抗甲状腺药物不良反应的再认识

抗甲状腺药物(ATD)是治疗甲状腺功能亢进症主要手段,其不良反应备受学者们关注.ATD常用药物为丙基硫氧嘧啶(PTU)和甲巯咪唑(MMI).总的来说,ATD治疗是安全且有效的,但其临床不良反应亦较常见,如对肝脏、血液系统的毒性作用、抗中性粒细胞胞浆抗体相关性肺小血管炎、低血糖、变态反应、肌肉损伤等,一般程度较轻,如能及时停用ATD则能够自行恢复,但亦可出现少见、严重的副作用,可能存在潜在致命的危险,故需引起临床医生的重视.MMI与PTU比较,其不良反应显著低于PTU,且前者大多具有剂量依赖性,后者与药物的剂量无显著相关.此外,PTU的肝毒性强于MMI,甚至可能发生致命性肝损伤和肝衰竭,在儿童甲亢治疗中推荐首选MMI.

Abstract：

Antithyroid drugs(ATD)is the main treatment for hyperthyroidism and its adverse reactions have been much concerned by physicians. Methimazole(MMI)and propylthiouracil(PTU)are the two common antitithyroid drugs used currently. Generally, the ATD are safe and effective, though their clinical adverse reactions are also relatively common. The toxic effects include liver damage and leukocytopenia, antineutrophil cytoplasmic antibody-associated pulmonary small-vessel vasculitis, hypoglycemia, allergic reactions, muscle impairment,and so on. They are usually reversible and disappear spontaneously when the drug is discontinued. However,the serious rare side effects can also occur and there may have potentially deadly threatening effects which need to be cautious for the clinicians. MMI is usually preferred over PTU because it has significantly fewer side effects. And unlike the dose-dependent side effects of MMI, there has no significant correlation between adverse reaction and drug dosage in using PTU. Moreover, PTU has more severe hepatotoxity than MMI, even fatal liver impairment and liver failure. The risk of liver damage from PTU is an important concern, particularly in children. For this reason, MMI is the first choice for treating children with hyperthyroidism.     

抗甲状腺药物的免疫抑制作用

抗甲状腺药物(ATD)自1941年开始用于临床治疗Graves病并甲状腺机能亢进症(下称Grave病并甲亢),现已有40多年历史。临床上常用的ATD有丙基硫氧咪啶(PTU)、甲硫咪唑或他巴唑(MMI,Tapazole)、甲亢平(CBZ).长期以来,人们对ATD的药理作用进行了大量的研究工作.过去已知ATD具有抑制甲状腺激素合成的作用.但近十多年来,许多学者通过临床、实验研究发现,ATD除上述作用外,还具有免疫抑制作用.本文介绍ATD的免疫抑制作用的研究近况。     

应加强对抗甲状腺药物治疗所致粒细胞缺乏症的认识

治疗甲状腺功能亢进症(甲亢)的药物,主要有甲巯咪唑(methimazole,MMI)及丙硫氧嘧啶(propyl-thiouracil,PTU).不良反应包括皮肤瘙痒、皮疹、白细胞减少、血管炎、药物性肝病等.当外周血中性粒细胞计数绝对值＜0.5×109/L时称为粒细胞缺乏症,易伴发各种感染,可出现败血症危及生命.因此,重视抗甲状腺药物(antithyroid drugs,ATD)所致的粒细胞缺乏症有重要意义.     

抗甲状腺药物诱导的抗中性粒细胞胞质抗体相关性小血管炎

以丙基硫氧嘧啶(Propylthiouracil,PTU)、他巴唑(Thiamazole,MMI)等为代表的抗甲状腺药物(Antithyroid drugs,ATD)广泛应用于临床甲状腺功能亢进的治疗,同时也是导致药物相关性血管炎最常见的原因之一,其临床特点与原发性小血管炎相比有其特殊之处。本文回顾性分析国内外相关文献,对本病临床特点加以综述,总结其诊治进展,以期指导临床。     

131I与抗甲状腺药物治疗甲亢性心脏病临床疗效比较

目的: 比较131I与抗甲状腺药物（ATD）治疗甲亢性心脏病的临床疗效。方法: 对226例甲亢性心脏病患者分别采用131I（151例）及ATD（75例）治疗,比较两组病例的临床疗效、治疗前后甲状腺激素水平、心电图及超声心动图变化情况。结果: 131I组的总有效率显著高于ATD组（P<0.01);且心功能改善及心电图好转率均显著高于ATD组（均P<0.01)。超声心动图检查:131I组患者LVEF、LVEDD、LVESD、SV及CO治疗后较治疗前显著改善(P<0.01);ATD组治疗前后差异无统计学意义;治疗后两组指标相比差异有统计学意义（P<0.01)。两组治疗后甲状腺激素水平较治疗前均显著降低（P<0.01),但两组治疗后甲状腺激素水平相比无统计学意义。131I组甲状腺功能减退（甲减）发生率显著高于ATD组（17% vs. 0%,P<0.01）。结论: 131I治疗甲亢性心脏病综合疗效优于ATD,缺点是甲减发生率高。     

^131I与抗甲状腺药物治疗甲亢性心脏病临床疗效比较

目的：比较^131I与抗甲状腺药物（ATD）治疗甲亢性心脏病的临床疗效。方法：对226例甲亢性心脏病患者分别采用^131I（151例）及ATD（75例）治疗,比较两组病例的临床疗效、治疗前后甲状腺激素水平、心电图及超声心动图变化情况。结果：^131I组的总有效率显著高于ATD组（P〈0.01）;且心功能改善及心电图好转率均显著高于ATD组（均P〈0.01）。超声心动图检查：^131 I组患者LVEF、LVEDD、LVESD、SV及CO治疗后较治疗前显著改善（P〈0.01）;ATD组治疗前后差异无统计学意义;治疗后两组指标相比差异有统计学意义（P〈0.01）。两组治疗后甲状腺激素水平较治疗前均显著降低（P〈0.01）,但两组治疗后甲状腺激素水平相比无统计学意义。^131I组甲状腺功能减退（甲减）发生率显著高于ATD组（17%vs.0%,P〈0.01）。结论：^131I治疗甲亢性心脏病综合疗效优于ATD,缺点是甲减发生率高。     

一例甲巯咪唑相关性椎管内血管炎经131I治疗后病情迅速进展

人工合成抗甲状腺药物(antithyroid drugs, ATD)用于治疗甲状腺功能亢进(甲亢)已有70多年的历史。抗甲状腺药物是一种被称为硫酰胺的分子, 通过干扰甲状腺过氧化物酶介导的甲状腺球蛋白中酪氨酸残基的碘化来抑制甲状腺激素的合成发挥作用。这类药物也被认为具有免疫抑制作用, 促进甲亢的缓解。甲巯咪唑(MMI)和丙基硫氧嘧啶(propylthiouracil, PTU)是治疗Graves病(GD)最常用的ATD, 其中ATD治疗能使大约60%的患者病情缓解[1]。ATD的不良反应多种多样, 包括白细胞减少和粒细胞缺乏症、肝功能损害、药物性皮疹、抗中性粒细胞胞浆抗体(antineutrophil cytoplasmic antibody, ANCA)阳性血管炎以及再生障碍性贫血等。GD患者ATD相关性血管炎的临床表现极为多样而且罕见, 因为小血管炎症可能影响任何器官。肾脏、肺和皮肤是最常受到疾病影响的器官[1]。此外, 关节痛、滑膜炎、移行性多关节炎、肌炎、巩膜炎、胸膜炎、鼻/口腔黏膜糜烂、心包炎、面瘫和肝炎均有报道[2]。据报道[3]1例GD患者经MMI治疗后发展为中枢神经系统...     

甲状腺功能亢进症的药物治疗

抗甲状腺药物(ATD)治疗的最佳方案要从药物的选择、具体剂量、给药方式、服药疗程、是否合用左旋甲状腺素(L-T4)、免疫抑制剂及其他影响患者缓解率的因素等多方面综合考虑.除妊娠期妇女外,目前大多数学者将甲硫咪唑(MMI)列为治疗甲状腺功能亢进症(甲亢)的首选药物.药物具体起始剂量可根据患者甲状腺的大小、甲亢病情的严重程...     

抗甲状腺药物对体外B、T细胞活性的影响

他巴唑(MMI)、丙基硫氧嘧啶(PTU)一类的抗甲状腺药物,通过阻断碘的有机化而用于控制甲亢GraVes 病。治疗中患者血清三碘甲腺原氨酸(T_3)、甲状腺素(T_4)下降,抗甲状腺刺激激素(TSH)受体抗     

甲状腺功能亢进合并白细胞减少症21例临床分析

甲状腺功能亢进症（甲亢）中一部分患者，尤其是Graves病甲亢（GD）常合并白细胞减少，甚至粒细胞缺乏时可诱发重症感染、败血症及甲亢危象等。给治疗带来困难，如不及时治疗，会危及生命。临床医生常常会感到棘手。因此提高甲亢病人白细胞水平对治疗甲亢至关重要。我院自2002年12月～2004年12月收集了门诊及住院甲亢合并白细胞减少病人21例，给予糖皮质激素结合抗甲状腺药物治疗，收到良好效果，分析如下。     

Antithyroid drugs during breastfeeding

Antithyroid drugs (ATDs) are widely used for the treatment of Graves’ disease (GD) in the general population. Over the past decade, there has been an increasing awareness that several disturbances of thyroid function may occur in mothers after delivery which may be more prevalent than previously appreciated. Exacerbation of immune reactions occurs 3–12 month following delivery. Management of hyperthyroidism during lactation requires special considerations and should be implemented to prevent any adverse outcomes in mother and neonate. Continuation of breastfeeding is safe and should be encouraged in hyperthyroid mothers taking ATDs, whether these are ATDs being continued after gestation or indeed ATD treatment initiated in the postpartum period. Given PTU hepatotoxicity concerns, experts currently recommend using low‐to‐moderate MMI doses as a first‐line therapy in lactating mothers. PTU should be reserved only as a second‐line agent for cases of severe hyperthyroidism (thyroid storm) and allergic reactions to previous MMI treatment. ATD should be administered in divided doses immediately following each feeding. Evaluation of thyroid function tests is advisable at least 3–4 weeks after the initiation of breastfeeding.     

The effect of propylthiouracil on the efficacy of radioiodine (I-131) therapy in graves hyperthyroidism

Aiming at evaluating the effect of antithyroid drugs on the efficacy of radioiodine treatment (RAI) we retrospectively analyzed 226 patients with Graves disease hyperthyroidism submitted to RAI between 1990 and 2001: 58 patients without any antithyroid drug (ATD) prior to RAI, 119 patients using propylthiouracil (PTU) and 49 patients using methimazole (MMI) prior to RAI. Clinical and laboratory parameters 1 year after RAI defined their clinical status (cured or not cured). High serum free T4 and 131-iodine uptake were negatively related with cure as well as lower RAI doses (mCi) and larger goiters (p< 0.05). The percentage of cured patients on PTU prior to RAI was 70.2% (84/119), while those on MMI was 85.7% (42/49), and 84.5% (49/58) of those without ATD prior to RAI (p= 0.034). On logistic regression analysis, free T4 > 4 ng/dl, large goiter, RAI dose < 10 mCi and PTU prior to RAI were related to lower cure rates. Compared to patients with no ATD prior to RAI, we concluded that the previous use of PTU implies in higher failure rates after RAI (OR= 3.13), an effect not observed in patients on MMI (OR= 1.28).     

Graves病合并妊娠

妊娠期甲状腺激素代谢的生理性改变使Graves病的诊治更加复杂。妊娠期Graves病必须使用抗甲状腺药物（ATD）治疗,尽可能使用最低剂量的ATD维持母体游离甲状腺素（n）于非孕期的正常高值附近是最理想的选择。胎儿甲状腺功能取决于通过胎盘屏障的促甲状腺激素（TSH）受体抗体（TRAb）与ATD之间的平衡。晚孕早期母体TRAb滴度升高是胎儿发生甲状腺功能亢进的一个危险因素,此时亦应行胎儿甲状腺超声检查。临床可以通过调整孕妇ATD用量治疗胎儿甲状腺功能亢进。若妊娠期Graves病未得到控制,或孕妇曾因Graves病行放射性碘治疗或甲状腺切除术,怀孕时TRAb仍阳性者,须于分娩时检测脐带血TSH及FT4（总甲状腺素）。     

甲状腺功能亢进症与妊娠

本文研究甲状腺功能亢进症（甲亢）伴妊娠的安全性,无论是妊娠或哺乳,首选丙基硫氧嘧啶,也可用他巴唑;调整抗甲状腺药物（ATD）剂量,以游离T4为指标。甲亢患者应选择妊娠时机。妊娠早期病情会加重,ATD剂量需增加,晚期由于免疫耐受,甲亢可缓解,需减少剂量或停药,产后甲亢易复发。     

药物治疗甲状腺功能亢进症患者不良反应的临床研究

目的探讨两种常见药物治疗甲状腺功能亢进症（甲亢）不良反应发生率,特别是出现抗中性粒细胞胞浆抗体（ANCA）阳性血管炎发生率和临床特点。方法将227例确诊的甲亢患者随机分为两组,分别给予硫脲类（121例）和咪唑类（106例）治疗。随访两组患者药物不良反应发生事件。采用间接免疫荧光法测定患者血清ANCA浓度,ELISA法测定血清抗蛋白酶3和髓过氧化物酶浓度。化学放光法测定甲状腺激素水平。结果硫脲类组患者不良反应为药物性皮疹8例（6．61％）,粒细胞减少4例（3．30％）,肝功能损害3例（2．48％）,ANCA阳性血管炎5例（4．13％）。咪唑类治疗甲亢不良反应药物性皮疹7例（6．60％）,粒细胞减少6例（5．66％）,肝功能损害3例（2．83％）,ANCA阳性血管炎0例。结论服用硫脲类和咪唑类两种药物治疗甲亢患者,药物性皮疹、肝功能受损和粒细胞减少发生率无显著性差异,但硫脲类组发生ANCA阳性血管炎比率明显高于咪唑类组。     

Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves' hyperthyroidism

OBJECTIVE: The present study was to compare the efficacy of a single daily dose of methimazole (MMI) and propylthiouracil (PTU) in the treatment of Graves' hyperthyroidism. BACKGROUND: Antithyroid drugs, MMI and PTU, are widely used in the treatment of hyperthyroidism. Previous studies in the treatment of hyperthyroidism with a single daily dose of antithyroid drugs have demonstrated a more favourable result with MMI. However, the efficacy of a single daily dose of PTU was inconsistent. In this study, we examined the therapeutic efficacy of single daily doses of MMI and PTU on the change of thyroid hormones and thyrotropin receptor antibodies (TRAb) levels. METHODS: Thirty patients with newly diagnosed Graves' hyperthyroidism were randomly divided into two groups, each receiving a single dose of either 15 mg MMI or 150 mg PTU daily for 12 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), total thyroxine (TT4), thyrotropin (TSH), free thyroxine (FT4), and TRAb levels at baseline and at the end of 4, 8 and 12 weeks during the study period. RESULTS: There was no significant difference in baseline thyroid function parameters. Serum TT3, TT4 and FT4 levels in the MMI-treated group were significantly lower than those of the PTU-treated group after 4 weeks and through the end of the study. MMI also has superior effect on reducing serum TRAb levels than PTU after 8 weeks and at the end of the study. CONCLUSION: During the 12-week treatment of Graves' hyperthyroidism, a single daily dose of 15 mg MMI was much more effective in the induction of euthyroidism than a single daily dose of 150 mg PTU. In the doses used in this study, MMI is preferable to PTU when a once-daily regimen of antithyroid drug is considered for the treatment of Graves' hyperthyroidism.     

Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease

CONTEXT: Although methimazole (MMI) and propylthiouracil (PTU) have long been used to treat hyperthyroidism caused by Graves' disease (GD), there is still no clear conclusion about the choice of drug or appropriate initial doses. OBJECTIVE: The aim of the study was to compare the MMI 30 mg/d treatment with the PTU 300 mg/d and MMI 15 mg/d treatment in terms of efficacy and adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Patients newly diagnosed with GD were randomly assigned to one of the three treatment regimens in a prospective study at four Japanese hospitals. MAIN OUTCOME MEASURES: Percentages of patients with normal serum free T(4) (FT4) or free T(3) (FT3) and frequency of adverse effects were measured at 4, 8, and 12 wk. RESULTS: MMI 30 mg/d normalized FT4 in more patients than PTU 300 mg/d and MMI 15 mg/d for the whole group (240 patients) at 12 wk (96.5 vs. 78.3%; P = 0.001; and 86.2%, P = 0.023, respectively). When patients were divided into two groups by initial FT4, in the group of the patients with severe hyperthyroidism (FT4, 7 ng/dl or more, 64 patients) MMI 30 mg/d normalized FT4 more effectively than PTU 300 mg/d at 8 and 12 wk and MMI 15 mg/d at 8 wk, respectively (P < 0.05). No remarkable difference between the treatments was observed in patients with initial FT4 less than 7 ng/dl. Adverse effects, especially mild hepatotoxicity, were higher with PTU and significantly lower with MMI 15 mg/d compared with MMI 30 mg/d. CONCLUSIONS: MMI 15 mg/d is suitable for mild and moderate GD, whereas MMI 30 mg/d is advisable for severe cases. PTU is not recommended for initial use.     

彩色多普勒超声检查在抗甲状腺药物治疗Graves病预后判断中的价值

毒性弥漫性甲状腺肿,即Graves病（GD）是甲状腺机能亢进的最常见的致病因素,抗甲状腺药物（ATD）是治疗GD选择较多的手段,但撤药后复发率高,部分患者预后不尽人意。预测ATD治疗GD预后的指标很多,但都不够完善。彩色多普勒超声在预测GD患者经ATD治疗后复发方面有一定价值。如诊断GD时彩色多普勒超声显示甲状腺体积明显增大,平均收缩期峰血流值和体积流量值分别高于139cm／s和195ml／min的患者治疗后复发可能性大。撤药后甲状腺低回声的程度越低,则GD缓解的可能性越大。这些指标均有利于临床医师更好地选择治疗方案并调整治疗周期,使GD患者的药物治疗达到更高的长期缓解率。