The effects of pioglitazone and rosiglitazone on liver function in hypothyroid rats.

OBJECTIVES: This study aimed to investigate the antioxidant effect of rosiglitazone (ROG) and pioglitazone (POG) on oxidative damage and dysfunction of hepatic tissue in hypothyroid rats. METHODS: The male rats were classified into six groups: (1) Control; (2) Hypothyroid, (3) Hypothyroid-POG 10, (4) Hypothyroid-POG 20, (5) Hypothyroid-ROG 2, and (6) Hypothyroid-ROG 4. To induction hypothyroidism in rats, propylthiouracil (PTU) (0.05 %w/v) was added to drinking water. In groups 2-6, besides PTU, the rats were also intraperitoneal administrated with 10 or 20 mg/kg POG or 2 or 4 mg/kg ROG for six weeks. Finally, after deep anesthesia, the blood was collected to measure the serum biochemical markers and hepatic tissue was separated for biochemical oxidative stress markers. RESULTS: Administration of PTU significantly reduced serum thyroxin concentration, total thiol levels, activity of superoxide dismutase (SOD) and catalase (CAT) enzymes, and increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (Alk-P) and malondialdehyde (MDA) in the liver. Additionally, our results showed that prescription of POG or ROG for six weeks to hypothyroid rats resulted in an improvement in liver dysfunction (decrease in serum levels of AST, ALT, and ALK-P) through reducing oxidative damage in hepatic tissue (increase in CAT, SOD, or total thiols and decrease in MDA levels). CONCLUSIONS: The findings of the present study presented that the IP administration of POG and ROG for six weeks improves liver dysfunction induced by hypothyroidism in juvenile rats by reducing oxidative damage.

Folic acid supplementation improved cognitive deficits associated with lithium administration during pregnancy in rat offspring.

INTRODUCTION: The present study aimed to analyse both neurobehavioural and biochemical results of neonates born of mothers exposed to different doses of lithium along with the groups that received lithium at the highest dose with folic acid as a preventive treatment. MATERIALS AND METHODS: Male and female rats were mated in separate cages, and pregnant rats were divided into eight first group as (1) vehicle; (2) propylthiouracil (PTU)-induced hypothyroidism; (3-4) received two different doses of lithium carbonate (15 and 30 mg/kg); (5-7) the highest doses of lithium (30 mg/kg) plus three different doses of folic acid (5, 10 and 15 mg/kg); and (8) received just folic acid (15 mg/kg). All treatments were dissolved in drinking water and continued until delivery, followed by returning to a regular diet without treatment. RESULTS: Lithium (30 mg/kg) disrupts both behavioural and biochemical markers, including TSH, T3 and T4 as measuring indicators to assess thyroid function, IL-10 and TNF-α as anti-inflammatory and inflammatory agents, respectively, malondialdehyde as an oxidative stress marker, alongside SOD, and catalase activity as antioxidant indicators. Besides, folic acid, almost at the highest dose (15 mg/kg), attenuated memory impairement and anxiety-like behaviour caused by lithium. Moreover, the groups treated with folic acid alone in comparison with vehicles demonstrated higher levels of antioxidant and anti-inflammatory indicators. CONCLUSION: According to the results, prenatal exposure to a high dose of lithium (30 mg/kg) leads to foetal neurodevelopmental disorder and growth restriction through various mechanisms more likely attributed to hypothyroidism, which means it should be either prohibited or prescribed cautiously during pregnancy.

Thymoquinone Upregulates Catalase Gene Expression and Preserves the Structure of the Renal Cortex of Propylthiouracil-Induced Hypothyroid Rats.

BACKGROUND: The association between hypothyroidism and renal diseases has been described in many studies. Nigella Sativa was among the recently reported natural product that has the potential to prevent renal tissue damage and fibrosis. The aim of this study was to evaluate the possible protective effect of thymoquinone on the structure of the renal cortex of hypothyroid rats and explore the mechanism behind it. METHODS: An experimental model of hypothyroidism was induced in adult male Wistar rats by administration of propylthiouracil (6 mg/kg/body weight). One hypothyroid group was treated with thymoquinone at the dose of 50 mg/kg/body weight and compared to the untreated group. Thyroid function and oxidant/antioxidant status were assessed in the serum. Catalase gene expression was assessed using the real-time polymerase chain reaction. The kidney was assessed both histologically and immunohistochemically. RESULTS: Administration of propylthiouracil resulted in a significant decrease in the serum levels of nitric oxide, reduced glutathione, and superoxide dismutase activity while the level of malondialdehyde significantly (p < 0.001) increased. Administration of thymoquinone alleviated this effect on the thyroid hormones and significantly increased the serum levels of antioxidants. Thymoquinone significantly (p < 0.001) upregulated catalase transcription by about 24-fold and could block the hypothyroidism-induced glomerular and tubular injury. CONCLUSION: Thymoquinone may have a potential protective effect against hypothyroidism-induced renal injury acting through the attenuation of the oxidative stress and upregulation of renal catalase gene expression.

Protective effects of a mixed plant extracts derived from Astragalus membranaceus and Laminaria japonica on PTU-induced hypothyroidism and liver damages.

Protective effects of a mixed hot water extracts of Astragalus membranaceus (AWE) and Laminaria japonica (LWE), AWE: LWE 85:15 (g/g; AL mix), were investigated against propylthiouracil (PTU)-induced hypothyroidism in rats. Rats were challenged with PTU, resulting in, increased thyroid gland weight, decreased liver weight and antioxidant activities, reduced serum tri-iodothyronine and thyroxine levels with increased thyroid stimulating hormone levels, and elevated serum aspartate aminotransferase level. However, orally administered AL mix with 100, 200, and 400 mg kg-1  day-1 , significantly inhibited such abnormalities, dose-dependently. Moreover, PTU-induced abnormal histological architecture of the rat thyroid gland and liver were also significantly ameliorated by an AL mix. The results suggested that, therapeutic use of AL mix for treating hypothyroidism can be characterized by its diversified active ingredients particularly iodine and ferulic acid as confirmed by phytochemical analyses. PRACTICAL APPLICATIONS: The AL mix has synergistic effects in modulating thyroid hormone synthesis and preventing liver damages in PTU-induced hypothyroid rats. These effects of AL mix are mainly related to its richness specifically in iodine and ferulic acid. The growing interests of iodine and ferulic acid in AL mix are principally due to their beneficial effects in releasing sufficient thyroid hormones in hypothyroid conditions and promoting liver-protective functions through its antioxidant and anti-inflammatory potentials, respectively. Moreover, the results of AL mix are well-matched with the effects of standard drug levothyroxine in the present study. Therefore, appropriate dosage of AL mix will be promising as new medicinal food for preventing thyroid dysfunctions and its related liver damages.

Aframomum melegueta prevents the ejaculatory complications of propylthiouracil-induced hypothyroidism in sexually experienced male rats: Evidence from intravaginal and fictive ejaculations.

OBJECTIVE: Hypothyroidism has been claimed to generate sexual dysfunctions such as ejaculatory disorders. Aframomum melegueta is an aphrodisiac plant with pro-ejaculatory properties. We investigated the protective effects of aqueous extract (AE) and methanolic extract (ME) of A. melegueta on the ejaculatory function of hypothyroid male rats. METHODS: Forty sexually experienced male rats were partitioned into 8 groups (5 rats per group) and treated for 28 d as follows: Group 1, Control; Group 2, propylthiouracil (PTU, 10 mg/kg) + distilled water (DW, 10 mL/kg); Group 3, PTU + 5% Tween 80 (10 mL/kg); Group 4, PTU + bromocriptine (6 mg/kg); Group 5, PTU + AE (20 mg/kg); Group 6, PTU + AE (100 mg/kg); Group 7, PTU + ME (20 mg/kg), and Group 8, PTU + ME (100 mg/kg). On days 0, 7, 14 and 28 of treatment, each male rat was paired with primed receptive female for measurement of ejaculatory latency time (ELT) and post-ejaculatory interval (PEI) for 1.5 h. On day 29, each male rat was urethane-anesthetized and the spinal cord was transected. Thereafter, following urethral/penile stimulations and intravenous injection of dopamine, contractions of the bulbospongiosus muscles and the intraseminal pressure were registered. After these recordings, blood was collected through the catheterization of abdominal artery and plasma was used for thyroid-stimulating hormone (TSH), prolactin and testosterone assays. RESULTS: PTU-induced hypothyroidism was characterized by a significant elevation (P < 0.001) of plasmatic TSH and prolactin levels, but a decline (P < 0.001) in plasmatic testosterone, compared to untreated group. ELT, PEI, contractions of the bulbospongiosus muscles and the intraseminal pressure were also altered by PTU treatment. On the contrary, A. melegueta extracts elevated testosterone (AE, 100 mg/kg, P < 0.01; ME, 100 mg/kg, P < 0.05) and decreased prolactin (AE, 100 mg/kg, P < 0.05; ME, 20 mg/kg, P < 0.05) levels, compared to corresponding controls. With regard to DW + PTU group, prolactin concentration was lowered (P < 0.05) in rats administered with bromocriptine. Treatment with A. melegueta extracts significantly prevented the lengthening of ELT (P < 0.05) and PEI (P < 0.001). Hypothyroid state also altered the fictive ejaculation by increasing the latency and decreasing the number and frequency of bulbospongiosus muscle contractions. There was also a decrease in the intraseminal pressure. These alterations were significantly (P < 0.05) alleviated in plant extract-treated groups. CONCLUSION: This study highlighted the ejaculatory disturbance of hypothyroidism in male rats and its prevention with A. melegueta extracts.

Gestational thyrotoxicosis, antithyroid drug use and neonatal outcomes within an integrated healthcare delivery system.

BACKGROUND: Increasing attention has focused on the prevalence and outcomes of hyperthyroidism in pregnancy, given concerns for hepatotoxicity and embryopathy associated with antithyroid drugs (ATDs). METHODS: In an integrated health care delivery system, we examined the prevalence of thyrotoxicosis and gestational ATD use (propylthiouracil [PTU] or methimazole [MMI]) in women with delivered pregnancies from 1996 to 2010. Birth outcomes were compared among all infants and those born to mothers with diagnosed thyrotoxicosis or ATD therapy during gestation, with examination of ATD-associated hepatotoxicity and congenital malformations in the latter subgroups. RESULTS: Among 453,586 mother-infant pairs (maternal age 29.7±6.0 years, 57.1% nonwhite), 3.77 per 1000 women had diagnosed thyrotoxicosis and 1.29 per 1000 had gestational ATD exposure (86.5% PTU, 5.1% MMI, 8.4% both). Maternal PTU-associated hepatotoxicity occurred with a frequency of 1.80 per 1000 pregnancies. Infants of mothers with diagnosed thyrotoxicosis (odds ratio [OR] 1.28, 95% confidence interval [CI 1.05-1.55]) or gestational ATD use (OR 1.31 [1.00-1.72]) had an increased risk of preterm birth compared to those born to mothers without thyrotoxicosis or ATD. The risk of neonatal intensive care unit (NICU) admission was also higher with maternal thyrotoxicosis (OR 1.30 [1.07-1.59]) and ATD exposure (OR 1.64 [CI 1.26-2.13]), adjusting for prematurity. Congenital malformation rates were low and similar among infants born to mothers with thyrotoxicosis or ATD exposure (30-44 per 1000 infants). CONCLUSIONS: Gestational ATD exposure occurred in 1.29 per 1000 mother-infant pairs while a much larger number had maternal diagnosed thyrotoxicosis but no drug exposure during pregnancy. Infants of mothers with gestational ATD use or diagnosed thyrotoxicosis were more likely to be preterm and admitted to the NICU. The rates of congenital malformation were low for mothers diagnosed with thyrotoxicosis and did not differ by ATD use. Among women with gestational PTU therapy, the frequency of PTU-associated hepatotoxicity was 1.8 per 1000 delivered pregnancies. These findings from a large, population-based cohort provide generalizable estimates of maternal and infant risks associated with maternal thyrotoxicosis and related pharmacotherapy.

Remission after potassium iodide therapy in patients with Graves' hyperthyroidism exhibiting thionamide-associated side effects.

CONTEXT: Thionamides have various side effects. OBJECTIVE: The effectiveness of potassium iodide (KI) was evaluated in hyperthyroid patients who experienced side effects to thionamides. DESIGN AND SETTING: An observational study was conducted at an academic medical center. PATIENTS: Among 1388 patients with Graves' hyperthyroidism treated with thionamides, 204 (14.7%) exhibited side effects, and 44 were treated with KI and followed for 17.6 (median; range, 8.6-28.4) years. MAIN OUTCOME MEASURES: The primary endpoint was the initial response to KI, and the secondary endpoint was the long-term prognosis. RESULTS: The conditions of 29 (65.9%) of the 44 patients were well controlled with KI alone (10-400 mg/d) (A group), and 17 (38.6%) patients went into remission after 7.4 (1.9-23.0) years. The conditions of 15 (34.1%) patients were not controlled with KI alone (B group), even at a high dose (100-750 mg/d), but seven patients (15.9%) were controlled with a combination of KI and low-dose thionamides, resulting in remission after 7.2 (2.8-10.8) years. The initial parameters did not predict the response to KI or long-term prognosis. However, remission occurred in 70.8% of the patients treated with less than 200 mg of KI, compared with 35.0% of the patients who required 200 mg or more of KI (P < .05). CONCLUSIONS: Among hyperthyroid patients with thionamide-associated side effects, KI therapy was effective in two-thirds of cases, and about 40% of the patients experienced remission after KI therapy alone. The chance of remission was small among the patients refractory to KI.

Antithyroid drug treatment for graves' disease in children: a long-term retrospective study at a single institution.

BACKGROUND: The management of Graves' disease (GD) in children is associated with a dilemma. Although the established initial treatment for GD in children is antithyroid drug (ATD) treatment, the remission rate in children is said to be lower than in adults, and severe propylthiouracil-induced adverse events (AEs) are an issue. Definitive treatments are effective, but they often result in permanent hypothyroidism and the need for lifelong T4 supplementation. OBJECTIVE: The objective of this study was to investigate the outcome of ATD treatment, identify significant predictors of a remission, and evaluate the AEs of ATDs in a large pediatric population of GD patients. METHODS: We retrospectively assessed the reports of 1138 children up to 18 years of age who had been newly diagnosed with GD at our institution between 1982 and 2006. Their median age at diagnosis was 16 years (range: 3-18 years), and there were 995 females and 143 males. All patients were initially treated with an ATD. Remission was defined as maintenance of euthyroidism for more than 12 months after discontinuing ATD treatment and the absence of any relapses during the follow-up period. RESULTS: Of the 1138 patients, 723 continued on ATD treatment, 271 underwent surgery or radioactive iodine therapy, and 144 dropped out. Of the 723 patients who continued on ATD treatment, ATD treatment was subsequently ongoing in 84 and was discontinued in 639 (median duration of treatment: 3.8 years; range: 0.3-24.8 years). Of the 639 patients who discontinued ATD treatment, 334 (46.2%) achieved a remission, 247 (34.2%) experienced a relapse, and 58 (8.0%) dropped out. The cumulative remission rate increased with the duration of ATD treatment up until five years. No significant predictors of a remission were identified. The overall incidences of AEs associated with methimazole and propylthiouracil were 21.4% and 18.8% respectively. There were no fatal AEs in our population. While most AEs (91.6%) occurred within the first three months of ATD treatment, 2.7% developed more than two years after the start of ATD treatment. Seven of the eight late-onset AEs were induced by propylthiouracil. CONCLUSION: Long-term ATD treatment is a useful treatment option for GD in children.

Levothyroxine replacement therapy with vitamin E supplementation prevents oxidative stress and cognitive deficit in experimental hypothyroidism.

Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status.

Curcumin and vitamin E modulate hepatic antioxidant gene expression in PTU-induced hypothyroid rats.

In the present study, regulatory role of vitamin E and curcumin on antioxidant gene (AOG) expression in hypothyroid rat liver is reported. Adult male rats were rendered hypothyroid by administration of 0.05 % 6-propyl-thiouracil in their drinking water, while vitamin E (200 mg/kg body weight) and curcumin (30 mg/kg body weight) were supplemented orally for 30 days. Expression of antioxidant genes (Cu/Zn-superoxide dismutase; SOD1, Mn superoxide dismutase; SOD2, catalase; CAT, glutathione peroxidase; GPx1 and glutathione reductase; GR) was evaluated using RT-PCR and Western blot analyses. The activities of antioxidant enzymes were measured in mitochondrial fraction (MF) and post-mitochondrial fraction (PMF) of rat liver. In addition measurement of glutathione redox status was also carried out in both the fractions. The enhanced transcripts of CAT, GPx1 and GR in hypothyroid rat liver were alleviated by administration of vitamin E and curcumin. Elevated levels of translated product of all AOGs in hypothyroid group were remained unchanged after antioxidant administration. However, enhanced SOD1, GPx1 and decreased GR activities in PMF were normalized by vitamin E and curcumin. Similarly the increased SOD2, GPx1 and decreased CAT activities in MF were also normalized by vitamin E and curcumin supplementation. Administration of vitamin E and curcumin enhanced mitochondrial GSH level; whereas the enhanced GSH level in PMF of hypothyroid rats was alleviated by vitamin E. Thus it can be concluded that besides the antioxidant role of vitamin E and curcumin, they also regulate hepatic antioxidant gene expression in hypothyroid rats.

Expression of antioxidant genes in renal cortex of PTU-induced hypothyroid rats: effect of vitamin E and curcumin.

The present study was undertaken to investigate the effect of vitamin E and curcumin on the expression of antioxidant genes in 6-propyl-2-thiouracil (PTU)-induced hypothyroid rat renal cortex. The levels of lipid peroxidation and protein carbonylation were increased in hypothyroid rat kidney. Co-administration of vitamin E and curcumin to hypothyroid rats resulted in amelioration of lipid peroxidation level, whereas curcumin alone alleviated the protein carbonylation level. The mRNA levels of SOD1 and SOD2 were decreased in hypothyroid rats. Decreased level of SOD1 transcripts was observed in hypothyroid rats supplemented with curcumin alone or co-administrated with vitamin E. Translated products of SOD1 and SOD2 in hypothyroid rats was elevated in response to supplementation of both the antioxidants. Decreased SOD1 and SOD2 activities in hypothyroid rats compared to control were either unaltered or further decreased in response to the antioxidants. Expressions of CAT at transcript and translate level along with its activity were down regulated in hypothyroid rats. Administration of vitamin E to hypothyroid rats resulted in elevated CAT mRNA level. In contrast, expression of CAT protein was elevated in response to both the antioxidants. However, CAT activity was unaltered in response to vitamin E and curcumin. GPx1 and GR mRNA level and the activity of glutathione peroxidase (GPx) were not affected in response to induced hypothyroidism. The activity of GPx was increased in response to vitamin E treatment, whereas decreased GR activity in hypothyroid rats was further declined by the administration of antioxidants. The over all results suggest that vitamin E and curcumin differentially modulate the altered antioxidant defence mechanism of rat kidney cortex under experimental hypothyroidism.

Drug-induced liver injury: a summary of recent advances.

INTRODUCTION: The knowledge base of drug-induced liver injury (DILI) continues to grow each year as additional drugs are identified as hepatotoxins. There is still a need to improve our ability to predict and diagnose DILI in the preclinical and post-approval settings. AREAS COVERED: This article presents the new and updated DILI registries for 2010, including the latest information on the causes and outcomes of non-acetaminophen DILI cases in the US Acute Liver Failure Study Group database. As DILI is still largely a diagnosis of exclusion, it is appropriate that causality assessment instruments are again the subject of considerable discussion. EXPERT OPINION: DILI research remains extremely active including studies aimed at being better able to identify causative agents, utilize potential biomarkers, predict who is at greatest risk of injury and manage outcomes. With respect to identifying DILI risk factors at the genetic level, the field is rapidly approaching the day where 'personalized medicine' (based on pharmacogenomics) will become a reality. A large single-center series from India reminds us that geography can influence the drugs responsible for liver injury; however, Hy's law remains universal. As our DILI knowledge continues to grow, it remains essential to keep abreast of the important changes reported each year.

Antineutrophil cytoplasmic antibody-positive vasculitis in a patient with graves disease: cross-reaction between propylthiouracil and methimazole.

OBJECTIVE: To alert clinicians about the risk of vasculitis and cross-reactivity of antithyroid medication. METHODS: We describe the clinical course and medical management of the study patient. RESULTS: A 25-year-old woman with hyperthyroidism developed antineutrophil cytoplasmic antibody-positive vasculitis after 15 months of propylthiouracil therapy. Her condition improved when propylthiouracil was withdrawn, but recurred when she was prescribed methimazole. Propylthiouracil and methimazole are commonly used antithyroid medications, and propylthiouracil is a well-recognized cause of drug-induced vasculitis. Cross-reactivity between the 2 drugs is likely, but it has not been reported previously with regard to vasculitis. Many patients with propylthiouracil-induced vasculitis have been switched to methimazole. CONCLUSIONS: Awareness of this rare, but potentially serious, adverse drug reaction is important because prompt discontinuation of medication is essential. Cross-reactivity between propylthiouracil and methimazole must be considered when selecting alternative therapies.

Reacción idiosincrásica fatal al propiltiouracilo / Fatal idiosyncratic reaction to propylthiouracilo

Se presenta una paciente con hipertiroidismo por una enfermedad autoinmune del tiroides que luego de 2 semanas de tratamiento con propiltiouracilo comenzó a presentar un rash generalizado acompañado de fiebre que evolucionó rápidamente a una insuficiencia hepática aguda, fallo multiorgánico y muerte. Se demostró en la necropsia la necrosis masiva del hígado. Se revisaron las afectaciones hepáticas inducidas por reacción idiosincrásicas a medicamentos. Se recomienda instruir a los pacientes sobre posibles síntomas de hepatotoxicidad, indicar pruebas hepáticas periódicamente a los hipertiroideos tratados con antitiroideos y evitar el uso simultáneo de fenobarbital(AU)

The case of a patient with hyperthyroidism due to an autoimmune disease of the thyroid glands that after two weeks of treatment with propylthiouracil presented a systemic rash accompanied with fever evolving quickly to an acute hepatic failure, multiorgan failure, and death, was presenetd. A massive liver necrosis was confirmed in the necropsy. The hepatic affectations induced by idiosyncratic drug reaction were reviewed. We suggest to instruct these patients on the possible symptoms of hepatotoxicity, to indicate periodical hepatic tests to hyperthyroid patients treated with antithyroid agents, and to avoid the simultaneous use of phenobarbital(AU)

Reacción idiosincrásica fatal al propiltiouracilo / Fatal idiosyncratic reaction to propylthiouracilo

Se presenta una paciente con hipertiroidismo por una enfermedad autoinmune del tiroides que luego de 2 semanas de tratamiento con propiltiouracilo comenzó a presentar un rash generalizado acompañado de fiebre que evolucionó rápidamente a una insuficiencia hepática aguda, fallo multiorgánico y muerte. Se demostró en la necropsia la necrosis masiva del hígado. Se revisaron las afectaciones hepáticas inducidas por reacción idiosincrásicas a medicamentos. Se recomienda instruir a los pacientes sobre posibles síntomas de hepatotoxicidad, indicar pruebas hepáticas periódicamente a los hipertiroideos tratados con antitiroideos y evitar el uso simultáneo de fenobarbital.

The case of a patient with hyperthyroidism due to an autoimmune disease of the thyroid glands that after two weeks of treatment with propylthiouracil presented a systemic rash accompanied with fever evolving quickly to an acute hepatic failure, multiorgan failure, and death, was presenetd. A massive liver necrosis was confirmed in the necropsy. The hepatic affectations induced by idiosyncratic drug reaction were reviewed. We suggest to instruct these patients on the possible symptoms of hepatotoxicity, to indicate periodical hepatic tests to hyperthyroid patients treated with antithyroid agents, and to avoid the simultaneous use of phenobarbital.

Detection of endocrine-modulating effects of the antithyroid acting drug 6-propyl-2-thiouracil in rats, based on the "Enhanced OECD Test Guideline 407".

The antithyroid acting drug propylthiouracil (PTU) was administered to male and female Wistar rats at 0, 0.1, 1, or 10mg/kg body weight for 4 weeks according to the draft protocol of the "Enhanced OECD Test Guideline 407" (enhanced TG 407) in order to investigate its suitability to detect endocrine-mediated effects. The study was conducted with two identical subsets of five animals per sex and dose each to provide data on sensitivity. The modified protocol includes the investigation of additional organ weights, pathology, and histopathology, of thyroid hormones, of spermatozoa, and of estrus cycle. At time of sacrifice, all females were in the diestrus stage as prescribed. Adverse effects were observed in the thyroid gland (hypertrophy/ hyperplasia) and the pituitary gland (hyperplasia of basophilic cells, hypoplasia of acidophilic cells) together with dose-related decreased serum triiodothyronine (T3) and thyroxine (T4) levels and increased thyroid stimulating hormone (TSH) levels. Other effects of PTU included decrease of organ weights, anaemia, impaired blood coagulation, and reduced activity of enzymes. Hence, some of the additional examined endpoints of the enhanced TG 407, e.g., examination of pituitary gland and thyroid hormones, were suitable to detect endocrine-modulating effects of propylthiouracil. Treatment of five animals provides sufficient sensitivity to detect the described adverse effects of propylthiouracil. The enhanced TG is currently under investigation in several laboratories, evaluation of all the results will allow determining its practicability as well as the most suitable additional endpoints.

High dose of (131)I therapy for the treatment of hyperthyroidism caused by Graves' disease.

Radioactive iodine ((131)I) has become the most widely used therapy for patients with hyperthyroidism caused by Graves' disease in the United States. There remains, however, significant variability among (131)I dosing regimens, and it is clear that most patients ultimately develop hypothyroidism after therapy. To avoid persistent hyperthyroidism, we adopted a high dose (131)I therapy protocol based on measurement of 24-h thyroid (123)I uptake designed to deliver 8 mCi (296 MBq) to the thyroid gland 24 h after (131)I administration. To evaluate the efficacy of this protocol, we reviewed our clinical experience over a 7-yr period. We treated 261 patients (219 women and 42 men) with hyperthyroidism caused by Graves' disease with (131)I [mean dose, 14.6 mCi (540 MBq)] between 1993 and 1999. Before treatment, 207 (79%) had received an antithyroid drug (109 propylthiouracil and 98 methimazole). We determined their thyroid status 1 yr after treatment in relation to age, pretreatment with an antithyroid drug, pretreatment thyroid size, and dose of (131)I retained in the thyroid 24 h after treatment. Among the 261 patients, 225 (86%) were euthyroid or hypothyroid 1 yr after treatment, and 36 patients (14%) had persistent hyperthyroidism and required a second treatment. The patients who had persistent hyperthyroidism were younger (P < 0.01), had larger thyroid glands (P < 0.01), higher pretreatment thyroid (123)I uptake values (P < 0.01), and higher serum T(4) concentrations (P < 0.01) and were more likely to have taken antithyroid medication before administration of (131)I (P = 0.01). Five of these patients developed transient hypothyroidism, followed by thyrotoxicosis. There was an asymptotic, inverse relationship between the retained dose of (131)I at 24 h and persistent hyperthyroidism, revealing a 5-10% failure rate despite delivery of up to 400 microCi (14.8 MBq)/g. A dose of (131)I that results in accumulation of 8 mCi (296 MBq) in the thyroid gland 24 h after administration is an effective treatment for the majority of patients with Graves' hyperthyroidism. Young patients with larger thyroid glands, higher serum T(4) concentrations, and higher 24-h thyroid (123)I uptake values, and those pretreated with antithyroid medication for greater than 4 months are at higher risk for treatment failure. A higher dose of (131)I may be advisable in such patients.

[Attempted suicide with 400 thyroxine pills: what happened to the physician-patient relationship?]. / Tentamen avec 400 comprimés de thyroxine: que s'est-il passé dans la relation médecin-malade?

Patient aged 49 who developed hypothyroidism after receiving 1131 for relapsing Graves' disease after treatment with propylthiouracil followed by homeopathy. Substitution with thyroxine (0.05 mg/day) was prescribed. Depressed by the perspective of a life long treatment, the patient swallowed 400 pills (20 mg). The evolution was uncomplicated after betablockers administration at hospital. One year later she became euthyroid without further medication. The occurrence of transient hypothyroidism after curitherapy is discussed. The importance of mutual participation in the patient/physician relationship is underlined in the framework of divergent conceptions of medicine.

Hyperparathyroidism induced by hypothyroidism.

The coexistence of hyperparathyroidism and thyroid tumors and/or chronic thyroiditis has raised the possibility of an etiologic relationship. The present study was designed to test the hypothesis that the chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Three groups of 24 rats each were treated for 12 weeks as follows: group 1 received propylthiouracil (PTU) in their deionized water; group 2 received PTU and thyroid hormone to suppress TSH and to serve as a control group for possible direct effects of PTU; and group 3 was not treated at all and served as another control group. At 12 weeks, 95% of group 1 rats (PTU only) showed hyperplasia of the parathyroids with a 30% mean increase in circulating parathormone.