Showing papers on "Propylthiouracil published in 1981"
TL;DR: Low doses of PTU, 300 mg or less daily, are thought to afford satisfactory control of maternal hyperthyroidism and are not believed to cause clinically evident thyroid dysfunction in the neonate.
Abstract: PROPYLTHIOURACIL (PTU) is a mainstay of medical treatment for hyperthyroidism during pregnancy.1 2 3 4 PTU inhibits thyroid-hormone synthesis, extrathyroidal conversion of thyroxine (T4) to 3,5,3′-triiodothyronine (T3), and deiodinative degradation of the hormonally inactive T4 metabolite 3,3′,5′-triiodothyronine (reverse T3 or rT3).5 6 7 8 PTU crosses the placenta, 4 and at high doses it may cause fetal goiter9 , 10 and hypothyroidism.3 Low doses of PTU, 300 mg or less daily, are thought to afford satisfactory control of maternal hyperthyroidism and are not believed to cause clinically evident thyroid dysfunction in the neonate.1 2 3 4 , 11 Neonatal goiters occur with maternal doses of 100 . . .
142 citations
TL;DR: The data indicate multihormonal regulation of EGF and protease in the mouse submandibular glands, although to a lesser degree than in intact animals.
Abstract: The structure of the granular convoluted tubules of the mouse submandibular gland is influenced by androgens, adrenal steroids, and thyroid hormones. We wished to investigate the effects of variations in hormonal status on the quantitative and qualitative distribution of two secretory products of these tubules, epidermal growth factor (EGF) and protease. The effects of the thyroid and adrenal glands on EGF content and protease activity of the submandibular glands of adult female mice were studied by RIAs (EGF), enzyme assays (protease), and immunocytochemical methods. In animals rendered chronically hypothyroid by propylthiouracil (4 months) or in animals which were adrenalectomized and ovariectomized (3 weeks), protease activity and EGF levels were reduced by 81–97%. The administration of testosterone induced these polypeptides even in hypothyroid animals. Daily administration of L-T4 (T4; 1 μg/ g BW) for 7 days increased EGF and protease activity 3.6-fold in intact mice and reversed the effect of hypoth...
84 citations
TL;DR: The choice between the antithyroid drugs is based more upon personal preference and experience than on strict pharmacological principles, as no important differences exist between these drugs with regard to the rate of remission or frequency of occurrence of serious adverse reactions.
Abstract: Organic antithyroid drugs used today include propylthiouracil and the mercaptoimidazolines, carbimazole and methimazole. They can be measured with accuracy and in small quantities in serum by gas-liquid chromatography, high performance liquid chromatography and radio-immunoassay. Bioavailability of these drugs varies from 80 to 95%. During absorption carbimazole, which itself is inactive, is completely converted to methimazole. The total volume of distribution is about 40L for methimazole and around 30L for propylthiouracil, which is about 80% protein-bound, while methimazole is virtually non-protein-bound. Drug transfer across the placenta and into breast milk is also higher for the more lipid-soluble methimazole than for propylthiouracil, which is excreted into breast milk only in small quantities so that no harmful effect to the suckling infant is to be expected. Both drugs are concentrated in the thyroid gland, exerting an effect on intrathyroidal iodine metabolism for periods exceeding those in which serum concentrations can be measured. Less than 10% of both drugs is excreted unchanged in the urine, but detailed metabolic pathways are unknown. The half-life of methimazole is 3 to 5 hours with a total clearance of about 200ml/minute. Propylthiouracil has a half-life of 1 to 2 hours with a clearance of around 120ml/min/m2. Some studies have shown an increased rate of metabolism of anti-thyroid drugs in hyperthyroidism, in particular for methimazole. No reliable information exists regarding pharmacokinetics of these agents in renal and hepatic failure or in children. The clearance of propylthiouracil is unchanged in the elderly. Several mechanisms for the inhibiting effect of these agents on intrathyroidal hormone metabolism have been suggested. In contrast to methimazole, propylthiouracil inhibits the peripheral conversion of thyroxine to triiodothyronine. Preliminary dose-response studies with propylthiouracil suggest a peak therapeutic serum concentration of above 4 micrograms/ml in the treatment of thyrotoxicosis. The choice between the antithyroid drugs is based more upon personal preference and experience than on strict pharmacological principles, as no important differences exist between these drugs with regard to the rate of remission or frequency of occurrence of serious adverse reactions.
68 citations
TL;DR: The present data suggest that the inhibition of T4 5'-deiodination observed during fasting, and its restoration by refeeding, may be related to the effects of feeding on insulin and glucagon release rather than on glucose per se.
Abstract: Primary cultured adult rat hepatocytes were used to study regulation of thyroid hormone deiodination. Control studies showed that these cells survived for at leas 4 d, during which time they actively deiodinated both the phenolic (5'-) and non-phenolic (5-) rings of L-thyroxine (T4),3,5,3'-triiodo-L-thyronine, and 3,3',5'-triiodothyronine. Increasing the substate concentration caused a decrease in fractional iodide release and a corresponding increase in conjugation with sulfate and glucuronide. Propylthiouracil strongly inhibited the 5'-deiodinase activity and caused only a slight decrease in 5-deiodinase activity. Thus, these monolayer-cultured cells preserved many of the properties of normal hepatocytes. Incubation with combinations of insulin, glucagon, and/or glucose for 5 h showed that insulin stimulated T4 5'-deiodination, whereas glucagon inhibited the insulin stimulation but had no effect in the absence of insulin. Glucose had no effect and did not alter the effect of the hormones. The insulin-enhanced deiodination increased between 1 and 5 h, which suggests that the previous inability to demonstrate an insulin effect was due to the short survival of the in vitro liver systems used in those studies. The present data suggest that the inhibition of T4 5'-deiodination observed during fasting, and its restoration by refeeding, may be related to the effects of feeding on insulin and glucagon release rather than on glucose per se.
59 citations
TL;DR: Data suggested that the thionamide drugs interfered with immunoglobulin production, rather than secretion, at concentrations which were likely to be present intrathyroidally in many treated patients.
Abstract: Previous studies have indicated that titers of thyroid-specific autoantibodies decrease in patients with autoimmune thyroid disease during antithyroid drug therapy. In keeping with these observations has been the accumulating evidence that such drugs may have an immunosuppressive action both in vivo and in vitro. To further analyze the mechanism of such activity, we have used an indirect hemolytic plaque assay based on protein A-coated sheep red blood cells and a specific plaqueforming cell (PFC) assay based on human thyroglobulin-linked sheep red blood cells. When freshly prepared peripheral mononuclear cells were exposed to increasing concentrations of methimazole or propylthiouracil (PTU), there was no significant effect on spontaneous plaque-forming cell responses (PFC). However, after incubation for more than 6 days with methimazole or PTU, there was a marked dose-related inhibition of pokeweed mitogen stimulated PFC, the degree of inhibition varying from one individual to another. Overall, there wer...
59 citations
TL;DR: In this paper, the authors have injected rats and mice with TSH three times a day for 4 d, while the animals were kept on an iodine-rich diet (HID) or a diet containing 0.15% propylthiouracil (PTU) or 1% sodium perchlorate (ClO4).
Abstract: Since Marine's observations some 50 years ago, it has been generally accepted that colloid goiters invariably result from colloid repletion of originally hyperplastic goiters after cessation of the goitrogenic stimulus. However, clinical observations suggest that many goiters never go through a stage of hyperplasia, but are colloid-rich from the beginning. We have injected rats and mice with thyrotropin (TSH), three times a day for 4 d, while the animals were kept on an iodine-rich diet (HID). Additional groups of animals were fed an iodine-poor diet (LID) or a diet containing 0.15% propylthiouracil (PTU) or 1% sodium perchlorate (ClO4). At intervals, thyroid weight, DNA, iodine and thyroglobulin content, thyroglobulin iodination, and intracellular droplet formation were measured. Histologic sections were also prepared and stained with periodic acid Schiff. Furthermore, thyroxine concentration was measured in the serum. Thyroglobulin content dropped by approximately 30% in HID animals but by 60% in all other groups 1 d after starting TSH. Thereafter, thyroglobulin reaccumulation occurred and droplet formation correspondingly decreased despite continuous heavy TSH stimulation. The largest amount of thyroglobulin was reaccumulated in HID animals followed by the PTU/LID groups, whereas no reaccumulation was observed in the ClO4 group. Reaccumulation of thyroglobulin only occurred if there was concomitant organification of at least some iodine. The subsequent phases of depletion and reaccumulation of thyroglobulin were mirrored by the morphology of the follicular lumina, the staining properties of the colloid and the serum T4 concentration. These observations suggest that endocytosis gradually becomes refractory to continuous TSH stimulation if a certain minimal amount of iodine is available for organic binding. Thus, primarily colloid-rich goiters may form in the presence of continuously higher than normal thyrotropin levels without a previous stage of follicular hyperplasia. The view should be revised that accumulation of colloid and intense thyrotropin stimulation are mutually exclusive events.
46 citations
TL;DR: It is indicated that hypothyroidism depressed the immunological system, while hyperthyroidism had no effect on antibody formation but depressed reactivity to Con A stimulation.
Abstract: Effects of the thyroidal state on certain immunological parameters were studied in four groups of male White Leghorn chicks. One group was fed with commercial chick mash and served as control, the second was supplemented with 0.1 % Propylthiouracil (PTU) in food, the third was supplemented with 0.025 % thyroxine in food, and the fourth was supplemented with 0.1 % PTU and 0.025 % thyroxine. Treatment with PTU (29 days) resulted in hypothyroidism evidenced by low T4 level, decreased oxygen consumption rate and decreased weight gain. Thyroxine treated group reached hyperthyroidism shown by high T4 level and increased oxygen consumption rate. When all chicks were immunized with SRBC, hemagglutinating antibody titer of PTU treated group was significantly lower than that of the other group while thyroxine treatment resulted in increased, but statistically not significant titers. At 36 days of age the chicks were killed. PTU treated group exhibited decreased thymus, spleen and bursa weights and low 3H thymidine incorporation after Con A stimulation of both spleen and thymus cells. Thyroxine treatment resulted as well in low 3H thymidine incorporation. These findings indicated that hypothyroidism depressed the immunological system, while hyperthyroidism had no effect on antibody formation but depressed reactivity to Con A stimulation.
39 citations
TL;DR: It is concluded that thyroid hormones regulate the number of α1-adrenoceptors in membranes of the rat cerebral cortex, leaving their affinities unchanged.
Abstract: The influence of thyroid hormones on the concentration and properties of alpha 1-adrenoceptors in a crude membrane fraction obtained from the rat cerebral cortex was investigated using the [3H]-WB 4101 binding assay. Animals were made hypothyroid by feeding 6-propyl-2-thiouracil for 8 weeks. Hyperthyroidism was induced by triiodothyronine injections (50 microgram/100 g body weight) for 9 days. 1. The binding of [3H]-WB 4101 was saturable and of high affinity in controls as well as in hyper- and hypothyroid animals. The maximal number of binding sites (Bmax), which amounted to 95 fmol/mg protein in control animals, was increased by 27% in cortical membranes from hyperthyroid rats and reduced by 23% in the hypothyroid group. 2. The reduction in [3H]-WB 4101 binding due to 6-propyl-2-thiouracil feeding was reversible by triiodothyronine treatment. 3. Dissociation constants (KD) calculated from saturation experiments (0.25 nM) or kinetic data (0.21 nM) remained unchanged in altered thyroid states. 4. Inhibition of [3H]-WB 4101 binding by adrenergic agonists and antagonists revealed no differences between euthyroid and hypothyroid animals. The higher affinity of prazosin to the binding sites compared with yohimbine indicated that [3H]-WB 4101 predominantly labeled alpha 1-adrenoceptors. It is concluded that thyroid hormones regulate the number of alpha 1-adrenoceptors in membranes of the rat cerebral cortex, leaving their affinities unchanged.
27 citations
TL;DR: The thiol-dependent thyroxine 5′-monodeiodinase is inhibited by propylthiouracil through its covalent binding, probably as mixed disulfide, to a site on the enzyme at which glutathione interacts either as a cosubstrate or reducing agent.
Abstract: When rat liver cytosol, dialyzed free of glutathione, was chromatographed on Sephadex G-100 after incubation with 35S-propylthiouracil, 2 peaks of bound radioactivity were observed, 1 of which contained nearly all the thyroxine 5′-monodeiodinase activity in rat liver cytosol. Binding of propylthiouracil to this peak was inhibited by glutathione but not by thyroxine. Approximately 25% of 35S -propylthiouracil initially bound to the thyroxine 5′-monodeiodinating activity peak remained bound after dialysis, precipitation with trichloroacetic acid, and multiple extractions with ethanol, methanol, and chloroform, suggesting that binding was at least in part covalent. Dialysis studies showed that the presumed covalent binding of 35S -propylthiouracil to the thyroxine 5′-monodeiodinase peak could be inhibited by glutathione, dithioerythritol, and unlabelled propylthiouracil but not by oxidized glutathione or thyroxine. Conversely, thyroxine binding was unaffected by thiol compounds. We studied the kinetics of thyroxine 5′-monodeiodi-nation by radioimmunoassay techniques using rat liver homogenates as source of enzyme and observed the dependence of enzymic reaction upon glutathione (Km = 2.4 mM). Propylthiouracil inhibited the reaction and this inhibition could be overcome with increasing glutathione concentrations. We conclude that the thiol-dependent thyroxine 5′-monodeiodinase is inhibited by propylthiouracil through its covalent binding, probably as mixed disulfide, to a site on the enzyme at which glutathione interacts either as a cosubstrate or reducing agent. This binding site is separate from the site at which thyroxine binds.
25 citations
Journal Article•
23 citations
TL;DR: Results suggest that TRH and TSH storage sites are dissimilar in the hypothyroid rat, and suggest that it might play a role in the storage or packaging of TSH.
Abstract: Previous studies have demonstrated immunocytochemical staining for beta chains of thyroid stimulating hormone (TSH-beta) in rough endoplasmic reticulum of pituitary cells hypertrophied after thyroidectomy ("thyroidectomy cells") (Moriarty CG(1976): J Histochem Cytochem (24:846; Moriarty GC, Tobin RB (1976): J Histochem Cytochem 24:1140). Here we report the localization of thyrotropin releasing hormone (TRH) in serial sections of the same pituitaries to determine if it could be found at similar sites. No staining for TRH was found in hypertrophied TSH cells formed 42 days after the surgery, or after 14, 34, and 70 days of propylthiouracil (PTU) treatment. The loss in immunostaining in the PTU-treated rats was correlated with radioimmunoassay (RIA) measurements that showed a 65% reduction in anterior pituitary TRH content after 34, 70, and 98 days of PTU treatment (from 22.9--7.8 pg/mg wet wt) and a 50% reduction in TSH content after 34 days of treatment. When thyroxine was administered to hypothyroid rats for 3 days before death, our previous studies had demonstrated intense staining for TSH in granules inside the rough endoplasmic reticulum. In this study, the radioimmunoassay showed that TSH content rose dramatically in the hypothyroid animals treated with PTU for 77 days and thyroxine for 2 days before death (from 8.5--64.1 mU/mg wet wt); however, the rise in TRH content was minimal (5.8--9.8 pg/mg wet wt). The immunocytochemical stain for TRH correlated well with the RIA showing a weak reaction mainly on small granules in the cytoplasm. No reaction for TRH was found in rough endoplasmic reticulum. These results suggest that TRH and TSH storage sites are dissimilar in the hypothyroid rat. The presence of stain for TRH in granules in the cytoplasm suggests that it might play a role in the storage or packaging of TSH. Its absence in profiles of rough endoplasmic reticulum staining intensely for TSH suggests that it is not synthesized at this site. No definite conclusions about its origin can be drawn at this time.
TL;DR: The data presented give no support to the concept that chronic ethanol ingestion results in hyperthyroidism or liver hypermetabolism and, consequently, the rationale for treatment of alcoholic hepatitis with the antithyroid drug, propylthiouracil, is incorrect.
Abstract: The effects of chronic ethanol consumption on thyroid hormone levels and the rates of whole animal and perfused liver oxygen consumption were determined to test the hypothesis that alcoholic liver damage is a result of thyroid mediated liver hypermetabolism (L. Videla, J. Bernstein, and Y. Israel: Biochem. J, 134: 507–514, 1973). Whole animal minimal oxygen consumption, a sensitive indicator of the effects of thyroid hormone (W. D. Denckla: J. Clin. Invest, 53:572–581, 1974) was unchanged in rats maintained 3 wk on a liquid diet containing 34% of the calories as ethanol (2.49 ± 0.06 ml of O2/min/1O0 g of fat-free body weight) when compared to animals fed an equicaloric sucrose containing liquid diet (2.61 ± 0.20 ml of 02/min/100 g of fat-free body weight) or Purina chow (2.50 ± 0.12 ml of O2/min/100 g of fat-free body weight). Ethanol treatment lowered serum thyroxine (5.09 ± 0.20 pg/100 ml) compared to sucrose-fed control rats (7.66 ± 0.40 pg/100 ml), while serum triiodothyronine was unaffected (59.3 ± 4.0 compared to 66.9 ± 3.1 ng/100 ml for controls). Measurement of O2 consumption in the isolated perfused rat liver showed no significant difference after chronic treatment with the ethanol diet compared to either the sucrose or chow control diets. Infusion of 10-7 M norepinephrine into the perfusion medium resulted in an approximately 22% increase in O2 consumption in ethanol-fed animal and sucrose controls, while a 31 % increase was observed for sucrose-treated animals given 10 μg of T3/kg of body weight/day for 3 wk. These data indicate that T3 potentiates the ability of norepinephrine to increase O2 consumption. The data presented give no support to the concept that chronic ethanol ingestion results in hyperthyroidism or liver hypermetabolism and, consequently, the rationale for treatment of alcoholic hepatitis with the antithyroid drug, propylthiouracil, is incorrect (H. Orrego, H. Ka-lant, Y. Israel, et al.: Gastroenterology, 76:105–115, 1979).
TL;DR: Results suggest that thyroid hormones promote the development of malic enzyme in the brain, and lower malate dehydrogenase activity than controls during the suckling period is suggested.
Abstract: Changes in the developmental pattern of cytoplasmic and mitochondrial malate dehydrogenase (decarboxylating; NADP+) activity in the brain of hypothyroid rats and the effect of triiodothyron
TL;DR: It is suggested that internal thyroid iodide is transported from its site of generation, the follicular cell, to its sites of organic binding,the follicular lumen, by perchlorate-sensitive transport, thereby partially preempting the effect whereby PTU causes accumulation of internal iodide in TSH-treated rats.
Abstract: Thyroid iodide labeled 72 h earlier with 131I was separated from organic iodine by polyacrylamide gel electrophoresis. The concentration of thyroid radioiodide was not significantly diminished 2 h after the administration of perchlorate (100 mg NaClO4) alone, but perchlorate reduced the rise in glandular radioiodide caused by simultaneously given TSH (1 IU). When propylthiouracil (PTU; 20 mg) was given along with it, perchlorate decreased thyroid radioiodide even in rats not treated with TSH. In rats given perchlorate, PTU caused a much slighter augmentation of the TSH-induced increase in the thyroid radioiodide concentration than in the absence of perchlorate. These results are interpreted as follows. Perchlorate-discharged iodide in rats not given TSH is largely transported iodide. Perchlorate can discharge intrathyroidally generated (internal) iodide too, but this is unequivocally reflected by a decrease in the thyroid iodide concentration only when the production of internal iodide is enhanced by TSH....
TL;DR: Two patients with metastatic choriocarcinoma complicated by severe thyrotoxicosis, leading to cardiac failure in one instance and thyroid crisis in the other, are described.
TL;DR: The site of iodination in the chronically stimulated, hyperplastic thyroid gland of rats is the follicular lumen, i.e. the same as that in the normal gland.
Abstract: We have tried to ascertain the site of iodination in the chronically stimulated, hyperplastic thyroid gland of rats. Rats were fed propylthiouracil in a commercial rat diet for 10 days. Then the diet was changed to a low iodine diet for 5 days. To label the gland, 10 mCi of 125I-iodide was injected into the left heart ventricle. Ten seconds later the animal was perfused through the left ventricle with a fixative solution containing a goitrogen to block further iodination, and stable iodide to help extract uncombined radioiodide. Electron microscopic autoradiographs prepared from the fixed thyroids show strong labeling over the lumen of the follicle and no consistent labeling of any other site or organelle. We conclude that the site of iodination in the chronically stimulated, hyperplastic thyroid is the follicular lumen, i.e. the same as that in the normal gland.
TL;DR: Results indicate that the apparent independence of pituitary-thyroid function from TRH control during early ontogenesis in the rat is primarily due to delayed maturation of the hypothalamic TRH system.
Abstract: Propylthiouracil fed to pregnant rats for the last week of gestation to induce maternal and fetal hypothyroidism induced a 3-fold rise in plasma TSH concentration in the newborn pups compared to a 4-fold rise in their mothers. Subcutaneous administration of 1 ng/g BW TRH caused a greater rise in plasma TSH in the hypothyroid pups than in their mothers. These results, in combination with published data, indicate that the apparent independence of pituitary-thyroid function from TRH control during early ontogenesis in the rat is primarily due to delayed maturation of the hypothalamic TRH system.
TL;DR: After male rats were injected daily with propylthiouracil, whale thyrotropin, or thyroxine for several days, the thyroid glands were examined for their ultrastructural localization of peroxidase and the dynamics and the physiological role of the intracellular peroxIDase are discussed.
Abstract: MATSUKAWA, S., MIHARA, S. and HOSOYA, T. Thyrotropin-Dependence of the Distribution of Peroxidase in Rat Thyroid Gland. Tohoku J. exp. Med., 1981, 133 (4), 431-443 -After male rats were injected daily with propylthiouracil, whale thyrotropin, or thyroxine for several days, the thyroid glands were examined for their ultrastructural localization of peroxidase. The propylthiouracil treatment caused a marked increase in the number of round, peroxidase-positive vesicles in the apical and middle regions of cytoplasm, and brought about a formation of granular reaction products in the colloid lumen adjacent to the elongated microvilli. Such changes became evident after 2 days of the drug treatment and increased with the time of the effect, until the whole colloid lumen was filled with the reaction products and very elongated microvilli. The effect of exogenous thyrotropin was essentially similar, to a lesser degree, to the drug effect mentioned above. The thyroxine treatment diminished the population of the small vesicles, as usually seen in the case of normal rat thyroids. When the thyroids of thyrotropin-stimulated and unstimulated rats were homogenized and fractionated into particulates fractions and a soluble fraction, almost all the peroxidase activity was contained in the former in both cases. Based on these results, the dynamics and the physiological role of the intracellular peroxidase are discussed.
TL;DR: The inability of head x-irradiated cTSH, suggests that moderate to high doses of x-IRradiation can impair the ability of the hypothalamic-hypophysial-thyroid axis to respond to a goitrogenic challenge.
Abstract: A RIA for canine TSH (cTSH) has been developed using a double antibody method. Rabbit anti-cTSH antisera was slightly cross-reactive with ovine TSH. No evidence of cross-reactivity was noted with human, bovine, rat TSH, or ovine LH. Serum cTSH in euthyroid dogs (9–10 yr of age; 7–14 kg) was 7.0 ± 0.9 ng/ml (mean ± SE; range, 2.7–7.9). Normal and x-irradiated (localized to the thyroid or cranium) dogs received 334 mg propylthiouracil (PTU) im in oil daily for 1 week as a goitrogenic challenge. A significant increase (P P P < 0.20, respectively) in thyroid-irradiated dogs, a significant decrease (P < 0.01) in T.i was observed in both normal and x-irradiated dogs maintained on PTU for 1 week. The inability of h...
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TL;DR: It is reported that modest doses of propylthiouracil ingested by mothers being treated for Graves' disease significantly reduce serum thyroxine in newborn babies.
Abstract: In this issue of the Journal Cheron et al. report that modest doses of propylthiouracil (PTU) ingested by mothers being treated for Graves' disease significantly reduce serum thyroxine in newborn i...
TL;DR: In an attempt to study the effects of thyroid hormones, antithyroid drugs and iodide on the conversion of thyroxine to triiodothyronine, the liver was obtained from normal, hypothyroid and hyperthyroid rats treated with T4 or T3.
Abstract: SUMMARY
In an attempt to study the effects of thyroid hormones, antithyroid drugs and iodide on the conversion of thyroxine (T4) to triiodothyronine (T3), the liver was obtained from normal, hypothyroid and hyperthyroid rats treated with T4 or T3. T4 was incubated with liver homogenates and generated T3 was measured.
1. The conversion of T4 to T3 was less in the liver homogenates from thyroidectomized, methylmercaptoimidazole (MMI)-treated and propylthiouracil (PTLT)-treated rats. The magnitude of decrease was the same in thyroidectomized and MMI-treated rats, but was greater in PTU-treated rats.
2. Administration of T4 and T3 to thyroidectomized and MMI-treated rats restored the converting activity. When excess T4 was administered, the converting activity was above normal. In contrast, administration of graded doses of T4 failed to restore the converting activity of the liver from PTU-treated rats.
3. In vitro addition of MMI failed to affect converting activity of the liver, but addition of excess iodide and PTU significantly depressed it.
TL;DR: It is suggested that a serum concentration of propylthiouracil above 4 to 5 micrograms/ml 1 h after an oral dose of 400 mg of the drug will secure a sufficient and rapid antithyroid effect during continuous therapy.
Abstract: 1 Correlation between the kinetics of propylthiouracil and its antithyroid effect was studied in 17 hyperthyroid patients. The serum concentration of propylthiouracil 1 h after an oral dose of 400 mg of hyperthyroid patients. The serum concentration of propylthiouracil 1 h after an oral dose of 400 mg of the drug was used as kinetic parameter as this concentration from the previous study was found to correlate significantly (r = 0.84, P less than 0.01) with the area under the serum concentration-time curve. 2 After 3 weeks of treatment with 200 mg propylthiouracil three times daily the serum concentration of propylthiouracil was correlated to the decrease in various thyroid parameters such as total and free indexes of serum thyroxine, triiodothyronine and reverse triiodothyronine. 3 Significant correlations were found between the serum concentration of propylthiouracil and all the measured thyroid variables except reverse triiodothyronine. The highest degree of correlation was obtained between serum propylthiouracil and the percentage decrease in total and free indexes of triiodothyronine (r = 0.63 and 0.70, respectively, P less than 0.01). 4 It is suggested that a serum concentration of propylthiouracil above 4 to 5 micrograms/ml 1 h after an oral dose of 400 mg of the drug will secure a sufficient and rapid antithyroid effect during continuous therapy.
Journal Article•
TL;DR: Clinically, inhibitors of conversion will increase serum total and free T4, however this finding per se does not proof hyperthyroidism as in some cases serum TSH will increase after i.v. injection of 400 micrograms TRH.
Abstract: Several drugs are known to interfere in thyroid hormone metabolism: 1) They can affect directly and specifically T4 to T3 conversion. This can be observed in vivo and in vitro. In vivo serum T3 concentrations will decrease and rT3 concentrations increase. Amiodarone, other iodinated compounds (cholecystographic agents: ipodate and iopanoic acid), propylthiouracil and propranolol are known to act in this way. 2) Other drugs which induce the hepatic capacity to catabolize drugs will also affect thyroid hormone metabolism, e.g. diphenylhydantoine. Clinically, inhibitors of conversion will increase serum total and free T4, however this finding per se does not proof hyperthyroidism as in some cases serum TSH will increase after i.v. injection of 400 micrograms TRH. Furthermore the increase in serum T4 can be explained in part by a low metabolic clearance rate, T4 production being barely increased.
TL;DR: It is concluded that the new commonly prescribed combination preparations retain the goitrogenic properties of the earlier sulphonamides.
Abstract: 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.
TL;DR: The anti‐thyroid drug, propylthiouracil (0.05% w/v in drinking water) was administered to rats for 3–4 weeks and Circulating levels of thyroxine and triiodothyronine were markedly decreased.
Abstract: SUMMARY
1. The anti-thyroid drug, propylthiouracil (0.05% w/v in drinking water) was administered to rats for 3–4 weeks. This treatment decreased the rate at which rats gained body weight but did not affect the weight of the vasa deferentia. Circulating levels of thyroxine and triiodothyronine were markedly decreased.
2. The potencies of postjunctional α-adrenoceptor agonists, 1-noradrenaline and 1-phenylephrine, in eliciting contraction of the epididymal end of the vas deferens were unaffected by propylthiouracil treatment. In contrast, the potency of the β-adrenoceptor agonist, 1-isoprenaline, in inhibiting field stimulation-induced twitches of the prostatic end of the vas deferens was decreased in tissues from propylthiouracil-treated rats. Thus hypothyroidism induced by propylthiouracil produced an apparent change in the properties of postjunctional β-adrenoceptors without a concomitant reciprocal change in the properties of postjunctional α-adrenoceptors.
3. Treatment of rats with propylthiouracil led to a small increase in the concentration of noradrenaline in the vas deferens, and a concomitant small increase in the rate of accumulation of 3 H-noradrenaline in in vitro experiments. Extra-neuronal uptake of 3H-isoprenaline was unaffected by propylthiouracil treatment.
4. The potencies of the prejunctional α-adrenoceptor agonists, xylazine and 1-noradrenaline, in producing inhibition of twitches evoked by field stimulation of preparations of the prostatic end of the vas deferens, were similar in preparations from propylthiouracil-treated and control rats, although the slope of the log dose-response curve to xylazine was decreased in the former group. Thus unequivocal changes in the properties of prejunctional α-adrenoceptors did not accompany the other prejunctional effects of propylthiouracil upon endogenous noradrenaline levels and neuronal uptake of 3H-noradrenaline in this organ.
TL;DR: The case of a 49-year-old woman who developed a goiter, mild symptoms of hyperthyroidism, and grossly elevated thyroid function tests after 2 years of treatment with lithium carbonate demonstrates that lithium carbonates cannot prevent agranulocytosis caused by propylthiouracil.
Abstract: The authors describe the case of a 49-year-old woman who developed a goiter, mild symptoms of hyperthyroidism, and grossly elevated thyroid function tests after 2 years of treatment with lithium carbonate. Thyroid microsomal autoantibodies were also present. She was retreated with propylthiouracil and improved, but within 3 months she developed agranulocytosis. Propylthiouracil was discontinued, and the patient was treated with antibiotics and recovered. She was then given 131I to control her hyperthyroidism. The case is an example of the rare association of hyperthyroidism with lithium, which usually suppresses thyroid function, and demonstrates that lithium carbonate cannot prevent agranulocytosis caused by propylthiouracil.
TL;DR: The observed modifications after thyroxine and TSH treatment affect both species of regulatory subunits to the same extent, whereas chronic stimulation by propylthiouracil for 30 days preferentially increases the type II regulatory subunit.
TL;DR: In vitro thyroid/medium concentration ratio (T/M) of 99mTc and 201Tl was decreased after 20' incubation with ouabain, an inhibitor of the Na+, K+, activated ATP-ase, however, perchlorate in vitro or in vivo failed to diminish the 200Tl T/M ratios or to affect the t 1/2 of 201TL in human subjects, whereas T/m of 201 Tl was depressed by KCl addition to
Abstract: Patients injected with 201Thallium (201Tl) for myocardial scanning present good thyroid visualization. Determinations in mice injected with 201Tl indicated a high thyroid/serum concentration ratio (T/S). The 201Tl biological half-life (t 1/2) in serum (30 - 135 s) was much shorter than in thyroid (53 - 55 h) for human subjects and experimental animals. The 1 h 201Tl T/S ratio was comparable to that of 131I and 99mTc, indicating presence of a gradient for 201Tl also. Increase of endogenous TSH induced by propylthiouracil led to a significant rise in in T/S for 99mTc, 131I and 201Tl, whereas TSH inhibition by feeding l-thyroxine led to decrease in T/S for 99mTc and 201Tl. In vitro thyroid/medium concentration ratio (T/M) of 99mTc and 201Tl was decreased after 20' incubation with ouabain, an inhibitor of the Na+, K+, activated ATP-ase. However, perchlorate in vitro or in vivo failed to diminish the 201Tl T/M ratios or to affect the t 1/2 of 201Tl in human subjects, whereas T/M of 201Tl was depressed by KCl addition to the medium.