Reference+
Elbers, L. P. B., Kastelein, J. J. P., & Sjouke, B. (2016). Thyroid Hormone Mimetics: The Past, Current Status and Future Challenges. Current Atherosclerosis Reports, 18(3), 14. https://doi.org/10.1007/s11883-016-0564-7
Info
FirstAuthor:: Elbers, L.P.B.
Author:: Kastelein, J.J.P.
Author:: Sjouke, B.
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Title:: Thyroid Hormone Mimetics: the Past, Current Status and Future Challenges
Year:: 2016
Citekey:: ElbersEtAl_2016_ThyroidHormoneMimetics
itemType:: journalArticle
Journal:: Current Atherosclerosis Reports
Volume:: 18
Issue:: 3
Pages:: 14
DOI:: 10.1007/s11883-016-0564-7
Link
Abstract
The association between thyroid hormone status and plasma levels of low-density lipoprotein cholesterol has raised the awareness for the development of thyroid hormone mimetics as lipid-lowering agents. The discovery of the two main types of thyroid hormone receptors (α and β) as well as the development of novel combinatorial chemistry providing organ specificity has drastically improved the selectivity of these compounds. In the past decades, several thyroid hormone mimetics have been investigated with the purpose of lowering low-density lipoprotein cholesterol levels. However, until now, none of the thyromimetics reached the stage of completing a phase III clinical trial without deleterious side effects. Here, we review the currently available literature on thyromimetics investigated for the treatment of dyslipidemia, their rise, their downfall and the challenges for the development of novel agents.
Blue: Important conclusions
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during the past decades, several thyromimetics have been developed with varying but convincing efficacies on atherogenic lipids and lipoproteins.
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none of the thyromimetics reached the stage of completing a phase III clinical trial without deleterious side effects.
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he development of TRβ-selective thyromimetics is complicated by the fact that endocrine physiology is highly complex and that the precise distribution of TRα and TRβ throughout the body is not completely elucidated to date.
Yellow: Interesting
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Since the 1950s, thyroid hormones have been shown to affect lipid homeostasis
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The TRα isoform is predominantly present in the brain, heart, and skeletal muscles, whereas TRβ is predominantly present in the liver and also in the brain
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Diiodothyropropionic acid (DITPA)
Green: Agree with the paper
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Thyroid hormone supplementation results in beneficial effects on lipid and lipoprotein concentrations in patients with hypothyroidism
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thyroid hormone increases the activity of the promotor of the human low-density lipoprotein receptor (LDLR) gene, resulting in increased LDLR expression and, as a consequence, decreased plasma LDL-C levels
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One of the first studies that tested the use of thyroid (hormone) to reduce plasma cholesterol in human was published in 1957 [12]. It was observed that administration of dried thyroid reduced plasma LDL-C levels,
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DITPA therapy resulted in a decrease in total cholesterol (TC) as well as LDL-C levels by ~20 and 30 %, respectively, in patients with congestive heart failure
Red: Disagree with the paper
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none of the thyromimetics reached the stage of completing a phase III clinical trial without deleterious side effects
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positive effects of LDL-C lowering were observed but the side effects, particularly related to an excess of adverse cardiovascular outcomes, resulted in the discontinuation
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Years later, tiratricol (triiodo-thyroacetic acid) was tested in human but this compound also had deleterious effects on the heart and led to increased bone turnover,
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therapy resulted in potentially deleterious effects on serum markers of both bone formation (osteocalcin) as well as turnover/degradation
Purple: To learn more
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The association between thyroid hormone status and plasma levels of low-density lipoprotein cholesterol has raised the awareness for the development of thyroid hormone mimetics as lipid-lowering agents.