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1.  Mitigation of Radiation Injury by Selective Stimulation of the LPA2 Receptor 
Biochimica et biophysica acta  2013;1831(1):117-125.
Due to its antiapoptotic action, derivatives of the lipid mediator lysophosphatidic acid (LPA) provide potential therapeutic utility in diseases associated with programmed cell death. Apoptosis is one of the major pathophysiological processes elicited by radiation injury to the organism. Consequently, therapeutic explorations applying compounds that mimic the antiapoptotic action of LPA have begun. Here we present a brief account of our decade-long drug discovery effort aimed at developing LPA mimics with a special focus on specific agonists of the LPA2 receptor subtype, which was found to be highly effective in protecting cells from apoptosis. We describe new evidence that 2-((3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid (GRI977143), a prototypic nonlipid agonist specific to the LPA2 receptor subtype, rescues apoptotically condemned cells in vitro and in vivo from injury caused by high-dose γ-irradiation. GRI977143 shows the features of a radiomitigator because it is effective in rescuing the lives of mice from deadly levels of radiation when administered 24 h after radiation exposure. Our findings suggest that by specifically activating LPA2 receptors GRI977143 activates the ERK1/2 prosurvival pathway, effectively reduces Bax translocation to the mitochondrion, attenuates the activation of initiator and effector caspases, reduces DNA fragmentation, and inhibits PARP-1 cleavage associated with γ-irradiation-induced apoptosis. GRI977143 also inhibits bystander apoptosis elicited by soluble proapoptotic mediators produced by irradiated cells. Thus, GRI977143 can serve as a prototype scaffold for lead optimization paving the way to more potent analogs amenable for therapeutic exploration.
PMCID: PMC3491361  PMID: 23127512
LPA; radiomitigator; radioprotection; apoptosis; bystander-apoptosis; distant effects of radiation exposure; countermeasure
2.  Incretin Therapy for Type 2 Diabetes in Spain: A Cost-Effectiveness Analysis of Liraglutide Versus Sitagliptin 
Diabetes Therapy  2013;4(2):417-430.
Treatment with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, which target the incretin axis, has the potential to improve glycemic control in type 2 diabetes patients without the weight gain associated with traditional therapies. To evaluate the relative cost-effectiveness of incretin therapies, the present study aimed to compare the long-term clinical and cost implications associated with liraglutide and sitagliptin in type 2 diabetes patients in Spain.
Data were taken from a randomized, controlled trial (NCT00700817) in which adults with type 2 diabetes failing metformin monotherapy were randomly allocated to receive either liraglutide 1.2 mg or sitagliptin 100 mg daily in addition to metformin. Long-term projections of clinical outcomes and direct costs (2012 EUR) based on observed treatment effects were made using a published and validated type 2 diabetes model. Costs were taken from published sources. Future costs and clinical benefits were discounted at 3% annually. Sensitivity analyses were performed.
Liraglutide was associated with improved discounted life expectancy (14.05 versus 13.91 years) and quality-adjusted life expectancy [9.04 versus 8.87 quality-adjusted life years (QALYs)] compared to sitagliptin. Improved clinical outcomes were driven by improved glycemic control, leading to reduced incidence of diabetes-related complications, including renal disease, cardiovascular disease, ophthalmic and diabetic foot complications. Liraglutide was associated with increased direct costs of EUR 2,297, yielding an incremental cost-effectiveness ratio of EUR 13,266 per QALY gained versus sitagliptin.
Liraglutide was projected to improve life expectancy, quality-adjusted life expectancy and reduce incidence of diabetes-related complication. Liraglutide is likely to be cost-effective versus sitagliptin from a healthcare payer perspective in Spain.
PMCID: PMC3889333  PMID: 24132613
Cost; Cost-effectiveness; DPP-4; GLP-1; Incretin; Liraglutide; Sitagliptin; Spain; Type 2 diabetes
3.  Multigene assays and molecular markers in breast cancer: systematic review of health economic analyses 
Breast cancer is the most common female cancer and is associated with a significant clinical and economic burden. Multigene assays and molecular markers represent an opportunity to direct chemotherapy only to patients likely to have significant benefit. This systematic review examines published health economic analyses to assess the support for adjuvant therapy decision making. Literature searches of PubMed, the Cochrane Library, and congress databases were carried out to identify economic evaluations of multigene assays and molecular markers published between 2002 and 2012. After screening and data extraction, study quality was assessed using the Quality of Health Economic Studies instrument. The review identified 29 publications that reported evaluations of two assays: Oncotype DX® and MammaPrint. Studies of both tests provided evidence that their routine use was cost saving or cost-effective versus conventional approaches. Benefits were driven by optimal allocation of adjuvant chemotherapy and reduction in chemotherapy utilization. Findings were sensitive to variation in the frequency of chemotherapy prescription, chemotherapy costs, and patients’ risk profiles. Evidence suggests that multigene assays are likely cost saving or cost-effective relative to current approaches to adjuvant therapy. They should benefit decision making in early-stage breast cancer in a variety of settings worldwide.
PMCID: PMC3695325  PMID: 23722312
Breast cancer; Gene expression profiling; Gene assay; Molecular diagnostic techniques; Health economics; Cost-effectiveness
4.  High-Throughput Assays to Measure Intracellular Ca2+ Mobilization in Cells that Express Recombinant S1P Receptor Subtypes 
Intracellular Ca2+ mobilization is a useful readout to screen for agonists or antagonists of G-protein coupled receptors (GPCRs). Here, we describe methods to conduct high-throughput screening of stably or transiently transfected HTC4 cells expressing the individual S1P1–5 receptor subtypes. The cells are grown in 96-well plates and loaded with the cell permeable fluorescent Ca2+ indicator dye Fura-2-AM. Changes in intracellular Ca2+ levels in response to S1P or test compounds are detected using a FlexStation II scanning fluorometer with integrated fluidics transfer capabilities.
PMCID: PMC3617928  PMID: 22528441
Calcium assay; G-protein coupled receptor; Sphingosine-1-phosphate; Lysophospholipid; FlexStation; EDG receptor
5.  (S)-FTY720-Vinylphosphonate, an Analogue of the Immunosuppressive Agent FTY720, Is a Pan-antagonist of Sphingosine 1-Phosphate GPCR Signaling and Inhibits Autotaxin Activity 
Cellular signalling  2010;22(10):1543-1553.
FTY720 (Fingolimod™), a synthetic analogue of sphingosine 1-phosphate (S1P), activates four of the five EDG-family S1P receptors and is in a phase-III clinical study for the treatment of multiple sclerosis. (S)-FTY720-phosphate (FTY720-P) causes S1P1 receptor internalization and targeting to the proteasomal degradative pathway, and thus acts as a functional antagonist of S1P1 by depleting the functional S1P1 receptor from the plasma membrane. Here we describe the pharmacological characterization of two unsaturated phosphonate enantiomers of FTY720, (R)- and (S)-FTY720-vinylphosphonate. (R)-FTY720-vinylphosphonate was a full agonist of S1P1 (EC50 20 ± 3 nM). In contrast, the (S) enantiomer failed to activate any of the five S1P GPCRs and was a full antagonist of S1P1,3,4 (Ki 384 nM, 39 nM, and 1190 nM, respectively) and a partial antagonist of S1P2, and S1P5. Both enantiomers dose-dependently inhibited lysophospholipase D (recombinant autotaxin) with Ki values in the low micromolar range, although with different enzyme kinetic mechanisms. When injected into mice, both enantiomers caused transient peripheral lymphopenia. (R)- and (S)-FTY720-vinylphosphonates activated ERK1/2, AKT, and exerted an antiapoptotic effect in camptothecin-treated IEC-6 intestinal epithelial cells, which primarily express S1P2 transcripts and traces of S1P5. (S)-FTY720-vinylphosphonate is the first pan-antagonist of S1P receptors and offers utility in probing S1P responses in vitro and in vivo. The biological effects of the (R)- and (S)-FTY720-vinylphosphonate analogues underscore the complexity of FTY720 cellular targets.
PMCID: PMC3446790  PMID: 20566326
FTY720; sphingosine 1-phosphate; lysophosphatidic acid; autotaxin; lysophospholipase D; lymphocyte egress; EDG receptor; inhibitor
6.  The Lysophosphatidic Acid Type 2 Receptor Is Required for Protection Against Radiation-Induced Intestinal Injury 
Gastroenterology  2007;132(5):1834-1851.
Background & Aims
We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. The objective of the present study was to evaluate the effect of octadecenyl thiophosphate (OTP), a novel rationally designed, metabolically stabilized LPA mimic, on radiation-induced apoptosis of intestinal epithelial cells in vitro and in vivo
The receptors and signaling pathways activated by OTP were examined in IEC-6 and RH7777 cell lines and wild-type and LPA1 and LPA2 knockout mice exposed to different apoptotic stimuli
OTP was more efficacious than LPA in reducing gamma irradiation–, camptothecin-, or tumor necrosis factor α/cycloheximide–induced apoptosis and caspase-3-8, and caspase-9 activity in the IEC-6 cell line. In RH7777 cells lacking LPA receptors, OTP selectively protected LPA2 but not LPA1 and LPA3 transfectants. In C57BL/6 and LPA1 knockout mice exposed to 15 Gy gamma irradiation, orally applied OTP reduced the number of apoptotic bodies and activated caspase-3–positive cells but was ineffective in LPA2 knockout mice. OTP, with higher efficacy than LPA, enhanced intestinal crypt survival in C57BL/6 mice but was without any effect in LPA2 knockout mice. Intraperitoneally administered OTP reduced death caused by lethal dose (LD)100/30 radiation by 50%.
Our data indicate that OTP is a highly effective antiapoptotic agent that engages similar prosurvival pathways to LPA through the LPA2 receptor subtype.
PMCID: PMC3446791  PMID: 17484878
7.  Cost-Effectiveness of Diabetes Case Management for Low-Income Populations 
Health Services Research  2007;42(5):1943-1959.
To evaluate the cost-effectiveness of Project Dulce, a culturally specific diabetes case management and self-management training program, in four cohorts defined by insurance status.
Data Sources/Study Setting
Clinical and cost data on 3,893 persons with diabetes participating in Project Dulce were used as inputs into a diabetes simulation model.
Study Design
The Center for Outcomes Research Diabetes Model, a published, peer-reviewed and validated simulation model of diabetes, was used to evaluate life expectancy, quality-adjusted life expectancy (QALY), cumulative incidence of complications and direct medical costs over patient lifetimes (40-year time horizon) from a third-party payer perspective. Cohort characteristics, treatment effects, and case management costs were derived using a difference in difference design comparing data from the Project Dulce program to a cohort of historical controls. Long-term costs were derived from published U.S. sources. Costs and clinical benefits were discounted at 3.0 percent per annum. Sensitivity analyses were performed.
Principal Findings
Incremental cost-effectiveness ratios of $10,141, $24,584, $44,941, and $69,587 per QALY gained were estimated for Project Dulce participants versus control in the uninsured, County Medical Services, Medi-Cal, and commercial insurance cohorts, respectively.
The Project Dulce diabetes case management program was associated with cost-effective improvements in quality-adjusted life expectancy and decreased incidence of diabetes-related complications over patient lifetimes. Diabetes case management may be particularly cost effective for low-income populations.
PMCID: PMC2254564  PMID: 17850527
Diabetes; case management; cost effectiveness; modeling; health insurance
8.  Chiral Vinylphosphonate and Phosphonate Analogues of the Immunosuppressive Agent FTY720 
The Journal of organic chemistry  2009;74(8):3192-3195.
The first enantioselective synthesis of chiral isosteric phosphonate analogues of FTY720 is described. One of these analogues, FTY720-(E)-vinylphosphonate (S)-5, but not its R enantiomer, elicited a potent anti-apoptotic effect in intestinal epithelial cells, suggesting that it exerts its action via the enantioselective activation of a receptor. (S)-5 failed to activate the sphingosine 1-phosphate type 1 (S1P1) receptor.
PMCID: PMC2747615  PMID: 19296586
9.  The consequences of delaying insulin initiation in UK type 2 diabetes patients failing oral hyperglycaemic agents: a modelling study 
Recent data have shown that type 2 diabetes patients in the UK delay initiating insulin on average for over 11 years after first being prescribed an oral medication. Using a published computer simulation model of diabetes we used UK-specific data to estimate the clinical consequences of immediately initiating insulin versus delaying initiation for periods in line with published estimates.
In the base case scenario simulated patients, with characteristics based on published UK data, were modelled as either initiating insulin immediately or delaying for 8 years. Clinical outcomes in terms of both life expectancy and quality-adjusted life expectancy and also diabetes-related complications (cumulative incidence and time to onset) were projected over a 35 year time horizon. Treatment effects associated with insulin use were taken from published studies and sensitivity analyses were performed around time to initiation of insulin, insulin efficacies and hypoglycaemia utilities.
For patients immediately initiating insulin there were increases in (undiscounted) life expectancy of 0.61 years and quality-adjusted life expectancy of 0.34 quality-adjusted life years versus delaying initiation for 8 years. There were also substantial reductions in cumulative incidence and time to onset of all diabetes-related complications with immediate versus delayed insulin initiation. Sensitivity analyses showed that a reduced delay in insulin initiation or change in insulin efficacy still demonstrated clinical benefits for immediate versus delayed initiation.
UK type 2 diabetes patients are at increased risk of a large number of diabetes-related complications due to an unnecessary delay in insulin initiation. Despite clear guidelines recommending tight glycaemic control this failure to begin insulin therapy promptly is likely to result in needlessly reduced life expectancy and compromised quality of life.
PMCID: PMC2761913  PMID: 19804622
10.  Lysophospholipid Signaling: Beyond the EDGs 
Biochimica et biophysica acta  2007;1780(3):597-605.
As our understanding of the myriads of biological effects caused by lysophospholipids expands we become witnesses to another miracle of nature that has endowed the simplest lysophospholipids with functions seemingly ubiquitous to every mammalian cell. A decade after the discovery of the EDG-family lysophospholipid receptors the field has gained unimaginable impetus explaining the biological effects of sphingosine-1-phoshate (S1P) and lysophosphatidic acid (LPA). The discovery of LPA receptors in the purinergic G protein-coupled receptor (GPCR) gene cluster refined this picture and added complexity to our concepts of lysophospholipid cell signaling. The intracellular lysophospholipid targets – identified and not yet identified – make us realize the dual – mediator and second messenger – roles of lysophospholipids. In this paper we provide new data obtained concerning LPA-elicited responses using cell lines naturally lacking or intentionally knocked out of many of the known LPA GPCR, widely used by investigators in the field as cells with LPA receptor “null background”. Our observations raise caution about the lack of LPA responsiveness in these cells and underline the unprecedented complexity and redundancy of lysophospholipid-evoked cellular responses.
PMCID: PMC2751795  PMID: 17931789
11.  Cost-Effectiveness of Intensified Versus Conventional Multifactorial Intervention in Type 2 Diabetes 
Diabetes Care  2008;31(8):1510-1515.
OBJECTIVE—To assess the cost-effectiveness of intensive versus conventional therapy for 8 years as applied in the Steno-2 study in patients with type 2 diabetes and microalbuminuria.
RESEARCH DESIGN AND METHODS—A Markov model was developed to incorporate event and risk data from Steno-2 and account Danish-specific costs to project life expectancy, quality-adjusted life expectancy (QALE), and lifetime direct medical costs expressed in year 2005 Euros. Clinical and cost outcomes were projected over patient lifetimes and discounted at 3% annually. Sensitivity analyses were performed.
RESULTS—Intensive treatment was associated with increased life expectancy, QALE, and lifetime costs compared with conventional treatment. Mean ± SD undiscounted life expectancy was 18.1 ± 7.9 years with intensive treatment and 16.2 ± 7.3 years with conventional treatment (difference 1.9 years). Discounted life expectancy was 13.4 ± 4.8 years with intensive treatment and 12.4 ± 4.5 years with conventional treatment. Lifetime costs (discounted) for intensive and conventional treatment were €45,521 ± 19,697 and €41,319 ± 27,500, respectively (difference €4,202). Increased costs with intensive treatment were due to increased pharmacy and consultation costs. Discounted QALE was 1.66 quality-adjusted life-years (QALYs) higher for intensive (10.2 ± 3.6 QALYs) versus conventional (8.6 ± 2.7 QALYs) treatment, resulting in an incremental cost-effectiveness ratio of €2,538 per QALY gained. This is considered a conservative estimate because accounting prescription of generic drugs and capturing indirect costs would further favor intensified therapy.
CONCLUSIONS—From a health care payer perspective in Denmark, intensive therapy was more cost-effective than conventional treatment. Assuming that patients in both arms were treated in a primary care setting, intensive therapy became dominant (cost- and lifesaving).
PMCID: PMC2494636  PMID: 18443195
13.  Cost-effectiveness of pioglitazone in type 2 diabetes patients with a history of macrovascular disease: a German perspective 
The aim of this study was to project health-economic outcomes relevant to the German setting for the addition of pioglitazone to existing treatment regimens in patients with type 2 diabetes, evidence of macrovascular disease and at high risk of cardiovascular events.
Event rates corresponding to macrovascular outcomes from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study of pioglitazone were used with a modified version of the CORE Diabetes Model to simulate outcomes over a 35-year time horizon. Direct medical costs were accounted from a healthcare payer perspective in year 2005 values. Germany specific costs were applied for patient treatment, hospitalization and management. Both costs and clinical benefits were discounted at 5.0% per annum.
Over patient lifetimes pioglitazone treatment improved undiscounted life expectancy by 0.406 years and improved quality-adjusted life expectancy by 0.120 quality-adjusted life years (QALYs) compared to placebo. Direct medical costs (treatment plus complication costs) were marginally higher for pioglitazone treatment and calculation of the incremental cost-effectiveness ratio (ICER) produced a value of €13,294 per QALY gained with the pioglitazone regimen versus placebo. Acceptability curve analysis showed that there was a 78.2% likelihood that pioglitazone would be considered cost-effective in Germany, using a "good value for money" threshold of €50,000 per QALY gained. Sensitivity analyses showed that the results were most sensitive to changes in the simulation time horizon. After adjustment for the potential stabilization of pancreatic β-cell function with pioglitazone treatment, the ICER was €6,667 per QALY gained for pioglitazone versus placebo.
The findings of this modelling analysis indicated that, for patients with a history of macrovascular disease, addition of pioglitazone to existing therapy reduces the long-term cumulative incidence of diabetes-complications at a cost that would be considered to represent good value for money in the German setting.
PMCID: PMC2688482  PMID: 19416529
The Journal of biological chemistry  2005;280(27):25849-25853.
In addition to activating members of the STAT transcription factor family, IFN α/β activates the NF-κ B transcription factor. To determine the role of the JAK-STAT pathway in NF-κ B activation by IFN, we examined NF-κ B activation in JAK1-deficient mutant human fibrosarcoma cells. In wild-type fibrosarcoma cells (2fTGH) IFN activates STAT1, STAT2 and STAT3, as well as NF-κB complexes comprised of p50 and p65. In contrast, in JAK1-deficient cells IFN induces NF-κB activation and NF-κB dependent gene transcription, but does not activate these STAT proteins and has no effect on STAT-dependent gene transcription. Expression of a catalytically-inactive TYK2 tyrosine kinase in JAK1-deficient cells, as well as in the highly IFN-sensitive Daudi lymphoblastoid cell line, abrogates NF-κB activation by IFN. Moreover, IFN does not promote NF-κB activation in TYK2-deficient mutant fibrosarcoma cells. Our results demonstrate a dichotomy between the classical JAK-STAT pathway and the NF-κB signaling pathway. In the IFN signaling pathway leading to STAT activation both JAK1 and TYK2 are essential, while NF-κB activation requires only TYK2.
PMCID: PMC1193649  PMID: 15883164

Results 1-15 (15)