Experimental Disease Models

The ideal future therapeutic advances for IBS are likely to be based on the treatment of the multiple components of this disorder, including both abdominal pain and bloating and multiple symptoms arising from dysmotility. Unfortunately, there is currently no animal model of IBS; thus, the experimental testing of new treatments is most challenging. Because IBS is a multifactorial disorder, it is unlikely that a single model (produced by a specific single insult or procedure) will ever be developed that mimics in full the diversity of the disorder in humans. Furthermore, the problem is compounded by the role of species differences in the physiology, pathophysiology, and pharmacology of the systems involved. For these reasons, select animal models have been developed to understand specific components of IBS or to test symptomatic treatment approaches independently of pathophysiology.

From the perspective of a researcher trying to understand IBS and its causes, the primary aim must be to find the condition or, more likely, the set of conditions that leads to the closest overall animal phenotype to the human IBS state. This area recently was reviewed extensively by two such researchers who have played significant roles in advancing our understanding of IBS pathophysiology.126 Mayer and Collins120 describe two broad categories of approaches taken to date are based upon either peripheral or central initial insults, and to these, they add a third growing area of genetic manipulation. They also consider the relationship of these models to symptoms in humans, the need for chronicity in its phenotype, the role of species and sex, and, perhaps most importantly, their predictive value with respect to therapeutic outcome. Researchers accept that it is not necessarily the case that we will ever be in a position in which we have a single model that mimics even one subset of IBS, but some attempts have led to interesting phenotypes that have encouraged continued effort. Notable examples of these are as follows:

1. The SERT knockout mouse, which produces a heavier and wetter stool than its wild-type littermates and has a colonic transit phenotype that is either increased (cf. diarrhea) or decreased (cf. constipation).104

2. The maternal separation model, which has its basis in mimicking stressful early life events and thus is based primarily upon a CNS disturbance manifesting itself in the periphery. The model has a phenotype of enhanced visceral sensitivity and altered colonic response to acute stress.127

3. The Trichanella spiralis PI-IBS model, which models the specific subset of PI-IBS and leads to intestinal dysmotility and colorectal hypersensitivity that outlasts the infection.128'129

4. The neonatal irritation model, which describes a long-lasting colorectal hypersensitivity and altered colonic function after either chemical or mechanical rectal irritation in neonatal life. The model has a most impressive chronicity, with the phenotype lasting several months.130

5. The postinflammatory-IBS model (trinitrobenzosulfonic acid (TNBS)), which shows a long-lasting (up to 60 days) colorectal hypersensitivity after intracolonic TNBS treatment in rats.131

All these models have advanced our understanding of the mechanisms that can lead to chronic visceral hypersensitivity, colonic dysmotility, and, perhaps, the resulting phenotypes of hyperalgesia and altered bowel function in patients with IBS. However, for the purposes of the drug discoverer and developer, the value of such models needs to be balanced with some other needs. Although active research within the industry is focused upon disorder pathophysiology and the hunt for an all-encompassing IBS model, in the absence of the perfect model, there is also a need to use technologies already available to evaluate new therapeutic approaches. This requirement necessitates the use of higher-throughput models that are primarily aimed at modeling or providing information around a single end point, rather than an entire disorder. Some of these techniques are better described as assays, rather than models, and this is an important distinction for the industrial scientist to bear in mind when considering the data or how to obtain it.

If we consider the scale of opportunity from the bottom up, in the IBS arena, we might perform the following actions:

1. Start with a simple assay of the effect of a tool compound upon normal GI transit, or visceral pain, regardless of pathophysiology. A positive effect here may provide the impetus for the development of new ligands at the target and for further studies in models.

2. Next, test whether the efficacy is reproduced in simple models of visceral hyperalgesia or dysmotility, for example, those employing acute inflammation or acute stress as insults.

3. Finally, end with a study of one or more of the more involved models of the disorder if any are available.

However, an argument exists in the IBS arena for placing more emphasis on point 2 than point 1 and for not stopping in the event of a negative outcome of the initial simple assays. This occurs because the effect of a target may become apparent only following some kind of insult to produce the model phenotype. Furthermore, this may be the optimal approach for treatment because an agent that only affected the model and not the assay may provide more of a normalizing influence (e.g., an antihyperalgesic or anticonstipation activity), rather than a direct inhibitory or stimulatory one (e.g., analgesic or direct prokinetic/laxative effect). The benefit in the clinic would be that normal processes should be left unaffected, and only those that had been disturbed would be attacked. However, the drawback here is the potential for false-positive results in preclinical development that do not translate to a benefit in clinical trials several years down the line, perhaps due to the mechanisms involved in the model not matching those at work in the disorder itself.

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

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