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PubMed2004

[Epitope mapping of myeloperoxidase antibodies in propylthiouracil-induced vasculitis and microscopic polyangiitis].

OBJECTIVE: To compare the epitopes of antibodies for myeloperoxidase (MPO) in the serum from patients with propylthiouracil (PTU) induced vasculitis and microscopic polyangiitis (MPA). METHODS: Serum samples from patients with PTU-induced vasculitis (n = 10) and MPA (n = 10) were collected and used to inhibit monoclonal antibodies against human MPO 3D8 and 6B9 and then affinity was purified, horseradish peroxidase conjugated and human MPO antibodies determined (Pab1-HRP, Pab2-HRP) in a competitive inhibition ELISA system using soluble human MPO as solid phase ligands. The Pab1-HRP and Pab2-HRP were affinity purified from plasma exchanges of a patient with PTU-induced vasculitis and a patient with MPA. The inhibition rates were evaluated and compared between PTU group and primary MPA group. RESULTS: In PTU group, all the 10 serum samples could inhibit 3D8; the average inhibition rate was 44.7%, 9/10 of the serum samples could inhibit 6B9; the average inhibition rate was 35.6%; In MPA group, all 10 serum samples could inhibit 3D8 and 6B9; the average inhibition rates were 68.4% and 62.2%. Serum in both groups could inhibit Pab1-HRP and the inhibition rates were both more than 80%; the average inhibition rate for Pab2-HRP in MPA group was significantly higher than that in PTU group (76.3% vs 58.9%, P < 0.01). CONCLUSIONS: MPO antibodies from patients with PTU-induced vasculitis and patients with primary MPA could recognize more than one epitopes on native MPO molecule. Although the epitopes were overlapping between the two groups, the epitopes of MPO antibodies from patients with PTU-induced vasculitis might be more restricted.

Adolescent↗
PubMed2005

[Anti-endothelial cell antibodies(AECA) are associated with disease activity of propylthiouracil induced antineutrophil cytoplasmic antibody (ANCA) positive vasculitis].

OBJECTIVE: To investigate the prevalence of anti-endothelial cell antibodies(AECA) and its possible role in the pathogenesis of propylthiouracil (PTU) induced ANCA positive vasculitis. METHODS: Sera from 11 patients with PTU induced ANCA positive vasculitis and 10 patients with PTU induced ANCA but without clinical vasculitis were studied. Soluble proteins from in vitro cultured human umbilical vein endothelial cells were used as antigens and immunoblotting technique was performed to identify the specific target antigens. RESULTS: In patients with PTU induced ANCA positive vasculitis group, 10 of the 11 patients in active phase were AECA positive and 7 of the 10 patients turned to negative in remission. AECA consisted of a group of heterogeneous antibodies. In patients with ANCA positive but without vasculitis, none was AECA positive. CONCLUSION: AECAs recognizing a variety of antigens could be found in sera from patients with PTU induced ANCA positive vasculitis and they had a much closer association with vasculitic disease activity compared with ANCA.

Adolescent↗
PubMed2005

[Clinical features and outcomes of hyperthyroidism patients positive in propylthiouracil-induced antineutrophil cytoplasmic antibody].

OBJECTIVE: To analyze the clinical features and outcomes of hyperthyroidism patients positive in propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA). METHODS: The clinical data, including the clinical manifestations, treatment, and outcomes of 45 PTU-induced ANCA positive patients with hyperthyroidism were prospectively studied. RESULTS: Seventeen of the 45 patients had clinically evident vasculitis and 28 of the 45 patients were not complicated by vasculitis. In the vasculitis group, 13 patients (76.5%) had renal involvement manifested by hematuria, proteinuria, and renal insufficiency. 7 of them (41.2%) had lung involvement and 6 of them had hemoptysis. Perinuclear ANCA (p-ANCA) was detected in all 17 patients and 16 of them (94.1%) were anti-myeloperoxidase antibodies (MPO-ANCA) positive. PTU was discontinued in all 17 patients and the treatment was switched over to methimazole (MMI) in 6 patients. Four patients with severe organ involvement received prednisone and immunosuppressant for 6 to 12 months. No relapse or death occurred during the follow-up period (8 to 60 months with a median of 30 months). All the 17 patients achieved clinical remission except for two that developed end stage renal disease due to late diagnosis. 27 of the 28 patients without vasculitis (96.4%) were p-ANCA positive and 14 of them (50.0%) were MPO-ANCA positive. PTU treatment was discontinued in 24 patients and switched over to MMI treatment in 15 patients, and 4 patients continued to take low dose PTU. No vasculitis manifestation occurred during the follow-up period (3 to 36 months with a median of 20 months). However, the ANCA titer declined slowly in most patients in both groups. CONCLUSION: PTU treatment should be discontinued without delay in the PTU-induced ANCA positive patients with hyperthyroidism. Treatment can be switched over to MMI when necessary. Patients with severe organ involvement should receive prednisone and immunosuppressant. No vasculitis relapse is found during the follow-up after withdrawal of PTU. However, ANCA may keep positive for a long time.

Adolescent↗
PubMedDate not supplied

Oxidation of propylthiouracil to reactive metabolites by activated neutrophils. Implications for agranulocytosis.

Propylthiouracil (PTU) is associated with idiosyncratic agranulocytosis that may be due to reactive metabolites generated from oxidative metabolism by neutrophils. Therefore, the metabolism of PTU was investigated in activated neutrophils. Three oxidized metabolites were observed on HPLC: PTU-disulfide, propyluracil-2-sulfinate, and propyluracil-2-sulfonate (PTU-SO3-). No metabolism was detected in cells that had not been activated. Metabolism was inhibited by sodium azide and by catalase. The same products were produced by myeloperoxidase (MPO) in an MPO/H2O2/Cl- system. PTU inhibited its own metabolism; however, complete conversion to PTU-SO3- could be achieved with optimal PTU concentrations. MPO/H2O2 without Cl- produced only slight metabolism. The PTU-sulfenyl chloride is a postulated intermediate. In the absence of chloride, oxidation might proceed through propyluracil-2-sulfenic acid. The sulfenyl chloride and PTU-SO3- are both chemically reactive with sulfhydryl compounds such as N-acetylcysteine. Such reactive metabolites, generated by activated neutrophils, may be involved in hypersensitivity reactions associated with PTU, such as agranulocytosis.

Agranulocytosis↗
PubMedDate not supplied

Propylthiouracil-induced hypersensitivity syndrome.

Propylthiouracil (PTU) is usually the first choice for the treatment of hyperthyroidism, but it has serious side effects such as hepatitis, cholestatic jaundice, splenomegaly and lupus-like syndrome, in addition to mild and common side effects like granulocytopenia, pruritus, urticaria and maculopapular or papular eruption. Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis is another serious side effect. A 14-year-old female receiving PTU treatment for hyperthyroidism was referred to our clinic with fever, cough and dyspnea. The PTU dosage was first decreased but pericardial, dermal and joint involvement ascribed to PTU developed later and the drug was discontinued. ANCA-positive vasculitis due to PTU was considered when tests revealed an ANCA-positive state. We suggest that severe multisystemic vasculitis due to PTU should be considered during PTU usage.

Adolescent↗
PubMed2006

Effect of propylthiouracil on the level of Schiff's bases in tissues of rats on diet with different doses of potassium iodide.

OBJECTIVES: Iodide administration to animals, living in iodine-deficient areas, can induce oxidative processes in the thyroid gland and increase concentration of lipid peroxidation (LPO). Propylthiouracil (PTU)--a well-known antithyroid drug--may also act as an antioxidant. There are some reports, which consider the protective ability of this drug against LPO. The goal of the study was to evaluate oxidative processes and the protective role of PTU in three rat organs during treatment with pharmacological doses of iodide. MATERIAL AND METHODS: Schiff's bases (SB) concentrations (a parameter of oxidative stress) were measured in liver, lung and kidney homogenates of male Wistar rats. For 2 weeks the animals received iodides in their diet in the following concentrations: Group 1--Controls (standard diet, approx. 0.7 mg of potassium iodide per kg; KI/kg); Group 2--diet containing 0.25 mg KI/kg; Group 3--diet with 4.0 mg KI/kg; Group 4--diet with 8.0 mg KI/kg. Group 5--standard diet with 0.1% of PTU in drinking water for two weeks. Subsequent tree groups (6-8) received KI in their diet in doses as above, respectively, together with PTU. RESULTS: We noted increased SB levels in the lungs and in the liver, compared to those observed in the control group. We also found decreased SB concentrations in liver and lung homogenates after the administration of PTU but, unexpectedly, the level of SB increased in kidney homogenates of all the groups. CONCLUSIONS: The results of this study indicate that iodine is involved in oxidative processes in different organs and PTU protects against iodine-induced oxidative stress.

Animals↗
PubMed2006

Propylthiouracil-related hemorrhagic diathesis: a case report and review of the literature.

We present an unusual case of a drug-related hemorrhagic diathesis. One month prior to admission, the patient was diagnosed at another medical center as having Graves' disease and propylthiouracil therapy (PTU) was initiated. Since clinical recovery was not achieved, the PTU was quickly increased to an unconventional daily dose of 1,000 mg. The patient was referred to our hospital because of spontaneous epistaxis, multiple ecchymoses and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), which developed soon after the increase in PTU dose. Drug-related hemorrhagic diathesis was considered, after other possible causes had been eliminated. To the best of our knowledge, this is the first reported case of spontaneous hemorrhage due to PTU use.

Adult↗
PubMed1976

Protection by propylthiouracil against carbon tetrachloride-induced liver damage.

Rats given a single intragastric dose of carbon tetrachloride (CCl4), 0.25, 0.50, or 1.0 ml per kg) showed a dose-dependent increase in SGOT, serum ornithine carbamyltransferase, and liver necrosis (graded histologically as 0 to 4+) 24 hr after the treatment. Daily intubation with propylthiouracil (PTU) for 10 days in doses of 5 to 50 mg per kg significantly reduced the elevation of SGOT activity, completely suppressed the serum ornithine carbamyltransferase changes, and reduced the degree of necrosis found 24 hr after the intragastric administration of CCl4. Similar protection was found when CCl4 was given intraperitoneally. When PTU was given in liguid diets for 6 days, protection against CCl4 was increased. PTU did not affect the absorption or covalent binding of 14CCl4 to lipids or proteins. Also, control and PTU-treated rats did not differ with respect to glucose-6-phosphatase activity and conjugated diene production after CCl4. Thus, it has been observed that PTU affords partial protection against some end-stage consequences of CCl4 liver injury such as cell necrosis and release of intracellular enzymes. However, PTU afforded no protection against early chemical effects such as covalent binding of CCl4 carbon, lipid peroxidation, or loss of glucose-6-phosphatase. Therefore, it is concluded that the mechanism of the PTU effect comes into play after the initial effects of CCl4 are exerted and in some unknown manner modulates the expression of these early effects.

Animals↗
PubMed1991

Propylthiouracil-associated hepatitis.

The case of a 43-year-old female with propylthiouracil-induced hepatitis is reported. The case is unique because the patient's liver function deteriorated 2 weeks after medication was discontinued.

Adult↗
PubMed1990

Effects of propylthiouracil on growth hormone and prolactin messenger ribonucleic acids in the rat pituitary.

The effects of hypothyroidism induced by propylthiouracil (PTU) treatment on growth hormone (GH) and prolactin (PRL) messenger ribonucleic acid (mRNA) levels were analyzed in adult female rat adenohypophyses by in situ hybridization histochemistry and Northern hybridization analyses. Twenty-eight days of PTU treatment produced a significant decrease in GH mRNA levels and a smaller decrease in PRL mRNA determined by both in situ hybridization histochemistry and Northern hybridization analyses. A combined procedure of in situ hybridization histochemistry followed by immunochemistry on the same sections revealed mammosomatotropic cells expressing GH mRNA and PRL protein in the same pituitary cells from all treatment groups. Cells expressing GH mRNA and thyroid-stimulating hormone protein were not detected by this method. Immunochemical staining revealed a decrease in GH cells and an increase in thyroid-stimulating hormone cells in hypothyroid rats. Cells expressing both GH and thyroid-stimulating hormone protein were not detected by immunostaining. These results indicate that hypothyroidism produces significant decreases in GH mRNA and also decreases PRL mRNA and that mammosomatotropic cells can be detected in pituitaries from normal and hypothyroid rats.

Animals↗
PubMed1990

Effects of propylthiouracil on the biodistribution of an iodine-131-labeled anti-myeloid antibody in normal dogs: dosimetry and clinical implications.

Despite the use of near maximal doses of chemoradiotherapy, tumor recurrence remains the most frequent cause of treatment failure following marrow transplantation for leukemia. We have previously demonstrated that it is possible to selectively deliver radiation to the marrow space. In that study an initial short half-life of the radionuclide was observed. In this study we attempted to prolong the retention of the radioiodine in marrow through the use of propylthiouracil (PTU). When administered to normal dogs, PTU pretreatment resulted in improved marrow localization of 131I-labeled DM-5. There was no appreciable loss of activity from the marrow during the 2-4 hr postinjection time interval; a finding in contrast to the control animals where marrow activity declined a mean 45 +/- 0.5% over the same time period. Additionally, in contrast to controls, a rise in plasma trichloroacetic acid (TCA) nonprecipitable activity was not demonstrated in the PTU treated group during this 2-4 hr period. These results suggest that PTU's inhibition of deiodinases resulted in longer residence time of the radionuclide in its target tissue without adversely affecting distribution to non-target organs.

Animals↗
PubMed1989

Dietary propylthiouracil and 17 beta-estradiol benzoate implant effects on liver carbohydrate and lipid metabolism in chicks.

1. Forty-eight chicks (21 days old) were implanted (+/- 50 mg 17-beta estradiol; EBI) and fed diets containing +/- 0.1% propylthiouracil (PTU) for 7 days to determine the role of gonadal hormones in the regulation of energy metabolism in the hypothyroid chick. 2. In vitro lipogenesis (IVL) and glucose production (NGP) were measured in liver explants. 3. Liver glycogen (GLY) metabolism was studied in particulate fractions (50,000 x g) of liver. 4. Glycogen synthetase activity (GLYSYN) was assayed in the presence of glucose-6-phosphate (G-6P; 0, 0.15 and 10 mM) to determine activation states. 5. PTU and EBI increased (P less than 0.05) both GLY concentration and GLYSYN activity in chicks but, did not increase G-6P activity ratios or the in vitro activation of GLYSYN. 6. Both PTU and EBI increased (P less than 0.05) IVL and NGP. 7. Estradiol magnifies the effects of PTU in chicks suggesting an interaction between thyroid status and gonadal function.

Animals↗
PubMed1987

Potassium perchlorate, potassium iodide, and propylthiouracil: promoting effect on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)-nitrosamine.

The effect of 1000 ppm potassium perchlorate (KClO4), 1000 ppm potassium iodide (KI) or 1000 ppm propylthiouracil (PTU) in the diet on the development of thyroid tumors was studied histologically and biochemically in Wistar rats given a single ip injection of 280 mg of N-bis(2-hydroxypropyl)nitrosamine (DHPN) per 100 g body weight. Basal diet containing 100 ppm KClO4, 1000 ppm KI or 1000 ppm PTU was given for 19 weeks from week 2 to week 20. The incidence of thyroid adenomas at the end of week 20 of the experiment was 100% (20/20) in rats treated with DHPN followed by KClO4, 85% (17/20) in rats given DHPN followed by KI, 95% (19/20) in rats given DHPN followed by PTU, and 5% (1/20) in rats given DHPN alone. The incidence of thyroid cancers was 100% (20/20) in rats treated with DHPN followed by KClO4, 65% (13/20) in rats treated with DHPN followed by KI and 0% (0/20) in rats treated with DHPN followed by or not followed by PTU. Rats given KClO4, KI or PTU alone and untreated rats had no thyroid tumors. The mean values of TSH in serum were 2.94 +/- 0.79 ng/ml in rats treated with DHPN followed by KClO4, 9.40 +/- 16.0 ng/ml in rats treated with DHPN followed by KI and 60.94 +/- 20.60 ng/ml in rats treated with DHPN followed by PTU. It was confirmed that (1) KClO4, PTU and KI promote the development of thyroid tumor in rats treated with DHPN, (2) the promoting effect of KClO4 or KI is stronger than that of PTU and (3) the value of TSH in serum is not parallel to the promoting effect on the development of thyroid tumor.

Animals↗
PubMed1988

Reduced acid protease activity in vitro of lysosomes from thyroid gland of rats chronically treated with propylthiouracil and perchlorate.

We have recently demonstrated that proteolytic activity of lysosomal acid proteases from papillary carcinoma is significantly higher than in morphologically normal thyroid tissue. In the present study the activity of lysosomal acid proteases from parenchymatous proliferated thyroid epithelium, induced by action of antithyroid substances, has been examined in an in vitro system using 125I-labelled rat thyroglobulin as a substrate. Thyroid lysosomes were isolated from rats treated chronically for 3-4 weeks with propylthiouracil (PTU, 0.1% in drinking water) and perchlorate (NaClO4, 200 mg/rat/day) by centrifugation between 800 and 20,000 x g. It was observed that, in contrast to human malignant thyroid tissue, the proteolytic activity of lysosomal acid proteases from antithyroid substance-induced hyperplastic goitre was markedly reduced in comparison with control thyroid tissue (29-50%). Since reduced activity of total lysosomal proteases was found both per unit of wet weight thyroid tissue and per unit of lysosomal proteins, the results suggest that changes in lysosomal enzymes may probably have more quantitative than qualitative nature.

Animals↗
PubMed1987

Induction of anionic glutathione transferases in rat liver by propylthiouracil.

The treatment of rats with propylthiouracil (PTU) resulted in an induction of not only cationic but also anionic glutathione (GSH) transferases. DE-52 column chromatography of the anionic GSH transferases divided into five main peaks (I-V). Peaks I-IV had a high activity toward 1-chloro-2,4-dinitrobenzene (CDNB). Peak V, which is a new form of the enzyme, showed high activity to ethacrynic acid. PTU induced peaks I and V, whereas phenobarbital increased the activity of only peak I.

Animals↗
PubMed1985

Influence of thyroxine and propylthiouracil administration on the intake of maternal milk in sucklings of the laboratory rat.

Young laboratory rats received a daily subcutaneous injection of thyroxine (T4) and propylthiouracil (PTU) in saline, from birth until the period of spontaneous weaning. The rate of growth and the time of eye opening as well as the spontaneous weaning was assessed. The intake of maternal milk was followed directly, i.e. by the transport of 85Sr in maternal milk from the maternal body to the sucklings. In the young treated with T4 the eyes opened earlier than in the young treated with PTU. The body mass differed in both groups between the 4th and 20th day of life (the T4 pups were heavier). The 85Sr transfer in maternal milk was higher in the PTU young from the 22nd day of life. The PTU sucklings weaned spontaneously one week later than those receiving T4. A hypothesis has been proposed on the primary significance of maturation of oral mechanisms of sucking for spontaneous weaning.

Animal Population Groups↗
PubMed1986

Effects of thyrotropin-releasing hormone on serum concentrations of thyroxine and triiodothyronine in healthy, thyroidectomized, thyroxine-treated, and propylthiouracil-treated dogs.

Effects of thyrotropin-releasing hormone (TRH) on serum concentrations of thyroid hormones were studied in 36 mixed-bred dogs. Dogs were randomly assigned to 7 groups. Significant increases (P less than 0.05) of serum thyroxine (T4) values occurred as early as 2 hours and reached a peak at 6 to 8 hours after IV injection of 300 to 1,100 micrograms of TRH. Thyroxine concentrations in response to a TRH dose greater than 500 micrograms were similar to those observed with the 300-micrograms dose. Transient coughing, vomiting, salivation, and defecation after large doses (900 and 1,100 micrograms) were observed. Mean serum T4 concentration decreased from 2.1 micrograms/dl to 0.9 micrograms/dl within 1 day of thyroidectomy. Clinical signs of hypothyroidism, including lethargy, dry coats, and diffuse alopecia, were present in 2 dogs at a month after surgical operation. Thyroxine concentrations were detectable for greater than 2 months. Injection (IV) of 700 micrograms of TRH 6 weeks after surgical operation had no effect on serum concentration of T4 in thyroidectomized dogs. In 5 T4-treated dogs, TRH (700 micrograms, IV) significantly increased the serum T4 value, indicating that pituitary thyrotropes were responsive to TRH, in spite of daily medication of 0.8 mg of T4. Four dogs were treated orally with 200 mg of propylthiouracil/day for 5 weeks. Intravenous injection of 700 micrograms of TRH in propylthiouracil-treated dogs had no effect on the serum T4 concentration, indicating that TRH had no effect on serum T4 values in these dogs during the experimental period. These results indicate that TRH can replace bovine thyrotropin for the canine thyroid function test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗