10 research outputs found
Help seeking for cardiac symptoms: Beyond the masculine-feminine binary
Empirical and theoretical literature suggests that stereotypical gender roles shape men's and women's health help-seeking behavior, and plays an important role in the treatment seeking delays of cardiac patients. We were interested in exploring the ways in which gender informs the experiences and help-seeking behavior of men and women who experienced the symptoms associated with acute cardiac events. We undertook 20 in-depth interviews between October 2007 and July 2008 with 11 men and 9 women recently diagnosed with an acute coronary syndrome in British Columbia, Canada. Participants were encouraged to tell their 'story' of the event that led to hospitalization and diagnosis, with a focus on the symptoms and decision making processes that occurred before and during the activation of health services: seeking the advice of others including colleagues, family members and healthcare professionals; calling 911; and attending an emergency department. Although we anticipated that distinctive patterns of help-seeking behavior aligned with stereotypical masculine and feminine ideals might emerge from our data, this was not always the case. We found some evidence of the influence of gender role ideology on the help-seeking behavior of both male and female participants. However, men's and women's experiences of seeking health care were not easily parsed into distinct binary gender patterns. Behavior that might stereotypically be considered to be 'masculine' or 'feminine' gender practice was shared by both male and female participants. Our findings undermine simple binary distinctions about gendered help-seeking prevalent in the literature, and contribute towards setting the direction of the future health policy and research agenda addressing the issue of gender and health help-seeking behavior.Canada Gender Femininity Masculinity Cardiovascular disease Cardiac symptoms Health-seeking behaviour
Inconsistent measurement of acute coronary syndrome patients’ pre-hospital delay in research: A review of the literature
Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7‑(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]‑9<i>H</i>‑carbazole-1-carboxamide (BMS-935177)
Bruton’s
tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine
kinases and plays a critical role in multiple cell types responsible
for numerous autoimmune diseases. This article will detail the structure–activity
relationships (SARs) leading to a novel second generation series of
potent and selective reversible carbazole inhibitors of BTK. With
an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable
safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroÂquinazolin-3-yl)Âphenyl]-9<i>H</i>-carbazole-1-carboxamide <b>6</b> (BMS-935177) was
selected to advance into clinical development
Discovery of 6‑Fluoro-5‑(<i>R</i>)‑(3‑(<i>S</i>)‑(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4<i>H</i>)‑yl)-2-methylphenyl)-2‑(<i>S</i>)‑(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro‑1<i>H</i>‑carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers
Bruton's tyrosine
kinase (BTK), a nonreceptor tyrosine kinase,
is a member of the Tec family of kinases. BTK plays an essential role
in B cell receptor (BCR)-mediated signaling as well as FcÎł receptor
signaling in monocytes and Fcε receptor signaling in mast cells
and basophils, all of which have been implicated in the pathophysiology
of autoimmune disease. As a result, inhibition of BTK is anticipated
to provide an effective strategy for the clinical treatment of autoimmune
diseases such as lupus and rheumatoid arthritis. This article details
the structure–activity relationships (SAR) leading to a novel
series of highly potent and selective carbazole and tetrahydrocarbazole
based, reversible inhibitors of BTK. Of particular interest is that
two atropisomeric centers were rotationally locked to provide a single,
stable atropisomer, resulting in enhanced potency and selectivity
as well as a reduction in safety liabilities. With significantly enhanced
potency and selectivity, excellent in vivo properties and efficacy,
and a very desirable tolerability and safety profile, <b>14f</b> (BMS-986142) was advanced into clinical studies
Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders
PI3Kδ plays an important role
controlling immune cell function and has therefore been identified
as a potential target for the treatment of immunological disorders.
This article highlights our work toward the identification of a potent,
selective, and efficacious PI3Kδ inhibitor. Through careful
SAR, the successful replacement of a polar pyrazole group by a simple
chloro or trifluoromethyl group led to improved Caco-2 permeability,
reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity
profile while maintaining potency in the CD69 hWB assay. The optimization
of the aryl substitution then identified a 4′-CN group that
improved the human/rodent correlation in microsomal metabolic stability.
Our lead molecule is very potent in PK/PD assays and highly efficacious
in a mouse collagen-induced arthritis model
Recommended from our members