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At least 19 recordsLinked to original sources
PubMed1996

Atom level electrotopological state indexes in QSAR: designing and testing antithyroid agents.

PURPOSE: To design antithyroid agents with less side effects, the electrotopological-state (E-state) indexes of thiourylene moiety (SN&S) was utilized as a guideline to develop five acrylic thiourylene-type compounds with reduced antioxidant property. METHODS: These agents were synthesized and screened for antithyroid activity in rats using 125I-thiocyanate discharge technique. In addition, chemiluminescence studies on the activated polymorphonuclear leukocytes (PMNLs) were also conducted to reveal antioxidant properties of the tested compounds. RESULTS: A linear relationship between the in vitro literature value of the formation constants of thiourylene-type compounds with iodine (Kc) and the SN&S was observed and utilized in designing those agents. At least one of the compounds (abouthiouzine) was found to have a potential value as an antithyroid agent. The relative efficacy of abouthiouzine [1-n-butyl-3(isonicotinamido)-2-thiourea], after equimolar dose, was 102% and 51.5% of that of propylthiouracil with respect to the rate of 125I-discharge and 125I-uptake, respectively. In addition, chemiluminescence studies on PMNLs revealed that abouthiouzine has slight oxidant property. Such properties may provide advantages in avoiding the iatrogenic hypothyroidism and antithyroid-induced immunological reactions. CONCLUSIONS: The E-state approach provides guidelines to economize efforts and cost of designing new antithyroid drugs.

Animals↗
PubMed1992

Examination of antithyroid effects of smoking products in cultured thyroid follicles: only thiocyanate is a potent antithyroid agent.

We studied the antithyroid action of cigarette smoking products (nicotine, cotinine, and thiocyanate) in the physiological culture system of porcine thyroid follicles. Iodide uptake, iodine organification, de novo thyroid hormone formation, and iodide efflux were measured in the presence of 0-200 mumol/l nicotine, cotinine, or potassium thiocyanate. Nicotine and cotinine did not inhibit iodide transport or thyroid hormone formation. Thiocyanate concentrations equivalent to serum levels of smokers showed three independent antithyroid actions: (i) inhibition of iodide transport, (ii) inhibition of iodine organification, and (iii) increased iodide efflux. Inhibition of iodide transport by thiocyanate was competitive with iodide and independent of TSH concentration. Thiocyanate did not inhibit TSH mediated cAMP production or Na+K+ ATPase activity, a sodium pump for iodide transport. When 50 mumol/l thiocyanate was added 2 h after incubation with iodide or when 1 mumol/l thiocyanate was added from the beginning of incubation, iodine organification was inhibited without changing iodide transport. De novo thyroid hormone formation was clearly inhibited by 50 mumol/l thiocyanate. Thiocyanate increased iodide efflux although the degrees of iodide efflux by 10 mumol/l and 100 mumol/l thiocyanate did not differ significantly. In summary, thiocyanate, a product of smoking, has three independent antithyroid activities. The data of iodide transport kinetics suggest that thiocyanate can be an antithyroid agent particularly in iodine deficiency.

Animals↗
PubMed2001

[Radioiodine therapy of Graves' disease--a dosimetric comparison of various therapy regimens of antithyroid agents].

AIM: Premedication with antithyroid drugs (ATD) compared to patients not pretreated with ATD causes a higher failure rate of radioiodine therapy (RITh) or demands higher therapeutical dosage of radioiodine (RI). For clinical reasons and because of accelerated iodine metabolism in hyperthyreosis a compensated thyroid metabolism is desirable. Aim of this study was to investigate the influence of ATD on the biokinetics of RI in case of Graves' disease in order to improve RITh of patients pre-treated with ATD. METHODS: 385 consecutive patients who underwent RITh because of Graves' disease for the first time were included: Group A (n = 74): RITh under continuous medication with ATD; Group B (n = 111): Application of RI under continuous medication with ATD, in case of insufficient RI-uptake or shortened effective RI-half-life ATD were stopped 1-5 days after RITh; Group C (n = 200): ATD were stopped 2 days prior to RITh in all patients. We examined the influence of ATD on RI-uptake and effective RI-half-life as well as the absorbed dose achieved on the thyroid in dependence of thyroid volume and applied RI-dosage [TEQ--therapy efficiency quotient, (2)]. RESULTS: In the RI-pretest (all patients under ATD) the RI-uptake was comparable in all three groups. During RITh RI-uptake, effective RI-half-life and therefore the TEQ were significantly higher in Group C as compared to Groups A and B (p < 0.001, respectively). In Group B the medication with ATD was stopped in 61 of 111 cases 1-5 days after RITh. In this subgroup the effective RI-half-life increased from 4.4 +/- 1.7 d to 5.1 +/- 1.6 d after stopping of ATD (p = 0.001). CONCLUSION: Stopping of ATD 2 days prior to RITh leads to an increased efficiency of about 50% compared to RITh carried out under ATD and therefore to a clear reduction of radiation exposure to the rest of the body with equal absorbed doses of the thyroid. Stopping of ATD shortly after RITh increases efficiency in case of short effective RI-half-life, but it is inferior to stopping ATD 2 days prior to RITh.

Adolescent↗
PubMedDate not supplied

[Blocking of the reaction of the pituitary gland to exogenic thyroxine after its administration together with an antithyroid agent].

It was experimentally revealed that 1-thyroxin administered in combination with an antithyroid preparation caused no depression of the thyrotropic function of the hypophysis whose activation was caused by the inhibitory action of the antithyroid agent on the thyroid gland. At the same time combined administration of the preparations failed to lead to the thyroxin inactivation. The "block effect" of the hypophysis response to the thyroxin administration persisted even with such low doses of antithyroid preparation which failed to depress the thyroid function, and, correspondingly, did not activate the thyrotropic hormone production by the hypophysis.

Animals↗
PubMed1987

Mutagenicity tests of the antithyroid agent thiamazole. Cytogenetic studies on male mice.

The mutagenic potential of thiamazole, an antithyroid agent, was investigated by an in vivo cytogenetic test and was compared with those of mitomycin C and vincristine. These drugs were subcutaneously injected into slc-ICR male mice either as a single dose or as multiple doses for 5 successive days. Thiamazole (90 or 180 mg/kg) did not increase the number of micronuclei in bone marrow cells. This drug also did not induce chromosomal aberrations in spermatogonium, spermatocyte, or bone marrow cells. On the other hand, mitomycin C (3.0 mg/kg) increased the appearance of chromosomal aberrations and micronuclei. Vincristine (0.2 mg/kg) induced bone marrow cells with a so called large micronucleus (d greater than or equal to D/4). These results suggest that thiamazole may not have significant effects on the genetic systems of mice.

Animals↗
PubMed1992

Effect of an antithyroid agent (propylthiouracil) and L-ascorbic acid on mixed-function oxidase and drug metabolism in hepatic microsomes of chickens.

1. The experiments were undertaken to determine if an antithyroid agent (propylthiouracil, PTU) and/or ascorbic acid (AA) affect mixed-function oxidase (MFO) in hepatic microsomes of male broiler chicks. 2. Feeding PTU increased the MFO activity in a dose-related manner. Addition of AA to the PTU-containing diet further increased the content of cytochromes P-450 and b5, but not the activities of NADPH-cytochrome c and NADH-cytochrome b5 reductase, and the drug-metabolizing enzymes. 3. Supplemental AA induced cytochrome b5 rather than cytochrome P-450.

Animals↗
PubMed2002

The antithyroid agent 6-n-propyl-2-thiouracil is a mechanism-based inactivator of the neuronal nitric oxide synthase isoform.

6-n-Propyl-2-thiouracil (6-PTU), the antithyroid agent, produces a time-, concentration-, and turnover-dependent inactivation of the NO synthetic capability of the neuronal nitric oxide synthase isoform irreversible by either arginine or (6R)-5,6,7,8-tetrahydro-L-biopterin. By contrast 6-PTU produces an inhibition of the cytokine-inducible and endothelial nitric oxide synthases fully reversible by arginine. The inactivation of neuronal nitric oxide synthase by 6-PTU follows first order kinetics, and is inhibited competitively by both arginine and (6R)-5,6,7,8-tetrahydro-L-biopterin, but is not accompanied by either a loss of heme-CO binding, heme fluorescence, or disassembly of dimeric structure. 2-Thiouracil behaves qualitatively identically to 6-PTU. Turnover-dependent inactivation of neuronal nitric oxide synthase by [2-14C]-2-thiouracil is accompanied by incorporation of radioactivity into the polypeptide chain. Ca2+-dependent NO formation by GH3 pituitary cells is inhibited by 6-PTU in a manner enhanced by depletion of either extracellular arginine or intracellular (6R)-5,6,7,8-tetrahydro-L-biopterin. These observations establish that 6-PTU is an alternate substrate, mechanism-based inactivator of the neuronal nitric oxide synthase isoform with the ability to suppress cellular NO formation.

Animals↗
PubMed1999

[Fever due to antithyroid agents].

Three patients, females aged 62, 67 and 32 years, were presented with fever and sore throat and had severe agranulocytosis (granulocyte count < 100/microliter). All had Graves' disease and were being treated with thiamazole 30 mg once a day. Thiamazole was discontinued and treatment with antibiotics initiated. None of the patients received granulocyte-colony stimulating factor (G-CSF). The mean recovery time of granulocytes was 9 days and there were no fatalities. Patients who receive antithyroid agents should be warned against the serious and potentially lethal side effect of agranulocytosis.

Adult↗
PubMed1974

Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents.

In 66 untreated patients with hyperthyroidism, serum triiodothyronine (T(3)) and thyroxine (T(4)) concentrations were measured by immunoassay. The mean T(3) level was 478+/-28 ng/100 ml (all values mean+/-SEM) and the T(4) was 20.6+/-0.6 mug/100 ml. The serum T(4)/T(3) ratio by weight was 48+/-2 as opposed to a value of 71+/-3 in euthyroid adults. There was a significant inverse correlation of the T(4)/T(3) ratios with serum T(3) (r=0.77; P<0.01) but not with serum T(4)(r=0.21). These results suggested that relative overproduction of T(3) is consistently present in patients with hyperthyroidism. To examine the acute effects of various antithyroid agents on serum T(3) and T(4) concentrations, iodide, propylthiouracil (PTU), and methylmercaptoimidazole (MMI) were given alone to mine patients, and serial T(3) and T(4) measurements were made. There was an acute decrease in serum T(3) over the first 5 days in the three iodide and three PTU-treated patients which was greater than that seen in the MMI group. This suggested that PTU and MMI had different effects on T(3) production. To compare the effects of PTU and MMI under conditions in which thyroidal hormone release was minimized, these drugs were given in combination with iodide. The mean daily dosage of PTU was 827 (n=11) and of MMI was 88 (n=8). In the PTU+iodide group, the initial serum T(3) concentration was 586+/-61 ng/100 ml and decreased significantly to 326+/-41 on day 1 and to 248+/-21 on days 2 and 3, respectively, and did not change further on days 4 and 5. In the MMI + iodide group, basal serum T(3) was 645+/-90 ng/100 ml and decreased to 568+/-81, 452+/-73, and 344+/-51 on days 1, 2, and 3, respectively, and did not change thereafter. While the initial T(3) concentrations in serum were not different in the PTU and MMI groups, the T(3) concentrations in the PTU patients were significantly lower on days 1 and 2 and during the apparent plateau period on days 3-5. Serum T(4) concentrations decreased gradually in both groups, from 23.9+/-2.0 mug/100 ml, initially, to 17.5+/-1.6 on day 5 in the PTU group and from 22.0+/-2.6 to 14.6+/-2.0 in the MMI-treated patients. The T(4) values were not significantly different at any time. These changes resulted in increases in the serum T(4)/T(3) ratios in both groups, but these ratios were substantially higher in the patients treated with PTU + iodide. The initial serum T(4)/T(3) ratio was 43+/-3 and increased to 74+/-7 and 88+/-7 on days 1 and 2 in the PTU group, reaching a plateau value of 91+/-7 during days 3-5. Comparable values for MMI-treated patients were 35+/-2, 42+/-3, 52+/-6, and 54+/-3 during the plateau period. Previous investigations have shown that PTU inhibits T(4) deiodination in hyperthyroid patients and decreases T(3) production from T(4) in animals. The greater acute decrease in serum T(3) and the higher serum T(4)/T(3) ratios in the PTU-treated patients seems best explained by an inhibition of peripheral T(3) production by this agent. This conclusion is further supported by a direct relationship between the T(4)/T(3) ratio on days 3-5 and the dose of PTU administered. These results further suggest that both thyroidal and extrathyroidal pathways contribute substantially to the apparent overproduction of T(3) in hyperthyroidism.

Antithyroid Agents↗