Objective The authors present data from a pilot research program initiated to develop, refine, and test the outcomes of Brief Problem-Solving Therapy in Home Care (PST-HC) that targets the needs of ...older adults identified with severe depressive symptoms in an acute home care setting. Methods A pilot randomized clinical trial compared the impact of PST-HC to usual care (UC) in a sample of older medically ill home care patients identified with severe depressive symptoms. Forty patients were randomly assigned to either six weekly sessions of PST-HC in their home or standard home care services. Depression, quality of life, and problem-solving ability were measured at baseline, posttreatment, three-month follow-up, and six-month follow-up by blinded evaluators. Results All 40 patients provided follow-up data. No differences between the two groups were found on any demographic variables. Outcome data suggested significant improvements in depression scores over time after PST-HC, relative to UC. PST-HC patients reported higher quality of life and problem-solving ability scores relative to UC. Conclusion Results suggest that PST-HC is well tolerated and holds promise for reducing persistent depressive symptoms. The authors discuss limitations in terms of the “real-world” applicability of this psychosocial treatment for late-life depression.
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7 − 12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. ...LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-gamma agonist, which were presumably due to the concomitant PPAR-alpha agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovascular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.
Novel tetrahydroisoquinolines have been developed as potent PPAR ligands.
Novel tetrahydroisoquinolines have been developed as potent PPAR ligands. Evaluation of these compounds in PPARγ responsive ...models of type 2 diabetes is described.
PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate (AMC) template.
PPAR ligands with varied subtype selectivity have been synthesized ...using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
Herein we describe a series of potent and selective PPARγ agonists with moderate PPARα affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF ...rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound
1b (
LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
Herein we describe a series of potent and selective PPARγ agonists with moderate PPARα affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound
1b (
LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
This study explored patient perspectives on family-centered care by examining a specific feature of this kind of care: sharing a single physician among multiple family members. Interviews were ...conducted with 41 patients in a large urban family practice residency-training program in upstate New York. Six themes emerged from the qualitative analysis. Three themes defined patients' stated reasons for sharing a single physician (efficiency, improved biomedical care, and improved psychosocial care), and 3 themes characterized patients' stated reasons for not sharing a single physician (pragmatic issues, confidentiality, and neither interest nor preference). This study provides practitioners of family medicine with insight into patient perspectives of sharing a single physician among multiple family members.
Abstract
Metastatic bone disease is common in multiple myeloma, breast, prostate, and lung cancer patients and is a frequent cause of morbidity in advanced disease. Metastatic bone tumors destroy ...bone and cause severe bone remodeling which leads to structural weakening and bone fractures and often results in severe bone pain in a large percentage of patients.
These studies examined tumor growth, bone erosion, and pain in a nude rat model. A surgical defect was created in the tibia, exposing the marrow cavity. Luciferase-expressing MDA-MB-231 mammary tumor cells were injected into the exposed bone cavity. Rats inoculated with tumor cells were treated with either doxorubicin (3 mg/kg/week, iv) or risedronate (80 ug/kg/day, ip). Animals were monitored weekly for tumor burden by optical imaging and for bone erosion by CT. In addition to clinical observations, weight bearing was measured using an incapacitance tester with separate force transducers for each hind paw.
Compared to controls, rats treated with doxorubicin demonstrated a significant decease in luminescence, indicating tumor growth inhibition (bone protection). Decreased luminescence correlated with sparing of the bone as measured by CT. In contrast, the bisphosphonate, risedronate, had limited effect on tumor growth, but preserved bone integrity. In both treatments, protection of bone was associated with normalization of weight-bearing. This finding supports the premise that pain in metastatic bone cancer is attributable to bone loss (destruction) and remodeling. Weight-bearing data correlated directly with clinical observations This model, leveraging multiple imaging modalities, enables longitudinal and quantitative assessment of tumor growth; bone loss, remodeling and sparing, and weight-bearing in test animals that provides a sensitive and robust screening tool to evaluate compounds for anti-tumor, bone-sparing and pain amelioration effects.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5325. doi:10.1158/1538-7445.AM2011-5325
Objective: Data are presented from a pilot research program initiated to develop, refine, and test the outcomes of problem-solving therapy that targets the needs of older adults with minor depression ...in home care settings. Method: A pilot randomized clinical trial compares the impact of problem-solving therapy for home care to treatment as usual in a sample of older, medically ill home care patients. Compared with 32 older home care participants randomized to the treatment as usual condition, 30 older home care participants in an intervention condition received brief problem-solving therapy. Results: Outcome data suggest significant improvements in depression symptomatology and problem-solving abilities after problem-solving therapy for home care, relative to treatment as usual. The experimental group was also more satisfied with treatment as compared to the control condition. Conclusion: Authors discuss results in terms of the “real-world” social work applicability of this psychosocial treatment for late-life depression.
A Tailored Therapy for the Metabolic Syndrome Etgen, Garret J.; Oldham, Brian A.; Johnson, William T. ...
Diabetes (New York, N.Y.),
04/2002, Letnik:
51, Številka:
4
Journal Article
Recenzirano
Odprti dostop
A Tailored Therapy for the Metabolic Syndrome
The Dual Peroxisome Proliferator-Activated Receptor-α/γ Agonist LY465608 Ameliorates Insulin Resistance and Diabetic Hyperglycemia
While Improving ...Cardiovascular Risk Factors in Preclinical Models
Garret J. Etgen 1 ,
Brian A. Oldham 1 ,
William T. Johnson 1 ,
Carol L. Broderick 1 ,
Chahrzad R. Montrose 1 ,
Joseph T. Brozinick 1 ,
Elizabeth A. Misener 1 ,
James S. Bean 2 ,
William R. Bensch 2 ,
Dawn A. Brooks 3 ,
Anthony J. Shuker 3 ,
Christopher J. Rito 3 ,
James R. McCarthy 3 ,
Robert J. Ardecky 4 ,
John S. Tyhonas 4 ,
Sharon L. Dana 5 ,
James M. Bilakovics 5 ,
James R. Paterniti, Jr 5 ,
Kathleen M. Ogilvie 5 ,
Sha Liu 5 and
Raymond F. Kauffman 2
1 Division of Endocrine Research, Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana
2 Division of Cardiovascular Research, Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana
3 Division of Discovery Chemistry, Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana
4 Department of Medicinal Chemistry, Ligand Pharmaceuticals, San Diego, California
5 Department of Pharmacology, Ligand Pharmaceuticals, San Diego, California
Abstract
A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-α/γ agonist, LY465608, was designed to
address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED 50 for glucose normalization of 3.8 mg · kg −1 · day −1 . Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker ( fa/fa ) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608
revealed metabolic changes distinct from a selective PPAR-γ agonist, which were presumably due to the concomitant PPAR-α agonism,
lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition
to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered
plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves
primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets
of type 2 diabetes and associated cardiovacular risk, including those facets involved in the development of micro- and macrovascular
complications, which are the major sources for morbidity and mortality in these patients.
Footnotes
Address correspondence and reprint requests to Garret J. Etgen, DC 0545, Eli Lilly, Indianapolis, IN 46285. E-mail: etgen_garret_j{at}lilly.com .
Received for publication 5 October 2001 and accepted in revised form 4 January 2002.
apo, apolipoprotein; apoA-I TG, apoA-I transgenic; DEXA, dual-energy X-ray analysis; PPAR, peroxisome proliferator-activated
receptor; RQ, respiratory quotient; TZD, thiazolidinedione.
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