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1.
Curr Med Res Opin ; 35(8): 1379-1385, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30793988

RESUMO

Purpose: The purpose of this study is to determine racial and ethnic disparities with the adherence to inhaled corticosteroids (ICSs) in adults with persistent asthma, and their association with healthcare expenditures. Methods: A retrospective, cross-sectional study using the Medical Expenditure Panel Survey (MEPS) 2013-2014 data included patients ≥18 years with persistent asthma. Median medication possession ratio (MPR) was used to dichotomize adherence levels. Multivariate regression analysis was conducted to ascertain the association between adherence and race/ethnicity. Total expenditures and association with adherence were analyzed using a generalized linear model with a log link function and gamma distribution. Unadjusted expenditures were compared after bootstrapping. Results: The average MPR of ICSs for the sample of 277 patients was 0.34. The average MPR level was 0.33 among whites, 0.37 among African-Americans and 0.35 among other minorities. The average MPR was 0.30 among Hispanics, and 0.35 among non-Hispanics. African-Americans were less likely to be adherent than whites (OR 0.95). Hispanics were less likely to be adherent (OR 0.4; CI 0.206-0.777). Higher adherence was associated with significantly higher total health expenditure than lower adherence ($19,223 vs. $12,840 respectively, p < .0001). African-Americans had slightly higher total expenditure compared to whites; however, other minorities had significantly lower health expenditures compared to whites (p = .01). Non-Hispanics spent significantly less on healthcare compared to Hispanics (p = .04). Conclusions: Valuable insight into the economic cost of the disparities as they relate to persistent asthma provides further evidence of possible ethnic inequities that warrant addressing.


Assuntos
Corticosteroides , Anti-Inflamatórios , Asma/tratamento farmacológico , Adesão à Medicação , Grupos Populacionais/estatística & dados numéricos , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Estudos Transversais , Gastos em Saúde/estatística & dados numéricos , Humanos , Adesão à Medicação/etnologia , Adesão à Medicação/estatística & dados numéricos , Estudos Retrospectivos , Adulto Jovem
2.
Artigo em Inglês | MEDLINE | ID: mdl-23341734

RESUMO

The problem of patients not taking medications as prescribed, also known as "lack of medication adherence," is widely discussed as an issue related to suboptimal outcomes and excess health care expenditure. Although medication adherence is defined as patients not taking medications as prescribed, there are two elements to it: first, those who fail to follow the medication regimen by skipping a dose or not following the instructions, resulting in poor adherence with prescribed medicines; and, second, the patient who does not take the medication at all or stops after the initial fill. The existing literature contains a lot of studies on the first element, but very little is known about those who stop taking their medication after the initial fill or do not take it at all. In this study, our focus is on identifying patients who fail to refill a prescription for essential medicines, such as asthma-controlling drugs. Using Medicaid claims datasets, this study analyzed a pediatric population diagnosed with persistent asthma that discontinued an essential controlling medication after the initial fill. We found that more than half of this population did not continue their medication after the first fill. While there might be many reasons behind the failure to refill such medications, our data indicate that race/ethnicity, comorbid illness, and type of Medicaid plan are potentially associated with such behavior. Future research is warranted to understand this issue further and identify specific factors causing such behavior, such that strategies may be formulated by which poor adherence can be minimized.

3.
Mol Pharmacol ; 82(6): 1162-73, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22968304

RESUMO

Lysophosphatidic acid (LPA) is a highly potent endogenous lipid mediator that protects and rescues cells from programmed cell death. Earlier work identified the LPA2 G protein-coupled receptor subtype as an important molecular target of LPA mediating antiapoptotic signaling. Here we describe the results of a virtual screen using single-reference similarity searching that yielded compounds 2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid (NSC12404), 2-((3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid (GRI977143), 4,5-dichloro-2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid (H2L5547924), and 2-((9,10-dioxo-9,10-dihydroanthracen-2-yl)carbamoyl) benzoic acid (H2L5828102), novel nonlipid and drug-like compounds that are specific for the LPA2 receptor subtype. We characterized the antiapoptotic action of one of these compounds, GRI977143, which was effective in reducing activation of caspases 3, 7, 8, and 9 and inhibited poly(ADP-ribose)polymerase 1 cleavage and DNA fragmentation in different extrinsic and intrinsic models of apoptosis in vitro. Furthermore, GRI977143 promoted carcinoma cell invasion of human umbilical vein endothelial cell monolayers and fibroblast proliferation. The antiapoptotic cellular signaling responses were present selectively in mouse embryonic fibroblast cells derived from LPA(1&2) double-knockout mice reconstituted with the LPA2 receptor and were absent in vector-transduced control cells. GRI977143 was an effective stimulator of extracellular signal-regulated kinase 1/2 activation and promoted the assembly of a macromolecular signaling complex consisting of LPA2, Na⁺ - H⁺ exchange regulatory factor 2, and thyroid receptor interacting protein 6, which has been shown previously to be a required step in LPA-induced antiapoptotic signaling. The present findings indicate that nonlipid LPA2-specific agonists represent an excellent starting point for development of lead compounds with potential therapeutic utility for preventing the programmed cell death involved in many types of degenerative and inflammatory diseases.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células CHO , Caspases/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetinae , Fragmentação do DNA/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas com Domínio LIM/metabolismo , Lisofosfolipídeos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Knockout , Invasividade Neoplásica , Fosfoproteínas/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Complexo de Endopeptidases do Proteassoma , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/metabolismo , Fatores de Transcrição/metabolismo , Proteína X Associada a bcl-2/metabolismo
4.
Biochem Soc Trans ; 40(1): 31-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22260662

RESUMO

LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX-LPA signalling axis an emerging target for cancer therapy.


Assuntos
Neoplasias/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Lisofosfolipídeos/metabolismo , Terapia de Alvo Molecular , Invasividade Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêutico , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
5.
ChemMedChem ; 6(5): 922-35, 2011 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-21465666

RESUMO

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D activity, which leads to generation of the growth-factor-like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4-tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues block ATX activity with K(i) values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed-mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30 b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose-dependent manner. The average terminal half-life for compound 22 is 10±5.4 h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30 b significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The 4-substituted benzylphosphonic acids and 6-substituted naphthalen-2-ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX-LPA-LPAR axis both in vitro and in vivo.


Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Complexos Multienzimáticos/antagonistas & inibidores , Naftalenos/química , Organofosfonatos/química , Compostos Organofosforados/química , Fosfodiesterase I/antagonistas & inibidores , Pirofosfatases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Camundongos , Complexos Multienzimáticos/metabolismo , Naftalenos/síntese química , Naftalenos/uso terapêutico , Invasividade Neoplásica , Metástase Neoplásica , Organofosfonatos/síntese química , Organofosfonatos/uso terapêutico , Compostos Organofosforados/síntese química , Compostos Organofosforados/uso terapêutico , Fosfodiesterase I/metabolismo , Diester Fosfórico Hidrolases , Pirofosfatases/metabolismo
6.
Bioorg Med Chem Lett ; 20(24): 7525-8, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21051230

RESUMO

Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA(5) GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA(5) compared to the R-stereoisomer. In contrast, no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics.


Assuntos
Ácidos Fosfatídicos/química , Animais , Modelos Animais de Doenças , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Lisofosfolipase/antagonistas & inibidores , Lisofosfolipase/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/metabolismo , Ácidos Fosfatídicos/síntese química , Ácidos Fosfatídicos/farmacologia , Fosfodiesterase I/antagonistas & inibidores , Fosfodiesterase I/metabolismo , Diester Fosfórico Hidrolases , Pirofosfatases/antagonistas & inibidores , Pirofosfatases/metabolismo , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/metabolismo , Estereoisomerismo
7.
Rapid Commun Mass Spectrom ; 22(5): 639-46, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18247407

RESUMO

A rapid method for quantitative chiral analysis of phthaloylglutamic acid and its dimethyl ester by Cook's kinetic method is demonstrated using electrospray ionization (ESI) and matrix-assisted laser desorption techniques. Transition-metal-bound complex ions containing the chiral phthaloylglutamic acid and its dimethyl ester are generated by ESI mass spectrometry and subjected to collision-induced dissociation. The ratio of the two competitive dissociation rates is related to the enantiomeric composition of the drug mixture. A seven-point calibration curve, derived from the kinetic method, allowed rapid quantitation of the enantiomeric excess of drug mixtures. In this paper, matrix-assisted laser desorption/ionization (MALDI) coupled with the linear ion trap (LIT) technique is evaluated for its applicability as a complementary technique to ESI for chiral discrimination and quantitation.


Assuntos
Glutamatos/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrometria de Massas em Tandem/métodos , Estereoisomerismo
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