RESUMEN
Background: Thyroid hormone (TH) appears to have a reparative action on the postinfarcted myocardium. This novel action was recently tested in a pilot, randomized, double-blind, placebo-controlled trial (ThyRepair). The present study performed a post-hoc analysis of data from the ThyRepair study to provide further insights into the novel actions of TH on the human postischemic myocardium. Methods: Data from 41 patients participating in the ThyRepair study (n = 20 placebo and n = 21 LT3) were included in the analysis. LT3 treatment started after stenting and continued intravenously for 48 h. All patients had cardiac magnetic resonance (CMR) at hospital discharge; left ventricular (LV) ejection fraction (LVEF%), LV end-diastolic volume index (LVEDVi; mL/m2), LV end-systolic volume index (LVESVi; mL/m2), infarct volume (IV), left ventricular mass index (LVMi) as edema index, and microvascular obstruction (MVO) were assessed. Patients were divided into two groups based on the median value of the IV: patients with IV ≤ 20% of the LV (group A) and patients with IV > 20% (group B). CMR measurements at discharge are expressed as mean ± SD. Results: In group A, the placebo and T3-treated groups had similar LVEF% (56.8 ± 10.2 vs. 52.2 ± 10.5), LVEDVi (90.9 ± 19.8 vs. 92.8 ± 14.5), and LVESVi (40.8 ± 18.2 vs. 44.9 ± 14.1) at discharge. In group B, LVEDVi and LVESVi were 112 ± 23.8 and 68.3 ± 21.5 for placebo vs. 91.8 ± 18.6 and 49.0 ± 14.0 for the T3-treated group, respectively, p < 0.05. LVEF% was significantly increased in the T3-treated group vs. placebo, 47.3 ± 6.5 vs. 39.9 ± 8.7, p < 0.05. In group B, CMR LVMi was lower in T3-treated patients vs. placebo but did not reach statistical significance (p = 0.1). MVO was 1.95 ± 2.2 in placebo vs. 0.84 ± 0.9 in the LT3-treated group, p = 0.15. Conclusion: The present study suggests that acute LT3 treatment may exert more favorable effects on the recovery of cardiac function in patients with large infarct size. Furthermore, it signals a potential effect of LT3 on myocardial edema and microvascular obstruction. These novel findings merit further investigation in large trials.
Asunto(s)
Función Ventricular Izquierda , Humanos , Masculino , Femenino , Método Doble Ciego , Persona de Mediana Edad , Anciano , Función Ventricular Izquierda/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Hormonas Tiroideas/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Proyectos Piloto , Triyodotironina/uso terapéutico , Triyodotironina/administración & dosificación , Triyodotironina/sangreRESUMEN
AIM: The hypothesis of this study is to determine the effects of intracerebroventricular (icv) prokineticin 2 infusion on food consumption and body weight and to elucidate whether it has effects on energy expenditure via the hypothalamus-pituitary-thyroid (HPT) axis in adipose tissue. MATERIAL AND METHODS: A total of 40 rats were used in the study and 4 groups were established: Control, Sham, Prokineticin 1.5 and Prokineticin 4.5 (n=10). Except for the Control group, rats were treated intracerebroventricularly via osmotic minipumps, the Sham group was infused with aCSF (vehicle), and the Prokineticin 1.5 and Prokineticin 4.5 groups were infused with 1.5 nMol and 4.5 nMol prokineticin 2, respectively. Food and water consumption and body weight were monitored during 7-day infusion in all groups. At the end of the infusion, the rats were decapitated and serum TSH, fT4 and fT3 levels were determined by ELISA. In addition, PGC-1α and UCP1 gene expression levels in white adipose tissue (WAT) and brown adipose tissue (BAT), TRH from rat hypothalamic tissue were determined by real-time PCR. RESULTS: Icv prokineticin 2 (4.5 nMol) infusion had no effect on water consumption but reduced daily food consumption and body weight (p<0.05). Icv prokineticin 2 (4.5 nMol) infusion significantly increased serum TSH, fT4 and fT3 levels when compared to Control and Sham groups (p<0.05). Also, icv prokineticin 2 (4.5 nMol) infusion increased the expression of TRH in the hypothalamus tissue and expression of PGC-1α UCP1 in the WAT and BAT (p<0.05). CONCLUSION: Icv prokineticin 2 (4.5 nMol) infusion may suppress food consumption via its receptors in the hypothalamus and reduce body weight by stimulating energy expenditure and thermogenesis in adipose tissue through the HPT axis.
Asunto(s)
Peso Corporal , Ingestión de Alimentos , Metabolismo Energético , Hormonas Gastrointestinales , Infusiones Intraventriculares , Glándula Tiroides , Animales , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Masculino , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Ratas , Hormonas Gastrointestinales/metabolismo , Hormonas Gastrointestinales/administración & dosificación , Proteína Desacopladora 1/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/administración & dosificación , Tirotropina/sangre , Tirotropina/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tiroxina/sangre , Tiroxina/administración & dosificación , Ingestión de Líquidos/efectos de los fármacos , Triyodotironina/administración & dosificación , Triyodotironina/sangre , Triyodotironina/farmacología , Ratas Wistar , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacosRESUMEN
Therapy with thyroid hormones normally is restricted to substitution therapy of patients with primary or secondary hypothyroidism. Typically, thyroid hormones are given orally. There are few indications for intravenous use of thyroid hormones. Indications for parenteral application are insufficient resorption of oral medications due to alterations of the gastrointestinal tract, partial or total loss of consciousness, sedation in the intensive care unit or shock. In almost all cases, levothyroxine is the therapy of choice including congenital hypothyroidism. In preterm infants with an altered thyroid hormone status, studies with thyroid hormones including intravenous liothyronine showed a normalisation of T3 levels and in some cases an amelioration of parameters of ventilation. A benefit for mortality or later morbidity could not be seen. Effects on neurological improvements later in life are under discussion. Decreased thyroid hormone levels are often found after cardiac surgery in infants and adults. Intravenous therapy with thyroid hormones improves the cardiac index, but in all other parameters investigated, no substantial effect on morbidity and mortality could be demonstrated. Oral liothyronine therapy in these situations was equivalent to an intravenous route of application. In myxoedema coma, intravenous levothyroxine is given for 3 to 10 days until the patient can take oral medication and normal resorption in the gastrointestinal tract is achieved by restoring at least peripheral euthyroidism. Intravenous levothyroxine is the standard in treating patients with myxoedema coma. A protective effect on the heart of i.v. levothyroxine in brain-dead organ donors may be possible.
Asunto(s)
Administración Intravenosa , Tiroxina , Triyodotironina , Humanos , Tiroxina/uso terapéutico , Tiroxina/administración & dosificación , Triyodotironina/uso terapéutico , Triyodotironina/administración & dosificaciónRESUMEN
Objective: A personalized simulation tool, p-THYROSIM, was developed (1) to better optimize replacement LT4 and LT4+LT3 dosing for hypothyroid patients, based on individual hormone levels, BMIs, and gender; and (2) to better understand how gender and BMI impact thyroid dynamical regulation over time in these patients. Methods: p-THYROSIM was developed by (1) modifying and refining THYROSIM, an established physiologically based mechanistic model of the system regulating serum T3, T4, and TSH level dynamics; (2) incorporating sex and BMI of individual patients into the model; and (3) quantifying it with 3 experimental datasets and validating it with a fourth containing data from distinct male and female patients across a wide range of BMIs. For validation, we compared our optimized predictions with previously published results on optimized LT4 monotherapies. We also optimized combination T3+T4 dosing and computed unmeasured residual thyroid function (RTF) across a wide range of BMIs from male and female patient data. Results: Compared with 3 other dosing methods, the accuracy of p-THYROSIM optimized dosages for LT4 monotherapy was better overall (53% vs. 44%, 43%, and 38%) and for extreme BMI patients (63% vs. ~51% low BMI, 48% vs. ~36% and 22% for high BMI). Optimal dosing for combination LT4+LT3 therapy and unmeasured RTFs was predictively computed with p-THYROSIM for male and female patients in low, normal, and high BMI ranges, yielding daily T3 doses of 5 to 7.5 µg of LT3 combined with 62.5-100 µg of LT4 for women or 75-125 µg of LT4 for men. Also, graphs of steady-state serum T3, T4, and TSH concentrations vs. RTF (range 0%-50%) for untreated patients showed that neither BMI nor gender had any effect on RTF predictions for our patient cohort data. Notably, the graphs provide a means for estimating unmeasurable RTFs for individual patients from their hormone measurements before treatment. Conclusions: p-THYROSIM can provide accurate monotherapies for male and female hypothyroid patients, personalized with their BMIs. Where combination therapy is warranted, our results predict that not much LT3 is needed in addition to LT4 to restore euthyroid levels, suggesting opportunities for further research exploring combination therapy with lower T3 doses and slow-releasing T3 formulations.
Asunto(s)
Hipotiroidismo , Modelación Específica para el Paciente , Tiroxina , Triyodotironina , Índice de Masa Corporal , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Masculino , Hormonas Tiroideas/administración & dosificación , Hormonas Tiroideas/sangre , Hormonas Tiroideas/farmacología , Hormonas Tiroideas/uso terapéutico , Tirotropina/sangre , Tiroxina/administración & dosificación , Tiroxina/sangre , Tiroxina/farmacología , Tiroxina/uso terapéutico , Triyodotironina/administración & dosificación , Triyodotironina/sangre , Triyodotironina/farmacología , Triyodotironina/uso terapéuticoRESUMEN
CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.
Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X/tratamiento farmacológico , Transportadores de Ácidos Monocarboxílicos/deficiencia , Hipotonía Muscular/tratamiento farmacológico , Atrofia Muscular/tratamiento farmacológico , Simportadores/deficiencia , Triyodotironina/análogos & derivados , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/sangre , Discapacidad Intelectual Ligada al Cromosoma X/genética , Persona de Mediana Edad , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonía Muscular/sangre , Hipotonía Muscular/genética , Atrofia Muscular/sangre , Atrofia Muscular/genética , Mutación , Estudios Retrospectivos , Simportadores/genética , Resultado del Tratamiento , Triyodotironina/administración & dosificación , Triyodotironina/efectos adversos , Triyodotironina/sangre , Adulto JovenRESUMEN
OBJECTIVES: Myxedema crisis, a fatal complication of severe hypothyroidism, is extremely rare in children and treatment guidelines are lacking. Since availability of intravenous levothyroxine is limited in resource poor settings, myxedema crisis can be treated with oral levothyroxine and/or oral liothyronine (if necessary), in the absence of cardiac risk factors, thus hastening the recovery and significantly decreasing the associated morbidity and mortality. In the background of untreated hypothyroidism, a possible association of ovarian hyperstimulation syndrome (OHSS) and reactive pituitary hyperplasia should be kept in mind, thus preventing unnecessary interventions. CASE PRESENTATION: A 13-year-old girl child with Down syndrome, presented with myxedema crisis, as initial presentation of untreated hypothyroidism. CONCLUSIONS: Annual screening, timely diagnosis of hypothyroidism, and early initiation of thyroid hormone supplementation will prevent associated physical and neurocognitive morbidity in children, especially those with Down syndrome. Importance of oral liothyronine supplementation in myxedema crisis, has been highlighted in this case report.
Asunto(s)
Síndrome de Down/complicaciones , Mixedema/tratamiento farmacológico , Síndrome de Hiperestimulación Ovárica/etiología , Adolescente , Femenino , Humanos , Hipotiroidismo/complicaciones , Mixedema/etiología , Tiroxina/administración & dosificación , Triyodotironina/administración & dosificaciónRESUMEN
Background: L-triiodothyronine (LT3) has been increasingly used in combination with levothyroxine in the treatment of hypothyroidism. A metal coordinated form of LT3, known as poly-zinc-liothyronine (PZL), avoided in rats the typical triiodothyronine (T3) peak seen after oral administration of LT3. Objectives: To evaluate in healthy volunteers (i) the pharmacokinetics (PK) of PZL-derived T3 after a single dose, (ii) the pharmacodynamics of PZL-derived T3, (iii) incidence of adverse events, and (iv) exploratory analysis of the sleep patterns after LT3, PZL, or placebo (PB) administration. Methods: Twelve healthy volunteers 18-50 years of age were recruited for a Phase 1, double-blind, randomized, single-dose PB-controlled, crossover study to compare PZL against LT3 or PB. Subjects were admitted three separate times to receive a randomly assigned capsule containing PB, 50 µg LT3, or 50 µg PZL, and were observed for 48 hours. A 2-week washout period separated each admission. Results: LT3-derived serum T3 levels exhibited the expected profile, with a Tmax at 2 hours and return to basal levels by 24-36 hours. PZL-derived serum T3 levels exhibited â¼30% lower Cmax that was 1 hour delayed and extended into a plateau that lasted up to 6 hours. This was followed by a lower but much longer plateau; by 24 hours serum T3 levels still exceeded ½ of Cmax. Thyrotropin levels were similarly reduced in both groups. Conclusion: PZL possesses the necessary properties to achieve a much improved T3 PK. PZL is on track to provide hypothyroid patients with stable levels of serum T3.
Asunto(s)
Triyodotironina/administración & dosificación , Triyodotironina/farmacocinética , Zinc/administración & dosificación , Adolescente , Adulto , Método Doble Ciego , Quimioterapia Combinada , Femenino , Terapia de Reemplazo de Hormonas , Humanos , Hipotiroidismo/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Cadmium (Cd) single and repeated exposure produces cognitive dysfunctions. Basal forebrain cholinergic neurons (BFCN) regulate cognitive functions. BFCN loss or cholinergic neurotransmission dysfunction leads to cognitive disabilities. Thyroid hormones (THs) maintain BFCN viability and functions, and Cd disrupts their levels. However, Cd-induced BFCN damages and THs disruption involvement was not studied. To research this we treated male Wistar rats intraperitoneally with Cd once (1 mg/kg) or repetitively for 28 days (0.1 mg/kg) with/without triiodothyronine (T3, 40 µg/kg/day). Cd increased thyroid-stimulating-hormone (TSH) and decreased T3 and tetraiodothyronine (T4). Cd altered cholinergic transmission and induced a more pronounced neurodegeneration on BFCN, mediated partially by THs reduction. Additionally, Cd antagonized muscarinic 1 receptor (M1R), overexpressed acetylcholinesterase S variant (AChE-S), downregulated AChE-R, M2R, M3R and M4R, and reduced AChE and choline acetyltransferase activities through THs disruption. These results may assist to discover cadmium mechanisms that induce cognitive disabilities, revealing a new possible therapeutic tool.
Asunto(s)
Prosencéfalo Basal/efectos de los fármacos , Cloruro de Cadmio/toxicidad , Neuronas Colinérgicas/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Masculino , Ratas Wistar , Receptor Muscarínico M1/efectos de los fármacos , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/administración & dosificación , Triyodotironina/sangreRESUMEN
Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on T-tubule (TT) structures, Ca2+ mobilization and contractility, and clustering of dyadic proteins. Thyroid hormone (TH) deficiency was induced in adult female rats by propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU or triiodo-L-thyronine (T3; 10 µg/kg/d) treatment for 2 weeks (PTU + T3). After in vivo echocardiographic and hemodynamic recordings, cardiomyocytes (CM) were isolated to record Ca2+ transients and contractility. TT organization was assessed by confocal microscopy, and STORM images were captured to measure ryanodine receptor (RyR2) cluster number and size, and L-type Ca2+ channel (LTCC, Cav1.2) co-localization. Expressed genes including two integral TT proteins, junctophilin-2 (Jph-2) and bridging integrator-1 (BIN1), were analyzed in left ventricular (LV) tissues and cultured CM using qPCR and RNA sequencing. The T3 dosage used normalized serum T3, and reversed adverse effects of TH deficiency on in vivo measures of cardiac function. Recordings of isolated CM indicated that T3 increased rates of Ca2+ release and re-uptake, resulting in increased velocities of sarcomere shortening and re-lengthening. TT periodicity was significantly decreased, with reduced transverse tubules but increased longitudinal tubules in TH-deficient CMs and LV tissue, and these structures were normalized by T3 treatment. Analysis of STORM data of PTU myocytes showed decreased RyR2 cluster numbers and RyR localizations within each cluster without significant changes in Cav1.2 localizations within RyR clusters. T3 treatment normalized RyR2 cluster size and number. qPCR and RNAseq analyses of LV and cultured CM showed that Jph2 expression was T3-responsive, and its increase with treatment may explain improved TT organization and RyR-LTCC coupling.
Asunto(s)
Señalización del Calcio/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Hipotiroidismo/tratamiento farmacológico , Triyodotironina/administración & dosificación , Animales , Calcio/metabolismo , Canales de Calcio Tipo L/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Hipotiroidismo/sangre , Hipotiroidismo/inducido químicamente , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Miocitos Cardíacos/metabolismo , Ratas , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Sarcolema/metabolismo , Sarcómeros/metabolismo , Resultado del Tratamiento , Triyodotironina/sangre , Función Ventricular/efectos de los fármacosRESUMEN
INTRODUCTION: Studies comparing levothyroxine (LT4) therapy with LT4â +â liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients. METHODOLOGY: Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4â +â LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect. RESULTS: Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component). CONCLUSIONS: As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4â +â T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4â +â LT3 or DTE.
Asunto(s)
Hipotiroidismo/tratamiento farmacológico , Glándula Tiroides/química , Tiroxina/administración & dosificación , Extractos de Tejidos/administración & dosificación , Triyodotironina/administración & dosificación , Adulto , Anciano , Estudios Cruzados , Desecación , Método Doble Ciego , Femenino , Terapia de Reemplazo de Hormonas/métodos , Humanos , Hipotiroidismo/fisiopatología , Masculino , Persona de Mediana Edad , Placebos , Estudios Prospectivos , Calidad de Vida , Encuestas y Cuestionarios , Resultado del Tratamiento , Triyodotironina/sangreRESUMEN
PURPOSE: The standard treatment of hypothyroidism is levothyroxine (LT4), which is available as tablets or soft-gel capsules in Denmark. This study aimed to investigate Danish endocrinologists' use of thyroid hormones in hypothyroid and euthyroid patients. METHODS: An e-mail with an invitation to participate in an online survey investigating practices about substitution with thyroid hormones was sent to all members of the Danish Endocrine Society (DES). RESULTS: Out of 488 eligible DES members, a total of 152 (31.2%) respondents were included in the analysis. The majority (94.1%) of responding DES members use LT4 as the treatment of choice. Other treatment options for hypothyroidism are also used, as 58.6% prescribe combination therapy with liothyronine (LT3) + LT4 in their clinical practice. LT4 + LT3 combination is preferred in patients with persistent symptoms of hypothyroidism despite biochemical euthyroidism on LT4 treatment. Over half of the respondents answered that thyroid hormone therapy is never indicated for euthyroid patients, but 42.1% will consider it for euthyroid infertile women with high antibody levels. In various conditions that could interfere with the absorption of LT4, most responding Danish endocrinologists prefer tablets and do not expect a significant difference when switching from one type of tablet formulation to another. CONCLUSION: The treatment of choice for hypothyroidism is LT4. Combination therapy with LT4 + LT3 is considered for patients with persistent symptoms. Even in the presence of conditions affecting bioavailability, responding Danish endocrinologists prefer LT4 tablets rather than newer LT4 formulations, such as soft-gel capsules.
Asunto(s)
Terapia de Reemplazo de Hormonas , Hipotiroidismo , Pautas de la Práctica en Medicina/estadística & datos numéricos , Tiroxina/administración & dosificación , Triyodotironina/administración & dosificación , Dinamarca/epidemiología , Composición de Medicamentos , Quimioterapia Combinada/métodos , Quimioterapia Combinada/estadística & datos numéricos , Endocrinólogos/estadística & datos numéricos , Terapia de Reemplazo de Hormonas/métodos , Terapia de Reemplazo de Hormonas/estadística & datos numéricos , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/diagnóstico , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/epidemiología , Selección de Paciente , Encuestas y Cuestionarios , Evaluación de Síntomas/métodos , Hormonas Tiroideas/administración & dosificaciónRESUMEN
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).
Asunto(s)
Instilación de Medicamentos , Pulmón/efectos de los fármacos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Triyodotironina/efectos adversos , Animales , Evaluación Preclínica de Medicamentos , Femenino , Intubación Intratraqueal/efectos adversos , Intubación Intratraqueal/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Triyodotironina/administración & dosificación , Triyodotironina/uso terapéuticoRESUMEN
Thyroxine (T4) promotes cell proliferation and tumor growth in prostate cancer models, but it is unknown if the increase in the triiodothyronine (T3)/T4 ratio could attenuate prostate tumor development. We assessed T3 effects on thyroid response, histology, proliferation, and apoptosis in the prostate of wild-type (WT) and TRAMP (transgenic adenocarcinoma of the mouse prostate) mice. Physiological doses of T3 were administered in the drinking water (2.5, 5 and 15 µg/100 g body weight) for 6 weeks. None of the doses modified the body weight or serum levels of testosterone, but all of them reduced serum T4 levels by 50%, and the highest dose increased the T3/T4 ratio in TRAMP. In WT, the highest dose of T3 decreased cyclin D1 levels (immunohistochemistry) but did not modify prostate weight or alter the epithelial morphology. In TRAMP, this dose reduced tumor growth by antiproliferative mechanisms independent of apoptosis, but it did not modify the intraluminal or fibromuscular invasion of tumors. In vitro, in the LNCaP prostate cancer cell line, we found that both T3 and T4 increased the number of viable cells (Trypan blue assay), and only T4 response was fully blocked in the presence of an integrin-binding inhibitor peptide (RGD, arginine-glycine-aspartate). In summary, our data show that the prostate was highly sensitive to physiological T3 doses and suggest that in vivo, an increase in the T3/T4 ratio could be associated with the reduced weight of prostate tumors. Longitudinal studies are required to understand the role of thyroid hormones in prostate cancer progression.
Asunto(s)
Adenocarcinoma/sangre , Peso Corporal/fisiología , Neoplasias de la Próstata/sangre , Tiroxina/sangre , Triyodotironina/sangre , Adenocarcinoma/patología , Animales , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratones , Neoplasias de la Próstata/patología , Testosterona/sangre , Triyodotironina/administración & dosificaciónRESUMEN
BACKGROUND: Low dose naltrexone (LDN) is reported to have beneficial effects in several autoimmune diseases. The purpose of this study was to examine whether starting LDN was followed by changes in the dispensing of thyroid hormones to patients with hypothyroidism. METHODS: We performed a quasi-experimental before-after study based on the Norwegian Prescription Database. Study participants were identified by using reimbursement codes for hypothyroidism. Cumulative dispensed Defined Daily Doses and the number of users of triiodothyronine (T3) and levothyroxine (LT4) 1 year before and after the first LDN prescription was compared in three groups based on LDN exposure. RESULTS: We identified 898 patients that met the inclusion criteria. There was no association between starting LDN and the subsequent dispensing of thyroid hormones. If anything, there was a tendency towards increasing LT4 consumption with increasing LDN exposure. CONCLUSION: The results of this study do not support claims of efficacy of LDN in hypothyroidism.
Asunto(s)
Hipotiroidismo/tratamiento farmacológico , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Hormonas Tiroideas/administración & dosificación , Estudios Controlados Antes y Después , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipotiroidismo/metabolismo , Hipotiroidismo/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tiroxina/administración & dosificación , Triyodotironina/administración & dosificaciónRESUMEN
Severe caloric-restriction compromises thyroid hormone (TH) status, apparently to save energy and proteins for enduring stress stimulus. However, a persistent decrease in TH levels may compromise heart function. We hypothesized that supplementation of low dose active TH or targeting hypoxia-inducible factor-1-alpha, HIF-1α (a strong activator of deiodinase enzyme that degrades peripheral active THs) will prevent deterioration of cardiac performance. Adult mice were subjected to acute fasting based on institutional animal protocols with ad libitum access to water. The following groups were studied: Control mice with free access to food; severe caloric restriction fasting only group; Fasting with Triiodo-l-Thyronine (T3); Fasting with HIF-1α inhibitor (BAY). Cardiac hemodynamic and electrophysiological studies were performed and role of long noncoding RNAs were explored. Following severe caloric-restriction, we found that body weights, and heart weights to a partial extent, were decreased. Low-dose T3 treatment attenuated left ventricular hemodynamic impairment in indices of cardiac contractility and relaxation. In electrophysiology studies, fasting mice developed atrial tachyarrhythmias upon induction. This reverted to control levels following T3 treatment. There was a significant increase in atrioventricular conduction time and significant decrease in heart rate following fasting. Both these changes were attenuated following T3 treatment. Furthermore, BAY partially improved hemodynamics. Compared to the severe caloric-restriction group, both T3 and BAY reduced MALAT1 and GAS5 long noncoding RNA expression. These new findings indicate that T3 and BAY protect from cardiac decompensation secondary to acute severe caloric-restriction partly mediated by long noncoding RNAs.
Asunto(s)
Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/prevención & control , Restricción Calórica/efectos adversos , Cardiotónicos/administración & dosificación , ARN Largo no Codificante/biosíntesis , Triyodotironina/administración & dosificación , Animales , Arritmias Cardíacas/etiología , Peso Corporal/fisiología , Restricción Calórica/métodos , Restricción Calórica/tendencias , Femenino , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The deiodinases regulate the activation and inactivation of Thyroid hormones (TH), in both physiological and pathological conditions. The three deiodinases, DIO1, DIO2 and DIO3, have different catalytic role and cellular and tissue distribution. Aim of this study is to evaluate a rat model of regional ischemia/reperfusion (I/R), the modification of cardiac main function after the administration of 6 µg/kg/day of triiodothyronine (T3), and the associated to DIO1, DIO2 and DIO3 gene expression. We also aim to study DIO1 and DIO2 protein levels in different left ventricular regions after an ischemic event. Four groups of rats were studied: sham-operated, sham-operated + T3, I/R rats and I/R rats + T3. DIO1, DIO2 and DIO3 expression were evaluated in I/R region (AAR: area-at-risk) and in a more distant region from ischemic wound (RZ: remote zone). In I/R group, circulating free-T3 (FT3) levels were significantly decreased with respect to basal values, whereas in I/R + T3 rats, FT3 levels were comparable to basal values. In AAR of I/R + T3 rats, DIO1 and DIO2 gene expression significantly increased with respect to sham. In RZ, DIO1 and DIO3 gene expression was significantly lower in sham and I/R rats when compared to I/R + T3. In sham + T3 group, DIO1 and DIO2 gene expression was not detectable, whereas DIO3 was significantly higher than in the other three groups. The present study gives interesting new insights on DIO1, DIO2 and DIO3 in the ischemic heart and their role in relation to T3-mediated amelioration of cardiac function and structure.
Asunto(s)
Corazón/fisiología , Yoduro Peroxidasa/metabolismo , Daño por Reperfusión/metabolismo , Hormonas Tiroideas/metabolismo , Triyodotironina/administración & dosificación , Animales , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Infusiones Intravenosas , Yoduro Peroxidasa/genética , Masculino , Ratas , Ratas Wistar , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patologíaRESUMEN
CONTEXT: It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist, and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure. EVIDENCE ACQUISITION: This review is based on a collection of primary and review literature gathered from a PubMed search of "hypothyroidism," "levothyroxine," "liothyronine," and "desiccated thyroid extract," among other keywords. PubMed searches were supplemented by Google Scholar and the authors' prior knowledge of the subject. EVIDENCE SYNTHESIS: In most LT4-treated patients, normalization of serum thyrotropin levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, for example, specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels. CONCLUSIONS: After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients who have persistent symptoms or metabolic abnormalities despite normalization of serum thyrotropin level. New clinical trials focused on symptomatic patients, genetic makeup, and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.
Asunto(s)
Terapia de Reemplazo de Hormonas , Hipotiroidismo/tratamiento farmacológico , Medicina de Precisión , Tiroxina/administración & dosificación , Resistencia a Medicamentos/efectos de los fármacos , Quimioterapia Combinada , Terapia de Reemplazo de Hormonas/métodos , Terapia de Reemplazo de Hormonas/normas , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/epidemiología , Pautas de la Práctica en Medicina/normas , Pautas de la Práctica en Medicina/estadística & datos numéricos , Pautas de la Práctica en Medicina/tendencias , Medicina de Precisión/métodos , Medicina de Precisión/tendencias , Pruebas de Función de la Tiroides , Tirotropina/sangre , Insuficiencia del Tratamiento , Triyodotironina/administración & dosificaciónRESUMEN
Despite its first description more than 75 years ago, effective treatment for "Allan-Herndon-Dudley-Syndrome (AHDS)", an X-linked thyroid hormone transporter defect, is unavailable. Mutations in the SLC16A2 gene have been discovered to be causative for AHDS in 2004, but a comprehensive understanding of the function of the encoded protein, monocarboxylate transporter 8 (MCT8), is incomplete. Patients with AHDS suffer from neurodevelopmental delay, as well as extrapyramidal (dystonia, chorea, athetosis), pyramidal (spasticity), and cerebellar symptoms (ataxia). This suggests an affection of the pyramidal tracts, basal ganglia, and cerebellum, most likely already during fetal brain development. The function of other brain areas relevant for mood, behavior, and vigilance seems to be intact. An optimal treatment strategy should thus aim to deliver T3 to these relevant structures at the correct time points during development. A potential therapeutic strategy meeting these needs might be the delivery of T3 via a "Trojan horse mechanism" by which T3 is delivered into target cells by a thyroid hormone transporter independent T3 internalization.
Asunto(s)
Ganglios Basales , Cerebelo , Discapacidad Intelectual Ligada al Cromosoma X/tratamiento farmacológico , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hipotonía Muscular/tratamiento farmacológico , Hipotonía Muscular/metabolismo , Hipotonía Muscular/fisiopatología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatología , Tractos Piramidales , Triyodotironina/administración & dosificación , Triyodotironina/metabolismo , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiopatología , Cerebelo/efectos de los fármacos , Cerebelo/fisiopatología , Humanos , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/fisiopatologíaRESUMEN
Patients who take levothyroxine monotherapy to treat hypothyroidism frequently experience residual symptoms despite TSH testing at target levels. Trials have been conducted to evaluate the potential benefit of combination therapy with levothyroxine and liothyronine, though results have not consistently demonstrated benefit. In addition to randomization, placebo-control, and masking, four additional design choices to consider include the study population, dosing strategy for levothyroxine and liothyronine, primary and secondary outcome selection, and statistical power. A thoughtful design that considers these features will increase the likelihood that a combination trial will be considered definitive and finally resolve the important question of whether combination therapy with levothyroxine and liothyronine is a better thyroid replacement strategy than levothyroxine monotherapy.
Asunto(s)
Ensayos Clínicos como Asunto/métodos , Terapia de Reemplazo de Hormonas/métodos , Hipotiroidismo/tratamiento farmacológico , Tiroxina/administración & dosificación , Triyodotironina/administración & dosificación , Biomarcadores Farmacológicos/análisis , Ensayos Clínicos como Asunto/normas , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Humanos , Hipotiroidismo/sangre , Selección de Paciente , Proyectos de Investigación/normas , Resultado del TratamientoRESUMEN
Spinal cord injury (SCI) is an incurable condition, in which a cascade of cellular and molecular events triggered by inflammation and excitotoxicity impairs endogenous regeneration, namely remyelination and axonal outgrowth. We designed a treatment solution based on an implantable biomaterial (electrospun poly (l-lactic acid) [PLLA]) loaded with ibuprofen and triiodothyronine (T3) to counteract inflammation, thus improving endogenous regeneration. In vivo efficacy was tested by implanting the drug-loaded PLLA in the rat model of T8 contusion SCI. We observed the expected recovery of locomotion beginning on day 7. In PLLA-implanted rats (i.e., controls), the recovery stabilized at 21 days post-lesion (DPL), after which no further improvement was observed. On the contrary, in PLLA + ibuprofen (Ibu) + T3 (PLLA-Ibu-T3) rats a further recovery and a significant treatment effect were observed, also confirmed by the gait analysis on 49 DPL. Glutamate release at 24 h and 8 DPL was reduced in PLLA-Ibu-T3- compared to PLLA-implanted rats, such as the estimated lesion volume at 60 DPL. The myelin- and 200-neurofilament-positive area fraction was higher in PLLA-Ibu-T3-implanted rats, where the percentage of astrocytes was significantly reduced. The implant of a PLLA electrospun scaffold loaded with Ibu and T3 significantly improves the endogenous regeneration, leading to an improvement of functional locomotion outcome in the SCI.