6-trifluoromethyl-2-thiouracil possesses anti-Toxoplasma gondii effect in vitro and in vivo with low hepatotoxicity.

Since pyrimethamine, the general therapeutic drug for toxoplasmosis, presents several adverse side effects, the need to develop and evaluate new drugs for the condition is critical. In this study, anti-Toxoplasma gondii activities of 3-[{2-((E)-furan-2-ylmethylene)hydrazinyl}methylene]-1,3-dihydroindol-2-one (ATT-5126) and 6-trifluoromethyl-2-thiouracil (KH-0562) were evaluated in vitro using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and in vivo by measuring amount of the tachyzoites in mice ascites. Biochemical parameters such as lipid peroxidation (LPO), glutathione (GSH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were also evaluated in livers of mice at 4 days post-infection. As a result, the ATT-5126 and KH-0562 showed anti-T. gondii activity in vitro. Treatment of ATT-5126 or KH-0562 decreased the amount of tachyzoites in T. gondii infected ICR mice. The relative weight of liver and spleen increased by T. gondii infection were decreased by treatment of ATT-5126 or KH-0562. The levels of LPO, ALT and AST, which are biochemical parameters involved in liver injury, were also significantly recovered by treatment of ATT-5126 or KH-0562 (p<0.05). In particular, the recovered levels by KH-0562 were similar to those of pyrimethamine-treated group (p<0.05). However, the level of GSH, which is an antioxidant indicator, showed insignificant statistics. The results suggest that KH-0562 show anti-T. gondii activities in vitro and in vivo with low hepatotoxicity. Therefore, KH-0562 may be a useful candidate for treating T. gondii infection.

Prevalence of antineutrophil cytoplasmic antibodies during treatment with benzylthiouracil.

BACKGROUND: 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. METHODS: ANCA were investigated by indirect immunofluoresence and enzyme linked immunosorbant assay in 159 patients with Graves' disease (86 untreated and 73 treated with BTU). RESULTS: 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. CONCLUSION: BTU therapy is characterised by a high prevalence of ANCA mainly but not exclusively directed against MPO. However, vasculitis remains a rare complication.

[Neutrophilic dermatosis associated with anti-neutrophilic cytoplasmic antibodies (ANCA) after benzylthiouracil therapy]. / Dermatose neutrophilique associée à des anticorps anticytoplasme des polynucléaires neutrophiles (ANCA) après prise de benzylthiouracile.

BACKGROUND: We report the case of a female patient who developed polymorphic expressions of neutrophilic dermatosis associated with p-ANCA while receiving benzylthiouracil for hyperthyroidism. CASE REPORT: 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. DISCUSSION: 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.

Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells.

Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2) (where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.

[Benzylthiouracil induced ANCA-positive vasculitis: study of three cases and review of the literature]. / Vascularite à anticorps anticytoplasme des polynucléaires neutrophiles induite par le benzylthiouracile: étude de trois observations et revue de la littérature.

INTRODUCTION: 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. CASES REPORT: 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. CONCLUSION: 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.

[Positivity of antineutrophil cytoplasmic antibodies in children: prevalence and etiologies]. / Positivité des anticorps anti-cytoplasme des polynucléaires neutrophiles chez l'enfant : prévalence et étiologies.

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.

Boron-containing thiouracil derivatives for neutron-capture therapy of melanoma.

Boron-containing derivatives of 2-thiouracil and 2,4-dithiouracil and the corresponding 6-propyl compounds, containing a dihydroxyboryl group in the 5-position, have been prepared. These compounds accumulate in B16 melanoma in mice in concentrations up to 30 micrograms of boron per gram tissue. The uptake persists. The toxicity of both 2-thiouracil derivatives is low. These compounds are therefore good candidates for boron neutron-capture therapy of malignant melanoma.

Synthesis and anticancer activity of 5-diethylaminomethyl derivatives and nitrogen mustards of uracil and 2-thiouracils.

Several 5-diethylaminomethyl derivatives and nitrogen mustards of uracil and 2-thiouracil have been synthesized and tested for their potential anticancer activity in vitro on KB cells and in vivo on Ehrlich carcinoma. Among the alkylating derivatives tested several showed cytotoxic activity in vitro and compound V [5-[bis(2-chloroethyl) amino] methyl-6-propyluracil hydrochloride] showed both in vitro and in vivo anticancer activity.

New radiotherapeutic techniques in nuclear ophthalmology.

Various aspects of radiotherapeutic techniques used in treating ocular tumors are discussed. Previous and current "standard" modalities are briefly reviewed, including beta and gamma emitters, 60Co, 125I, and charged particles. In particular, emphasis is placed upon techniques under development that use biomolecules to physiologically target radioactive or stable isotopes to ocular melanoma. These procedures include 35S-thiouracil, 127I-deoxyuridine in conjunction with irradiation with photons from 145Sm, neutron capture therapy, and various combinations of the above. Thiouracil shows particular promise because of its incorporation during malanin synthesis in growing melanoma. Radiosensitization and stimulation of Auger cascades via introduction of iodine in DNA followed by irradiation with activating photons of appropriate energy (from 145Sm) has been shown to be effective in vitro. Various molecules may be used to transport boron to ocular melanoma, including thiouracil, thus allowing selective irradiation of tumor cells via 10B (n, alpha) 7Li reaction.

Melanin-affinic thioureas as selective melanoma seekers.

2-Thiouracil and some related thioureas are receiving growing interest as selective melanoma seekers. They are incorporated into growing melanin, apparently due to covalent binding to dopaquinone, and the adduct is gradually trapped in the melanin polymer during its formation. To be clinically useful in melanoma scanning, thiouracil has been radioiodinated, and 5-iodo-2-thiouracil (ITU) was found to be localized in melanotic melanoma as selectively as thiouracil. Clinical trials with ITU, for the detection of malignant melanoma, are in progress, and the results so far are promising. Treatment with [35S]thiouracil has been performed on melanoma-bearing mice. The radiodoses needed for cure, however, were very high, which makes clinical application hazardous. Boron neutron capture therapy, on the other hand, might be a better approach. The technique is based on the irradiation of tumours with slow neutrons from an external source after the accumulation of boron in tumour tissue and clearance from normal tissues. Boron-10 undergoes instantaneous nuclear fission through the reaction 10B(n,alpha)7Li, and the emitted particles are efficient in cell killing. Boronated thioureas have been synthesized in various laboratories, and data from experiments on melanoma-bearing mice indicate that some of these compounds accumulate in the tumours in concentrations necessary for successful treatment.

Antitumor effect of 2-thio-4-hydrazinouracil on transplantable tumors.

The cytostatic activity of 2-thio-4-hydrazinouracil (THU) on some transplantable tumors has been studied. A strong effect of this compound (between 60% and 100% suppression) has been found in the case of Myeloma P-8 (MOPC-21) and Sarcoma 180 (Crocker). A less pronounced effect has been observed on Yoshida sarcoma, while the development of Jensen sarcoma is not influenced.

The effects of thiouracil and thyroxine on resistance to heat shock.

Adult White Plymouth Rock hens were submitted to a heat shock of 42.2 C. It was demonstrated that .1% thiouracil fed for 4 weeks prior to heat stress significantly increased survival time. Administration of DL-thyroxine administered at the rate of 4 micrograms/100 g body weight injected on day of testing did not alter survival time. However, survival under heat shock was significantly reduced if DL-thyroxine was administered daily for 3 days prior to testing. White Rocks exhibited significantly longer survival time under heat shock than Single Comb White Leghorns, and females of both breeds exhibited significantly longer survival time their male counterparts. Treatment with DL-thyroxine greatly reduced the survival time differences between breeds and sex. The implications of these findings for applied breeding programs are discussed.

Effect of thiouracil on response to heat stress of White Leghorn lines selected for fast and slow gain in two temperatures.

Four lines of White Leghorns previously selected for fast and slow gain from 5 to 9 weeks of age in a hot (32.2 C) and in a cold (21.1 C) selection environment were grown from 5 to 9 weeks in the same two temperature environments. Samples of 32 females from each line of the third generation grown in each temperature environment from 5 to 9 weeks of age were divided into two groups; one received .2% thiouracil in the diet for a 5-day period and the other did not. The temperature was then increased to 40.6 C until 52.8% of all birds had died. The percentages of mortality of lines, rearing environments, and thiouracil treatments were then analyzed. An increase of 64.8% mortality from acute heat stress for birds reared in the cold environment was significant, but the differences among the four selected lines were not. The presence of thiouracil in the diet significantly reduced mortality from heat stress by 16.4%. There were no significant interactions between thiouracil treatments and selected lines or rearing environments.

Management of patients with diffuse toxic goitre in Ireland, a country with low iodine intake.

The present study was undertaken to examine the response rate of thyrotoxicosis in patients with diffuse toxic goitre to thiouracil drug treatment for 1 year in an Irish population, reported to have a low iodine intake. Evidence exists that a low iodine intake is associated with a high long-term remission rate for drug treatment of diffuse toxic goitre. Seventy-five patients participated with 45% of patients entering into long-term remission which has been maintained for a mean of 52.5 +/- 38.8 months. Fifty-five per cent of patients demonstrated relapse at a mean of 7.4 +/- 10.4 months following the withdrawal of thiouracil treatment. These findings were similar to those reported from countries with abundant iodine intake. The data in the present study confirms the usefulness of drug treatment for diffuse toxic goitre in an Irish population but the reported iodine deficiency does not appear to confer a particular advantage.

[Prognosis of Graves disease treated with different modalities of therapy].

A retrospective study on the prognosis of Graves disease was carried out. 224 cases, whose treatment has been stopped for 6 months to more than 10 years, were divided into 3 groups. 82 cases received long-term antithyroid drug therapy, 100 cases were treated with radioactive 131I and 42 cases had subtotal thyroidectomy. The prognosis was evaluated for 4 items according to clinical and laboratory investigations. The cured rate of long-term drug therapy in this study was higher than that reported by most of other authors, 131I therapy was the best among the 3 modalites of therapy. The incidence of permanent hypothyroidism was fairly low in the thyroidectomy group. 97.3% of the patients with exophthalmos showed improvement after treatment in all the 3 groups.

[Vasculitis with renal and pulmonary involvement in a patient receiving benzylthiouracil for Graves disease]. / Une vascularite associant une atteinte rénale et pulmonaire au cours d'une maladie de Basedow traitée par le benzylthiouracile.

INTRODUCTION: 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. EXEGESIS: 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. CONCLUSION: Some cases of vasculitis associated with anti-thyroid drug treatment are reported.

[Benzylthiouracil induced ANCA-positive vasculitis]. / Vascularite à anticorps anticytoplasme de polynucléaires neutrophiles induite par le benzylthio-uracile.

INTRODUCTION: 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. OBSERVATION: 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. CONCLUSION: 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.

[Treatment of Basedow-Graves disease in pregnancy]. / Basedow--Graves-kór kezelése terhességben.

UNLABELLED: Thyrostatic treatment of pregnant women with Graves' disease is a special problem. Observation of 46 pregnancies of 35 women suffering from Graves' disease has been summarized. The outcome was successful in 45 cases. Methimazole and propylthiouracil was administered to the patients without thyroxine. Therapy was needed for the two thirds of the mothers. At the end of the second trimester the thyrostatic agent could have been withdrawn in the 77% of the cases. Antithyroid treatment administered in low dose at the time of conception did not affect the outcome. Premature delivery rate and the number of neonates with low weight did not increased. Transient hyperthyrotropinaemia was observed in one case. Likewise, one infant suffered from neonatal thyrotoxicosis. 37% of the mothers had postpartal recurrence of hyperthyroidism. CONCLUSIONS: the free thyroxin level monitoring is essential during thyrostatic treatment. Thyrotropin receptor antibody investigation, having predictive value for neonatal thyrotoxicosis, should be done, too. Postpartal thyroid control is necessary for elucidate a hyperthyroid relapse, the rate of which was almost 40%.