ABSTRACT
Critical feminist research addresses social inequities, encourages equitable partnerships between researchers and participants, and acknowledges that research can be inherently political. Building upon critical feminist research practices, community-based participatory research, and social and structural epidemiology, we propose the approach of critical feminist epidemiology. A critical feminist epidemiology approach can study community and population health inequities with an eye towards identifying interventions that reduce inequities, through research processes that center the lived experiences of people from minoritized genders. We describe how our interdisciplinary, community-led team used a critical feminist epidemiology approach for an applied public health research project. Mujeres Unidas y Activas, a community organizing non-profit led by and for Latina and Indigenous immigrant women, partnered with academic researchers to conduct community-led research around how their approach to building community power affected the health and wellbeing of organization members and their families. Critical feminist epidemiology is a promising approach for conducting research that is grounded in and relevant to the lives of women and gender expansive people. Building upon social epidemiology and community-based participatory research, critical feminist epidemiology can be a useful research approach to generate novel evidence to inform action towards health equity for communities and populations.
ABSTRACT
BACKGROUND: This randomized, placebo-controlled study assessed the safety, tolerability, and immunogenicity of live virus zoster vaccine (ZV) in individuals receiving chronic/maintenance systemic corticosteroid therapy (daily dose equivalent of 5-20mg prednisone) for ≥2 weeks prior to vaccination and ≥6 weeks postvaccination. METHODS: Subjects were followed for adverse experiences (AEs), exposure to varicella or herpes zoster (HZ), or development of varicella/varicella-like or HZ/HZ-like rashes for 42 days postvaccination (primary safety follow-up period) and for serious AEs (SAEs) through Day 182 postvaccination (secondary follow-up period). Varicella-zoster virus (VZV) antibody titers by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and at Week 6 postvaccination. RESULTS: The proportions of subjects reporting systemic AEs and SAEs were similar in both groups. A higher percentage of subjects reported injection-site AEs in the ZV group (21.5%) than in the placebo group (12.1%). One SAE of ophthalmic HZ (onset Day 16 postvaccination) was reported in the ZV group and deemed vaccine-related by the study investigator; however, PCR testing confirmed the presence of wild-type (not vaccine strain) VZV. Geometric mean titer (GMT) at 6 weeks postvaccination was higher for ZV recipients than placebo recipients, with estimated geometric mean fold rises (GMFR) of 2.3 (CI: 2.0, 2.7) and 1.1 (CI: 1.0, 1.2) respectfully. CONCLUSIONS: In adults ≥60 years old on chronic/maintenance corticosteroids, ZV was generally well tolerated and immunogenic. The VZV-specific gpELISA antibody GMT at 6 weeks postvaccination and the GMFR from baseline to 6 weeks postvaccination were higher in the ZV group than in the placebo group.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Herpes Zoster Vaccine/adverse effects , Herpes Zoster Vaccine/immunology , Immunosuppressive Agents/therapeutic use , Aged , Aged, 80 and over , Antibodies, Viral/blood , Chickenpox/epidemiology , Chickenpox/prevention & control , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Enzyme-Linked Immunosorbent Assay , Female , Follow-Up Studies , Herpes Zoster/epidemiology , Herpes Zoster/prevention & control , Herpes Zoster Vaccine/administration & dosage , Humans , Male , Middle Aged , Placebos/administration & dosage , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/adverse effects , Vaccines, Attenuated/immunologyABSTRACT
BACKGROUND: Prior clinical studies of zoster vaccine enrolled subjects without a history of herpes zoster (HZ), so there are limited data on safety and immunogenicity in vaccinees with a prior history of HZ. This study was conducted to evaluate the safety and immunogenicity of zoster vaccine recipients who had a prior episode of HZ. METHODS: A total of 101 subjects > or = 50 years of age with a prior history of HZ were enrolled. They were stratified by number of years since their HZ (5 to 9 years and > or = 10 years, in an approximate 2:1 ratio), and randomized 1:1 to one of two vaccination groups. On day 1, Group I was administered zoster vaccine and Group II received placebo. At week 4, Group I received placebo and Group II received zoster vaccine. Subjects were followed for adverse experiences (AEs), exposure to varicella or HZ, and development of any varicella/varicella-like or HZ/HZ-like rashes, for 28 days after each injection. Blood samples were obtained prior to study injection on day 1 and week 4, and at week 8. Serum was assessed for varicella-zoster virus (VZV) antibody concentration by glycoprotein enzyme-linked immunosorbent assay. RESULTS: No serious AEs were reported within the 28-day safety follow-up period following any vaccination. Although a higher percentage of subjects reported injection-site AEs after receiving zoster vaccine than did placebo recipients, the proportion of subjects reporting systemic clinical AEs was similar in both groups. Zoster vaccine induced a VZV antibody response at 4 weeks post-vaccination. The estimated geometric mean titer (GMT) ratio (vaccine/placebo) was 2.07 (95% CI: 1.48, 2.88). The geometric mean fold-rise (GMFR) from prevaccination to week 4 post-vaccination was 2.1 in zoster vaccine recipients, versus 1.0 in placebo recipients. CONCLUSIONS: In HZ history-positive adults > or = 50 years of age, zoster vaccine: (1) was well tolerated; and (2) significantly boosted the level of VZV antibody from baseline to 4 weeks post-vaccination as measured by GMT and GMFR. These data support the Advisory Committee on Immunization Practices' recommendation for routine zoster vaccination for all immunocompetent persons >/=60 years of age irrespective of HZ history.
Subject(s)
Herpes Zoster Vaccine/immunology , Herpes Zoster/prevention & control , Aged , Aged, 80 and over , Antibodies, Viral/blood , Antibody Formation , Cross-Over Studies , Double-Blind Method , Female , Herpes Zoster/immunology , Herpes Zoster Vaccine/adverse effects , Humans , Male , Middle Aged , United StatesABSTRACT
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
Subject(s)
Nitriles/chemical synthesis , Nitriles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Dogs , Macaca mulatta , Molecular Structure , Nitriles/chemistry , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Rats , Sensitivity and Specificity , Structure-Activity Relationship , Thiazoles/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
Subject(s)
Aminopyridines/chemical synthesis , Potassium Channels, Voltage-Gated/metabolism , Pyridines/chemical synthesis , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Biological Availability , Cell Line , Dogs , ERG1 Potassium Channel , Electrocardiography/drug effects , Ether-A-Go-Go Potassium Channels , In Vitro Techniques , Lung/enzymology , Macaca mulatta , Male , Mice , Microsomes, Liver/metabolism , Phosphorylation , Pyridines/pharmacokinetics , Pyridines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tissue Distribution , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
Subject(s)
Amines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amines/chemical synthesis , Binding Sites , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Molecular , Protein Binding , Protein Conformation/drug effects , Structure-Activity Relationship , Thermodynamics , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Binding Sites , Biological Availability , Cell Membrane Permeability , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Models, Molecular , Molecular Structure , Solubility , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Drug Design , Humans , Molecular Structure , Solubility , Structure-Activity RelationshipABSTRACT
A strategy for antagonizing vascular endothelial growth factor (VEGF) -induced angiogenesis is to inhibit the kinase activity of its receptor, kinase insert domain-containing receptor (KDR), the first committed and perhaps the last unique step in the VEGF signaling cascade. We synthesized a novel ATP-competitive KDR tyrosine kinase inhibitor that potently suppresses human and mouse KDR activity in enzyme (IC(50) = 7.8-19.5 nM) and cell-based assays (IC(50) = 8 nM). The compound was bioavailable in vivo, leading to a dose-dependent decrease in basal- and VEGF-stimulated KDR tyrosine phosphorylation in lungs from naïve and tumor-bearing mice (IC(50) = 23 nM). Pharmacokinetics and pharmacodynamics guided drug dose selection for antitumor efficacy studies. HT1080 nude mice xenografts were treated orally twice daily with vehicle, or 33 or 133 mg/kg of compound. These doses afforded trough plasma concentrations approximately equal to the IC(50) for inhibition of KDR autophosphorylation in vivo for the 33 mg/kg group, and higher than the IC(99) for the 133 mg/kg group. Chronic treatment at these doses was well-tolerated and resulted in dose-dependent inhibition of tumor growth, decreased tumor vascularization, decreased proliferation, and enhanced cell death. Antitumor efficacy correlated with inhibition of KDR tyrosine phosphorylation in the tumor, as well as in a surrogate tissue (lung). Pharmacokinetics and pharmacodynamics assessment indicated that the degree of tumor growth inhibition correlated directly with the extent of inhibition of KDR tyrosine phosphorylation in tumor or lung at trough. These observations highlight the need to design antiangiogenic drug regimens to ensure constant target suppression and to take advantage of PD end points to guide dose selection.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Fibrosarcoma/drug therapy , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacokinetics , Animals , Antineoplastic Agents/administration & dosage , Biological Availability , Cell Division/drug effects , Cell Line, Tumor , Enzyme Inhibitors/administration & dosage , Fibrosarcoma/pathology , Humans , Mice , Mice, Nude , Phosphorylation , Transplantation, Heterologous , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.
Subject(s)
Cation Transport Proteins/metabolism , Enzyme Inhibitors/pharmacokinetics , Potassium Channels, Voltage-Gated , Potassium Channels/metabolism , Quinolones/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Cell Line , Dogs , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels , Humans , Microsomes, Liver/enzymology , Protein Binding/physiology , Quinolones/chemistry , Rats , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Indoles/chemical synthesis , Indoles/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Biological Availability , Cell Line , Half-Life , Indoles/pharmacology , Inhibitory Concentration 50 , Rats , Structure-Activity RelationshipABSTRACT
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Chemical Phenomena , Chemistry, Physical , Dogs , Drug Design , Enzyme Inhibitors/pharmacokinetics , Half-Life , Hydrogen-Ion Concentration , Indicators and Reagents , Molecular Conformation , Rats , Structure-Activity RelationshipABSTRACT
2,4-Disubstituted pyrimidines were synthesized as a novel class of KDR kinase inhibitors. Evaluation of the SAR of the screening lead compound 1 (KDR IC(50)=105 nM, Cell IC(50)=8% inhibition at 500 nM) led to the potent 3,5-dimethylaniline derivative 2d (KDR IC(50)=6 nM, cell IC(50)=19 nM).
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Pyrimidines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cells, Cultured , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Pyrimidines/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Cell Division/drug effects , Cell Line , Endothelium, Vascular/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Metabolic Clearance Rate , Pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described.