初始小剂量甲巯咪唑对Graves病甲亢患者甲状腺功能和Visfatin、TNF-α、IL-6水平的影响

目的:分析初始小剂量甲巯咪唑治疗对Graves病甲状腺功能亢进症(甲亢)患者甲状腺功能和内脂素(Visfatin)、肿瘤坏死因子-α(Tumor necrosis factor-alpha, TNF-α)、白介素-6(Interleukin-6, IL-6)水平的影响。方法:选择我院2017年1月-2018年6月诊治的125例Graves病甲亢患者,根据入院编号随机数字表法分为两组。对照组63例给予甲硫咪唑15 mg/次,2次/d;研究组62例给予甲硫咪唑10 mg/次,2次/d,两组均连续治疗6个月,对比两组治疗总有效率、治疗前后甲状腺功能和血清Visfatin、TNF-α、IL-6水平的变化。结果:治疗后,研究组的治疗总有效率显著高于对照组(90.32%vs. 77.78%,P<0.05);两组患者的甲状腺功能指标血清游离三碘甲状腺原氨酸(Free triiodothyronine, FT3)、血清游离甲状腺素(FT4)水平均显著降低、敏感促甲状腺激素(Sensitive thyroid stimulating hormone, s TSH)水平均显著升高,且研究组以上指标变化较对照组更显著(P<0.05);两组患者的血清Visfatin、TNF-α、IL-6水平均较治疗前显著下降,且研究组以上指标均显著低于对照组(P<0.05)。结论:初始小剂量(10 mg/次)甲巯咪唑治疗Graves病甲亢的疗效显著优于甲硫咪唑15 mg/次治疗,可能与其有效改善患者的甲状腺功能和血清Visfatin、TNF-α、IL-6等炎症因子水平有关。     

Methimazole complexes of platinum(II): Synthesis, characterization and redox behavior

A variety of platinum(II) complexes of methimazole (2-mercapto-1-methylimidazole; HImS = neutral form and ImS = thiolate form), coordinated in both thione and thiolate forms, have been isolated by reacting methimazole with [PtCl(terpy)]Cl (terpy = 2,2′:6′,2″ terpyridine), [PtCl₂(bipy)] (bipy = bipyridine), [PtCl₂(o-phen)] (o-phen = o-phenanthroline), [PtCl₂(CH₃CN)₂] and [PtCl₂(COD)] (COD = 1,5-cyclooctadiene). These complexes were characterized by electronic absorption, IR and NMR (¹H, ¹³C, ¹⁹⁵Pt) spectroscopies. Molecular structure of [Pt(bipy)(HImS)₂]Cl₂·3H₂O (3a·3H₂O) has been established by single crystal X-ray crystallography. Platinum thiolate complex, [Pt(ImS)₂(HImS)₂] (5), could be obtained by treatment of [Pt(HImS)₄]Cl₂ with sodium methoxide in methanol. The solution of 5 in organic solvents yielded bi- and tri-nuclear platinum complexes. The effect of diimine ligands on oxidation of methimazole moiety in the complexes has been studied by electrochemical oxidation and pulse radiolytic oxidation employing specific one-electron oxidant, radical.     

Inhibitory effects of novel synthetic methimazole derivatives on mushroom tyrosinase and melanogenesis

In this study, we synthesized 4 methimazole (2-mercapto-1-methylimidazole, MMI) derivatives. The kinetics of inhibition on mushroom tyrosinase by methimazole and its derivatives were investigated. The results indicated that tert-butyl 3-methyl-2-sulfanylidene-2,3-dihydro-1H-imidazole-1-carboxylate (compound 3; 3), 2-mercaptoimidazole (MI; compound 1; 1) and MMI (compound 2; 2) significantly inhibited tyrosinase activity in a dose-dependent manner, exhibiting an IC₅₀ value of 1.50 mM, 4.11 mM, and 1.43 mM. However, compound 4 (4), compound 5 (5), and compound 6 (6) exerted no inhibitory effect on mushroom tyrosinase activity. Kinetic analysis indicated that 3 was a noncompetitive tyrosinase inhibitor, whereas both 1 and 2 were exhibited as mixed-type tyrosinase inhibitors. Furthermore, 3 exerted a potent inhibitory effect on intracellular melanin formation in the B16/F10 murine melanoma cells and did not cause cytotoxicity, as 1 and 2 did.     

Oxidation Products and Antioxidant Markers in Plasma of Patients with Graves' Disease and Toxic Multinodular Goiter: Effect of Methimazole Treatment

Oxidative stress plays an important role in hyperthyroidism-induced tissue damage, as well as in development of autoimmune disorders. To clarify influence of thyroid metabolic status and autoimmune factors on blood extracellular indices of reactive oxygen species (ROS) generation and free radical scavenging in hyperthyroidism, we studied patients with newly diagnosed and untreated Graves' disease without infiltrative ophthalmopathy (17 female and 8 male, aged 41.8±8.9) and toxic multinodular goiter (15 female and 9 male, aged 48.4±10.1) under the same antithyroid treatment protocol. Initially and after achievement of stable euthyroidism with methimazole, plasma levels of hydrogen peroxide (H²O²), lipid hydroperoxides (ROOH) and ceruloplasmin (CP) and serum concentrations of thiobarbituric acid-reacting substances (TBARS) were determined. Similarly, activities of plasma superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were assayed. The results were compared to those of age- and sex-matched controls. Average duration of hyperthyroidism and treatment period were similar in both patients groups. H²O², ROOH and TBARS concentrations were significantly higher in hyperthyroid patients compared to controls. Hyperthyroidism caused an evident increase in SOD and CAT activities and CP level, as well as a decrease in GPx and GR activities. Achievement of euthyroidism resulted in normalization of all analyzed parameters in both hyperthyroid patients groups. These findings suggest that the changes in blood extracellular indices of oxidative stress and free radical scavenging in hyperthyroid patients are influenced by thyroid metabolic status, and are not directly dependent on autoimmune factors present in Graves' disease.     

Selenium analogues of antithyroid drugs--recent developments

Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase (TPO)/H(2)O(2)/iodide system and deiodinated to its active form (T3) by a selenocysteine-containing enzyme, iodothyronine deiodinase (ID). The activation of thyroid-stimulating hormone (TSH) receptor by auto-antibodies leads to 'hyperthyroidism', a life-threatening disease which is treated by antithyroid drugs such as 6-propyl-2-thiouracil (PTU) and methimazole (MMI). The present review describes the biological activities of a number of S/Se derivatives bearing the methimazole pharmacophore. It is shown that the isosteric substitutions in the existing drugs lead to compounds that can effectively and reversibly inhibit the heme-containing lactoperoxidase (LPO). In contrast to methimazole, the selenium analogue, MSeI, does not interfere with the enzyme directly, but it inhibits LPO by reducing the H(2)O(2) that is required for the oxidation of the Fe-center in LPO. These studies reveal that the degradation of the intracellular H(2)O(2) by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland, as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on H(2)O(2) can reversibly inhibit the thyroid peroxidase, such drugs could be of great importance in the treatment of hyperthyroidism.     

比索洛尔联合甲巯咪唑治疗甲状腺功能亢进合并快速心律失常疗效观察

目的探讨比索洛尔与甲巯咪唑对甲状腺功能亢进(甲亢)合并快速心律失常的临床治疗效果。方法选择2015年1~12月在我院接受治疗的甲亢合并快速心律失常患者78例,随机分为对照组和观察组各39例,对照组给予甲巯咪唑单药治疗,观察组给予比索洛尔联合甲巯咪唑治疗,比较两组临床疗效。结果观察组治疗有效率为92.31%,显著高于对照组的74.36%(χ2=7.65,P0.05);观察组治疗后的FT3、FT4、TSH均显著低于对照组,且观察组的FT3/FT4相对更高(t=10.34、13.50、13.43、12.54,均P0.05);观察组的不良事件发生率和不良反应发生率均显著低于对照组(χ2=5.43、6.17,P0.05)。结论比索洛尔联合甲巯咪唑治疗甲亢合并快速心律失常患者的效果确切,能有效改善患者症状,降低不良事件发生率,具有较高的推广应用价值。     

Bioinorganic chemistry aspects of the inhibition of thyroid hormone biosynthesis by anti-hyperthyroid drugs

In this paper, the synthesis and characterization of thiones and selones having N,N-disubstituted imidazole are described. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by ⁷⁷Se NMR spectroscopy and the ⁷⁷Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution. The thermal isomerization of some S- and Se-substituted methyl and benzyl imidazole derivatives to produce the thermodynamically more stable N-substituted derivatives are described. A structure-activity correlation was attempted on the inhibition of LPO-catalyzed oxidation and iodination reactions by several thiouracil compounds, which indicate that the presence of an n-propyl group in PTU is important for an efficient inhibition. In contrast to the S- and Se-substituted derivatives, the selones produced by thermal isomerization exhibited efficient inhibition, indicating the importance of reactive selone (zwitterionic) moiety in the inhibition. The inhibition data on carbimazole (CBZ) support the assumption that CBZ acts as a prodrug, requiring a conversion to methimazole (MMI) for its inhibitory action on thyroid peroxidase.     

碘131与他巴唑治疗甲状腺功能亢进症的临床疗效比较

目的:观察和比较碘131与他巴唑治疗甲状腺功能亢进症的临床疗效及安全性。方法:选取2012年1月至2016年1月于我院确诊并治疗的甲状腺功能亢进患者282例,根据随机数字表法分为碘131治疗组和药物治疗组,碘131治疗组采用131I进行治疗,药物治疗组采用他巴唑口服治疗。比较两组患者的临床疗效,治疗前后血清TSH(thyroid stimulating hormone,促甲状腺激素)、FT(free triiodothyronine,游离三碘甲状腺原氨酸)、FT4(free thyroxine concentration assay,血清游离甲状腺素)水平及TRAb(TRAB thyrotropin receptor antibodies,促甲状腺激素受体抗体)阳性率的变化及治疗期间不良反应的发生情况(心功能、肝功能、肾功能、甲状腺功能下降、白细胞减少),并对患者进行6个月的随访,记录和比较患者甲亢复发情况。结果:治疗后,碘131治疗组的总有效率为92.9%,显著高于药物治疗组(64.5%,P0.05);两组患者血清TSH水平较治疗前显著升高,而血清FT3、FT4水平及TRAb阳性率均较治疗前显著降低(P0.05),且碘131治疗组血清TSH水平明显高于碘131治疗组,而血清FT3、FT4水平及TRAb阳性率明显低于碘131治疗组(P0.05);碘131治疗组复发率及总不良反应发生率均明显低于药物治疗组(P0.05)。结论:碘131对甲状腺功能亢进症的疗效优于他巴唑口服治疗,可明显增加血清TSH水平,降低血清FT3、FT4水平及TRAb阳性率,且患者复发率及不良反应发生率均较低。     

Effect of thyroid deficiency on Go α-subunit isoforms in developing rat cerebral cortex

Postnatal development of G_o isoforms in rat cerebral cortex was studied by SDS-PAGE and immunoblotting. When rat cerebral cortical membranes were resolved on separating gels containing 9% acrylamide and 8 M urea, three electrophoretically distinct G_o-immunoreactive proteins were evident. Comparison of their electrophoretic mobilities and partial tryptic digest pattern with recombinant G_o1 or G_o1-specific antibody revealed that the slowest and intermediate-migrating bands represent unmodified and fatty acylated forms of G_o1 protein, respectively. The fastestmigrating band corresponds to G_o2. While the fatty acylated form of G_o1 is the predominant species, its appearance paralleled that observed for G_o2 in developing rat cortex. Perinatal hypothyroidism induced by methimazole treatment did not significantly alter the appearance of cerebral cortical G_o1 and G_o2 between days 1 and 22 postpartum. Our findings support the earlier idea that heterogeneity of G_o proteins in mammalian brain is likely the result of different co- or post-translational processings of each splice variant of G_o. While the appearance of G_o isoforms is developmentally regulated, they likely do not play an obligatory role in neonatal brain development. Alternatively, the expression of G_o isoforms in developing rat cortex may be controlled by an intrinsic signal(s) that is independent of the thyroid status.     

Oxidation products and antioxidant markers in plasma of patients with Graves' disease and toxic multinodular goiter: effect of methimazole treatment

Oxidative stress plays an important role in hyperthyroidism-induced tissue damage, as well as in development of autoimmune disorders. To clarify influence of thyroid metabolic status and autoimmune factors on blood extracellular indices of reactive oxygen species (ROS) generation and free radical scavenging in hyperthyroidism, we studied patients with newly diagnosed and untreated Graves' disease without infiltrative ophthalmopathy (17 female and 8 male, aged 41.8±8.9) and toxic multinodular goiter (15 female and 9 male, aged 48.4±10.1) under the same antithyroid treatment protocol. Initially and after achievement of stable euthyroidism with methimazole, plasma levels of hydrogen peroxide (H₂O₂), lipid hydroperoxides (ROOH) and ceruloplasmin (CP) and serum concentrations of thiobarbituric acid-reacting substances (TBARS) were determined. Similarly, activities of plasma superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were assayed. The results were compared to those of age- and sex-matched controls. Average duration of hyperthyroidism and treatment period were similar in both patients groups. H₂O₂, ROOH and TBARS concentrations were significantly higher in hyperthyroid patients compared to controls. Hyperthyroidism caused an evident increase in SOD and CAT activities and CP level, as well as a decrease in GPx and GR activities. Achievement of euthyroidism resulted in normalization of all analyzed parameters in both hyperthyroid patients groups. These findings suggest that the changes in blood extracellular indices of oxidative stress and free radical scavenging in hyperthyroid patients are influenced by thyroid metabolic status, and are not directly dependent on autoimmune factors present in Graves' disease.