IRRITABLE BOWEL SYNDROME Section 1

Disease Definition Irritable bowel syndrome is the most common gastrointestinal disease affecting a large number of people. The main characteristics are abdominal pain, discomfort and bloating along with altered bowel habits. The path physiology of Irritable Bowel Syndrome is mainly associated with the Brain-Gut axis: abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction and mucosal inflammation. Prevalence The prevalence of Irritable Bowel Syndrome varies from country to country. It is observed more in females than in males. It affects nearly 10-15% of the American population The prevalence rate in India is approximately 4.27.9% while in the United Kingdom it is 12%. Reports indicate 0.82% in Beijing, 8.6% in Singapore and 14% in Pakistan.

Target The main target for the drug in irritable Bowel Syndrome is the C23 receptor. It is expressed in the gastrointestinal tract of humans. The C23 receptor is specific to cholinergic neurons in human sub mucosal and myenteric plexuses.

Section 2
Drug Definition WR1234 is a C23 receptor agonist it selectively binds to C23 receptor in the gastrointestinal tract and produces analgesic effect. Mechanism of action WR1234 is a selective and potent C23 receptor agonist. The activation of C23 receptor by WR1234 helps in the release of proctatin. The proctatin is released from human colon. The release of proctatin activates proctatin receptors.

 Thus producing an analgesic effect reducing visceral hypersensitivity. WR1234 has shown cholinergic contraction inhibition in human as well as isolated rat colon.

Section 3
Target Identification WR1234 is a potent C23 receptor agonist. It selectively binds to the C23 receptor in the gastrointestinal tract and produces proctatin. The proctatin released activates proctatin receptors which induces an analgesic effect. The C23 receptor is also a capable inhibitor of cholinergic contractions when tested in human and isolated rat colon. Target validation:

Preclinical Evaluation WR1234 was tested on human colon strips it produced a significant relaxation at doses as low as 0.1 micro molar. In anaesthetized female dog in which colonic irritation was induced WR1234 produced a maximal increase in defecation reflex threshold and decreased rectal pressure. Using various animal models WR1234 was tested and it showed inhibition of cholinergic contraction, reduced visceral pain and also reduced fecal weight. WR1234 was absorbed in the gastrointestinal tract with absolute bioavailability of 30%, 43% and 46% in rat, dog and monkey respectively. With an intravenous dose the volume of distribution was greater while the plasma concentration was moderate in rats. With an oral dose the route of elimination was majorly through faeces and a minor amount was eliminated through urine. The drug-related radioactive substance was recirculated and metabolic turnover of WR1234 was low in human liver microsomes.

 Toxicology studies were carried out and no specific end organ toxicity was observed by either the oral or intravenous route. No harmful effects on reproduction and development were observed. WR1234 doesnt produce any genotoxic hazard. The clinical evaluation of WR1234 was carried out in three phase 1 studies; the studies reported that WR1234 has a median Tmax of 2h and mean t-half of 6-7.5hrs. A phase 1 study including both young and elderly male and female subjects showed that elderly females had higher exposure and the pharmacokinetics of WR1234 was both age and gender dependent. However the plasma-protein binding of both WR1234 and metabolite is independent. The studies reported an elevation in blood pressure and HR in the elderly. Another study reported that the solution formulation has higher Cmax and thus higher absorption than powdered form. In a phase 2 study of 360 IBS patients, the patients were given doses of 10, 25, 50, 100 and 200mg once for 12 weeks. Reports indicated that doses up to 100mg were safe and well tolerated with no significant changes in blood pressure and heart rate. However

AEs were reported like headache, nasopharyngitis, upper respiratory tract infection and fatigue. Patients treated with 200mg doses showed an increase in blood pressure and heart rate but were relieved from diarrhea and pain as well as abdominal distension and discomfort.