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1.
Eur J Pharmacol ; 912: 174606, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34717926

RESUMO

The 3-iodothyronamine (T1AM) and 3-iodothryoacetic acid (TA1), are endogenous occurring compounds structurally related with thyroid hormones (THs, the pro-hormone T4 and the active hormone T3) initially proposed as possible mediators of the rapid effects of T3. However, after years from their identification, the physio-pathological meaning of T1AM and TA1 tissue levels remains an unsolved issue while pharmacological evidence indicates both compounds promote in rodents central and peripheral effects with mechanisms which remain mostly elusive. Pharmacodynamics of T1AM includes the recognition of G-coupled receptors, ion channels but also biotransformation into an active metabolite, i.e. the TA1. Furthermore, long term T1AM treatment associates with post-translational modifications of cell proteins. Such array of signaling may represent an added value, rather than a limit, equipping T1AM to play different functions depending on local expression of targets and enzymes involved in its biotransformation. Up to date, no information regarding TA1 mechanistic is available. We here review some of the main findings describing effects of T1AM (and TA1) which suggest these compounds interplay with the histaminergic system. These data reveal T1AM and TA1 are part of a network of signals involved in neuronal plasticity including neuroprotection and suggest T1AM and TA1 as lead compounds for a novel class of atypical psychoactive drugs.


Assuntos
Histamina/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Tironinas/farmacologia , Animais , Humanos , Fármacos Neuroprotetores/uso terapêutico , Receptores Histamínicos/metabolismo , Tironinas/uso terapêutico
2.
Int J Mol Sci ; 21(6)2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32183490

RESUMO

In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Síndrome Metabólica , Doenças Neurodegenerativas , Receptores Acoplados a Proteínas G/metabolismo , Tironinas/uso terapêutico , Animais , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia
3.
Med Sci Monit ; 26: e923195, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32162616

RESUMO

BACKGROUND The thyroid hormone metabolite 3-iodothyronamine (T1AM) is rapidly emerging as promising compound of decreasing heart rate and lowering cardiac output. The aim of our study was to fully understand the molecular mechanism of T1AM on cardiomyocytes and its potential targets in cardiovascular diseases. MATERIAL AND METHODS We developed an in vitro myocardial ischemia-reperfusion injury model of AC-16 cells by hypoxia-reoxygenation injury. Cell viability of AC-16 cells was detected using CCK-8 assay and apoptosis was detected by flow cytometry. RNA-seq was used to characterize the gene expression in H/R-induced AC-16 cells after T1AM treatment. The mRNA levels of FoxO1, PPARalpha, Akt, and GCK and the protein levels of PPARalpha, GCK, and components of the Akt/FoxO1 pathway were detected by qRT-PCR and Western blotting, respectively. RESULTS Exogenous T1AM increased the H/R-induced AC-16 cell viability in a relatively low concentration. A total of 210 DEGs, including 142 upregulated and 68 downregulated genes, were determined in H/R-induced AC-16 cells treated with or without T1AM. A Venn diagram showed 135 common DEGs. The FoxO signaling pathway was identified via KEGG enrichment analysis of these 135 DEGs. Moreover, T1AM mediated hypometabolism and reduced the apoptosis of H/R-induced AC-16 cells via the Akt/FoxO1 pathway. CONCLUSIONS Exogenous T1AM protects against cell injury induced by H/R in AC-16 cells via regulation of the FoxO signaling pathway. Our results suggest that T1AM can play a preventive role in myocardial H/R injury and also provide new insight for clinical management of AMI patients.


Assuntos
Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Tironinas/farmacologia , Apoptose/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Humanos , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tironinas/uso terapêutico
4.
Thyroid ; 28(10): 1387-1397, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30129879

RESUMO

BACKGROUND: 3-Iodothyroacetic acid (TA1) is among the thyroid hormone (T3) metabolites that can acutely modify behavior in mice. This study aimed to investigate whether TA1 is also able to reduce neuron hyper-excitability and protect from excitotoxic damage. METHODS: CD1 male mice were treated intraperitoneally with saline solution or TA1 (4, 7, 11, or 33 µg/kg) before receiving 90 mg/kg pentylenetrazole subcutaneously. The following parameters were measured: latency to first seizure onset, number of mice experiencing seizures, hippocampal levels of c-fos, and PI3K/AKT activation levels. Organotypic hippocampal slices were exposed to vehicle or to 5 µM kainic acid (KA) in the absence or presence of 0.01-10 µM TA1. In another set of experiments, slices were exposed to vehicle or 5 µM KA in the absence or presence of 10 µM T3, 3,5,3'-triiodothyroacetic acid (TRIAC), T1AM, thyronamine (T0AM), or thyroacetic acid (TA0). Neuronal cell death was measured fluorimetically. The ability of TA1 and T3, TRIAC, T1AM, T0A, and TA0 to activate the PI3K/AKT cascade was evaluated by Western blot. The effect of TA1 on KA-induced currents in CA3 neurons was evaluated by patch clamp recordings on acute hippocampal slices. RESULTS: TA1 (7 and 11 µg/kg) significantly reduced the number of mice showing convulsions and increased their latency of onset, restored pentylenetrazole-induced reduction of hippocampal c-fos levels, activated the PI3K/AKT, and reduced GSK-3ß activity. In rat organotypic hippocampal slices, TA1 reduced KA-induced cell death by activating the PI3K/AKT cascade and increasing GSK-3ß phosphorylation levels. Protection against KA toxicity was also exerted by T3 and other T3 metabolites studied. TA1 did not interact at KA receptors. Both the anticonvulsant and neuroprotective effects of TA1 were abolished by pretreating mice or organotypic hippocampal slices with pyrilamine, an histamine type 1 receptor antagonist (10 mg/kg or 1 µM, respectively). CONCLUSIONS: TA1 exerts anticonvulsant activity and is neuroprotective in vivo and in vitro. These findings extend the current knowledge on the pharmacological profile of TA1 and indicate possible novel clinical use for this T3 metabolite.


Assuntos
Anticonvulsivantes/uso terapêutico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Convulsões/tratamento farmacológico , Tironinas/uso terapêutico , Animais , Anticonvulsivantes/farmacologia , Morte Celular/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Convulsões/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Int J Mol Sci ; 19(5)2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29786646

RESUMO

Obesity is a complex disease associated with environmental and genetic factors. 3-Iodothyronamine (T1AM) has revealed great potential as an effective weight loss drug. We used metabolomics and associated transcriptional gene and protein expression analysis to investigate the tissue specific metabolic reprogramming effects of subchronic T1AM treatment at two pharmacological daily doses (10 and 25 mg/kg) on targeted metabolic pathways. Multi-analytical results indicated that T1AM at 25 mg/kg can act as a novel master regulator of both glucose and lipid metabolism in mice through sirtuin-mediated pathways. In liver, we observed an increased gene and protein expression of Sirt6 (a master gene regulator of glucose) and Gck (glucose kinase) and a decreased expression of Sirt4 (a negative regulator of fatty acids oxidation (FAO)), whereas in white adipose tissue only Sirt6 was increased. Metabolomics analysis supported physiological changes at both doses with most increases in FAO, glycolysis indicators and the mitochondrial substrate, at the highest dose of T1AM. Together our results suggest that T1AM acts through sirtuin-mediated pathways to metabolically reprogram fatty acid and glucose metabolism possibly through small molecules signaling. Our novel mechanistic findings indicate that T1AM has a great potential as a drug for the treatment of obesity and possibly diabetes.


Assuntos
Fármacos Antiobesidade/farmacologia , Proteínas Mitocondriais/genética , Obesidade/metabolismo , Sirtuínas/genética , Tironinas/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/uso terapêutico , Ácidos Graxos/metabolismo , Feminino , Quinases do Centro Germinativo , Glucose/metabolismo , Glicólise , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Proteínas Mitocondriais/metabolismo , Obesidade/tratamento farmacológico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Sirtuínas/metabolismo , Tironinas/uso terapêutico
6.
Ann Clin Lab Sci ; 48(6): 736-742, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30610043

RESUMO

This study aims to show how 3-iodothyronamine (T1AM) protects against spinal cord injury (SCI) in rats. We randomly divided adult female Sprague-Dawley rats (N=54) into three equal groups: (1) untreated control (n=18) (2) T1AM (n=18) (3) T1AM+EPPTB (n=18). The clamp method was used to produce SCI at the T10 segment, and the following data were collected 3, 5, and 7 days after the injury plus treatment. The mean BBB scores of both the control and T1AM+EPPTB groups were 1.5±0.5, 3.5±0.5, and 4.5±0.5 on days 3, 5, and 7 after SCI, respectively, whereas those for the T1AM group were 3.3±0.5, 5.3±0.5, and 7.5±0.5, a significant difference from the first two groups mentioned on each day (all P values <0.05). Although HE staining indicated that all three groups displayed neuronal degeneration and necrosis, disorganized spinal cord tissue structure, proliferation of glial cells, and spinal cord porosis, the damage was less in the T1AM group than in the other two groups. The number of apoptotic cells gradually increased in all three groups. However, while the mean numbers of apoptotic cells in the control (9.8%±2.6%, 14.2%±5.9%, 57.2%±15.1%) and T1AM+EPPTB groups (9.1%±3.0%, 13.4%±6.3%, 57.4%±11.1%) on days 3, 5, and 7, respectively, were not significantly different from each other, those in the T1AM group (2.3%±1.4%, 7.6%±1.8%, 36.1%±9.9%) were significantly lower than those in both the other groups at each time point (all P values <0.05). Thus, T1AM is involved in the apoptosis pathway through stimulation of TAAR1. The T1AM-TAAR1 interaction decreased spinal cord neuron apoptosis, reduced secondary SCI, and promoted hind limb motor function recovery in rats with SCI.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Tironinas/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Marcação In Situ das Extremidades Cortadas , Injeções Intraperitoneais , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/fisiopatologia
8.
Endocr Rev ; 32(1): 64-80, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20880963

RESUMO

Thyronamines (TAMs) are a newly identified class of endogenous signaling compounds. Their structure is identical to that of thyroid hormone and deiodinated thyroid hormone derivatives, except that TAMs do not possess a carboxylate group. Despite some initial publications dating back to the 1950s, TAMs did not develop into an independent area of research until 2004, when they were rediscovered as potential ligands to a class of G protein-coupled receptors called trace-amine associated receptors. Since this discovery, two representatives of TAMs, namely 3-iodothyronamine (3-T(1)AM) and thyronamine (T(0)AM), have been detected in vivo. Intraperitoneal or central injection of 3-T(1)AM or T(0)AM into mice, rats, or Djungarian hamsters caused various prompt effects, such as metabolic depression, hypothermia, negative chronotropy, negative inotropy, hyperglycemia, reduction of the respiratory quotient, ketonuria, and reduction of fat mass. Although their physiological function remains elusive, 3-T(1)AM and T(0)AM have already revealed promising therapeutic potential because they represent the only endogenous compounds inducing hypothermia as a prophylactic or acute treatment of stroke and might thus be expected to cause fewer side effects than synthetic compounds. This review article summarizes the still somewhat scattered data on TAMs obtained both recently and more than 20 yr ago to yield a complete and updated picture of the current state of TAM research.


Assuntos
Receptores Acoplados a Proteínas G/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Cricetinae , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hiperglicemia/induzido quimicamente , Hipotermia/induzido quimicamente , Hipotermia/metabolismo , Cetose/induzido quimicamente , Masculino , Camundongos , Ratos , Receptores dos Hormônios Tireóideos/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/tratamento farmacológico , Tironinas/análise , Tironinas/metabolismo , Tironinas/farmacologia , Tironinas/uso terapêutico
9.
Mol Biosyst ; 6(8): 1338-44, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20623079

RESUMO

3-Iodothyronamine (T(1)AM) is an endogenous thyroid hormone derivative with distinct biological effects that are largely opposite those of thyroid hormone. Administration of T(1)AM to rodents results in rapid and profound reduction in body temperature, heart rate, and metabolism. The structural similarities between thyroxine, T(1)AM, and monoamine neurotransmitters suggest an intriguing role for T(1)AM as both a neuromodulator and a hormone-like molecule that may constitute a part of thyroid hormone action. Several recent studies into its molecular mechanisms of action have shown that T(1)AM can target extracellular receptors such as the trace amine-associated receptors and the alpha(2A) adrenergic receptor, modulate the membrane transport of neurotransmitters, and serve as a substrate of specific membrane transport cellular uptake machinery. This review discusses recent T(1)AM studies, focusing on both the observed in vivo effects of T(1)AM administration and its actions at the molecular level.


Assuntos
Endocrinologia/tendências , Hormônios Tireóideos/fisiologia , Tironinas/fisiologia , Animais , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/metabolismo , Sistema Endócrino/fisiologia , Humanos , Modelos Biológicos , Tironinas/metabolismo , Tironinas/farmacologia , Tironinas/uso terapêutico
10.
Eur J Heart Fail ; 4(5): 577-82, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12413499

RESUMO

Thyroid hormone has multiple direct and indirect effects on the heart and the vasculature. Many signs and symptoms of thyroid dysfunction are manifest by the cardiovascular system. Furthermore, many cardiovascular diseases are adversely affected by the concomitant presence of either hyper- or hypothyroidism: it is still being debated whether these alterations are the consequence of increased cardiac workload alone or are due to the intrinsic properties of thyroid hormone. There are three potential mechanisms by which thyroid hormone might exert a cardiovascular action: (1) direct effects at the cellular level (inotropic and chronotropic effect); (2) interaction with the sympathetic nervous system; and (3) alteration of the peripheral circulation through changes in preload, afterload and energy metabolism. We treated 54 adult and seven pediatric patients suffering from severe low cardiac output in different clinical conditions with a mean bolus dosage of 2+/-1.5 microg h(-1) of T(3), followed by a continuous infusion of 0.4+/-0.3 microg h(-1) for a mean duration of 48+/-12 h. In 45 patients, stabilization of the hemodynamic situation with a decrease in inotropic support requirement was observed; however, in 11 patients no beneficial effects were observed. From this experience we suggest that T(3) treatment may improve hemodynamics in a substantial proportion of cardiac and cardiosurgical patients in whom more conventional treatment is unsuccessful.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Tironinas/uso terapêutico , Adolescente , Adulto , Criança , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Suíça , Tironinas/sangue
11.
Eur J Obstet Gynecol Reprod Biol ; 99(2): 188-94, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11788169

RESUMO

OBJECTIVE: To test whether the combined application of dexamethasone (DEXA) and 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) induces the synthesis of surfactant protein A (SP-A) mRNA at a higher rate than both substances given alone? STUDY DESIGN: Organoid culture of fetal rat lungs (Wistar rats; day 19 of gestation) was prepared. After 48h of incubation we added DEXA (10(-5), 10(-7), 10(-8) and 10(-9)mol/l), DIMIT (10(-5), 10(-7) and 10(-9)mol/l) and the combination of DEXA in 10(-8)mol/l with various concentrations of DIMIT. After another 48h of incubation, northern blot and hybridization with a 32P-labeled SP-A cDNA probe was performed. One-way-variance-analysis with a Scheffé-test, Levene-test and one-sample-t-test were used for statistical analysis. RESULTS: DEXA alone above 10(-8)mol/l resulted in a significant increase, DIMIT resulted in a decrease of SP-A mRNA induction. Combined application of DIMIT and DEXA resulted in a significant increase compared to the controls. Compared to DEXA alone in 10(-8)mol/l, we found an increased induction, but the data were not significant. CONCLUSIONS: The combined application of DEXA and DIMIT shows a higher induction of SP-A mRNA than both drugs given alone.


Assuntos
Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Tironinas/administração & dosagem , Animais , Northern Blotting , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Recém-Nascido , Técnicas de Cultura de Órgãos , Gravidez , Proteolipídeos/biossíntese , Proteolipídeos/genética , Proteína A Associada a Surfactante Pulmonar , Proteínas Associadas a Surfactantes Pulmonares , Surfactantes Pulmonares/biossíntese , Surfactantes Pulmonares/genética , RNA Mensageiro/análise , Ratos , Ratos Wistar , Tironinas/uso terapêutico
12.
Semin Perinatol ; 8(4): 283-92, 1984 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-6093266

RESUMO

Despite the proven efficacy of glucocorticoids for the prevention of RDS, this treatment is not effective in every case. One possible approach to improving the outcome is combined treatment with thyroid hormone and corticosteroid. Thyroid hormones accelerate morphological development and surfactant production in animals after treatment in vivo. With lung tissue in culture, T3 enhances phospholipid synthesis, apparently acting at different biochemical sites from those stimulated by corticosteroids. The effects of T3 are mediated through nuclear receptors, indicating that physiologic concentrations of T3 are stimulatory in the fetal lung. Furthermore, the developmental pattern for endogenous T3, as well as effects of thyroidectomy in fetal lambs, support the concept that endogenous thyroid hormones contribute to the timing of normal lung maturation in vivo. Combined treatment with thyroid hormones and glucocorticoids produces additive or supra-additive effects on phosphatidylcholine synthesis in the fetal lungs of rats, rabbits, and humans. The enhanced and faster response with both hormones v glucocorticoid alone suggests that clinical benefit might occur after shorter treatment intervals than currently observed with corticosteroid therapy. As there is little placental transfer of T3 and T4 in humans, maternal treatment with these hormones is not likely to be a useful approach for fetal therapy. Potentially, such therapy could be achieved by intraamniotic injection of T3 or T4, maternal treatment with synthetic thyroid hormones that pass the placenta, or by maternal treatment with TRH. This latter approach has been shown to elevate T3 levels in the cord blood of infants at term, mimicking the normal surge immediately after birth. If additional animal studies confirm the benefit of combined therapy on pulmonary function, clinical trials with glucocorticoid plus thyroid hormone may be appropriate in the near future.


Assuntos
Glucocorticoides/uso terapêutico , Pulmão/embriologia , Hormônios Tireóideos/uso terapêutico , Animais , Quimioterapia Combinada , Feminino , Maturidade dos Órgãos Fetais/efeitos dos fármacos , Humanos , Técnicas In Vitro , Recém-Nascido , Pulmão/efeitos dos fármacos , Fosfatidilcolinas/biossíntese , Gravidez , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Receptores dos Hormônios Tireóideos , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Glândula Tireoide/fisiopatologia , Tironinas/uso terapêutico , Tiroxina/uso terapêutico , Tri-Iodotironina/uso terapêutico
13.
Sem Hop ; 60(2): 85-9, 1984 Jan 19.
Artigo em Francês | MEDLINE | ID: mdl-6322330

RESUMO

The authors, in reporting 7 personal cases, confront their findings with previously published data. The study of cases presented as myxedema comas consistently demonstrates a precipitating cause, which in itself can produce a low T3 and T4 syndrome. The occurrence of such a cause in a patient with hypothyroidism can lead to acute decompensation, but should such conditions be considered as myxedema comas since treatment is above all aimed against the acute aggression?


Assuntos
Coma/etiologia , Mixedema/complicações , Idoso , Coma/tratamento farmacológico , Feminino , Humanos , Masculino , Tironinas/uso terapêutico , Tireotropina/sangue , Tiroxina/sangue
14.
Endocrinology ; 111(1): 132-5, 1982 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7084108

RESUMO

Placental transfer of iodothyronines is minimal in most species. The nonhalogenated thyroid hormone analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) was administered to pregnant ewes to determine if this compound could prevent cretinism in the thyroidectomized fetal lamb. Pharmacokinetic studies comparing [125I]T3 and [3H]DIMIT resulted in fetal-maternal ratios for [3H]DIMIT which were 5- to 10-fold higher than the ratios for [125I]T3, suggestive of preferential transport of DIMIT across the placenta. Subsequently, DIMIT was administered to three pregnant ewes after hysterotomy and fetal thyroidectomy at 95-98 days gestation. Intramuscular DIMIT (1200-2000 micrograms/day) caused suppression of maternal T4 concentrations from a mean of 4.9 micrograms/dl before hysterotomy to less than 1 micrograms/dl within 1-2 weeks. All three thyroidectomized lambs had clinical signs of cretinism at birth and died. Skeletal and lung maturation were delayed in these animals, all of whom had undetectable serum T4 concentrations. In contrast to DIMIT's proven thyromimetic activity in other fetal animal models, this thyroid hormone analog failed to prevent cretinism in thyroidectomized fetal lambs even when administered to the ewe at a dose that suppressed maternal thyroid function.


Assuntos
Hipotireoidismo Congênito/tratamento farmacológico , Doenças Fetais/tratamento farmacológico , Tironinas/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Feminino , Cinética , Gravidez , Ovinos , Tireoidectomia , Tironinas/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangue
15.
J Clin Invest ; 68(6): 1605-9, 1981 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-7033290

RESUMO

Diabetes mellitus in pregnancy is associated with neonatal respiratory distress syndrome due to impaired synthesis of fetal lung surfactant. Pharmacologic agents that promote fetal lung maturity are diabetogenic and have limited use in the management of diabetic pregnancy for prevention of respiratory distress syndrome. Maternal administration of a thyroid analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) results in significant enhancement of fetal lung phospholipid synthesis and accelerated lung maturity. We therefore studied the effects of DIMIT (0.5 mg/kg per d, s.c.) administration to pregnant alloxan-diabetic rabbits on days 25 and 26 of gestation. DIMIT treatment of diabetic maternal rabbits (DD) was associated with reduction of maternal blood glucose (115 +/- 13 vs. 275 +/- 72 mg/dl, P less than 0.05) and fetal glucose (64 +/- 6 vs. 274 +/- 47 mg/dl, P less than 0.001) compared with saline-injected diabetic (D) mothers. Reduction of fetal insulin levels was also associated with maternal DIMIT therapy in diabetic rabbits (56 +/- 5 (D) vs. 24 +/- 4 microunits/ml, P less than 0.001). Maternal diabetes resulted in significant reduction of fetal lung weight (370 +/- 20 vs. 520 +/- 30 mg, P less than 0.005) and lung protein content (6.5 +/- 0.7 vs. 8.7 +/- 0.7 mg/gm, P less than 0.005), which were restored to normal in offspring of DIMIT-treated diabetic rabbits. Maternal DIMIT administration caused significant reduction in fetal lung glycogen content in control (62 +/- 5.8 vs. 25 +/- 5.9 micrograms/mg protein, P less than 0.001) and diabetic (56 +/- 7 vs. 34 +/- 5 micrograms/mg protein, P less than 0.02) offspring. Whereas maternal diabetes was associated with reduction of all major phospholipid species in fetal lung-comprising surfactant, these were restored with DIMIT therapy. The results demonstrate that short-term maternal administration of DIMIT in pregnant diabetic rabbits not only promotes fetal lung phospholipid synthesis, but also appears to ameliorate maternal hyperglycemia. Thus, DIMIT is of potential benefit in the management of diabetic pregnancy.


Assuntos
Pulmão/efeitos dos fármacos , Fosfolipídeos/biossíntese , Gravidez em Diabéticas/tratamento farmacológico , Surfactantes Pulmonares/análise , Tironinas/uso terapêutico , Animais , Peso ao Nascer/efeitos dos fármacos , Glicemia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Sangue Fetal , Idade Gestacional , Insulina/sangue , Pulmão/embriologia , Pulmão/metabolismo , Troca Materno-Fetal , Tamanho do Órgão , Fosfolipídeos/análise , Gravidez , Gravidez em Diabéticas/sangue , Coelhos , Tironinas/farmacologia
18.
Probl Endokrinol (Mosk) ; 22(5): 16-21, 1976.
Artigo em Russo | MEDLINE | ID: mdl-1023178

RESUMO

In studying the erythrocytometric peripheral blood indices in patients with hypothyroidism there was revealed an increase of the mean diameter, mean volume and thickness of the red blood cells. There was revealed that in the process of 4-week replacement therapy with lyothyronine-2-hydrochloride the patients with mild and moderately severe affection displayed an increase of the mean diameter of erythrocytes, a reduction of their thickness and volume and a fall of microcyte count. As to the patients with severe hypothyroidism--they show no significant dynamics of the erythrocytometric indices after one month of treatment.


Assuntos
Eritrócitos/citologia , Hipotireoidismo/sangue , Adulto , Idoso , Contagem de Eritrócitos , Seguimentos , Hematócrito , Humanos , Hipotireoidismo/tratamento farmacológico , Métodos , Pessoa de Meia-Idade , Tironinas/uso terapêutico
19.
Arch Otolaryngol ; 101(9): 574-6, 1975 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1164243

RESUMO

We review the world literature on lingual thyroid. One of our cases of lingual thyroid is added to this body of information specifically because of the patient's unusual lack of any response to hormonal suppression treatment. This behavior was suggestive of a malignant neoplasm and was, in our opinion, indication for excisional biopsy, even without any of the usual symptoms associated with lingual thyroid. To our knowledge, this behavior has not been previously reported.


Assuntos
Glândula Tireoide/anormalidades , Adolescente , Feminino , Humanos , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/etiologia , Glândula Tireoide/cirurgia , Hormônios Tireóideos/uso terapêutico , Neoplasias da Glândula Tireoide/complicações , Tironinas/uso terapêutico , Língua/anormalidades
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