THE EFFECT OF AMIODARONE ON THE CONTROL OF HYPERTHYROIDISM BY PROPYLTHIOURACIL

We studied the efficacy of amiodarone (800, 600, 400 and 200 mg orally daily during weeks 1, 2, 3 and 4, respectively) plus propylthiouracil (PTU, 100 mg orally every 8 h) in comparison to PTU alone in the early treatment (28 days) of Graves' disease patients. Circulating T3 and T4 decreased earlier and more markedly in the amiodarone plus PTU-treated group. An initial rise of circulating rT3 above the base-line value followed by a gradual decline was observed in the former group while only a decline below the base-line values was observed in the latter group. The resting pulse rate decreased and body weight increased significantly in the amiodarone plus PTU-treated group. In the PTU-treated group, significant weight gain was observed later in the course of treatment while no significant reduction in pulse rate was observed. No major side-effects of amiodarone were observed during the course of treatment. This study suggested that the combination of amiodarone and PTU was more efficacious than PTU alone in reducing circulating T3, T4 and clinical hyperthyroidism early in the course of treatment of patients with Graves' disease. This regimen has an additional potential advantage because of the antiarrhythmic property of amiodarone, especially in situations when a beta-blocker is contraindicated.     

EFFECT OF THYROXINE ON THE INACTIVATION OF THYROTROPHIN-RELEASING HORMONE BY RAT AND HUMAN PLASMA

The inactivation of synthetic [³H]thyrotrophin-releasing hormone (TRH) by plasma was studied in rats treated with propylthiouracil (PTU) alone or with PTU and thyroxine. 48 h after the onset of treatment with thyroxine, the capacity of rat plasma to inactivate [³H]TRH was significantly increased. The percentage of deamidation of TRH to TRH-free acid was increased 2-fold after 4 days of administration of thyroid hormone. The inactivation of TRH by plasma from hypothyroid patients was compared to that obtained from hyperthyroid patients. Extraction of human plasma incubated with [³H]TRH, followed by thin-layer electrophoresis, showed that transformation of [³H]TRH into TRH-free acid was 44% higher in plasma from hyperthyroid than from hypothyroid patients (P < 0.05). These data suggest that the inactivation process of TRH by blood proteins could be an important factor in the regulation of the hypothalamo-hypophyseal-thyroid axis in rat and man.     

甲状腺素对前列腺素（PGE1）免疫抑制作用的拮抗作用

同步检测前列腺素组、甲状腺片拮抗组BALB/C纯系小鼠血清T_3、T_4的水平及相应免疫指标的变化。结果显示甲状腺片(1.2μg/日/g体重)对免疫抑制剂前列腺素E_1(PGE_1 10~(-8)mol/L)具有一定的拮抗作用,发现甲状腺素可逆转前列腺素抑制BALB/c小鼠腹腔渗出巨噬细胞(Mφ)吞噬活性及抗体形成细胞的活性,可明显增高脾脏NK细胞对小鼠腹水型肝癌细胞(Hepa系)的杀伤作用。     

THE EFFECT OF MINOR INCREMENTS IN PLASMA THYROXINE ON HEART RATE AND URINARY SODIUM EXCRETION

We studied day/night (D:N) patterns of urinary sodium excretion and the 24 hour ambulatory electrocardiogram in seven normal subjects before and during the administration of T4. Thyroxine increased thyroid hormone levels within the normal range and inhibited the plasma TSH response to TRH. This was associated with a significant decrease in D:N sodium excretion (P less than 0.01) and D:N urine flow (P less than 0.01), a significant increase in mean nocturnal heart rate (P less than 0.01), and a lesser increment in mean daytime heart rate (P less than 0.05). These responses to small changes in thyroid hormone levels suggest that the anterior pituitary is not alone in recognising minor thyroid hormone excess. The clinical implication is that some patients with a normal T3 and T4 but an impaired TSH response to TRH might benefit from antithyroid treatment.     

EFFECT OF HEPARIN ON SERUM FREE THYROXINE LINKED TO POST-HEPARIN LIPOLYTIC ACTIVITY

A possible association between free T4 (fT4) changes, occuring after heparin administration, and the post-heparin lipolytic activity, i.e., the release of lipases and the lipolysis of triglycerides to non-esterified fatty acids (NEFAs) was studied. In 19 patients heparin increased mean fT4 values obtained by equilibrium dialysis from 23·4 to 38·6 pmol/l (P<0·01) and mean fT4 values measured by GammaCoat two-step RIA from 17·0 to 24·1 pmol/l (P < 0·01), the results of the two methods agreeing well (r_S= 0·88). Concurrently, NEFAs increased from a mean of 0·55 to 2·20 mmol/l (P < 0·01) and fT4 increases were significantly correlated with post-heparin NEFAs (r_S= 0·69, P < 0·001). In vitro addition of palmitic acid to sera increased fT4 concentrations to values similar to those observed in vivo. Post-heparin fT4 increases were also strongly correlated to the concentrations of triglycerides (r_S= 0·63, P < 0·01). Hypertrig-lyceridaemia was associated with pronounced fT4 increases after heparin administration, and normolipidaemia with moderate or no changes. These results suggest that the effect of heparin on fT4 is linked to the activation of lipases by heparin and is mediated by NEFAs, which, at high concentrations, compete with thyroxine for binding proteins.     

COMPUTED TOMOGRAPHY OF THE PITUITARY FOSSA IN PRIMARY HYPOTHYROIDISM. EFFECT OF THYROXINE TREATMENT

Computed tomography of the pituitary fossa was performed in 12 patients with primary hypothyroidism before and after thyroxine treatment. In three, herniation of the diaphragma sellae precluded accurate measurement of the density of the hypophysis. Eight of the remaining patients showed abnormally increased density of the pituitary gland after intravenous injection of contrast substance which was significantly correlated with the serum TSH-level (r = 0.913, P less than 0.001). After thyroxine treatment the intrasellar density decreased substantially in all but one. We suggest that the observed contrast enhancement reflects increased pituitary circulation associated with the augmented function of TSH-producing cells in response to thyroid hormone deficiency.     

EVALUATION OF T4 AND T3 BINDING KINETICS IN THE THYROXINE BINDING GLOBULIN ABNORMALITY OF AUSTRALIAN ABORIGINES

Low serum total T4 associated with subnormal concentrations of thyroxine binding globulin (TBG) has been reported in up to 40% of euthyroid Australian aborigines. It has been suggested that these subjects show both diminished concentration of TBG and reduced TBG affinity for T4 (Sarne et al., 1985). We have compared 12 euthyroid aborigines with low T4 (total T4 44 +/- 5 nmol/l) and aborigines with normal T4 (T4 99 +/- 9 nmol/l, n = 12) using measurements of free T4 and T3 by equilibrium dialysis. TBG was measured both by RIA (Henning, Berlin, FRG) and a method dependent on T4 binding (Corning Immophase). Aborigines with low T4 showed lower levels of free T4 (12.6 +/- 0.6 cf. 18.7 +/- 1.0 pM), free T4 index (66 +/- 8 cf. 98 +/- 13), total T3 (1.1 +/- 0.2 cf. 1.6 +/- 0.3 nmol/l), TBG RIA (14.0 +/- 0.6 cf. 25.0 +/- 1.2 ng/l), and TBG Immophase (9.0 +/- 0.5 cf. 22.0 +/- 1.2 mg/l) (P less than 0.01), but free T3 (5.3 +/- 0.4 cf. 4.7 +/- 0.4 pM) and TSH (1.9 +/- 0.2 cf. 1.8 +/- 0.2 mU/l) were not significantly different from the values found in aborigines with normal T4. Scatchard analysis of T4 and T3 binding was performed using serum diluted 1 : 20,000 for T4 and 1 : 500 for T3 (barbitone buffer pH 8.6, 4 degrees C, dextran-coated charcoal separation). In euthyroid low T4 aborigines compared to those with normal T4, both T4 capacity (106 +/- 14 cf. 238 +/- 13 nM, P less than 0.01) and affinity (5.05 X 10(10) cf. 8.47 X 10(10) M-1, P less than 0.05) were significantly reduced. Similarly, both T3 capacity (62 +/- 10 cf. 154 +/- 16 nM, P less than 0.01) and affinity (1.67 X 10(9) cf. 2.28 X 10(9) M-1, P less than 0.02) were reduced. A substantial minority of euthyroid Australian aborigines have a TBG variant characterized by both reduced capacity and affinity of T4 and T3. These findings suggest that TBG may be both qualitatively and quantitatively abnormal in these subjects.     

THE INFLUENCE OF CARBAMAZEPINE ON THYROID HORMONES AND THYROXINE BINDING GLOBULIN IN HYPOTHYROID PATIENTS SUBSTITUTED WITH THYROXINE

Carbamazepine (CBZ) decreases the serum concentration of thyroid hormones. It is proposed that CBZ increases the extra-thyroidal metabolism of thyroid hormones. In order to test this hypothesis CBZ was given to nine hypothyroid patients substituted with thyroxine (T4). A significant decrease in serum concentrations of T4, calculated free T4 (FT4), triiodothyronine (T3), and calculated free T3 (FT3) was found after 3 weeks of CBZ medication. The serum concentrations of TSH and the T4:T3 ratios were unaltered, while the serum concentrations of T4-binding globulin (TBG) increased markedly in eight of the nine patients. These findings support the hypothesis of a CBZ induced increase in the extra-thyroidal metabolism of thyroid hormones.     

胺碘酮生物利用度比较及其临床意义

本文对四种国产胺碘酮(乙胺碘呋酮)片或胶囊与法国Cordarone片剂的相对生物利用度进行了比较。结果显示国产制剂分别为Cordarone的55.6%,77.0%,85.4%及91.7%,无一种能达Cordarne水平,并对此结果的临床意义进行了讨论。     

EFFECT OF ORAL THYROTROPHIN-RELEASING HORMONE ON SERUM THYROXINE IN GROWTH HORMONE DEFICIENT AND NORMAL CHILDREN

Oral administration of synthetic TRH in a dose of 80 mg/1-73 m-2 at 0 and 12 h to normal and constitutionally small children caused a significant increase of total serum thyroxine (T4) within 6-24 h. The mean maximal T4 increment was +3-7 plus or minus 1-1 and +3-8 plus or minus 1-2 mug/dl (mean plus or minus 1 SD) respectively in the two groups. Of seventeen euthyroid GH deficient children, fifteen showed a normal and two patients a slightly subnormal response. Of fifteen hypothyroid GH deficient children nine had a prompt and normal increase of serum T4 indicating primary TRH deficiency. Two had a delayed T4 response and four had no response, even after prolonged stimulation. The localization of the primary defect in these latter subjects with severe hypothyroidism can not be made by measuring T4 only, since the thyroid gland may become unresponsive to TSH after longstanding TSH deficiency. TSH measurements are necessary in these circumstances for a clear localization of the primary defect. One GH deficient patient with hypothalamic TRH deficiency was treated with high oral TRH doses for 7 months and showed no side effects.     

THE RADIOIMMUNOASSAY OF THYROXINE IN UNEXTRACTED HUMAN SERUM

A specific, accurate, precise and simple radioimmunoassay for thyroxine (T₄) in small volumes of unextracted serum is described. It discriminates well between levels found in different states of thyroid function. Levels in euthyroid subjects range between 4.3 and 11.2 μg/100 ml (mean 7.7); in untreated hyperthyroid subjects, 13.2-25.6 μg/100 ml (mean 19.2); and in untreated hypothyroid subjects undetectable to 2.6 μg/100 ml (mean 1.4). There is satisfactory correlation with competitive protein binding and protein bound iodine methods. Because of its advantages over previous techniques, it is suggested that T₄ radioimmunoassay will become the routine method of assessing thyroid status.
The measurement of serum thyroxine (T₄) is the single most important test in the routine laboratory assessment of thyroid status. Ideally the T₄ assay should be specific, cheap, simple and have a high sample capacity. Thyroxine is determined most commonly in serum extracts by competitive protein binding (CPB) methods (Murphy & Pattee, 1964; Ekins et al ., 1969) or, indirectly, by estimation of serum protein bound iodine (PBI). Both techniques require the processing of relatively large volumes of serum before assay. The PBI method has the added disadvantage of measuring iodine-containing compounds other than thyroxine (Acland, 1971).
We report here a specific, precise and simple radioimmunoassay for thyroxine in unextracted human serum and its application to the assessment of thyroid status. It has significant advantages over CPB, PBI and previous radioimmunoassay methods.