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Steven Goldman - One of the best experts on this subject based on the ideXlab platform.

  • ditpa 3 5 diiodothyropropionic acid a thyroid Hormone Analog to treat heart failure phase ii trial veterans affairs cooperative study
    Circulation, 2009
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    Background—In animal studies and a pilot trial in patients with congestive heart failure, the thyroid Hormone Analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results—This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n57 to DITPA, n29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure–specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (20%), low-density lipoprotein cholesterol (30%), and body weight (11 lb). Thyroid-stimulating Hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions—DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure. (Circulation. 2009;119:3093-3100.)

  • ditpa a thyroid Hormone Analog to treat heart failure phase ii trial va cooperative study
    Journal of Cardiac Failure, 2008
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    DITPA, a Thyroid Hormone Analog to Treat Heart Failure: Phase II Trial VA Cooperative Study Steven Goldman*, Madeline McCarren*, Eugene Morkin, Paul Ladenson, Robert Edson, Stuart Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie Barnhill, Terrence O’Brien, Inder Anand, Alberta Warner, Mark Dunlap, Brack Hattle, John Erikson, Mei-Chiung Shih, Phil Lavori; Southern Arizona VA Health Care System, Tucson, AZ; VA Center for Medication Safety, Hines, IL; University of Arizona Health Sciences, Tucson, AZ; Johns Hopkins University, Baltimore, MD; Palo Alto CSP Coordinating Center, Palo Alto, CA; CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, NM; VA Medical Center, Charleston, SC; Minneapolis VA Medical Center, Minneapolis, MN; Greater Los Angeles Healthcare System, Los Angeles, CA; Louis Stokes VA Healthcare System, Cleveland, OH; VA Eastern Colorado Health Care System, Denver, CO; South Texas Veterans Health Care System, San Antonio, TX

  • a thyroid Hormone Analog stimulates angiogenesis in the post infarcted rat heart
    Journal of Molecular and Cellular Cardiology, 1998
    Co-Authors: Robert J Tomanek, Steven Goldman, Eugene Morkin, Bridget M Zimmerman, Padma R Suvarna, Gregory D Pennock
    Abstract:

    Abstract In view of the evidence that thyroid Hormone administration has angiogenic effects on the hypertrophic myocardium, we tested the hypothesis that the capillary supply in the hypertrophic myocardium surviving infarction would be improved by administration of the thyroid Hormone Analog, diiodothyroproprionic acid (DITPA). We administered DITPA (MI-DITPA) or saline (MI-saline), s.c., to rats for 10 days following experimental infarction of the left ventricle (LV). Morphometric methods were used to assess capillarity and myocyte cross-sectional area in three regions of the left ventricle: (1) border (next to the scar of infarction); (2) adjacent (next to the border); and (3) remote (interventricular septum). Infarct size ranged from 20–85% of the LV free-wall, and both groups had similar mean infarct size. Capillary length density (L v ) was significantly higher in the remote region of the treated group than in the MI-saline rats. L v in the border region, which experienced the most marked increase in cardiocyte cross-sectional area, was not significantly lower than in the other regions, indicating a more marked angiogenic response. In hearts with large infarcts (≥40%) L v in the border region was higher in the DITPA group than in the non-treated rats. In the MI-DITPA group, cardiocyte size in the border region was positively correlated with that of the other regions, which contrasts with the negative correlations noted for the MI-saline rats. These data suggest that DITPA therapy (1) may improve maximal perfusion potential of the hypertrophied myocardium surviving a myocardial infarction, and (2) is selectively effective in the border region of hearts with large infarcts.

Jamie G Barnhill - One of the best experts on this subject based on the ideXlab platform.

  • ditpa 3 5 diiodothyropropionic acid a thyroid Hormone Analog to treat heart failure phase ii trial veterans affairs cooperative study
    Circulation, 2009
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    Background—In animal studies and a pilot trial in patients with congestive heart failure, the thyroid Hormone Analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results—This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n57 to DITPA, n29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure–specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (20%), low-density lipoprotein cholesterol (30%), and body weight (11 lb). Thyroid-stimulating Hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions—DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure. (Circulation. 2009;119:3093-3100.)

  • ditpa a thyroid Hormone Analog to treat heart failure phase ii trial va cooperative study
    Journal of Cardiac Failure, 2008
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    DITPA, a Thyroid Hormone Analog to Treat Heart Failure: Phase II Trial VA Cooperative Study Steven Goldman*, Madeline McCarren*, Eugene Morkin, Paul Ladenson, Robert Edson, Stuart Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie Barnhill, Terrence O’Brien, Inder Anand, Alberta Warner, Mark Dunlap, Brack Hattle, John Erikson, Mei-Chiung Shih, Phil Lavori; Southern Arizona VA Health Care System, Tucson, AZ; VA Center for Medication Safety, Hines, IL; University of Arizona Health Sciences, Tucson, AZ; Johns Hopkins University, Baltimore, MD; Palo Alto CSP Coordinating Center, Palo Alto, CA; CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, NM; VA Medical Center, Charleston, SC; Minneapolis VA Medical Center, Minneapolis, MN; Greater Los Angeles Healthcare System, Los Angeles, CA; Louis Stokes VA Healthcare System, Cleveland, OH; VA Eastern Colorado Health Care System, Denver, CO; South Texas Veterans Health Care System, San Antonio, TX

Paul W. Ladenson - One of the best experts on this subject based on the ideXlab platform.

  • ditpa 3 5 diiodothyropropionic acid a thyroid Hormone Analog to treat heart failure phase ii trial veterans affairs cooperative study
    Circulation, 2009
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    Background—In animal studies and a pilot trial in patients with congestive heart failure, the thyroid Hormone Analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results—This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n57 to DITPA, n29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure–specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (20%), low-density lipoprotein cholesterol (30%), and body weight (11 lb). Thyroid-stimulating Hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions—DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure. (Circulation. 2009;119:3093-3100.)

  • ditpa a thyroid Hormone Analog to treat heart failure phase ii trial va cooperative study
    Journal of Cardiac Failure, 2008
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    DITPA, a Thyroid Hormone Analog to Treat Heart Failure: Phase II Trial VA Cooperative Study Steven Goldman*, Madeline McCarren*, Eugene Morkin, Paul Ladenson, Robert Edson, Stuart Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie Barnhill, Terrence O’Brien, Inder Anand, Alberta Warner, Mark Dunlap, Brack Hattle, John Erikson, Mei-Chiung Shih, Phil Lavori; Southern Arizona VA Health Care System, Tucson, AZ; VA Center for Medication Safety, Hines, IL; University of Arizona Health Sciences, Tucson, AZ; Johns Hopkins University, Baltimore, MD; Palo Alto CSP Coordinating Center, Palo Alto, CA; CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, NM; VA Medical Center, Charleston, SC; Minneapolis VA Medical Center, Minneapolis, MN; Greater Los Angeles Healthcare System, Los Angeles, CA; Louis Stokes VA Healthcare System, Cleveland, OH; VA Eastern Colorado Health Care System, Denver, CO; South Texas Veterans Health Care System, San Antonio, TX

  • Organ-specific effects of tiratricol: A thyroid Hormone Analog with hepatic, not pituitary, superagonist effects
    Journal of Clinical Endocrinology and Metabolism, 1992
    Co-Authors: Steven I Sherman, Paul W. Ladenson
    Abstract:

    Tiratricol has been used to suppress pituitary TSH secretion, with reported attenuation of extrapituitary thyromimetic effects. A randomized, double-blind trial was performed to define precisely the tissue-specific thyromimetic actions of tiratricol. Ten athyreotic patients, treated for thyroid carcinoma, were randomly assigned to receive L-T4 sodium 0.7 micrograms/kg daily and either tiratricol 10 micrograms/kg or placebo twice daily. The daily dose of L-T4 was increased by 25-50 micrograms increments until the TRH-stimulated TSH level was less than 0.1 mU/L. After measurement of biochemical and physiological parameters of thyroid Hormone actions, patients crossed treatment groups. Patients required 46% less L-T4 to achieve equivalent TSH suppression when taking tiratricol. Hepatic effects were enhanced by tiratricol administration, with significant increases in sex Hormone binding globulin and ferritin concentrations, 14% and 37%, respectively. Levels of serum cholesterol, LDL cholesterol, and apolipoprotein B were reduced by 7%, 10%, and 13%, respectively, during tiratricol therapy. Triglyceride levels also declined, but there were no changes of high density lipoprotein cholesterol or apolipoproteins AI and AII. Resting metabolic rate, body weight, urea nitrogen excretion, and symptoms did not differ between the two treatment regimens. Cardiovascular function, as reflected by mean arterial pressure and pulse wave arrival time, was not different during tiratricol therapy. Skeletal metabolic activity was affected by tiratricol, with marked elevation of osteocalcin without significant change in serum calcium, PTH, and urinary calcium and hydroxyproline excretion. Tiratricol has increased hepatic and skeletal actions of potential therapeutic value, but does not have enhanced thyromimetic activity specific to the pituitary gland.

Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.

  • the thyroid Hormone Analog ditpa ameliorates metabolic parameters of male mice with mct8 deficiency
    Endocrinology, 2015
    Co-Authors: Alfonso Massimiliano Ferrara, Xiao Hui Liao, Roy E Weiss, Alexandra M Dumitrescu, Samuel Refetoff
    Abstract:

    Mutations in the gene encoding the thyroid Hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid Hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH Analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid Hormone Analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

  • placenta passage of the thyroid Hormone Analog ditpa to male wild type and mct8 deficient mice
    Endocrinology, 2014
    Co-Authors: Alfonso Massimiliano Ferrara, Xiao Hui Liao, Roy E Weiss, Alexandra M Dumitrescu, Pilar Gilibanez, Juan Bernal, Samuel Refetoff
    Abstract:

    Monocarboxylate transporter 8 (MCT8) deficiency causes severe X-linked intellectual and neuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid Hormone (TH) deprivation in brain and excess in peripheral tissues. The TH Analog diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8-deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8-deficient embryos to determine whether DITPA, when given prenatally, crosses the placenta and affects the serum TFTs and cerebral cortex of embryos. After depletion of the endogenous TH, Mct8-heterozygous pregnant dams carrying both wild-type (Wt) and Mct8-deficient (Mct8KO) male embryos were given DITPA. Effects were compared with those treated with levothyroxine (L-T4). With DITPA treatment, serum DITPA concentration was not different in the two genotyp...

  • a thyroid Hormone Analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport
    Endocrinology, 2009
    Co-Authors: Caterina Di Cosmo, Xiao Hui Liao, Roy E Weiss, Alexandra M Dumitrescu, Samuel Refetoff
    Abstract:

    Mutations of the thyroid Hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent. We tested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given three different doses of DITPA. Effects were compared with treatment with two doses of l-T4. As expected, physiological doses of l-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 suppressed TSH in the Wt mice, normalized TSH and brain D2 in Mct8KO mice, but produced a thyrotoxic effect on liver D1 in both genotypes. In contrast DITPA produced similar effects on TSH, D2, and D1 in both Wt and Mct8KO mice. The higher dose fully normalized all measurements and other parameters of TH action. Thus, DITPA is relatively MCT8 independent for entry into the brain and corrects the TH deficit in Mct8KO mice without causing thyrotoxic effect in liver. The potential clinical utility of this Analog to patients with MCT8 mutations requires further studies.

Eugene Morkin - One of the best experts on this subject based on the ideXlab platform.

  • ditpa 3 5 diiodothyropropionic acid a thyroid Hormone Analog to treat heart failure phase ii trial veterans affairs cooperative study
    Circulation, 2009
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    Background—In animal studies and a pilot trial in patients with congestive heart failure, the thyroid Hormone Analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results—This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n57 to DITPA, n29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure–specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (20%), low-density lipoprotein cholesterol (30%), and body weight (11 lb). Thyroid-stimulating Hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions—DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure. (Circulation. 2009;119:3093-3100.)

  • ditpa a thyroid Hormone Analog to treat heart failure phase ii trial va cooperative study
    Journal of Cardiac Failure, 2008
    Co-Authors: Steven Goldman, Paul W. Ladenson, Madeline Mccarren, Eugene Morkin, Robert Edson, Stuart R Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie G Barnhill
    Abstract:

    DITPA, a Thyroid Hormone Analog to Treat Heart Failure: Phase II Trial VA Cooperative Study Steven Goldman*, Madeline McCarren*, Eugene Morkin, Paul Ladenson, Robert Edson, Stuart Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie Barnhill, Terrence O’Brien, Inder Anand, Alberta Warner, Mark Dunlap, Brack Hattle, John Erikson, Mei-Chiung Shih, Phil Lavori; Southern Arizona VA Health Care System, Tucson, AZ; VA Center for Medication Safety, Hines, IL; University of Arizona Health Sciences, Tucson, AZ; Johns Hopkins University, Baltimore, MD; Palo Alto CSP Coordinating Center, Palo Alto, CA; CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, NM; VA Medical Center, Charleston, SC; Minneapolis VA Medical Center, Minneapolis, MN; Greater Los Angeles Healthcare System, Los Angeles, CA; Louis Stokes VA Healthcare System, Cleveland, OH; VA Eastern Colorado Health Care System, Denver, CO; South Texas Veterans Health Care System, San Antonio, TX

  • a thyroid Hormone Analog stimulates angiogenesis in the post infarcted rat heart
    Journal of Molecular and Cellular Cardiology, 1998
    Co-Authors: Robert J Tomanek, Steven Goldman, Eugene Morkin, Bridget M Zimmerman, Padma R Suvarna, Gregory D Pennock
    Abstract:

    Abstract In view of the evidence that thyroid Hormone administration has angiogenic effects on the hypertrophic myocardium, we tested the hypothesis that the capillary supply in the hypertrophic myocardium surviving infarction would be improved by administration of the thyroid Hormone Analog, diiodothyroproprionic acid (DITPA). We administered DITPA (MI-DITPA) or saline (MI-saline), s.c., to rats for 10 days following experimental infarction of the left ventricle (LV). Morphometric methods were used to assess capillarity and myocyte cross-sectional area in three regions of the left ventricle: (1) border (next to the scar of infarction); (2) adjacent (next to the border); and (3) remote (interventricular septum). Infarct size ranged from 20–85% of the LV free-wall, and both groups had similar mean infarct size. Capillary length density (L v ) was significantly higher in the remote region of the treated group than in the MI-saline rats. L v in the border region, which experienced the most marked increase in cardiocyte cross-sectional area, was not significantly lower than in the other regions, indicating a more marked angiogenic response. In hearts with large infarcts (≥40%) L v in the border region was higher in the DITPA group than in the non-treated rats. In the MI-DITPA group, cardiocyte size in the border region was positively correlated with that of the other regions, which contrasts with the negative correlations noted for the MI-saline rats. These data suggest that DITPA therapy (1) may improve maximal perfusion potential of the hypertrophied myocardium surviving a myocardial infarction, and (2) is selectively effective in the border region of hearts with large infarcts.