Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.

Leishmaniasis, a neglected tropical disease caused by species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides () that possess potent antileishmanial activity but poor aqueous solubility.

Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents.

Leishmaniasis, a disease caused by protozoa of the species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of parasites with good selectivity relative to the host macrophages.

Antimalarial activity of 2,6-dibenzylidenecyclohexanone derivatives.

Malaria remains one of the deadliest infectious diseases worldwide and continues to infect hundreds of millions of individuals each year. Here we report the discovery and derivatization of a series of 2,6-dibenzylidenecyclohexanones targeting the chloroquine-sensitive 3D7 strain of Plasmodium falciparum . While the initial lead compound displayed significant toxicity in a human cell proliferation assay, we were able to identify a derivative with no detectable toxicity and sub-micromolar potency.

Improvement of Oral Bioavailability of Pyrazolo-Pyridone Inhibitors of the Interaction of DCN1/2 and UBE2M.

The cullin-RING ubiquitin ligases (CRLs) are ubiquitin E3 enzymes that play a key role in controlling proteasomal degradation and are activated by neddylation. We previously reported inhibitors that target CRL activation by disrupting the interaction of defective in cullin neddylation 1 (DCN1), a CRL neddylation co-E3, and UBE2M, a neddylation E2. Our first-generation inhibitors possessed poor oral bioavailability and fairly rapid clearance that hindered the study of acute inhibition of DCN-controlled CRL activity in vivo.

Identification of Plasmodium falciparum heat shock 90 inhibitors via molecular docking.

A virtual screen was performed to identify anti-malarial compounds targeting Plasmodium falciparum heat shock 90 protein by applying a series of drug-like and commercial availability filters to compounds in the ZINC database, resulting in a virtual library of more than 13 million candidates. The goal of the virtual screen was to identify novel compounds which could serve as a starting point for the development of antimalarials with a mode of action different from anything currently used in the clinic. The screen targeted the ATP binding pocket of the highly conserved Plasmodium heat shock 90 protein, as this protein is critical to the survival of the parasite and has several significant structural differences from the human homolog.

Evaluation of 1,1-cyclopropylidene as a thioether isostere in the 4-thio-thienopyrimidine (TTP) series of antimalarials.

The 4-(heteroarylthio)thieno[2,3-d]pyrimidine (TTP) series of antimalarials, represented by 1 and 17, potently inhibit proliferation of the 3D7 strain of P. falciparum (EC 70-100 nM), but suffer from oxidative metabolism. The 1,1-cyclopropylidene isosteres 6 and 16 were designed to obviate this drawback.

Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4-]pyridines.

Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo[3,4-]pyridines targeting , the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines.

Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein.

A series of tetrahydro-β-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.

Gastric emptying of milk in infants and children up to 5 years of age: normative data and influencing factors.

Background: Gastric emptying scintigraphy is widely used in infants and children, but there is a lack of age-specific normative data.

Objective: The objectives of this retrospective study were: 1) to establish a range of gastric emptying of milk or formula as a surrogate for normal gastric emptying in infants and young children ≤5 years of age, and 2) to investigate the effects of patient age, feeding volume, feeding route and gastroesophageal reflux on gastric emptying.

Materials And Methods: The reports of 5,136 gastric emptying studies of children ≤5 years of age performed at Children's National Medical Center from January 1990 to August 2012 were reviewed.

Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease.

BackgroundN-methyl-D-aspartate receptor activation has been implicated in the pathobiology of inflammatory, nociceptive and neuropathic pain, opioid tolerance, opioid-induced hyperalgesia, and central sensitization. Some of those mechanisms underlie sickle cell disease(SCD)-associated pain.MethodsWe conducted an exploratory cohort study of SCD patients who during vaso-occlusive episodes (VOEs) received subanesthetic doses of the N-methyl-D-aspartate receptor antagonist, ketamine, as an adjunct to opioids.

Subanesthetic ketamine for pain management in hospitalized children, adolescents, and young adults: a single-center cohort study.

Background: Subanesthetic doses of ketamine, an -methyl-d-aspartate receptor antagonist used as an adjuvant to opioid for the treatment of pain in adults with acute and chronic pain, have been shown, in some instances, to improve pain intensity and to decrease opioid intake. However, less is known about the role of ketamine in pain management in children, adolescents, and young adults.

Purpose: We examined the effects of subanesthetic ketamine on pain intensity and opioid intake in children, adolescents, and young adults with acute and chronic pain syndromes treated in an inpatient setting.

Retrospective comparison of the Low Risk Ankle Rules and the Ottawa Ankle Rules in a pediatric population.

Background: A recent multicenter prospective Canadian study presented prospective evidence supporting the Low Risk Ankle Rules (LRAR) as a means of reducing the number of ankle radiographs ordered for children presenting with an ankle injury while maintaining nearly 100% sensitivity. This is in contrast to a previous prospective study which showed that this rule yielded only 87% sensitivity.

Objective: It is important to further investigate the LRAR and compare them with the already validated Ottawa Ankle Rules (OAR) to potentially curb healthcare costs and decrease unnecessary radiation exposure without compromising diagnostic accuracy.

Moving from efficacy to effectiveness: red palm oil's role in preventing vitamin A deficiency.

Vitamin A deficiency is one of the most widespread nutritional deficiencies worldwide. Hundreds of millions of children and tens of millions of women living in Sub-Saharan Africa and Southeast Asia are at particularly high risk of the adverse health consequences associated with this largely preventable condition. Red palm oil comes from oil palms that are traditionally grown in tropical regions of West Africa and are now cultivated on a large-scale commercial basis in Southeast Asia.

Is the exclusion of children under 24 months from anthelmintic treatment justifiable?

There are no reports documenting toxicity or adverse effects after treatment of children aged < 24 months with benzimidazole derivatives and there is an urgent need to clarify this point in light of the potential detrimental effect that soil-transmitted helminthiasis has on this age-group. A total of 653 treatments (317 mebendazole 500 mg; 336 placebo) were administered in 1996/97 to 212 children aged < 24 months as part of a 1-year anthelmintic drug study conducted among preschool-age children in Tanzania. Data on fever, cough, diarrhoea, dysentery and acute respiratory illness were collected 1 week following the treatment.