Liothyronine Research Articles

Changes in electrical parameters of the heart in an experimental model of malignant tumor growth during of hyperthyroidism

Experimental and clinical studies demonstrate the possibility of modulating the development of malignant tumors in thyroid imbalance, in particular hyperthyroidism, which negatively affects the electrophysiology of the heart. In an experimental model of tumor growth during of hyperthyroidism, activation of the tumor was shown.Aim: To study electrophysiological parameters of the mouse heart at the initial stages of transplantable tumor growth during of hyperthyroidism.Material and Methods. In female mice of the C57BL/6 line (n = 20) was created a model of melanoma B16/F10 growth during of hyperthyroidism, which was induced by daily intraperitoneal administration of liothyronine sodium (T3) for a long time and confirmed by determining the content of thyroid-stimulating hormone and triiodothyronine in the blood using the radioimmune method. On the 5th day of T3 administration, the melanoma was transplanted. ECG was recorded non-invasively (ecgTUN- NEL, ecgAVG software, emka TECHNOLOGIES, France) on the 1st and 3rd days of T3 administration, in groups with a tumor – on the 6th day after its transplantation.Results. Pathological changes were revealed: in the group with hyperthyroidism – rhythm irregularity, decrease the amplitude of P and T below the isoline, widening of the QRS, on the 3rd day – the death of 1 mouse was noted due to large-focal myocardial infarction; in the group with melanoma – only sinus arrhythmia and decreased heart rate; in the group with a combination of pathologies – an almost normal ECG, with the exception of an increase in P amplitude and a slight increase in QRS.Conclusion. Already in the early stages of hyperthyroidism or tumor growth, there was a violation of myocardial depolarization/ repolarization processes, capable of causing even death of the animal. In case of comorbidity, the majority of ECG parameters normalized, indicating the inclusion of compensatory mechanisms in the interaction of pathologies. The results demonstrate the need for a deeper study of the mechanisms of interaction of several simultaneously existing pathologies in the body.

Features of the functioning of the hypothalamic-pituitary-thyroid axis in mice with Lewis carcinoma on the background of induced hyperthyroidism

Thyroid hormones (TH) influence the processes of cell proliferation and differentiation, but their role in the processes of carcinogenesis is contradictory. The purpose of the study. To study the effect of induced hyperthyroidism in mice of both sexes with intertwined Lewis carcinoma (LLC) on the activity of the hypothalamic-pituitary-thyroid axis (GGT). Materials and methods. The experimental model was mixed-sex mice of the C57BL/6 line with subcutaneously transplanted LLC on the background of induced hyperthyroidism (main group). Two control groups were used: control group I – mice with sodium liothyronine- induced hyperthyroidism and control group II – mice with subcutaneously transplanted LLC. On the 25th day after tumor transplantation, the level of thyrotropin- releasing hormone (TRH), thyroid- stimulating hormone (TSH), triiodothyronine (T3), total and free thyroxine (T4, FT4) was determined in the homogenates of GGT organs and in blood serum. Results. In female mice, hyperthyroidism caused an increase in the level of TRH in the hypothalamus and a decrease in TSH in the pituitary gland; in males, a decrease in TRH only in the hypothalamus. In control group II, euthyroid disorder syndrome developed: In mice of both sexes, serum levels of T4 and FT4 were found to decrease against the background of unchanged T3 levels and an increase in TSH content only in females. In the females of the main group, an increase in the level of TSH in the thyroid gland caused a decrease in T3 content in 73 % of animals against the background of normal T4 and elevated FT4 levels, in 27 % of females the T3 level increased. In males, in 73 % of the observations, the T3 level was increased against the background of high T4 and FT4 values and unchanged TSH levels. In the skin and LLC samples of the mice of the main group, an increase in T3 levels was noted. Conclusion. The growth of LLC against the background of hyperthyroidism is a process with multifactorial effects. High levels of T3 in blood serum and skin stimulated the proliferation of tumor cells, which led to the formation of subcutaneous tumors of a larger volume in the mice of the main group. Sex differences in the GGT response indicate different mechanisms that implement pathological processes.

Thyroid hormone controls the timing of cochlear ribbon synapse maturation

Ribbon synapses in the cochlear hair cells are subject to extensive pruning and maturation processes before hearing onset. Previous studies have highlighted the pivotal role of thyroid hormone (TH) in this developmental process, yet the detailed mechanisms are largely unknown. In this study, we found that the thyroid hormone receptor α (Thrα) is expressed in both sensory epithelium and spiral ganglion neurons in mice. Hypothyroidism, induced by Pax8 gene knockout, significantly delays the synaptic pruning during postnatal development in mice. Detailed spatiotemporal analysis of ribbon synapse distribution reveals that synaptic maturation involves not only ribbon pruning but also their migration, both of which are notably delayed in the cochlea of Pax8 knockout mice. Intriguingly, postnatal hyperthyroidism, induced by intraperitoneal injections of liothyronine sodium (T3), accelerates the pruning of ribbon synapses to the mature state without affecting the auditory functions. Our findings suggest that thyroid hormone does not play a deterministic role but rather controls the timing of cochlear ribbon synapse maturation.

Chiral LC-MS/MS method for the discrimination of triiodothyronine enantiomers on a crown ether-based chiral stationary phase.

Considering the greater pharmaceutical and clinical interest of triiodothyronine (T3 ) thyroid hormone, an effective D/L-T3 enantiomer separation was performed on a crown ether-based chiral stationary phase by LC-MS/MS. In optimal analytical condition and selected reaction monitoring mode, the two enantiomers of T3 were baseline separated within 10min. The limit of detection and limit of quantitation were found to be 0.05 and 0.10ng/μl; 0.20 and 0.50 ng/μl for D- and L-T3 , respectively. During validation, this method proved to be feasible, accurate as well as enantioselective and sensitive for the resolution of T3 enantiomers. For commercial D- and L-T3 chemicals, the enantiomeric impurities as the other enantiomer were 0.11% and 4.61%. On the other hand, the impurity as D-T3 for commercial pharmaceutical products (liothyronine sodium tablets, two suppliers) was 0.68% and 6.57%.

Effect of thyroid hormones administration on urinary endogenous steroid profile of the athlete biological passport.

This work focused on the possible alterations of the markers of the steroidal module of the athlete biological passport, considering samples of athletes declaring and not-declaring the supplementation of thyroid hormones (TH) in the Doping Control Form (DCF). Concentrations of 5α-androstane-3α,17β-diol (5α-Adiol), 5β-androstane-3α,17β-diol (5β-Adiol), testosterone (T), androsterone (A), etiocholanolone (Etio), epitestosterone (E), pregnanediol (PD), dehydroepiandrosterone (DHEA), and 11β-hydroxy-androsterone (OHA) were calculated using internal standards and external calibration by gas chromatography-tandem mass spectrometry. Also, ratios between the above biomarkers were also estimated. The data set was composed of samples from females and males declaring and not-declaring TH supplementation in the DCF. To corroborate these observations, a controlled urinary excretion study was carried out with multiple doses of sodium liothyronine (T3). Female data showed significant differences for the concentrations of 5α-Adiol, A, DHEA, E, OHA, and T and the ratio A/Etio between FD and FND groups, whereas the male groups only showed significant differences in OHA concentration. In both cases, males and females declaring the consumption of levothyroxine showed narrower data distribution and diminished percentiles from 17% to 67% with respect to the not-declaring corresponding groups (p< 0.05). Concentrations of 5α-metabolites showed a higher depression for the FND, and both FD and MD groups showed a peculiar behavior for the PD concentrations. The controlled study agreed with the observations, mainly for the female group with significant differences for concentrations of E, Etio, 5α-Adiol, and 5β-Adiol after TH administration. The interpretation of the steroid markers of the ABP should consider TH administrations.

High Performance Liquid Chromatography Method Development and Validation for Separation of Liothyronine Sodium Related Substances Using a Quality by Design Approach

The application of the Quality by Design (QbD) principles in developing a novel high performance liquid chromatography (HPLC) method for the analysis of liothyronine sodium related substances for finished product using Fusion QbD® software is explored. The effect of various chromatographic parameters including, column stationary phase, initial hold time and gradient time on separations were systematically investigated. Results show that optimal separations of these compounds in a standard solution can be achieved using a X Bridge C18 column (150 mm × 4.6 μm, 5m), maintained at sample temperature 15°C by using pH 2.0 buffer solution as mobile phase-A and methanol as mobile phase-B with a flow rate of 1.0 ml/min at 225 nm of detection and a gradient time of 38 minutes. The injection volume is 200 μl. Pre-validation studies of the method were performed and all the parameters met the acceptance criteria. The results are demonstrated that optimized method is selective, linear, precise, repeatable and accurate.

Detection and Characterization of an Unknown Impurity in Levothyroxine Sodium Tablets by UHPLC, LC/MS, MS/MS and MS/MS/MS

Impurities in the active ingredient of a drug are very important for the quality and reliability of the finished product. Therefore, the identification of these impurities constitutes reliability for patients using the drug. Levothyroxine sodium has known but also unknown impurities. Liothyronine sodium is known as the most common impurity of Levothyroxine sodium. Thought to be more active than levothyroxine and with a rapid (few hours) onset and short duration of action, liothyronine sodium is used in the treatment of hypothyroidism, particularly in the cases of hypothyroid coma. In our study, besides known impurities of Levothyroxine sodium, some unknown impurities were observed in samples that were exposed to heat. In these unknown impurities, the most important one that increases the fastest with the temperature that will affect the quality of the product is the impurity at RRT 0.6, according to our impurity method which was developed in-house. The impurity that increases with temperature has been defined by various identification studies, including MS/MS analysis, LC-UV detection etc. The degradation product, which was initially characterized by its retention time as RRT 0.6, was subsequently identified to be a lactose adduct of Levothyroxine API, which is formed by a Maillard reaction between Levothyroxine and lactose.

A Preclinical Safety Study of Thyroid Hormone Instilled into the Lungs of Healthy Rats-an Investigational Therapy for ARDS.

Acute respiratory distress syndrome (ARDS) is a severe, life-threatening form of respiratory failure characterized by pulmonary edema, inflammation, and hypoxemia due to reduced alveolar fluid clearance (AFC). Alveolar fluid clearance is required for recovery and effective gas exchange, and higher rates of AFC are associated with reduced mortality. Thyroid hormones play multiple roles in lung function, and L-3,5,3'-triiodothyronine (T3) has multiple effects on lung alveolar type II cells. T3 enhances AFC in normal adult rat lungs when administered intramuscularly and in normal or hypoxia-injured lungs when given intratracheally. The safety of a commercially available formulation of liothyronine sodium (synthetic T3) administered intratracheally was assessed in an Investigational New Drug Application-enabling toxicology study in healthy rats. Instillation of the commercial formulation of T3 without modification rapidly caused tracheal injury and often mortality. Intratracheal instillation of T3 that was reformulated and brought to a neutral pH at the maximum feasible dose of 2.73 µg T3 in 300 µl for 5 consecutive days had no clinically relevant T3-related adverse clinical, histopathologic, or clinical pathology findings. There were no unscheduled deaths that could be attributed to the reformulated T3 or control articles, no differences in the lung weights, and no macroscopic or microscopic findings considered to be related to treatment with T3. This preclinical safety study has paved the way for a phase I/II study to determine the safety and tolerability of a T3 formulation delivered into the lungs of patients with ARDS, including coronavirus disease 2019-associated ARDS, and to measure the effect on extravascular lung water in these patients. SIGNIFICANCE STATEMENT: There is growing interest in treating lung disease with thyroid hormone [triiodothyronine (T3)] in pulmonary edema and acute respiratory distress syndrome (ARDS). However, there is not any published experience on the impact of direct administration of T3 into the lung. An essential step is to determine the safety of multiple doses of T3 administered in a relevant animal species. This study enabled Food and Drug Administration approval of a phase I/II clinical trial of T3 instillation in patients with ARDS, including coronavirus disease 2019-associated ARDS (T3-ARDS ClinicalTrials.gov Identifier NCT04115514).

Liothyronine abuse

Liothyronine abuse

復温時のショックにリオチロニンナトリウム（L–T3）が奏効した粘液水腫性昏睡の1例(Myxedema coma with shock during rewarming period managed effectively with liothyronine sodium: a case report)

要旨粘液水腫性昏睡は緊急度が高い救急内分泌疾患である。低体温症の合併頻度が高いにもかかわらず，復温方法には一定の見解が得られておらず，また，ホルモン治療には議論の余地が残されている。60歳代の女性が，寒い冬の夜に低体温症を来し，当センターへ救急搬送となった。来院時は，心拍数51/分，血圧125/80mmHg，呼吸数15/分，Glasgow coma scale E3V4M5，体温30.4℃であった。血液検査で遊離トリヨードサイロニン（FT3）と遊離サイロキシン（FT4）が低下しCO2ナルコーシスを伴っていたため，甲状腺機能低下症および粘液水腫性昏睡と診断した。中心静脈留置型経皮的体温調節装置システムを用いて復温したところショックへと状態が悪化し，人工呼吸管理や心血管作動薬の調節を必要とした。搬入5時間後，および7時間半後にレボチロキシンナトリウム（L–T4）を2度にわたり経管投与したが効果に乏しく，搬入19時間後にリオチロニンナトリウム（L–T3）を投与したところ循環動態が改善した。第10病日まで心血管作動薬の継続が必要であったが，第26病日に人工呼吸器から離脱できた。ホルモンの内服調節などを行い，第54病日に自宅退院した。迅速にL–T3が利用でき，先行投与または復温と同時投与できれば，ショックを避け得る，もしくは軽減でき得る可能性が，本症例経験より示唆された。

Liothyronine abuse

Liothyronine abuse

Diagnosis and treatment of intra-abdominal infection complicated with hypothyroidism

Intra-abdominal infection complicated with hypothyroidism is very common. It mostly featured decreased T3, with or without decreased T4, and without elevated thyroid stimulating hormone(TSH). This particular type of hypothyroidism was called "low T3 syndrome" or "thyroid illness syndrome", and is called "non-thyroid illness syndrome" increasingly in recent years. Its pathogenesis has not been fully understood, and probably is associated with abnormality of hypothalamic-pituitary-thyroid axis, disorder of peripheral thyroid hormone metabolism, change in thyroid hormone binding protein, regulation of triiodothyronine receptors, effect of cytokines, and lack of trace element selenium. Intra-abdominal infection complicated with hypothyroidism should be differentiated from primary hypothyroidism, which may be one cause of mental depression, insufficient anabolism, and poor tissue healing. Therefore, the changes of T3 and T4 levels should be actively monitored in patients with severe or prolonged intra-abdominal infection. Whether treatment is needed for intra-abdominal infection complicated with hypothyroidism remains controversial. T3 replacement therapy may improve prognosis. When low T3 syndrome presents as a disease-mediated hypothyroidism, we recommend the use of levothyroxine(L-T4) or liothyronine (L-T3) treatment to improve the prognosis of critical patients. Enteral nutrition can improve hypothyroidism and has good efficacy for enterocutaneous fistula patients with intra-abdominal infection.

Was NHS overcharged for liothyronine?

Was NHS overcharged for liothyronine?

Impurity profiling of liothyronine sodium by means of reversed phase HPLC, high resolution mass spectrometry, on-line H/D exchange and UV/Vis absorption

For the first time, a comprehensive investigation of the impurity profile of the synthetic thyroid API (active pharmaceutical ingredient) liothyronine sodium (LT3Na) was performed by using reversed phase HPLC and advanced structural elucidation techniques including high resolution tandem mass spectrometry (HRMS/MS) and on-line hydrogen-deuterium (H/D) exchange. Overall, 39 compounds were characterized and 25 of these related substances were previously unknown to literature. The impurity classification system recently developed for the closely related API levothyroxine sodium (LT4Na) could be applied to the newly characterized liothyronine sodium impurities resulting in a wholistic thyroid API impurity classification system. Furthermore, the mass-spectrometric CID-fragmentation of specific related substances was discussed and rationalized by detailed fragmentation pathways. Moreover, the UV/Vis absorption characteristics of the API and selected impurities were investigated to corroborate chemical structure assignments derived from MS data.

Replacement therapy of hypothyroidism: Whether the use of levothyroxine is adequate?

Hypothyroidism is a common endocrine disease. Its treatment depends on thyroid hormone replacement therapy. Currently, levothyroxine(L-T4)is the preparation recommended by many guidelines. However, there are some L-T4-treated patients with normal TSH levels and persistent non-specific symptoms and discomforts. Therefore, combination therapy with L-T4and liothyronine(L-T3)has been considered as an alternative option for hypothyroidism. However, more prospective studies are needed to provide evidence-based effects for this kind of regimen. (Chin J Endocrinol Metab, 2015, 31: 296-299) Key words: Hypothyroidism; Levothyroxine; Combination therapy

Anesthetic experience in a clinically euthyroid patient with hyperthyroxinemia and suspected impairment of T4 to T3 conversion: a case report.

We report an anesthetic experience in a clinically euthyroid patient with hyperthyroxinemia (elevated free thyroxine, fT4 and normal 3, 5, 3'-L-triiodothyronine, T3) and suspected impairment of conversion from T4 to T3. Despite marked hyperthyroxinemia, this patient's perioperative hemodynamic profile was suspected to be the result of hypothyroidism, in reference to the presence of T4 to T3 conversion disorder. We suspected that pretreatment with antithyroid medication before surgery, surgical stress and anesthesia may have contributed to the decreased T3 level after surgery. She was treated with liothyronine sodium (T3) after surgery which restored her hemodynamic profile to normal. Anesthesiologists may be aware of potential risk and caveats of inducing hypothyroidism in patients with euthyroid hyperthyroxinemia and T4 to T3 conversion impairment.

Resistant Hypothyroidism? Consider Liothyronine

Resistant Hypothyroidism? Consider Liothyronine

Hypothyroidism after 131I‐monoclonal antibody treatment of neuroblastoma

To determine the prevalence of and risk factors for primary hypothyroidism following treatment with a radiolabeled monoclonal antibody ((131)I-3F8) in children with neuroblastoma. In the current study, we assessed thyroid function in 51 neuroblastoma patients who survived for > or =3 months after treatment with (131)I-3F8 (a murine IgG3 monoclonal antibody that reacts with the ganglioside GD2) at 4 mCi/kg/day x 5 days (total 20 mCi/kg). Prior therapy in all subjects included dose-intensive chemotherapy; 13 subjects also received external beam radiation to the neck. Oral iodide and liothyronine sodium (T3) were administered for protection of the thyroid gland. Thirty-two of 51 subjects (63%) developed hormonal evidence of primary hypothyroidism. The median time to hypothyroidism after treatment with (131)I-3F8 was 6.4 months. The probability of developing hypothyroidism was 56% at 2 years following treatment with (131)I-3F8. There was evidence for an association between thyroidal uptake of (131)I and development of hypothyroidism (hazard ratio 1.83, 95% confidence interval 0.91-3.30; P = 0.09). We conclude that hormonal evidence of primary hypothyroidism developed in a majority of subjects treated with (131)I-3F8, despite pretreatment with oral iodide plus liothyronine sodium. Alternative strategies for thyroid gland protection are needed.

Comparative bioavailability of different formulations of levothyroxine and liothyronine in healthy volunteers

To evaluate the relative bioavailability of T4 sodium and liothyronine sodium (T3), administered in single doses as oral solution (drops) and tablet forms, according to two separate study protocols. Twenty-four healthy, male volunteers were included in both studies. Two test drugs containing T4 or T3 (T4-Ibsa and T3-Ibsa, respectively) were compared to two reference drugs, ie Eutirox 100 and Ti-tre tablets, respectively. A single oral dose of 100 microg (1 ml or 1 tablet) of T4 and 20 microg (1 ml or 1 tablet) of T3 were administered with an open, randomized, crossover design. T4 and T3 serum concentrations were determined by a validated immunoassay in electro-chemo-luminescence method. Study 1: after administration of T4-Ibsa oral solution, Cmax was 14.26+/-0.61 microg/dl, AUC0-t was 282.70 +/-14.29 microg/dl/h, Tmax was 2.71+/-0.25 h. After administration of Eutirox 100 tablets, Cmax was 14.34+/-0.59 microg/dl, AUC0-t was 279.42+/-9.59 microg/dl/h and Tmax was 2.65+/-0.23 h. The 90% confidence interval ratios between test/reference drugs were 1.01 for AUC0-t and 0.99 for Cmax. Study 2: after administration of T3-Ibsa oral solution, Cmax was 3.19+/-0.25 ng/ml, AUC0-t was 44.79+/-2.15 ng/ml/h and Tmax was 2.31+/-0.25 h. After administration of Ti-tre tablets, Cmax was 3.16+/-0.23 ng/ml, AUC0-t was 45.19+/-2.19 ng/ml/h and Tmax was 2.44+/-0.34 h. The 90% confidence interval ratios between test /reference drugs were 0.99 for AUC0-t and 1.01 for Cmax. The bioavailability of the two oral solutions (T4-Ibsa and T3-Ibsa oral solutions) and the corresponding tablet forms (Eutirox 100 and Ti-tre tablets) were confirmed and they can be considered bioequivalent and therapeutically interchangeable.

L-Thyroxine plus Liothyronine in Hypothyroidism

<scp>l</scp>-Thyroxine plus Liothyronine in Hypothyroidism