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1.
Health Aff (Millwood) ; 38(9): 1537-1541, 2019 09.
Article in English | MEDLINE | ID: mdl-31479363

ABSTRACT

Following the implementation of the Affordable Care Act's contraceptive coverage requirement, privately insured women's out-of-pocket spending for contraception declined and their use of long-acting reversible contraceptives (LARCs) increased. Claims data through 2016 show a continued increase in LARC insertions but an increase in out-of-pocket spending for intrauterine devices.


Subject(s)
Contraception/trends , Financing, Personal , Insurance Coverage , Patient Protection and Affordable Care Act , Adolescent , Adult , Contraception/statistics & numerical data , Databases, Factual , Female , Financing, Personal/statistics & numerical data , Humans , Middle Aged , Young Adult
2.
Womens Health Issues ; 28(3): 219-223, 2018.
Article in English | MEDLINE | ID: mdl-29544988

ABSTRACT

OBJECTIVES: The Affordable Care Act (ACA) contraceptive coverage mandate issued in August 2012 requires most private health insurance plans to cover all U.S. Food and Drug Administration-approved contraceptive methods without cost sharing. We evaluate the impact of this policy on out-of-pocket costs and use of long-acting reversible contraceptives (LARCs) and other prescription methods through 2014. METHODS: Data from Truven Health MarketScan were used to examine out-of-pocket costs and contraceptive use patterns for all reversible prescription contraceptives before and after the implementation of the contraceptive mandate for privately insured women ages 13 to 45. Costs were estimated by combining copayment, coinsurance, and deductible payments for both contraception and insertion fees for LARCs. Contraceptive use rates were examined and multivariable logistic regression analysis of LARC insertions before and after the ACA was conducted. RESULTS: Out-of-pocket costs for all reversible contraceptives, including LARCs, decreased sharply after the ACA contraceptive mandate. The greatest proportion of women in each year was oral contraceptive users (24.3%-26.1%). Rates of new LARC insertions increased significantly after the ACA, when controlling for cohort year, age group, geographic region, and rural versus urban setting (adjusted odds ratio, 1.03; 95% confidence interval, 1.02-1.04). CONCLUSIONS: Our study adds to the current literature with the inclusion of 2014 data and confirms previous findings of a post-ACA decrease in out-of-pocket contraceptive costs. In addition, there was a small but statistically significant increase in LARC insertions after the ACA. This finding indicates the importance of reduced cost sharing for increasing use of the most effective contraceptives.


Subject(s)
Contraception Behavior/statistics & numerical data , Contraception/economics , Insurance Coverage/economics , Patient Protection and Affordable Care Act/economics , Adolescent , Adult , Contraception/statistics & numerical data , Cost Sharing/economics , Female , Health Expenditures/statistics & numerical data , Humans , Middle Aged , Prescriptions/economics , United States , Young Adult
3.
Med Clin North Am ; 100(5): 1101-10, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27542429

ABSTRACT

When screening for cancer in older adults, it is important to consider the risks of screening, how long it takes to benefit from screening, and the patient's comorbidities and life expectancy. Delivering high-value care requires the consideration of evidence-based screening guidelines and careful selection of patients. This article considers the impact of cancer. It explores perspectives on the costs of common cancer screening tests, illustrates how using life expectancy can help clinicians determine who will benefit most from screening, and provides tools to help clinicians discuss with their older patients when it may be appropriate to stop screening for cancer.


Subject(s)
Breast Neoplasms/diagnostic imaging , Colorectal Neoplasms/diagnosis , Early Detection of Cancer , Life Expectancy , Lung Neoplasms/diagnostic imaging , Prostatic Neoplasms/diagnosis , Aged , Cost-Benefit Analysis , Early Detection of Cancer/economics , Female , Humans , Male , Mammography , Practice Guidelines as Topic , Tomography, X-Ray Computed
4.
Bioorg Med Chem ; 17(16): 6123-36, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19632123

ABSTRACT

In the search for bioactive sphingosine 1-phosphate (S1P) receptor ligands, a series of 2-amino-2-heterocyclic-propanols were synthesized. These molecules were discovered to be substrates of human-sphingosine kinases 1 and 2 (SPHK1 and SPHK2). When phosphorylated, the resultant phosphates showed varied activities at the five sphingosine-1-phosphate (S1P) receptors (S1P(1-5)). Agonism at S1P(1) was displayed in vivo by induction of lymphopenia. A stereochemical preference of the quaternary carbon was crucial for phosphorylation by the kinases and alters binding affinities at the S1P receptors. Oxazole and oxadiazole compounds are superior kinase substrates to FTY720, the prototypical prodrug immunomodulator, fingolimod (FTY720). The oxazole-derived structure was the most active for human SPHK2. Imidazole analogues were less active substrates for SPHKs, but more potent and selective agonists of the S1P(1) receptor; additionally, the imidazole class of compounds rendered mice lymphopenic.


Subject(s)
Immunosuppressive Agents/chemical synthesis , Prodrugs/chemical synthesis , Propanols/chemical synthesis , Propylene Glycols/chemistry , Receptors, Lysosphingolipid/agonists , Sphingosine/analogs & derivatives , Animals , Fingolimod Hydrochloride , Humans , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Lymphopenia/chemically induced , Mice , Prodrugs/chemistry , Prodrugs/pharmacology , Propanols/chemistry , Propylene Glycols/chemical synthesis , Propylene Glycols/pharmacology , Receptors, Lysosphingolipid/metabolism , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacology , Structure-Activity Relationship
5.
Biochem J ; 419(3): 611-8, 2009 May 01.
Article in English | MEDLINE | ID: mdl-19215222

ABSTRACT

LPA (lysophosphatidic acid) is a lipid mediator that stimulates cell proliferation and growth, and is involved in physiological and pathological processes such as wound healing, platelet activation, angiogenesis and the growth of tumours. Therefore defining the mechanisms of LPA production and degradation are of interest in understanding the regulation of these processes. Extracellular LPA synthesis is relatively well understood, whereas the mechanisms of its degradation are not. One route of LPA degradation is dephosphorylation. A candidate enzyme is the integral membrane exophosphatase LPP1 (lipid phosphate phosphohydrolase type 1). In the present paper, we report the development of a mouse wherein the LPP1 gene (Ppap2a) was disrupted. The homozygous mice, which are phenotypically unremarkable, generally lack Ppap2a mRNA, and multiple tissues exhibit a substantial (35-95%) reduction in LPA phosphatase activity. Compared with wild-type littermates, Ppap2a(tr/tr) animals have increased levels of plasma LPA, and LPA injected intravenously is metabolized at a 4-fold lower rate. Our results demonstrate that LPA is rapidly metabolized in the bloodstream and that LPP1 is an important determinant of this turnover. These results indicate that LPP1 is a catabolic enzyme for LPA in vivo.


Subject(s)
Extracellular Space/metabolism , Lysophospholipids/metabolism , Phosphatidate Phosphatase/metabolism , Animals , Base Sequence , Gene Expression Regulation, Enzymologic , Lysophospholipids/blood , Mice , Molecular Sequence Data , Organ Specificity , Phosphatidate Phosphatase/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism
6.
J Med Chem ; 50(25): 6428-35, 2007 Dec 13.
Article in English | MEDLINE | ID: mdl-17994678

ABSTRACT

Compound 1 (FTY720, Fingolimod) represents a new generation of immunosuppressant that modulates lymphocyte trafficking by interacting with the S1P(1) receptor. Compound 1 also provides a template molecule for studying the molecular biology of S1P receptors and related enzymes (kinases and phosphatases). In this study, two conformationally constrained analogues of 1 ( 3a and 3c) were asymmetrically synthesized in high optical purity. In vitro assessment documented that both analogues are Sphk2 substrates, their phosphorylated species are potent S1P(1) receptor agonists, and 3a-P is a potent S1P 3 antagonist. After oral administration in mice, both compounds evoked lymphopenia, but their duration of action differed markedly.


Subject(s)
Immunologic Factors/chemical synthesis , Prodrugs/chemical synthesis , Propylene Glycols/chemical synthesis , Receptors, Lysosphingolipid/agonists , Receptors, Lysosphingolipid/antagonists & inhibitors , Sphingosine/analogs & derivatives , Animals , Calcium/metabolism , Cell Line , Cricetinae , Cricetulus , Fingolimod Hydrochloride , Humans , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Mice , Phosphorylation , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Prodrugs/chemistry , Prodrugs/pharmacology , Propylene Glycols/chemistry , Propylene Glycols/pharmacology , Radioligand Assay , Sphingosine/chemical synthesis , Sphingosine/chemistry , Sphingosine/pharmacology , Stereoisomerism , Structure-Activity Relationship
7.
Bioorg Med Chem ; 15(2): 663-77, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-17113298

ABSTRACT

The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphate (S1P) receptors (S1P(1-5)). To this end, the syntheses of phosphoserine mimetics-selectively protected and optically active phosphonoserines-are described. In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. meta-substituted arylamide phosphonates were discovered to be antagonists of the S1P(1) and S1P(3) receptors. When administered to mice, an antagonist blocked the lymphopenia evoked by a S1P receptor agonist and caused capillary leakage in both lung and kidney.


Subject(s)
Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Receptors, Lysosphingolipid/agonists , Receptors, Lysosphingolipid/antagonists & inhibitors , Animals , Capillary Permeability/drug effects , Cell Line , Guanosine Triphosphate/metabolism , Indicators and Reagents , Lymphopenia/chemically induced , Lymphopenia/prevention & control , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred C57BL , Molecular Conformation , Optical Rotation , Tissue Distribution
8.
J Biol Chem ; 280(44): 36865-72, 2005 Nov 04.
Article in English | MEDLINE | ID: mdl-16093248

ABSTRACT

Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper and T effector cells to be retained in secondary lymphoid tissue and away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated sphingosine kinase 2 (SPHK2) null mice to demonstrate that this kinase is responsible for FTY720 phosphorylation and thereby its subsequent actions on the immune system. Both systemic and lymphocyte-localized sources of SPHK2 contributed to FTY720 induced lymphopenia. Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases. Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism.


Subject(s)
Immunosuppressive Agents/toxicity , Lymphocytes/drug effects , Lymphocytes/enzymology , Lymphopenia , Phosphotransferases (Alcohol Group Acceptor)/physiology , Propylene Glycols/toxicity , Animals , Fingolimod Hydrochloride , Flow Cytometry , Homozygote , Immunosuppressive Agents/metabolism , Lymphopenia/chemically induced , Lymphopenia/enzymology , Lysophospholipids/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation/drug effects , Phosphotransferases (Alcohol Group Acceptor)/genetics , Prodrugs/metabolism , Prodrugs/toxicity , Propylene Glycols/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sphingosine/analogs & derivatives , Sphingosine/metabolism
9.
Bioorg Med Chem Lett ; 15(20): 4470-4, 2005 Oct 15.
Article in English | MEDLINE | ID: mdl-16125386

ABSTRACT

Phosphothioates may provide metabolic stability when compared to their phosphate counterparts, while retaining the potency and efficacy as agonists at sphingosine-1-phosphate (S1P) G-protein coupled receptors. Unlike their phosphate precursors, phosphothioate compounds with S1P-receptor profiles similar to that of FTY720, an emerging immunomodulator, were shown to evoke prolonged lymphopenia in vivo. Analysis of mouse plasma concentrations for a series of related alcohol/phosphate/phosphothioate compounds showed the conversion of the phosphate to alcohol. These preliminary data highlight the importance of metabolic regulation of S1P receptor ligands.


Subject(s)
Receptors, Lysosphingolipid/agonists , Thionucleotides/chemical synthesis , Thionucleotides/pharmacology , Magnetic Resonance Spectroscopy , Thionucleotides/chemistry
10.
Am J Respir Crit Care Med ; 165(7): 922-6, 2002 Apr 01.
Article in English | MEDLINE | ID: mdl-11934715

ABSTRACT

S-nitrosoglutathione (GSNO), a naturally occurring constituent of airway lining fluid, enhances ciliary motility, relaxes airway smooth muscle, inhibits airway epithelial amiloride-sensitive sodium transport, and prevents pathogen replication. Remarkably, airway levels of GSNO are low in patients with cystic fibrosis (CF). We hypothesized that replacement of airway GSNO would improve gas exchange in CF. In a double-blind, placebo controlled study, we administered 0.05 ml/kg of 10 mM GSNO or phosphate buffered saline by aerosol to patients with CF and followed oxygen saturation, spirometry, respiratory rate, blood pressure, heart rate, and expired nitric oxide (NO). Nine patients received GSNO and 11 placebo. GSNO inhalation was associated with a modest but sustained increase in oxygen saturation at all time points. Expired NO increased in the low ppb range with GSNO treatment, peaking at 5 minutes but remaining above baseline at 30 minutes. There were no adverse effects. We conclude that GSNO is well tolerated in patients with CF and improves oxygenation through a mechanism that may be independent of free NO. Further, GSNO breakdown increases expired NO. We suggest that therapy aimed at restoring endogenous GSNO levels in the CF airway may merit study.


Subject(s)
Cystic Fibrosis/physiopathology , S-Nitrosoglutathione/administration & dosage , Administration, Inhalation , Adolescent , Adult , Aerosols , Breath Tests , Child , Cystic Fibrosis/drug therapy , Double-Blind Method , Forced Expiratory Volume , Humans , Nitric Oxide/analysis , Oxygen/blood , Pulmonary Gas Exchange/drug effects , Vital Capacity
11.
Am J Respir Crit Care Med ; 165(3): 387-90, 2002 Feb 01.
Article in English | MEDLINE | ID: mdl-11818326

ABSTRACT

Denitrifying bacteria metabolize nitrogen oxides through assimilatory and dissimilatory pathways. These redox reactions may affect lung physiology. We hypothesized that airway colonization with denitrifying bacteria could alter nitrogen balance in the cystic fibrosis (CF) airway. We measured airway nitrogen redox species before and after antimicrobial therapy for Pseudomonas aeruginosa in patients with CF. We also studied ammonium (NH(4)(+)) and nitric oxide (NO) metabolism in clinical strains of P. aeruginosa in vitro and in CF sputum ex vivo. Ammonium concentrations in both sputum and tracheal aspirates decreased with therapy. Nitric oxide reductase (NOR) was present in clinical strains of P. aeruginosa, which both produced NH(4)(+) and consumed NO. Further, NO consumption by CF sputum was inhibited by tobramycin ex vivo. We conclude that treatment of pseudomonal lung infections is associated with decreased NH(4)(+) concentrations in the CF airways. In epithelial cells, NH(4)(+) inhibits chloride transport, and nitrogen oxides inhibit amiloride-sensitive sodium transport and augment chloride transport. We speculate that normalization of airway nitrogen redox balance could contribute to the beneficial effects of antipseudomonal therapy on lung function in CF.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Cystic Fibrosis/metabolism , Nitrogen/metabolism , Pseudomonas Infections/drug therapy , Ammonia/metabolism , Cystic Fibrosis/complications , Humans , Oxidation-Reduction , Pseudomonas Infections/complications
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