thiouracil and benzylthiouracil

Vasculitis associated to antineutrophil cytoplasmic antibodies is a rare complication of therapy with antithyroid medication. They were mainly reported in patients treated with propylthiouracil and rarely with benzylthiouracil.. We report a 22-year-old woman treated with benzylthiouracil for Graves' disease, who developed a vasculitic skin involvement. The presence of antineutrophil cytoplasmic antibodies with anti-myeloperoxidase specificity was documented. The discontinuation of benzylthiouracil was followed by a complete disappearance of skin lesions and of antineutrophil cytoplasmic antibodies.. To our knowledge, only ten cases of antineutrophil cytoplasmic antibodies vasculitis induced by benzylthiouracil have been previously reported in the literature. Our patient was characterized by the occurrence of isolated cutaneous vasculitis, without renal involvement. Early discontinuation of benzylthiouracil may have prevented the occurrence of severe visceral complication.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Ecchymosis; Female; Graves Disease; Humans; Thiouracil; Withholding Treatment

Vasculitis is a rare complication of antithyroid drugs reported with propylthiouracil, carbimazole, methimazole and we describe the first case with benzylthyouracil. Renal involvement during thyroid auto-immune diseases and during vasculitis as complication of antithyroid drugs will be discussed.. We present a case study of 28-year-old female patient with Graves' disease diagnosed in 1996 and treated by benzylthiouracil for 2 years. The thyroid function was poorly controlled, so surgical treatment was indicated in May 1998. One month later, she developed vasculitis with pulmonary and renal involvement. Her renal function deteriorated rapidly. On admission, the additional laboratory findings showed hematuria, proteinuria of 1.44 g/day and serum creatinine level at 1000 mumol/l. She had myeloperoxidase-anti neutrophil cytoplasmic antibody, antithyroglobulin and antimicrosome antibodies. A renal biopsy revealed pauci-immune crescentic glomerulonephritis with 75% sclerous crescents. Chest-X-ray showed unilateral alveolar shadowing and a bronchio-alveolar lavage revealed lymphocytic alveolitis. She was treated with high dose of prednisolone and cyclophosphamide. After a follow-up of 18 months, the serum creatinine level decreased at 186 mumol/l and chest-X-ray returned to normal.. Some cases of vasculitis associated with anti-thyroid drug treatment are reported.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Female; Glomerulonephritis; Graves Disease; Humans; Lung Diseases, Interstitial; Thiouracil; Vasculitis

The crystal structures of dimorphic benzylthiouracil, a drug against hyperthyroidism, have been redetermined and the atom coordinates of the two independent molecules of form I have been obtained for the first time. The dimorphism convincingly demonstrates the conformational versatility of the benzylthiouracil molecule. It has been established through calorimetric studies that the low-temperature form II transforms endothermically (Δ

Topics: Crystallization; Humans; Hyperthyroidism; Pharmaceutical Preparations; Pressure; Thiouracil

In adults, anti-neutrophil cytoplasmic antibodies (ANCA) are considered as serological markers of several diseases, especially vasculitis and glomerulonephritis. Since ANCA are rarely positive in children, few data about the clinical relevance of these auto-antibodies in pediatric population have been reported. Therefore, our study aims to describe the spectrum of disorders associated with positive ANCA in Tunisian children. This study had been carried out over a period of 12 years and a half. All patients under the age of 15 for whom ANCA screening was performed in our laboratory were included. Clinical data were collected retrospectively. Indirect immunofluorescence (IFI) technique for ANCA detection was performed using PNN smears fixed with ethanol, formalin and, if necessary, methanol. Positive results were tested using immunodot to characterize the antigenic targets (myeloperoxydase (MPO) and proteinase 3 (PR3)). Our results showed that 410/5,990 (6.8%) laboratory requests for ANCA screening were for children. Forty (9.7%) requests were positive (24 children). Clinical data were available for 19 patients only. Sex-ratio (F/M) was 1.25. The mean age was 9 years and a half (3-15 years). The most frequent IIF patterns were x-ANCA (n=12) and p-ANCA (n=7). In our patients, the most frequent conditions associated to ANCA were treatment with benzylthiouracil for hypothyroidism (n=6), inflammatory bowel disease (n=4) and hemolytic anemia (n=4). In conclusion, the positivity of ANCA in children seems to be a rare event. Associated conditions include clinical disorders specific to the pediatric population. Treatment with benzylthiouracil is an etiology to be taken into consideration.

Topics: Adolescent; Anemia, Hemolytic; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Blood Chemical Analysis; Child; Child, Preschool; Female; Fluorescent Antibody Technique, Indirect; Glomerulonephritis; Humans; Hypothyroidism; Inflammatory Bowel Diseases; Male; Prevalence; Retrospective Studies; Seroepidemiologic Studies; Thiouracil; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Middle Aged; Thiouracil; Vasculitis

Antineutrophil cytoplasmic antibodies are classical serological markers of small-vessels vasculitis. However, they have been described in many other pathological situations. The aim of this study was to determine through our experience, the main antineutrophil cytoplasmic antibodies-associated diseases and to investigate antigen targets of these antibodies. Forty complete observations of antineutrophil cytoplasmic antibodies (ANCA) positive patients either by indirect immunofluorescence or by enzyme immunoassay were analysed. Only five (12.5%) patients have small-vessels vasculitis. Among these, antineutrophil cytoplasmic antibodies were detected only by Elisa in one patient and they were exclusively directed against bactericidal permeability increasing protein in another one. Our study confirms the presence of antineutrophil cytoplasmic antibodies in different diseases. It demonstrates that antineutrophil cytoplasmic antibodies should be investigated by Elisa when indirect immunofluorescence is negative. In small-vessels vasculitis, Proteinase 3 and myeloperoxidase are mainly but not exclusively the antigenic targets of antineutrophil cytoplasmic antibodies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Autoimmune Diseases; Child; Connective Tissue Diseases; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Humans; Infections; Inflammation; Male; Mass Screening; Middle Aged; Myeloblastin; Peroxidase; Thiouracil; Vasculitis; Young Adult

Drug induced antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis is a rare complication associated especially with propylthiouracil (PTU). Prevalence of ANCA in patients receiving PTU is well established. Few cases of vasculitis were also reported with benzylthiouracil (BTU). The objective of this study is to clarify the prevalence of ANCA in patients receiving BTU.. ANCA were investigated by indirect immunofluoresence and enzyme linked immunosorbant assay in 159 patients with Graves' disease (86 untreated and 73 treated with BTU).. ANCA were positive in three (3.5%) untreated patients and 27 (37%) treated ones. Titres of ANCA varied between 1:20 and 1:200. There was a significant association between BTU treatment and ANCA (p<0.001). ANCA were directed against myeloperoxidase (MPO) in 28 (93.3%) patients. Median treatment duration was 24 months (ranges 0.5 to 144 months). There was no significant association between treatment duration and ANCA. Vasculitis was found in two (2.7%) treated patients. One patient has developed isolated cutaneous vasculitis and the other one a pulmonary vasculitis with diffuse alveolar haemorrhage.. BTU therapy is characterised by a high prevalence of ANCA mainly but not exclusively directed against MPO. However, vasculitis remains a rare complication.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Autoantigens; Autoimmune Diseases; Child; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Graves Disease; Humans; Male; Middle Aged; Peroxidase; Thiouracil; Vasculitis; Young Adult

We report the case of a female patient who developed polymorphic expressions of neutrophilic dermatosis associated with p-ANCA while receiving benzylthiouracil for hyperthyroidism.. A 41-year-old-woman was treated with benzylthiouracil for Basedow's disease. After 21 months of therapy, she developed fever with different expressions of neutrophilic dermatosis: pyoderma gangrenosum of feet, Sweet's syndrome of the forearms and the face. Biopsies confirmed the diagnosis of neutrophilic dermatosis. The histological examination of a skin specimen taken from the developing border of a foot lesion showed polynuclear neutrophilic infiltration with leucocytoclastic vasculitis and the presence of anti-myeloperoxydase p-ANCA. Abdominal ultrasound showed multiple splenic microabscesses. The myelogram, gastroscopy and colonoscopy findings were normal. Benzylthiouracil was stopped and systemic corticosteroid therapy resulted in regression of the skin lesions and splenic microabscesses.. Different types of neutrophilic dermatosis were described in our case, confirming the notion of neutrophilic dermatosis continuum. The occurrence of neutrophilic dermatosis and p-ANCA after benzylthiouracil therapy suggests the involvement of polynuclear neutrophils in a common pathogenic mechanism. However, to date there have been no other reports analogous to ours, and inclusion of neutrophilic dermatosis as a benzylthiouracil-induced adverse effect would require confirmation by other instances of such associations.

Topics: Adult; Antithyroid Agents; Biopsy; Female; Graves Disease; Humans; Neutrophils; Pyoderma Gangrenosum; Skin Diseases; Thiouracil

Vasculitis with antineutrophilic cytoplasmic antibodies (ANCA) have been reported in patients treated with anti-thyroid drugs, especially propylthiouracil. Benzylthiouracil, which exhibits similar structural likeness with propylthiouracil, has been recently observed to be associated with Anca-positive vasculitis.. We present a study of three women with Grave's disease aged 21, 37 and 40 years, who were treated with benzylthiouracil. These patients developed vasculitis characterized by constitutional symptoms (two patients), joint pain (two patients), renal involvement (two patients), pulmonary hemorrhage (one patient) and multiple neuropathy (one patient). All patients presented p-ANCA with anti-MPO pattern. Discontinuation of benzylthiouracil and treatment with corticosteroids improved systemic involvement in all patients.. Much like other anti-thyroid drugs, benzylthiouracil can be associated with ANCA-positive vasculitis. Because of the gravity of this complication, clinical monitoring is recommended in patients taking benzylthiouracil. If vasculitis develops, the anti-thyroid drug should be discontinued and corticosteroid treatment, with immunosuppressors in some cases, is initiated.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Enzyme-Linked Immunosorbent Assay; Female; Graves Disease; Humans; Immunosuppressive Agents; Myelography; Peroxidase; Thiouracil; Vasculitis; Young Adult

The effect of the thyroid activity on the formation of lipid peroxidation and on liver and heart antioxidant enzyme activities was investigated in Wistar rats. Hypothyroidism and hyperthyroidism conditions were induced for five weeks by the administration of 0.05% benzythiouracile (BTU) and L-thyroxine sodium salt (0.0012%), in drinking water, respectively. No significant effect was observed on the rates of both lipid peroxidation and the vitamin E in hepatic and cardiac tissues of hypothyroidism rats compared to the controls, contrary to the hyperthyroidism rats, which expressed a pronounced increase. The increased glutathione peroxidase activity in rats suffering from hyperthyroidism was associated with a fall of the reduced glutathione in the homogenate and a marked increase in the glutathione reductase activity. An increase in superoxide dismutase and catalase activities was also recorded in hyperthyroidism. Our results explain the thyroid activity variation in relation to the lipid peroxidation and the tissular contents of the enzymatic and the non-enzymatic antioxidants. To conclude, our results show the occurrence of a state of oxidizing stress in relation to hyperthyroidism.

Topics: Animals; Body Weight; Catalase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hyperthyroidism; Hypothyroidism; Lipid Peroxidation; Liver; Male; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Thiouracil; Thyroid Gland; Thyroxine

Vasculitis associated to antineutrophil cytoplasmic antibodies (ANCA) is a rare complication of therapy with antithyroid medication. They were mainly described in patients treated with propylthiouracil (PTU), carbimazole, methimazole and rarely by benzylthiouracil (Basden). We report a case of 12-years-old girl treated by benzylthiouracil for Grave's disease who developed after 2 years vasculitis associated with cutaneous involvement (generalized ulcer necrotic purpura) and glomerulonephritis with proteinuria of 24 hours at 26 mg/kg/day, microscopic hematuria and renal failure with creatinemia level at 135 micromol/l. The ANCA type antiMPO (myeloperoxidase) was positive. The histology study of the renal needle biopsy was in favour with focal necrotizing glomerulonephritisand crescents with different evolutive stages. The discontinuation of benzylthiouracil and the treatment by the corticoids involved a disappearance of cutaneous lesions, a negative result of proteinuria, a normalization of the renal function (creatinemia=84 micromol/l) and a disappearance of hematuria and ANCA. These results permitted to announce hypothesis that benzylthiouracil was implicated in development of vasculitis associated to ANCA.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Child; Female; Graves Disease; Hematuria; Humans; Kidney Diseases; Thiouracil; Treatment Outcome; Uridine Phosphorylase; Vasculitis

Benzylthiouracil has been recently observed to be associated with antineutrophil cytoplasmic antibody-positive vasculitis, resulting in crescentic glomerulonephritis. We report an 8-year-old girl treated with benzylthiouracil for Graves's disease who developed an ANCA-positive vasculitis with pulmonary hemorrhage. She responded to corticosteroids and discontinuation of benzylthiouracil. This represents the first pediatric case of benzylthiouracil-induced diffuse alveolar hemorrhage.

Topics: Antibodies, Antineutrophil Cytoplasmic; Child; Female; Graves Disease; Hemorrhage; Humans; Lung Diseases; Thiouracil; Vasculitis

Several cases of vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) have been reported in patients treated with synthetic anti-thyroid drugs but only 2 cases have incriminated benzylthiouracil.. A 36 year-old woman, 3 years after treatment with benzylthiouracil, rapidly developed progressive kidney failure, related to a pauci-immune extra-capillary glomerular nephropathy and necrotic vasculitis lesions. The search for p-ANCA was positive with anti-myeloperoxidase specificity. She was treated with corticosteroids and 6 monthly intravenous pulses of cyclophosphamide substituted by azathioprine. Renal failure and proteinuria significantly improved. However the high level of p-ANCA.. ANCA vascularities are a rare but serious complication of treatment with synthetic thiouracile-type anti-thyroid drugs. The ANCA must be measured when confronted with a systemic manifestation during treatment.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Antinuclear; Female; Humans; Hyperthyroidism; Thiouracil; Uridine Phosphorylase; Vasculitis

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Glomerulonephritis; Humans; Peroxidase; Thiouracil

Vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) have been reported in patients suffering from Graves' disease treated with anti-thyroid drugs and especially propylthiouracil (PTU).. We report a case of Graves' disease treated with benzylthiouracil (Basdène). This therapy was complicated by acute renal insufficiency due to crescentic glomerulonephritis associated with pANCA. After benzylthiouracil withdrawal and under corticosteroids, renal insufficiency, biological inflammation and pANCA levels decreased.. Similar vasculitis associated with pANCA secondary to anti-thyroid drugs, especially propylthiouracil, were described. This suggests a causal relation between drug and vasculitis. To our best knowledge, it is the first case of vasculitis secondary to benzylthiouracil.

Topics: Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Graves Disease; Humans; Male; Middle Aged; Thiouracil; Uridine Phosphorylase; Vasculitis

The binding of drugs to human serum albumin determines the drug distribution through the systemic circulation and its pharmacological effects on the organism. Then, with the aim of obtaining information concerning the drug structural features which favour their binding on seroalbumin we have studied the seroalbumin binding to the heterocyclic drugs such as warfarin, propylthiouracil and cromoglycate and to similar compounds such as 4-hydroxy-coumarin, 3-acetylcoumarin, coumarin, benzylthiouracil, propyluracil, thiouracil, chromone and chromanol. These compounds were competitively displaced by warfarin at their primary binding sites on seroalbumin. The comparative analysis of the binding data showed that heterocyclic compounds such as benzopyranes (coumarins and chromanol) and benzyl pyrimidines with 4-hydroxyl groups bind specifically in the warfarin binding site. Then, 4-hydroxyl-bencene heterocycles will displace other ligands from the subdomain IIA of the seroalbumin molecule. Therefore, we can predict that the administration concomitant of warfarin, cromoglycate, propylthiouracil and analogous heterocyclic drugs involves the displacement of the drug without 4-hydroxyl and benzyl groups, increasing their free fraction in serum and the amount of active drug.

Topics: 4-Hydroxycoumarins; Benzopyrans; Binding, Competitive; Chromans; Humans; Kinetics; Protein Binding; Pyrimidines; Serum Albumin; Structure-Activity Relationship; Thiouracil; Warfarin

Seventy-nine nucleobase analogs were evaluated as potential inhibitors of Toxoplasma gondii uridine phosphorylase (UrdPase), and the apparent Ki (appKi) values for these compounds were determined. Based on the inhibition data, a structure-activity relationship for the binding of nucleobase analogs to the enzyme was formulated, using uracil as a reference compound. Two compounds were identified as very potent inhibitors of T. gondii UrdPase, 5-benzyloxybenzylbarbituric acid and 5-benzyloxybenzyluracil, which had appKi values of 0.32 and 2.5 microM, respectively. A comparison of the results from the present study, with similar studies on mammalian UrdPase and thymidine phosphorylase (dThdPase) (Niedzwicki et al., Biochem Pharmacol 32: 399-415, 1993) revealed that there are both similarities and differences between the catalytic site of T. gondii UrdPase and the catalytic sites of the mammalian enzymes with respect to binding of uracil analogs. One compound, 6-benzyl-2-thiouracil, was identified as a potent, specific inhibitor (appKi = 14 microM) of T. gondii UrdPase, relative to mammalian UrdPase and dThdPase.

Topics: Animals; Binding Sites; Drug Evaluation, Preclinical; Structure-Activity Relationship; Thiouracil; Toxoplasma; Uracil; Uridine Phosphorylase

Sixteen cases of pediatric hyperthyroidism treated by antithyroid drugs are reported. First-line treatment with carbimazole in a mean dose of 19 mg/m2 initially and 7 mg/m2 after one year ensured control of the disease within 6 weeks. Mean follow-up was 4 years. Only two children were able to discontinue the drug, after 9.1 years and 4.6 years. Two other patients had thyroidectomy, after 6.7 years and 3.4 years. The main disadvantages of antithyroid drugs are the need for prolonged treatment and the risk of recurrence. An attempt at treatment discontinuation is warranted in patients with good disease control of 2 to 3 years duration, goiter size reduction, improved exophthalmos, and decreased anti-TSH receptor antibodies.

Topics: Autoantibodies; Autoimmune Diseases; Body Mass Index; Carbimazole; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Hyperthyroidism; Infant; Male; Recurrence; Thiouracil; Thyroglobulin; Thyroid Function Tests; Thyroidectomy

Thiocarbamides were converted to their di-N-pentafluorobenzyl (PFB) derivatives and analysed by gas chromatography/negative-ion chemical-ionization mass spectrometry with methane as reagent gas. The PFB derivatives of the 2-thiouracils gave mass spectra in which the ion current was carried largely by an ion arising from [M-PFB]-. The derivative was used in the determination of the uptake and metabolism of thiocarbamides by cultures of melanoma cells.

Topics: Gas Chromatography-Mass Spectrometry; Melanoma; Methimazole; Methylthiouracil; Propylthiouracil; Thiouracil; Tumor Cells, Cultured

Treatment of amiodarone iodine-induced thyrotoxicosis is often unsuccessful. Nevertheless, severe forms require a rapidly efficient therapy. Twelve patients with severe amiodarone iodine-induced thyrotoxicosis, as demonstrated on clinical and biological findings, were studied. After amiodarone withdrawal, 6 patients (group A) were treated with thionamides alone (carbimazole 60 mg daily and benzylthiouracile 1.5 g daily), and 6 patients (group B) received in addition to the same antithyroid drugs prednisone, 0.50 to 1.25 mg/kg/day for 40 days; in group A, T4 levels did not change over the study period of 40 days; T3 levels decreased only after 30 days; clinical status did not improve. In group B: T3 and T4 levels decreased dramatically at 10 days of treatment, to values significantly lower than in group A; clinical improvement occurred mainly in patients treated with high doses of prednisone; elevated thyroglobulin levels diminished rapidly. Improvement was maintained after cessation of prednisone. The rapid effect of prednisone suggests an impairement of proteolysis of thyroglobulin possibly due to a lysosomal action.

Topics: Adult; Aged; Amiodarone; Carbimazole; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Prednisone; Thiouracil; Thyroid Hormones; Thyrotoxicosis

The binding interactions of some thioureylene compounds to human serum albumin were studied in vitro by ultraviolet spectroscopy and equilibrium dialysis. Binding of 6-n-propyl-2-thiouracil, 6-n-benzyl-2-thiouracil and 2-thiouracil to human serum albumin results in a red shift of the ultraviolet absorption maximum, suggesting that the binding site is a hydrophobic area of the protein. Bindings of 6-n-propyl-2-thiouracil and 6-n-benzyl-2-thiouracil to human serum albumin are characterized by two classes of sites while 6-n-propyl-uracil and 2-thiouracil bind to one low-affinity binding site. In addition, an identification of those sites was performed by measuring the displacement of these drugs. The data show that the moderate-affinity site is common with the warfarin site while the low-affinity site is likely to be shared by benzodiazepines. It is concluded that the binding is enhanced by the hydrophobicity of the substituent in the thioureylene compounds, and it is further shown that thiol-group substitutions in the thioureylene ring will weaken the binding.

Topics: Antithyroid Agents; Diazepam; Humans; Propylthiouracil; Serum Albumin; Spectrophotometry, Ultraviolet; Thiouracil; Uracil; Warfarin

Topics: Adrenal Glands; Histology; Juxtaglomerular Apparatus; Kidney Glomerulus; Pharmacology; Rats; Research; Sex; Thiouracil; Thyroxine

Topics: Gonads; Humans; Liver; Thiouracil