-
PloS One 2012Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of...
BACKGROUND
Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed.
METHODS
We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis.
RESULTS
When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.
Topics: Animals; Antithyroid Agents; Embryo, Mammalian; Embryonic Development; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Heart; Male; Methimazole; Mice; Mice, Inbred C57BL; Pregnancy; Propylthiouracil; Signal Transduction; Teratogens
PubMed: 22529993
DOI: 10.1371/journal.pone.0035213 -
Bioorganic Chemistry Dec 2023Lactoperoxidase was previously used as a model enzyme to test the inhibitory activity of selenium analogs of anti-thyroid drugs with...
Lactoperoxidase was previously used as a model enzyme to test the inhibitory activity of selenium analogs of anti-thyroid drugs with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) as a substrate. Peroxidases oxidize ABTS to a metastable radical ABTS, which is readily reduced by many antioxidants, including thiol-containing compounds, and it has been used for decades to measure antioxidant activity in biological samples. We showed that anti-thyroid drugs 6-n-propyl-2-thiouracil, methimazole, and selenium analogs of methimazole also reduced it rapidly. This reaction may explain the anti-thyroid action of many other compounds, particularly natural antioxidants, which may reduce the oxidized form of iodine and/or tyrosyl radicals generated by thyroid peroxidase thus decreasing the production of thyroid hormones. However, influence of selenium analogs of methimazole on the rate of hydrogen peroxide consumption during oxidation of ABTS by lactoperoxidase was moderate. Direct hydrogen peroxide reduction, proposed before as their mechanism of action, cannot therefore account for the observed inhibitory effects. 1-Methylimidazole-2-selone and its diselenide were oxidized by ABTS to relatively stable seleninic acid, which decomposed slowly to selenite and 1-methylimidazole. In contrast, oxidation of 1,3-dimethylimidazole-2-selone gave selenite and 1,3-dimethylimidazolium cation. Accumulation of the corresponding seleninic acid was not observed.
Topics: Antioxidants; Cations; Hydrogen Peroxide; Lactoperoxidase; Methimazole; Oxidation-Reduction; Selenious Acid; Selenium; Propylthiouracil
PubMed: 37788560
DOI: 10.1016/j.bioorg.2023.106891 -
Internal Medicine (Tokyo, Japan) 2017Neuromuscular disorders associated with hyperthyroidism have several variations in their clinical phenotype, such as ophthalmopathy, periodic paralysis, and thyrotoxic...
Neuromuscular disorders associated with hyperthyroidism have several variations in their clinical phenotype, such as ophthalmopathy, periodic paralysis, and thyrotoxic myopathy. We herein report an unusual case of thyrotoxic myopathy presenting as unilateral drop foot. Histopathological examinations of the left tibialis anterior muscle showed marked variation in the fiber size, mild inflammatory cell infiltration, and necrotic and regenerated muscle fibers with predominantly type 1 fiber atrophy. Medical treatment with propylthiouracil resulted in complete improvement of the left drop foot. This case expands the phenotype of thyrotoxicosis and suggests that thyrotoxicosis be considered as a possible cause of unilateral drop foot.
Topics: Adolescent; Antithyroid Agents; Biopsy; Female; Gait Disorders, Neurologic; Humans; Magnetic Resonance Imaging; Muscle, Skeletal; Muscular Diseases; Necrosis; Paralysis; Propylthiouracil; Thyrotoxicosis
PubMed: 28768980
DOI: 10.2169/internalmedicine.56.8374 -
Journal of Lipid Research Nov 1982Hyperalphalipoproteinemia, characterized by increased plasma concentrations of apoA-I and of HDL lipid and protein, was observed in rats treated with triiodothyronine...
Hyperalphalipoproteinemia, characterized by increased plasma concentrations of apoA-I and of HDL lipid and protein, was observed in rats treated with triiodothyronine (T(3)) for 7 days. The increase in the plasma HDL apoproteins was general for apoC, apoE plus A-IV, and apoA-I, as determined by isoelectric focusing. Hypotriglyceridemia, characterized by decreased concentrations of VLDL and apoB, was also observed in the hyperthyroid state. Although in the mildly hypothyroid animals (propylthiouracil-treated), hepatic metabolism of free fatty acid is shifted toward esterification to triglyceride and VLDL formation, as we reported previously, plasma HDL and apoA-I concentrations were not different from control plasma values, while the d 1.006-1.063 g/ml (IDL + LDL) lipoprotein fraction tended to be increased. In general, the proportion of apoE in the (IDL + LDL) fraction of the hypothyroid rat was greater than in controls and hyperthyroid animals, while the proportion of apoE tended to be lower in VLDL from both hypo- and hyperthyroid rats than in VLDL from controls. An enhanced release of apoA-I by perfused livers isolated from rats treated with T(3) was also observed; this enhanced output of apoA-I may explain, in part, the hyperalphalipoproteinemia observed in these rats. The depressed net output of apoA-I in vitro by perfused livers from rats treated with propylthiouracil (PTU) was not expressed in a statistically significant diminished plasma concentration of HDL or apoA-I in the intact animals. Treatment with T(3) also resulted in modification of the content of essential fatty acids in various lipid classes. Linoleic acid residues were significantly reduced and arachidonic acid content was increased in plasma phospholipids and esterified cholesterol in T(3)-treated rats. However, the relative fatty acid composition of unesterified fatty acids and triglyceride fatty acids was not altered by T(3) treatment. PTU treatment had no effect on fatty acid distribution in any of the plasma lipids. Secretion of biliary lipids was increased in perfused livers from T(3)-treated rats, while treatment with PTU did not affect release of lipids in the bile. These observations suggest a regulatory role for thyroid hormones that determine concentration and composition of plasma HDL and other lipoproteins.-Wilcox, H. G., W. G. Keyes, T. A. Hale, R. Frank, D. W. Morgan, and M. Heimberg. Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats.
Topics: Animals; Apolipoprotein A-I; Apolipoproteins; Cholesterol; Isoelectric Focusing; Lipids; Lipoproteins; Male; Phospholipids; Propylthiouracil; Rats; Rats, Inbred Strains; Triiodothyronine
PubMed: 6816881
DOI: No ID Found -
Scientific Reports Aug 2017Several studies have suggested a possible relationship between polymorphic variants of the taste receptors genes and the acceptance, liking and intake of food and...
Several studies have suggested a possible relationship between polymorphic variants of the taste receptors genes and the acceptance, liking and intake of food and beverages. In the last decade investigators have attempted to link the individual ability to taste 6-n-propylthiouracil (PROP) and the sensations, such as astringency and bitterness, elicited by wine or its components, but with contradictory results. We have used the genotype instead of the phenotype (responsiveness to PROP or other tastants), to test the possible relation between genetic variability and the perception of wine characteristic in 528 subjects from Italy and the Czech Republic. We observed several interesting associations, among which the association between several TAS2R38 gene single nucleotide polymorphisms (P = 0.002) and the TAS2R16-rs6466849 polymorphism with wine sourness P = 0.0003). These associations were consistent in both populations, even though the country of origin was an important factor in the two models, thus indicating therefore that genetics alongside cultural factors also play a significant role in the individual liking of wine.
Topics: Adult; Alleles; Czech Republic; Female; Gene Frequency; Genetic Association Studies; Genotype; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Propylthiouracil; Taste; Taste Buds; Taste Perception; Wine
PubMed: 28835712
DOI: 10.1038/s41598-017-08946-3 -
Hormone Research in Paediatrics 2010Graves' disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. Caused by immunologic stimulation of the thyroid-stimulating hormone... (Review)
Review
BACKGROUND/AIMS
Graves' disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. Caused by immunologic stimulation of the thyroid-stimulating hormone receptor, lasting remission occurs in only a minority of pediatric patients with GD, including children treated with antithyroid drugs (ATDs) for many years. Thus the majority of pediatric patients with GD will need thyroidectomy or treatment with radioactive iodine (RAI; (131)I).
RESULTS
When ATDs are used in children, only methimazole should be used. Propylthiouracil is associated with an unacceptable risk of severe liver injury in children and should never be used as first-line therapy. If remission (defined as normal thyroid function off ATDs) is not achieved after 1 or 2 years of ATD therapy, (131)I or surgery may be considered, with the choice influenced by the age of the individual. When (131)I is used, administered doses should be >150 μCi/g of thyroid tissue. When surgery is performed, near total or total thyroidectomy is recommended.
CONCLUSION
Choosing a treatment approach for childhood GD is often a difficult and highly personal decision. Discussion of the advantages and risks of each therapeutic option is essential to help the patient and family select a treatment option.
Topics: Antithyroid Agents; Child; Graves Disease; Humans; Iodine Radioisotopes; Methimazole; Propylthiouracil
PubMed: 20924158
DOI: 10.1159/000320028 -
Journal of the National Medical... Dec 1979A 10-year-old girl initially presented with clinical features and thyroid function tests consistent with hyperthyroidism. She was treated with propylthiouracil, 100 mg,...
A 10-year-old girl initially presented with clinical features and thyroid function tests consistent with hyperthyroidism. She was treated with propylthiouracil, 100 mg, three times a day. She developed jaundice and hepatitis following treatment with propylthiouracil for 40 days. Clinical features of hepatitis improved after the discontinuation of propylthiouracil and she became euthyroid. At this time, an immunofluorescent technique revealed antibodies consistent with autoimmune thyroiditis. From this report, it appears that hepatitis is one of the infrequent complications of treatment with propylthiouracil and transient hyperthyroidism may be associated with autoimmune thyroiditis.
Topics: Chemical and Drug Induced Liver Injury; Child; Female; Humans; Hyperthyroidism; Jaundice; Propylthiouracil
PubMed: 522183
DOI: No ID Found -
Internal Medicine (Tokyo, Japan) 2013
Topics: Cryoglobulinemia; Female; Humans; Middle Aged; Propylthiouracil; Vasculitis
PubMed: 23995008
DOI: 10.2169/internalmedicine.52.0739 -
British Journal of Clinical Pharmacology Oct 2021Maternal antithyroid drug (ATD) use during pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this... (Meta-Analysis)
Meta-Analysis
Antithyroid drug use during pregnancy and the risk of birth defects in offspring: systematic review and meta-analysis of observational studies with methodological considerations.
AIMS
Maternal antithyroid drug (ATD) use during pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this risk and how it compares to untreated hyperthyroidism due to methodological limitations of previous studies.
METHODS
Systematic review of MEDLINE and EMBASE identifying observational studies examining ATD use during pregnancy and risk of birth defects by 28 August 2020. Data were extracted on study characteristics, effect estimates and comparator groups. Adjusted effect estimates were pooled using a random-effects generic inverse variance method and absolute risk calculated.
RESULTS
Seven cohort studies and 1 case-control study involving 6 212 322 pregnancies and 388 976 birth defects were identified reporting regression effect estimates. Compared to an unexposed population comparison, the association between ATD use during pregnancy and birth defects in offspring was: adjusted risk ratio (aRR) 1.16 95% confidence interval (CI) 1.08-1.25 for propylthiouracil (PTU); aRR 1.28 95%CI 1.06-1.54 for methimazole/carbimazole (MMI/CMZ); aRR 1.51, 95%CI 1.16-1.97 for both MMI/CMZ and PTU; and aRR 1.15 95%CI 1.02-1.29 for untreated hyperthyroidism. The excess risk of any and major birth defects per 1000, respectively, was: 10.2 and 1.3 for PTU; 17.8 and 2.3 for MMI/CMZ; 32.5 and 4.1 for both MMI/CMZ and PTU; and 9.6 and 1.2 for untreated hyperthyroidism.
CONCLUSIONS
When appropriately analysed the risk of birth defects associated with ATD use in pregnancy is attenuated. Although still elevated, the risk of birth defects is smallest with PTU compared to MMI/CMZ and may be similar to that of untreated hyperthyroidism.
Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Case-Control Studies; Female; Humans; Hyperthyroidism; Methimazole; Observational Studies as Topic; Pregnancy; Pregnancy Complications; Propylthiouracil
PubMed: 33783857
DOI: 10.1111/bcp.14805 -
Clinical and Experimental Immunology Aug 1988Carbimazole and Propylthiouracil (PTU) are widely used in the treatment of Graves' disease, although controversy still exists as to whether or not they have any direct... (Comparative Study)
Comparative Study
Carbimazole and Propylthiouracil (PTU) are widely used in the treatment of Graves' disease, although controversy still exists as to whether or not they have any direct effect on the immune system. While many previous studies have investigated the possible effects of one or other of these drugs on the immune system only a few have directly compared the effects of equivalent doses of each drug. This study aimed to examine the effects of both drugs, during the initial 8 weeks of treatment, on various biochemical and immunological parameters. The results obtained showed that while thyroid hormone levels fell at similar rates in both treatment groups, TRAb levels and T cell subset abnormalities returned towards normal more rapidly in patients receiving Carbimazole compared to PTU. These results indicate that the effects of Carbimazole on TRAb levels and T cell subset abnormalities are not due solely to its action in controlling the biochemical features of Graves' disease and provide indirect evidence of an action on the immune system in vivo.
Topics: Adult; Autoantibodies; Carbimazole; Female; Graves Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Propylthiouracil; Receptors, Thyrotropin; T-Lymphocytes; Thyroxine; Triiodothyronine
PubMed: 3263234
DOI: No ID Found