Antithyroid Activity Research Articles

Neonatal hypothyroidism: recent developments

This chapter summarizes recent developments in the field of sporadic congenital hypothyroidism (CH) and transient neonatal hypothyroidism detected by systematic neonatal thyroid screening. The incidence of CH detected by screening is about 1 in 4000 births in North America, Europe and Australia; it is lower (1 in 7000) in Japan. The aetiology remains unknown; genetic and environmental factors are possibly involved. The role of autoimmunity has recently been studied extensively. Antithyroglobulin (ATA) and antimicrosomal antibodies are not involved; the possible role of thyroid growth blocking antibodies (TGBAb) of maternal origin remains controversial. Evaluation of clinical signs, bone maturation, serum T4 and the position and size of the thyroid by scintigraphy at the time of diagnosis in CH infants are important because these variables are related to the final psychoneuro-intellectual prognosis, irrespective of the adequacy of therapy. Thyroid echography always distinguishes a normal thyroid in the neonate but cannot define precisely the type of thyroid dysgenesis, if present (e.g. ectopic, athyreosis). The determination of serum Tg contributes to the diagnosis but its specificity and sensitivity are insufficient to replace thyroid scintigraphy. Therapy by LT4, at an initial dose of 25-50 micrograms/day in full-term infants, is universally recommended. The objective of therapy is to reach as soon as possible and to maintain serum concentrations of total and free T4 at the upper limits of normal for age. Serum TSH should decrease as rapidly as possible below 20 microU/ml and then remain within the normal range. Persistent hyperthyrotropinaemia in spite of normal serum T4 has to be avoided as it could represent poor compliance and/or insufficient therapy. Programmes of 10 to 14 years of follow-up of CH infants have now shown that the neuropsychointellectual prognosis of CH is excellent in all cases when therapy and psychosocial environment are adequate. Although still within the normal range, IQ is somewhat lower in spite of appropriate therapy in cases of severe prenatal hypothyroidism and some transient and correctable neurological signs occasionally occur. In Western countries transient neonatal hypothyroidism is usually due to iodine deficiency or iodine excess; the newborn infant is hypersensitive to the antithyroid action of an extraphysiological supply of iodine. TSH binding inhibitor immunoglobulins (TBII) of maternal origin occasionally cause transient neonatal hypothyroidism. In developing countries with severe iodine deficiency and endemic goitre, the incidence of thyroid failure in the newborn can be as high as 1 in 10.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthesis and antithyroid activity of 6‐n‐propyl‐5‐arylazo‐2‐thiouracils†

The synthesis of several 6‐n‐propyl‐5‐arylazo‐2‐thiouracil derivatives was achieved. The antithyroid activity of these derivatives has been determined using iodine‐125‐thiocyanate discharge technique in rats, and 6‐n‐propyl‐2‐thiouracil (PTU) as a standard. None of the 5‐arylazo‐2‐thiouracil analogs showed antithyroid activity as compared to PTU. The structure‐activity relationships (SAR) of position 5 in the PTU molecule and the requirements for better binding to the proposed receptor are discussed.

Inhibitory effects of antithyroid drugs on oxygen radical formation in human neutrophils

The effects of antithyroid drugs and related agents on human neutrophil function were studied. Neutrophil function was mainly assessed through oxygen radical formation as determined by chemiluminescence (CL) response, superoxide anion (O-2) generation and hydrogen peroxide production. Propylthiouracil (PTU) at a therapeutic concentration (10 micrograms/ml) inhibited CL response evoked by phorbol myristate acetate (PMA) and other stimulators. The inhibitory effect was not enhanced by pre-incubation of neutrophils with PTU and not exerted through a direct cytotoxic effect of the drug. It was not related to the kind of stimulators to evoke CL response in neutrophils either. However, the inhibitory effect disappeared when PTU was removed from the reaction mixture for CL response. PTU did not inhibit O-2 generation but markedly inhibited hydrogen peroxide production in neutrophils or activity of hydrogen peroxide in vitro. Morphologically, the unique change of cellular configuration of chemotactic neutrophils caused by N-formyl-methionyl-leucyl-phenylalanine (FMLP) was not influenced with PTU. Since hydrogen peroxide is mainly derived from O-2, these observations suggest that PTU may have a scavenger effect on hydrogen peroxide activity. Inhibition of CL response in neutrophils was also demonstrated with methimazole (MMI), thiouracil and thiourea, but not with imidazole and uracil, which suggests that their inhibitory effect on CL response in neutrophils may be closely related to the antithyroid activity.

Effects ofLithospermum officinaleand Related Plants on Hypophyseal and Thyroid Hormones in the Rat

AbstractThe antihormonal activity of Lithospermum officinale (Boraginaceae) and Lycopus virginicus and other Lamiaceae has been investigated in the rat. L. officinale cold water freeze dried extracts (FDE) significantly lowered thyroid hormone content in the serum whereas an inactivated extract exhibited a considerable loss of biological activity. The efficacy of different plant extracts greatly depended on the extraction procedure: extraction of powdered leaves with boiling water or ethanol yielded FDEs without thyroid hormone-lowering capacity. The chemical oxidation of a hot-water (100°C) extract by KMnO4 served to reintroduce the antihormonal effectiveness. In a goiter suppression test, the chronic administration of L. officinale FDE greatly suppressed TSH-levels and consequently goiter weight. The antithyrotropic and antithyroidal activity of a variety of plant extracts was accompanied by an additional prolactin diminution. Lithospermum officinale exhibited a strong antigonadotropic effectiveness and...

Preliminary Observations on the Effect of Dietary Brussels Sprouts on Thyroid Function

Brassica vegetables are the major source of glucosinolates in the human diet. Certain glucosinolates are readily converted into goitrogenic species, notably 5-vinyloxazolidine-2-thione and thiocyanate ion. The effect of dietary Brussels sprouts, a particularly rich source of such glucosinolates, on thyroid function has been examined. Inclusion of cooked Brussels sprouts (150 g daily for 4 weeks) into a normal diet of 10 volunteer subjects had no effect on thyroid function as determined by measurement of thyrotrophic hormone, thyroxine and tri-iodothyronine even though the sprouts contained high concentrations (220 mg/100 g) of glucosinolates. In view of the reported antithyroid activity of 5-vinyloxazolidine-2-thione it is suggested that this lack of activity of cooked Brussels sprouts is due to inactivation during cooking of myrosinase, the specific glucosinolate-degrading enzyme.

Secondary Antithyroid Action of Drugs in Relation to Structure

Molecular interactions between iodine and disulfiram, clomethiazole, and tolnaftate were investigated by electron spectroscopy. Iodine forms charge transfer complexes with these molecules, with 1:1 stoichiometry and of the n-σ type. The formation constants were compared with those obtained with antithyroid molecules. Only disulfiram appears to have any effect on the intrathyroid cycle of iodine.

Anti-thyroid activity of purified thymus gland extract in male wistar rats

The effect of a purified bovine thymus gland extract (Dr. Kurt Mulli, GmbH, Hamburg, West Germany) was studied in 12-week old male Wistar rats on the following: thyroid weights and morphology, T3-T4 serum levels, thyroid lactic dehydrogenase, ATP-ase, acid phosphatase, and non-specific esterase activities. Thymus extract was administered intramuscularly daily for 21 days at doses of 0.5, 1.0 and 2.0 ml/kg. Measurements were made on day 3, 7, 14 and 21 of treatment. Thyroid histology and enzyme activity were studied only on 21-day specimens. Thymus extract significantly decreased average thyroid gland weights in a dose-dependent manner irrespective of treatment duration. T3 serum levels were consistently lower in thymus-treated rats irrespective of treatment dose or duration. Changes from control levels were not statistically significant due to large standard deviations. T4 serum levels were significantly lower than control levels in rats treated with thymus extract for 14 and 21 days. Histology of thyroids from 21-day treated animals revealed a marked reduction in both thyroid follicle size and colloid content with an increase in connective tissue, resorption vacuoles and hyperemia. Histochemical study of thyroid enzyme activity showed lactic dehydrogenase increase in follicle epithelial cells, acid phosphatase increase in follicle epithelial cells and decrease in interstitium, ATP-ase increase in granular storage area and non-specific esterase increase in follicle epithelial cell. The data suggest the presence of an unidentified specific anti-thyroid factor(s) in the thymus gland extract.

Synergistic effect of bronchodilators with the antithyroid action of iodine

Synergistic effect of bronchodilators with the antithyroid action of iodine

In vitro measurement of antithyroid compounds and environmental goitrogens.

A specific, sensitive, and reproducible in vitro assay for antithyroid compounds and environmental goitrogens has been used to investigate antithyroid activity (AA) in small samples of water supplying 15 localities in endemic and nonendemic goiter areas of western Colombia. A significant positive correlation was observed between goiter prevalence and AA in water collected from the pipelines of these localities. Samples at the water source showed only borderline significance. No significant correlation was observed in waters between AA and total hardness (ppm) or concentrations of Ca, Mg, sulfates, chlorides, silicates, nitrates, and iodine. AA was also demonstrated by this in vitro assay in well water previously shown experimentally to be goitrogenic and that supplied the endemic goiter district of Candelaria town in western Colombia. In contrast, water from the well supplying the area of lower endemicity was found to possess little AA. These results provide experimental support for epidemiological observations that demonstrate a relationship between the sources of drinking water and goiter prevalence rates, and are consistent with previous findings indicating that organic antithyroid compounds contaminate water supplies in areas where goiter persists despite adequate iodine supplementation.

Anti-thyroid activity of purified thymus gland extract in male wistar rats

Anti-thyroid activity of purified thymus gland extract in male wistar rats

EFFECTS OF TRIMETHOPRIM AND SULPHONAMIDE PREPARATIONS ON THE PITUITARY–THYROID AXIS OF RODENTS

The effects on pituitary-thyroid function of the commonly prescribed anti-bacterial preparations co-trimoxazole and co-trifamole, and their component drugs, have been studied in the rat and compared to the changes caused by propylthiouracil. Co-trimoxazole and co-trifamole, in doses 20-fold in excess of a pharmacological dose administered for 10 days, produced marked changes in hormone levels consistent with blocking of hyperplastic goitre formation, were also demonstrated. Propylthiouracil produced less marked changes of thyroid hormone levels but higher levels of thyroid-stimulating hormone. Pharmacological doses of co-trimoxazole and co-trifamole and sulphamoxole, the sulphonamide component of co-trifamole, caused significant changes in thyroid hormone levels consistent with anti-thyroidal activity. In contrast, there was no evidence that trimethoprim, which is common to both preparations, or sulphamethoxazole, the sulphonamide component of co-trimoxazole, had an anti-thyroidal action, indeed, serum thyroxine levels were significantly increased at pharmacological dosage. We have concluded that the new commonly prescribed combination preparations retain the goitrogenic properties of the earlier sulphonamides.

Dithiobiuret toxicity in the rat: Evidence for latency and cumulative dose thresholds

Treatment of rats with 2,4-dithiobiuret (DTB) causes a delayed onset skeletal muscle weakness which was detected by a rotarod test. Daily doses of 0.125 mg/kg failed to cause muscle weakness after 52 days of treatment (cumulative dose = 6.5 mg/kg). However, daily doses of DTB ranging from 0.25 to 16 mg/kg caused muscle weakness, and the onset of this weakness was determined by either a latency threshold of 3–4 days or a cumulative dose threshold of 4–5 mg/kg. At daily doses greater than 1 mg/kg, the latency threshold determined the onset of toxicity; at daily doses of 0.25–1 mg/kg the cumulative dose threshold was the determining factor. The basis for these thresholds is not known. When DTB treatment was stopped after the first day of toxicity, rats treated with 0.25–1 mg/kg/day regained normal rotarod performance within 2–5 days. However, rats treated with 2 mg/kg/day or more, died between 0 and 2 days of stopping treatment. Distribution and elimination studies revealed that urine was the main route of elimination of DTB-derived 14C and that feces was a minor route. Inasmuch as only 70–75% of a daily dose was eliminated in the first 24 hr, when administered at the rate of 0.25, 0.5, and 1 mg/kg/day, DTB-derived 14C accumulated in rats maintained on these dosing regimens. On the second day of rotarod test failure, the body burden of DTB equivalents in the three dosage groups ranged from 0.7 to 1 mg/kg. The highest concentration of DTB-derived 14C was found in the thyroid gland. However, accumulation of DTB in the thyroid and its potential antithyroid action are probably not responsible for toxicity. The most important finding was the demonstration that latency and cumulative dose thresholds determine the onset of DTB intoxication. The cause of these thresholds, if determined, may ultimately lead to an understanding of the mechanism of the toxicity of DTB.

Thyroid-Blocking Activity of Chlorpropamide in a Diabetic Patient With Hyperthyroidism

To the Editor. —The oral hypoglycemic agents, the sulfonylurea compounds, are used by many physicians in the treatment of patients with insulinindependent diabetes mellitus. In addition to the well-known hypoglycemic actions of the sulfonylurea compounds, they also exert a less-recognized antithyroid activity similar to propylthiouracil. 1-3 This antithyroid activity of the sulfonylurea compounds is much weaker in comparison to propylthiouracil, and, in the usual therapeutic range, patients receiving sulfonylurea compounds do not manifest a hypothyroid state. 2,4 However, Hunton et al 5 have found a high incidence of hypothyroidism in their diabetic population receiving sulfonylurea compounds. Little is known about the antithyroid action of sulfonylurea compounds in diabetic patients with hyperthyroidism. Brown and Solomon 6 reported that carbutamide had no effect on thyroid function in two patients with hyperthyroidism. A patient with diabetes mellitus and hyperthyroidism had normal thyroid study results induced by chlorpropamide. Report of a Case.

Thionamides and analogues: A reapraisal of antithyroid and thyroid carcinogenic effects

As commonly depicted, in the thione form, thionamides (including thiourea and its derivatives) bear little resemblance to thyroid hormone. However, if placed in the thiol resonance form, these molecules are noted to structurally mimic the end of the tyrosine molecule (the precursor of thyroid hormone). Alternatively, tyrosine written in the -one configuration resembles the thionamides. This permits a better appreciation of why the thionamides may themselves be iodinated by thyroid peroxidase in some cases, and under other circumstances induce changes in the enzyme. The thiol resonant form can be written for naturally occurring goitrin, and for thiobarbituric acids with antithyroid activity. An hydroxyl resonant configuration can be drawn for the antithyroid compound 3-hydroxy-4-pyridone. Tetramethylthiourea is a thyroid carcinogen in rats. The compound can not be readily placed in the thiol resonant configuration; it also contains 2 methyl groups at both ends of the molecule. The hair dye 2,4-diaminoanisole sulfate induces thyroid neoplasms in rats. A similarity is pointed out both to tyrosine and to lower potency antithyroid aminobenzenes (described by Astwood and coworkers). Pyrazole, known to produce thyroid necrosis, is seen to have a distinct resemblance to the opposite end of several of these compounds.

Histological changes in the thyroid gland of the mouse following treatment with 1, 1, 3-tricyano-2-amino-1-propene.

1,1,3-tricyano-2-amino-1-propene (malononitrile dimer), administered intraperitoneally to mice, induced histological changes in the thyroid gland 6 h after drug administration. The histology of the thyroid gland is normal up to 16 h after drug treatment. Pathological conditions characteristic of hyperthyroidism are observed after 16 h of the drug treatment. By 48 h, the thyroid again appeared normal. The antithyroid action of the drug is attributed to the initial acute inhibition of the organic binding of iodine causing supression in the formation of thyroxine, which is later compensated.

Antithyroid and antiperoxidase activity of tropolone and 3-hydroxy-4-pyrone

Tropolone (TR) and 3-hydroxy-4-pyrone were investigated for antithyroid activity following the finding that the 2-hydroxy-oxo pyridine, 3-hydroxy-4(1H)-pyridone (DHP, I), is goitrogenic. Both compounds inhibited the thyroidal uptake of radioiodine in rats and resembled the thioamide drugs in inhibiting the organic binding of iodine by the thyroid gland rather than the trapping of iodide, but were weaker binding inhibitors than 6-methyl-2-thiouracil (MeTU). Both compounds also inhibited the iodination of bovine serum albumin and thyroglobulin, catalyzed by thyroidperoxidase (TPO), lactoperoxidase (LPO), chloroperoxidase (CPO) and horseradish peroxidase (HPO) in vitro. The inhibitory effect of TR but not that of 3-hydroxy-4-pyrone was antagonized by ferrous ions. When fed to mice at levels of intake expected to produce goitre both compounds were toxic and caused severe liver damage. Thyroid enlargement was not observed in any of these feeiding experiments, but the thyroids of mice fed 0.1% TR showed moderate hyperplasia. It was concluded that both compounds are weakly goitrogenic. Hyperactivity was observed in the mice fed TR which may be associated with inhibition of catechol methyl transferase (COMT).

Rapid conversion of carbimazole to methimazole in serum; evidence for an enzymatic mechanism.

Carbimazole (CBZ) is one of the major drugs currently used for the treatment of Graves' disease. It is a carbethoxy derivative of methimazole (MMI), originally developed in the hope of obtaining a longer acting drug than methimazole. In the present study we have demonstrated that carbimazole is rapidly converted to methimazole in vitro by serum from rats and humans, and we have obtained evidence that this conversion is enzymatic. Experiments with [35S] CBZ in rats showed that the drug is so rapidly transformed to MMI after i.v. injection (within 3 min) that very little of the unchanged drug would be expected to reach the thyroid gland. The antithyroid action of CBZ in rats, therefore, can be ascribed entirely to the MMI to which it is rapidly converted. Although no experiments were performed with human subjects in vivo, the very rapid conversion of CBZ to MMI by human serum in vitro suggests that the antithyroid action of CBZ in humans can also be attributed to MMI. The original expectation of a longer acting drug has, therefore, not been met by CBZ. On the basis of the studies reported here there appears to be no advantage in using CBZ in preference to MMI for the treatment of Graves' disease. Although the in vivo action of CBZ must be attributed to its rapid conversion to MMI, the drug does possess inherent antithyroid activity. This was shown in the present study by the finding that CBZ is as potent as MMI in blocking thyroid peroxidase-catalysed iodination of thyroglobulin.

SYNTHESIS OF 1,3-THIAZANE-2,4-DIONE AND 2-THIO-5,6-DIHYDROURACIL AND THEIR DERIVATIVES

Abstract 1,3-Thiazane-2,4-diones and 2-thio-5,6-dihydrouracils belong to biologically interesting groups of compounds. The 5-ethyl-6-phenyl derivative (Dolitrone) of the former has shown marked activity as an intravenous general anaesthetic. Several derivatives of 2-thio-5,6-dihydrouracil have been reported to possess antitubercular and antithyroid activity. In the present study these two groups of compounds have been synthesised from common starting materials, namely, different α,β-unsaturated acids and thiourea.

Goitrogenic principle from castor seeds

Ricinine, a principal alkaloid isolated from the castor-cake, has been studied for its antithyroid activity. Its effect on goiter production and thyroid hormonogenesis has been compared with the known goitrogen, propylthiouracil. The data presented herein reveal that ricinine is a potent goitrogen.

Coordination behaviour of antithyroid drugs against the Fe(I)(NO)2 group in solution: ESR and FT-NMR study.

The binding sites of some types of antithyroid drugs in the presence of the Fe(I)(NO)2 paramagnetic probe were investigated. Coordination behaviour in solution of different structured ligands was determined by means of ESR parameters and 13C FT-NMR spectra. Selective isotopic substitution with 15NO combined with computer simultation was used to elucidate overlapping ESR patterns. A correlation between chemical structure and antithyroid activity of the pharmacological bases is suggested.