Showing papers on "Propylthiouracil published in 1976"

Exposure of thyroid slices to thyroid-stimulating hormone induces refractoriness of the cyclic AMP system to subsequent hormone stimulation.

Abstract: These studies evaluated the influence of an initial exposure of thyroid slices to thyroid-stimulating hormone (TSH) on the subsequent responsiveness to the hormone. Bovine thyroid slices were incubated with or without 50 mU/ml TSH for varying periods and then incubated in hormone-free medium for varying periods. Subsequently, slices were incubated for 20 min with 10 mM theophylline and with or without TSH. Cylic AMP was measured after the third incubation. Phosphodiesterase and adenylate cylase were assayed in homogenates prepared from slices after the second incubation. In some experiments prostaglandin E1, puromycin, thyroxine, and triiodothyronine and propylthiouracil were included in the media. In other experiments, low does of TSH (1 AND 10 mU/ml) were used instead of 50 mU/ml. Slices previously exposed to TSH have decreased responsiveness of the adenylate cyclase-cylic AMP system. Such refractoriness is hormone specific since initial exposure to prostaglandin E1 decreases the subsequent response to this substance but not to TSH. Refractoriness to TSH develops only when the first incubation is at least 30 min. It is not reversed by 5 h of incubation without hormone. Incubation of thyroid slices with puromycin does not eliminate refractoriness. The decreased response to TSH cannot be explained by release of thyroxine, triiodothyronine, or iodide from the slices. Phosphodiesterase activity is not increased during the refractory period. The decreased cyclic AMP response to TSH is associated with diminished response of adenylate cyclase activity to the hormone. Guanosine triphosphate (1 mM) increased adenylate cyclase activity in both control and TSH treated tissue, but the effect was significantly less in the latter. Although with guanosine triphosphate, TSH increased adenylate cyclase activity in TSH treated tissue, the enzyme activity was still less than that present in control tissue incubated with guanosine triphosphate and TSH. NaF caused an equivalent stimulation of adenylate cyclase in both control and TSH treated tissue. These results suggest that the refractoriness represents an alteration in hormone binding or the coupling of the bound hormone to the adenylate cyclase activity rather than any modification of the catalytic site of the enzyme.

Drug metabolism in thyroid disease

Abstract: Thyroid dysfunction can influence the physiological disposition of drugs. Depending on the pharmacokinetic properties of the individual drug, changes in the rate of metabolism ranging from profound to moderate or negligible have been observed. Since renal function is also influenced by thyroid disease, changes in renal elimination of drugs which are excreted in the urine mainly as unchanged drugs have to be considered as another reason for altered drugs disposition in thyroid disease. In patients with thyrotoxicosis lower, and in patients with myxoedema, higher, digitalis plasma levels have been observed. The altered disposition of cardiac glycosides in thyroid dysfunction can be attributed to changes in renal elimination and metabolism. These findings may be the kinetic correlate for the clinical observation that larger than the usual dose of digitalis is required in thyrotoxic patients and lower in hypothyroid patients. Antipyrene half-lives are very much shortened during hyperthyroidism and prolonged appreciably during hypothyroidism. The alterations in the disposition of these drugs seen during thyroid dysfunction can be ascribed to changes in its rate of metabolism which is controlled by the levels of circulating thyroid hormones. N-demethylation of aminopyrine is depressed both in hyper- and hypothyroid patients as compared with euthyroid subjects. Changes in the half-life of this drug were observed only during hypothyroidism. The physiological disposition of the antithyroid drug propylthiouracil is not changed during thyrotoxicosis. A decrease in plasma half-life of methimazole is however, observed during hyperthyroidism, whereas in hypothyroid patients half-life is increased. The few data available so far do not allow general prediction of how thyroid disease could alter drug metabolism in man.

Thyrotoxicosis secondary to involvement of the thyroid with malignant lymphoma.

Abstract: A patient with malignant lymphoma devel oped goiter and thy rotoxicosis during the course of her disease. A thyroid biopsy revealed involvement of the thyroid gland with a malignant lymphoma. This was associated with the high levels of circulating thyroglobulin and thyroid hormones. The patient was treated with propylthiouracil, local radiotherapy, and nitrogen mustard and prednisone. The patient became euthyroid with the disappearance of goiter. Circulating levels of thyroglobulin and thyroid hormones returned to the normal range.

The in vitro suppression of lectin induced 3h-thymidine incorporation into dna of peripheral blood lymphocytes after the addition of propylthiouracil.

Abstract: A possible in vitro immunosuppressive role of propylthiouracil (PTU) was investigated by culturing peripheral blood lymphocytes (PBL) from normal subjects with plant lectins in the presence of PTU added at the onset of culture or near the time of peak cell division. When added at the onset of culture PTU caused a dose-related suppression of lectin stimulated 3H-thymidine uptake with an average of approximately 50% suppression at a PTU concentration of 100 μg/ml. When added at the time of peak cell division however, marked suppression was produced by 10 μg/ml of PTU. Prolonged remissions in patients with Graves' disease treated with PTU, and possibly other antithyroid drugs, may thus be due to an immunosuppressive role of the drug rather than the natural evolution of the disease.

Thyroid Function and Insulin Secretion from the Perfused Pancreas in the Rat

Abstract: The influence of thyroid function on the kinetics of glucose-induced insulin secretion from theisolated perfused rat pancreas has been studied. L-Thyroxine (L-T4) administration did not modify the immediate insulin secretory response of the perfused pancreas to glucose. L-Triiodothyronine(L-T3) treatment as well as propylthiouracil (PTU)treatment decreased the immediate insulin secretory response of the pancreas slightly. Only thyroidectomy(Tx) reduced the immediate secretory response of the pancreas significantly. L-T4and L-T3 treatmentinhibited the late phase of glucose-induced insulin secretion from the isolated perfused rat pancreas, whereas Tx and PTU treatment resulted in increased insulin secretion. D-Thyroxine (D-T4) did not affect glucose-induced insulin release from the pancreas. Concomitantly, several parameters indicative of thyroid function were determined in these animals. When changes in body weight, rectal temperature,plasma glucose, plasma cholesterol, and plasmabutanol-extractable iodine...

Thyroid Hormone and Cell Formation in the Developing Rat Cerebellum

Abstract: Effects of neonatal hyperthyroidism on cell formation in the developing rat cerebellum were reinvestigated. Administration at birth of excessive doses of thyroxine or triiodothyronine led to an early stimulation of cell acquisition, followed by a permanent deficit of cells in the cerebellum. The corrective effects of physiological doses of thyroxine on the troubles of the histological and biochemical development of the cerebellum in thyroid-deficient animals were also studied. As early as 6 days, cell maturation and formation were already retarded in animals treated with propylthiouracil, but, as previously reported, cell formation was prolonged and the final number of cells was normal. Administration to thyroid-deficient animals of progressively increasing doses of thyroxine, nearly equal to the amounts of hormone secreted by the thyroid gland of the developing normal rat, returned the evolution of the cerebellar wet weight and of the cerebellar DNA to normal, as well as the histological maturation of the cerebellum, even if it did not entirely correct the retardation of body growth. These results are consistent with the view that thyroid hormone early stimulates maturation of the cerebellar germinative cells and subsequently interacts with cell formation in the cerebellum, and that this action is physiological.

Immunological: reactions involving leukocytes: III. Agranulocytosis induced by antithyroid drugs.

Abstract: A method has previously been described which detected xenogeneic and allogeneic antibodies to human granulocytes by their inhibition of the normal phagocytosis-associated hexose monophosphate shunt (HMS) activity. This method was used to study three patients with acute agranulocytosis secondary to antithyroid drug administration. Two patients with methimazole and one patient with propylthiouracil induced agranulocytosis were studied. Serum samples from each of these three patients taken during the acute phase of agranulocytosis had inhibitory effects on phagocytosis-associated HMS activity in leukocytes from both normal donors and the patients after their full recovery from agranulocytosis. IgM but not IgG prepared from acute sera in two patients was also inhibitory. Disruption of IgM disulfide bonds by dithiothreitol destroyed its inhibitory activity. The possibility of drug-dependent immune destruction of leukocytes in these patients is discussed.

Control of Cell Growth. II. Requirement of Thyroid Hormones for the In Vivo EstrogenDependent Growth of Rat Pituitary Tumor Cells

Abstract: Further examination of rat pituitary cell line GH3/C14 showed that at least the physiologic concentration of L-thyroxine was required for estrogen-dependent growth in vivo. Two L-thyroxine synthesis inhibitors, 6-n-propyl-2-thiouracil (propylthiouracil) and 1-methylimidazole-2-thiol (methimazole), were administered concurrently with estrogen to GH3/C14-inoculated hosts. Propylthiouracil administration to estrogen-treated males, intact females, and estrogen-treated ovariectomized females inhibited tumor formation by 93, greater than 95, and 68%, respectively, as compared to tumor formation in controls not treated with propylthiouracil. Methimazole treatment of estrogen-primed males and intact females inhibited tumor formation by 78 and 95%, respectively. Concentrations of total L-thyroxine and free L-thyroixine in sera from normal and inhibitor-treated hosts were depressed 70-80% by propylthiouracil and 60-70% by methimazole. Administration of either drug caused greater inhibition of tumor growth than of total body weight gain. In addition, the administration of a combination of L-thyroxine and L-triiodothyronine to male rats promoted tumor formation even in the absence of exogenous estrogen.

Inhibition of cerebellar dendrite development in neonatal thyroid deficiency

Abstract: Inhibition of cerebellar dendrite development in neonatal thyroid deficiency Thyroid hormone deficiency was induced in neonatal rats by propylthiouracil. Serum thyroxine levels were assayed and thyroid tissue was examined to assess the clinical condition. At 8, 14, 20, 30 and 42 days after birth, age-matched controls and hypothyroid animals were killed by perfusion. Nissl stains, Golgi preparations, and electron microscopy were done on the cortex of Lobules IX and X of the developing cerebellum. Measurements of the molecular layer revealed that at 8 days, controls are slightly but significantly wider, but at 20 days the difference is much greater and remains so even at 42 days. Golgi studies show deceleration and distortion of development of the Purkinje cell dendritic tree in the abnormal rats. Spine counts of the spiny branchlets on these dendrites show the same incidence per linear micrometer as the age-matched controls, but linear measurements of the branchlets show that the deficient animals have shorter branchlets and regions where spines are absent. Electron microscopy shows that if a spine does develop, it appears similar in control and hypothyroid animals at comparable ages. The effect of the abnormal Purkinje cell dendritic arborization on synaptogenesis in the molecular layer is discussed.

Effects of hyperthyroidism and hypothyroidism on rat growth hormone release induced by thyrotropin-releasing hormone.

Abstract: The effect of synthetic thyrotropin-releasing hormone (TRH) on the release of growth hormone (GH) and thyroid-stimulating hormone (TSH) was investigated in euthyroid, hypothyroid, and hyperthyroid rats under urethane anesthesia. In euthyroid control rats, intravenous injection of TRH (200 ng/100 g BW) resulted in a significant increase in both plasma GH and TSH. In rats made hypothyroid by treatment with propylthiouracil or by thyroidectomy, basal GH and TSH levels were significantly elevated with exaggerated responses to TRH. In contrast, plasma GH and TSH responses to TRH were both significantly inhibited in rats made hyperthyroid by L-thyroxine (T4) treatment. These results suggest that altered thyroid status influences GH release as well as TSH secretion induced by TRH in rats.

Effect of thyroxine on the inactivation of thyrotrophin‐releasing hormone by rat and human plasma

Abstract: SUMMARY The inactivation of synthetic [3H]thyrotrophin-releasing hormone (TRH) by plasma was studied in rats treated with propylthiouracil (PTU) alone or with PTU and thyroxine. 48 h after the onset of treatment with thyroxine, the capacity of rat plasma to inactivate [3H]TRH was significantly increased. The percentage of deamidation of TRH to TRH-free acid was increased 2-fold after 4 days of administration of thyroid hormone. The inactivation of TRH by plasma from hypothyroid patients was compared to that obtained from hyperthyroid patients. Extraction of human plasma incubated with [3H]TRH, followed by thin-layer electrophoresis, showed that transformation of [3H]TRH into TRH-free acid was 44% higher in plasma from hyperthyroid than from hypothyroid patients (P < 0.05). These data suggest that the inactivation process of TRH by blood proteins could be an important factor in the regulation of the hypothalamo-hypophyseal-thyroid axis in rat and man.

Thyroid supression tests during drug treatiment of hyperthyroidism

Abstract: In fifteen hyperthyroid patients treated for 5 or more consecutive years with propylthiouracil four or more yearly prognostic 'suppression' tests (Cassidy & VanderLaan, 1960) were done. In nine of the fifteen patients there was a progressive diminution over a period of 3-6 years in the values of these suppressed uptakes to 20% or below. Eight of these nine patients have remained euthyroid off therapy for 1-8 years (average 3-1 years). None have become hypothyroid. The data suggest a gradual continuing change in thyroid function over the course of years in some hyperthyroid patients on antithyroid therapy. This may be a long-term effect of the drug and may have prognostic significance.

Thyroid status and carbonic anhydrase levels in mouse erythrocytes.

Abstract: SummaryCarbonic anhydrase I (CA I) levels in mouse erythrocytes are influenced by thyroid status, while carbonic anhydrase II (CA II) levels appear to be unaffected. Adding propylthiouracil to the diets of normal mice (C57BL/6J) resulted in elevated erythrocyte CA I levels, while thyroid powder produced decreased levels. Panhypopi-tuitary mutants (DW/J dw/dw) have increased levels of erythrocyte CA I in comparison to their normal litter mates (DW/J + /?). These increased levels were decreased by adding thyroid powder to their diets.We are indebted to Drs. Elizabeth Russell and Samuel Boyer for providing research facilities and comments on the manuscript, to Drs. Wes Beamer and Gary Chase for advice, and to Ms. Sharon K. Stroup for research assistance.

Influence of thyroid hormone on norepinephrine metabolism in rat brain during maturation.

Abstract: The effect of thyroid hormone on norepinephrine (NE) metabolism was investigated in various regions of the developing rat brain. Neonatal hypothyroidism, induced by daily propylthiouracil injection starting at birth, caused an increase in NE levels in the brain stem and hypothalamus. The turnover of brain NE, as indicated by its rate of depletion following alpha-methyl-p-tyrosine administration, was decreased in the hypothalamus of 30-day-old hypothyroid rats but was unchanged in the brain stem and basal ganglia. The activities of monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) were decreased in certain brain regions of hypothyroid rats. The data suggest that thyroid hormone may influence the ontogenic patterns of NE metabolism in the brain.

Inhibitory effect of large doses of propylthiouracil and methimazole on an increase of thyroid radioiodine release in response to thyrotropin.

Abstract: Thyroidal radioiodine release increased shortly after a single injection of small doses of PTU, while moderate doses of MMI produced a similar increase of thyroidal radioiodine release with a latency of 7-9 hr. Large doses of PTU and MMI failed to augment thyroidal radioiodine release for at least 29 to 34 hr after the initial administration of goitrogens, although plasma TSH increased significantly because of goitrogen administration. An increase of thyroid hormone release in response to exogenous TSH was depressed by PTU and MMI in rats and mice treated with T4. Since this depression of TSH action only continued for a short period in spite of continuous administration of goitrogens, and since final thyroidal radioiodine release rate was similar to that produced by small doses of PTU, the effects mentioned were not simply due to general toxic action of goitrogens. It is suggested that large doses of PTU and MMI not only block thyroid hormone synthesis but also interfere with the action of TSH on thyroid hormone secretion.

Effects of postnatal thyroxine administration on brain development, response to postnatal androgen and thyroid regulation in female rats.

Abstract: Some developmental and functional manifestations of thyroxine (T4) administered on the first 2 days of postnatal life were studied in the female rat. Brain myelinogenesis estimated by brain esterified cholesterol concentration, and brain myelin age estimated by brain total cholesterol concentration, were subsequently determined. Thyroxine treatment resulted in a greater concentration of esterified cholesterol in the brain that saline treatment, but the latter appeared to delay the normal increase shown by non-injected controls. Thyroxine treatment resulted in total and free cholesterol levels similar to those of non-injected controls, these again being greater than those in saline-treated rats. Cholesterol concentrations in liver and serum were not affected by T4 or saline treatment. Administration of T4 to female rats before administration of 1-25 mg testosterone propionate on day 7 resulted in an ovarian and uterine weight response to human chorionic gonadotrophin (HCG, 1 i.u./day on days 23-26) on day 27 that was greater than that in litter-mates given saline at birth before testosterone propionate and HCG treatment. Postnatal T4 treatment alone in the female was also associated with a reduced thyroid and pituitary gland enlargement after 7 days of propylthiouracil feeding (0-015% in tap water, days 24-31 of life) when compared with either saline or non-injected controls.

Agranulocytosis secondary to methimazole therapy: report of two cases.

Abstract: Seventy-three cases of thyrotoxicosis were treated at Lloyd Noland Hospital with methimazole, propylthiouracil or both. Two cases of agranulocytosis occurred (2.7%) secondary to methimazole. Both responded to hospitalization, reverse isolation, and antibiotic coverage with complete recovery of the peripheral blood picture. The toxicity of methimazole is noted. The need for careful monitoring of blood counts during therapy and immediate discontinuance of the drug at the first clinical sign of granulocytopenia is stressed.

Effects of hypophysectomy and short- and long-term propylthiouracil treatment on the rat thyroid

Abstract: The follicular architecture of the thyroid gland of the rat following experimentally induced states of hypo- and hyperactivity was investigated by scanning electron microscopy and the findings correlated with both light and transmission electron-microscopic observations. By scanning electron microscopy, the microvilli on the apical surfaces of the follicular cells showed the most striking changes; following hypophysectomy, the cells were flattened and the microvilli had decreased in both size and number, whereas following propylthiouracil (PTU) administration the epithelial cells were enlarged, and marked hyperplasia and hypertrophy of the microvilli was present. Of particular interest is that the changes observed following PTU appeared to be identical in short- and long-term PTU-treated rats. Similarly, the heterogeneity of the follicular cells observed within the follicles was maintained under the various experimental conditions. Although the functional significance of these observations is not quite clear, it appears justifiable to assume that a reduction of luminal surface area of the follicular epithelial cell may hinder, whereas an increase may facilitate transport process across the apical cell membrane.

Clinical study on early changes in thyroid function of hyperthyroidism treated with propylthiouracil and a relatively small dose of iodide.

Abstract: In order to compare the acute effects of three kinds of antithyroid agents of iodide (I-), propylthiouracil (PTU) and PTU combined with iodide (PTU+I-) on thyroid function in hyperthyroid patients with diffuse goiter, serum concentrations of thyroxine (T4), triiodothyronine (T3), T3-resin sponge uptake (T3-RU) and free thyroxine index (FT4I) were employed as thyroid function parameters. In the group given iodine (1 mg/day) as iodinated-lecithine, the initial values of T4, T3, T3-RU and FT4I were 20.9 +/- 1.6 microng/100 ml (T4), greater than 740 ng/100 ml (T3), 49.5 +/- 2.3% (T3-RU) and 14.7 +/- 1.8 (FT4I). At the end of one week of therapy, they decreased clearly to 15.6 +/- 2.2 microng/100 ml, 457 +/- 87 ng/100 ml, 42.2 +/- 4.0% and 9.7 +/- 2.4. The so-called "escape phenomenon" from iodide inhibition was observed in serum T4, T3-RU and FT4I values at the end of two weeks of iodide therapy, while serum T3 continued to decrease but the value of T3 was far outside of the normal range. In the PTU group (300 mg/day), thyroid function parameters were 22.5 +/- 0.8 microng/100 ml (T4), greater than 592 ng/100 ml (T3), 54.9 +/- 1.0% (T3-RU) and 18.7 +/- 1.0 (FT4I) before treatment. They decreased continually week by week. At the end of four-week treatment with PTU, the value of each thyroid function parameter was 11.1 +/- 1.9 microng/100 ml, 229 +/- 56 ng/100 ml, 36.6 +/- 4.4% and 5.7 +/- 1.7. In the group of hyperthyroidism simultaneously given both PTU and iodide (300 mg/PTU and 1 mg/iodine), these thyroid function parameters decreased as well as in the group treated with PTU alone for more than two weeks. More rapid or significant decrease of T4, T3, T3-RU and ft4i in PTU+I- group than in PTU group was observed in the present study. These results suggested strongly that iodide alone was not an adequate therapy for hyperthyroidism as well known and they were also compatible with the idea that the concomitant administration of PTU and iodide was more effective in the early phase of therapy of hyperthyroidism than PTU alone.

Hyperthyroidism in Graves Disease: Current Trends in Management and Diagnosis

Abstract: Douglas Biggs, MD, Senior Assistant Resident in Medicine, Jewish Hospital of St Louis, Assistant in Medicine, Washington University School of Medicine: A 19-year-old woman was admitted to Jewish Hospital for thyroid surgery in August 1974. In April 1973, she was examined because of excessive weight loss and fatigue. The thyroid gland was enlarged diffusely five to six times; a Murphy-Patte T 4 level was greater than 20μg/100 ml, and a six-hour sodiumiodide I 131 thyroid uptake was greater than 60%. The scan showed a diffusely enlarged gland, without nodules. Therapy with propylthiouracil, 100 mg four times a day, was started at that time. The dose of propylthiouracil was gradually increased during the next year, but the clinical response was less than adequate. In June 1974, the dosage of propylthiouracil was increased to 400 mg four times a day. After two months on this dosage regimen, the patient remained hyperthyroid clinically,

An increase of liver uptake of thyroxine, an initial step of an increased fecal loss of thyroxine in response to propylthiouracil in rats.

Abstract: Propylthiouracil augmented fecal loss of thyroxine (T4), but methimazole was without effect in this respect in rats. In vitro uptake of labeled T4 by the liver was significantly enhanced by a small amount of propylthiouracil in the presence of dilute rat plasma. Methimazole was without effect under comparable conditions. In contrast, propylthiouracil and methimazole failed to affect in vitro uptake of labeled T4 by the kidney and diaphragm in the presence of dilute rat plasma. Since deiodination of T4 does not occur in the presence of dilute rat plasma, it is suggested that propylthiouracil specifically stimulates liver uptake of T4 as an initial step of an increase of biliary-fecal excretion of T4 in rats.

Clinical observations on thyroid crisis

Abstract: Thyroid crisis is an exaggerated or decompensated stage of thyrotoxicosis. Although the clinical features and precipitating causes are well known, the pathogenesis of thyroid crisis remains obscure.Six patients with thyrotoxicosis and typical features of thyroid crisis were studied. The serum levels of protein-bound-iodine (PBI) observed in crisis do not differ significantly from the value observed in 10 patients with uncomplicated thyrotoxicosis. In a case of crisis, both serum thyroxine and triiodothyronine levels were slightly elevated during the crisis compared to the value found before crisis and markedly decreased after an extensive treatment with Lugol's solution, propylthiouracil, propranolol and steroid. The precise contributions of adrenal cortex or medulla on the thyroid crisis have not been determined.It should be pointed out that serum concentrations of thyroid hormones in crisis are not discernibly different from those in uncomplicated thyrotoxicosis. The pathogenesis of thyroid crisis may be related to the increased susceptibility of peripheral tissues to a given dose of thyroid hormones, including possible increased free hormone concentrations.

A comparison of the effect of propylthiouracil on the respiration of thyroid slices from humans, chickens and rats.

Abstract: 1. The QO2 of thyroid slices from hyperthyroid patients treated with propylthiouracil (PTU) was 140% that of slices from euthyroid patients. Similar results were obtained using thyroid slices from PTU fed and control chickens. 2. PTU feeding caused thyroid hyperplasia, increased QO2 more than could be accounted for by the hyperplasia but neither increased QO2 of muscle, cerebral cortex or spleen nor altered serum T4 levels. 3. PTU in drinking water increased the size and vascularity of thyroids from control but not hypophysectomized rats and had no effect on QO2. 4. The observations made on human, chicken and rat thryoid apparently reflect the effects of TSH rather than a direct action of PTU.