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. Herein, we report studies to improve the pharmacokinetic performance of the pyrazolo-pyridone inhibitors. The current best inhibitor, 40, inhibits the interaction of DCN1 and UBE2M, blocks NEDD8 transfer in biochemical assays, thermally stabilizes cellular DCN1, and inhibits anchorage-independent growth in a DCN1 amplified squamous cell carcinoma cell line. Additionally, we demonstrate that a single oral 50 mg/kg dose sustains plasma exposures above the biochemical IC90 for 24 h in mice.

Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4-b]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-b]pyridines targeting Plasmodium falciparum, the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar in vitro 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. In addition, our hit compounds show good activity against the liver stage of the parasite but little activity against the gametocyte stage. Parasitological profiles, including rate of killing, docking, and molecular dynamics studies, suggest that our compounds may target the Qo binding site of cytochrome bc1.

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

A series of tetrahydro-ß-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.

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

BACKGROUND: Subanesthetic doses of ketamine, an N-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. METHODS: This is a longitudinal cohort study of patients treated with subanesthetic ketamine infusions in regular patient care units in a tertiary pediatric hospital. Primary outcomes included changes in pain scores and morphine-equivalent intake. RESULTS: The study cohort included 230 different patients who during 360 separate hospital admissions received subanesthetic ketamine infusions for pain management. Overall, ketamine infusions were associated with significant reductions in mean pain scores from baseline (mean pain scores 6.64 [95% CI: 6.38-6.90]) to those recorded on the day after discontinuation of ketamine (mean pain scores 4.38 [95% CI: 4.06-4.69]), p<0.001. Importantly, the effect of ketamine on pain scores varied according to clinical diagnosis (p=0.011), infusion duration (p=0.004), and pain location (p=0.004). Interestingly, greater reductions in pain scores were observed in patients with cancer pain and patients with pain associated with pancreatitis and Crohn's disease. There were no records of psychotomimetic side effects requiring therapy. CONCLUSION: These data suggest that administration of subanesthetic ketamine for pain management is feasible and safe in regular inpatient care units and may benefit children, adolescents, and young adults with acute and chronic pain. This study is informative and can be helpful in determining sample and effect sizes when planning clinical trials to determine the role of subanesthetic ketamine infusions for pain management in pediatric patients.

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. Red palm oil is the richest naturally occurring source of beta-carotene, a carotenoid that the human body can convert into usable vitamin A (retinol). This paper reviews a series of key intervention studies designed to investigate the impact of using red palm oil-based interventions to improve vitamin A status. These included studies from Africa, Asia, and Latin America in which red palm oil was used (or proposed for use) (1) as a dietary supplement, (2) as an in-home fortificant, (3) to fortify foods used for distribution in targeted supplementary feeding programs, and (4) to fortify staple food products. Overall, the results suggest that red palm oil is highly efficacious in improving vitamin A status among populations at risk of vitamin A deficiency. The time has come to move beyond trials of biological efficacy and focus on conducting operational research projects, effectiveness trials, and cost-benefit analyses that will help expand the use of red palm oil in areas where it is likely to be well accepted but remains underutilized as a dietary source of provitamin A.