The Origin of Antithyroid Drugs

T4 is converted to T3 within cells by specific deiodinases, which also deactivate thyroid hormones, by converting T4 into reverse T3, and T3 into diiodothyronine. A complex of T3, its intracellular thyroid hormone receptor, and the thyroid hormone-responsive element alters the transcription of a large number of genes to mediate the pleiotropic physiological actions of thyroid hormones. LT4 was introduced into the therapeutic armamentarium in the USA in the 1950s without a requirement for regulatory oversight. This situation is very different today, with increasingly close regulatory attention paid to the standards of manufacture of LT4 products. This has led to the development of new formulations of LT4, with more accurate and reproducible dosing, designed to improve the accuracy and reproducibility of exposure to LT4 for a patient taking this medication. The first attempts at iodine supplementation, either using a tincture of iodine, or with iodised salt, followed during the following decade 4.

Thyroxine and treatment of hypothyroidism: seven decades of experience

The relationship between levels of T4 and TSH is not linear, however, as decreasing the level of T4 by half results in an increase in the TSH level of as much as 100-fold 32. Large changes in TSH are clearly more amenable to accurate measurement than the accompanying relatively much smaller changes in T4. Accordingly, the management of hypothyroidism is now based on normalisation of the circulating TSH level to within a reference range for this parameter derived from a healthy population 33–35. Synthroid is a man-made hormone, identical to the hormone made by the thyroid gland and has the same effect onthe body. It replaces the amount of hormone the thyroid is unable to or can no longer make, helping to restore your thyroid hormone levels to the range they need to be.

In this case, it is Goliath, the pharmaceutical industry, known as Big Pharma, that wins. The loser is the patient who is prescribed the less effective, more expensive product. “With over 5 million thyroid blood tests every year and more than 1 million taking the hormone, these are still important questions for a large number of people.” Dextrothyroxine is the mirror form of levothyroxine with the opposite, non-natural chirality.

Early Beginnings: Growing Understanding of the Thyroid

Our natural treatments have helped over 33,000 individuals with hypothyroidism, adrenal fatigue, menopause, perimenopause, low testosterone, allergies, candida, detoxification and nutritional deficiencies. Amongst other things, delegates at the meeting discussed 21st Century issues with thyroid hormone replacements. In the peripheral tissues, thyroid hormone-sensitive target cells of the body take up T4 and T3 via transmembrane carriers.

This was partly due to limitations of chemically synthesised LT4, which was produced as an acid and had limited bioavailability before the synthesis of a sodium salt of in 1949 21. This preparation entered clinical use in that year in the USA, and entered clinical use in Europe some years later. The early attempts at thyroid replacement via “organ therapy” (as the practice of administration of extracts of animal organs became known), described briefly in the previous section, were taking place at a time when this practice was becoming widespread in the management of other conditions 20. For example, a report by a leading physician in France on the allegedly rejuvenating effects of self-injection with animal testicular extracts led to great enthusiasm for this practice among other physicians. Eventually, a growing association with widespread quackery in the hands of other practitioners led to a general discrediting of the principle of “organotherapy” 20, 21.

• The early attempts at thyroid replacement via “organ therapy” (as the practice of administration of extracts of animal organs became known), described briefly in the previous section, were taking place at a time when this practice was becoming widespread in the management of other conditions 20.
• SYNTHROID® (levothyroxine sodium) tablets, for oral use is a prescription, man-made thyroid hormone that is used to treat a condition called hypothyroidism in adults and children, including infants.
• Maintenance doses of l-thyroxine ranged from 200 to 500 mcg/d before the institution of the TSH assay and then became typically closer to 100 to 150 mcg/d (Appendix Table).
• Remarkably, the latter study showed that psychological measures improve in patients receiving combination therapy until serum TSH level is normal (6).
• The case tells the story of Synthroid from its development in 1958 as the first synthetic thyroxine molecule to its competition against generic equivalents in 2004.
• Indeed, Semon’s role in the unfolding thyroid story deserves much better recognition.

The case tells the story of Synthroid from its development in 1958 as the first synthetic thyroxine molecule to its competition against generic equivalents in 2004. The case introduces students to the pharmaceutical industry, its practices, and some of the complexities of pricing and drug choice, with drug manufacturers, insurance companies, physicians, pharmacists, and patients all playing a role. Because Synthroid was developed and introduced before FDA regulations and drug standards of identity were fully established, it was difficult for competitors to get their drugs certified as identical to Synthroid. Through a series of efforts with physicians, especially endocrinologists, Synthroid’s owners were able to maintain the perception for 46 years that Synthroid was uniquely effective.

• L-Thyroxine was the first synthetic molecule used to treat hypothyroidism (23) and was shown to be efficacious as monotherapy for myxedema (24).
• The clinical significance of this was not fully understood because many patients appeared clinically euthyroid with a BMR between −20% and −10% (36, 37).
• The development of reliable and specific assays for thyroid hormones contributed greatly to understanding the importance and function of the thyroid and facilitated individualised treatment.
• In fact, between the years 1991 and 1997, there were ten recalls of levothyroxine sodium tablets, involving more than 100 million tablets.
• It does this by creating thyroid hormones that are then circulated through the bloodstream to different parts of the body.

Because of the rapidity and transiency of improvement (12), it was hypothesized that symptoms improved by absorption of the “juice” of the donor gland (14). A Medline search was initiated using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence. Pertinent articles of interest were identified by title and where available abstract for further review.

Because of this surge in symptomatic patients, some clinicians advocated titrating dose by symptoms rather than serum TSH, reminiscent of the period before the 1970s (69). The association between hypothyroidism and energy expenditure was suspected clinically, and the discovery of lower O2 consumption in myxedema provided an early diagnostic tool (19). The naproxen synthroid development of a device to assess energy expenditure through measurement of the basal metabolic rate (BMR) in humans proved to be useful for not only diagnosis but also titration of therapy (20). The scale was calibrated so that a normal BMR reference range would be around 0%, whereas athyreotic individuals could have a BMR of about −40% (21).

• A Medline search was initiated using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence.
• Along the way, many clinical and experimental studies, enhancements in technology, and improved LT4 preparations have increased greatly our ability to deliver optimal care for hypothyroidism, based on the therapeutic administration of LT4.
• Students are challenged to consider options to maintain the drug’s unit volume, revenue, and/or profit in these difficult circumstances.

L-Thyroxine monotherapy, the novel and physiologically savvy method for treatment of hypothyroidism, contrasted with the traditional approach of natural thyroid preparations that was marred by potency concerns. In less than a decade, there was a major shift in treatment of hypothyroidism such that normalization of TSH with l-thyroxine monotherapy became the new standard of care (Appendix Table) (52). Many clinicians advocated for this to be first-line therapy and for patients previously treated with desiccated thyroid to be transitioned to l-thyroxine monotherapy (50). The development of TSH radioimmunoassay (43) provided the first sensitive and specific marker of systemic thyroid hormone status (Figure). Clinicians could now titrate therapy to achieve a serum TSH within the normal range as a specific marker of replacement adequacy (44). For patients who were once treated with doses that normalized their symptoms, BMR, or serum PBI, the use of serum TSH revealed such doses to be typically supratherapeutic (45, 46).

The substance that would come to be known as thyroxine (T4) was isolated in the USA in 1915 and fully chemically characterised in 1926 (and published the following year 18). It was also established that LT4 had greater biological activity than a racemic mixture. The discovery of triiodothyronine (T3) as a “normal constituent of the organic iodine fraction of the plasma” of subjects with normal thyroid function or hyperthyroidism followed in 1952 19. The likely reason for this dismissive outburst lay at the feet of that medical colossus, Charles Édouard Brown-Séquard, the French neurologist and physiologist. A kind of scientific Ulysses, he had held university chairs in Richmond, Virginia and in Harvard, Paris, Geneva and Paris again.2 He declined the chair of physiology in Glasgow because of the weather! The story goes that he once refused a colossal fee of £10,000 to see a wealthy American patient in Italy because he did not think he was the best person to advise and, besides, private practice interfered with research!