Kinin B1 receptors as a therapeutic target for inflammation

Introduction: Kinins are peptide mediators exerting their pro-inflammatory actions by the selective stimulation of two distinct G-protein coupled receptors, termed BKB1R and BKB2R. While BKB2R is constitutively expressed in a multitude of tissues, BKB1R is hardly expressed at baseline but highly inducible by inflammatory mediators. In particular, BKB1R was shown to be involved in the pathogenesis of numerous inflammatory diseases.

Areas covered: This review intends to evaluate the therapeutic potential of substances interacting with the BKB1R. To this purpose we summarize the published literature on animal studies with antagonists and knockout mice for this receptor.

Expert Opinion: In most cases the pharmacological inhibition of BKB1R or its genetic deletion was beneficial for the outcome of the disease in animal models. Therefore, several companies have developed BKB1R antagonists and tested them in phase I and II clinical trials. However, none of the developed BKB1R antagonists was further developed for clinical use. We discuss possible reasons for this failure of translation of preclinical findings on BKB1R antagonists into the clinic.     

Bradykinin receptors as a therapeutic target

Biologically-active kinins, including bradykinin (BK) and Lys⁰-BK (kallidin), are short-lived peptide mediators predominantly generated by the enzymatic action of kallikreins on kininogen precursors. A diverse spectrum of physiological and pathological actions attributed to local kinin production is a consequence of the activation of G-protein-coupled receptors (GPCRs). Currently, two major subtypes of kinin receptor, designated B₁ and B₂, are recognised, although there is much evidence for pharmacological heterogeneity, particularly within the B₂ receptors. Considering these facts and the widespread distribution of kinin receptors in many human tissues, it is no surprise that the therapeutic potential of kinins and kinin receptor antagonists remains the focus of numerous investigations. Studies in animals and animal tissues, instrumental in elucidating the biological roles of kinins, are well-documented in numerous excellent reviews. Unfortunately, and despite the enormous potential illustrated by animal studies, attempts to develop kinin analogues as therapeutic agents to combat human disease have largely proven disappointing. Consequently, this review selectively focuses upon studies that are directly relevant to the targeting of human BK receptors as a therapeutic intervention. In addition to providing a succinct review of well-documented pathological conditions to which kinin receptors contribute, the authors have also included more recent data that illustrate new avenues for the therapeutic application of kinin analogues.     

Bradykinin receptors as a therapeutic target

Biologically-active kinins, including bradykinin (BK) and Lys(0)-BK (kallidin), are short-lived peptide mediators predominantly generated by the enzymatic action of kallikreins on kininogen precursors. A diverse spectrum of physiological and pathological actions attributed to local kinin production is a consequence of the activation of G-protein-coupled receptors (GPCRs). Currently, two major subtypes of kinin receptor, designated B(1) and B(2), are recognised, although there is much evidence for pharmacological heterogeneity, particularly within the B(2) receptors. Considering these facts and the widespread distribution of kinin receptors in many human tissues, it is no surprise that the therapeutic potential of kinins and kinin receptor antagonists remains the focus of numerous investigations. Studies in animals and animal tissues, instrumental in elucidating the biological roles of kinins, are well-documented in numerous excellent reviews. Unfortunately, and despite the enormous potential illustrated by animal studies, attempts to develop kinin analogues as therapeutic agents to combat human disease have largely proven disappointing. Consequently, this review selectively focuses upon studies that are directly relevant to the targeting of human BK receptors as a therapeutic intervention. In addition to providing a succinct review of well-documented pathological conditions to which kinin receptors contribute, the authors have also included more recent data that illustrate new avenues for the therapeutic application of kinin analogues.     

Atypical antipsychotics as a possible treatment option for irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder (FGID) that is characterised by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Although the pathophysiology of IBS is not fully understood, it is believed that psychiatric comorbidities are highly common in such patients. A variety of psychotropic medications are widely used in the treatment of IBS, particularly older antidepressants such as tricyclic antidepressants (TCAs).

Areas covered: With the advent of newer antidepressant classes with better safety and tolerability compared with TCAs, such as serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), clinicians now have more advanced treatment options for treating IBS. Additionally, some atypical antipsychotics (AAs) have recently received approval for treatment of major depressive disorder (MDD). Some AAs may have potentials based on their pharmacodynamic profile and proven benefit for mood symptoms, pain, anxiety and sleep disturbances. This article describes the potential rationale, clinical data and practical aspects involved in the use of AAs for patients with IBS.

Expert opinion: Atypical antipsychotics (AAs) may have a role in the treatment of irritable bowel syndrome (IBS) based on the currently available findings, although there is no clear evidence, and a number of clinical issues to be addressed in the use of AAs for the treatment of IBS.     

Quaternary ammonium derivatives as spasmolytics for irritable bowel syndrome

Quaternary ammonium derivatives such as cimetropium, n-butyl scopolammonium, otilonium and pinaverium bromide have been discovered and developed as potent spasmolytics of the gastrointestinal tract. Their pharmacological activity has been proven in both "in vivo" and "in vitro" studies of hypermotility. "In vitro" experiments showed that they possess antimuscarinic activity at nM level but only pinaverium and otilonium are endowed with calcium channel blocker properties. These latter compounds relaxed the gastrointestinal smooth muscle mainly through a specific inhibition of calcium ion influx through L-type voltage operated calcium channels. Molecular pharmacology trials have indicated that pinaverium and otilonium can bind specific subunits of the calcium channel in the external surface of the plasma membrane and in this way they block the machinery of the contraction. Recent evidence showed that otilonium is able to bind tachykinin NK(2) receptors and not only inhibits one of the major contractile agents but can reduce the activation of afferent nerves devoted to the passage of sensory signals from the periphery to the central nervous system. Thanks to their typical physico-chemical characteristics, they are poorly absorbed by the systemic circulation and generally remain in the gastrointestinal tract where they exert the muscle relaxant activity by a local activity. Some differences exists in the absorption among these compounds: both n-butyl scopolammonium and cimetropium are partially taken up in the bloodstream, pinaverium has a low absorption (8-10 %) but is endowed with an excellent hepato-biliary excretion and otilonium, which has the lowest absorption (3 %), is almost totally excreted by faeces. Quaternary ammonium derivatives are widely used for the treatment of irritable bowel syndrome and recent meta-analyses have supported their efficacy in this disease. Due to its therapeutic index, the use of n-butyl scopolammonium is more indicated to treat acute colics than a chronic disease such as irritable bowel syndrome. Taking into consideration the published trials carried out with validated methodology in irritable bowel syndrome, cimetropium and otilonium are the best demonstrated drugs for the improvement in global assessment, pain and abdominal distension.     

Microecology as a target for therapeutic intervention in inflammatory bowel disease

The gastrointestinal tract is populated by several hundred grams of bacteria. Recognition of the symbiosis between bacteria and host is drawing particular attention to the implications of bacteria in human health. Probiotics are living microorganisms that upon ingestion in certain numbers exert health benefits. Prebiotics are non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of a limited number of gut bacteria. In inflammatory bowel disease (IBD), the gut flora is the key factor driving the inflammatory process that leads to intestinal lesions. Interaction of certain commensal bacteria with the gut mucosa triggers mucosal inflammation. However, certain probiotic strains are able to downregulate inflammatory pathways. Restoring the microbial balance with prebiotics and probiotics offers promise for the control of IBD.     

Enteric P2X receptors as potential targets for drug treatment of the irritable bowel syndrome

The irritable bowel syndrome (IBS) is a gastrointestinal motility disorder affecting millions of patients. IBS symptoms include diarrhea, constipation and pain. The etiology of IBS is due partly to changes in the function of nerves supplying the gastrointestinal tract, immune system activation and to psychological factors. P2X receptors are multimeric ATP-gated cation channels expressed by neuronal and non-neuronal cells. Sensory nerve endings in the gastrointestinal tract express P2X receptors. ATP released from gastrointestinal cells activates P2X receptors on sensory nerve endings to stimulate motor reflexes and to transmit nociceptive signals. Antagonists acting at P2X receptors on sensory nerves could attenuate abdominal pain in IBS patients. Primary afferent neurons intrinsic to the gut, and enteric motor- and interneurons express P2X receptors. These neurons participate in motor reflexes. Agonists acting at enteric P2X receptors may enhance gastrointestinal propulsion and secretion, and these drugs could be useful for treating constipation-predominant IBS. Antagonists acting at enteric P2X receptors would decrease propulsion and secretion and they might be useful for treating diarrhea-predominant IBS. Current knowledge of P2X receptor distribution and function in the gut of laboratory animals provides a rational basis for further exploration of the therapeutic potential for drugs acting at P2X receptors in IBS patients. However, more information about P2X receptor distribution and function in the human gastrointestinal tract is needed. Data on the distribution and function of P2X receptors on gastrointestinal immune cells would also provide insights into the therapeutic potential of P2X receptor agents in IBS.     

Emerging drugs for irritable bowel syndrome

Irritable bowel syndrome is extremely common and its severity is widely underestimated. Unfortunately, the current pharmacological treatment of this condition is far from satisfactory which might suggest that it would be an area in which the pharmaceutical industry would take a great interest. However, drug development in this field, especially in relation to 5-hydroxytryptamine (5-HT), has been beset by difficulties with side effects and, what some authorities would claim, an unnecessarily strict regulatory climate based on the perception that irritable bowel syndrome is not a particularly serious condition. This has resulted in a rapid withdrawal from the scene by a number of companies although with the identification of some potential new therapeutic targets, the area has not been totally abandoned.     

Tegaserod for constipation-predominant irritable bowel syndrome

Tegaserod, a selective and partial agonist at the 5-hydroxytryptamine (5-HT [serotonin]) receptor subtype 4 (5-HT4), is the only United States Food and Drug Administration-approved drug for the treatment of constipation-predominant irritable bowel syndrome (IBS) in women. The drug's stimulation of 5-HT4 receptors on intestinal enterocytes increases peristaltic activity and fluid secretion into the gut lumen, facilitating stool passage. In addition, affinity of tegaserod for 5-HT4 receptors modulates visceral sensitivity, which helps alleviate abdominal pain associated with constipation-predominant IBS. The drug's pharmacokinetic and pharmacodynamic parameters do not differ significantly with age or sex. Tegaserod safely and effectively relieves overall gastrointestinal symptoms and abdominal discomfort and normalizes bowel habits in patients with constipation-predominant IBS. It is associated with few drug interactions. In clinical studies, tegaserod was well tolerated, and its adverse-effect profile was similar to that of placebo. Severe diarrhea, as well as abdominal pain, flatulence, headache, and nausea, were the most commonly reported events. Patients who experience severe diarrhea should discontinue the drug. With the data available, tegaserod remains an option for patients with constipation-predominant IBS.     

肠易激综合征的药物治疗

肠易激综合征(IBS)是临床常见的功能性肠道疾病,其基本病因尚未完全阐明,因而目前尚缺乏特异性药物治疗手段.目前临床IBS治疗仍是以对症治疗为主的综合性治疗,包括饮食治疗、药物治疗和心理治疗等,解痉剂、止泻剂、缓泻剂、抗菌药物及微生态制剂等均能用于IBS的治疗.     

The value of a general therapeutic approach in subjects with irritable bowel syndrome

BACKGROUND: The general therapeutic approach is the cornerstone in the management of irritable bowel syndrome, but the effect is poorly documented. AIM: To evaluate the effect of the general therapeutic approach for irritable bowel syndrome. METHODS: Subjects with irritable bowel syndrome identified in a public screening were included. Scores for abdominal symptom (range 0-12), musculoskeletal pain and mood disorders were calculated. After exclusion of other disorders, a doctor presented irritable bowel syndrome as a positive diagnosis, gave information, reassurance and lifestyle advice, but no pharmacotherapy. A dietician gave dietary advice. There was a follow-up after 6 months. RESULTS: Sixty-five persons (females/males: 44/21) with mean age 49 years (range 31-76) were included, 31 (48%) were recommended dietary changes. Twenty subjects (31%) had satisfactory relief of symptoms after 6 months. The scores for abdominal symptom was reduced from 3.1 to 2.2 (P = 0.007), the reduction was 2.2 in the diarrhoea-predominant group given advice compared with 0.4 in the other subjects (P = 0.035). Previous consultations for the complaints, visits for psychiatric disorders, and presence of mood disorders were predictors of persistent complaints. CONCLUSIONS: There was a significant relief of symptoms after 6 months, those with psychological co-morbidity responded less well. The effect of dietary advice was only seen in those with diarrhoea-predominant irritable bowel syndrome.     

Emerging drugs for irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common chronic gastrointestinal disorders, yet its pathophysiology is incompletely understood and pharmacological treatments remain unsatisfactory. Current therapeutic choices include a range of drugs aimed at normalising bowel habits, reducing pain or treating comorbid psychological symptoms. However, this individual symptom-targeted approach remains unsatisfactory in terms of global symptom relief and patient satisfaction. In the last decade, further characterisation of IBS pathophysiology has provided new and exciting targets at different levels of the brain–gut axis for the development of several candidate drugs. Advances in clinical trial design will help to evaluate these compounds in different IBS patient populations.     

Emerging drugs for irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common chronic gastrointestinal disorders, yet its pathophysiology is incompletely understood and pharmacological treatments remain unsatisfactory. Current therapeutic choices include a range of drugs aimed at normalising bowel habits, reducing pain or treating comorbid psychological symptoms. However, this individual symptom-targeted approach remains unsatisfactory in terms of global symptom relief and patient satisfaction. In the last decade, further characterisation of IBS pathophysiology has provided new and exciting targets at different levels of the brain-gut axis for the development of several candidate drugs. Advances in clinical trial design will help to evaluate these compounds in different IBS patient populations.