Treatment of type II hyperlipoproteinemia with d-thyroxine

Rakow, Alexander; Klör, Hans‐Ulrich; Kuter, Eren; Ditschuneit, H.

doi:10.1016/0021-9150(76)90129-5

Cited by 14 publications

(4 citation statements)

References 24 publications

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“…The effects of T 3 on cholesterol are similar in TR␣ 1 Ϫ͞Ϫ animals relative to WT. This lowering is likely due to a decrease in LDL cholesterol, because Ͼ90% of the total plasma cholesterol in these animals is the LDL form (27)(28)(29)(30)(31)(32). Thus, under these conditions, cholesterol lowering is primarily regulated by TR␤, MV O 2 by both TR␤ and -␣, and HR mostly by TR␣.…”

Section: Methodsmentioning

confidence: 99%

Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

Grover

Mellström

Liu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

207

182

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Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TR␤ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TR␣ appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TR␤ activation on metabolic rate and HR with either TR␣1 ؊͞؊ mice or the selective TR␤ agonist KB-141 in mice, rats, and monkeys. 3,5,3 -triiodi-L-thyronine (T3) had a greater effect on increasing HR in WT than in TR␣ ؊͞؊ mice (ED15 values of 34 and 469 nmol͞kg͞day, respectively). T 3 increased metabolic rate [whole body oxygen consumption (MV O 2 )] in both WT and TR␣ ؊͞؊ mice, but the effect in the TR␣ 1 ؊͞؊ mice at the highest dose was half that of the WT mice. Thus, stimulation of MV O 2 is likely due to both TR␣ and -␤. T3 had equivalent potency for cholesterol reduction in WT and TR␣ ؊͞؊ mice. KB-141 increased MVO 2 with selectivities of 16.5-and 11.2-fold vs. HR in WT and TR␣ 1 ؊͞؊ mice, respectively. KB-141 also increased MV O 2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TR␤-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).O besity and atherosclerosis are important medical problems with major impact on morbidity and mortality. Current treatments for obesity have shown limited efficacy and safety; therefore, there is a need for improved therapies (1). A major risk factor for atherosclerosis is low-density lipoprotein (LDL) cholesterol. Although there are excellent treatments for elevated LDL cholesterol, therapeutic goals are commonly not met. As targets for lowering of cholesterol become more aggressive, there is a need for more modalities to meet these goals. Lipoprotein (a) [Lp(a)] is an important risk factor, elevated in many patients with premature atherosclerosis, and few therapies lower Lp(a) (2).Thyroid hormones reduce body weight, LDL cholesterol, and Lp(a); thus, exploitation of these properties may be useful for therapy (3-6). Unfortunately, endogenous thyroid hormones are nonselective and produce undesirable side effects, particularly cardiac stimulation (7,8). Development of thyromimetics devoid of cardiac effects could have therapeutic potential as antiobesity and lipid-lowering agents.Thyroid hormone receptors (TRs) are divided into two primary subtypes (TR␣ and -␤), which are the products of two genes of the superfamily of nuclear hormone receptors (4, 7). TRs mediate distinct physiologic effects due to differences in tissue abundance or receptor-specific activity (9). Studies in patients with th...

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Section: Methodsmentioning

confidence: 99%

Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

Grover

Mellström

Liu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

207

182

View full text Add to dashboard Cite

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“…Several compounds were tested for TR-binding, but the results are not shown here as they all are R 1 -position amino or nitro intermediates, consequently not adding any informative value to this discussion. Shortly afterwards, Bayer published a patent of related 5-benzyl, 5-phenoxy or 5-phenylthio-substituted indazole derivatives (39) for the treatment of similar diseases mentioned [134]. These compounds act as thyroid receptor modulators but were also claimed to have higher specificity and fewer side effects, in particular cardiovascular side effects, than known thyroid hormone preparations.…”

Section: Replacement Of the R 4 ′-Hydroxy Groupmentioning

confidence: 99%

“…Administration of tissue and isoform-selective TR-agonists can have a multitude of beneficial effects on lipid metabolism, without undesirable cardiac and catabolic effects as evident by axitirome and other compounds [16,19,37,38]. LDL-C levels and triglyceride levels are reduced in both animals and humans, and the cholesterol-lowering effect of thyroid hormone is mainly mediated by an elevated expression of hepatic LDL receptors and increased cholesterol metabolism and excretion [39][40][41]. HDL cholesterol may be maintained or increased in some animal models.…”

Section: Metabolic Diseasesmentioning

confidence: 99%

Therapeutic thyroid hormone ligand patents 1998 – 2003

Malm¹

2004

Expert Opinion on Therapeutic Patents

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“…In einer weiteren Mitteilung wird auf eine weitere Komplikation dieser di/itetischen Behandlung eingegangen werden, nhmlich einer gewissen Verarmung des Organismus an Linolsfiure [29]. In einer weiteren Mitteilung wird auf eine weitere Komplikation dieser di/itetischen Behandlung eingegangen werden, nhmlich einer gewissen Verarmung des Organismus an Linolsfiure [29].…”

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Dietary problems in the management of type I hyperlipoproteinemia

Rakow¹,

Klör²,

Leupold

et al. 1976

Klin Wochenschr

Self Cite

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The therapeutic effect of different diets varying in long chain and medium chain triglycerides, carbohydrate, and protein was tested in two siblings with type I hyperlipoproteinemia. Despite administration of an extremely fat reduced diet ( less than 5 g daily), a normalization of plasma TG could not be obtained because-as a consequence of its high carbohydrate and/or its MCT content-it resulted in a considerable increase in pre-beta-lipoproteins. As life long dietary therapy has to be maintained, the risks of a normal therapy has to be maintained, the risks of a normal fat containing diet (mainly bouts of pancreatitis) and those of a carbohydrate and MCT rich diet (premature atherosclerosis) are to be carefully considered. On the basis of our data we therefore suggest the following dietary regimen: 1. Reduced intake of long chain triglycerides (less than 30 gms per day), but with sufficient amounts of essential fatty acids (4-6 gms linoleate daily). 2. The carbohydrates should not exceed 50% of total calories and ought to consist mainly of starch. 3. The caloric deficit thus generated should be balanced by a high protein intake. This is faciliated by applying a specially protein-enriched food. 4. Medium chanin triglycerides may be necessary when adherence to the protein-rich diet turns out to be bad.

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Treatment of type II hyperlipoproteinemia with d-thyroxine

Cited by 14 publications

References 24 publications

Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability

Therapeutic thyroid hormone ligand patents 1998 – 2003

Dietary problems in the management of type I hyperlipoproteinemia

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