Inactive

Chronic pain is among the most common reasons for seeking medical attention and is reported by 20 to 50 percent of patients seen in primary care. While the CDC in their 2016 Guidelines recommends init... Chronic pain is among the most common reasons for seeking medical attention and is reported by 20 to 50 percent of patients seen in primary care. While the CDC in their 2016 Guidelines recommends initial treatment of non-cancer chronic pain with acetaminophen and NSAIDs, these agents feature black box warnings for serious cardiovascular and gastrointestinal adverse events, and acetaminophen has known hepatotoxicity. Most notably, both classes of analgesics have documented limited efficacy. Opioids are effective, but their associated tolerance and dependence has contributed to the current abuse epidemic, and their respiratory depressant actions contribute to significant abuse-related mortality. Development of a fast-acting, highly effective analgesic for the treatment of non-cancer chronic pain that is devoid of the common, well-recognized side effects of opioids which act predominantly at mu (?)-opioid receptors, is therefore a priority to break the cycle of pain-prescription-dependence-overdose. NES100 is a microparticulate dosage form of leu-enkephalin(L-ENK) prepared by the encapsulation of L-ENK in an IP-protected molecular envelope technology (MET). L-ENK is an naturally occurring enkephalin which preferentially binds to ?-opioid receptors to produce analgesic benefits without the associated respiratory depression typically noted from ?-opioid receptor binding. MET, aka GCPQ (N-palmitoyl-N-monomethyl-N, N-dimethyl-N, N, N-trimethyl-6-O-glycolchitosan), is a modified amphiphilic chitosan derivative polymer that self-assembles in aqueous media. The polymer used to make the nanoparticles confers a positive surface charge to the nanoparticles and the particles stick to and integrate into mucosal surfaces present in the nasal cavity. This “mucointegration” may enhance the residence time of the nanoparticulate peptide in the nares, enabling the prolonged delivery of L-ENK. The polymer nanoparticles encapsulating L-ENK is then able to transport L-ENK exclusively to the brain via the intranasal route with essentially no peripheral exposure. In preliminary animal studies with intranasal administration, NES100 has been found to have analgesic properties comparable to morphine, yet does not exhibit analgesic tolerance. Importantly, it is active in morphine-tolerant animals, and has restricted activity to the CNS avoiding undesirable peripheral side-effects. Intranasal NES100 reverses the hyperalgesia induced by intraplantar injection of Complete Freund’s Adjuvant (CFA) as measured using von Frey filaments, and is effective against ongoing neuropathic pain in a conditioned placement preference (CPP) model using spinal nerve ligation (SNL). The objective of this order conduct dose-response assays to evaluate the interactions between indicated compounds (NES100 and its ingredients) and a set of safety-relevant targets which showed interaction in previous study. NCATS is in need of performing an in vitro pharmacology safety assessment of three compounds. The total cost to the contractors for the performance of binding or functional assays to evaluate the dose-response interactions of a set of safety-relevant targets which showed interaction in previous study and our indicated compounds.