Disruption of thyroid hormone homeostasis in Ugt1a-deficient Gunn rats by microsomal enzyme inducers is not due to enhanced thyroxine glucuronidation

Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) are thought to increase glucuronidation of thyroxine (T₄), thus reducing serum T₄, and subsequently increasing thyroid stimulating hormone (TSH). Ugt1a1 and Ugt1a6 mediate T₄ glucuronidation. Therefore, this experiment determined the involvement of Ugt1a enzymes in increased T₄ glucuronidation, decreased serum T₄, and increased TSH after MEI treatment. Male Wistar and Ugt1a-deficient Wistar (Gunn) rats were fed a control diet or diet containing pregnenolone-16α-carbonitrile (PCN; 800 ppm), 3-methylcholanthrene (3-MC; 200 ppm), or Aroclor 1254 (PCB; 100 ppm) for 7 days. Serum T₄, triiodothyronine (T₃), and TSH concentrations, hepatic T₄/T₃ glucuronidation, and thyroid histology and follicular cell proliferation were investigated. PCN, 3-MC, and PCB treatments decreased serum T₄, whereas serum T₃ was maintained in both Gunn and Wistar rats (except for PCB treatment). TSH was increased in Wistar and Gunn rats after PCN (130 and 277%) or PCB treatment (72 and 60%). T₄ glucuronidation in Wistar rats was increased after PCN (298%), 3-MC (85%), and PCB (450%), but was extremely low in Gunn rats, and unchanged after MEI. T₃ glucuronidation was increased after PCN (121%) or PCB (58%) in Wistar rats, but only PCN increased T₃ glucuronidation in Gunn rats (43%). PCN treatment induced thyroid morphological changes and increased follicular cell proliferation in both strains. These data demonstrate that T₄ glucuronidation cannot be increased in Ugt1a-deficient Gunn rats. Thus, the decrease in serum T₄, increase in TSH, and increase in thyroid cell proliferation after MEI are not dependent on increased T₄ glucuronidation, and cannot be attributed to Ugt1a enzymes.     

Effects of manganese ions on thyroid function in rat

Rats were treated with MnSO₄, H₂O (1 mg/100 g/day, SC) for a period of 5 weeks. Thyroxine (T₄) and triiodothyronine (T₃) levels were measured in thyroid by radioimmunoassay. T₄, T₃ and thyroid-stimulating hormone (TSH) levels were also estimated by radioimmunoassay in serum. Manganese treatment produced no change in thyroid T₄ and T₃ levels but induced a significant decrease in serum T₄, T₃ and TSH levels. This decrease can be interpreted as the result of a pituitary alteration which appears to be related to the high accumulation of manganese in the pituitary gland.     

Long-term amiodarone therapy raises serum cholesterol

Summary Serum total cholesterol and triglyceride levels were measured in 12 patients before and 3, 6 and 9 months after treatment with amiodarone. In addition, we monitored serum T₄, T₃, reverse T₃ and TSH levels. Amiodarone and its desethyl metabolite levels were measured on each occasion.Serum total cholesterol and T₄ levels rose from 5.95 mmol/l, and 102.7 mmol/l respectively at baseline to 6.95 and 115.8 at 6 months and reverse T₃ increased at 3, 6 and 9 months from baseline. Serum triglycerides did not change. No relationship existed between cholesterol, T₄ and T₃ and amiodarone (or its metabolite) levels nor between cholesterol and thyroid hormone levels.These data demonstrate that amiodarone therapy is associated with an elevation in serum cholesterol. This may have clinical implications in view of the current widespread use of the drug.     

EFFECTS OF TCDD ON THYROID HORMONE HOMEOSTASIS IN THE RAT

A physiological dosimetric model was constructed to describe the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on circulating thyroid hormones in the rat and to test the hypothesis that these hormonal changes cause chronically elevated serum thyrotropin (thyroid stimulating hormone, TSH), which mediates growth promotion and may lead to thyroid tumors in TCDD-treated rats. The model included diffusion restricted distribution of TCDD among compartments for liver, kidney, white fat, slowly and rapidly perfused tissues, and the thyroxine-sensitive tissues brown fat, pituitary, and thyroid. Blood was distributed among major vessels and the capillary beds of the tissues. Metabolism of TCDD was limited to the liver. Secretion of 3,5,3′-triiodothyronine (T₃) and thyroxine (3,5,3′,5′-tetraiodothyronine, T₄) from the thyroid was modeled as stimulated by circulating TSH, whose release from the pituitary was regulated by the hypothalamic peptides thyrotropin releasing hormone (activating) and somatostatin (inhibiting). Release of these peptides was represented as inhibited and activated, respectively, by circulating T₄. Binding proteins for T₃ and T₄ and metabolism of the hormones by deiodination were included in thyroxine-sensitive tissues. Induction of hepatic UDP-glucuronosyltransferase-1*6 (UGT), the enzyme which glucuronidates T₄, was modeled as induced by the complex formed between TCDD and the aryl hydrocarbon receptor. The computed extent of deiodination, primacy of the thyroid in generating T₃ from T₄, dependence of liver and kidney on locally produced T₃, and export of T₃ formed in the pituitary agreed with experimental observations. The model reproduced the observed decrease in circulating T₄ and elevated serum TSH following chronic administration of TCDD. The altered levels were attributed to the increased clearance of T₄ by the induced UGT and the consequent modification of feedback control of hormone releases. These results are consistent with the hypothesis of growth stimulation by elevated TSH, but measured values of this hormone in blood of rats vary over a large range, and the change induced by TCDD is often small. Measured UGT levels are less variable and the increase in this protein is much greater, suggesting that this response may be a more reliable biomarker for effects of TCDD on the thyroid.     

Association between organophosphate pesticides exposure and thyroid hormones in floriculture workers

The ability of organophosphate pesticides to disturb thyroid gland function has been demonstrated by experimental studies on animal, but evidence of such effects on human remains scarce. The aim of this study was to assess the association between exposure to organophosphate compounds and serum levels of thyroid hormones in floriculture workers. A longitudinal study was conducted on 136 male subjects from the State of Mexico and Morelos, Mexico, occupationally exposed to organophosphate pesticides, during agricultural periods of high (rainy season) and low (dry season) levels of pesticide application. Using a structured questionnaire, a survey was carried out on sociodemographic characteristics, anthropometry, clinical history, alcohol and tobacco consumption, residential chemical exposure, and occupational history. Urine and blood samples were taken the day after pesticide application to determine urine dialkylphosphate (DAP) levels, serum levels of TSH, total T₃, total T₄, serum PON1 activity, and serum p,p′-DEE levels. The analysis of the association between DAP levels and thyroid hormonal profile was carried out using multivariate generalized estimating equation (GEE) models. Our results showed an increase in both TSH and T₄ hormones in serum associated with a increase in total dimethylphosphate levels (ΣDMP) in urine (p-trend < 0.001) and a decrease in total T₃ serum levels with an increase of ΣDMP levels in the urine (p-trend = 0.053). These results suggest that exposure to organophosphate pesticides may be responsible of increasing TSH and T₄ serum hormone levels and decreasing T₃ serum hormone levels, therefore supporting the hypothesis that organophosphate pesticides act as endocrine disruptors in humans.     

Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer

AimTo evaluate the impact of genetic polymorphisms in uridine 5′-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T₄; 3,5,3′,5′-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC).MethodsPatients (n = 268) submitted to total thyroidectomy and ablation by ¹³¹I, under T₄ therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T₄ dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables.ResultsA regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T₄ dosage. The association of T₄ dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T₄ glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T₄ dosage.ConclusionUGT1A haplotypes associate with T₄ dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted.     

THYROID FUNCTION AND EFFECTS ON REPRODUCTION IN EWES EXPOSED TO THE ORGANOCHLORINE PESTICIDES LINDANE OR PENTACHLOROPHENOL (PCP) FROM CONCEPTION

There is concern over the potential endocrine-modulating effects of long-term exposure to pesticides. In this study, ewe lambs were exposed to lindane and pentachlorophenol (PCP) from conception to necropsy at 67 wk of age. The ewe lambs (and their mothers) were given untreated feed (n = 6) or feed treated with 1 mg/kg body weight/day of lindane (n=8) or PCP (n=13). Estrus was synchronized at 32 wk of age, and ewe lambs were exposed to vasectomized rams. Ewe lambs were then exposed to intact rams during the following two natural estrous periods and subsequent reproductive performance was monitored. Serum was collected every 2 wk during development, daily during the synchronized cycle and frequently (every 15-60 min) for 6-18 h either with or without stimulation with thyroid-stimulating hormone ( TSH) during the synchronized luteal phase or TSH/thyroid-releasing hormone (TRH) at 65-66 wk of age. Ewe lambs fed a PCP-treated diet had a significantly reduced serum concentration of both T₄ and free T₄, and a reduction in the magnitude and duration of the T₄ and free T₄ response to TSH, despite normal endogenous levels of TSH and a normal TSH response to TRH. PCP exposure had a less detrimental influence on unstimulated T ₃ levels; however, the T₃ (but not reverse T₃) response to TSH was markedly reduced in PCP-treated ewe lambs. Ewe lambs given lindane also had a significantly reduced serum concentration of T₄; however, despite continued exposure to lindane, T₄ levels returned to normal by 10 wk of age. Detrimental effects on reproductive function were only seen following estrous synchronization when both PCP and lindane exposure reduced the number of corpora lutea (CL) and total CL volume and increased luteinizing hormone (LH) pulse frequency. In addition, lindane-treated ewes had shorter estrous cycles and lower luteal progesterone concentrations. No marked effects of pesticides were seen on fertility following mating during natural estrous periods. In conclusion, the pesticides affected reproduction only after estrous synchronization, whereas PCP consistently disrupted thyroid function, most likely through a direct effect on the thyroid gland.     

薯蓣皂苷元的制备及其抗甲亢活性研究

目的 考查薯蓣皂苷元对甲亢大鼠的活性。方法 穿山龙饮片用含1.5 mol·L^-1硫酸的75%乙醇水溶液在沸水浴中回流提取4.5 h,再经柱层析法分离、精制纯化得薯蓣皂苷元提取物,并进行结构表征。采用优甲乐灌胃法制作大鼠甲亢模型,并将大鼠随机分成正常对照组、甲亢模型组、甲巯咪唑治疗组、薯蓣皂苷元治疗组(低、中、高剂量),分别于给药21 d后测定大鼠血清中T₃、T₄及TSH值。结果 薯蓣皂苷元提取制备工艺正确适当,所得薯蓣皂苷元提取物经氢谱、碳谱、质谱和高效液相色谱表征确定为薯蓣皂苷元。与甲亢模型组比较,薯蓣皂苷元治疗组(低、中、高)血清中T₃、T₄和TSH值均有不同程度改善。结论 薯蓣皂苷元制备工艺合理可行,得率较高。薯蓣皂苷元可使甲亢大鼠的各项甲状腺功能血清值恢复正常,还可增加其体质量,功效与甲巯咪唑相似,值得进一步研究。     

Evaluation of hypothalamus‐pituitary‐thyroid axis function by chronic perchlorate exposure in male rats

Perchlorate is a widespread endocrine disruptor that was previously correlated with increased serum TSH levels and decreased thyroid hormones production both in animals and humans. Even so, the regulation of gene/protein expression in the hypothalamus, pituitary and thyroid by chronic perchlorate exposure was not completely elucidated. Therefore, this study aimed to investigate the underlying mechanisms involved in the disruption of hypothalamus‐pituitary‐thyroid axis by chronic perchlorate exposure. Male Wistar rats were treated or not with NaClO₄ in the drinking water (35 mg/Kg/day) for 60 days. Thereafter, hormone/cytokines serum levels were measured through multiplex assays; genes/proteins expression were investigated by qPCR/Western Blotting and thyroid morphology was evaluated through histological analysis. Serum TSH levels were increased and serum T₄/T₃ levels were decreased in perchlorate‐treated animals. This treatment also altered the thyrotropin‐releasing hormone mRNA/protein content in the hypothalamus. Additionally, the expression of both subunits of TSH were increased in the pituitary of perchlorate‐treated rats, which also presented significant alterations in the thyroid morphology/gene expression. Furthermore, perchlorate exposure reduced liver Dio1 mRNA expression and increased the content of pro‐inflammatory cytokines in the thyroid and the serum. In conclusion, our study adds novel findings about the perchlorate‐induced disruption of the hypothalamus‐pituitary‐thyroid axis gene/protein expression in male rats. The data presented herein also suggest that perchlorate induces thyroid and systemic inflammation through the increased production of cytokines. Taken together, our results suggest that perchlorate contamination should be monitored, especially in the individuals most susceptible to the deleterious effects of reduced levels of thyroid hormones.     

Systems Pharmacology Modeling of Drug-Induced Modulation of Thyroid Hormones in Dogs and Translation to Human

Purpose

To develop a systems pharmacology model based on hormone physiology and pharmacokinetic-pharmacodynamic concepts describing the impact of thyroperoxidase (TPO) inhibition on thyroid hormone homeostasis in the dog and to predict drug-induced changes in thyroid hormones in humans.

Methods

A population model was developed based on a simultaneous analysis of concentration-time data of T₄, T₃ and TSH in dogs following once daily oral dosing for up to 6-months of a myeloperoxidase inhibitor (MPO-IN1) with TPO inhibiting properties. The model consisted of linked turnover compartments for T₄, T₃ and TSH including a negative feedback from T₄ on TSH concentrations.

Results

The model could well describe the concentration-time profiles of thyroid hormones in dog. Successful model validation was performed by predicting the hormone concentrations during 1-month administration of MPO-IN2 based on its in vitro dog TPO inhibition potency. Using human thyroid hormone turnover rates and TPO inhibitory potency, the human T₄ and TSH concentrations upon MPO-IN1 treatment were predicted well_.

Conclusions

The model provides a scientific framework for the prediction of drug induced effects on plasma thyroid hormones concentrations in humans via TPO inhibition based on results obtained in in vitro and animal studies.     

Effect of amiodarone on serum T4 and T3 levels in hyperthyroid patients treated with methimazole

Summary We investigated the course of thyroid hormones levels in the serum of hyperthyroid patients acutely treated with amiodarone. Ten patients were treated either with amiodarone, 3 × 400 mg daily for 3 days in addition to methimazole, 3 × 20 mg daily for 10 days (Group I;n=5) or with a placebo plus methimazole at the same doses (Group II;n=5). Basal T₃, T₄ and rT₃ serum concentrations were: 297 ng/dl, 16.6 µg/dl and 507 pg/dl, respectively in Group I and 377 ng/dl, 17.6 µg/dl and 362 pg/dl in Group II (NS). Compared with basal values, the drop in serum T₃ concentration became significant on Day 1 in Group I, but not until day 5 in Group II. The decrease in serum T₃ concentration was significantly higher in Group I than in Group II from Day 1 to Day 7. In Group I, T₄ concentration was significantly lower on Days 2, 4 and 6; the percentage drop in T₄ calculated from the areas under the curves was higher and the T₃/T₄ ratio lower on Days 3–5, 7 and 9; rT₃ was higher on Days 4 and 5 and its rise was significant on Days 1, 3 and 4. During the follow-up period a transient rise in T₄ and T₃ concentrations was observed in two patients in Group I when the methimazole dosage was tapered or stopped because of agranulocytosis. In conclusion, in our hyperthyroid patients, amiodarone in conjunction with methimazole induced a greater fall in T₃ and T₄ than did methimazole alone.     

Thyroid Status and Hepatic Thyroxine Deiodinating Activity under High-Dose Long-Term Nitrendipine

Abstract: The influence of high doses of oral nitrendipine on the hypophyseal-thyroid axis and on peripheral thyroxine metabolism was studied in baboons. Administration of 320 mg oral nitrendipine per kg body weight (b.wt.) for three months caused a hypothyroid state with decreased values for thyroxine and reverse triiodothyronine, elevated TSH, but unchanged triiodothyronine; the lower doses investigated (24 and 48 mg/kg b.wt.) were without any effect. High doses of nitrendipine concomitantly increased hepatic 5′-deiodinating activity by a rise in V_max, which could be attributed to an increase in the deiodinating enzyme content. Normal T₃ serum levels in the presence of low T₄ serum concentrations under high dose nitrendipine can be ascribed, at least in part, to the enhanced peripheral 5′-deiodination.     

EFFECT OF MEFENAMIC ACID ON PLASMA PROTEIN-THYROID HORMONE INTERACTION, MONODEIODINATION OF THYROXINE, URINARY EXCRETION OF TRI-IODOTHYRONINE AND THYROTROPIN REGULATION

1. A single oral dose of mefenamic acid significantly depressed plasma thyroxine (T₄) within 3 h in man. Similarly, mefenamic acid depressed plasma T₄ within 3 h in thyroidectomized, T₄-maintained rats. 2. Plasma free fractions of T₄ and tri-iodothyronine (T₃) increased significantly after a single oral administration of mefenamic acid in man. In vitro addition of mefenamic acid to plasma also increased the plasma free fraction of T₄. 3. Three times more T₃ was excreted into urine after an acute administration of mefenamic acid. 4. In vitro conversion of T₄ to T₃ by liver homogenate was stimulated when T₄ was displaced from plasma binding protein by mefenamic acid. 5. Pituitary content of T₃ increased when mefenamic acid displaced T₄ and T₃ from the binding protein. Simultaneously, thyrotropin (TSH) secretion in response to thyrotropin releasing hormone (TRH) was completely blocked by mefenamic acid. 6. Prolactin release in response to TRH and luteinizing hormone (LH) and follicle stimulating hormone (FSH) release in response to luteinizing hormone releasing hormone (LH-RH) were not affected by mefenamic acid. 7. It is concluded that mefenamic acid displaces T₃ and T₄ from their plasma binding protein and more T₄ and T₃ are available to peripheral tissues for excretion, degradation and TSH regulation.     

Teratogenicity of nitrofen (2,4-dichloro-4′-nitrodiphenyl ether) and its effects on thyroid function in the rat

Nitrofen is a herbicide with potent teratogenic activity in rodent species. Previous studies have indicated that this agent has a stereochemical structure similar to thyroid hormone, and that exposure of adult mice results in depression of thryoxine (T₄) levels. The present study was undertaken to determine if teratogenic exposure to nitrofen alters pituitarythyroid function in nonpregnant, pregnant, and fetal rats, and if these potential alterations could be related to induction of birth defects. In adult thyroparathyroidectomized (TPTX) female rats, nitrofen exposure for 2 weeks resulted in a significant suppression of thyrotropin-stimulating hormone (TSH) levels. When a single dose of nitrofen was administered to euthyroid female rats, a trend toward reduction (p = 0.058) in the release of TSH after a thyrotropin-releasing hormone )TRH) challenge was observed 4 and 5 hr after exposure. Pregnant euthryoid rats given a single dose of nitrofen on Day 11 of gestation had significantly depressed TSH and T₄ levels, and fetal T₄ levels were markedly depressed at term. Administration of T₄ on Day 2 through 22 of pregnancy plus nitrofen on Day 9 through 11 to TPTX dams resulted in a 70% reduction in the frequency of malformed fetuses, especially in regard to the frequency of heart anomalies, compared to nitrofen exposure alone. Competitive displacement studies in radioimmunoassays for T₄ and T₃ indicated that a nitrofen metabolite (4-hydroxy-2,5-dichloro-4′-aminodiphenyl ether) competed with [¹²⁵I]T₃ for antibody binding, while the parent compound and six isolated metabolites failed to compete with [¹²⁵I]T₄ for antibody binding. These results have been interpreted to indicate that nitrofen teratogenicity is mediated at least in part by alterations in maternal and/or fetal thyroid hormone status, and may be due to a premature and pharmacologic exposure to the embryo to a nitrofen-derived, T₃-active metabolite.     

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。     

Effects of chronic exposure to triclosan on reproductive and thyroid endpoints in the adult Wistar female rat

Triclosan (TCS), an antibacterial, has been shown to be an endocrine disruptor in the rat. Previously, subchronic TCS treatment to female rats was found to advance puberty and potentiate the effect of ethinyl estradiol (EE) on uterine growth when EE and TCS were co-administered prior to weaning. In the pubertal study, a decrease in serum thyroxine (T₄) concentrations with no significant change in serum thyroid-stimulating hormone (TSH) was also observed. The purpose of the present study was to further characterize the influence of TCS on the reproductive and thyroid axes of the female rat using a chronic exposure regimen. Female Wistar rats were exposed by oral gavage to vehicle control, EE (1 μg/kg), or TCS (2.35, 4.69, 9.375 or 37.5 mg/kg) for 8 months and estrous cyclicity monitored. Although a divergent pattern of reproductive senescence appeared to emerge from 5 to 11 months of age between controls and EE-treated females, no significant difference in cyclicity was noted between TCS-treated and control females. A higher % control females displayed persistent diestrus (PD) by the end of the study, whereas animals administered with positive control (EE) were predominately persistent estrus (PE). Thyroxine concentration was significantly decreased in TCS-administered 9.375 and 37.5 mg/kg groups, with no marked effects on TSH levels, thyroid tissue weight, or histology. Results demonstrate that a long-term exposure to TCS did not significantly alter estrous cyclicity or timing of reproductive senescence in females but suppressed T₄ levels at a lower dose than previously observed.     

The effects of omeprazole on endocrine function in man

Summary We have assessed the effect of omeprazole on various endocrine functions in man. Eight healthy subjects took 60 mg omeprazole or placebo daily for 1 week in a double-blind, randomized, cross-over study. On Day 7 basal concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), prolactin, testosterone, thyroid-stimulating hormone (TSH), and serum thyroxine (T₄) and tri-iodothyronine (T₃) were measured, followed by the gonadotrophin response to luteinising hormone releasing hormone (LHRH) and the prolactin and TSH responses to thyrotrophin releasing hormone (TRH).There were no differences in basal or stimulated values between omeprazole and placebo.In a second study, a further 8 subjects were similarly treated, and on Day 7 serial measurements of cortisol and 11-deoxycortisol were made before and for 2.5 h after intravenous adrenocorticotrophin (ACTH).There were no differences in basal values or pattern of response to ACTH for either hormone.Omeprazole in clinical practice is unlikely to cause any significant interference in endocrine function.     

Subchronic Toxicity Study in Rats with 1-Methyl-3-propylimidazole-2-thione (PTI): Effects on the Thyroid

A 90-day gavage study was performed to evaluate the sub-chronictoxicity of 1-methyl-3-propylimidazole-2-thione (PTI) when administeredto Crl:CD BR rats. PTI is a chemical catalyst and is structurallysimilar to the thioureas, which are known to adversely affectthe thyroid. Therefore, this study was designed to investigatethe effects of PTI on the thyroid. Male and female rats weredosed with 0,5,10,25, or 75 mg PTI/kg/day for 13 weeks. Clinicalpathology examinations and pathology examination were performedand the following were measured periodically: serum T₃, T₄,and TSH, hepatic UDP- glucuronyltransferase activity, and cellproliferation of the thyroid and liver. Under the conditionsof this study, the overall no-observed-adverse-effect level(NOAEL) for the subchronic effects of PTI in male and femalerats was 10 mg PTI/kg/day. The NOAEL was based on the effectson the thyroid gland in male and female rats dosed with 25 and75 mg PTI/kg/day, as well as the hepatic centrilobular fattychange, increased severity of chronic progressive nephropathy,fatty change in the adrenal medulla, and the substantial reductionin body weight and body weight gain. The primary target organswere the thyroid and liver. Alterations in thyroid hormones(T₃, T₄, and TSH) occurred predominantly at 25 and 75 mg/kg/day.Toxicologically significant alterations in T₃, T₄, and TSH levels,cell proliferation, and UDP-glucuronyltransferase activity occurredin rats dosed with 25 and 75 mg/kg/day, which correlated withorgan weight and histopathological effects. Additionally, theeffect of PTI on thyroid peroxidase activity, a key step inthyroid hormone synthesis, was evaluated in vitro using microswinethyroid microsomes. PTI was shown to inhibit thyroid peroxidase,with an IC50 of 0.02 M. These data suggest that PTI enhancesthe excretion of T₄ via induction of glucuronyltransferase andinhibits thyroid hormone synthesis via a direct affect on thyroidperoxidase. Both of these effects contribute to the disruptionof the hypo-thalamic-pituitary-thyroid axis and result in sustainedelevation of TSH and the corresponding thyroid hypertrophy andhyperplasia.     

Small doses of droperidol do not present relevant torsadogenic actions: a double-blind,ondansetron-controlled study

AIM

Drugs used for postoperative nausea and vomiting prophylaxis are believed to provoke torsadogenic changes in cardiac repolarization. The aim of this study was to assess the effect of small doses of droperidol on the parameters of cardiac repolarization, including the QT_c interval and transmural dispersion of repolarization.

METHODS

A total of 75 patients were randomly allocated to receive 0.625 or 1.25 mg droperidol or 8 mg ondansetron. The QT_c interval was calculated using Bazett''s formula and the Framingham correction. The transmural dispersion of repolarization was determined as T_peak–T_end time.

RESULTS

Transient QT prolongation, corrected with both formulae, followed 1.25 mg of droperidol 10 min after administration. No change in the QT_c value was observed in the other groups. When corrected with Bazett''s formula, QT_c was prolonged above 480 ms in two patients receiving 1.25 mg droperidol (at the 10^th and 20^th minute of the study) and in one receiving ondansetron. No patients developed a QT_cB prolongation over 500 ms. No increase above 480 ms was observed relative to the Framingham correction method. There were no significant differences in the T_peak–T_end time either between or within the groups.

CONCLUSION

In men without cardiovascular disorders small doses (1.25 mg) of droperidol prophylaxis induced transient QT_c prolongation without changes in transmural dispersion of repolarization. The apparently low risk of the drug applies only in low risk male patients with a low pro-QT_c score.     

Effect of short-term ozone exposure on exogenous thyroxine levels in thyroidectomized and hypophysectomized rats

Short-term ozone exposure (1 ppm × 24 hr) of male rats results in a significant reduction of circulating thyroid hormones and thyroid stimulating hormone (TSH). The reduction of thyroid hormone levels after ozone exposure has been hypothesized as a possible adaptive mechanism to enhance survival of rats during ozone exposure. In this study, we investigated the effect of ozone on thyroid hormone (T₄) levels in thyroidectomized and hypophysectomized rats which received exogenous T₄ in the drinking water. Groups of normal, intact rats, thyroidectomized rats maintained on T₄ at doses ranging from 75 to 1000 μg/liter, and hypophysectomized rats maintained on 300 μg T₄/liter were exposed to ozone (1 ppm × 24 hr). Plasma T₄ concentrations were significantly reduced after ozone exposure, and the results indicated that the higher the circulating T₄ levels before exposure the more they were reduced after ozone exposure. This reduction in T₄ levels cannot be accounted for in these animals by reduced pituitary TSH levels or the effects of fasting, but is likely to be due to peripheral changes in plasma thyroid binding proteins initiated by ozone exposure.