Pre-clinical evaluation of DT-001, a small molecule antagonist of MD2-TLR4 for utility in the treatment of pain.

Project Summary AbstractUpwards ofmillion individuals are afflicted by chronic pain in the US alonewithmillion of these individuals suffering from neuropathic painOn a global scalechronic pain affectsbillion individualswithwho endure lower back painFrom a clinical perspectivethe International Association for the Study of Pain approximates thatinpatients present with painand on an annual basisinpatients are typically identified as suffering from chronic painIndeedpain is the primary motivation for patients who seek medical attentionThe types of chronic pain reported are variable and may include back painheadachepelvic and musculoskeletal painwith clearly higher incidences among laborers and geriatric patientsFurthera continually increasing frequency of chronic pain stems from known causes including injuriessurgeriescancerand HIV AIDSApproximatelyof chronic pain arises from trauma and surgerywhile moderate to severe pain is experienced bypatients with advanced cancer or HIV AIDSand chronic non cancer pain is reported byof elderly patientsOn a global scalethe World Health Organization estimates thatof individuals do not receive sufficient treatment for severe painA point of additional importance is that these chronic pain patients represent the primary end user of analgesicswhich has largely been opiatesThe societal consequence of the wide spread use of opiates has been profound and the need for alternative efficacious therapies is now appreciated at all levelsChronic persistent post operative painCPOPis a devastating outcome from any type of surgical procedureIts incidence is anywhere betweendepending on the type of surgerywith thoracotomies showing one of the highest annual incidences ofGiven that millions of patientsapproximatelymillion yearly based on incidenceare affected by CPOPthe results are increased direct medical costsincreased indirect medical costs due to decreased productivityand associated negative effects on an individual s physical functioningpsychological stateand quality of lifeGiven these extensive public health and economic consequences there is a resurgence of research in the area of preventative analgesiaThe highest incidence of CPOP is reported after limb amputationsthoracotomiescardiac surgeryand breast surgeryBased on the current understandingthe criteria for CPOP has been as followsPain that develops and increases in intensity after the surgical procedureThe pain ismonths of duration and affects quality of lifeThe pain is continuation of acute post surgical pain or develops after an asymptomatic periodThe pain is in the surgical field or follows a nerve distribution or dermatome that is near or within the surgical fieldOther causes of pain have been excludedGiven a high incidence of post operative pain in post thoracotomy patients post lung cancerwe have focused our proposal on this patient populationThe goal of this project is to evaluate a novel small molecule antagonist of MDTLRDTin preclinical models of surgical pain representative of persistent post operative painIn collaboration with University of CaliforniaSan DiegoDTwill be evaluated for its ability to block the development of neuropathic pain statesThese studies will evaluate dose escalating efficacy of DTin rats in formalin and spinal nerve injurySNImodels using both intrathecal and intravenous routes of administrationTissues will be preserved to assess functional effects on relevant pain centers for analysis by RaftWith demonstration of efficacythese studies will determine the optimal dose and route of administration of DTand guide a development path to IND and eventually clinical trials Project Narrative The goal of this project is to determine an approach to advance a novel small molecule antagonist of MDTLRDTto phasea clinical trials for persistent post operative painThe management of pain following surgery remains an area of clear unmet medical need