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PubMed2005

Preparation and in vitro evaluation of propylthiouracil microspheres made of Eudragit RL 100 and cellulose acetate butyrate polymers using the emulsion-solvent evaporation method.

The objectives of this investigation are to evaluate the encapsulation efficiency of the anti-thyroid agent 6-n-propyl-2-thiouracil using two polymers of different characteristics (cellulose acetate butyrate polymer, (CAB-551-0.01) and ammonio methacrylate copolymer (Eudragit RL 100) and to study the effect of this encapsulation on the drug release properties. Polymers were used separately and in combination to prepare different microspheres. Also, the effect of polymer solution phase viscosity was studied for each of the polymers and for their combinations. An Ostwald viscometer was used to evaluate the relative viscosities of polymer solution phases and their combinations. Microspheres with 25% theoretical drug loading of 6-n-propyl-2-thiouracil core material were prepared by the emulsion solvent evaporation method. Microspheres prepared from CAB-551-0.01, which has higher relative polymer phase viscosity than Eudragit RL 100, showed significantly lower drug release rates and a noticeable lag time. Polymer combinations of CAB-551-0.01 and Eudragit RL 100 (1:1) showed an interesting synergistic increase in relative polymer solution viscosities at all concentrations. Unlike microspheres prepared from the two polymers separately which follow Higuchi spherical matrix release kinetics, microspheres prepared using a combination (1:1) of the two polymers showed near zero order with faster rates compared to those prepared using CAB-551-0.01 equivalent polymer concentrations. The results of this study suggest that 6-n-propyl-2-thiouracil was successfully and efficiently encapsulated and release rates of matrix microspheres are related to polymer solution phase viscosity, but when polymer combinations were used other factors such as structural effects must be considered.

Cellulose↗
PubMed2001

Method for the analysis of thyreostats in meat tissue using gas chromatography with nitrogen phosphorus detection and tandem mass spectrometric confirmation.

An analytical method not requiring a mercury column cleanup step is described for the isolation and detection of four thyreostatic agents in meat tissue. The use of these growth promotants in livestock has been banned by regulatory agencies. The meat tissue is homogenized with acetonitrile-water, centrifuged, and the supernatant is partitioned with petroleum ether. The acetonitrile-water is concentrated and then passed through a silica-gel column. The solvent is then removed and the residue derivatized with N-methyl-N-(trimethylsilyl)-trifluoroacetamide. The total amount of organic solvent used for the analysis is merely 35 mL. The derivatized thyreostats are detected and quantitated by gas chromatography (GC) equipped with a nitrogen-phosphorus detector. Percent recoveries from fortified meat tissue (n = 6) at the 0.1-microg/g (parts per million) level are 93.5 +/- 2.9 for 2-thiouracil, 90.3 +/- 3.0 for tapazole, 87.5 +/- 2.9 for 6-methyl-2-thiouracil, and 85.1 +/- 5.8 for 6-n-propyl-2-thiouracil. For the confirmation of analyte identities, GC-tandem mass spectrometry with an ion-trap instrument is used. The estimated minimum level for a reliable measurement is 0.050 microg/g in meat tissue.

Animals↗
PubMedDate not supplied

Boron neutron capture therapy for malignant melanoma: an experimental approach.

Previous studies have shown that some thioamides, e.g., thiouracil, are incorporated as false precursors into melanin during its synthesis. If boronated analogs of the thioamides share this property, the melanin of melanotic melanomas offers a possibility for specific tumoural uptake and retention of boron as a basis for neutron capture therapy. We report on the synthesis of boronated 1H-1,2,4-triazole-3-thiol (B-TZT), boronated 5-carboxy-2-thiouracil (B-CTU), and boronated 5-diethylaminomethyl-2-thiouracil (B-DEAMTU) and the localization of these substances in melanotic melanomas transplanted to mice. The distribution in the mice was studied by boron neutron capture radiography. B-TZT and B-CTU showed the highest tumour:normal tissue concentration ratios, with tumour:liver ratios of about 4 and tumour:muscle ratios of about 14; B-DEAMTU showed corresponding ratios of 1.4 and 5, respectively. The absolute concentration of boron in the tumours, however, was more than three times higher in the mice injected with B-TZT, compared with B-CTU. The results suggest that B-TZT may be the most promising compound of the three tested with regard to possible therapy of melanotic melanomas.

Animals↗
PubMed1995

New thioureas and related substances intended for melanoma targeting.

Thiouracil and a few related drugs are known to be melanoma-seeking agents owing to specific incorporation into nascent melanin. The melanin-affinic properties are apparently due to binding to intermediates, preferably dopaquinone, produced in the melanin synthetic pathway by tyrosinase-catalysed oxidation of tyrosine. In the present paper, in vitro screening methods have been used for the identification of possible melanoma seekers according to the above principle. The binding of test substance to dopaquinone suppressed dopachrome formation by the withdrawal of dopaquinone from the reaction of the mixture, and the decrease in dopachrome concentration was monitored spectrophotometrically at 475 nm. In order to eliminate false results caused by tyrosinase inhibition, which also will decrease the dopachrome concentration, the oxygen consumption was followed potentiometrically. To avoid the effect of tyrosinase inhibition on dopachrome formation, additional experiments with autoxidation of L-dopa in the presence of test substance were performed. Of the 22 substances (mainly thioureylenes and thioamides) studied, 4,5,6-triamino-2(H)- pyrimidinehtionsulfate, trithiocyanuric acid, 2-thiouracil, 6-methyl-2-thiouracil, and 4- amino-2-mercaptopyrimidine most effectively decreased the dopachrome formation with no or little inhibition of tyrosinase activity. They should therefore be regarded as potential melanoma seekers. In a complementary autoradiographic study on the uptake of the potent tyrosinase inhibitor mercaptobenzothiazole (MBT) in B 16 melanoma transplanted to mice, it was found that strong tyrosinase inhibition seems to decrease incorporation into melanin in vitro. MBT was partially accumulated in restricted areas of the tumor which may be explained by the molar dose injected.

Animals↗
PubMed2002

Synthesis and antiherpesvirus activities of 5-alkyl-2-thiopyrimidine nucleoside analogues.

Twenty 5-alkyl-2-thiopyrimidine nucleosides were newly synthesized and examined for antiviral activities against herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). In this study, 2'-deoxy-5-alkyl-2-thiocytidine analogues had lower 50% effective concentration (EC50) values against HSV-1, and 2'-deoxy-5-alkyl-2-thiouridine analogues showed lower EC50 against VZV than their congeners of arabinoside form. Among the compounds examined, 2'-deoxy-5-ethyl and 5-propyl-2-thiocytidine (TN-53 and TN-54) were most potent and selective anti-HSV compounds. Their EC50s were 0.04 and 0.15 microM, and selectivity indexes were more than 7,215 and 1,849, respectively. On the other hand, 2'-deoxy-5-propyl-2-thiouridine (TN-51), 5-bromovinyl-2-thiouracil arabinoside (TN-65) and 5-styryl-2-thiouracil arabinoside (TN-67) were most potent and selective anti-VZV compounds. Their EC50s were 3.1, 3.8 and 2.6 pM for CaQu strain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities against thymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosine arabinoside compounds showed marginal anti-CMV activities (EC50s were 57-159 pM). All of the five alkyl-2-thio-pyrimidine nucleoside analogues examined were not cytotoxic to human lymphoblastoid cells (RPM18226) and human embryonic fibroblast cells (MRC-5) at 240 microM (100 microg/ml) or more. Regarding the structure-activity relationship of 5-alkyl-2-thiopyrimidine nucleoside analogues, the following remarks will be noted. Elongation of 5-alkyl chain (methyl to ethyl) of 2-thiocytosine in both deoxyribosyl and arabinosyl nucleosides increased anti-HSV-1 activity but not anti-VZV activity. Furthermore, elongation of the same chain (ethyl to propyl) of 2-thiodeoxyuridine increased anti-VZV activity whereas it did not in the case of 2-thiouracil arabinosides.

Antiviral Agents↗
PubMed1992

Novel uracil derivatives: newly synthesized centrally acting agents.

A series of 1-amino-5-substituted uracils and their 4-thio or 2,4-dithio substituted analogues were synthesized and assayed for anti-conflict activity in rats and anesthetic activity in mice. 1-Amino-5-halogenouracils 3b-e, 1-amino-4-thiouracil (9a), and 1-amino-5-halogeno-4-thiouracils 9c, d showed both anti-conflict and anesthetic activities. The most active compound was 1-amino-5-chloro-4-thiouracil (9d) which showed anxiolytic activity at 2 mg/kg of oral administration (p.o.) on a modified Geller-Seifter conflict schedule. Its minimum effective dose (MED) was lower than that of diazepam. The 50 percent effective dose (ED50) for anesthetic activity in mice of the compound (9d) was 32.9 mg/kg, p.o.

Anesthetics↗
PubMed1979

The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats.

Mice fed a diet containing 1% (w/w) 3-hydroxy-4(1H)-pyridone (DHP) developed goitre even with a diet high in iodine whereas mimosine (0.5% w/w) did not produce goitre even with a low-iodine diet. Thyroid enlargement was apparent (measured morphometrically) by the 7th week and was advanced by the 11th week. Histologically the goitre was hyperplastic in type. No marked histological changes were found in other organs of mice fed DHP or any organs of mice fed mimosine, except for some atrophy of hair follicles. A single intragastric dose of DHP inhibited the uptake of 125I by the thyroid in the rat but an equivalent dose of mimosine did not. Evidence is presented that the inhibition occurs at the iodine binding step, as with methyl thiouracil, rather than at the iodide trapping step, as with thiocyanate. Chronic treatment of mice with DHP, as with 6-methyl thiouracil, increased the avidity of the thyroid in taking up 125I. The major conjugated form of DHP in mammals, DHP-3-O-glucuronide, was almost as effective a goitrogen as the unconjugated compound when given by mouth but considerably less active than the free form in the blood stream. It was concluded that DHP is a potent antithyroid compound of the thiouracil type with low general toxicity, since mammals can tolerate a level of intake sufficient to produce goitre in spite of iodine supplementation.

Animals↗
PubMed1951

The use of antithyroid drugs.

The preoperative use of antithyroid drugs is mandatory if surgical treatment of complicated hyperthyroidism is contemplated. Six months to a year may be required for suitable preparation. The long-term use of antithyroid drugs is less effective for the "cure" of hyperthyroidism than is operation or the use of radioactive iodine. Propyl and methyl thiouracil are the antithyroid drugs of choice. Either of these thiouracil derivatives is capable of producing leukopenia. The antithyroid drugs exert no favorable effect on exophthalmos. The antithyroid drugs are suitable for the control of hyperthyroidism during pregnancy. The patient probably should not be kept hypothyroid during pregnancy but rather in a state of mild hyperthyroidism.

Antithyroid Agents↗
PubMed1992

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.

Adult↗
PubMed1976

Inhibition of turnip yellow mosaic virus synthesis by pyrimidine analogues.

The pyrimidine analogues 2-thiouracil, 2-thiouridine, 6-azauracil and 6-azauridine all inhibited the synthesis of turnip yellow mosaic virus (TYMV) and increased the synthesis of empty virus protein shells in infected Chinese cabbage leaf discs. Uracil and uridine reversed these effects. 2-Thiouracil also reduced the UTP pool in TYMV infected leaf discs. The results are consistent with the suggestion that these analogues or their in vivo derivatives affect virus synthesis by inhibiting the biosynthesis of uridylic acid, possibly by inhibiting orotidylic acid decarboxylase.

Azauridine↗
PubMed1979

Melanoprotein: absence of a direct melanin-protein relationship in chick embryo melanocytes.

Short-term synthesis of radioactivity labeled melanin (using DL-[2-14C]tyrosine or 2-[2-14C]thiouracil) by chick retinal pigment tissues in vitro was not influenced by inhibitors of protein synthesis, puromycin and cycloheximide. Co-ordinate synthesis of protein is, therefore, unnecessary for melanin synthesis, and melanoproteins must represent secondary interactions between melanin and protein. Melanin was isolated from chick embryo feather germs by extracting the proteins with hot dodecyl sulfate/mercaptoethanol. Melanin isolated from tissues incubated previously in L-[U-14C]valine medium had no associated radioactivity compared to the radioactivity of melanin prepared from tissues incubated in DL-[2-14C]tyrosine or 2-[2-14C]thiouracil. If melanoproteins exist at all, they are non-covalently bonded associations of melanin and melanosomal proteins.

Animals↗
PubMed1991

Relationship of thyroid status to growth hormone and insulin-like growth factor-I (IGF-I) in plasma and IGF-I mRNA in liver and skeletal muscle of cattle.

Steers were made hyperthyroid or hypothyroid to study the effects of physiological alterations in thyroid hormone status on plasma growth hormone (GH) profiles, plasma insulin-like growth factor-I (IGF-I) concentrations, and relative abundance of IGF-I mRNA in skeletal muscle and liver. Eighteen yearling crossbred steers (360 to 420 kg) were randomly allotted to hyperthyroid (subcutaneous injection 0.6 microgram/kg BW L-thyroxine for 10 d), hypothyroid (oral thiouracil; 0.25% diet plus 12.5 g capsule/d for 17 d), or control (subcutaneous injection 0.9% NaCl) treatment groups. Blood samples were taken for measurement of GH, IGF-I, thyroxine (T4) and triiodothyronine (T3) by RIA. Samples of liver and skeletal muscle were taken by biopsy for measurement of IGF-I mRNA by solution hybridization. Steers receiving thiouracil had 57 and 53% (P less than .05) lower T4 and T3, respectively, than control steers (84.1 and 1.7 ng/ml). The hyperthyroid steers had 228 and 65% greater (P less than .05) T4 and T3 than control steers. Neither increased nor decreased thyroid status had any significant effects on plasma GH profiles, liver IGF-I mRNA, or plasma concentration of IGF-I. There was no effect of thyroid hormone alteration on skeletal muscle IGF-I mRNA concentrations. The results of this study suggest that short-term changes in thyroid status of cattle had no major impact on the GH-IGF-I axis or skeletal muscle IGF-I mRNA.

Animals↗
PubMed1988

Interaction of propylthiouracil and its precursors with horseradish peroxidase.

Interactions of horseradish peroxidase with propylthiouracil, thiouracil, propyluracil and uracil lead to the formation of complexes that exhibit different absorption spectra which can be attributed to the perturbation of peroxidase as the result of the drug-binding on a polar site in the protein. In this paper, by dilatometry and viscometry structural alterations in horseradish peroxidase were detected from its interaction with propylthiouracil and thiouracil only, and the physiological inhibition of peroxidase for these antithyroid drugs seems to be through structural alterations in the protein.

Horseradish Peroxidase↗
PubMed2000

Effect of thione primers on bonding of noble metal alloys with an adhesive resin.

OBJECTIVES: The purpose of the current study was to evaluate the effects of two metal conditioners on the bond durability of an adhesive resin joined to noble metal alloys by comparing pre- and post-thermocycling bond strengths. METHODS: Two different sizes of disk specimens (10 and 8mm in diameter by 2.5mm thickness) were prepared from silver-indium (Ag-In-Zn, Salivan), silver-palladium-copper-gold (Ag-Pd-Cu, Castwell M.C.12), metal-ceramic gold (Au-Pt-Pd, Degudent-Universal), metal-ceramic palladium (Pd-Ga-Co, PTM 88), type IV gold (type IV, Casting Gold) alloys, and pure silver (pure Ag). The specimens were air-abraded with 50-microm grain sized alumina, conditioned either with a thiouracil primer (Metaltite) or with a thione-phosphate primer (Alloy Primer), then bonded with an adhesive resin (Super-Bond Opaque). Shear bond strengths were determined both before and after repeated thermocycling (4 degrees C and 60 degrees C, 1min each, 100, 000cycles). The results were compared by analysis of variance and post-hoc multiple comparison intervals. RESULTS: The average post-thermocycling bond strengths in MPa (n=8) generated with the thiouracil primed and thione-phosphate primed groups, respectively, were: 3.4 and 5.8 for the Ag-In-Zn alloy, 40.4 and 37.7 for the Ag-Pd-Cu alloy, 26.4 and 33.5 for the Au-Pt-Pd alloy, 27.4 and 36.6 for the Pd-Ga-Co alloy, 40.2 and 40.3 for the type IV alloy, and 37.3 and 32.4 for the pure Ag. The Ag-In-Zn alloy exhibited significantly lower bond strength than the other alloys, whereas the Ag-Pd-Cu and type IV alloys exhibited the greatest magnitude of bond strength for both primers (p<0.05). CONCLUSIONS: It can be concluded that the combined use of either of the two thione primers and the adhesive resin is effective for bonding the metal/alloys examined, with the exception of the Ag-In-Zn alloy.

Adhesiveness↗
PubMed2001

Structural chemistry of some new azo complexes.

The preparation of 2-thiouracil (H2L) and its 5-(2-thiazolylazo)thiouracil (H2L') complexes with CoII, NiII, CuII, ZnII and CdII are reported. The new complexes have been characterized by elemental analyses, solid reflectance, infrared spectra and magnetic susceptibilities. These measurements suggest that, the ligand is bound to the metal ion through nitrogen and/or sulphur atom behaving as mono- or bidentate ligand. Thermal decomposition studies of these metal complexes are explained to give more information on the structure of the investigated chelates. On the basis of the v(OH) bending frequencies and the insolubility of the complexes in common organic solvents, polymeric structures have been proposed.

Metals↗
PubMed2001

Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues.

A deficiency in apoptosis is one of the key events in the proliferation and resistance of malignant cells to antitumor agents; for these reasons, the search for apoptosis-inducing drugs represents a valuable approach for the development of novel anticancer therapies. In this study we report the first example of conformationally restrained analogues of ceramide (compounds 1-4), where the polar portion of the molecule has been replaced by a thiouracil (1, 3) or uracil (2, 4) ring. The evaluation of their biologic activity on CCRF-CEM human leukemia cells demonstrated that the most active was compound 1 followed by compound 2 (mean 50% inhibition of cell proliferation [IC(50)] 1.7 and 7.9 microM, respectively), while compounds 3 and 4 were inactive, as were uracil, thiouracil, and 5,6-dimethyluracil, the pyrimidine moieties of compounds 1-4. For comparison, the IC(50) of the reference substance, the cell-permeable C2-ceramide, was 31.6 microM. Compounds 1 and 2 and C2-ceramide were able to trigger apoptosis, as shown by the occurrence of DNA and nuclear fragmentation, and to release cytochrome c from treated cells. The treatment of female CD-1 nu/nu athymic mice bearing a WiDr human colon xenograft with the most active compound 1 at 2, 10, 50, and 200 mg/kg ip daily for 10 days resulted in an antitumor effect that was equivalent at 50 mg/kg or superior (200 mg/kg) to that of cyclophosphamide, 20 mg/kg ip daily, delivered on the same schedule, with markedly lower systemic toxicity. In conclusion, the present study demonstrates that the new ceramide analogues 1 and 2 are characterized by in vitro and in vivo antitumor activity and low toxicity.

Animals↗
PubMed1986

Multiple crosslinks of proteins S7, S9, S13 to domains 3 and 4 of 16S RNA in the 30S particle.

Functionally active 70S ribosomes containing 4-thiouracil in place of uracil (substitution level 2%) were prepared by an in vivo substitution method. RNA-protein crosslinks were introduced by 366 nm photoactivation of 4-thiouracil in the purified 30S subunits. Seven single stranded M13 probes containing rDNA inserts complementary to domains 3 and 4 of 16S RNA were constructed. These inserts approximately 100 nucleotides long starting at nucleotide 868 and ending at the 3' OH terminus were used to select contiguous RNA sections. The proteins covalently linked to each selected RNA section were identified by 2D gel electrophoresis. Proteins S7, S9, S13 were shown to be efficiently crosslinked to multiple sites belonging to both domains.

DNA Restriction Enzymes↗
PubMed2006

Intra- and intermolecular interactions in small bioactive molecules: cooperative features from experimental and theoretical charge-density analysis.

The topological features of the charge densities, rho(r), of three bioactive molecules, 2-thiouracil [2,3-dihydro-2-thioxopyrimidin-4(1H)-one], cytosine [4-aminopyrimidin-2(1H)-one] monohydrate and salicylic acid (2-hydroxybenzoic acid), have been determined from high-resolution X-ray diffraction data at 90 K. The corresponding results are compared with the periodic theoretical calculations, based on theoretical structure factors, performed using DFT (density-functional theory) at the B3LYP/6-31G** level. The molecules pack in the crystal lattices via weak intermolecular interactions as well as strong hydrogen bonds. All the chemical bonds, including the intra- and intermolecular interactions in all three compounds, have been quantitatively described by topological analysis based on Bader's quantum theory of 'Atoms In Molecules'. The roles of interactions such as C-H...O, C-H...S, C-H...pi and pi...pi have been investigated quantitatively in the presence of strong hydrogen bonds such as O-H...O, N-H...O and N-H...S, based on the criteria proposed by Koch and Popelier to characterize hydrogen bonds and van der Waals interactions. The features of weak intermolecular interactions, such as S...S in 2-thiouracil, the hydrogen bonds generated from the water molecule in cytosine monohydrate and the formation of the dimer via strong hydrogen bonds in salicylic acid, are highlighted on a quantum basis. Three-dimensional electrostatic potentials over the molecular surfaces emphasize the preferable binding sites in the structure and the interaction features of the atoms in the molecules, which are crucial for drug-receptor recognition.

Crystallography, X-Ray↗