Successful Use of Kidneys from a Deceased Donor with Active Herpes Zoster Infection.

BACKGROUND: The limited donor pool and increasing recipient wait list require a reevaluation of kidney organ suitability for transplantation. Use of higher infectious risk organs that were previously discarded may help improve access to transplantation and reduce patient mortality without placing patients at a higher risk of poor posttransplant outcomes. There is very little data available regarding the safe use of kidney organs from deceased donors with varicella zoster virus infection at the time of organ retrieval. Case Presentation. Here, we report a case of successful transplantation of both kidneys from a deceased donor with active herpes zoster infection at the time of organ retrieval. Recipients were treated preemptively with acyclovir. At 4 months posttransplant, both kidney recipients experienced no infectious complications and were off dialysis with functioning transplant grafts. CONCLUSIONS: The use of kidney organs from donors with active herpes zoster infection appears to be a safe option to expand the kidney donor pool.

Chiral tridentate bis(oxazol-2-ylimino) isoindoline-based pincer ligands: isolation and characterization via deligation from in situ prepared Cd-ligand complexes.

The first isolation and structural characterization of a series of chiral trinitrogen 1,3-bis(4,5-dihydrooxazol-2-ylimino)isoindoline-based pincer ligands are reported. Cadmium complexes, isolated as Cd(L2X)2 where L2X is the deprotonated form of L2XH = 1,3-bis(4,5-dihydro-4-(R)-phenyloxazol-2-ylimino)-isoindoline ((R,R)-5H) or 1,3-bis(4,5-dihydro-4-(S)-iso-propyloxazol-2-ylimino)isoindoline ((S,S)-6H) were prepared in situ via traditional or microwave-based techniques with the latter being more efficient but less able to be scaled up at this time. Ligands (R,R)-5H and (S,S)-6H were isolated via deligation from their respective cadmium complexes using a thiol-based ligand exchange protocol. The characterization of ligands and their respective cadmium complexes, in both the solid (X-ray crystallography) and solution (NMR spectroscopy) states are reported. Pd((S,S)-6)(OAc) is reported as a proof-of-concept of the ability to prepare 1 : 1 ligand to metal ratio complexes that are believed to be necessary as potential enantioselective catalysts.

COVID-19 Data Utilization in North Carolina: Qualitative Analysis of Stakeholder Experiences.

BACKGROUND: As the world faced the pandemic caused by the novel coronavirus disease 2019 (COVID-19), medical professionals, technologists, community leaders, and policy makers sought to understand how best to leverage data for public health surveillance and community education. With this complex public health problem, North Carolinians relied on data from state, federal, and global health organizations to increase their understanding of the pandemic and guide decision-making. OBJECTIVE: We aimed to describe the role that stakeholders involved in COVID-19-related data played in managing the pandemic in North Carolina. The study investigated the processes used by organizations throughout the state in using, collecting, and reporting COVID-19 data. METHODS: We used an exploratory qualitative study design to investigate North Carolina's COVID-19 data collection efforts. To better understand these processes, key informant interviews were conducted with employees from organizations that collected COVID-19 data across the state. We developed an interview guide, and open-ended semistructured interviews were conducted during the period from June through November 2020. Interviews lasted between 30 and 45 minutes and were conducted by data scientists by videoconference. Data were subsequently analyzed using qualitative data analysis software. RESULTS: Results indicated that electronic health records were primary sources of COVID-19 data. Often, data were also used to create dashboards to inform the public or other health professionals, to aid in decision-making, or for reporting purposes. Cross-sector collaboration was cited as a major success. Consistency among metrics and data definitions, data collection processes, and contact tracing were cited as challenges. CONCLUSIONS: Findings suggest that, during future outbreaks, organizations across regions could benefit from data centralization and data governance. Data should be publicly accessible and in a user-friendly format. Additionally, established cross-sector collaboration networks are demonstrably beneficial for public health professionals across the state as these established relationships facilitate a rapid response to evolving public health challenges.

Discovery of Arylsulfonamide Nav1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile.

The voltage-gated sodium channel Nav1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Nav1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Nav1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Nav1.7 inhibitors to afford improved selectivity over Nav1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro-in vivo correlations from Nav1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Nav1.7, selectivity over Nav1.5 and Nav1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.

Nav1.7 target modulation and efficacy can be measured in nonhuman primate assays.

Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.

Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor-Positive Allosteric Modulator BNC375.

Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.

Randomised controlled trial of a video intervention and behaviour contract to improve medication adherence after renal transplantation: the VECTOR study protocol.

INTRODUCTION: Non-adherence after kidney transplantation contributes to increased rejections, hospitalisations and healthcare expenditures. Although effective adherence interventions are sorely needed, increasing education and support to transplant recipients demands greater use of care providers' time and resources in a healthcare system that is stretched. The objective of this clinical trial is to determine the effectiveness of an electronically delivered video series and adherence behaviour contract on improving medication adherence to immunosuppressant medications. METHODS AND ANALYSIS: A multicentre, parallel arm, randomised controlled trial will be conducted with four sites across North America (Saskatoon, Calgary, Halifax, Chicago). Adult patients will be randomised (1:1) to either the intervention (ie, home-based video education +behaviour contract plus usual care) or usual care alone. De novo transplant recipients will be enrolled prior to their hospital discharge and will be provided with electronic access to the video intervention (immediately) and adherence contract (1 month post-transplant). Follow-up electronic surveys will be provided at 3 and 12 months postenrolment. The primary outcome will be adherence at 12 months post-transplant, as measured by self-report Basel Assessment of Adherence to Immunosuppressive medications and immunosuppressant levels. Secondary outcomes include the difference in knowledge score between the intervention and control in groups (measured by the Kidney Transplant Understanding Tool); differences in self-efficacy (Generalised Self-efficacy Scale), Beliefs of Medicine Questionnaire (BMQ), quality of life (Short Form-12), patient satisfaction and cost utilisation. The study aims to recruit at least 200 participants across participating sites. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Saskatchewan Behavioural Ethics Committee (Beh 18-63), and all patients provide informed consent prior to participating. This educational intervention aims to improve information retention and self-efficacy, leading to improved medication adherence after kidney transplantation, at low cost, with little impact to existing healthcare personnel. If proven beneficial, delivery can be easily implemented into standard of care. TRIAL REGISTRATION NUMBER: NCT03540121; Pre-results.

Accessing Ambiphilic Phosphine Boronates through C-H Borylation by an Unforeseen Cationic Iridium Complex.

Ambiphilic molecules, which contain a Lewis base and Lewis acid, are of great interest based on their unique ability to activate small molecules. Phosphine boronates are one class of these substrates that have interesting catalytic activity. Direct access to these phosphine boronates is described through the iridium-catalyzed C-H borylation of phosphines. An unconventional cationic iridium catalyst was identified as optimal for a range of phosphines, providing good yields and selectivity across a diverse class of phosphine boronates (isolated as the borane-protected phosphine). A complimentary catalyst system (quinoline-based silane ligand with [(COD)IrOMe]2 ) was optimal for biphenyl-based phosphines. Selective polyborylation was also shown providing bis- and tris-borylated phosphines. Deprotection of the phosphine boronate provided free ambiphilic phosphine boronates, which do not have detectable interactions between the phosphorus and boron atoms in solution or the solid state.

C-reactive protein levels in acute respiratory exacerbations of cystic fibrosis.

C-reactive protein (CRP) levels increase in response to bacterial infection and have been used to guide the use of antibiotics. We assessed CRP levels in a cohort of patients with cystic fibrosis (CF) admitted to hospital with an exacerbation of their lung disease, requiring treatment with broad-spectrum antibiotics. In this group, most subjects had CRP levels of less than 20 mg/L, including patients who had pneumonia. The clinical utility of the CRP in guiding antibiotic use in exacerbations of CF is limited.

Role of magnesium supplementation in the treatment of depression: A randomized clinical trial.

Current treatment options for depression are limited by efficacy, cost, availability, side effects, and acceptability to patients. Several studies have looked at the association between magnesium and depression, yet its role in symptom management is unclear. The objective of this trial was to test whether supplementation with over-the-counter magnesium chloride improves symptoms of depression. An open-label, blocked, randomized, cross-over trial was carried out in outpatient primary care clinics on 126 adults (mean age 52; 38% male) diagnosed with and currently experiencing mild-to-moderate symptoms with Patient Health Questionnaire-9 (PHQ-9) scores of 5-19. The intervention was 6 weeks of active treatment (248 mg of elemental magnesium per day) compared to 6 weeks of control (no treatment). Assessments of depression symptoms were completed at bi-weekly phone calls. The primary outcome was the net difference in the change in depression symptoms from baseline to the end of each treatment period. Secondary outcomes included changes in anxiety symptoms as well as adherence to the supplement regimen, appearance of adverse effects, and intention to use magnesium supplements in the future. Between June 2015 and May 2016, 112 participants provided analyzable data. Consumption of magnesium chloride for 6 weeks resulted in a clinically significant net improvement in PHQ-9 scores of -6.0 points (CI -7.9, -4.2; P<0.001) and net improvement in Generalized Anxiety Disorders-7 scores of -4.5 points (CI -6.6, -2.4; P<0.001). Average adherence was 83% by pill count. The supplements were well tolerated and 61% of participants reported they would use magnesium in the future. Similar effects were observed regardless of age, gender, baseline severity of depression, baseline magnesium level, or use of antidepressant treatments. Effects were observed within two weeks. Magnesium is effective for mild-to-moderate depression in adults. It works quickly and is well tolerated without the need for close monitoring for toxicity.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice.

The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.

Thiocyanate-Ligated Heterobimetallic {PtM} Lantern Complexes Including a Ferromagnetically Coupled 1D Coordination Polymer.

A series of heterobimetallic lantern complexes with the central unit {PtM(SAc)4(NCS)} have been prepared and thoroughly characterized. The {Na(15C5)}[PtM(SAc)4(NCS)] series, 1 (Co), 2 (Ni), 3 (Zn), are discrete compounds in the solid state, whereas the {Na(12C4)2)}[PtM(SAc)4(NCS)] series, 4 (Co), 5 (Ni), 6 (Zn), and 7 (Mn), are ion-separated species. Compound 7 is the first {PtMn} lantern of any bridging ligand (carboxylate, amide, etc.). Monomeric 1-7 have M(2+), necessitating counter cations that have been prepared as {(15C5)Na}(+) and {(12C4)2Na}(+) variants, none of which form extended structures. In contrast, neutral [PtCr(tba)4(NCS)]∞ 8 forms a coordination polymer of {PtCr}(+) units linked by (NCS)(-) in a zigzag chain. All eight compounds have been thoroughly characterized and analyzed in comparison to a previously reported family of compounds. Crystal structures are presented for compounds 1-6 and 8, and solution magnetic susceptibility measurements are presented for compounds 1, 2, 4, 5, and 7. Further structural analysis of dimerized {PtM} units reinforces the empirical observation that greater charge density along the Pt-M vector leads to more Pt···Pt interactions in the solid state. Four structural classes, one new, of {MPt}···{PtM} units are presented. Solid state magnetic characterization of 8 reveals a ferromagnetic interaction in the {PtCr(NCS)} chain between the Cr centers of J/kB = 1.7(4) K.

Primer for nutritionists: Managing the side effects of antidepressants.

Depression is a chronic disease affecting a significant portion of the U.S. POPULATION: Due to the popularity of ADs most nutrition professionals working in the outpatient setting will encounter patients taking one of these medications. Nutritionist can assist patients in managing the short and long term side effects of ADs and, taking into account other nutritional issues, improve overall wellbeing of the patient. The objective of this paper is to identify what side effects nutritionists can help manage, provide the information necessary to help nutritionists feel comfortable assisting with that management, and, as a result, play a valuable role in the team that is vested in the health and wellbeing of the patient.

Increases in intravenous magnesium use among hospitalized patients: an institution cross-sectional experience.

BACKGROUND: Among hospitalized patients, indications for the measurement of magnesium levels and treatment of hypomagnesemia with intravenous magnesium are not well defined. Recently, there have been reports of worldwide shortages of intravenous magnesium sulphate. OBJECTIVE: To examine secular trends in the administration of intravenous magnesium on hospital wards at a tertiary care institution. The secondary objective is to identify factors associated with magnesium use among admitted patients. METHODS: Retrospective cross-section review of hospitalized patients at a single Canadian tertiary care center. Utilization of non-parental nutrition intravenous magnesium from 2003 to 2013 stratified by hospital ward was examined. In addition, patient level data from select wards (including medical and surgical services) was examined at early and more recent time period (4/2006 versus 4/2013). RESULTS: Among the 248,329 hospitalized patients, intravenous magnesium use increased by 2.86 fold from 2003 to 2013. Not all wards had an increase whereas some had nearly a 10 fold increase in use. In the sample (n = 769), (adjusting for admission magnesium level, presence of an indication for intravenous magnesium, ward location, comorbidity and demographics) intravenous magnesium administration was higher (25.8 % versus 5.5 %) in 2013 versus 2006 (OR 13.91 (95 % CI, 6.21-31.17, p < 0.001). Despite this increase in intravenous magnesium administration, <3 % of patients were admitted on oral magnesium in 2006 and 2013. For patients receiving intravenous magnesium only a minority were discharged on oral therapy despite low levels. CONCLUSIONS: This center has witnessed a considerable increase in the use of in-hospital intravenous magnesium over the last 6 years that cannot be explained for by medical indications. The risks and benefits of this therapy deserve further study. If this change in practice is representative of other North American hospitals, it may be responsible for recent drug shortages.

CONTEXTE: Les indications concernant la mesure des niveaux sanguins de magnésium et le traitement de l'hypomagnésémie par infusion intraveineuse de magnésium chez les patients hospitalisés sont mal définies. On a récemment rapporté des pénuries à l'échelle mondiale de sulfate de magnésium destiné à l'infusion intraveineuse. OBJECTIFS: D'une part, examiner les tendances séculaires en matière d'administration de magnésium par voie intraveineuse dans divers services hospitaliers d'un centre de soins tertiaires. D'autre part, déterminer les facteurs associés à l'utilisation du magnésium chez les patients hospitalisés. MÉTHODES: Étude transversale et rétrospective auprès des patients hospitalisés dans un seul centre canadien de soins tertiaire. On a étudié un échantillon qui témoigne du recours à l'administration intraveineuse de magnésium, de 2003 à 2013, en stratifiant par service hospitalier. RÉSULTATS: Chez les 248 329 patients hospitalisés, le recours à l'infusion de magnésium par voie intraveineuse a augmenté de 2,86 fois entre 2003 et 2013. Dans certains services, aucune augmentation n'a été notée alors que dans d'autres, l'utilisation a augmenté de près de 10 fois. Dans l'échantillon (n = 769), (ajusté selon le taux de magnésium administré, la présence d'une indication nécessitant une infusion de magnésium, l'emplacement des services, la comorbidité et les données démographiques), l'administration de magnésium par voie intraveineuse était plus fréquente (25,8 % par rapport à 5,5 %) en 2013 qu'en 2006 (RIA = 13,91 (IC, 95 %, 6,21-31,17, p < 0,001). Malgré cette augmentation de l'utilisation du magnésium par voie intraveineuse, <3 % des patients avaient été admis pour administration orale de magnésium en 2006 et en 2013. Parmi les patients qui ne recevaient le magnésium que par voie intraveineuse, seule une minorité avait reçu son congé avec une thérapie par voie orale, en dépit des faibles taux. CONCLUSION: Nous avons observé une augmentation considérable dans l'utilisation de l'infusion de magnésium par voie intraveineuse en milieu hospitalier au cours des 6 dernières années, ce qui n'est pas justifié par des indications d'ordre médical. Les avantages et les risques que comporte cette thérapie méritent une étude approfondie. Ce changement de pratique, s'il s'observe dans d'autres hôpitaux nord-américains, pourrait expliquer les récentes pénuries de médicaments.

Synthesis of a phosphapyracene via metal-mediated cyclization: structural and reactivity effects of acenaphthene precursors.

Metal-mediated synthesis of a new heterocycle, 1-phenyl-phosphapyracene (Ph-4, Ph-PyraPhos), by tandem phosphination/cyclization of peri-substituted 5-bromo-6-chloromethylacenaphthene (3) was investigated for comparison to Pt-catalyzed formation of 1-phosphaacenaphthenes (2, AcePhos) from the analogous naphthalene precursor (1). Reaction of PH2Ph with , NaOSiMe3 and a Cu catalyst gave ; a Pt catalyst yielded PHPh(CH2Ar) (Ph-11, Ar = 5-Br-acenaphthyl). Deprotonation of a complex of this secondary phosphine, [Pt((R,R)-Me-DuPhos)(Ph)(PHPh(CH2Ar))][PF6] (17), generated the phosphido intermediate Pt((R,R)-Me-DuPhos)(Ph)(PPhCH2Ar) (Ph-8), which cyclized to give [Pt((R,R)-Me-DuPhos)(Ph)(Ph-PyraPhos)][PF6] (18). Treatment of P-8 with silver triflate gave 18 and the cyclometalated phosphine complex [Pt((R,R)-Me-DuPhos)(κ(2)-(P,C)-5-Ph2PCH2-6-C12H8)][PF6] (21), which might form via Pt(iv) intermediates. The effects of the added "ace" bridge on structure and reactivity are discussed.

Phosphine-directed C-H borylation reactions: facile and selective access to ambiphilic phosphine boronate esters.

Ambiphilic ligands have received considerable attention over the last two decades due to their unique reactivity as organocatalysts and ligands. The iridium-catalyzed C-H borylation of phosphines is described in which the phosphine is used as a directing group to provide selective formation of arylboronate esters with unique scaffolds of ambiphilic compounds. A variety of aryl and benzylic phosphines were subjected to the reaction conditions, selectively providing stable, isolable boronate esters upon protection of the phosphine as the borane complex. After purification, the phosphine-substituted boronate esters could be deprotected and isolated in pure form.

Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.

We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.