Showing papers on "Propylthiouracil published in 1972"

Propylthiouracil inhibits the conversion of L-thyroxine to L-triiodothyronine. An explanation of the antithyroxine effect of propylthiouracil and evidence supporting the concept that triiodothyronine is the active thyroid hormone.

Abstract: 6-n-propylthiouracil (PTU) administered to male Sprague-Dawley rats maintained on 2 and 5 mug L-thyroxine (T(4))/100 g body weight resulted in a marked reduction in the rate of conversion of L-thyroxine to L-triiodothyronine (T(3)). These effects could not be ascribed to induced hypothyroidism since the group maintained on 5 mug T(4)/day had normal levels of liver mitochondrial alpha glycerophosphate dehydrogenase. In confirmation of previous studies, PTU also reduced the fractional rate of deiodination of T(3). These observations provide a possible explanation of the many published observations indicating that PTU antagonizes the tissue effects of T(4) but not of T(3). The data suggest that monodeiodination of T(4) but not of T(3) is essential before hormonal effects can be manifested at the cellular level.

Studies of a sibship with apparent hereditary resistance to the intracellular action of thyroid hormone.

Abstract: Further studies are presented on a previously described sibship 1 with a familial syndrome combining deaf mutism, delayed bone maturition, stippled epiphyses, goiter, and high levels of circulating thyroid hormone in the presence of euthyroid clinical state. Seventy-five to 90% of the circulating iodinated compounds were L-thyroxine and L-triiodothyronine by chromatography, ability to bind to thyroxine-binding globulin, L-amino acid oxidase digestion, and precipitation to constant specific activity. The usual basic laboratory tests were normal, and there was no direct evidence of endocrine disease other than that of the thyroid. Although all standard tests of thyroid function, with the exception of the basal metabolic rate (BMR), were typically those of hyperthyroidism, the patients appeared clinically euthyroid. This diagnosis is supported by the normal BMR, serum lipids, cholesterol, tyrosine, enzymes and albumin metabolism, and by normal caloric intake, dentition, and steady growth. Certain tissues appeared to be resistant to thyroid hormone action. We observed delayed bone age, epiphyseal stippling, and low hydroxyproline excretion. Sensorineural deafness, congenital nystagmus, elevated serum carotene, and possibly metachromasia in the cultured skin fibroblasts were also suggestive of hypothyroidism. Endogenous pituitary thyrotropin secretion was not completely suppresed by the high, blood hormone level. Administration of 1 mg/day L-T 4 or 375 μg/day L-T 3 produced some effect on connective tissues. Thyroid gland activity was only partially suppressed with such treatment. Administration of the acetic acid analogue of triiodothyronine had no effect other than thyroid gland suppression, attributed to the liberation of large amounts of iodine. β-Adrenergic blockage and 45 days of propylthiouracil therapy also failed to produce detectable effects. Labeled thyroxine and triiodothyronine studies indicate that these hormones penetrate the liver and other tissues normally or even at an excess rate and are degrated three- to five fold more rapidly than normal. Progressive amelioration of the syndrome has been noted over the past 6–7 yr. The etiology of this syndrome remains unclear. It appears to date to be a congenital. inherited metabolic and possibly transient defect associated with variable degrees of intracellular resistance to the action of thyroid hormone, which has been partially compensated by excess hormone production.

Influence of Thyroid Hormones on Enzyme Activities of Myelinating Rat Central‐Nervous Tissues

Abstract: The effects of triiodothyronine administration and of hypothyroidism on the rapidly developing enzymes UDP galactose: sphingosine galactosyltransferase and 2′:3′-nucleotide 3′-phosphohydrolase associated with central nervous system myelination were investigated. The activity of these enzymes in the spinal cords of young rats injected daily with triiodothyronine up to sacrifice on day 5 was significantly increased over control animals. In normal animals, circulating plasma thyroxine increased gradually from the second postnatal day to a maximum value at days 15–17. Rats, born of mothers treated with n-propylthiouracil from the thirteenth day of pregnancy, did not exhibit the increase in plasma thyroxine. Determination of the specific activity of these enzymes in central nervous tissue of such hypothyroid rats at day 12 showed a significant reduction compared with normal animals. Intraperitoneal injection of the hypothyroid rats with triiodothyronine on day 8 resulted in a partial restoration of the activity of the enzymes in brain and of 2′:3′-nucleotide 3′-phosphohydrolase in spinal cord when assayed on day 12. Restoration of UDPgalactose: sphingosine galactosyltransferase activity did not occur in the spinal cord of such animals. However, when hypothyroid rats were injected with triiodothyronine on days 1, 4, and 7, the psychosine-synthesising activity in their spinal cords on day 8 was restored to that of normal animals. This suggests that there is a critical period during the first 8 days of postnatal life when thyroid hormone levels must be adequate in order that spinal cord activity of this enzyme develops normally. It is concluded that the flux in circulating thyroid hormone is a factor in the normal development of these enzymes.

The acclumulation of 35 S-antithyroid drugs by the thyroid gland.

Abstract: Accumulation of 35S-radioactivity by the thyroid gland was found after administration of equimolar doses of 35S-labelled thiouracil, methylthiouracil, propyl thiouracil, methimazole and carbimazole to rats. Thin-layer chromatography showed an accumulation of the parent drug in the case of methimazole, propylthiouracil, methylthiouracil and thiouracil. When carbimazole was given, an accumulation of methimazole was demonstrated in the thyroid. Propylthiouracil administration produced the largest amount of drug in the thyroid and thiouracil the least. In man both 35S-radioactivity and the parent drug accumulated in the normal thyroid after administration of methimazole and propylthiouracil. When carbimazole was given, methimazole accumulated in the thyroid. In six thyroid tumors little or no accumulation of the antithyroid drug was found.

Alterations in circulating estradiol-17 in male patients with Graves's disease.

Abstract: Serum concentrations of estradiol-17β (E2), gonadotropins and long acting thyroid stimulator were studied in 10 consecutive male patients with active Graves's disease. Serum E2 was elevated in all patients before therapy. In two men with gynecomastia the concentrations were as high as those observed in normal women. The per cent dialyzable E2 was significantly reduced in hyperthyroid males as compared to normal males and was similar to that seen in eugonadal women; but the absolute concentration of unbound E2, evaluated in one prepubertal and five adult patients without gynecomastia, was elevated in four of the five adults. The mean serum concentrations of luteinizing and follicle-stimulating hormones were also higher in the hyperthyroid men than in normal men. Serum E2 fell gradually and consistently during effective treatment of hyperthyroidism with propylthiouracil. Neither the occurrence of gynecomastia nor the serum concentration of E2 correlated with serum concentration of long acting thyro...

Thyrotropin Secretion in Genetically Obese Rats

Abstract: The hypothalamic-pituitary-thyroid axis has been studied in genetically obese rats, in lean littermates and littermates which became obese following hypothalamic injury (lesioned). After exposure to cold (3°C), the half-life for thyroid radioactivity in the genetically obese rats decreased from 4.73 d to 2.44 d; the plasma FFA showed no elevation and body temperature fell significantly. Lean littermates had a decrease in thyroidal half-life from 1.73 d to 0.92 d, showed the expected rise in FFA but had no fall in body temperature. Lesioned rats had no change in release of thyroid iodine but increased their FFA, and showed no significant change in body temperature. In rats maintained at 18°C the weight of the pituitary was significantly reduced in the genetic obese rats, but the concentration of thyrotropin (TSH) was similar in lean and genetically obese rats. Plasma TSH in fatties rose slightly after feeding a diet supplemented with propylthiouracil. Plasma TSH did not rise when genetic obese rats were fe...

Propylthiouracil: absorption, metabolism and excretion in the albino rat

Abstract: 6- n -Propyl-2-thiouracil-6-14C was administered to Sprague-Dawley rats of either sex i.v., i.p. or p.o. at a dose of 20 mg/kg. Sustained plasma levels of radioactivity resulted after i.p. and p.o. doses. Equilibrium dialysis indicated that 57% of the drug in the plasma was protein bound. The drug had no particular affinity for any tissue. Propylthiouracil was found to have low aqueous solubility and chloroform/water partition coefficients. Between 75 and 90% of the administered radioactivity was excreted in the urine and approximately 15% appeared in the bile. Since negligible radioactivity appeared in the feces, the drug was completely absorbed and an enterohepatic circulation was present. The half-life of urinary excretion of radioactivity was four to six hours regardless of the route of administration. Only 9 to 15% of the administered dose was excreted as unchanged drug in the 24-hour urine. The major urinary metabolite was propylthiouracil glucuronide, which accounted for 40 to 48% of the administered dose in 24-hour urine samples. The other urinary metabolite, which accounted for 10 to 16% of the administered dose in 24 hours, has not yet been completely characterized. The major biliary metabolite was determined to be a glucuronide conjugate of propylthiouracil but different from the major urinary metabolite.

TSH-Induced Release of 5-Hydroxytryptamine and Histamine from Rat Thyroid Mast Cells

Abstract: The effect of TSH on rat thyroid mast cells was investigated by a combination of chemical, histochemical, electron microscopical, and bio-assay procedures. In T4-pretreated rats, a single iv injection of TSH reduced the concentration of 5-hydroxytryptamine (5-HT) and histamine in thyroid mast cells, whereas mast cells outside the thyroid seemed unaffected. In rats kept on propylthiouracil and iodine-poor diet for 4 weeks, plasma TSH levels were raised ten-fold. At the same time, follicle cells and mast cells in the thyroid increased in number, but the concentration of S-HT and histamine in individual thyroid mast cells was reduced. Ultrastructurally, there were no overt signs of mast cell degranulation, whether upon short-term or long-term TSH stimulation. It is concluded that, in the rat, TSH induces a release of 5-HT and histamine from intrathyroidal mast cells, which seems to occur without any concomitant degranulation. This release may be involved in the process of thyroid hormone secretion. (Endocrin...

Decreased post-heparin lipases in Graves's disease.

Abstract: The plasma post-heparin lipolytic activity (PHLA) and post-heparin monoglyceridase activity (PHMA) were determined in patients with Graves's disease and treated toxic nodular goiter. Both enzymes were markedly reduced in patients with active Graves's disease. Fasting serum triglycerides were normal or slightly below normal despite low post-heparin lipases. In these patients, restudied after propranolol therapy or within six months of euthyroid control with 131l, propylthiouracil or methimazole, PHLA and PHMA remained below normal. A separate group of patients with treated Graves's disease, who were euthyroid for as long as six years, also had low post-heparin lipases. Enzyme activity did not correlate with the presence of the long acting thyroid stimulator. In contrast, patients with treated toxic nodular goiter had normal PHLA and PHMA. Control subjects made hypermetabolic with tri-iodothyronine or thyroxine had normal post-heparin enzyme activities. Persistently low PHLA and PHMA may be a marke...

Lack of positive correlation between adenyl cyclase activity and iodide transport in rat thyroids.

Abstract: Adenyl cyclase activity was determined in 9000 X g pellets of thyroid homogenates from a) intact rats that received no medication vs propylthiouracil (PTU) treatment for 20 days; b) untreated hypophysectomized rats vs similar rats injected with TSH (1 U) and PTU (20 mg) daily for 3 days, and c) hypophysectomized rats which were given no TSH or a single dose (1 U) of the hormone. In experiment c), thyroids for enzyme assay were removed 10 or 30–45 min after the injection of TSH. Thyroidal iodide transport was measured by the thyroid—serum radioiodide concentration (T/S) ratio, which averaged 69 vs 219 in the intact and PTU—treated rats, 5.2 vs 185 in untreated hypophysectomized rats and those injected with TSH+ PTU, and 4.4 vs 81 and 5.2 vs 78, respectively, in 2 groups of hypophysectomized rats and similar rats treated with TSH 24 hr before they were killed. In spite of the stimulation of the thyroid by endogenous or exogenous TSH reflected by these marked rises in the T/S ratios, adenyl cyclase activity ...

Ototoxic Reaction to Propylthiouracil

Abstract: A case of ototoxic reaction to propylthiouracil occurred in a patient with thyrotoxocosis. The patient developed both symptoms of systemic lupus erythematosus and a unilateral, sensorineural hearing impairment. The hearing loss was diagnosed as cochlear, although certain retrocochlear symptoms were evident. Termination of drug therapy led to recovery from both physical symptoms and the auditory impairment. Careful management of patients receiving propylthiouracil and further research are indicated.

An explanation of the antithyroxine effect of propylthiouracil and evidence supporting the concept that triiodothyronine is the active thyroid hormone

Abstract: A B S T R A C T 6-n-propylthiouracil (PTU) administered to male Sprague-Dawley rats maintained on 2 and 5 Ag L-thyroxine (T4)/100 g body weight resulted in a marked reduction in the rate of conversion of L-thyroxine to L-triiodothyronine (Ts). These effects could not be ascribed to induced hypothyroidism since the group maintained on 5 *g T4/day had normal levels of liver mitochondrial alpha glycerophosphate dehydrogenase. In confirmation of previous studies, PTU also reduced the fractional rate of deiodination of T&. These observations provide a possible explanation of the many published observations indicating that PTU antagonizes the tissue effects of T4 but not of T3. The data suggest that monodeiodination of To but not of T8 is essential before hormonal effects can be manifested at the cellular level.

Possible importance of thyroidal iodine compartments in the adaptation of thyroid hormone secretion to antithyroid drugs.

Abstract: Rats with either normal thyroid glands, hyperplastic goiters or colloid goiters were given 125I in the drinking water for 28 days. A single injection of 131I was then given and 4 hr later further hormone biosynthesis was blocked with propylthiouracil. During the following seven days the various isotopes of protein-bound iodine (PBI) in serum were measured. In rats with normal glands, the 131I-PBI derived from the young label declined rapidly while the 127I-PBI stayed nearly constant. The 125I-PBI (old label) declined at an intermediate rate. In hyperplastic goiters the 131I-PBI and the 125I-PBI declined at the same rate and only slightly faster than the 127I-PBI. In colloid goiters the 127I-PBI and the 125I-PBI declined very little and at an identical slow rate, while the 131I-PBI concentration dropped nearly at the same fast rate as in normal glands and in hyperplastic goiters. The data suggest that the two labels are distributed in different compartments of intrathyroidal hormone. The young label (131I)...

Hypotriglyceridemic activity of 5,5'-diphenyl-2-thiohydantoin (DPTH).

Abstract: DPTH is a lipophilic compound which has similar pharmacological properties to 5,59-diphenylhydantoin. Oral administration of DPTH to rats caused a 60 to 80% decrease in serum triglyceride concentration. Dose-response characteristics for lipid lowering over the range 0.5 to 200 mg/kg/day were determined after a two- and a nine-day dosage regimen. The dose-related decrease in serum triglyceride was accompanied by a dose-related increase in liver and thyroid weight and liver total lipid and phospholipid content. A hypotriglyceridemic effect was not seen with equivalent doses of 5,59-diphenylhydantoin or with the antithyroid substances, thiouracil, propylthiouracil, methylthiouracil and methimazole. In contrast to know antihyperlipidemic agents, DPTH had little lowering effect on serum cholesterol or phospholipid levels and at the higher doses studied DPTH had an elevating effect on serum cholesterol and phospholipid concentration. All the observed drug-induced effects were readily reversible upon withdrawal of the drug. It is suggested that DPTH lowers serum triglycerides by a mechanism unrelated to its antithyroid properties and differing from that of known antihyperlipidemic agents.

Sympathetic Blockade in Hyperthyroidism: Preoperative Management Following Toxic Reaction to Antithyroid Drugs

Abstract: The antithyroid drugs propylthiouracil and methimazole are commonly used in the treatment of hyperthyroidism. The incidence of overall toxic drug reactions to these antithyroid drugs have been reported to vary from 6% to 9% 1-3 ; however, the incidence of serious side effects, including agranulocytosis, is approximately 0.3% to 0.6% in a large series. 4 Subsequent management of the hyperthyroidism in those patients who develop drug toxic reaction becomes a problem, especially in the younger age group where alternative forms of treatment are limited. During the past few years sympathetic blocking drugs, including guanethidine sulfate 5 and propranolol hydrochloride, 6-9 have been advocated as ancillary agents in the treatment of hyperthyroidism. The use of propranolol as a means of preparing hyperthyroid patients for thyroidectomy has also been suggested. 10 This report details the course of three hyperthyroid patients who developed toxic reactions to antithyroid drugs and in whom thyroidectomy was successfully

Effects of Methimazole and Propylthiouracil on Blood Disappearance and Urinary Excretion of Iodide in the Rat

Abstract: SummaryRegardless of the dose of MT administered, MT decreased the rate of disappearance of radioiodide from the blood for at least 25 hr by depressing urinary excretion of iodide in thyroidectomized, thyroxine-maintained rats fed LID. This effect of MT was lessened in rats fed HID. In contrast, PTU augmented disappearance of blood iodide during the first 60 min after radioiodine injection. This effect was apparently related to the dose of PTU administered. It is concluded that MT and PTU have different mode of action on extrathyroidal iodine metabolism in the rat.

Importance of diet for reaction of bile acid pattern to altered thyroid function.

Abstract: Hamsters were fed with commercial chow and with a gallstone inducing diet. These two basic diets were given both unsupplemented and with supplements of I-thyroxine and propylthiouracil respectively. No significant differences in the total biliary bile acid concentration were observed between the different groups. In the groups fed chow the administration of thyroxine induced a decrease of the cholic acid/chenodeoxycholic acid ratio. With propylthiouracil this ratio was slightly higher than in controls. In the groups fed the gallstone inducing diet an opposite effect was observed: a shift towards cholic acid in the hyperthyroid animals and a shift towards chenodeoxycholic acid in those fed with propylthiouracil. The diet may be a factor of importance in explaining the differences in the reaction of the bile acid pattern to altered thyroid function which have been observed between man and the experimental animal.

Light- and electron microscopic investigations on the median eminence of the pigeon after TSH and PTU treatment.

Abstract: 1. The effects of TSH and PTU treatment with thyroid stimulating hormone and propylthiouracil on the structure of median eminence of the pigeon have been studied by light- and electron microscopy.