Abstract:
Administration of a therapeutically effective amount of 3,5-diiodothyropropionic acid stimulates weight loss in patients, lowers triglyceride levels and reduces risk of death or progression of coronary heart disease in patients with metabolic syndrome.

Description:
CROSS REFERENCE TO RELATED APPLICATION  
       [0001]    This application is a continuation-in-part of co-pending application Ser. No. 10/818,541, filed Apr. 5, 2004, which is, in turn a continuation-in-part of U.S. application Ser. No. 10/368,755, filed Feb. 18, 2003, now U.S. Pat. No. 6,716,877 issued Apr. 6, 2004, which is, in turn a continuation-in-part of U.S. application Ser. No. 09/774,994, filed Jan. 31, 2001, now U.S. Pat. No. 6,534,676, issued Mar. 18, 2003. 
     
    
     BACKGROUND OF THE INVENTION AND DISCUSSION OF THE PRIOR ART  
       [0002]    Researchers at the Centers for Disease Control and Prevention (CDC) estimated that as many as 47 million Americans may exhibit a cluster of medical conditions (a “metabolic syndrome”) characterized by abdominal obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, high blood pressure, and elevated fasting blood glucose [1]. Having three or more traits of metabolic syndrome significantly increases the risk of dying from coronary heart disease or cardiovascular disease. It has also been reported that patients with even one or two metabolic syndrome traits, or those with metabolic syndrome but without diabetes also were at increased risk for death from coronary heart disease or cardiovascular disease. 
         [0003]    Obesity and atherosclerosis have a major impact on morbidity and mortality in the United States and many other countries. Elevated cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is a major risk factor for atherosclerosis. Thyroid hormone replacement in hypothyroid individuals reduces total cholesterol and LDL-cholesterol [2-4]. An excess of thyroid hormone in thyrotoxicosis causes weight loss. The weight loss consists not only of fat but also muscle mass and even myopathy can be observed [5]. 
         [0004]    The ability of thyroid hormone to lower cholesterol when given to hypothyroid individuals prompted efforts to design analogs that take advantage of these properties in the treatment of hypercholesterolemia. This action is the result of an accelerated LDL-cholesterol clearance rate [6-8]. T 3  increases levels of both the hepatic LDL receptor [9] and its mRNA [10]. Additional thyroid hormone actions on lipid metabolism include increasing the activity of lipoprotein lipase [11]. 
         [0005]    Numerous studies have been carried out to synthesize thyroid hormone analogs that mimic the actions of the natural hormones. The objective of most of these efforts has been to develop thyromimetics that lower plasma cholesterol without adverse cardiac effects. A series of thyroxine analogs and methods of synthesis are described in U.S. Pat. No. 3,109,023. Thyroid hormone agonists that are highly selective for the thyroid hormone receptor (TR) β-subtype are described in U.S. Pat. No. 5,883,294 and WO 00/39077. U.S. Pat No. 5,284,971 describes a class of thyromimetics, which have the distinguishing characteristic of a sulfonyl bridge in the diphenyl core. 
         [0006]    The usual method employed in treating obesity has been reduction of caloric intake either by reduced caloric diet or appetite suppression. An alternative method is to stimulate metabolic rate in adipose tissue. For example U.S. Pat Nos. 4,451,465, 4,772,631, 4,977,148 and 4,999,377 disclose compounds possessing thermogenic properties at dosages causing few or no deleterious side-effects, such as cardiac stimulation. Further pharmaceutical compositions including those selective for the β-type thyroid hormone receptor have been taught by Cornelius et al. in US 2002/0035153 A1. A representative compound of this type, N-[4-[3′[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate (CGS-26214) reportedly is devoid of significant cardiovascular effects but possess significant thermogenic properties. Accordingly, CGS-26214 and related compounds are useful in the treatment of obesity and related conditions in humans and companion animals. According to Cornelius et al. compounds related to CGS-26214 may be combined with an anorectic agent such as phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a Neuropeptide Y antagonist, a cholecystokinin-A agonist, etc. Whereas administration of a selective β-agonist would compensate for endogenous hormones in terms of TRβ stimulation it may not significantly activate TRα, which could cause a relative hypothyroidism or could cause increased hepatic toxicity. Also, there is no information on whether weight loss would be selective for fat or would include muscle as well. 
         [0007]    Goglia and Lanni in W02005009433 describe the use of a breakdown product of thyroid hormone (3,5-diiodothyronine) as a regulator of lipid metabolism to stimulate burning of fatty acid in mitochondria. T 3 , which is largely derived from T 4  by the action of monodeiodinases, has been thought to be the major active form of thyroid hormone. It has been reported that 3,5-diiodothyronine (3,5-T 2 ) is able to directly increase mitochondrial respiration by increasing the burning of fatty acids. In keeping with the stimulation of mitochondrial respiration, fatty acid oxidation rate was increased by 3,5-T 2 . In rats fed a high-fat diet long-term treatment with 3,5-T 2  reportedly decreased weight gain. These effects were observed without suppression of TSH or evidence of hyperthyroidism. 3,5-T 2  also was given to four volunteers in daily doses between 15 and 90 microgram/kg. There was a reduction in plasma levels of triglycerides from 140-70 mg/dL and cholesterol from 241 mg/dL to 210 mg/dL. The resulting metabolic rate increased in a dose dependent manner reaching a maximum increase of 40% (from 1770 Kcal to 2400 Kcal per day). Fat mass was reduced in the range of 10 to 15%. There was no significant change in plasma levels of free T 3  and free T 4 . 
         [0008]    The actions of 3,5-T 2  and T 3  on mitochondrial respiration can be distinguished by differences in the time course of the response [12]. Changes in resting metabolic rate in hypothyroid rats treated with a single injection of 3,5-T 2  started 6-12 hours after infection with the maximal stimulation at 28-30 hours. By contrast injection of T 3  increased resting metabolic rate that started 25-30 hours after injection and lasted 5-6 days. At the mitochondrial level stimulation is very rapid after injection of 3,5-T 2 , occurring within 1 hour. 
         [0009]    In my parent application, now U.S. Pat. No. 6,534,676, I describe and claim the use of a thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) for treating patients with congestive heart failure. More particularly, as reported in my aforesaid U.S. Pat. No. 6,534,676, DITPA has been shown to improve left ventricular (LV) performance in post-infarction experimental models of heart failure when administered alone or in combination with an angiotension I-converting enzyme inhibitor. Cholesterol was significantly reduced in heart failure patients receiving DITPA after two and four weeks treatment, P&lt;0.05 and P&lt;0.1, respectively. In addition, it was noted that triglycerides were significantly reduced in these heart failure patients at two and four weeks of treatment with P&lt;0.05 and P&lt;0.005, respectively. 
         [0010]    3,5-T 2  and DITPA differ only in the side chain attached to the inner phenolic ring. In each case, the side chain consists of 3 carbons, ending in an amino acid group in 3,5-T 2  and a carboxylic acid in DITPA. The structural similarity suggests the compounds should have some physiologic similarities. As reported in my aforesaid U.S. Pat. No. 6,534,676 normal volunteers and patients with heart failure indicate two such similarities: 1) There was significant weight loss in heart failure patients, who were obese and poorly conditioned, but no significant loss in volunteers who were more active and free of significant heart disease; and 2) Unexpectedly, there was a decrease not only in total cholesterol and LDL-cholesterol but also a highly significant decrease in triglycerides (P=0.005). A decrease in triglycerides also was seen with administration of 3,5-T 2 , but to my knowledge, has not previously been reported either with thyroid replacement in hypothyroidism or in the case of thyroid hormone analogs [13]. 
       SUMMARY OF THE INVENTION  
       [0011]    The new and surprising effect I have found is that administration of 3,5-diiodothyropropionic acid (DITPA) not only reduces total cholesterol and low-density lipoprotein (LDL) cholesterol when it is administered to overweight euthyroid individuals, it stimulates weight loss, and also reduces triglycerides, particularly in overweight individuals. 
         [0012]    Adipose tissue is the largest storehouse of energy in the body (in the form of triglycerides) and typically makes up 15-20% or more of the body weight in men and 20-25% or more of the body weight in women. Thyroid hormones exert a wide range of effects on lipid metabolism. In the thyrotoxic state lipid mobilization, synthesis and degradation are all accelerated. Degradation of most lipids is stimulated out of proportion to synthesis and as a consequence body lipid deposits are depleted. Thus, administration of DITPA is seen to stimulate weight loss and lower hypertriglyceridemia, particularly in overweight patients, and may be used to treat or to reduce risk of death or progression of coronary heart disease (CHD) in patients with metabolic syndrome. 
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0013]    DITPA was synthesized following good manufacturing procedures by coupling dianisoleiodium trifluoroacetate with ethyl-3-(3,5-diiodo-4-hydroxyphenyl)-propionate followed by removal of the methyl and ethyl protective groups as described in my aforesaid U.S. Pat. No. 6,534,676. 
         [0014]    The effects of administering DITPA were studied in 7 volunteers all but one of whom had normal weight. Study participants were men between the ages of 27 and 52 years. Of note, there was an average weight loss of only 0.6 kg for the group, or 0.7% of their initial weight, which did not attain statistical significant (P=0.13). Body Mass Index (BMI) was calculated as a meaning of judging obesity. BMI is a measure of body fat based on height and weight that applies to both men and women. Excluding the one overweight individual BMI ranged from 21.0 to 26.7 (average 25.0). (The range of normal weight for men is 20.7 to 26.4, marginally over weight 26.4 to 27.8, overweight 27.8 to 31.1, and very obese is greater than 31.1). BMI was calculated using the BMI calculator at the National Heart, Lung, and Blood Institute web site (nhlbisupport/com/bmi/). BMI and lipid data for the six volunteers of normal body weight are summarized in Table I A&amp;B: 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE I (a) 
               
             
             
               
                   
               
               
                 Healthy Volunteers Treated with DITPA 
               
             
          
           
               
                   
                   
                 BMI 
               
               
                   
                 Initials 
                 (kg/m 2 ) 
               
               
                   
                   
               
             
          
           
               
                   
                 T. M. 
                 24.4 
               
               
                   
                 T. V. 
                 24.4 
               
               
                   
                 K. L. 
                 27.4 
               
               
                   
                 A. M. 
                 26.7 
               
               
                   
                 J. B. 
                 21.0 
               
               
                   
                 R. F. 
                 26.1 
               
               
                   
                 Mean 
                 25.0 
               
               
                   
                 SE 
                 0.9 
               
               
                   
                   
               
             
          
         
       
     
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                 TABLE 1 (b) 
               
             
             
               
                   
               
               
                 Healthy Volunteers Treated with DITPA 
               
             
          
           
               
                   
                 Cholesterol 
                 LDL-C 
                 HDL-C 
                 Triglycerides 
               
               
                 Initials 
                 mg/dL 
                 mg/dL 
                 mg/dL 
                 mg/dL 
               
               
                   
               
             
          
           
               
                 Baseline: 
                   
                   
                   
                   
               
               
                 T M 
                 190 
                 112.6 
                 53 
                 122 
               
               
                 T V 
                 181 
                 119.6 
                 25 
                 182 
               
               
                 K L 
                 320 
                   
                   
                 538 
               
               
                 A M 
                 191 
                 160.4 
                 9 
                 108 
               
               
                 J B 
                 133 
                 75.4 
                 41 
                 83 
               
               
                 R F 
                 198 
                 139.8 
                 37 
                 106 
               
               
                 Mean 
                 202.2 
                 121.6 
                 33.7 
                 189.8 
               
               
                 SE 
                 25.4 
                 14.2 
                 7.5 
                 71.0 
               
               
                 After 2 weeks: 
               
               
                 T M 
                 191 
                 120.6 
                 50 
                 102 
               
               
                 T V 
                 141 
                 86.8 
                 31 
                 116 
               
               
                 K L 
                 298 
                 142.6 
                 36 
                 597 
               
               
                 A M 
                 164 
                 102.2 
                 28 
                 169 
               
               
                 J B 
                 94 
                 47.4 
                 30 
                 83 
               
               
                 R F 
                 149 
                 90.2 
                 38 
                 104 
               
               
                 Mean 
                 172.8 
                 98.3 
                 35.5 
                 195.2 
               
               
                 SE 
                 28.2 
                 12.3 
                 3.3 
                 81.2 
               
               
                 After 4 weeks: 
               
               
                 T M 
                 187 
                 109.4 
                 52 
                 128 
               
               
                 T V 
                 122 
                 71 
                 27 
                 120 
               
               
                 K L 
                 305 
                 137 
                 31 
                 685 
               
               
                 A M 
                 168 
                   
                   
                 106 
               
               
                 J B 
                 79 
                   
                   
                 68 
               
               
                 R F 
                 182 
                 118.2 
                 45 
                 94 
               
               
                 Mean 
                 173.8 
                 108.9 
                 38.8 
                 200.2 
               
               
                 SE 
                 31.2 
                 13.9 
                 5.9 
                 97.4 
               
               
                   
               
             
          
         
       
     
         [0015]    Cholesterol levels ranged from 133 mg/dL to 320 mg/dL (average 202.2±25.4 mg/dL), LDL-cholesterol 121.6±14.2, HDL-cholesterol 33.7±7.5. Triglycerides levels ranged from 83 mg/dL to 538 mg/dL (average 189.8±71.1 mg/dL) before treatment. On day 1, these normal volunteers were started on 1.875 mg/kg DITPA in two divided doses per day. This treatment regimen was continued for two weeks. At the end of the second week, the dose was doubled to 3.75 mg/kg and the volunteers were treated for two additional weeks. 
         [0016]    After two weeks of treatment with DITPA cholesterol levels were decreased to an average of 172.8±28.2 mg/dL, LDL-cholesterol to 98.3±13.3 mg/dL. HDL-cholesterol and triglycerides were unchanged at 35.5±3.3 mg/dL and 195.2±81.2 mg/dL, respectively. After four weeks of treatment cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride levels were essentially unchanged from values after 2 weeks of treatment. Note that triglyceride levels in the one individual (K. L.) with very high triglyceride levels, was unaffected by treatment. Thus treatment with DITPA in individuals of normal body weight lowered cholesterol and LDL-cholesterol but did not cause weight loss or a decrease in triglycerides. 
         [0017]    Treatment was repeated with a second group of 8 patients with heart failure. (One patient with heart failure treated with DITPA reported in U.S. Pat. No. 6,716,877 was excluded because no lipid data were available at baseline.) Those in the second group had Body Mass Indices ranging from 21.0 to 30.3 (average 32.2, which was in the obese range). The patients in this group received an initial dose of 1.875 mg/kg for two weeks, which was doubled to 3.75 mg/kg for two additional weeks. As reported earlier, heart failure patients receiving DITPA experienced an average weight loss of 4 kg or 4.0% of their initial body weight (P=0.059). 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE II (a) 
               
             
             
               
                   
               
               
                 Heart Failure Patients Treated with DITPA 
               
             
          
           
               
                   
                   
                 BMI 
               
               
                   
                 Initials 
                 (kg/m 2 ) 
               
               
                   
                   
               
             
          
           
               
                   
                 R. V. 
                 45.5 
               
               
                   
                 J. G. 
                 36.2 
               
               
                   
                 F. R. 
                 28.1 
               
               
                   
                 E. C. 
                 30.2 
               
               
                   
                 J. D. 
                 30.0 
               
               
                   
                 J. F. 
                 31.3 
               
               
                   
                 W. P. 
                 36.9 
               
               
                   
                 C. H. 
                 23.9 
               
               
                   
                 Mean 
                 31.5 
               
               
                   
                 SE 
                 2.4 
               
               
                   
                   
               
             
          
         
       
     
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                 TABLE II (b) 
               
             
             
               
                   
               
               
                 Heart Failure Patients Treated with DITPA 
               
             
          
           
               
                   
                 Cholesterol 
                 LDL-C 
                 HDL-C 
                 Triglycerides 
               
               
                 Initials 
                 mg/dL 
                 mg/dL 
                 mg/dL 
                 mg/dL 
               
               
                   
               
             
          
           
               
                 Baseline: 
                   
                   
                   
                   
               
               
                 R. V. 
                 195 
                 141 
                 27 
                 133 
               
               
                 J. G. 
                 217 
                 104 
                 23 
                 449 
               
               
                 F. R. 
                 102 
                 48 
                 30 
                 119 
               
               
                 E. C. 
                 144 
                 62 
                 38 
                 219 
               
               
                 J. D. 
                 186 
                 94 
                 28 
                 321 
               
               
                 J. F. 
                 241 
                 167 
                 48 
                 128 
               
               
                 W. P. 
                 168 
                 89 
                 31 
                 238 
               
               
                 C. H. 
                 233 
                 152 
                 37 
                 222 
               
               
                 Mean 
                 185.8 
                 107.1 
                 32.8 
                 228.6 
               
               
                 SE 
                 16.6 
                 15.1 
                 2.8 
                 39.8 
               
               
                 After 2 weeks: 
               
               
                 R. V. 
                 161 
                 107 
                 30 
                 120 
               
               
                 J. G. 
                 150 
                 88 
                 20 
                 208 
               
               
                 F. R. 
                 106 
                 55 
                 27 
                 119 
               
               
                 E. C. 
                 128 
                 50 
                 32 
                 228 
               
               
                 J. D. 
                 176 
                 88 
                 28 
                 300 
               
               
                 J. F. 
                 244 
                 177 
                 41 
                 131 
               
               
                 W. P. 
                 177 
                 81 
                 34 
                 312 
               
               
                 C. H. 
                 190 
                 99 
                 28 
                 317 
               
               
                 Mean 
                 166.5 
                 93.1 
                 30.0 
                 216.9 
               
               
                 SE 
                 14.8 
                 13.9 
                 2.1 
                 30.6 
               
               
                 After 4 weeks: 
               
               
                 R. V. 
                 143 
                 102 
                 26 
                 77 
               
               
                 J. G. 
                 125 
                 69 
                 20 
                 179 
               
               
                 F. R. 
                 83 
                 43 
                 26 
                 69 
               
               
                 E. C. 
                 107 
                 41 
                 31 
                 176 
               
               
                 J. D. 
                 144 
                 77 
                 26 
                 205 
               
               
                 J. F. 
                 243 
                 172 
                 52 
                 93 
               
               
                 W. P. 
                 127 
                 68 
                 32 
                 135 
               
               
                 C. H. 
                 189 
                 102 
                 36 
                 253 
               
               
                 Mean 
                 145.1 
                 84.3 
                 31.1 
                 148.4 
               
               
                 SE 
                 17.7 
                 14.9 
                 3.4 
                 23.3 
               
               
                   
               
             
          
         
       
     
         [0018]    At baseline average cholesterol values were 185.8±16.6 mg/dL, LDL-cholesterol 107.1±15.1 mg/dL, HDL-cholesterol 32.8±2.8 mg/dL and triglycerides 228.6±39.8 mg/dL. After two weeks of treatment with DITPA cholesterol decreased to 166.5±14.8 mg/dL, LDL-cholesterol to 93.1±13.9 mg/dL and triglycerides to 216.9±30.6 mg/dL. After four weeks of treatment cholesterol decreased to 145.1±17.7, LDL-cholesterol to 84.3±14.9 and triglycerides to 148.4±23.3. The decrease in triglycerides of 35% is comparable to that reported by Goglia and Lanni in normal volunteers treated with 3,5-T 2 . Of particular interest, the two patients (J. G. and J. D.), with triglycerides of greater than 300, had decreases in triglycerides of 60% and 36%, respectively. 
         [0019]    It is thus seen that administration of DITPA caused a greater decrease in weight of overweight individuals than those of normal body weight. Triglycerides also were decreased to a greater extent in overweight individuals. In these individuals, the triglycerides were decreased both in those with normal and elevated triglycerides levels. 
         [0020]    As used herein, the terms “overweight individuals” and “overweight patients” are those individuals or patients having a Body Mass Index of 30 or more. 
         [0021]    As used herein, “therapeutically effective amounts” or “effective dose levels” for achieving weight loss and lowering of triglyceride levels of overweight individuals were 0.1 to 10.0 mg/kg daily, preferably 1.875 to 3.75 mg/kg daily. Preferably, the daily doses were divided in half and administered twice daily. 
         [0022]    While the invention has been described in detail in treating humans in accordance with certain preferred embodiments the invention also advantageously may be used for treating overweight animals such as dogs and cats, and other domesticated animals. Also, while administration of DITPA appears to reduce triglycerides, particularly in overweight individuals, individuals of normal weight also may benefit by a reduction of triglycerides from administration of DITPA in accordance with the present invention. Moreover, DITPA advantageously may be combined with one of the conventional lipid/triglyceride lowering therapeutic agents such as HMG CoA reductase inhibitors commonly referred to as ‘statins’, e.g., atorvastatin (Lipitor), simvastatin (Zocor), fluvastatin (Lescol), lovastatin (Mevacor), rosuvastatin (Crestor), and pravastatin (Pravachol) or the like. Niacin and inhibitors of cholesterol absorption such as ezetimibe (Zetia) also may be combined with DITPA. For treatment of hypertriglyceridemia fibric acid derivative such as gemfibrozil (Lopid), fenofibrate (Tricor), etc. may be combined with DITPA. Still other modifications and changes therein may be made without departing from the spirit and scope of the invention. 
       APPENDIX 
     REFERENCES  
       [0000]    
       
         1. Ford E S, Giles W H, Dietz W H: Prevalence of the metabolic syndrome among US adults. Findings from the third national health and nutrition examination survey. JAMA 287:356-359, 2002 
         2. Mason R L, Hunt H M, Hurxthal L M: Blood cholesterol values in hyperthyroidism and hypothyroidism: their significance. N Eng J Med 203:1273-1278, 1930 
         3. Peters J P, Man E B: The significance of serum cholesterol in thyroid disease. J Clin Invest 29:1-11, 1950 
         4. Ladenson P W, Goldenheim P D, Ridgway E C: Rapid pituitary and peripheral tissue responses to intravenous L-triiodothyronine in hypothyroidism. J Clin Endocrinol Metab 56:1252-1259, 1983. 
         5.  The Thyroid. A Fundamental and Clinical Text.  6 th  Ed., Editors: L. E. Braverman and R. D. Utiger, J. B. Lippincott Co., pp. 489-490. 
         6. Walton K W, Campbell D A, Tonks E L: The significance of alterations in serum lipids in thyroid dysfunction. I. The relation between serum lipoprotein, carotenoids and vitamin A in hypothyroidism and thyrotoxicosis. Clin Sci 29:199-215, 1965. 
         7. Walton K W, Scott P J, Dykes P W, Davies J W: The significance of alternations in serum lipids in thyroid dysfunction. II. Alterations of metabolism and turnover of 131-I-low-density lipoproteins in hypothyroidism and thyrotoxicosis. Clin Sci 29:217-238 
         8. Abrams J J, Grundy S M: Cholesterol metabolism in hypothyroidism and hyperthyroidism in man. J Lipid Res 22:323-338, 1981. 
         9. Staels B. Van Tol A, Chan L, Will H M, Verhoeven G A, Auwerx J: Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase, and low-density lipoprotein receptor in rats. Endocrinology 127:1145-1152. 
         10. Salter A M, Hayashi R, Al-Seeni M, Brown N F, Bruce J, Sorensen O, et al.: Effects of hypothyroidism and high-fat feeding on mRNA concentrations for the low-density lipoprotein receptor and on acyl-CoA:cholesterol acyltransferase activities in rat liver. Biochem J 276:825-832, 1991. 
         11. Packer C J, Shepard J, Lindsay G M, Gaw A, Taskinen M R: Thyroid replacement therapy and its influence on postheparin plasma lipases and apolipoprotein-β metabolism in hypothyroidism. J Clin Endocrinol Metab 76:1209-1216, 1993. 
         12. Moreno M, Lanni A., Lombardi A, Goglia F: How the thyroid controls metabolism in the rat: different roles for triiodothyronine and diiodothyronines. J Physiol (London) 505:529-538, 1997. 
         13. Morkin E, Ladenson P, Goldman S, Adamson C: Thyroid hormone analogs for treatment of hypercholesterolemia and heart failure: past, present and future prospects. J Mol Cell Cardiol 37:1137-1146, 2004.