A toolbox approach to revealing a series of naphthocarbazoles to showcase photocatalytic reductive syntheses.

The development of highly reducing photocatalysts to functionalize arenes via the generation of reactive aryl radicals under mild and environmentally benign reaction conditions has emerged as a noteworthy approach in the realm of organic synthesis. Herein, we report a readily synthesized series of novel naphthocarbazole derivatives (NCs) as organo-photocatalysts, which, upon irradiation under 390 nm light, acquire high reducing power to catalyze several reductive transformations. The promising properties revealed by in depth photophysical and electrochemical studies ( = -1.9 V to -2.07 V vs. SCE, τ = 5.59 to 7.12 ns) demonstrate NCs to be versatile catalysts, and notably, rational variation of the substituents (NC1-NC6) modulates their success as efficient photoreductants. Detailed DFT calculations of the frontier MO diagrams and energy levels revealed them to be non-donor-acceptor type molecular scaffolds. The applicability of the NCs as catalysts was demonstrated in reductive dehalogenative borylation, phosphorylation, and dehydrohalide intramolecular C-C coupling reactions, as well as the dimerization of carbonyls and imines. Visible-light-irradiated selective reductive desulfonylation from heteroaromatics and peptides further enhances their synthetic utility.

BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extraterminal Domain Proteins, in Patients with Selected Advanced Solid Tumors: Results from a Phase 1/2a Trial.

This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75-4.5 mg), B (14 days on, 7 days off; 2.0-3.0 mg), and C (7 days on, 14 days off; 2.0-4.5 mg). Eighty-three patients were enrolled and received ≥1 BMS-986158 dose. Diarrhea (43%) and thrombocytopenia (39%) were the most common treatment-related adverse events (TRAEs). A lower incidence of TRAEs was found with schedules A (72%) and C (72%) vs. B (100%). Stable disease was achieved in 12 (26.1%), 3 (37.5%), and 9 (31.0%) patients on schedules A, B, and C, respectively. Two patients on schedule A with a 4.5-mg starting dose (ovarian cancer, n = 1; nuclear protein in testis [NUT] carcinoma, n = 1) experienced a partial response. BMS-986158 demonstrated rapid-to-moderate absorption (median time to maximum observed plasma concentration, 1-4 h). As expected with an epigenetic modifier, expression changes in select BET-regulated genes occurred with BMS-986158 treatment. Schedule A dosing (5 days on, 2 days off) yielded tolerable safety, preliminary antitumor activity, and a dose-proportional PK profile.

Lack of association between generic brittleness and neuropsychiatric measures in patients with epilepsy.

PURPOSE: In a prior bioequivalence study, generic brittle (GB) patients with epilepsy who were considered at risk of worsened seizures or drug side effects from switching antiepileptic drug (AED) formulations demonstrated no significant difference in their drug levels when switched between a brand and generic AED. An alternative basis for being GB may relate to having a personality or mindset that predisposes to poor outcomes from a formulation switch. The objective of this study was to explore whether GB patients with epilepsy could be differentiated from not GB patients based on standardized measures of personality, mood, outlook, and beliefs. METHODS: This was an exploratory, observational, case-control, non-therapeutic study in patients with epilepsy. Patient interviews were conducted, and histories were collected, yielding each patient (n = 148) to be determined as GB or not GB. Eight neuropsychiatry tests were administered to n = 127 of these patients. Tests included Neuroticism Extraversion Openness Personality Inventory 3 (NEO-PI 3), Life Orientation Test-Revised (LOT-R), Quality of Life in Epilepsy Inventory-89 (QOLIE-89), Adverse Childhood Experiences Score (ACE), Physical Symptoms Questionnaire or Patient Health Questionnaire-15 (PHQ-15), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), and the Beliefs About Medicines Questionnaire Epilepsy (BMQ-Epilepsy). A total of 23 Chi squared analyses, along with logistical regression, were performed to assess which tests and sub-elements associated with GB status. RESULTS: None of the neuropsychiatry tests or their sub-elements differentiated GB patients from not GB patients. Results implicate that standardized measures of personality, mood, outlook, and beliefs about their healthcare do not differ between GB and not GB patients with epilepsy, possibly because generic brittleness is caused by factors that neuropsychiatry tests do not measure. CONCLUSIONS: We hypothesized that being GB may relate to having a personality or mindset that predisposes patients to attributing poor outcomes to a formulation switch. However, findings here in patients with epilepsy did not uncover neuropsychiatric factors that predict which patients were GB and which were not GB.

The effects of spray drying, HPMCAS grade, and compression speed on the compaction properties of itraconazole-HPMCAS spray dried dispersions.

Spray dried dispersions (SDDs) have the potential to dramatically improve the oral bioavailability of drugs with poor water solubility. However, SDDs tend to have material attributes, such as small particle size, low bulk density, and poor flowability, which are undesirable for downstream processing such as tableting. The objective was to perform a comprehensive compaction characterization of both physical mixtures and SDDs consisting of itraconazole (ITZ) and hypromellose acetate succinate (HPMCAS) to elucidate process and material influences on compressibility and compactibility. We fabricated SDDs with 20% ITZ as a model BCS Class 2 drug and 80% HPMCAS as a polymer carrier. Results indicate that SDDs, as well physical mixtures of ITZ and HPMCAS, were easily deformable with similar compressibility profiles across all compression speeds. Analysis of Heckel plots revealed that yield pressures were fairly low for both physical mixtures and SDDs (43.97-59.75 MPa), indicative of ductile materials. SDDs had a much greater propensity to laminate, especially at higher compression speeds, compared to physical mixtures. This difference is likely due to the higher elastic recovery of SDDs. However, for intact tablets, the mechanical strength of compacts from SDDs tended to be higher than those produced from physical mixtures, likely due to the much smaller particle size of the SDDs. Importantly, examination of the compacts with differential scanning calorimetry did not detect any drug crystallization as a result of compaction. In conclusion, while spray drying did not significantly alter the compressibility of binary mixtures ITZ and HPMCAS, it dramatically impacted compactibility and tabletability, increasing elastic recovery, and making the mixtures more prone to lamination. However, at low compression speeds, SDDs produced tablets with higher tensile strength than physical mixtures.

Lack of Association of Generic Brittle Status with Genetics and Physiologic Measures in Patients with Epilepsy.

PURPOSE: A patient was denoted to be generic brittle (GB) if they had a negative opinion about generics (e.g. prior history of a switch problem) or took the innovator brand of their most problematic anti-epileptic drug (AED) when generic was available. The aim of this hypothesis-generating study was to assess possible genetic and physiologic differences between GB and not GB patients with epilepsy. METHODS: Patients (n = 148) with epilepsy were previously characterized as being either GB or not GB. Blood was collected from each subject for genotyping and physiologic testing. Genotyping for 24 single nucleotide polymorphisms (SNPs) and two copy number variants (CNVs) was performed across 12 genes in each patient. Forty-four physiologic tests were conducted in each patient. Chi square analysis was performed to assess for associations between genotyping results and GB status, as well as between physiologic test results and GB status. RESULTS: No SNP or CNV discriminated GB status in genetic analysis (genotype or allele frequency). Physiologic test results in this study were not associated with GB status. CONCLUSIONS: Questions from neurologists and patients about generics is frequently based on applicability of generic drug standards to individual subjects. However, findings here in patients with epilepsy did not uncover genetic or physiologic reasons that explained which patients were GB and which were not GB.

Relationship of antiepileptic drugs to generic brittleness in patients with epilepsy.

PURPOSE: The purpose of the study was to assess if any antiepileptic drug (AED) was associated with patients being generic brittle (GB) and if any specific AED caused - and was not merely associated with - more frequent switch problems. METHODS: Chi square and binary logistical regression analysis were performed, using a previously described study in patients with epilepsy who were routinely followed at the University of Maryland epilepsy outpatient clinic in Baltimore, Maryland. Determination of generic brittleness mirrored clinical practice and included patient opinion about generic formulations, usually based on a history of worsened seizures or side effects with prior AED formulation switching. The dataset included a total of 148 patients, who took 30 different AED formulations. Patients collectively took 530 AED formulation products. RESULTS: Taking lamotrigine immediate release (IR) tablets was associated with a greater probability of being GB and tended to cause more frequent switch problems. Interestingly, six AEDs - Vimpat tablet, carbamazepine IR tablet, phenobarbital (any formulation), gabapentin capsule, Lyrica capsules, and phenytoin (any formulation) - were associated with a reduced probability of being GB, although perhaps not through greater efficacy and tolerability, or better formulation quality. Since tablet and capsule appearance may influence patient perceptions and clinical outcomes, it was observed that the six AEDs less associated with being GB also tended to have fewer generics, and hence possibly lessen treatment uncertainties from the patient perspective. A patient taking more AEDs had significantly increased odds of having a switch problem. An additional observation was that, when a generic was available for their most problematic AED, GB patients took a generic AED only 50% of the time, while not GB patients took a generic AED all the time. CONCLUSIONS: Taking lamotrigine IR tablets was associated with a greater probability of being GB and tended to cause more frequent switch problems than other AEDs in this cohort of patients. Six AEDs were associated with a reduced probability of being GB. The lower number of different generics for these six drugs may result in greater patient certainty in medication identity, due to greater consistency in medication color, shape, and size, and hence less generic skepticism or generic brittleness. Also, patients taking more AEDs showed increased odds of a switch problem.

'Our village is dependent on us. That's why we can't leave our work'. Characterizing mechanisms of motivation to perform among Accredited Social Health Activists (ASHA) in Bihar.

Community health workers (CHWs) play major roles in delivering primary healthcare services, linking communities to the formal health system and addressing the social determinants of health. Available evidence suggests that the performance of CHW programmes in low- and middle-income countries can be influenced by context-dependent causal mechanisms such as motivation to perform. There are gaps regarding what these mechanisms are, and what their contribution is to CHW performance. We used a theory-driven case study to characterize motivational mechanisms among Accredited Social Health Activists (ASHAs) in Bihar, India. Data were collected through semi-structured interviews with CHWs and focus group discussions with beneficiary women. Data were coded using a combined deductive and inductive approach. We found that ASHAs were motivated by a sense of autonomy and self-empowerment; a sense of competence, connection and community service; satisfaction of basic financial needs; social recognition; and feedback and answerability. Findings highlight the potential of ASHAs' intrinsic motivation to increase their commitment to communities and identification with the health system and of programme implementation and management challenges as sources of work dissatisfaction. Efforts to nurture and sustain ASHAs' intrinsic motivation while addressing these challenges are necessary for improving the performance of Bihar's ASHA programme. Further research is needed to characterize the dynamic interactions between ASHAs' motivation, commitment, job satisfaction and overall performance; also, to understand how work motivation is sustained or lost through time. This can inform policy and managerial reforms to improve ASHA programme's performance.

Exploring generic brittleness and the demographic factors for its susceptibility in patients with epilepsy.

PURPOSE: The purpose of this study was to provide an algorithm for generic brittleness and to elucidate the demographic factors that anticipate generic brittleness for patients with epilepsy. METHODS: This exploratory, observational, and nontherapeutic study was conducted in patients with epilepsy who were routinely followed at the University of Maryland epilepsy outpatient clinic in Baltimore, Maryland. Patients were taking at least one antiepileptic drug (AED) for treatment of epilepsy. Based on patient interview and medical history, 12 demographic factors were collected. Each patient was assessed to be either generic brittle (GB) or not GB. Demographic factors were subjected to binary logistical regression and other statistical tests, to elucidate determinants of GB status. RESULTS: N = 148 patients completed the study. An algorithm to define whether a patient was GB or not GB was devised. The two elements that defined GB status are as follows: patient opinion about generics and (if needed) whether patients were currently taking brand or generic of their most problematic AED. About 40% of patients were GB. From binary logistical regression, two demographic factors that contributed to patients being GB were whether a patient was currently taking a problem AED and total number of current medications for a patient, with odds ratios of 4.06 (95% confidence interval [CI] from 1.53 to 10.81) and 1.10 (95% CI from 1.003 to 1.21), respectively. Of the patients on a problem AED, 46.9% were GB, while only 18.2% of patients not currently on a problem AED were GB. The total number of current medications ranged from 1 to 22, with mode of four medications. From regression, for each additional medication that a patient took, the odds of being GB increased 1.10-fold. Although patient seizure and adverse event history was not employed to define GB status, being GB was associated with less seizure control and greater adverse events. CONCLUSIONS: An algorithm for generic brittleness was derived, and about 40% of patients were GB, usually due to prior history of a switch problem. Two demographic factors favored patients being GB: whether the patient was currently taking a problem AED and the total number of current medications.

Idiopathic infantile pyoderma gangrenosum with stridor responsive to infliximab.

A 4-month-old female infant presented with widespread pyoderma gangrenosum associated with stridor, presumed secondary to tracheal involvement. No underlying cause was revealed despite extensive investigation. Treatment with immunosuppressive agents only partially suppressed disease activity. Complete resolution followed treatment with infliximab. We review this rare condition in infants and discuss treatment with infliximab not previously described in this age group.