How can we develop better antispasmodics for irritable bowel syndrome?

ABSTRACT

Introduction: Irritable bowel syndrome (IBS) is a prevalent gastrointestinal (GI) disease. Antispasmodics are a heterogeneous group of drugs that tackle IBS-associated altered bowel habit and abdominal pain. However, some studies have shown their failure to exhibit benefit over placebo. Considering the place of antispasmodics in managing key symptoms of IBS, there is a growing need for developing more efficacious and safe antispasmodics.

Areas covered: The authors discuss the role of rational drug design (RDD) in developing new antispasmodics with desired features. Furthermore, they review the potential pharmacological targets and herbal medicines with spasmolytic activity. In addition, the authors present the recent findings concerning novel mechanisms involved in GI motility modulation as well as the potential antispasmodic role of drugs used in other conditions.

Expert opinion: To develop better antispasmodics, it will be essential to gain a deeper insight into the underlying mechanisms involved in IBS-induced dysmotility and to uncover GI-specific receptors that regulating motility. New antispasmodics with GI-restricted and the multi-targeting features can be developed via implementation of RDD. Furthermore, the modification of current antispasmodics by formulation technologies might expedite the development of better antispasmodics. To conclude, the complex nature of IBS means that future successful drug discovery will require a multi-disciplinary approach.

KEYWORDS:

• Irritable bowel syndrome
• drug discovery
• new techniques

Article highlights

• A better antispasmodic must be able to target ‘multiple’ receptors ‘selectively’ in GI in order to obtain the highest efficacy and safety profile. We have limited the target receptors to the GI because the relationship between pathways in the gut, brain and the immune system is still vague.

• In order to design better antispasmodics, we need an improved understanding of the IBS pathophysiology and the motility-modulatory mechanisms that are impaired and need to be manipulated.

• A way to design a selective antispasmodic is to identify motility-regulating receptors that are expressed in the GI with minimal effects in other organs. This demands deeper insight and knowledge of pharmacologic targets uniquely expressed in GI

• An antispasmodic with poor oral absorption tends to result in less adverse effects due to GI-limited characteristics. Therefore, altering the pharmacokinetics of the available antispasmodics may provide a short cut to more safe drugs.

• Since the dominant approach in the development of antispasmodics for IBS is modulation of GI motility through alteration of GI SMCs contraction, any factor influencing GI motility can be a potential pharmacologic target including VIP, purinergic system, opioids, and serotonin systems.

• Development of a novel drug molecule contains great risks, therefore, modification of current antispasmodics or taking advantage of drugs indicated for similar conditions appears very attractive. Formulation technologies provide this opportunity to enhance colon delivery of antispasmodics to increase the concentration of the drug in the site of action and avoid adverse effects

• Some herbal medicines have shown benefit by alleviating IBS-like symptoms upon empirical use. Evaluation of these medicines may expedite the discovery of a novel antispasmodic by introducing new compounds with spasmolytic feature that may lay a foundation for a synthetic drug.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.