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There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N‐(3‐chloro‐4‐fluorophenyl)‐2‐methyl‐2‐{[4‐methyl‐3‐(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low‐nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter‐screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification., New roads to novel chemotypes: Compound selection from the TCAMS library (GSK), followed by iterative rounds of inhibitor design and synthesis afforded a single‐digit nanomolar inhibitor of P. falciparum (3D7), based on an aminoacetamide core. Compound 28 is a potent antimalarial and displayed excellent selectivity in a mammalian counter‐screen. This compound could be used as a suitable chemical tool for drug target identification or as a lead compound for further optimization.

Approximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacements of the metabolically labile piperazine ring and use of plate-based arrays for quick diversity scoping. We discuss the success of these strategies within the context of this series and highlight the challenges faced in phenotypic programs when attempting to improve the pharmacokinetic profile of compounds whilst maintaining potency against the desired target.

Twenty eight new N

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Background and Objectives: Providing pasteurized donor human milk (DHM) to healthy newborns is an emerging practice. The content of hospital policies that govern this practice is unknown. Materials and Methods: We collected policies from 15 Northeast U.S. hospitals through (1) a 2017 survey on DHM use and (2) an e-mail listserv of levels 1 and 2 newborn care staff maintained by a regional milk bank. Two authors reviewed each policy and identified how they addressed three predetermined themes: who is eligible to receive DHM, how DHM is used and described, and how lactation is supported. Responses were compared, discussed, and reconciled. Level 1 newborn care was defined as basic care for healthy newborns ≥35 weeks' gestation. Results: Thirteen of 15 policies stated criteria for DHM eligibility, most commonly as a bridge until mother's supply comes in (73%) or for infant medical conditions (67%). All required consent for DHM. Most did not limit number of days infants could receive DHM (60%). Nine specified that DHM be discarded 24 hours after thaw, whereas five recommended discarding at 48 hours. Although many (53%) policies endorsed human milk as the preferred diet for newborns, only 27% specifically endorsed DHM as the preferred supplementation type. Parent education (73%) was emphasized, but few (27%) discussed the importance of establishing mother's milk supply. Conclusions: Many DHM policies address eligibility criteria for receiving DHM and show how to provide DHM, but few address how to support lactation while DHM is provided, which may be crucial for optimizing long-term breastfeeding outcomes.

Graphical abstract, Highlights • Identification of soft drug S1PR agonists. • Development of a process for the evaluation of topical esterase soft drugs. • Study skin and plasma esterase SAR., The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.

Pasteurized donor human milk ("donor milk") is an alternative to formula for supplementation of breastfed infants. We conducted a survey to determine (1) prevalence, trends, and hospital-level correlates of donor milk use for healthy newborns in the northeast United States and (2) clinician knowledge and opinions regarding this practice.We conducted parallel surveys of clinicians (88% nurse and/or lactation consultant) at (1) all birth hospitals in Massachusetts (MA) and (2) all birth hospitals served by a northeast United States milk bank. We asked about hospital use of donor milk for newborns ≥35 weeks' gestation and receiving Level I care in well nursery, hospital-related factors we hypothesized would be associated with this practice, and clinician knowledge and opinions about donor milk use.35/46 (76%) of MA birth hospitals and 51/69 (74%) of hospitals served by the milk bank responded; 71 unique hospitals were included. Twenty-nine percent of MA birth hospitals and 43% of hospitals served by the milk bank reported using donor milk for healthy newborns. Hospitals that used donor milk for healthy newborns had higher exclusive breastfeeding at hospital discharge than hospitals that did not (77% versus 56%, p = 0.02). Eighty-three percent of respondents agreed or strongly agreed that using donor milk is an effective way to increase the hospital's exclusive breastfeeding rate.Many northeast United States birth hospitals currently use donor milk for healthy newborns. This practice is associated with higher exclusive breastfeeding at hospital discharge. Relationships with breastfeeding after discharge and related outcomes are unknown.

Banked donor milk (BDM) has historically been used as an alternative to formula for preterm infants. Recently, BDM has been endorsed by two national organizations for use in healthy infants. We sought to quantify utilization trends and characteristics of mothers and their healthy newborns who received BDM during their postpartum stay between 2013 and 2016 at a single academic medical center.In this observational study, we used a clinical log to identify all infants who received BDM in the well-baby nursery between July 2013 and June 2016. From this log, we abstracted data on the numbers of babies who received BDM, the quantity of BDM provided, and indications for usage. We also collected clinical data from the medical records of a subset of corresponding mothers and infants.BDM utilization increased over time in healthy infants, with 0.04% of infants before July 2014 receiving BDM compared with 4.7% in July 2015 to June 2016. During the same periods, the number of bottles provided per infant also increased, from 0.6 bottles per infant to 4.6 bottles per infant. The most common indications for providing BDM were parent/caregiver request (19%) and excessive weight loss/dehydration (17%).At our center, the use of BDM for healthy infants increased substantially over the study period. More research is urgently needed to understand the repercussions of this practice on resource utilization as well as short- and long-term breastfeeding and health outcomes.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is a life threatening global health problem with only two drugs available for treatment (benznidazole and nifurtimox), both having variable efficacy in the chronic stage of the disease and high rates of adverse drug reactions. Inhibitors of sterol 14α-demethylase (CYP51) have proven effective against T. cruzi in vitro and in vivo in animal models of Chagas disease. Consequently two azole inhibitors of CYP51 (posaconazole and ravuconazole) have recently entered clinical development by the Drugs for Neglected Diseases initiative. Further new drug treatments for this disease are however still urgently required, particularly having a different mode of action to CYP51 in order to balance the overall risk in the drug discovery portfolio. This need has now been further strengthened by the very recent reports of treatment failure in the clinic for both posaconazole and ravuconazole. To this end and to prevent enrichment of drug candidates against a single target, there is a clear need for a robust high throughput assay for CYP51 inhibition in order to evaluate compounds active against T. cruzi arising from phenotypic screens. A high throughput fluorescence based functional assay using recombinantly expressed T. cruzi CYP51 (Tulahuen strain) is presented here that meets this requirement. This assay has proved valuable in prioritising medicinal chemistry resource on only those T. cruzi active series arising from a phenotypic screening campaign where it is clear that the predominant mode of action is likely not via inhibition of CYP51., Author Summary Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), is endemic in Latin America and emerging in North America and Europe through human migration. It is a severe global health problem with 8–10 million people infected and an estimated 12,000 deaths annually. Current treatment options are poorly efficacious and have severe side effects. New drugs are therefore urgently required. Two of these potential new drugs, posaconazole and ravuconazole, both targeting an enzyme in T. cruzi called CYP51, have recently failed in clinical development. Therefore, in light of these recent clinical failures and in order to better balance the overall risk in the drug discovery portfolio for Chagas disease, it has become prudent to assess whether new chemical start points for drug discovery programmes have a mode of action predominantly driven by T. cruzi CYP51 inhibition. In this paper we report a fluorescence based assay to determine whether compounds inhibit T. cruzi CYP51. This provides a high throughput screen to help prioritise medicinal chemistry resource on those T. cruzi active new chemical series that do not have a mode of action predominantly driven by CYP51 inhibition.

Background: The emergency department (ED) is an environment fraught with increasing patient volumes, competing priorities, fluctuating information, and ad hoc interprofessional clinical teams. Limited time is available to reflect on and discuss clinical experiences, policies, or research with others on the involved team. Online resources, such as webcasts and blogs, offer an accessible platform for emergency shift workers to engage in interprofessional discussion and education. Objective: Our objective was to explore the current opportunities for shared learning and discussion and to discover the potential of online resources to foster and facilitate interprofessional education within an academic tertiary emergency department community. Methods: A qualitative study using semistructured interviews was conducted to solicit participants’ views of the current culture of IPE in the ED, the potential value of introducing new online resources and technology in support of IPE, and possible barriers to uptake. Participation was voluntary and participants provided verbal informed consent. Results: Online resources discussed included webcasts, interactive discussion forums, websites, and dashboard with links to central repositories. Identified barriers to uptake of new online resources were an unwillingness to “work” off-shift, a dislike of static one-directional communication, concerns with confidentiality, and the suggestion that new resources would be used by only a select few. Conclusions: Owing to the sensitive dynamics of emergency medicine—and the preference among its professional staff to foster interprofessional discussion and education through personal engagement, in an unhurried, non-stressful environment—introducing and investing in online resources should be undertaken with caution. [J Med Internet Res 2014;16(6):e162]

Objectifs: Cette vérification rétrospective des dossiers a permis d'examiner les données démographiques, les examens, la prise en charge et les résultats des patients adultes souffrant de diabète sucré qui se sont présentés aux services des urgences (SU) au Canada. Méthodes: Tous les sites ont mené une recherche dans leurs dossiers médicaux électroniques à l'aide des codes de la Classification internationale des maladies, dixième révision, pour relever les visites aux SU entre 2008 et 2010 qui étaient liées à l'hypoglycémie. Les caractéristiques des patients, les données démographiques, la prise en charge aux SU, les ressources des SU et les résultats sont rapportés. Résultats: Un total de 1039 patients de plus de 17 ans ont été inclus dans l'étude; 347 (33,4 %) ont été classifiés comme étant des cas de diabète de type 1 et 692 (66,6 %) ont été classifiés comme étant des cas de diabète de type 2. Les patients souffrant du diabète de type 2 étaient beaucoup plus âgés (73 ans vs 49 ans; p

Background Although it is now widely recognized that reductions in maternal mortality and improvements in women's health cannot be achieved through simple, vertical strategies, few programs have provided successful models for how to integrate services into a comprehensive program for maternal health. We report our experience in rural Lesotho, where Partners In Health (PIH) in partnership with the Ministry of Health and Social Welfare implemented a program that provides comprehensive care of pregnant women from the community to the clinic level. Methods Between May and July 2009, PIH trained 100 women, many of whom were former traditional birth attendants, to serve as clinic-affiliated maternal health workers. They received performance-based incentives for accompanying pregnant women during antenatal care (ANC) visits and facility-based delivery. A nurse-midwife provided ANC and delivery care and supervised the maternal health workers. To overcome geographic barriers to delivering at the clinic, women who lived far from the clinic stayed at a maternal lying-in house prior to their expected delivery dates. We analyzed data routinely collected from delivery and ANC registers to compare service utilization before and after implementation of the program. Results After the establishment of the program, the average number first ANC visits increased from 20 to 31 per month. The clinic recorded 178 deliveries in the first year of the program and 216 in the second year, compared to 46 in the year preceding the program. During the first two years of the program, 49 women with complications were successfully transported to the district hospital, and no maternal deaths occurred among the women served by the program. Conclusions Our results demonstrate that it is possible to achieve dramatic improvements in the utilization of maternal health services and facility-based delivery by strengthening human resource capacity, implementing active follow-up in the community, and de-incentivizing home births.