History of the three thyroid medications
Because naturally occurring substances, including thyroid hormone, cannot be patented, these products have a lower profit margin, and the companies that make them do not have millions of dollars at their disposal for marketing. In future, we may hope to see improved methods of delivery for both synthetic and natural T3-based therapies. The short half-life of T3 is cited as an inconvenience to patients, yet the “trouble” of taking several doses per day is a ridiculous obstacle to place in the way of improved health.
Effect of Radioimmunoassay-Based Thyroid Function Tests
In 2004, however, the FDA declared several competitive products to be bioequivalent to Synthroid, which posed a significant challenge to its owner, Abbott Laboratories. Students are challenged to consider options to maintain the drug’s unit volume, revenue, and/or profit in these difficult circumstances. The (A) case provides background on the history of the drug, the pharmaceutical industry and its marketing practices, and hypothyroidism and its treatment, and it concludes in 2004 as Abbott’s marketers face the impending challenge of defending the Synthroid business against generic competition.
Medical
- Improved outcomes for these subjects following empirical treatment with crude thyroid extracts spurred further research, and isolation, characterisation, and chemical synthesis of LT4 and triiodothyronine (T3) followed in the first half of the twentieth century.
- Monotherapy with LT4 has been the mainstay of management of hypothyroidism from about 1970.
- The short half-life of T3 is cited as an inconvenience to patients, yet the “trouble” of taking several doses per day is a ridiculous obstacle to place in the way of improved health.
- There is no suggestion of this in the British Medical Journal’s detailed transcription of the proceedings,1 nor in the exceedingly brief original written minutes of the meeting (an extended account must have been written up at some later point for the BMJ).
- “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.”
Monotherapy with LT4 has been the mainstay of management of hypothyroidism from about 1970. Thyroid research is far from complete, however, and further research into several outstanding clinical issues will continue to shape LT4-based therapy in the future. Studies of several animal models indicate that maintaining normal serum T3 levels is a biological priority (5). Although the clinical significance of relatively low serum T3 in humans is not well-defined (1), evidence shows that elevating serum T3 through the administration of both l-thyroxine and l-triiodothyronine has benefited some patients (6, 7).
These were not designed as superiority trials, their therapeutic goals were the normalization of serum PBI or BMR, and doses were dramatically higher than used today. For example, desiccated thyroid and intravenous l-thyroxine monotherapy normalized BMR, pulse, and body weight in myxedema (29), l-triiodothyronine monotherapy was likewise effective (30), and the potency of l-triiodothyronine exceeded that of l-thyroxine (31). The introduction of pharmaceutical preparations of synthetic thyroid hormones and establishment of monotherapy with LT4 as the standard of care for hypothyroidism opened up a prospect of delivery of stable, reproducible therapy tailored to the needs of the individual patient. To achieve this, it was necessary to measure circulating levels of thyroid hormones accurately and reproducibly. These assays made it possible to accurately determine the thyroid status of patients with all degrees of severity of thyroid dysfunction and facilitated a leap in our understanding of the physiology of the thyroid gland.
Gross and Pitt rivers found that L-T3 was 5 times as more potent than L-Thyroxine at inhibiting the release of TSH from the pituitary gland. They also found that when both were delivered orally rather than subcutaneously (by injection), L-T3 was approximately twice as effective as thyroxine. I discuss them in chronological order, from the earliest thyroid medication to the most recently invented. The thyroid is a small butterfly-shaped gland located at the base of the neck, just below the Adam’s apple. It’sresponsible for controlling the body’s metabolism, or the rate at which the body converts food into energy, and for making sure the brain, heart, liver, kidneys, and other organs are working properly. Once thyroid hormone was found to work by Dr Murray, many other forms of hormone replacement were subsequently developed, like insulin for diabetes and oestrogen hormone replacement for the menopause.
Levothyroxine
In the 1960s, the use of oral combinations of LT4 and T3 became widely used in the management of hypothyroidism, due to an assumption that delivery of both thyroid hormones would mimic the natural function of the thyroid gland 25. In addition, as thyroid extracts were essentially the reference product for clinical trials at this time, studies comparing thyroid extracts and LT4 + combinations gave broadly similar clinical results. In addition, it was discovered in the 1970s that about 80% of T3 in peripheral tissues is derived from local conversion from T4 by local deiodinases, rather than from the thyroid 27.
- A clinical trial investigating symptoms found that patients receiving l-thyroxine monotherapy, even with a normal TSH, displayed substantial impairment in psychological well-being compared with controls of similar age and sex (3).
- It took considerable time for synthesised LT4 to become the mainstay of treatment for hypothyroidism, however.
- Initial treatment strategies were largely insufficient and primarily symptom directed, including hot baths and institutionalization (12).
The (B) case describes what Abbott actually did to maintain its share in the United States and outlines its strategy in India, a market without patent protection for pharmaceuticals. Effectiveness is the most important criterion in synthroid morphine choosing a thyroid replacement product. Natural thyroid extracts have been in use for over a century and were approved by the FDA in 1939, a year after the passage of the Food, Drug, and Cosmetic Act.
A conference hosted by Newcastle University and the British Thyroid Association focused on recent treatment advances in thyroid disease and hormone replacement strategies. Triiodothyronine (T3) was first discovered in 1952, and was synthesized as Liothyronine in the same year. It was found to be far more potent than Levothyroxine in reducing pituitary inflammation, thyroid inflammation, and blood levels of cholesterol, and in raising the depressed basal metabolic rate that characterized hypothyroidism. In a 2017 survey of over 12,000 patients by the American Thyroid Association, patients gave DTE the highest rating compared with L-T4 monotherapy and T3/T4 combination therapy. Research continues into the management of hypothyroidism, and Table 1 highlights several important issues that remain unresolved 28, 32, 41–47.
As well as being used to treat thyroid under-activity in adults, thyroxine also works for babies who are born without a thyroid gland, and can be a critical factor for successful pregnancy and fertility in younger women. Currently the use of L-T3 therapy is seeing a revival as part of synthetic “combination therapy” alongside L-T4. At a current cost of only six pence per day, thyroxine medication for thyroid under-activity revolutionised the treatment of this common condition and this treatment is still in the top 10 of all medications prescribed in the world. “Considering that the idea of a ‘hormone’ hadn’t even been invented at this time, Dr Murray made a remarkable medical advance; one that millions of people continue to benefit from. Mackenzie went into detail of his patient’s condition during a sequence of pre-treatment hospitalizations ‘In order that it may not be imagined that the effect of treatment could be attributed simply to residence in the hospital’.
Towards the Modern Era in the Management of Hypothyroidism
Delegates travelled from as far afield as Australia and the USA to participate in the two-day event at Newcastle’s Centre for Life, which took place May 12-13. Synthetic Liothyronine has been used either alone or in combination with Levothyroxine since Liothyronine was first discovered.
