Showing papers on "Propylthiouracil published in 2019"

Drug-induced immune neutropenia/agranulocytosis.

Abstract: Neutrophils are the most abundant white blood cell in blood and play a critical role in preventing infections as part of the innate immune system. Reduction in neutrophils below an absolute count of 500 cells/pL is termed severe neutropenia or agranulocytosis. Drug-induced immune neutropenia (DIIN) occurs when drug-dependent antibodies form against neutrophil membrane glycoproteins and cause neutrophil destruction. Affected patients have fever, chills, and infections; severe infections left untreated can result in death. Treatment with granulocyte colony-stimulating factor can hasten neutrophil recovery. Cumulative data show that severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs ranges from approximately 1.6 to 15.4 cases per million population per year. Drugs most often associated with neutropenia or agranulocytosis include dipyrone, diclofenac, ticlopidine, calcium dobesilate, spironolactone, antithyroid drugs (e.g., propylthiouracil), carbamazepine, sulfamethoxazole- trimethoprim, [3-lactam antibiotics, clozapine, levamisole, and vancomycin. Assays used for detection of neutrophil drug-dependent antibodies (DDAbs) include flow cytometry, monoclonal antibody immobilization of granulocyte antigens, enzyme-linked immunosorbent assay, immunoblotting, granulocyte agglutination, and granulocytotoxicity. However, testing for neutrophil DDAbs is rarely performed owing to its complexity and lack of availability. Mechanisms proposed for DIIN have not been rigorously studied, but those that have been studied include drug- or hapten-induced antibody formation and autoantibody production against drug metabolite or protein adducts covalently attached to neutrophil membrane proteins. This review will address acute, severe neutropenia caused by neutrophil-reactive antibodies induced by nonchemotherapy drugs-DIIN

Thyroid function and thyroid disorders during pregnancy: a review and care pathway.

Abstract: To review the literature on thyroid function and thyroid disorders during pregnancy. A detailed literature research on MEDLINE, Cochrane library, EMBASE, NLH, ClinicalTrials.gov, and Google Scholar databases was done up to January 2018 with restriction to English language about articles regarding thyroid diseases and pregnancy. Thyroid hormone deficiencies are known to be detrimental for the development of the fetus. In particular, the function of the central nervous system might be impaired, causing low intelligence quotient, and mental retardation. Overt and subclinical dysfunctions of the thyroid disease should be treated appropriately in pregnancy, aiming to maintain euthyroidism. Thyroxine (T4) replacement therapy should reduce thyrotropin (TSH) concentration to the recently suggested fixed upper limits of 2.5 mU/l (first and second trimester) and 3.0 mU/l (third trimester). Overt hyperthyroidism during pregnancy is relatively uncommon but needs prompt treatment due to the increased risk of preterm delivery, congenital malformations, and fetal death. The use of antithyroid drug (methimazole, propylthiouracil, carbimazole) is the first choice for treating overt hyperthyroidism, although they are not free of side effects. Subclinical hyperthyroidism tends to be asymptomatic and no pharmacological treatment is usually needed. Gestational transient hyperthyroidism is a self-limited non-autoimmune form of hyperthyroidism with negative antibody against TSH receptors, that is related to hCG-induced thyroid hormone secretion. The vast majority of these patients does not require antithyroid therapy, although administration of low doses of β-blocker may by useful in very symptomatic patients. Normal maternal thyroid function is essential in pregnancy to avoid adverse maternal and fetal outcomes.

Thyroid Hormone Disruptors Interfere with Molecular Pathways of Eye Development and Function in Zebrafish.

Abstract: The effects of thyroid hormone disrupting chemicals (THDCs) on eye development of zebrafish were investigated. We expected THDC exposure to cause transcriptional changes of vision-related genes, which find their phenotypic anchoring in eye malformations and dysfunction, as observed in our previous studies. Zebrafish were exposed from 0 to 5 days post fertilization (dpf) to either propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, or tetrabromobisphenol-A (TBBPA), which interacts with thyroid hormone receptors. Full genome microarray analyses of RNA isolated from eye tissue revealed that the number of affected transcripts was substantially higher in PTU- than in TBBPA-treated larvae. However, multiple components of phototransduction (e.g., phosphodiesterase, opsins) were responsive to both THDC exposures. Yet, the response pattern for the gene ontology (GO)-class “sensory perception” differed between treatments, with over 90% down-regulation in PTU-exposed fish, compared to over 80% up-regulation in TBBPA-exposed fish. Additionally, the reversibility of effects after recovery in clean water for three days was investigated. Transcriptional patterns in the eyes were still altered and partly overlapped between 5 and 8 dpf, showing that no full recovery occurred within the time period investigated. However, pathways involved in repair mechanisms were significantly upregulated, which indicates activation of regeneration processes.

CLARITY-BPA: Bisphenol A or Propylthiouracil on Thyroid Function and Effects in the Developing Male and Female Rat Brain.

Abstract: The CLARITY-BPA experiment, a large collaboration between the National Institute of Environmental Health Sciences, the National Toxicology Program, and the US Food and Drug Administration, is designed to test the effects of bisphenol A (BPA) on a variety of endocrine systems and end points. The specific aim of this subproject was to test the effect of BPA exposure on thyroid functions and thyroid hormone action in the developing brain. Timed-pregnant National Center for Toxicological Research Sprague-Dawley rats (strain code 23) were dosed by gavage with vehicle control (0.3% carboxymethylcellulose) or one of five doses of BPA [2.5, 25, 250, 2500, or 25,000 µg/kg body weight (bw) per day] or ethinyl estradiol (EE) at 0.05 or 0.50 µg/kg bw/d (n = 8 for each group) beginning on gestational day 6. Beginning on postnatal day (PND) 1 (day of birth is PND 0), the pups were directly gavaged with the same dose of vehicle, BPA, or EE. We also obtained a group of animals treated with 3 ppm propylthiouracil in the drinking water and an equal number of concordant controls. Neither BPA nor EE affected serum thyroid hormones or thyroid hormone‒sensitive end points in the developing brain at PND 15. In contrast, propylthiouracil (PTU) reduced serum T4 to the expected degree (80% reduction) and elevated serum TSH. Few effects of PTU were observed in the male brain and none in the female brain. As a result, it is difficult to interpret the negative effects of BPA on the thyroid in this rat strain because the thyroid system appears to respond differently from that of other rat strains.

Inhibitory effects of methimazole and propylthiouracil on iodotyrosine deiodinase 1 in thyrocytes.

Abstract: Methimazole (MMI) and propylthiouracil (PTU) are commonly used for the treatment of Graves' disease. They share similar inhibitory effects on thyroid hormone biosynthesis by interfering with thyroid peroxidase (TPO)-mediated oxidation and organification of iodine. However, their potential effects on other thyroid functional molecules have not been explored in depth. To identify novel effects of MMI and PTU, DNA microarray analysis, real-time PCR, Western blotting, immunofluorescence staining and confocal laser scanning microscopy were performed using FRTL-5 rat thyroid cells. DNA microarray analysis indicated that both MMI and PTU suppress iodotyrosine deiodinase 1 (Iyd, Dehal1) mRNA levels. Further studies revealed that Dehal1 mRNA levels was stimulated by TSH, insulin and serum, while it was suppressed by iodine and a follicular concentration of thyroglobulin. MMI and PTU significantly suppressed Dehal1 expression induced by TSH, insulin and serum. On the other hand, although MMI suppressed Dehal1 expression in the absence of TSH, PTU only weakly suppressed Dehal1 without TSH. These results suggest that PTU and MMI may use different mechanisms to regulate Dehal1 expression, and TSH may play essential and differential roles in mediating PTU and MMI signals in thyrocytes. The drugs also inhibited re-distribution of Dehal1 protein into newly formed lysosomes following thyroglobulin endocytosis. These findings imply complex and multifaceted regulation of Dehal1 in the thyroid and suggest that MMI and PTU modulate Dehal1 expression and distribution of the protein in thyrocytes to exert their effect.

Role of ashwagandha methanolic extract in the regulation of thyroid profile in hypothyroidism modeled rats

Abstract: This study aimed to evaluate the anti-hypothyroidism potential of ashwagandha methanolic extract (AME). This target was performed through induction of animal model of hypothyroidism by propylthiouracil. After 1 month from treatments, blood samples were collected for biochemical determinations, and liver and kidney were removed for the determination of oxidative stress markers and thyroid gland was removed for histopathological examination. The total phenolic compounds in the extract and the in vitro radical scavenging activity of extract were also determined. The results revealed that the induction of hypothyroidism by propylthiouracil induced a significant increase in serum TSH level but it induced significant decreases in the levels of total T3, free T3, free T4, and total T4 hormones compared with the control values. Also, serum glucose, Il-6, and body weight gain increased significantly while Il-10 and blood hemoglobin levels showed significant decrease. Induction of hypothyroidism increased also the levels of hepatic and renal MDA and NO and decreased significantly the values of GSH, GPx and Na+/ K+-ATPase. Both AME and the anti-hypothyroidism drug significantly ameliorated the changes occurred in the levels of the above parameters and improved histological picture of thyroid gland but with different degrees; where ashwagandha methanolic extract showed the strongest effect. We can conclude that ashwagandha methanolic extract treatment improves thyroid function by ameliorating thyroid hormones and by preventing oxidative stress.

Chavibetol corrects thyrotoxicosis through alterations in thyroid peroxidase.

Abstract: Thyrotoxicosis is a clinical syndrome that commonly results from excess secretion and/or release of thyroid hormones in the circulation. It affects most of the body systems and if not treated properly may lead to serious health problems. In this investigation, we isolated a phenolic compound, chavibetol (CHV) from Piper betel leaf and evaluated its possible ameliorative effects in thyrotoxicosis of rats. Adult female rats were rendered thyrotoxic by the administration of l-thyroxine (l-T4) at 500 μg/kg/day, i.p., for 12 days, and then chavibetol (20.0 mg/kg, p.o.) was administered for 2 weeks. l-T4 administration elevated the concentration of serum thyroxine and triiodothyronine, activities of alanineaminotransferase and aspartate aminotransferase, and decreased the thyrotropin level as well as the expression of thyroid peroxidase (TPO). Further, it increased the activities of hepatic 5′mono-deiodinase-I, glucose-6--phosphatase, sodium-potasium-ATPase, and lipid peroxidation, and depleted the cellular antioxidants. However, chavibetol treatment to thyrotoxic rats normalized almost all these indices including TPO and also preserved the integrity of thyroid tissues suggesting its potential to correct thyrotoxicosis. Effects of CHV were more or less similar to a conventional antithyroid drug, propylthiouracil (PTU).

Associations of HLA genotypes with antithyroid drug‐induced agranulocytosis: a systematic review and meta‐analysis of pharmacogenomics studies

Abstract: Aims Antithyroid drug (ATD)-induced agranulocytosis is a life-threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD-induced agranulocytosis. To examine the associations between HLA genotypes and ATD-induced agranulocytosis, we conducted a systematic review and meta-analysis of pharmacogenomics studies. Methods We searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case-control studies on the associations between HLA genotypes with ATD-induced agranulocytosis. The Newcastle-Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random-effects model meta-analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD-induced agranulocytosis. Results We included 5 studies with 142 ATD-induced agranulocytosis cases, 1529 matched ATD-tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD-induced agranulocytosis was associated with HLA-B*27:05 (OR 10.97; 95% CI 0.75-159.99), HLA-B*38:02 (OR 19.85; 95% CI 7.94-49.57) and HLA-DRB1*08:03 (OR 5.29; 95% CI 3.44-8.14). After excluding propylthiouracil, the associations of ATD-induced agranulocytosis with HLA-B*27:05 and HLA-B*38:02 were strengthened (OR being 20.61 (95% CI 5.21-81.58) and 40.59 (95% CI 13.24-124.47), respectively). The associations of ATD-induced agranulocytosis with HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86-14.07), 36.43 (95% CI 12.80-103.70) and 5.42 (95% CI 2.36-12.47), respectively). HLA-B*27:05, HLA-B*38:02, and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis. Conclusions HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.

Preventive effects of Aframomum melegueta extracts on the reproductive complications of propylthiouracil-induced hypothyroidism in male rat.

Abstract: Recent studies have demonstrated that hypothyroidism is associated with infertility. This work was undertaken to evaluate the protective effects of Aframomum melegueta on testicular functions and fertility of hypothyroid male rats. Male rats were orally treated with propylthiouracil (PTU: 10 mg/kg) in combination with plant aqueous or methanol seed extract (20 and 100 mg/kg) for 56 days. Vitamin E and clomiphene citrate served as positive controls. On day 47 of treatment, each male was mated with two adult females for fertilization potential evaluation. At the end of the treatment, genital sex organ weights, sperm characteristics, testicular histology, oxidative status, plasmatic hormones and fertility potential were evaluated. Results indicated that PTU created hypothyroidism characterised by a significant increase in TSH with reduction of T3 and T4. PTU also lowered genital sex organ weights, sperm count, viability and motility, plasmatic levels of luteinising hormone, follicle-stimulating hormone and testosterone, and increased prolactin, cholesterol and testicular oxidative stress. Alteration in sperm morphology, testis and epididymis histology, and fertilization potential was also noticed. Co-administration with A. melegueta extracts successfully reversed PTU-induced infertility without any effect on thyroid hormones. These results provide evidence that A. melegueta has a protective effect on fertility in hypothyroid condition.

Hippocampal Up-Regulation of Apolipoprotein D in a Rat Model of Maternal Hypo- and Hyperthyroidism: Implication of Oxidative Stress

Abstract: Thyroid disorders impair various functions of the hippocampus where thyroid hormone receptors are localized in the brain. Hyper and hypothyroidism are associated with large changes in brain oxidative stress. Apolipoprotein D (APOD) is a conserved glycoprotein that increased in response to oxidative stress in the brain and has been suggested function as an antioxidant in the brain. Thus, the goal of this work was to explore the effect of maternal hypo- and hyperthyroidism on the Apod expression in the pup’s brain regarding changes in oxidative stress. For induction hypo and hyperthyroidism in adult female rats, 100 ppm propylthiouracil (PTU) and 8 ppm levothyroxine administrated 1 month before copulation to the week 3 after delivery in drinking water. The hippocampal region of rat pups was isolated and used for immunohistochemistry and quantitative RT-PCR on postnatal day (PND)5, PND10 and PND20. Results revealed that APOD over-expressed in both hypo- and hyperthyroid groups on PND5, PND10, and PND20. There was a proportional increase between the Apod expression and oxidative stress in the hyperthyroid group but not the hypothyroid in different days. Regarding the wide functions of thyroid hormones, oxidative stress does not suggest to be the only mechanism that involves Apod gene expression in thyroid disturbances.

Systemic p-ANCA vasculitis with fatal outcome, arising in the setting of methimazole use.

Abstract: Here we report a fatal case of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) due to methimazole use in a 64-year-old woman. She was initially hospitalized for abdominal pain and possible colitis, and subsequently developed hematuria, renal failure, and hemoptysis. The serologic work-up revealed positive antinuclear antibody (ANA) and perinuclear-antineutrophilic cytoplasm antibodies (p-ANCA), with positive antimyeloperoxidase. Three weeks following admission, the patient was found to be pulseless, and expired. At autopsy, microscopic review included widespread transmural necrotizing vasculitis and crescentic glomerulonephritis in the kidney, and diffuse pulmonary alveolar hemorrhage; focal coronary artery intimal vasculitis and necrotizing pericarditis were also noted. Several drugs have been associated with the development of ANCA-positive diseases, including propylthiouracil, hydralazine, allopurinol, penicillamine, and levamisole in cocaine. Association of ANCA vasculitis with methimazole exposure is less known, and severe presentation with fatal outcome, as seen in our patient, is exceedingly rare. We reviewed clinical and histopathologic features of drug-induced ANCA vasculitis associated with methimazole to raise awareness of this potentially life-threatening complication associated with this agent.

Increased Risk of Antithyroid Drug Agranulocytosis Associated with Amiodarone-Induced Thyrotoxicosis: A Population-Based Cohort Study

Abstract: Background: Agranulocytosis occurs in 0.2–0.5% of patients treated with the antithyroid drugs (ATDs) methimazole and propylthiouracil. The objectives of this study were to evaluate the risk of ATD-...

Gastroschisis Following Treatment with High-Dose Methimazole in Pregnancy: A Case Report.

Abstract: Hyperthyroidism in pregnancy is associated with a increased incidence of low birth weight, preterm birth and admission to the neonatal intensive care unit. However, available treatment options are limited. In this report, we present a case of fetal gastroschisis with a history of intrauterine exposure to methimazole. A 37-year-old woman was diagnosed with Grave’s disease 3 years before her pregnancy. She had a poor response to propylthiouracil and required high-dose methimazole before her pregnancy. During the first trimester, she received methimazole 120 mg/day. After her 12th week of pregnancy, she received block-and-replace therapy (levothyroxine [LT4] 50 µg/day) because of the risk of hypothyroidism, and the dose of methimazole was downtitrated to 60 mg/day. Fetal ultrasonography showed fetal growth retardation and gastroschisis at gestational week 33. The relationship between the very high doses of methimazole in the first trimester of pregnancy and the incidence of gastroschisis in this patient was not fully understood because evidence of a relationship between the use of antithyroid drugs in the first trimester and congenital abnormalities in the fetus is lacking. Furthermore block-and-replace therapy is not recommended in pregnancy because it requires a higher dose of methimazole. We recommend preconception counseling and early screening of thyroid function. The counseling should include the best timeline for pregnancy and a discussion of the risks and benefits of hyperthyroidism treatment options.

Fulminant hepatitis and elevated levels of sIL-2R in thyroid storm

Abstract: We report the case of a 48-year-old man with thyroid storm associated with fulminant hepatitis and elevated levels of soluble interleukin-2 receptor (sIL-2R). Fatigue, low-grade fever, shortness of breath, and weight loss developed over several months. The patient was admitted to the hospital because of tachycardia-induced heart failure and liver dysfunction. Graves’ disease with heart failure was diagnosed. He was treated with methimazole, inorganic iodide, and a β-blocker. On the day after admission, he became unconscious with a high fever and was transferred to the intensive care unit. Cardiogenic shock with atrial flutter was treated with intra-aortic balloon pumping and cardioversion. Hyperthyroidism decreased over 10 days, but hepatic failure developed. He was diagnosed with thyroid storm accompanied by fulminant hepatitis. Laboratory investigations revealed elevated levels of sIL-2R (9770 U/mL). The fulminant hepatitis was refractory to plasma exchange and plasma filtration with dialysis, and no donors for liver transplantation were available. He died of hemoperitoneum and gastrointestinal hemorrhage due to fulminant hepatitis 62 days after admission. Elevated circulating levels of sIL-2R might be a marker of poor prognosis in thyroid storm with fulminant hepatitis. Learning points: The prognosis of thyroid storm when fulminant hepatitis occurs is poor. Liver transplantation is the preferred treatment for fulminant hepatitis induced by thyroid storm refractory to plasma exchange. Elevated levels of soluble interleukin-2 receptor might be a marker of poor prognosis in patients with thyroid storm. Patient Demographics: Adult, Male, Asian - Japanese, Japan Clinical Overview: Heart, Liver, Thyroid, Thyroxine (T4), Triiodothyronine (T3), TSH, Liver failure, Fulminant hepatitis*, Thyroid storm, Graves' disease Diagnosis and Treatment: Fatigue, Pyrexia, Breathing difficulties, Dyspnoea, Weight loss, Tachycardia, Heart failure, Atrial fibrillation, Hyperthyroidism, Cardiogenic shock, Cardiomegaly, Liver dysfunction*, Goitre, Hyperhidrosis, Oedema, Hypoglycaemia, Renal failure, Coagulopathy, Hyperammonemia*, Jaundice, Hypoxia, Metabolic acidosis, Soluble IL-2 receptor*, Alanine aminotransferase, Aspartate transaminase, FT4, CT scan, Bilirubin, Transaminase, X-ray, Echocardiogram, Albumin, Lactate dehydrogenase, Alkaline phosphatase, Glucose (blood), Creatinine, Calcium (serum), C-reactive protein, Potassium, Ammonia, Brain natriuretic peptide, FT3, TSH, Thyroid antibodies, Prothrombin time, Plasma exchange, Dialysis, Intra-aortic balloon pumping*, Methimazole, Potassium iodide, Beta-blockers, Hydrocortisone, Glucocorticoids, Landiolol hydrochloride*, Glucose, Propylthiouracil Related Disciplines: Cardiology, Gastroenterology Publication Details: Unique/unexpected symptoms or presentations of a disease, September, 2019 Background Thyroid storm is a rare, life-threatening complication of Graves’ disease (1). Liver dysfunction in thyroid storm is induced by hepatic ischemia, dysfunction of hepatic metabolism, direct injury from thyrotoxicity, and anti-thyroid drugs (2). Fulminant hepatitis with thyroid storm causes multiple organ failure and is associated with poor prognosis. Interleukin-2 (IL-2) is a cytokine produced by CD4-positive T cells. IL-2 binds to IL-2 receptor expressed on the cell surface, thereby activating T cells, B cells, natural killer cells, monocytes, and macrophages (3). Activated lymphocytes produce and release IL-2 receptor from the cell surface, which can be measured as soluble interleukin-2 receptor (sIL-2R). Multiple organ failure develops as a result of cytokine storm in some patients; circulating levels of sIL-2R are increased. Here, we report a case of thyroid storm with elevated levels of sIL-2R. The patient could not be rescued with plasma exchange for fulminant hepatitis.

Impact of Spirulina on Propylthiouracil - Induced Hypothyroidism in Albino Rats, A Histological, Immunohistochemical and Biochemical Approach

Abstract: Background: Hypothyroidism is a decrease in the production of the thyroid hormones and leads to gland dysfunction. Spirulina used as an antioxidant and supposed as antihypothyroidic agent.Objective: This study was carried out to investigate the impact of Spirulina on PTU-induced hypothyroidism in rats.Materials and Methods: The rats were divided into six groups, control group (G1), hypothyroid group (G2), SP-500 treated group (G3), SP-1000 treated group (G4), PTU+SP-500 treated group (G5) and PTU+SP-1000 treated group (G6). Thyroid gland was examined using biochemical, histological, and immunohistochemical studies. Duration of treatments were for 14 days.Results: A significant decline in the body weight gain was exhibited. Biochemically, a significant decrease in T3 and T4 hormone levels in the PTU-group and a substantial increase in groups treated with Spirulina alone. While PTU+ Spirulina treated groups revealed normal hormonal levels more or less similar to the control group. Histological changes such as congestion of the blood capillaries, follicular dilatation, and vacuolar degeneration of some follicular cells were exhibited in hypothyroid group G2 and Spirulina treated-groups (G3andG4). Hyperplastic cells with hyperchromatic nuclei, depleted vacuolated-thyroglobulin, and a significant increase in the epithelial heights and the follicular diameters, were observed. Immunohistochemically, low expression of the proliferative cellular marker KI-67 was expressed in the PTU and PTU+Spirulina treated groups. While negative expression of KI-67 in Spirulina treated groups was recorded.Conclusion: Administration of Spirulina alone displayed signs of hyperactivity on the thyroid gland, but it has a mild protective role in the PTU-induced hypothyroidism groups. Therefore, caution should be used in extrapolating these results to the human being situation within different doses and durations.

Propylthiouracil-induced agranulocytosis as a rare complication of antithyroid drugs in a patient with Graves' disease.

Abstract: SUMMARY INTRODUCTION: Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism. Antithyroid drugs (ATDs) are available as therapy. Agranulocytosis is a rare but potentially fatal complication of this therapy. In this study, we report agranulocytosis induced by propylthiouracil (PTU) in a patient with GD and the difficulties of clinical management. CASE: RNBA, male, 30 years old, with GD, treated with propylthiouracil (PTU). He progressed with pharyngotonsillitis. Then, PTU was suspended and antibiotic, filgrastim, propranolol, and prednisone were initiated. Due to the decompensation of hyperthyroidism, lithium carbonate, dexamethasone, and Lugol's solution were introduced. Total thyroidectomy (TT) was performed with satisfactory postoperative progression. DISCUSSION: We describe here the case of a young male patient with GD. For the treatment of hyperthyroidism, thioamides are effective options. Agranulocytosis induced by ATDs is a rare complication defined as the occurrence of a granulocyte count <500/mm3 after the use of ATDs. PTU was suspended, and filgrastim and antibiotics were prescribed. Radioiodine (RAI) or surgery are therapeutic alternatives. Due to problems with ATD use, a total thyroidectomy was proposed. The preoperative preparation was performed with beta-blocker, glucocorticoid, lithium carbonate, and Lugol solution. Cholestyramine is also an option for controlling hyperthyroidism. TT was performed without postoperative complications. CONCLUSION: Thionamide-induced agranulocytosis is a rare complication. With a contraindication to ATDs, RAI and surgery are definitive therapeutic options in GD. Beta-blockers, glucocorticoids, lithium carbonate, iodine, and cholestyramine may be an adjunctive therapy for hyperthyroidism.

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

Abstract: 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

Aplastic anemia secondary to propylthiouracil: A rare and life-threatening adverse effect:

Abstract: BackgroundPropylthiouracil has been in use for more than half a century for the treatment of hyperthyroidism. While it is largely known to cause agranulocytosis, its association with aplastic anemia is rarely heard of. Our case will be the third in literature to suggest aplastic anemia as a manifestation of propylthiouracil, which unfortunately culminated in the death of the patient.CaseA 67-year-old female, with recently diagnosed metastatic adenocarcinoma of the lung, developed hyperthyroidism after being started on Nivolumab and Iplimumab. After she developed atrial fibrillation, she was started on propylthiouracil to control the thyroid activity. Soon after that, she was admitted with severe neutropenia, which progressed to pancytopenia confirmed as aplastic anemia on a bone marrow biopsy. Despite discontinuation of propylthiouracil and aggressive treatment, she developed septic shock and multi-organ failure, leading to her death.ConclusionAplastic anemia has been sparingly reported as an extremely ra...

Protective effects of melatonin on mitochondrial injury and neonatal neuron apoptosis induced by maternal hypothyroidism

Abstract: In the current study, we reported the beneficial effects of melatonin in preventing neonatal neuronal apoptosis induced by maternal hypothyroidism. During the gestation and early lactation stages, the mother rats were given propylthiouracil (PTU) to inhibit their thyroid gland activity which resulted in the increased serum TSH and reduced T4 levels. This maternal hypothyroidism caused neuronal apoptosis of their pups, particularly in the CA3 area of hippocampus. Melatonin administration preserved function of thyroid gland and significantly reduced the apoptosis. Further studies have uncovered the potentially protective mechanisms of melatonin, that is, as a mitochondrial targeted antioxidant, melatonin preserves the mitochondrial outer membrane, inhibits the release of cytochrome C from mitochondria to cytoplasm and down regulates the gene expressions of Bax, along with caspases 3 and 9. Thus, melatonin breaks the mitochondria related apoptotic pathway to suppress the neuronal apoptosis induced by the maternal hypothyroidism. Considering the limited remedies to effectively treat hypothyroidism associated neonatal brain damage, melatonin may provide an alternative method for this disorder.

Effect of altered thyroid status on the incidence of colon tumors induced by methylnitrosourea in rats

Abstract: Aim. The present study was designed to determine whether medically induced hyper- and hypothyroidism effect on incidence of colon tumors induced by methylnitrosourea (MNU) burden in rats. Methods. Female rats ( n = 88) were randomly divided into four groups: I (euthyroid-control), II (hyperthyroid caused by liothyronine), III (hyperthyroid caused by L-thyroxine) and IV (hypothyroid caused by propylthiouracil (PTU), also 11 rats were intact control. Colon carcinogenesis was induced with a four intrarectal instillation of MNU (4 mg in 0.5 ml saline solution) one time per week. Liothyronine (100 ± 10 µg per 100 g of animal weight 1 time per day), L-thyroxin (100 ± 10 µg per 100 g of animal weight 1 time per day) and propylthiouracil (PTU, 2,0 ± 0,15 mg per 100 g of animal weight 1 time per day) were administered intragastrically through an atraumatic probe daily, starting from the day of the last intrarectal instillation of MNU. Rats were sacrificed at 216 days after experiment beginning, and the total colon were excised, fixed for histology and analyzed. Results. Drug inhibition of thyroid hormone function by PTU resulted in a decrease in the incidence of MNU-induced colon tumors and amounted to 27.3%. The incidence of colon tumors in the hyperthyroid group caused by L-thyroxine was 70.0% ( F -test – 0.012, χ 2 – 7.67; p < 0.05 compared with the hypothyroid group).

Effect of antithyroid drugs on the occurrence of antibodies against type 2 deiodinase (DIO2), which are involved in hyperthyroid Graves’ disease influencing the therapeutic efficacy

Abstract: Graves’ disease is an organ-specific autoimmune disease with hyperthyroidism, diffuse goiter and autoantibodies against TSH receptor, thyroid peroxidase (TPO) and/or thyroglobulin (Tg). Graves’ hyperthyroidism is characterized by T3 dominance due to the conversion of T4 into T3 through type 1 and 2 deiodinase enzymes (DIO1, DIO2). Methimazole (MMI) and propylthiouracil (PTU) therapies inhibit thyroid hormone synthesis blocking the activity of deiodinase and TPO enzymes. The study investigated the occurrence of autoantibodies against DIO2 peptides (cys- and hom-peptides) with the effect of antithyroid drugs on their frequencies in 78 patients with Graves’ disease and 30 controls. In hyperthyroidism, the presence of DIO2 peptide antibodies was as follows: 20 and 11 cases out of 51 for cys- and hom-peptide antibodies, respectively, of whom 8 cases possessed antibodies against both peptides. Antithyroid drugs differently influenced their frequencies, which were greater in PTU than in MMI (3/6 vs 13/45 cases, P < 0.016 for cys- and 0/6 vs 2/45 cases for hom-peptide antibodies). Antibodies against both peptides demonstrated more reduced levels of anti-TPO (P < 0.003) and anti-Tg antibodies (P < 0.002) compared with those without peptide antibodies. PTU compared with MMI increased the levels of TSH receptor antibodies (32.5 UI/l vs 2.68 IU/l, P < 0.009). MMI treatment led to more reduced FT3 levels and FT3/FT4 ratios in hyperthyroid Graves’ ophthalmopathy (P < 0.028 for FT3, P < 0.007 for FT3/FT4 ratio). In conclusion, the presence of DIO2 peptide antibodies is connected to Graves’ hyperthyroidism influencing the levels of antibodies against TPO, Tg and TSH receptor, as well as the therapeutic efficacy of antithyroid drugs.

Dynamics of morphological parameters of the thyroid gland in hypertensive SHR rats upon administration of propylthiouracil.

Abstract: Background. The main clinical manifestations of thyroid gland (TG) diseases are associated with the influence of thyroid hormones on the cardiovascular system. At the same time, hypothyroidism as well as hyperthyroidism increase the risk of arterial hypertension. Based on this, the development of an experimental model that combines thyroid pathology and hypertension is relevant. From this point of view, the hypertensive SHR rats is a valuable object of study, since the course of arterial hypertension in these animals corresponds to the signs of human hypertension. Objective. Study of the dynamics of the morphological parameters of the thyroid gland in SHR rats with prolonged administration of propylthiouracil (PTU). Methods. Female SHR rats were used in the experiments; drinking water contained a 0.1% solution of PTU. TG was taken on the 17 th , 25 th , 31 st , 39 th and 47 th days of the experiment, subjected to histological examination and staining with hematoxylin / eosin according to standard methods. We analyzed the average height of the follicular epithelium, the average follicle area, the nuclear cytoplasmic ratio (NCR) of thyrocytes, the ratio of the number of thyrocytes to fibroblasts per 50 μm 2 (T/FB). Results. It was established that the height of the epithelium, NCR, and the area of the follicles change irregularly during the intake of PTU: at first, fluctuations of indicators are observed, and starting from 31 st day they are stabilized. In general, after 47 days of receiving PTU, the average height of the follicular epithelium increased by 0.7 μm, the average area of the follicles – by 182 μm2, and NCR – by 0.11. In the stroma of the gland, activation of fibroblast proliferation was observed as evidenced by a decrease in the T/FB ratio from 2.87 to 0.54. Conclusion. When using a solution for drinking with 0.1% PTU for 47 days characteristic changes of hypertrophy and hyperplasia are observed in the thyroid tissue of hypertensive SHR rats. Stabilization of morphological parameters is observed after 30 days of taking PTU.

Antineutrophil cytoplasmic antibodies in patients treated with methimazole: a prospective Brazilian study.

Abstract: Introduction The side effects of antithyroid drugs are well known. Antineutrophil cytoplasmic antibody-associated vasculitis is a severe adverse reaction. Most studies evaluating antineutrophil cytoplasmic antibodies related to antithyroid drugs have been carried out with patients treated with propylthiouracil, but less information is available for methimazole. Furthermore, most studies that investigated antineutrophil cytoplasmic antibodies related to antithyroid drugs were conducted on Asian populations. Objective To evaluate the frequency of antineutrophil cytoplasmic antibodies and antineutrophil cytoplasmic antibodies-positive vasculitis in an adult population of Brazilian patients treated with methimazole. Methods This was a prospective study. We evaluated patients ≥18 years with Graves’ disease who have been using methimazole for at least 6 months (Group A, n = 36); with Grave's disease who had been previously treated with methimazole but no longer used this medication for at least 6 months (Group B, n = 33), and with nodular disease who have been using methimazole for at least 6 months (Group C, n = 13). Results ANCA were detected in 17 patients (20.7%). Four patients (4.9%) had a strong antineutrophil cytoplasmic antibodies-positive test. The frequency of antineutrophil cytoplasmic antibodies was similar in the groups. When Groups A and B were pooled and compared to Group C to evaluate the influence of Grave's disease, and when Groups A and C were pooled and compared to Group B to evaluate the influence of methimazole discontinuation, no difference was found in the frequency of antineutrophil cytoplasmic antibodies. No difference was observed in sex, age, etiology of hyperthyroidism, anti-TSH receptor antibodies, dose or time of methimazole use between patients with versus without antineutrophil cytoplasmic antibodies. The titers of these antibodies were not correlated with the dose or time of methimazole use. None of the antineutrophil cytoplasmic antibodies-positive patient had clinical event that could potentially result from vasculitis. Conclusion This clinical study of a Brazilian population shows a considerable frequency of antineutrophil cytoplasmic antibodies in patients treated with methimazole but the clinical repercussion of these findings remains undefined.

Propylthiouracil‐induced vasculitis in carbimazole‐refractory Graves disease

Abstract: A 59yearold woman with carbimazolerefractory Graves disease presented with fever and extensive necrotising rash (Figure) 2 weeks after commencing propylthiouracil therapy. Investigations revealed undetectable thyroidstimulating hormone (< 0.004 mIU/L; reference interval [RI], 0.400–5.00 mIU/L), elevated levels of T3 (7 pmol/L; RI, 2.6–6 pmol/L) and T4 (22 pmol/L; RI, 9–19 pmol/L), raised Creactive protein (61 mg/L; RI, < 5 mg/L), and the presence of perinuclear antineutrophil cytoplasmic antibodies with elevated antiproteinase 3 antibodies. This was consistent with small vessel vasculitis and a persistent hyperthyroid state. Skin biopsy demonstrated leukocytoclastic vasculitis, a rare side effect of propylthiouracil therapy.1 A tapering course of prednisolone and mycophenolate was commenced. Areas of skin necrosis were managed with debridement and splitskin grafting. Graves disease was treated with total thyroidectomy. Competing interests: No relevant disclosures. ■

Activation of GLP-1 and Glucagon Receptors Regulates Bile Homeostasis Independent of Thyroid Hormone.

Abstract: Background Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. Methods We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). Results Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. Conclusion Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.

A response to the letter to the editor on Shaikh et al. Aplastic anemia secondary to propylthiouracil: A rare and life-threatening adverse effect:

Abstract: 1. Kopp B, Crauste-Manciet S, Guibert A, et al. Environmental and biological monitoring of platinum containing drugs in two hospital pharmacies using positive air pressure isolators. Ann Occup Hyg 2013; 57: 374–383. 2. Ndaw S, Denis F, Marsan P, et al. Biological monitoring of occupational exposure to 5-fluorouracil: urinary a-fluoro-ß-alanine assay by high performance liquid chromatography tandem mass spectrometry in health care personnel. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 2630–2634. 3. Konate A, Poupon J, Villa A, et al. Evaluation of environmental contamination by platinum and exposure risk for healthcare workers during a heated intraperitoneal perioperative chemotherapy (HIPEC) procedure. J Surg Oncol 2011; 103: 6–9. 4. Sabatini L, Barbieri A, Lodi V, et al. Biological monitoring of occupational exposure to antineoplastic drugs in hospital settings. Med Lav 2012; 103: 394–401. 5. Villarini M, Dominici L, Piccinini R, et al. Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs. Mutagenesis 2011; 26: 359–369. 6. Association Paritaire Pour la Santé et la Sécurité du Travail du Secteur Affaires Sociales. Prevention guide, Safe handling of hazardous drugs, www.asstsas.qc.ca/ sites/default/files/publications/documents/Guides_ Broch_Depl/GP65A_hazardous_drugs.pdf (2008, accessed 8 December 18 2017). 7. Ordre des Pharmaciens du Québec. Norme 2014.02 – préparation de produits stériles dangereux en pharmacie. Montréal (QC), www.opq.org/fr-CA/publications/ normes-de-pratique-et-lignes-directrices/ (2014, accessed 18 December 2017). 8. United States Pharmacopeia. USP General Chapter <800> Hazardous drugs – handling in healthcare settings, www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare (accessed 21 December 2017). 9. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs, www.osha.gov/SLTC/hazardousdrugs/controlling_ occex_hazardousdrugs.html#surveillance (accessed 18 December 2017). C Tanguay and JF Bussières Département de Pharmacie, Unité de Recherche en Pratique Pharmaceutique, CHU Sainte-Justine, Montréal, Québec, Canada Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada

Effect of Soybean, Virgin Coconut and Moringa oleifera Seed Oils on the Propylthiouracil Induced Hypothyroidism in Rats

Abstract: This study investigated the possible effect of soybean, virgin coconut and Moringa oleifera seed oils for 8 weeks on Propylthiouracil (PTU) induced hypothyroidism in rats. Thirty five male albino rats were divided into two main groups; Group (I) (7 rats) was fed only basal diet and served as a negative control group. Group (II) (28 rat) were injected with (10 mg / kg / day PTU) for 15 day to cause hypothyroidism, then divided into 4 subgroups: namely control positive group based on basal diet, and 2, 3 and 4 subgroup were treated orally with dose of 5ml/kg BW oils of Soybean (SO), Virgin coconut (VCO) and M.oleifera seeds (MOO), respectively beside basal diet. The results showed that PTU exposed rats showed significant decrease (P≤0.05) in serum FT3, FT4 levels and significant increase (P≤0.05) in serum TSH levels. The orall treatement with SO, VCO and MOO was significantly increased FT4 and FT3, while decreased the level of TSH comparing with the positive control group. It was also reduced level of malondialdehyde (MDA) level, significantly, increased activity of liver antioxidant enzymes-superoxide dismutase (SOD) and improved liver functions and lipid profile compared with the positive control group. So, it could be concluded that oils of soybean, virgin coconut and M. oleifera seed oils improve the role of thyroid by raising thyroid hormones and reducing oxidative stress in patients with hypothyroidism.