View source for Prucalopride

{{drugbox
| IUPAC_name        = 4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide
| image             = Prucalopride.png
| width             = 220
| CAS_number        = 179474-81-8
| synonyms          = 
| ATC_prefix        = A03
| ATC_suffix        = AE04
| PubChem           = 3052762
| IUPHAR_ligand = 243
| DrugBank          = 
| C = 18 | H = 26 | Cl = 1 | N = 3 | O = 3
| molecular_weight  = 367.870 g/mol
| smiles            = COCCCN1CCC(CC1)NC(=O)C2=CC(=C(C3=C2OCC3)N)Cl
| bioavailability   = 
| protein_bound     = 
| metabolism        = 
| elimination_half-life = 
| excretion         = 
| pregnancy_AU      =  <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US      =  <!-- A / B            / C / D / X -->
| pregnancy_category=  
| legal_AU          =  <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA          =  
| legal_UK          =  
| legal_US          =  
| legal_status      = 
| routes_of_administration = Oral
| licence_EU        = Resolor
}}
'''Prucalopride''' (brand name '''Resolor''', developed by [[Movetis]]) is a [[pharmaceutical drug|drug]] acting as a selective, high affinity [[5-HT4 receptor|5-HT<sub>4</sub> receptor]] [[agonist]]<ref name="Briejer">{{pmid|11438309}}</ref> which targets the impaired motility associated with chronic [[constipation]], thus normalising bowel movements.<ref>{{pmid|10205205}}</ref><ref>{{pmid|11159875}}</ref><ref>{{pmid|11696108}}</ref><ref name="Tack">{{pmid|18987031}}</ref>

== Mechanism of action ==
Prucalopride, a first in class dihydrobenzofurancarboxamide, is a selective, high affinity [[serotonin]] (5-HT<sub>4</sub>) receptor agonist with enterokinetic activities.<ref name="SmPC">SmPC. Summary of product characteristics Resolor (prucalopride) October, 2009: '''1-9'''.</ref> Prucalopride alters colonic motility patterns via serotonin 5-HT<sub>4</sub> receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force to [[defecation]].

The observed effects are exerted via highly selective action on 5-HT<sub>4</sub> receptors<ref name="SmPC" />: prucalopride has >150-fold higher affinity for 5-HT<sub>4</sub> receptors than for other receptors.<ref name="Briejer" /><ref name="DeMaeyer">{{cite journal|last1=De Maeyer|first1=JH|last2=Lefebvre|first2=RA|last3=Schuurkes|first3=JA|title=5-HT(4) receptor agonists: similar but not the same|journal=Neurogastroenterol Motil|date=Feb 2008|volume=20|issue=2|pages=99–112|pmid=18199093|doi=10.1111/j.1365-2982.2007.01059.x|doi_brokendate=2010-03-10}}</ref> Prucalopride differs from other 5-HT<sub>4</sub> agonists such as [[tegaserod]] and [[cisapride]], which at therapeutic concentrations also  interact with other receptors (5-HT<sub>1B/D</sub> and the cardiac human ether-a-go-go K<sup>+</sup> channel respectively) and this may account for the adverse [[cardiovascular]] events that have resulted in the restricted availability of these drugs.<ref name="DeMaeyer" /> [[Clinical trials]] evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.<ref name="SmPC" />

== Pharmacokinetics ==
Prucalopride is rapidly absorbed ([[CMax|C<sub>max</sub>]] attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. [[Metabolism]] is not the major route of elimination. ''In vitro'', human liver metabolism is very slow and only minor amounts of [[Metabolite|metabolites]] are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in [[urine]] and at least 6% in [[faeces]]). [[Renal excretion]] of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours,<ref>{{pmid|19911858}}</ref> and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.<ref name="SmPC" />

''In vitro'' data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.<ref name="SmPC" />

== Efficacy == 
The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week.<ref name="Tack" /><ref name="Camilleri">{{pmid|18509121}}</ref><ref name="Quigley">{{pmid|19035970}}</ref> Further measures are improvements in PAC-QOL<ref>{{pmid|16036506}}</ref> (a quality of life measure) and PAC-SYM<ref>{{pmid|10522604}}</ref> (a range of [[stool]], [[abdominal]], and [[rectal]] symptoms associated with chronic constipation). Infrequent bowel movements, [[bloating]], straining, [[abdominal pain]], and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.<ref>{{cite journal|pmid=17305761|year=2007|last1=Johanson|first1=JF|last2=Kralstein|first2=J|title=Chronic constipation: a survey of the patient perspective.|volume=25|issue=5|pages=599–608|doi=10.1111/j.1365-2036.2006.03238.x|journal=Alimentary pharmacology & therapeutics}}</ref><ref>{{pmid|9269805}}</ref><ref>{{pmid|19467522}}</ref><ref>{{pmid|11721760}}</ref><ref>{{pmid|17593068}}</ref>

In three large, well designed clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with [[placebo]].<ref name="Tack" /><ref name="Camilleri" /><ref name="Quigley" /> There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants).<ref name="Tack" /><ref name="Camilleri" /><ref name="Quigley" /> The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.<ref>{{cite journal|last1=Camilleri|first1=M|last2=Beyens|first2=G|last3=Kerstens|first3=R|last4=Vandeplassche|first4=L|title=Long-term follow-up of safety and satisfaction with bowel function in response to oral prucalopride in patients with chronic constipation [Abstract]|journal=Gastroenterology|year=2009|volume=136|issue=Suppl 1|page=160}}</ref><ref>{{cite journal|last1=Van Outryve|first1=MJ|last2=Beyens|first2=G|last3=Kerstens|first3=R|last4=Vandeplassche|first4=L|title=Long-term follow-up study of oral prucalopride (Resolor®) administered to patients with chronic constipation [Abstract T1400]|journal=Gastroenterology|year=2008|volume=134|issue=4 (suppl 1)|page=A547}}</ref>

== Side effects ==
Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are [[headache]] and [[gastrointestinal]] symptoms (abdominal pain, [[nausea]] or [[diarrhoea]]). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.<ref name="SmPC" />

== Prescribing information ==
In the EEA, prucalopride is approved for the [[symptomatic treatment]] of chronic constipation in women in whom [[laxatives]] fail to provide adequate relief. The recommended dosage in adults is 2 mg administered orally once daily; exceeding this dosage is not expected to increase efficacy. The recommended starting dose in elderly patients (>65 years) is 1 mg once daily; thereafter the dosage can be increased to 2 mg once daily, if needed.<ref name="SmPC" />

== Contraindications ==
Prucalopride is contraindicated where there is [[hypersensitivity]] to the active substance or to any of the [[excipients]], [[renal impairment]] requiring dialysis, [[intestinal]] [[intestinal perforation|perforation]] or [[intestinal obstruction|obstruction]] due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the [[intestinal tract]], such as [[Crohn’s disease]], and [[ulcerative colitis]] and [[toxic megacolon]]/megarectum.<ref name="SmPC" />

== References ==
{{reflist|2}}

== External links ==
*[http://www.ema.europa.eu/humandocs/Humans/EPAR/resolor/resolor.htm European Medicines Agency -EPAR]
*[http://www.movetis.com/products/resolor-prucalopride Resolor® (prucalopride)- Movetis]
{{Serotonergics}}
{{Drugs for functional gastrointestinal disorders}}

[[Category:Motility stimulants]]
[[Category:Serotonin receptor agonists]]
[[Category:Benzofurans]]
[[Category:Piperidines]]
[[Category:Ethers]]
[[Category:Amides]]
[[Category:Organochlorides]]
[[Category:2Fix]]