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Disease definition
Irritable Bowel Syndrome is a most common chronic lower Gastrointestinal tract condition marked by recurring symptoms of abdominal pain, swelling and distention of abdomen and bowel dysfunction, characterized constipation, loose bowels (diarrhea) or alternating episodes of both in the absence of structural, anatomical, biochemical abnormalities.
Disease prevelance
According to the 2013 statistics the rate of prevalence for IBS worldwide is about 923% and U.S IBS Prevalence rate ranges from 10-15%. It was estimated that about 30% (5%severe and 25%moderate) of the prevalent population with IBS have consulted health care professionals and about 70% population with mild functional bowel disorder have not consulted in 2013. Studies carried out in the U.S annually showed between 2.4-3.5 millions general practioner visit for IBS.(International foundation for functional gastrointestinal disorders,2013)
Target definition
A biological target C23 receptor is located on the digestive tract in humans and it is the target towards which a highly selective and potent agonist drug WR1234 is directed to bind in the treatment of irritable bowel syndrome. Binding of the agonist drug (WR1234) to the C23 receptor then exerts a pharmacological response.
Definition of drug/compound
WR1234 is a highly selective C23 receptor agonist inhibiting cholinergic contraction in human colon.
Mechanism of action
Mechanism of WR1234 is based on the fact that it slows down the visceral hypersensitivity on activation of C23 receptor, receptor activation then produces endogenous pain reliving substance i.e. Proctatin from gastrointestinal tract. Activation of proctatin receptor present on some afferent nerve fiber then produces an analgesic effect. As WR 1234 responded to the release of proctatin from human isolated colon. It is concluded that activation of C23 receptor increases proctatin release and activation of proctatin receptor could produce an analgesic effect.
Target validation
Experiment done in wt mice and k/o mice showed that when the drug agonizes the C23 receptor, it slows down the gastrointestinal transit in wt mice but not in k/o mice. These drug receptor binding have also shown to relax gastrointestinal smooth muscle in different species, and to stop continuous cholinergic contraction in human and rat isolated colon. C23 agonist is also involved in relaxing precontracted human colon longitudinal and circular muscle.
Compound Screening
NO SUCH INFORMATION IS AVAILABLE
Preclinical evaluation
DMPK STUDIES
Pharmacokinetic study of WR1234was done in rat, dog, monkey. In solution of rat, dog and monkey the absolute bioavailability observed was 30%, 43%and 46%. By intravenous administration of WR1234 in rat Volume of distribution was greater (~2.8L/Kg), with moderate plasma clearance (19.9-29.3mL/min/kg) then in dog and monkey. By oral administration the elimination of WR1234 in rat, dog and monkey was greater via the feaces (85-99%) and only small amount was eliminated via urine.
TOXICOLOGY STUDIES An embryo fetal developmental toxicity, genetic and repeated dose toxicity was
performed in mice, rat, rabbit and monkey with WR1234. No observed adverse effect level observed in: 26 weeks rat study was 500mg/kg/day 52 weeks monkey study was 250 mg/kg/day During both study no signs of organ toxicity has been observed.
Genetic study presented that no genotoxic hazard with WR1234 in human will be
observed.
INVITRO STUDIES
The study was carried out using human colon strips where WR1234 had shown significant relaxation and suppression of spontaneous activity at lo concentration of 0.01-10M.
INVIVO STUDIES
Studies on anesthetized female dogs indicated that an intravenous dose of 3mg/kgWR1234 elicited an increase in defecation reflex threshold and decreased rectal pressure.
Clinical Evaluation
Pharmacokinetic Results of completed 1st 3 out of 6 phase 1 study showed that median t max of WR1234 and WR8593 was 2h and 4h approximately.
Mean t of WR1234 and WR8593 was 6-7.5h and 5-6h. This study demonstrated that doses up to 200mg were well tolerated. Occurrence of adverse event and changes in blood pressure and heart rate were not dose dependent.
Next phase 1 study showed that single doses of 100mg tablet administered orally were well tolerated in young and elderly male and female subjects.
Plasma protein binding of WR1234= 99.3% and WR8593 =99.1%. It was the first clinical study to assess protein binding of metabolite. Pharmacokinetic result of another phase 1 study estimated that absorption rate of single oral dose of 40mg WR1234 was higher when administered as solution then powder via Intel site Companion capsule.
Next phase 1 was comparison study in healthy subjects betweenWR1234 200mg modified release, extended release and gastro-retentive formulation to 100mg BID immediate release tablet.
Result of phase 2 completed studies indicated that WR1234 was found incurable for abdominal pain and relief from diarrhea at 100mg doses but was curable at 200mg doses.
INDEX
SRNO TOPIC 1. SECTION 1:Disease and target background Disease definition Disease prevalence Target definition 2. SECTION 2:Drug /compound background Definition of drug/compound Mechanism of action 3. SECTION 3:Drug discovery process this drug went through Target identification Target validation Compound screening Lead identification and optimization Preclinical evaluation Clinical evaluation 4. SECTION 4: Summary and conclusion 5. REFERENCE PAGE NO 1
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