavanserin (a selective 5-HT2AR inverse agonist) facilitated antipsychotic dose and side-effect reductions. Selective 5-HT3R antagonists (ondansetron, tropisetron and granisetron) showed positive results on negative symptoms and/or cognitive impairments in phase II trials. Adjunctive ondansetron has now entered a phase III trial for such indications. Finally, 5-HTA5R and 5-HT7R antagonists have shown procognitive actions in animal models of schizophrenia. These novel serotonergic drugs seem promising for improving the current treatment of schizophrenia.     

儿童术后呕吐的预防性干预策略

目的研究并比较阿扎司琼、昂丹司琼、托烷司琼、地塞米松和胃复安预防儿童术后呕吐（POV）的效果。方法 600例择期行腹股沟斜疝疝囊高扎术患儿,随机分为6组（n=100）,分别在术毕时静注阿扎司琼（A组）、昂丹司琼（B组）、托烷司琼（C组）、地塞米松（D组）、胃复安（E组）和空白生理盐水（F组）。观察并比较患儿术后24h POV发生情况。结果 A、B、C、D、E组POV的发生率（1%、3%、4%、8%、17%）均明显低于F组（29%,P〈0.05）;A、B、C和D组组间比较差异无统计学意义,但A、B、C和D组POV发生率均明显低于E组（P〈0.05）。结论阿扎司琼、昂丹司琼、托烷司琼、地塞米松和胃复安均能有效预防儿童POV的发生,但5-HT3受体拮抗剂为儿童首选预防药。     

Antagonism of baclofen's effects on rat striatal 5-HT metabolism: A model for 5-HT agonistic properties?

The increase in the rat striatal concentration of 5-hydroxyindoleacetic acid (5-HIAA) elicited by baclofen was antagonized by the 5-HT antagonists pipamperone (10/30 mg/kg i.p.), cyproheptadine (30 mg/kg i.p.), methiothepin (1 mg/kg i.p.), and GP 50 302 (1/3 mg/kg i.p.), but not by cinanserin (1–30 mg/kg i.p.), pizotifen (1–10 mg/kg i.p.), spiroperdol (0.1–1 mg/kg i.p.), or haloperidol (0.1–1 mg/kg i.p.). The 5-HT agonists, m-chlorophenylpiperazine (1 mg/kg i.p.) and MK 212 (3/10 mg/kg i.p.) also showed an antagonistic effect. Methysergide (5–20 mg/kg i.p.) and quipazine (2.5/5 mg/kg i.p.) were previously shown to act similarly, whereas mianserin (5–20 mg/kg i.p.) was inactive and methergoline at lower doses (0.25–0.5 mg/kg i.p.) increased the effect of baclofen, which was reversed at higher doses (1 mg/kg i.p.). The alterations by these compounds of the 5-HT increase elicited by baclofen were more or less similar; however, they were less clear-cut and occurred at higher doses. These interactions were not the result of interferences of the compounds with the absorption, distribution, or metabolism of baclofen nor with its effect on the nigrostriatal dopaminergic system, since the increase in dopamine concentrations it caused was not affected by any of the compounds. A comparison of our results with published data on the antagonism of 5-hydroxytryptophan-induced head twitches, on spiroperidol or 5-HT displacement, on 5-HT-stimulated adenylate cyclase, and with electrophysiological results suggests that the antagonistic effect of compounds interfering with the 5-HIAA elevating action of baclofen is not related to 5-HT receptor blocking properties of these drugs, Instead, it seems to be much more related to 5-HT agonists properties. It is speculated that this model might reveal presynaptic agonistic properties of drugs, but more data are needed to confirm or reject this.     

Pharmacological analysis of the myoclonus induced by 5-hydroxytryptophan in the guinea pig suggests the presence of multiple 5-hydroxytryptamine receptors in the brain

Myoclonus induced in guinea pigs by administration of l-5-hydroxytryptophan (5-HTP) appears to be due to stimulation of central 5-HT receptors. Dose-dependent myoclonus was induced by administration of 5-HTP (with carbidopa pretreatment), l-tryptophan and tryptamine (both with pargyline pretreatment). and also by N,N-dimethyltryptamine, 5-metoxy-N,N-dimethyltryptamine and d-lysergic acid diethylamide (LSD). The synthetic 5-HT agonists quipazine, MK-212 and 1-(m-trifluoromethylphenyl) piperazine, however, evoked only occasional myoclonus at toxic doses. Antagonists of 5-HT receptors differed markedly in their ability to inhibit 5-HTP-induced myoclonus; while methergoline and cyproheptadine were potent inhibitors, mianserin, methysergide and BW 501C67 only caused effective inhibition in large doses. Similarly, 5-HT re-uptake blockers showed different activities in potentiating the effects of a threshold dose of 5-HTP; myoclonus was greatly potentiated by chlorimipramine, paroxetine and Org 6582, while femoxetine, fluoxetine and desmethylimipramine were only weakly active.The lack of uniform effects of the 5-HT agonists, antagonists and re-uptake blockers studied is not attributable entirely to their variable actions on central 5-HT mechanisms, to their effects on other brain neuronal pathways, or to differences in cerebral penetration. The data may provide functional evidence for a multiplicity of cerebral 5-HT receptors.     

The rationale,efficacy and safety evidence for tegaserod in the treatment of irritable bowel syndrome

A growing body of evidence implicates abnormal serotonergic regulation of gastrointestinal function in the pathogenesis of the irritable bowel syndrome (IBS). Drugs targeting this system are therefore attractive concepts. The partial 5-HT₄ receptor agonist tegaserod might be predicted to have positive therapeutic effects on a constipated and uncomfortable gut. However, IBS runs a chronic, benign course and carries no associated mortality, so it is imperative that the safety profile of new pharmacological agents made available to physicians is exemplary. The authors review the evidence for 5-HT in the aetiology of IBS and its symptoms, and the data available concerning the partial 5-HT₄ receptor agonist tegaserod, in terms of rationale, efficacy and safety.     

Review of tegaserod in the treatment of irritable bowel syndrome

Tegaserod is a drug in a new class of compounds called aminoguanidine indoles and is structurally similar to serotonin (5-HT) with modifications that make the drug selective for the 5-HT₄ receptor. Tegaserod has a stimulatory effect on gastrointestinal (GI) motility that has been demonstrated in animal studies and in healthy adults. Tegaserod also increases GI secretion and reduces rectal sensitivity. Tegaserod is currently approved by the FDA for the treatment of women with constipation-predominant irritable bowel syndrome (C-IBS). Eight large Phase III clinical trials involving > 5000 IBS patients support the clinical efficacy of tegaserod in this group of patients. Patients who were treated with tegaserod had an overall improvement in IBS symptoms (Subject’s Assessment of Global Relief) as well as in secondary end points, such as abdominal pain and discomfort, stool consistency, change in bowel movements and relief of bloating. Tegaserod was well-tolerated. The most common adverse reaction in clinical trials was diarrhoea, which was usually temporary and mild, although severe diarrhoea requiring hospitalisation has been rarely (< 1%) reported.     

Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer’s disease

Introduction: There are significant efforts invested into the discovery and development of novel treatments for Alzheimer’s disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development.

Areas covered: The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words ‘5-HT6?, ‘cognition’, ‘dementia’, ‘Alzheimer’s disease’, ‘Phase II’ and ‘Phase III’ in various databases and from conference abstracts.

Expert opinion: After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.     

Alzheimer's disease R&D: Patent activity 1990–1994

The application of molecular biological techniques has revealed the existence of gene products encoding several novel putative receptors for the neurotransmitter 5-hydroxytryptamine (5-HT). For most of these novel receptors, no prior pharmacological or functional data existed, and the present challenges to pharmacologists are to identify tools to study these gene products, to determine whether or not they function as endogenous receptors and to determine potential therapeutic uses of ligands for these receptors. Here, we review work detailing the cloning and characterisation of the 5-HT₆ receptor, its distribution and evidence for functional responses mediated by naturally-occurring 5-HT₆ receptors.     

Pasteur Euroconference on Future Therapies for an Anxious World

The aim of this meeting was to explore the molecular targets for tomorrow’s drugs with a group of European and North American speakers from the pharmaceutical industry and academia presenting both data and ideas. Several speakers considered 5-hydroxytryptamine_1B/D (5-HT_1B/D) receptor antagonists to be a promising target for the treatment of obsessive compulsive disorders (OCD). 5-HT moduline, a peptide modulator of the 5-HT_1B/D receptor, presents a potentially subtle way of intervention. No clinical data are as yet available on 5-HT_1B/D receptor antagonists. The paradox of agonists, partial agonists and antagonists at the 5-HT_1A receptor (all having anxiolytic activity in animal models) was discussed. Although the 5-HT_1A agonists tested in clinical trials to date have been disappointing, the clinical potential of 5-HT_1A antagonists still has to be evaluated. Similarly, both agonists and antagonists at the 5-HT_2C receptor have been shown to be active in animal models of anxiety. It seems, however, that 5-HT_2C agonists may have a therapeutic potential in panic disorders and OCD, while the antagonists may be more appropriate in generalised anxiety. Cholecystokinin (CCK) has been shown to be implicated in panic attacks which can be induced by agonists at the CCK-B subtype. CCK-B antagonists are thus potential antipanic agents although this has not yet been confirmed by clinical trials. Finally, inhibition of glutamatergic neurotransmission produces anxiolytic effects in a wide-range of animal models and the new antagonists at the metabotropic glutamate receptors may have potential as anti-anxiety agents. This report focuses on the presentations that addressed novel drug candidates or potential new drug targets.     

2008—2010年复旦大学附属肿瘤医院5-羟色胺3受体阻断剂临床应用分析

目的:统计我院2008—2010年临床5-羟色胺3(5-HT3)受体阻断剂使用情况和发展趋势,探讨合理使用要点。方法:对我院3年来5-HT3受体阻断剂使用情况进行回顾性分析,统计药品的销售数量、金额、类别,分析临床用药趋势。结果:5-HT3受体阻断剂总体用量呈快速增长,品种使用显示出明显的变化趋势。结论:3年来5-HT3受体阻断剂总体用量增长,长半衰期品种受临床欢迎。     

Effect of 5-HT2 receptor antagonist ergolines and their desisopropyl metabolites on rabbit platelet aggregation in vitro and ex vivo

Amesergide and LY215840 are potent and long-lasting 5-HT₂ receptor antagonists after oral administration to animals. In animals, these ergolines are metabolized to their desisopropyl ergoline congeners which have lower affinity (40–60 nM) at 5-HT₂ receptors in the rat relative to higher 5-HT₂ receptor affinity (2–3 nM) at the cloned human 5-HT₂ receptor. Because amesergide and LY215840 are effective in rabbit models of thrombosis, we asked whether their efficacy in the rabbit was related in part to the activity of both the parent and desisopropyl metabolites at rabbit platelet 5-HT₂ receptors. Platelet aggregation responses were first optimized to ADP and the combination of ADP and serotonin with regard to platelet number (300,000 platelets/μl of plasma) and time (70 to 140 min after platelet harvest). In ex vivo studies, both amesergide and LY215840 (3.0 mg/kg p.o.) showed similar and marked antagonism of rabbit platelet 5-HT₂ receptors at 1 and 24 h after their oral administration to rabbits. Furthermore, the desisopropyl ergoline metabolites of both amesergide and LY215840 inhibited serotonin-amplified platelet aggregation responses in vitro as did amesergide and LY215840. Thus, these studies add support to the hypothesis that the desisopropyl metabolites of amesergide and LY215840 may contribute to the oral antithrombotic efficacy of the parent molecules in rabbits.     

肠易激综合征治疗药物的评价

目的 :评价肠易激综合征药物治疗的疗效、不良反应和药物经济学 ,以供临床用药参考。方法 :通过查阅近期国内、外相关文献总结、分析。结果与结论 :目前肠易激综合征尚无确切的治疗方法 ,主要是对症治疗和综合治疗 ,包括患者教育、心理疗法、饮食调整等 ,而药物治疗主要在于改善胃肠道动力 ,解除肠管痉挛 ,减轻肠管扩张以及抗菌消炎等 ,并且尽可能实施个体化治疗方案     

肠应激综合征治疗药物的进展与应用评价

目的:评价肠易激综合征药物治疗的疗效、不良反应和药物经济学,以供临床用药参考。方法:通过查阅近期国内、外相关文献总结、分析。结果与结论:目前肠易激综合征尚无确切的治疗方法,主要是对症治疗和综合治疗,包括患者教育、心理疗法、饮食调整等,而药物治疗主要在于改善胃肠道动力,解除肠管痉挛,减轻肠管扩张以及抗菌消炎等,并且尽可能实施个体化治疗方案。