NADPH-d/NOS reactivity in the lumbar dorsal horn of congenitally hypothyroid pups before and after formalin pain induction

We have previously demonstrated that congenitally hypothyroid rat pups exhibit altered behavioral response to formalin pain induction during postnatal period. In the present study, using NADPH-diaphorase histochemistry and NOS immunostaining, we investigated the effect of congenital hypothyroidism on the NOS expression in spinal cord of intact neonates at postnatal days of 15 and 21. We also examined the effect of thyroid dysfunction on the NADPH-d/NOS expression in response to formalin nociception. Congenital hypothyroidism induced by propylthiouracil (PTU) treatment started from gestational day 16 and continued to postnatal day 15 or 21. Congenitally hypothyroid pups exhibited marked reduction in NADPH-d reactive cells (84% and 66% in P15 and P21, respectively; P < 0.001) and NOS-ir cells (52% and 91% in P15 and P21, respectively; P < 0.001) in superficial lumbar dorsal horn laminae (I–II) as compared to that of normal pups. Moreover, in congenitally hypothyroid pups the NADPH-d/NOS expression following hindpaw formalin injection did not change significantly. Our results demonstrate that congenital hypothyroidism affect developmental expression of NOS in spinal dorsal horn, which may in part explain the altered behavioral pain response as we previously reported in hypothyroid pups.     

Thyroid hormone can restore the audiogenic seizure susceptibility of hypothyroid DBA/2J mice

The audiogenic seizure (AS) susceptibility of $\text{DBA}\text{2}\text{J}$ (D2) mice could be suppressed by administration of the antithyroid drug 6-n-propyl-2-thiouracil from 3 days before birth until the time of AS testing (19 days after birth). This treatment effectively induced hypothyroidism. The AS susceptibility of these mice, however, could be almost completely restored by thyroxine replacement from postnatal day 1 through postnatal day 17. The restoration of AS susceptibility by thyroxine replacement was not accompanied by a corresponding restoration of normal serum thyroxine and estimated free thyroxine levels. These observations suggest that thyroid hormone may influence AS susceptibility at some early critical stage of brain development and may be an important requirement for the development of AS susceptibility in D2 mice.     

Preliminary evaluation of an in utero-lactation assay using 6-n-propyl-2-thiouracil

In this preliminary study, the potential of an in utero-lactation assay to detect thyroid effectors was evaluated by treating three dams/group with 6-n-propyl-2-thiouracil (PTU), a known thyroid antagonist, by oral gavage at doses of 0, 0.0032, 0.016, 0.08 and 0.4 mg/kg/day during fetal organogenesis and lactation. Hearing disturbances and an elevated relative thyroid weight were observed in offspring of both sexes in the 0.4 mg/kg/day group. The Biel-type water T-maze test showed an increase in the number of errors made by females in the 0.4 mg/kg/day group. Histopathologically, flattening of follicular epithelium, a decrease in resorptive colloid droplets, degeneration of follicular epithelium, and hyperplasia of follicular epithelium were observed in males belonging to the 0.4 mg/kg/day group. Histopathological abnormalities were also observed in some offspring belonging to the 0.08 mg/kg/day group. In the dams, hypertrophy of the follicular epithelium of the thyroid was observed in the 0.4 mg/kg/day group. Although we could not explain the mechanism for the difference in the effects seen in the offspring and the dams, the effect of PTU in utero through lactational exposure is apparently different from that resulting from exposure in homeostatically mature rats. Most reports studying PTU have involved administration in water or in food, and reports on the oral gavage of PTU during the fetal organogenesis and lactation period are very rare. This assumes that dosages >0.4 mg/kg/day would also produce clear anti-thyroid effects by oral gavage and, possibly, emphasizes that dosages <0.4 mg/kg/day did not have a noticeable effect. Based on the present results, a study to determine the reproducibility of the data in a much larger number of dams will be performed to confirm the findings in the present study, and to evaluate other endpoints, such as hormonal evaluation of dams and their offspring, sexual developmental landmarks, and fertility of the offspring.     

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T_4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.     

A comparison of potency differences among thyroid peroxidase (TPO) inhibitors to induce developmental toxicity and other thyroid gland-linked toxicities in humans and rats

The potencies of resorcinol, 6-propylthiouracil (PTU) and methimazole (MMI) for inducing developmental toxicity and neurotoxicity were compared in pregnant rats, regarded as valid model for human thyroid toxicity. Profound differences on maternal thyroid hormone levels (THs), maternal toxicity as well as developmental and neurotoxicity sequelae occurred. Resorcinol affected none of those end points. PTU and MMI caused significant effects. Therapy with either PTU or MMI during the first trimester of human pregnancy can cause reductions of maternal THs, accompanied by disruptions of prenatal development. Clinical MMI studies show sporadic evidence of teratogenic effects, with equivocal relation to thyroid peroxidase (TPO) inhibition. In recent decades no MMI associated prenatal toxicity has been reported, an outcome possibly related to carefully managed therapy. Orally administered resorcinol was rapidly absorbed, metabolized and excreted and was undetectable in the thyroid. In contrast, PTU or MMI accumulated. Resorcinol’s potency to inhibit TPO was profoundly lower than that of PTU or MMI. Quantum chemical calculations may explain low resorcinol reactivity with TPO. Thus, distinctions in the target organ and the TPO inhibitory potency between these chemicals are likely contributing to different reductions of maternal THs levels and affecting the potency to cause developmental toxicity and neurotoxicity.     

Propylthiouracil-associated liver failure presenting as probable autoimmune hepatitis in a child with Graves' disease

This case describes a young girl with Graves' disease, who presented with fulminant hepatic failure 9 months into propylthiouracil (PTU) therapy. Her clinical presentation was consistent with 'probable autoimmune hepatitis,' as defined by the International Autoimmune Hepatitis Group scoring system. Despite discontinuation of PTU and high-dose steroid therapy, she required liver transplantation. Subsequent pathology could not definitively rule out autoimmune hepatitis. PTU is an important cause of drug-related liver failure in children, and clinicians should be mindful that it is frequently used in patients who already have an underlying risk of autoimmune liver disease.     

托莫西汀和阿立哌唑治疗儿童注意缺陷多动障碍的疗效比较

目的比较托莫西汀和阿立哌唑治疗儿童注意缺陷多动障碍的临床疗效。方法收集2015年1月—2016年1月在大连市第七人民医院诊治的88例注意缺陷多动障碍患者,根据用药方案的不同分为对照组和治疗组,每组各44例。对照组患儿口服阿立哌唑片,1片/次,每晚1次。治疗组患儿口服盐酸托莫西汀胶囊,初始剂量为每天0.5 mg/kg,治疗过程中根据临床反应及耐药性进行剂量调整,每天最大剂量为1.4 mg/kg。两组患儿均连续治疗6周。比较两组患儿临床效果、SNAP-IV量表评分、数字划消失误率和Conners父母量表测验结果。结果治疗后,对照组和治疗组的总有效率分别为81.82%、97.73%,两组总有效率比较差异具有统计学意义(P0.05)。治疗后,两组患儿SNAP-IV量表评分、数字划消失误率和Conners父母量表测验结果均显著改善,同组治疗前后比较差异具有统计学意义(P0.05);且治疗后治疗组患儿上述观察指标比对照组的改善更明显,两组比较差异有统计学意义(P0.05)。结论托莫西汀治疗注意缺陷多动障碍临床效果显著,有利于患者认知功能的改善,具有一定的临床推广应用价值。     

Perfect storm: Therapeutic plasma exchange for a patient with thyroid storm

Thyroid storm is a potentially lethal complication of hyperthyroidism with increased thyroid hormones and exaggerated symptoms of thyrotoxicosis. First‐line therapy includes methimazole (MMI) or propylthiouracil (PTU) to block production of thyroid hormones as a bridge toward definitive surgical treatment. Untreated thyroid storm has a mortality rate of up to 30%; this is particularly alarming when patients cannot tolerate or fail pharmacotherapy, especially if they cannot undergo thyroidectomy. Therapeutic plasma exchange (TPE) is an ASFA category III indication for thyroid storm, meaning the optimum role of this therapy is not established, and there are a limited number of cases in the literature. Yet TPE can remove T3 and T4 bound to albumin, autoantibodies, catecholamines and cytokines and is likely beneficial for these patients. We report a patient with thyroid storm who could not tolerate PTU, subsequently failed therapy with MMI, and was not appropriate for thyroidectomy. TPE was therefore performed daily for 4 days (1.0 plasma volume with 5% albumin replacement and 2 U of plasma). Over the treatment course, the patient's thyroid hormones normalized and symptoms of thyroid storm largely resolved; his T3 decreased from 2.27 to 0.81 ng/mL (normal 0.8‐2.0), T4 decreased from 4.8 to 1.7 ng/mL (0.8‐1.8), heart rate normalized, altered mental status improved, and he converted to normal sinus rhythm. He was ultimately discharged in euthyroid state. He experienced no side effects from his TPE procedures. TPE is a safe and effective treatment for thyroid storm when conventional treatments are not successful or appropriate.     

PTU-induced hypothyroidism modulates antioxidant defence status in the developing cerebellum

The objective of the present study was to evaluate the effect of 6-n-propylthiouracil (PTU)-induced hypothyroidism on oxidative stress parameters, expression of antioxidant defence enzymes, cell proliferation and apoptosis in the developing cerebellum. PTU challenged neonates showed significant decrease in serum T₃ and T₄ levels and marked increase in TSH levels. Significantly elevated levels of cerebellar H₂O₂ and lipid peroxidation were observed in 7 days old hypothyroid rats, along with increased activities of superoxide dismutase and glutathione peroxidase and decline in catalase activity. In 30 days old hypothyroid rats, a significant decline in cerebellar lipid peroxidation, superoxide dismutase and glutathione peroxidase activity and expression was observed along with an up-regulation in catalase activity and expression. Expression of antioxidant enzymes was studied by Western blot and semi-quantitative rt-PCR. A distinct increase in cell proliferation as indicated by proliferating cell nuclear antigen (PCNA) immunoreactivity was observed in the internal granular layer of cerebellum of 7 days old hypothyroid rats and significant drop in PCNA positive cells in the cerebellar molecular layer and internal granular layer of 30 days old PTU treated rats as compared to controls. In situ end labeling by TUNEL assay showed increased apoptosis in cerebellum of hypothyroid rats in comparison to controls. These results suggest that the antioxidant defence system of the developing cerebellum is sensitive to thyroid hormone deficiency and consequent alterations in oxidative stress status may play a role in regulation of cell proliferation of the cerebellum during neonatal brain development.     

Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis in a patient with a predisposition to autoimmune abnormalities

 A 65-year-old woman with a history of primary biliary cirrhosis was diagnosed as having myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated crescentic glomerulonephritis (GN) during propylthiouracil (PTU) therapy for Graves' disease. Antinuclear antibodies, as well as various thyroid-associated autoantibodies, had been detected since the diagnosis of Graves' disease was made. The patient carried human leukocyte antigens (HLAs) DR4 and DR9, the two HLA haplotypes that have been reported to be related to ANCA-associated vasculitis. Withdrawal of PTU and the administration of prednisolone resulted in a decrease in the titer of MPO-ANCA, together with an improvement in renal function. It is suggested that in addition to the PTU therapy, her genetic predisposition to autoimmunity had played a role in the production of MPO-ANCA and the development of crescentic GN. Received: January 29, 2002 / Accepted: August 28, 2002