Antithyroid Activity Research Articles

Comparison of the effects of thiouracil, propylthiouracil, and methimazole on I 131 metabolism by the chick thyroid and measurements of thyroxine secretion rates

The effects of thiouracil, propylthiouracil, and methimazole (1-methyl-2-mercapto-imidazole) on I 131 metabolism in the chick thyroid and thyroxine secretion rates were studied. Thiouracil, propylthiouracil, and methimazole, when fed to 5-week-old cockerels at a 0.1% level in the diet, decreased thyroidal I 131 uptake to 62, 21, and 13% of that of a normally fed group, respectively. The feeding of thiouracil, propylthiouracil, and methimazole at a 0.1% level in the diet increased the release rate of thyroidal I 131 to 2.4, 3.4, and 4.1 times, respectively, that in the chick fed a normal diet. In addition, similar values about 1.5 μg/100 gm body weight per day were obtained in the estimation of the thyroxine secretion rate of 5–6-week-old cockerels both by the goiter prevention assay and by the radioiodine assay with thiouracil, propylthiouracil or methimazole as the goitrogen. The results of both assays revealed that the employed doses of the goitrogens had little effect on thyroxine secretion rates in 6–7-week-old cockerels. Thiouracil feeding at a 0.1% level in diet of 9-week-old cockerels, which had fecal fistulas for the separate collection of the urine and feces, increased (20–30%) fecal excretion and decreased (by 10%) the deiodination of radiothyroxine, compared with the nongoitrogen-treated birds. The feeding of methimazole had no such effects. The feeding of potassium perchlorate to the 13-week-old cockerels having fecal fistulas, at a 1% level in diet, severely inhibited the thyroidal uptake of I 131 recycled from metabolized radiothyroxine, but it did not increase fecal excretion of radiothyroxine. The administration of propylthiouracil to these birds increased fecal excretion by 30%, and it decreased the deiodination of radiothyroxine by 15%; methimazole had no effect. Thus, although methimazole has a stronger antithyroidal activity than thiouracil, it does not increase the fecal excretion of thyroxine as thiouracil does in the chick. The rate of thyroxine secretion is not affected by the different goitrogens.

PROPYLTHIOURACIL IN ACUTE HEMORRHAGIC PANCREATITIS.

The mortality rate in acute hemorrhagic pancreatitis remains high despite all therapeutic measures and much experimental work. Theoretically it would seem that any measure tending to suppress the activity of the pancreas would aid in the management of this disease. Reid and Kossa8have shown that thiourea and its analogues owe their antithyroid action, in part at least, to their antioxidant property in all organs and tissues. As a consequence, there is a decrease in the amount of energy released, less product formed, and the organ placed at rest. Propylthiouracil appears to be the most active in lowering the metabolic activity in the various organs, and particularly in the pancreas. In a preliminary report, we11have shown that propylthiouracil given both preoperatively and also after the onset of pancreatitis, is effective in lowering mortality rate by slowing pancreatic activity. In an analogous study, using hypothermia to suppress pancreatic

EFFECT OF AMPHENONE B ON DEVELOPMENT OF RENAL HYPERTENSION IN RATS

The effect of Amphenone B on development of renal hypertension was studied in rats whose kidneys were encapsulated with latex envelopes. The compound was administered in the diet for 13 weeks at dose levels of 0.1 and 0.3% by weight. Both dose levels of Amphenone B were equally effective in preventing rise of systolic blood pressure to the level of untreated, renal-encapsulated controls although both doses of the drug allowed modest rises of pressure to occur. Growth was inhibited by the drug. Amphenone B depressed thyroid activity as assessed by increased release rate of radioactive iodide from the thyroid gland; decreased resting metabolic rate; decreased growth; decreased food intake; and increased thyroid size. The protection against development of hypertension afforded by this compound may be related, at least in part, to its antithyroid activity.

EFFECT OF AMPHENONE B ON DEVELOPMENT OF RENAL HYPERTENSION IN RATS

The effect of Amphenone B on development of renal hypertension was studied in rats whose kidneys were encapsulated with latex envelopes. The compound was administered in the diet for 13 weeks at dose levels of 0.1 and 0.3% by weight. Both dose levels of Amphenone B were equally effective in preventing rise of systolic blood pressure to the level of untreated, renal-encapsulated controls although both doses of the drug allowed modest rises of pressure to occur. Growth was inhibited by the drug. Amphenone B depressed thyroid activity as assessed by increased release rate of radioactive iodide from the thyroid gland; decreased resting metabolic rate; decreased growth; decreased food intake; and increased thyroid size. The protection against development of hypertension afforded by this compound may be related, at least in part, to its antithyroid activity.

Studies on Endemic Goitre III an Investigation of the Antithyroid Aotivities of Isothiocyanates and Derivatives With Observations on Fractions of Milk From Goitrous Areas

Certain isothiocyanates and thioureas, in particular 3-methylsulphonylpropyl isothiocyanate (cheirolin) and dicheirolin thiourea, were tested for their antithyroid activity by an acute 1311 test and by chronic administration to rats. Cheirolin proved more active in the acute test than n-propyl isothiocyanate, but dicheirolin thiourea, the major product resulting from the incubation of cheirolin with rumen liquor, was without activity, whereas di-n-propylthiourea had a marked effect. Dicheirolin thiourea was also inactive when tested in the human. The response to cheirolin when chronically administered, either as such or in the form of its thioglucoside present in turnip weed fruit, appeared to be less than in the acute test. Its possible mode of action is discussed.

Antithyroid activity of a tranquilizer.

IN recent years a new class of drugs, the tranquilizers, has been introduced into clinical medicine, and these have become popular in the handling of many difficult clinical problems. The use of these drugs has been accompanied by the appearance of a variety of toxic reactions, often allergic, similar to those seen with other drugs. The purpose of the present paper is to report the antithyroid activity of one tranquilizer, amphenidone, and to point out that such well defined pharmacologic effects may escape detection by the usual methods of investigating the toxicity of new drugs.During the past several years . . .

Comparison of the Effects of Propylthiouracil and Sulfadiazine on Thyroidal Biosynthesis and the Manner in Which They Are Influenced by Supplemental Iodide1

Sulfadiazine (SD) and propylthiouracil (PTU) were administered to rats parenterally or in the diet for varying periods of time and over a wide dosage range. The effects of these drugs on thyroid weight and biosynthetic processes were compared. Both were qualitatively similar in their antithyroid activity. Coupling of iodinated tyrosines to form iodothyronines was most readily inhibited, then iodination of monoiodotyrosine, while iodination of tyrosine was much more resistant to inhibition. Supplementary iodide decreased the goiter produced by PTU but not that produced by SD. Iodide did not alter the effect of PTU on thyroidal biosynthesis but increased that of SD at least 1,000-fold. A marked potentiation of the inhibitory effect of SD was produced by as little as 10 ng KI daily, while a complete inhibition of all organic binding of iodine was produced with SD plus 100 jug KI daily. Iodide maximally potentiated the inhibitory effect of SD within 24 hours. No definite inhibition of thyroidal biosynthesis w...

Effect of antithyroid compounds on the deiodination of thyroxine in the rat.

Sixty compounds were tested for their capacity to inhibit the deiodination of thyroxine. Most of these compounds had antithyroid activity and others were structurally related. Estradiol, testosterone, cortisone and salicylate were tested because of their possible importance in deiodination. Sixteen compounds were found to inhibit the deiodination of thyroxine, and 5-n-propyl-2- thiouracil was the most effective of all. Sodium salicylate increased the deiodination of thyroxine. The effectiveness in inhibiting deiodination of thyroxine did not correlate with antithyroid activity.

Antithyroid activity of some 1-alkyl imidazolidine 2-thiones.

Es wurden an Ratten einige 1-Alkyl-imidazolidin-2-thione auf ihre thyreostatische Wirkung gepruft. Das 1-Athyl und das 1-Isopropylderivat sind in ihrer Wirkung mit Neomercazol vergleichbar.

The antithyroid activity of the anticoagulant phenylindanedione.

SUMMARY 1. The anticoagulant drug phenylindanedione (PID) reduced the uptake of 131I by the rat thyroid as effectively as propylthiouracil (PTU) in a dosage of 0·3 m-mole/kg body weight. The effect of PID lasted for a shorter time, and at smaller doses PTU was much more effective than PID. 2. Chromatography of digested thyroid tissue showed that PID exerts its antithyroid action by blocking the organic binding of iodine. 3. Vitamin K1 did not overcome the antithyroid action of PID. Among other anticoagulants and chemically related compounds tested only phthiocol was found to have an antithyroid effect. 4. In five out of seven patients receiving PID the 48 hr thyroid 131I uptake was at or below the lower limit of the normal range. Three of these patients were retested after stopping PID, in each case the thyroid uptake was markedly increased. 5. The chemical grouping was noted to be common to phthiocol, PID, and various other antithyroid compounds. The anticoagulant action of PID has also been attributed to this configuration, and the suggestion is made that this is the active grouping in the antithyroid action of PID and phthiocol, and that a vitamin K-like substance may be concerned in thyroxine as well as prothrombin synthesis.

The action of 1,1,3-tricyano-2-amino-1-propene (U-9189) on the thyroid gland of the rat and its effects in human thyrotoxicosis.

Studies of the antithyroid action of 1,1,3-tricyano-2-amino-1-propene (U-9189) were performed. In rats, this agent induces acute inhibition of the organic binding of iodine, suppresses the formation of thyroxine, and inhibits the conversion of monoiodotyrosine to diiodotyrosine. Following prolonged administration, these actions are supplemented by inhibition of the thyroidal iodide-concentrating mechanism. The antithyroid actions of U-9189 apparently also obtain in man, since this agent is capable of ameliorating human thyrotoxicosis. However, a high incidence of toxic reactions was observed in a small number of patients so treated.

Comparison of the effects of various goitrogens on the biosynthesis of thyroid hormones in vitro.

ABSTRACT The effect of various goitrogens on in vitro biosynthesis of thyroid horhomes was studied. The compounds in decreasing order of relative activity to completely inhibit DIT formation were 1-methyl-2-mercaptoimidazole (MIA), thiouracil (TU); propylthiouracil PTU) and goitrin; thiourea and methylthiouracil (MTU). Those in decreasing order of relative activity to completely inhibit MIT formation were MIA; PTU, MTU, TU and thiourea; goitrin. Of the compounds tested MIA was thus the most potent inhibitor of the rat thyroid gland in vitro. The conversion of monoiodotyrosine to diiodotyrosine was more sensitive to every goitrogen than the iodination of tyrosine to form monoiodotyrosine. The modes of action of these antithyroid drugs seemed to be approximately the same, except for goitrin, which showed very weak inhibition of MIT formation. Progoitrin, the precursor of goitrin, did not seem to possess any antithyroid activity.

Hydriodic acid-induced myxedema followed by recovery and thyroidal failure.

Despite widespread use of potassium iodide and syrup of hydriodic acid in pulmonary disease, goiter and myxedema are rare and only recently described complications of iodide therapy. The possibility exists that when hypothyroidism and goiter do develop during treatment with iodide-containing medicine, some preexisting defect in thyroidal metabolism may result in marked sensitivity to an antithyroid action of iodide. In an attempt to demonstrate such an abnormality, several techniques have been applied to the study of a patient who developed flagrant myxedema during prolonged ingestion of syrup of hydriodic acid. Report of a Case A 67-year-old white widow was admitted to the hospital because of lethargy, intolerance to cold, and hoarseness. One year prior to admission she developed a chronic cough for which she was given syrup of hydriodic acid. Although her cough subsided, she continued to take 6 teaspoonfuls of the syrup daily (420 mg. of hydriodic acid) until

DER EINFLUSS VON ANORGANISCHEM JOD UND VON RONTGENKONTRASTMITTELN AUF DIE ANTITHYREOIDALE WIRKUNG VON KALIUMPERCHLORAT

1) Administration of iodine containing X-ray contrast material (Urografin, Biligrafin) to perchlorate-treated rats is followed by changes in the thyroid gland that could correspond to the inhibition of the action of perchlorate by liberated iodine. 2) Potassium iodide completely inhibits the antithyroid action of perchlorate, in a ratio of 1/1 – 1/1000 (iodide/perchlorate). A preoperative plummer treatment of patients who would be given perchlorate is contraindicated, as well as the combined therapy of perchlorate and iodide in order to prevent enlargement of the thyroid gland.

ANTI-THYROID ACTIVITY OF 2-MERCAPTOPYRAZINE

ANTI-THYROID ACTIVITY OF 2-MERCAPTOPYRAZINE

ANTI-THYROID ACTIVITY OF PYRIDAZ-3-THIONE

ANTI-THYROID ACTIVITY OF PYRIDAZ-3-THIONE

Anti-Thyroid Action of β-Aminoethylisothiouronium Dibromide in Rats

DURING the development of a screening test for goitrogenic activity of drugs, β-aminoethylisothiouronium dibromide, a radiation protective agent1, was observed to have anti-thyroid activity. In view of possible long-term administration of this substance for prophylactic protection against irradiation, we are reporting our findings.

A mechanism of action for antithyroid activity or reserpine.

Summary1) Endogenous dehydrogenase enzyme activity of the thyroid was quantitated employing the tetrazolium technic. Reserpine and thyroxin significantly lowered enzyme activity, whereas thyrotropin and thiouracil significantly raised it. Thyrotropin, either exogenous or endogenous in origin, prevented reduction of enzyme activity achieved by administration of reserpine alone. 2) The suggestion that these effects are a reflection of thyrotropin activity upon the thyroid is discussed. It is proposed that reserpine does have an antithyroid action and that this action is the result of its effect upon the elaboration or release of thyrotropin by the pituitary.

Antithyroid activity of thiohydantoins.

The antithyroid activity of 2-thiohydantoin and some derivatives has been measured in rats, after a single dose and, also, after daily administration for 6 weeks. 2-Thiohydantoin and its 5-alkyl derivatives from 5-methyl to 5-sec-butyl- showed considerable antithyroid activity at a dose of 0.05 m.mole/kg. by mouth, but 5-n-hexyl-2-thiohydantoin had insignificant activity at this dose level. The presence of polar groups in the 5-substituent was associated with reduction or complete loss of activity. By the single-dose technique, 2-thiohydantoin was more potent than its 5-alkyl derivatives. The opposite result was obtained by other methods of assessment after 42 days of treatment. Some of the possible factors involved are discussed especially in relation to the difficulty of comparing results obtained by the different methods of assessment. The acute toxicity of 2-thiohydantoin and of its 5-methyl and 5-ethyl derivatives is reported. No toxic effects were found after daily administration of several 2-thiohydantoins at a dose of 50 mg./kg. for 6 weeks.

Effect of thiouracil on serum and liver cholesterol of the athyreotic rat.

Thiouracil (0.5%) was added to the diet of athyreotic rats for a 2-week period and serum and liver cholesterol concentrations compared to those of athyreotic controls. Thiouracil administration resulted in an increase in mean serum cholesterol and a decrease in mean liver cholesterol. Hepatic synthesis of cholesterol from C14 acetate was not significantly influenced by thiouracil. It is concluded that thiouracil, by altering the plasma-liver partition of cholesterol, exerts a hypercholesterolemic effect which is independent of its antithyroid action.