RESUMO
BACKGROUND: Coronary heart disease is common in Type 2 diabetes and often requires cardiac surgery. However poorer outcomes have been reported including increased rates of post-operative infection and prolonged hospital stay. AIM: The aim of the study was to determine the feasibility and acceptability of a specialist consultation model (pre-operative medical and educational intervention) for type 2 diabetes in the cardiac surgery setting. METHODS: Twenty four patients were assigned usual care or to the intervention group. The intervention group were assessed by a diabetes clinical nurse consultant, dietitian, and endocrinologist during a pre-operative visit. Specific diabetes questionnaires were administered, education was delivered, and protocol-driven changes to the medical regimen were instituted. Length of stay, incidence of post-operative complications, and number of post-operative inpatient review endocrinology visits required were recorded. RESULTS: Twenty four patients with a pre-operative HbA(1c) greater than 6.5% (48 mmol/mol) were studied (17 males and 7 females). In the usual care group (n = 15), HbA(1c) pre-operatively was 7.2% (55.2 mmol/mol) compared to 10.1% (86.9 mmol/mol) in the intervention group (n = 9). Six weeks post-operatively HbA(1c) fell significantly in the intervention group by 1.9% (to 8.2% [66.1 mmol/mol]) compared to a reduction of 1.2% (to 7.0% [53 mmol/mol]) in the usual care group (p < 0.05). No significant differences were observed in length of stay in intensive care or in total hospital stay between the groups: length of ICU stay 54 h for intervention versus 47 h for usual care, total hospital stay (mean 8 days for both); or in rates of post-operative infection. Differences were seen between in the diabetes questionnaires: in the Problem Areas in Diabetes questionnaire and in the Diabetes Treatment Satisfaction Questionnaire (p = 0.048). CONCLUSION: This small pilot feasibility study suggests there is potential benefit in the acute optimisation of diabetes treatment before elective cardiac surgery.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Diabetes Mellitus Tipo 2/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pré-OperatóriosRESUMO
BACKGROUND: Recombinant human thyroid-stimulating hormone (Thyrogen; Genzyme Corporation, Cambridge, MA, USA) (rhTSH)-stimulated serum thyroglobulin (Tg) (stim-Tg) and (131)I whole-body scanning (WBS) have been reported to allow follow up of patients with thyroid cancer without the symptoms of thyroxine withdrawal and with equivalent diagnostic information to that obtained after thyroxine withdrawal. The aim of the study was to report results of rhTSH use at the Alfred Hospital, Melbourne, from 1999 to 2006 and in particular to examine the significance of detectable serum Tg after rhTSH in relation to thyroid cancer staging and to compare the sensitivity of rhTSH-stimulated serum Tg to whole-body (131)I scanning (WBS) in the detection of residual and recurrent thyroid cancer. METHODS: The study was a retrospective chart review. RESULTS: In 90 patients, rhTSH was used for 96 diagnostic episodes and 18 doses of rhTSH were used to facilitate treatment with (131)I. In stages I and II cancer (n = 42), of three patients with stim-Tg 1-2 microg/L, none had identifiable disease, and the three patients who had stim-Tg >2 microg/L did not experience recurrent disease during follow up. In contrast, in stages III and IV cancer (n = 43) 2 of 5 with stim-Tg 1-2 microg/L had identifiable disease and 7 of 10 with stim-Tg >2 microg/L had identifiable disease. In Tg-positive, WBS-negative disease, further imaging identified persistent/recurrent disease. CONCLUSION: rhTSH was effective and safe in the management of thyroid cancer follow up for diagnosis of persistent/recurrent cancer and to enable (131)I treatment. In no case did rhTSH-stimulated WBS identify the presence of disease not also identified by raised basal Tg or stim-Tg. Therefore, in low risk cancer WBS may be omitted.
Assuntos
Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Tireotropina , Adolescente , Adulto , Idoso , Pré-Escolar , Feminino , Seguimentos , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Proteínas Recombinantes , Estudos Retrospectivos , Tireoglobulina/sangue , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/patologia , Imagem Corporal Total , Adulto JovemRESUMO
Cellular uptake of T3 was examined using rat H4 hepatoma cells. Uptake of [125I]T3 (10(-11) M) from serum-free medium was measured as the cell-associated counts retained by washed cells (2 X 10(6) per well). Displaceable uptake was 84% of total uptake at 2 min (2.9% of total counts). T4, tetraiodothyroacetic acid, triiodothyroacetic acid, rT3, and D-T3 were 2-5% as effective as T3 in displacing uptake. Nonequilibrium kinetics indicated a half-maximal uptake at 680 nM T3 with approximately 7 million sites per cell. Displaceable uptake was time and temperature dependent and was 73% inhibited by 2 mM KCN and 52% by 10 mM bacitracin but not by 2 mM ouabain or 10 microM cytochalasin B. Phloretin, 100 microM, inhibited uptake by 66%. T3 uptake was directly related to the free T3 concentration over the range of albumin concentrations, 0-10 g/liter. The nonbile acid cholephil compounds, bromosulfophthalein, iopanoic acid, and indocyanine green (all 100 microM) inhibited T3 uptake to 62%, 17%, and 5% of control, respectively. Taurocholate, methylaminoisobutyric acid, and oleic acid were noninhibitory. The half-inhibitory concentrations of reactive nonsteroidal antiinflammatory drugs were: meclofenamic acid (25 microM), mefenamic acid (45 microM), fenclofenac (69 microM), flufenamic acid (100 microM), and diclofenac (230 microM). Aspirin, ibuprofen, oxyphenbutazone, and phenylbutazone (all 100 microM) were noninhibitory. Diphenylhydantoin inhibited uptake to 50% at 75 microM. These findings suggest that T3 uptake by cultured rat hepatocytes is by an energy-dependent, saturable, stereo-selective mechanism that is dependent on cell membrane proteins. This mechanism appears to be shared by a number of other ligands, including nonbile acid cholephils and several nonsteroidal antiinflammatory drugs of the anthranilic and phenylacetic acid classes, as well as diphenylhydantoin. The bile acid taurocholate, oleic acid, and a probe for type A amino acid uptake were inactive. The extent to which these effects may modify expression of thyroid hormone action remains to be established.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Verde de Indocianina/farmacologia , Ácido Iopanoico/farmacologia , Neoplasias Hepáticas Experimentais/metabolismo , Fenitoína/farmacologia , Sulfobromoftaleína/farmacologia , Tri-Iodotironina/metabolismo , Ácidos Aminoisobutíricos/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Cinética , Ácido Oleico , Ácidos Oleicos/farmacologia , Ratos , Ácido Taurocólico/farmacologiaRESUMO
Both thyroid hormone and carbohydrate feeding are known to influence hepatic gene expression in vivo. In order to determine whether these compounds act directly on the liver, we have utilized an isolated adult rat hepatocyte culture to examine the in vitro influence of either T3 or glucose on a wide range of mRNA activities. RNA was extracted from hepatocyte cultures, translated in the rabbit reticulocyte system, and the translated products separated by two-dimensional gel electrophoresis. We have found a strong similarity between the hepatic mRNA response to T3 administered either to the animal or added to the culture medium and between the response to high carbohydrate feeding and an increase in the medium glucose concentration. Our studies suggest that the isolated hepatocyte culture is a useful model for the study of the influence of hormones and metabolites on the expression of specific mRNA's.
Assuntos
Genes/efeitos dos fármacos , Glucose/metabolismo , Fígado/metabolismo , RNA Mensageiro/genética , Tri-Iodotironina/farmacologia , Animais , Células Cultivadas , Cinética , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos EndogâmicosRESUMO
Previous studies have suggested that there is an interrelationship between responses mediated by retinoic acid (RA) and those to thyroid hormone (T3). These experiments have used transfected gene constructs, often in receptor-negative cells. To study the relationship between RA- and T3-mediated responses in intact human cells, we incubated HepG2 cells for 4 days in serum-free medium with T3 and/or RA or 9-cis-RA. Measured responses were stimulation of secreted sex hormone-binding globulin (SHBG) or inhibition of secreted T4-binding globulin (TBG). T3 induced a dose-responsive increase in SHBG secretion that was maximal at 10nM (206 +/- 24% of untreated value) and half-maximal at 0.36 +/- 0.16 nM T3. RA and 9-cis-RA, up to 100 nM, induced a slight fall in SHBG secretion to 79 +/- 9% and 88 +/- 9%, respectively. T3 induction of SHBG secretion was significantly attenuated in cells coincubated with T3(0-10nM) and RA. With T3 (10 nM) together with RA (3, 10, or 100 nM), the maximal SHBG responses were reduced to 193 +/- 24%, 151 +/- 5% and 132 +/- 30%, respectively. With T3 and 9-cis-RA (100 nM), maximal stimulation was 169 +/- 20%. Importantly, the effective half-maximal stimulatory concentration of T3 in the presence of either retinoid (3-100 nM) was unchanged at 0.3 nM T3. In addition, the inhibitory effect of 9-cis RA could not be overcome even with 300 nM T3. The threshold for the RA effect was between 0.3-1 nM, with half-maximal inhibition at 30 nM. 9-cis-RA was approximately 10-fold less potent than RA. Preliminary studies suggested that changes in SHBG messenger RNA levels were similar to those in secreted SHBG. No effect was observed with vitamin D or clofibrate, either alone or combined with T3. Conversely, T3 reduced TBG secretion, with maximal suppression to 74 +/- 5% of the control value at a T3 concentration of 10 nM. RA alone reduced TBG secretion to 76% of the control value. RA did not attenuate the effect of T3, and the two agents combined showed no synergism. Neither T3 nor RA, alone or in combination, influenced secreted total protein or albumin. RA did not alter the concentration of nuclear T3-binding sites. These data suggest that retinoids act via a gene-dependent mechanism to modulate maximal, but not half-maximal, responses to T3 in HepG2 cells with the specificity of RA greater than that of 9-cis-RA.
Assuntos
Tretinoína/farmacologia , Tri-Iodotironina/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Clofibrato/farmacologia , Relação Dose-Resposta a Droga , Humanos , Globulina de Ligação a Hormônio Sexual/metabolismo , Estereoisomerismo , Proteínas de Ligação a Tiroxina/metabolismo , Células Tumorais Cultivadas , Vitamina D/farmacologiaRESUMO
Migration inhibition of purified peripheral T lymphocytes in response to pancreatic islet cell antigen or thyroid antigen was used to study cell-mediated immune mechanisms in patients with diabetes mellitus (IDDM) and Graves' disease (GD). In response to islet cell antigen, T lymphocytes of subjects with IDDM for less than 3 yr exhibited migration inhibition, whereas those of normal subjects, noninsulin dependent diabetics, and subjects with IDDM for longer than 3 yr did not. Admixture of T lymphocytes from normal subjects with T lymphocytes from patients with IDDM for less than 3 yr substantially ameliorated the migration inhibition of the IDDM subjects to islet cell antigen. Migration of T lymphocytes from GD subjects was markedly inhibited by thyroid antigen and marginally inhibited by islet cell antigen. Admixture of GD T lymphocytes significantly ameliorated the migration inhibition of IDDM T lymphocytes to islet cell antigen, despite sensitization to thyroid antigen of the GD T lymphocytes. We conclude: 1) sensitization to islet cell antigen in IDDM of recent onset is confirmed; 2) the ability of normal and GD T lymphocytes to ameliorate the migration inhibition of IDDM T lymphocytes strongly suggests correction of deficient suppressor T lymphocyte function; 3) the ability of GD T lymphocytes to ameliorate migration inhibition of IDDM T lymphocytes to islet cell antigen is evidence for an antigen-specific rather than a generalized suppressor T lymphocyte defect in GD; and 4) similarly, the normalization of migration index of GD T lymphocytes in response to thyroid antigen by those IDDM T lymphocytes not sensitized to thyroid antigen is again evidence for an antigen-specific and not a generalized suppressor T lymphocyte defect in IDDM.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Doença de Graves/imunologia , Linfócitos T Reguladores/fisiologia , Antígenos/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , Imunidade Celular , Ilhotas Pancreáticas/imunologia , Fatores Inibidores da Migração de Leucócitos/análise , Glândula Tireoide/imunologiaRESUMO
T-Lymphocyte sensitization in Graves' disease (GD) and Hashimoto's thyroiditis (HT) was studied by an indirect migration inhibition factor test using normal T-lymphocytes as second stage indicator cells. In the first stage, mononuclear cells or T-lymphocytes, fractionated by the standard Ficoll-Hypaque procedure from the blood of patients with untreated GD and HT, were cultured in Eagle's medium containing thyroid antigen, and their cell-free supernatants were saved. Normal T-lymphocytes as second stage indicator cells were packed in capillary tubes and placed in planchettes with the above supernatants to complete the indirect migration inhibition factor test. Inhibition of the migration of indicator T-lymphocytes was demonstrated when either GD or HT culture supernatants were employed. Moreover, there was a good correlation between the indirect using the culture supernatants and the direct migration inhibition factor test using mononuclear cells or T-lymphocytes. On the other hand, in both direct and indirect migration inhibition factor tests using mononuclear cells and mononuclear cell culture supernatants, respectively, in the presence of human liver antigen as a nonspecific antigen, there was no significant difference between controls and patients. From these results, we can conclude that GD and HT T-lymphocytes are sensitized to thyroid antigen and produce the lymphokine, migration inhibition factor, into the supernatant when exposed to this antigen.
Assuntos
Doença de Graves/imunologia , Linfócitos T/imunologia , Tireoidite Autoimune/imunologia , Adulto , Inibição de Migração Celular , Feminino , Humanos , Fatores Inibidores da Migração de Leucócitos/imunologia , Masculino , Métodos , Pessoa de Meia-Idade , Monócitos/imunologiaRESUMO
We directly compared the competitor potency for serum T4 binding of 11 nonsteroidal antiinflammatory drugs; the diuretics furosemide, ethacrynic acid, and bumetanide; diphenylhydantoin; the cholecystographic contrast agents iopanoate and ipodate; and six long-chain nonesterified fatty acids (NEFA) using equilibrium dialysis. To avoid artefacts that occur in competitor studies with diluted serum or isolated binding proteins, we used undiluted normal serum, with drugs added at concentrations that achieved high therapeutic total and free serum levels at equilibrium. Drug addition was based on the measured free fraction of each drug in serum. The free T4 fraction in normal serum (Tris buffer, pH 7.4; 37 C) was between 1.40 X 10(-4) and 1.53 X 10(-4). Drug-induced increases in T4 free fraction were: fenclofenac, 90%; aspirin, 62%; meclofenamic acid, 39%; diflunisal, 37%; mefenamic acid, 31%; and furosemide, 31%. Significant increases of 7-15% occurred with diclofenac, flufenamic acid, phenylbutazone, and diphenylhydantoin. Indomethacin, ketoprofen, tolmetin, ethacrynic acid, bumetanide, iopanoate, and ipodate were inactive at the concentrations studied. Addition of 2.0 mmol/L oleic acid had a negligible effect, but 3.5 mmol/L oleic acid inhibited T3 and T4 binding significantly. Other long chain NEFA (addition of 1.5 mmol/L) gave increases in free T4 fraction as follows: arachidonic acid, 26%; linolenic acid, 23%; and linoleic acid, 11%. Stearic and palmitic acids were inactive. The effect of 5 mmol/L oleic acid in serum could be reproduced by addition of 0.5 mmol/L to serum diluted 1:10, indicating that protein binding of NEFA is the major determinant that limits their competitor potency. These findings provide a basis for anticipating which potential inhibitors may cause important changes in serum thyroid hormone binding. The time course of such effects will be influenced by the pharmacokinetics of the inhibitor itself as well as the equilibrium findings described here.
Assuntos
Ácidos Graxos não Esterificados/farmacologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacologia , Ligação Competitiva , Meios de Contraste/sangue , Meios de Contraste/farmacologia , Diuréticos/sangue , Diuréticos/farmacologia , Ácidos Graxos não Esterificados/sangue , Humanos , Ácido Oleico , Ácidos Oleicos/farmacologia , Fenitoína/sangue , Fenitoína/farmacologia , Receptores dos Hormônios Tireóideos/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Long chain nonesterified fatty acids and various drugs may share albumin-binding sites in common. We questioned whether serum binding of T4 could be indirectly influenced by displacement of drug competitors from these sites by nonesterified fatty acids. The influence of oleic acid on drug-induced inhibition of [125I]T4 binding was measured by equilibrium dialysis, using undiluted serum in order to avoid dilution-related artefacts. Oleic acid (1 mmol/L) alone did not inhibit serum protein binding of T4, but this concentration augmented the inhibitory effects on T4 binding of diflunisal, mefenamic acid, meclofenamic acid, and aspirin. This effect increased with increasing concentrations of mefenamic acid, meclofenamic acid, and furosemide. The T4-displacing effect of fenclofenac was not augmented by oleic acid. The mechanism of these interactions was studied by examining 1) oleic acid effects on drug binding, and 2) drug effects on oleic acid binding in undiluted serum. Increments in added oleic acid (0.5-2.0 mmol/L) progressively increased the mean unbound fractions of [14C]aspirin, [14C] diflunisal, and [14C]furosemide, but did not displace [14C]fenclofenac. At the relevant total and free drug concentrations, the inhibitory effect of oleic acid on drug binding and its influence on drug-induced displacement of T4 were concordant in the order: meclofenamic acid greater than aspirin greater than mefenamic acid greater than diflunisal greater than furosemide greater than fenclofenac. In contrast, drug-induced increases in the unbound fraction of [14C]oleic acid did not correlate with augmentation of T4 displacement. We conclude that synergistic effects of oleic acid and drugs on T4 binding result from drug displacement by oleic acid, rather than the reverse effect. Hence, substances that increase the unbound concentration of a competitor by displacing it from albumin can increase its T4-displacing potency. Interactions between various ligands may exert a greater hormone-displacing effect than the sum of each alone.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Furosemida/farmacologia , Ácidos Oleicos/farmacologia , Proteínas de Ligação a Tiroxina/metabolismo , Tiroxina/sangue , Anti-Inflamatórios não Esteroides/sangue , Aspirina/sangue , Ligação Competitiva , Diflunisal/sangue , Diflunisal/farmacologia , Furosemida/sangue , Humanos , Cinética , Ácido Meclofenâmico/sangue , Ácido Meclofenâmico/farmacologia , Ácido Mefenâmico/sangue , Ácido Mefenâmico/farmacologia , Ácido Oleico , Ácidos Oleicos/sangue , Fenilacetatos/sangue , Fenilacetatos/farmacologia , Proteínas de Ligação a Tiroxina/efeitos dos fármacosRESUMO
The allo-suppressor effect of normal T lymphocytes on the production of migration inhibition factor by sensitized T lymphocytes of Graves' disease in response to human thyroid antigen has been studied further by a modified migration inhibition factor test employing purified T lymphocyte preparations. The production of migration inhibition factor was consistently abolished when normal T lymphocytes were mixed with the Graves' disease lymphocytes in various ratios (1:9, 2:8, and 5:5). However, pretreatment of the normal T lymphocytes with cimetidine (an H-2 histamine receptor antagonist) led to a demonstrable loss in their allo-suppressor properties, whereas pretreatment with chlorpheniramine (an H-1 histamine receptor antagonist) had no such effect. These studies indicate that a subset of normal T lymphocytes bearing H-2 histamine receptors suppresses the production or release of migration inhibition factor by sensitized T lymphocytes, and further suggest the possibility that there may be an abnormality in the H-2 receptors on Graves' disease suppressor T lymphocytes. It is conceivable that this defect is fundamental in the pathogenesis of Graves' disease.
Assuntos
Doença de Graves/imunologia , Receptores Histamínicos H2/imunologia , Receptores Histamínicos/imunologia , Linfócitos T/imunologia , Adulto , Clorfeniramina/farmacologia , Cimetidina/farmacologia , Feminino , Humanos , Fatores Inibidores da Migração de Leucócitos/biossíntese , Masculino , Pessoa de Meia-Idade , Receptores Histamínicos H2/efeitos dos fármacos , Linfócitos T/efeitos dos fármacosRESUMO
A mutation at codon 119 in the transthyretin (TTR) gene leads to a substitution of methionine for threonine at this position in the circulating protein. As the amino acid at position 119 is located in the T4 binding channel, mutations here may affect the binding of T4 by TTR. A previous study has shown an increase in the amount of hormone carried by the TTRMet119 variant. To determine whether this increase in binding was due to a change in affinity or capacity, TTR was partially purified from normal individuals and those with the TTRMet119 mutation. The isolation procedure was a rapid, single step passage through Blue Sepharose. With normal serum, the resulting protein bound T4 with a single site of intermediate affinity (Ka, 1.63 +/- 0.36 x 10(7) L/mol). No sites of higher or lower affinity were detected. Comparisons of binding capacity and immunoreactive TTR concentrations showed that the preparations bound T4 with a molar ratio between 1-2. With TTRMet119 serum, the T4 affinity was approximately doubled [Ka, 3.40 +/- 0.76 x 10(7) L/mol (+/- SD); P < 0.001] with no change in binding capacity. This doubling in affinity explains the observed T4 levels of about 120 nmol/L in individuals with this mutation. Binding of rT3 to TTRMet119 was increased approximately 5-fold over normal. Identical experiments with TTRGly54, in which glycine is substituted for glutamine, showed that the T4 affinity of this variant was unchanged from normal. These results suggest that the TTRMet119 mutation leads to secretion of a normal concentration of TTR that has a raised affinity for T4. Depending on their location, mutations in the TTR gene may lead to an increase or no change in T4 binding by the secreted protein.
Assuntos
Variação Genética , Pré-Albumina/metabolismo , Tiroxina/metabolismo , Glutamatos/análise , Ácido Glutâmico , Glicina/análise , Humanos , Lactente , Metionina/análise , Métodos , Mutação/genética , Pré-Albumina/análise , Pré-Albumina/genética , Ligação Proteica , Treonina/análise , Tiroxina/análiseRESUMO
In a prospective study of critically ill hypothyroxinemic we assessed the relationship between serum TSH and T4 during the return of serum T4 to normal during recovery. In this longitudinal study of 60 patients with a variety of critical illnesses, including burns, septicemia, and acute renal failure, serum T4 fell to less than 2.7 micrograms/dl (35 nmol/liter) in 24 patients, of whom 14 survived with return of T4 to normal. A rise in total T4 of more than 1.9 microgram/dl (25 nmol/liter) within 96 h occurred 13 times in 10 patients, while 4 patients had slower increases in T4. All 13 episodes of rapid T4 rise [1.7 +/- 0.8 (+/- SD) to 5.6 +/- 2.1 micrograms/dl] were associated with a marked increase in serum TSH (1.1 +/- 0.8 to 7.0 +/- 5.2 mU/liter), and TSH was transiently above normal during 8 episodes of T4 recovery. In the 6 episodes with sampling less than 6 h apart, the TSH rise consistently preceded the T4 rise. In the 4 patients who received dopamine, TSH and T4 remained low until cessation of therapy. During the TSH rise, only minor changes, which could not account for the increase in total T4, occurred in T4-binding globulin (12.9 +/- 3.3 to 14.8 +/- 3.3 mg/liter), prealbumin (208 +/- 73 to 234 +/- 82 mg/liter), and albumin (28.3 +/- 2.9 to 31.9 +/- 2.9 g/liter). Mean free T4 increased (0.60 +/- 0.34 to 1.45 +/- 0.56 ng/dl), as did total T3 (16 +/- 14 to 76 +/- 44 ng/dl), during the phase of TSH rise, suggesting that the increase in TSH was not simply a consequence of diminished negative feedback due to increased plasma binding. The very close and consistent temporal relationship between TSH and T4 during the recovery phase suggests that TSH may have an essential role in the return of T4 to normal during recovery from critical nonthyroidal illness.
Assuntos
Tireotropina/sangue , Tiroxina/sangue , Adulto , Idoso , Queimaduras/sangue , Proteínas de Transporte/sangue , Cuidados Críticos , Dopamina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de TempoRESUMO
We examined the effect of 26 drugs on T4 binding to transthyretin (TTR; prealbumin) and T4-binding globulin (TBG) by determining their ability to inhibit [125I]T4 binding to TTR isolated from normal human plasma and to serum diluted 1:10,000, respectively. The hierarchies for drug inhibition of T4 binding differed greatly for these two proteins. Relative to T4, the drugs were much more potent inhibitors of [125I]T4 binding to TTR than to TBG. Compounds of the anthranilic acid class, such as flufenamic, meclofenamic, and mefenamic acids, interacted particularly strongly with TTR. Flufenamic acid was more potent than T4 itself in inhibiting [125I]T4 binding [175 +/- 17% (+/- SD); cf. T4; n = 3; P less than 0.001], while mefenamic acid, diflunisal, and meclofenamic acid were 20-26% as potent as T4 in their interaction with TTR. The reactivity of diclofenac, fenclofenac, indomethacin, sulindac, and the diuretic ethacrynic acid was 0.8-2.1% relative to that of T4. In contrast, furosemide, the drug most highly reactive with TBG, was only 0.11 +/- 0.03% (n = 7) as potent as T4, followed by meclofenamic acid greater than mefenamic acid greater than fenclofenac greater than flufenamic acid greater than diflunisal greater than milrinone. Aspirin and sodium salicylate were, respectively, 0.05% and 0.20% as active as unlabeled T4 as inhibitors of [125I]T4 binding to TTR, but these compounds had only 3-4 x 10(-6)% of the activity of T4 for TBG binding. Diphenylhydantoin had no detectable effect on T4 binding to TTR and was 2.9 x 10(-4)% as reactive as T4 with TBG. Amiodarone did not interact with either binding site. Drug interactions with TTR may be important when this protein becomes a major circulating T4-binding protein, as in patients with complete or partial TBG deficiency, or when serum T4 is markedly elevated. Such interactions may also be important where TTR is the dominant tissue T4-binding protein, as in the choroid plexus. In addition, the drug competitors described here may be useful as probes to further define the structural basis for specific ligand interactions with different classes of T4-binding sites.
Assuntos
Diflunisal/farmacologia , Ácido Flufenâmico/farmacologia , Ácido Mefenâmico/farmacologia , Pré-Albumina/metabolismo , Salicilatos/farmacologia , Proteínas de Ligação a Tiroxina/metabolismo , Tiroxina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva , Transporte Biológico , Concentração de Íons de Hidrogênio , Relação Estrutura-Atividade , Tri-Iodotironina/metabolismoRESUMO
A sensitive [125I]-T4 binding assay was used to measure serum T4-binding globulin (TBG) in 60 individuals selected on the basis of their total circulating T3 concentrations, and a relationship between TBG and circulating thyroid hormone levels in humans was confirmed. There was a significant correlation between serum TBG and T3 or free T4 index. TBG secretion and TBG messenger ribonucleic acid (mRNA) production were studied with a continuous culture of the human hepatoblastoma cell line, HepG2. Cells were maintained in serum-free media for experimental manipulations. The addition of 100 nmol/L T3 to the cell medium resulted in a time-dependent down-regulation of TBG mRNA to 33 +/- 6% (+/- SD, n = 4) of untreated control levels by 24 h. Suppression of TBG mRNA was first detectable at 8 h (57% of untreated control levels). The effect of T3 was dose-responsive, with half-maximal suppression of TBG mRNA occurring at a bioavailable T3 concentration of approximately 30 pmol/L. The effect of T3 on TBG mRNA was not caused by a change in mRNA stability. Proteins secreted by HepG2 cells bound T4 with an affinity identical to that of normal circulating TBG. Cell secretion of TBG was parallel to total protein secretion and consistent with a TBG secretion rate of 50 ng/10(6) cells per day. Variations in the concentration of secreted binding protein in the presence of T3 corresponded to the changes observed in TBG mRNA. These data show that circulating TBG concentration is negatively correlated with total serum T3 in vivo. The corresponding down-regulation observed between TBG mRNA and secreted protein in HepG2 cells suggests that this effect is the result of the action of T3 on cellular TBG mRNA synthesis.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Ligação a Tiroxina/biossíntese , Tri-Iodotironina/farmacologia , Linhagem Celular , Hepatoblastoma , Humanos , Cinética , Neoplasias Hepáticas , RNA Mensageiro/biossíntese , Tiroxina/metabolismo , Proteínas de Ligação a Tiroxina/metabolismo , Células Tumorais CultivadasRESUMO
The diuretic furosemide inhibits serum protein binding of T4 in equilibrium dialysis, dextran-charcoal, and competitive ligand binding separation systems and displaces [125I]T4 from isolated preparations of T4-binding globulin (TBG), prealbumin, and albumin. Equilibrium dialysis studies of undiluted normal serum showed that about 10 micrograms/ml furosemide increased the free T4 and free T3 fractions. Displacement occurred at lower drug concentrations in sera with subnormal albumin and TBG levels. Binding of [14C]furosemide to TBG was inhibited by unlabeled T4, suggesting that furosemide and T4 share a common binding site. A single oral dose of 500 mg furosemide given to five patients maintained on peritoneal dialysis increased the percentage of charcoal uptake of [125I]T4 (using serum diluted 1:10) from 4.1 +/- 1.0 (+/- SE) to 10.8 +/- 4.3 (P less than 0.01) after 2 h, while decreasing total T3 from 75 +/- 5 to 56 +/- 13 ng/dl (P less than 0.01) and total T4 from 6.7 +/- 0.9 to 4.8 +/- 0.8 micrograms/dl (P less than 0.01) after 5 h. Various ligands inhibited [125I]T4 binding to serum proteins in the following relative molar relationship: T4, 1; furosemide, 1.5 X 10(3); fenclofenac, 2 X 10(4); mefenamic acid. 2.5 X 10(4); diphenylhydantoin, 4 X 10[4); ethacrynic acid, 10(5); heparin 5 X 10(5); 2-hydroxybenzoylglycine, 10(6); and sodium salicylate, 1.5 X 10(6). These studies demonstrate that furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T4 and T3 levels. The drug is much more potent on a molar basis than other drug inhibitors of T4 binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T4 or T3. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T4- and T3-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness. The significance of this drug in reports of impaired hormone and drug binding in renal failure requires further assessment.
Assuntos
Furosemida/sangue , Receptores de Superfície Celular/metabolismo , Proteínas de Ligação a Tiroxina/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangue , Ligação Competitiva , Carvão Vegetal , Dextranos , Diálise , Furosemida/farmacologia , Humanos , Técnicas In Vitro , Nefropatias/sangue , Cinética , Ligantes , Diálise Peritoneal , Pré-Albumina/metabolismo , Receptores dos Hormônios Tireóideos , Albumina Sérica/metabolismoRESUMO
Responses of the pituitary-thyroid axis and T4 binding to plasma proteins were studied in three kindreds with familial euthyroid T4 excess, an autosomal dominant condition in which affected subjects have high concentrations of plasma T4 with a high free T4 index, but normal free T4 by equilibrium dialysis. Treatment of affected subjects with exogenous T4 or T3 led to gradual suppression of TSH secretion when the free level of T4 or T3 increased above normal. When total T4 was reduced toward normal by potassium iodide treatment or previous subtotal thyroidectomy, the findings suggested mild hormone deficiency. In affected subjects from all three families, equilibrium dialysis showed increased [125I]T4 binding, with evidence of abnormal high capacity binding when an excess of unlabeled T4 was added. In contrast, T3 binding showed no major abnormality. Serum concentrations of T4-binding globulin, prealbumin, and albumin were normal, but gel electrophoresis and immunoprecipitation of binding proteins indicated that 25-30% of tracer [125I]T4 was albumin bound (normal, 10-12%). Abnormal binding, studied by an adsorption separation system in the presence of T4 excess, was inhibited by increments of barbitone. These findings suggest that T4 excess is an appropriate response to abnormal T4 binding so as to maintain normal free T4. The excess bound T4 is associated with a normal quantity of albumin. The basis for increased T4-albumin binding remains to be determined.
Assuntos
Albumina Sérica/metabolismo , Doenças da Glândula Tireoide/genética , Tiroxina/sangue , Adolescente , Adulto , alfa-Globulinas/metabolismo , Barbital/farmacologia , Feminino , Humanos , Masculino , Ligação Proteica/efeitos dos fármacos , Doenças da Glândula Tireoide/sangue , Tireotropina/sangue , Hormônio Liberador de Tireotropina , Proteínas de Ligação a Tiroxina/metabolismo , Tri-IodotironinaRESUMO
Serum samples taken from four patients who had low serum T4 concentrations (less than 2 micrograms/dl) during severe non-thyroidal illness were found to contain a heat-stable, dialyzable inhibitor of 125I T4 binding to plasma proteins. Inhibitory activity coincided with high dose furosemide treatment for oliguric renal failure. Inhibition was proportional to the serum furosemide concentration and the effect was reproduced in vitro by addition of furosemide to normal serum. The inhibitory effect diminished with serum dilution while maintaining the same relative concentration of furosemide. A time-course study in one patient demonstrated a close temporal relationship between high serum concentrations of furosemide and subnormal T4, associated with T3 resin uptake values compatible with increased occupancy of T4-binding globulin by a competitor. These findings demonstrate that furosemide in high concentrations can inhibit T4 binding in plasma and may be a factor contributing to the development of the low T4 state in critical illness.
Assuntos
Furosemida/farmacologia , Tiroxina/sangue , Injúria Renal Aguda/sangue , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Ligação Proteica/efeitos dos fármacosRESUMO
GH treatment in adults with GH deficiency has numerous beneficial effects, but most studies have been small. We report the results of an Australian multicenter, randomized, double-blind, placebo-controlled trial of the effects of recombinant human GH treatment in adults with GH deficiency. GH deficiency was defined as a peak serum GH of < 5 mU/liter in response to insulin-induced hypoglycemia. Patients were randomly assigned to receive either GH (0.125 U/kg per week for 1 month and 0.25 U/kg per week for 5 months) or placebo. After 6 months, all patients received GH. The primary end points were biochemical responses, body composition, quality of life, and safety. One hundred sixty-six patients (72 females and 91 males) with a mean age of 40 +/- 1 yr (+/- SEM; range 17-67 yr) were recruited. Serum insulin-like growth factor-I (IGF-I) increased from a standard deviation score of -2.64 +/- 0.27 (range -8.8 +3.82; n = 78) to +1.08 +/- 2.87 (range -7.21 to +6.42) at 6 months in the GH/GH group; 38% of the whole group were above the age-specific reference range following treatment [17.6% and 68.9% with subnormal (< 2 SD) or normal (+/- 2 SD) pretreatment levels, respectively]. Fasting total cholesterol (P = 0.042) and low-density lipoprotein cholesterol (P = 0.006) decreased over the first 6 months. Fat-free mass increased in the first 6 months whether measured by bioelectrical impedance (P < 0.001) or dual energy x-ray absorptiometry (DEXA; P < 0.001). Total-body water increased in the first 6 months whether measured by bioelectrical impedance (P < 0.001) or deuterium dilution (P = 0.002). Fat mass measured by DEXA (P < 0.001), skinfold thicknesses (P < 0.001), and waist/hip ratio (P = 0.001) decreased in the first 6 months. Most changes in body composition were complete by 3 months of treatment and maintained to 12 months. Whole-body bone mineral density (BMD) (by DEXA) was unaffected by GH treatment. Self-reported quality of life was considered good before treatment, and beneficial treatment effects were observed for energy, pain, and emotional reaction as assessed by the Nottingham Health Profile. In the initial 6 months, adverse effects were reported by 84% of patients in the GH and 75% in the placebo group, with more symptoms relating to fluid retention in the GH group (48% vs. 30%; P = 0.016). Such symptoms were mild and resolved in 70% of patients despite continued treatment. Resting blood pressure did not change over the initial 6 months. In summary, GH treatment in adults with GH deficiency resulted in 1) prominent increases in serum IGF-I at the doses employed, in some cases to supraphysiological levels; 2) modest decreases in total- and low-density lipoprotein cholesterol, together with substantial reductions in total-body and truncal fat mass consistent with an improved cardiovascular risk profile; 3) substantial increases in lean tissue mass; and 4) modest improvements in perceived quality of life. The excessive IGF-I response and side-effect profile suggests that lower doses of GH may be a required for prolonged GH treatment in adults with severe GH deficiency.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Qualidade de Vida , Adulto , Análise de Variância , Austrália , Pressão Sanguínea , Densidade Óssea/efeitos dos fármacos , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dexametasona , Método Duplo-Cego , Emoções , Feminino , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/sangue , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Placebos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Triglicerídeos/sangue , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
The synthesis of a series of mono- and disubstituted N-phenylanthranilic acids is described. Substituents on the phenyl ring include Cl, CN, OH, CF3, Br, I, CH3, OCH3, and OCF2CF2H. These compounds have been tested for their inhibitory effect on triiodothyronine (T3) uptake by H4 hepatocytes. The nonsteroidal antiinflammatory drugs flufenamic acid, mefenamic acid, and meclofenamic acid and the structurally related compounds 2,3-dimethyldiphenylamine and diclofenac were also tested. The most potent compounds were found to be, in order of decreasing activity, meclofenamic acid (2,6-Cl2,3-CH3), flufenamic acid (3-CF3), mefenamic acid (2,3-(CH3)2), and the compounds with 3,5-Cl2 and 3-OCF2CF2H substituents. The least potent compounds had 3-CN and 3-OH substituents. An analysis of quantitative structure-activity relationships (QSAR) for the series of phenylanthranilic acids showed that the inhibition of T3 uptake is highly dependent on the hydrophobicity of the compound. The relationship between uptake inhibition and the calculated octanol-water partition coefficient (clogP) was found to be parabolic, with optimum inhibitory activity found when the clogP of the phenylanthranilic acid was 5.7. It was also found that the 1-carboxylic acid group of the phenylanthranilic acids was not a prerequisite for uptake inhibition to occur, but its removal or alteration resulted in reduced inhibition.
Assuntos
Fígado/metabolismo , Tri-Iodotironina/metabolismo , ortoaminobenzoatos/química , Animais , Fenômenos Químicos , Físico-Química , Ácido Flufenâmico/farmacologia , Fígado/efeitos dos fármacos , Neoplasias Hepáticas Experimentais , Ácido Meclofenâmico/farmacologia , Ácido Mefenâmico/farmacologia , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , ortoaminobenzoatos/farmacologiaRESUMO
The choice of treatment for hyperthyroidism should be preceded by considering: (a) whether the diagnosis is correct; (b) the severity of the disorder; (c) the cause of the thyroid hormone excess; (d) factors such as patient age, size of goitre, associated diseases, previous treatment, and (e) patient preference. If hyperthyroidism appears to be severe, a judgement based on clinical rather than biochemical features, there is generally no safe alternative to the initial use of a drug from the thioamide thioureylene group (carbimazole, methimazole or propylthiouracil) to make the patient euthyroid as rapidly as possible. There are numerous different schedules for the use of these drugs, alone or in conjunction with surgery, radioactive iodine, or drugs such as beta-blocking agents, iodide or thyroxine. Patients can be made euthyroid with reasonable certainty, but an underlying abnormality often remains. The patient's understanding of the natural history of his or her condition is crucial in achieving adequate follow-up.