Showing papers on "Propylthiouracil published in 1985"

The economy of isometric force development, myosin isoenzyme pattern and myofibrillar ATPase activity in normal and hypothyroid rat myocardium.

Abstract: Hypothyroidism was induced in Wistar-Kyoto rats by adding propylthiouracil to the drinking water (0.8 mg/ml). Initial heat, total activity-related heat, and resting heat rate were measured in left ventricular papillary muscle preparations of propylthiouracil-treated and control rats contracting isometrically at 12 beats/min (21 degrees C), using Hill type, planar vacuum-deposited bismuth and antimony thermopiles. In the propylthiouracil preparations, relative to control, time-to-peak tension increased from 288 +/- 27 (mean +/- SD) to 411 +/- 25 msec (P less than 0.001), dp/dtmax decreased from 38.3 +/- 9.5 to 20.4 +/- 3.5 g X mm-2/sec (P less than 0.001), and peak developed tension decreased from 6.11 +/- 1.75 to 4.64 +/- 0.89 g X mm-2 (P less than 0.05). In the propylthiouracil preparations, initial heat was significantly (P less than 0.001) reduced by 27 or 43% when normalized to peak twitch tension or tension-time integral, respectively. In experiments where the papillary muscles were tetanized, the slope of the linear function of total activity-related heat versus tension-time integral was decreased by 43% (P less than 0.001) in the propylthiouracil preparations, indicating an improved economy of isometric tension maintenance. The predominant myosin isoenzyme of the left ventricular wall, as well as the papillary muscle myocardium, was the V3 variety in the propylthiouracil animals, in contrast to V1 in the controls. Myofibrillar actomyosin calcium-magnesium-stimulated adenosine triphosphatase activity was significantly (P less than 0.02) decreased from 55 +/- 18 (control) to 31 +/- 8 nmol inorganic phosphate ion/mg X min (propylthiouracil).(ABSTRACT TRUNCATED AT 250 WORDS)

Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats.

Abstract: Previous reports suggest that a type II iodothyronine 5'-deiodinase may become the main enzymatic pathway for extrathyroidal triiodothyronine (T3) generation when the enzyme levels are sufficiently elevated and/or liver and kidney type I 5'-deiodinase activity is depressed. The present studies assessed the potential of brown adipose tissue (BAT) type II 5'-deiodinase to generate T3 for the plasma pool. BAT 5'-deiodination (BAT 5'D) was stimulated by either short- (4 h) or long-term (7 wk) cold exposure (4 degrees C). Long-term cold exposure increased thyroxine (T4) secretion 40-60% and extrathyroidal T3 production three-fold. In cold-adapted rats treated with propylthiouracil (PTU), extrathyroidal T3 production was 10-fold higher than in PTU-treated rats maintained at room temperature. Cold did not stimulate liver or kidney 5'D, but the cold-adapted rats showed a six- to eightfold higher BAT 5'D content. PTU caused greater than 95% inhibition of liver and kidney 5'D, but did not affect BAT 5'D. Thyroidectomized rats maintained on 0.8 micrograms of T4/100 g of body weight (BW) per day were acutely exposed to 4 degrees C. In rats given 10 mg of PTU/100 g of BW, 4 h of cold exposure still caused a 12-fold increase in BAT 5'D, a 2.3-fold increase in plasma T3 production, and a 4.8-fold increment in the locally produced T3 in BAT itself. All these responses were abolished by pretreatment with the alpha 1-antiadrenergic drug prazosin. Regardless of the ambient temperature, liver 5'D activity was greater than 90% inhibited by PTU. These results indicate that BAT can be a major source of plasma T3 under suitable circumstances such as acute or chronic exposure to cold. Furthermore, BAT 5'D activity affects BAT T3 content itself, suggesting that thyroid hormone may have a previously unrecognized role in augmenting the thermogenic response of this tissue to sympathetic stimulation. Such interactions may be especially important during the early neonatal period in humans, a time of marked thermogenic stress.

Heat exposure and hypothyroid conditions decrease hydrogen peroxide generation in liver mitochondria

Abstract: Exposure of rats to heat (39 +/- 1 degree C) decreased H2O2 generation in mitochondria of the liver, but not of the kidney or the heart. The effect was obtained with three substrates, succinate, glycerol 1-phosphate and choline, with a decrease to 50% in the first 2-3 days of exposure, and a further decrease on longer exposure. The dehydrogenase activity with only glycerol 1-phosphate decreased, which is indicative of the hypothyroid condition, whereas choline dehydrogenase activity remained unchanged and that of succinate dehydrogenase decreased on long exposure. The serum concentration of thyroxine decreased in heat-exposed rats. Thyroxine treatment of rats increased H2O2 generation. Hypothyroid conditions obtained by treatment with propylthiouracil or thyroidectomy caused a decrease in H2O2 generation and changes in dehydrogenase activities similar to those with heat exposure. Treatment of heat-exposed or thyroidectomized rats with thyroxine stimulated H2O2 generation by a mechanism apparently involving fresh protein synthesis. The results indicate that H2O2 generation in mitochondria of heat-exposed animals is determined by thyroid status.

Hepatotoxicity from antithyroid drugs.

Abstract: We review the cases of hepatic injury from propylthiouracil, methimazole and carbimazole in the English language literature and compare them to cases of agranulocytosis in a recent review. The data on hepatotoxicity confirm the findings for agranulocytosis that low-dose methimazole is safer than propylthiouracil and that methimazole toxicity is more common over 40 years old. In contrast, propylthiouracil hepatotoxicity often occurs in younger patients. Most cases of hepatic injury occur in the first few months of drug therapy as with agranulocytosis. The reason that methimazole typically causes cholestatic hepatitis while propylthiouracil causes cytotoxic hepatitis remains unknown.

Characterization of Thyrotropin-Induced Increase in Iodothyronine Monodeiodinating Activity in Mice*

Abstract: To further characterize the effect of TSH administration on thyroid iodothyronine monodeiodinating activity, we have evaluated the in vitro conversion of T4 to T3 (outer ring deiodination) and T3 to 3,3'-diiodothyronine (T2; inner ring deiodination) by mouse thyroid, liver, and kidney homogenates, comparing tissues from TSH-treated mice (0.1-200 mU bovine TSH, ip, for 1-3 days) with tissues from saline-treated controls. The in vitro conversion activity was studied in the presence of 1-20 mM dithiothreitol; most of the studies were carried out at 4 mM. Studies were carried out at optimal pH 6.5 for outer ring and 7.8 for inner ring deiodination. The iodothyronine monodeiodinase in mouse thyroid is similar to the ones in liver and kidney. It is heat labile (inactivated at 56 C for 5 min), inhibited by propylthiouracil (0.2 mM) and ipodate (0.2 mM), and unaffected by methimazole (up to 20 mM), ascorbate (up to 0.1 M) or KI (up to 20 mM). The mean +/- SE baseline rates of T4 to T3 and T3 to T2 conversion were 100 +/- 6.3 and 56.5 +/- 2.9 pmol/mg thyroid protein X 30 min at 37 C, respectively. A significant increase in each conversion activity was found after TSH treatment (0.2 U, ip, daily for 3 days); T4 to T3 conversion rose to 282 +/- 15.4, and T3 to T2 increased to 153 +/- 7.4 pmol/mg thyroid protein (P less than 0.001). A 12.8% increase in thyroid weight was found in the TSH-treated group (P less than 0.03 compared with saline control group). Similar but less marked increased in monodeiodinating activities were seen in the liver. A minimal but significant increase in inner ring monodeiodination with no significant increase in T4 to T3 converting activity was found in kidney, which, in the mouse, has markedly less outer ring deiodinase than liver or thyroid. The iodothyronine monodeiodinating activities did not increase until 12 h in thyroid and 48 h in liver after the first dose of TSH. Significant increases in T4 to T3 and T3 to T2 conversion were seen with doses of TSH as low as 0.1 mU (ip, daily for 3 days), and there was a linear dose-response thereafter. The decay of the increased iodothyronine monodeiodinating activities after a single dose of TSH (0.2 U) appeared to be linear, with a decay t 1/2 of 1.3 days for T4 to T3 conversion and about 1.0 day for T3 to T2 conversion.(ABSTRACT TRUNCATED AT 400 WORDS)

Propylthiouracil levels in hyperthyroid patients unresponsive to large doses. Evidence of poor patient compliance

Abstract: Nine patients with hyperthyroidism due to Graves' disease did not respond to therapy with very large doses (800 to 2000 mg/d) of propylthiouracil. In eight patients, studies showed propylt...

Effect of propylthiouracil dose on serum thyroxine, growth, and weaning in young rats.

Abstract: The antithyroid drug propylthiouracil (PTU) is a potent inducer of hypothyroidism in the rat. To evaluate the effects of PTU on serum thyroxine (T4) concentration, growth, and weaning progression during development, five doses of PTU (0.0001, 0.0005, 0.001, 0.005, and 0.01 g/100 ml) were administered to infant rats via drinking water of the dam. The highest dose, 0.01%, is commonly used in developmental studies. The results indicate that 0.001% PTU creates hypothyroid pups without the debilitating characteristics of pups raised on 0.01% PTU. A second experiment examined the effects of 0.001% PTU on serum T4 concentration, growth, and weaning progression during the fourth postnatal week. Serum T4 concentration was depressed throughout the study period to 25% of controls. The hypothyroid pups continued to grow, although they were significantly smaller than untreated controls. Weaning was initiated by postnatal day 22 and completed on day 29. For normal untreated pups, weaning is initiated by day 17 and completed by day 26. Thus hypothyroidism delays but does not abolish the weaning process.

Hepatitis associated with propylthiouracil treatment.

Abstract: A 12-year-old girl with hyperthyroidism who had started treatment with propylthiouracil (PTU) 100 mg tid developed hepatitis. The drug was stopped, and the clinical and laboratory findings of hepatitis disappeared within a week. She was not receiving other drugs that could cause hepatic damage, and investigations for various viral agents were negative. This is the ninth report of PTU-induced hepatitis. The clinical picture is similar to that of viral hepatitis. Recovery usually occurs after withdrawal of the drug, but there have been two fatal cases of PTU-induced hepatitis.

Cytochemical localization of peroxidase and hydrogen-peroxide-producing NAD(P)H-oxidase in thyroid follicular cells of propylthiouracil-treated rats.

Abstract: The distribution of endogenous peroxidase and hydrogen-peroxide-producing NAD(P)H-oxidase, which are essential enzymes for the iodination of thyroglobulin, was cytochemically determined in the thyroid follicular cells of propylthiouracil (PTU)-treated rats. Peroxidase activity was determined using the diaminobenzidine technique. The presence of NAD(P)H-oxidase was determined using H2O2 generated by the enzyme; the reaction requires NAD(P)H as a substrate and cerous ions for the formation of an electron-dense precipitate. Peroxidase activity was found in the developed rough endoplasmic reticulum (rER) and Golgi apparatus, but it was also associated with the apical plasma membrane; NAD(P)H-oxidase activity was localized on the apical plasma membrane. The presence of both enzymes on the apical plasma membrane implies that the iodination of thyroglobulin occurs at the apical surface of the follicular cell in the TSH-stimulated state which follows PTU treatment.

Changes in plasma concentrations of thyroxine and triiodothyronine in beef steers fed different levels of propylthiouracil.

Abstract: Three Latin-square trials were conducted to determine the effects of feeding the thyroid depressant propylthiouracil (PTU) on plasma concentrations of thyroxine (T4) and triiodothyronine (T3) in feedlot steers. In trial 1, four steers were fed 0, 1, 2 or 4 mg PTU/kg body weight daily during five 35-d experimental periods. In trial 2, eight steers were fed 0, .5, 1 or 2 mg PTU/kg body weight daily during five 28-d periods. In trial 3, three steers were fed 0, 1 or 4 mg PTU/kg body weight daily during the first 3 d in each of three 28-d periods. In general, feeding PTU caused increases in plasma T4 concentrations that peaked 5 to 7 d after feeding started. Concurrently, T3 concentrations tended to decrease when PTU was fed. The effects of PTU on hormone concentrations were apparent within approximately 1 to 4 h after PTU feeding started. Furthermore, when PTU was not fed, T4 and T3 concentrations appeared to have rhythmic cycles of 90 and 111 min, respectively, and PTU treatment appeared to interrupt this cyclical pattern. After the initial PTU response, the dose response relationship between PTU level and plasma hormone concentration was not linear. Both 4 and 2 mg PTU appeared to depress both T4 and T3 concentrations, suggesting direct inhibition of the thyroid gland and, for the 1-mg PTU treatment, T4 tended to stabilize at concentrations significantly greater than for 0 mg PTU, while T3 concentrations for 1 mg PTU were slightly lower than for 0 mg PTU.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphological and functional changes during thyroid hyperplasia and involution in C3H mice: effects of iodine and 3,5,3'-triiodothyronine during involution.

Abstract: Involution of thyroid hyperplasia was induced in mice by discontinuing a goitrogenic treatment (low iodine diet plus 0.25% propylthiouracil for 10 days) and returning either to a moderate iodine diet (MID; 1 microgram I/day) alone or associated with T3 administration (1 microgram/day) or to a high iodine diet (HID; 10 micrograms I/day) alone or associated with T3 treatment. Thyroid involution was studied by morphological, stereological, and biochemical methods after 2, 4, 6, and 8 days of involution. Age-paired, HID-fed animals were used as controls. When the involution was induced by MID, the glands resumed a normal morphological aspect. The synthesis and secretion of T3 were highly stimulated on day 2, but decreased thereafter. Plasma T4 levels reached a plateau at 50% of the control value from days 2-8. The administration of T3 together with MID accelerated the involution of hyperplasia and colloid accumulation in the follicular lumina. The synthesis and secretion of T3 and T4 remained lower than those in controls. When the involution was induced by HID, the thyroid weight remained higher than that in controls or in any involuting groups. The number of follicles and epithelial cells as well as the glandular thyroglobulin content were twice the control values. A Wolff-Chaikoff effect was evident on day 4, and hypothyroidism persisted. When HID was supplemented with T3 treatment, glandular weight and morphology were normal, but the Wolff-Chaikoff effect occurred earlier. In conclusion, the iodine dose given after a goitrogenic treatment must be carefully controlled; a high but physiological dose can have deleterious effects, whereas a small dose is beneficial. T3 prevents the deleterious effects of HID, but the thyroid enters a resting state.

Compensatory cell proliferation and growth in the rat heart after postnatal hypothyroidism.

Abstract: Measurement of total DNA, RNA, and protein as well as weight of the heart in male rats at 10, 25, 50, and 90 postnatal days revealed that hypothyroidism, as induced by administration from birth of the goitrogen propylthiouracil (PTU), results in highly significant reductions in cardiac cell proliferation and cell growth. These inhibitory effects on hyperplastic and hypertrophic growths were less drastic during the suckling period than during the postweaning period. In the latter period, heart growth of the hypothyroid animals was found to remain at a standstill with regard to all the parameters measured. When, after 25 days of hypothyroidism, PTU treatment was discontinued, the retarded heart showed marked signs of rehabilitation and compensatory development. Indeed, by day 90, total DNA content had essentially compensated for its deficit but total RNA, protein content, and weight, though showing marked compensatory surges (from 80-90% deficit to 20-30%), were not yet fully compensated. The results clearly indicate that the growing heart has a marked ability to be rehabilitated from severe hypothyroid retardation, showing within 2 mo full compensation of cell number and nearly complete compensation of cell growth. It is suggested that rehabilitation of the heart is brought about by physiological restoration not only of the thyroid hormones but also of growth hormone and possibly other thyroid-dependent growth factors.

Effects of thyroid hormone deficiency on glial constituents in developing cerebellum of the rat.

Abstract: Rat litters were treated daily from birth with the antithyroid drug propylthiouracil for 2 or 4 weeks, respectively. Transverse cryostat sections of cerebellar cortex with underlying white matter were incubated with antiserum against glial fibrillary acidic protein. Semiquantitative microscopic evaluations showed a marked decrease in width of the molecular layer in thyroid deficient animals 2 weeks postnatally, as compared to controls. Also, the well delineated GFA-positive glial cell layer extending along the border between white matter and the internal granular layer was absent in thyroid deficient animals. The density of GFA immunoreactivity was increased in white matter in the experimental group. No effects of thyroid deficiency on GFA immunoreactivity could be found after 4 weeks of treatment, indicating a transient disturbance of glial development in the thyroid deficient cerebellum.

Propylthiouracil-associated hepatitis.

Abstract: To the Editor. —We read with interest the article by Hanson 1 in the May 1984Archiveswherein he reviewed the literature on hepatitis associated with propylthiouracil. We concur that propylthiouracil-induced hepatitis is a difficult diagnosis to establish and agree with the practical diagnostic criteria that he proposed. We believe we recently encountered the first male child with propylthiouracil-associated hepatitis. This would tend to suggest that the higher incidence of propylthiouracil-induced reactions among female patients merely reflects the predominance of female patients being treated medically for hyperthyroidism. Report of a Case. —Our patient was a 12-year-old boy who presented with a three- to four-week history of symptoms of hyperthyroidism and unilateral mild exophthalmos. Physical examination confirmed the presence of moderate toxicity. His thyroid gland felt smooth and was diffusely enlarged, measuring 3 × 2 cm in each lobe. A bruit was audible over the gland. Laboratory data revealed a serum

Coupling of Iodotyrosine Catalyzed by Human Thyroid Peroxidase in Vitro

Abstract: The coupling of iodotyrosine (coupling reaction) i s one of the least studied in the formation of thyroid hormone, particularly in human thyroid diseases. This paper describes a method of measuring iodotyrosine coupling catalyzed by human thyroid peroxidase (TPO) in vitro. There were two important requirements to demonstrate the coupling reaction: 1) thyro-globulin with a low thyroid hormone content, and 2) partially purified TPO. Thyroglobulin with low thyroid hormone content was obtained from Grave's and follicular adenoma tissues after propylthiouracil (PTU) therapy and L-T4 therapy, respectively. TPO was prepared from Graves' thyroid by solubilizing the 100,000 × g pellet of thyroid homogenate with sodium deoxycho-late and trypsin, followed by Sephacryl S-300 gel filtration. Before the coupling reaction, thyroglobulin was iodinated with chloramine-T and potassium iodide, followed by dialysis. The coupling reaction was carried out by incubating newly iodinated thyroglobulin with TPO, diiodotyrosine, a ...

Fine structural aspects of the black thyroid induced by minocycline, and the effects of a low iodine diet, propylthiouracil, thyroxine tablet and TSH, on the black discoloration of the rat thyroid.

Abstract: Fine structural aspects of the effect of minocycline, an antibiotic of the tetracycline group, on the rat thyroid were studied. In all the rats administered minocycline (100 mg/kg/day) for 21 days, diffuse black discoloration of the thyroid gland occurred. However, when the rats were fed on a low iodine diet, given propylthiouracil (PTU) or thyroxine tablet with minocycline the black pigmentation of the thyroid gland did not take place. On the other hand, black discoloration of the thyroid was accelerated in the rats administered TSH and minocycline simultaneously. Ultrastructurally, numerous dense bodies containing highly electron-dense deposits were seen in the supranuclear region of the follicular epithelial cells of the black thyroid. These dense bodies, which showed positive acid phosphatase activity, are considered to be lysosomes containing minocycline or its derivatives. It is speculated that minocycline is taken up into follicular epithelial cells with iodine, and that the black discoloration of the thyroid gland is intimately related to iodine metabolism.

A comparison of the effects of propylthiouracil and methimazol on circulating thyroid hormones and various measures of peripheral thyroid hormone effects in thyrotoxic patients

Abstract: Two groups of patients with newly diagnosed thyrotoxicosis were treated with propylthiouracil (PTU) 400 mg every 6 h for 4 days followed by methimazol (MMI) 40 mg every 6 h for 4 days or by MMI for 4 days followed by PTU for 4 days. The shift from MMI to PTU induced a considerable decrease in serum T3 while shift from PTU to MMI led to an increase in serum T3. Serum T4 decreased gradually during the whole treatment period. The opposite variations in serum T3 were accompanied by similar opposite variations in basal metabolic rate (BMR) (P less than 0.001). Hence the rapid variations in serum T3 which can be induced by PTU in thyrotoxic patients, are followed by rapid alterations in the thyrotoxic state as evaluated by BMR.

Influences of Feeding of High-Iodine Eggs on Hypo- and Hyperthyroid Rats

Abstract: The effects of the feeding of high-iodine eggs to rats with an abnormal thyroid status were investigated. Rats were fed for one week on a commercial diet supplemented with propylthiouracil (PTU) (10 mg/100 g diet) or thyroxine-Na (240 micrograms/100 g diet) respectively, to induce hypo- or hyperthyroidism, and then further fed for 4 weeks on the respective drug-supplemented diets, containing 1% (w/w) of either ordinary or high-iodine egg powder. Control (euthyroid) rats were maintained on the commercial diet. The induction of a hypothyroid state resulted in thyroid hyperplasia, with decreased thyroid iodine content, altered serum thyroid relating hormone levels (increased TSH and decreased T3 and T4), elevated serum total cholesterol and reduced serum triacylglycerol (TG) levels, and also increased muscle and adipose tissue lipoprotein lipase (LPL) activities. In contrast, in the hyperthyroid animals, thyroid atrophy, as well as decreased serum TSH and increased T3 and T4 levels, was associated with reduced serum total cholesterol level and muscle LPL activity. There were no essential differences between animals given high-iodine and ordinary eggs in either hypo- or hyperthyroid state, although the effects of PTU treatment on the thyroid and serum TG level appeared to be slightly lesser in rats given high-iodine eggs than in those given ordinary eggs. It is concluded that high-iodine eggs did not have any side-effect on either hypo- or hyperthyroid rat in this study.

Iopanoic acid is of minimal benefit in the treatment of severe hyperthyroidism: conclusions from a case study

Abstract: SUMMARY Iopanoic acid (1 g/d) was used together with propylthiouracil (1200 mg/d) in the treatment of a patient with very severe hyperthyroidism and associated cardiac failure. Although serum total T3 decreased by 75% within 48 h and reached normal after 72 h, free T3 levels did not fall to normal. Total and free T4 remained markedly elevated and features of hyperthyroidism persisted. Estimations of theoretical in vivo occupancy of nuclear thyroid hormone receptors, based on serum free T4 and free T3, suggest that the marked decrease in total T3 would not result in a corresponding decrease in thyroid hormone action. Hence, estimates of potential benefit from oral cholecystographic contrast agents, based only on measurements of total T3, may be unduly optimistic. When temporary agranulocytosis developed in this patient, the prior use of iopanoic acid, by markedly reducing thyroidal iodine uptake, restricted the therapeutic options. Caution should, therefore, be exercised in the use of iodine-containing contrast media as adjunctive antithyroid agents.

Thyrotropin-releasing hormone and insulin release: in vitro studies with islets of normal and dysthyroid mice.

Abstract: Pancreatic islets contain large-quantities of thyrotropin-releasing hormone (TRH) and of its metabolite Histidyl-Proline diketopiperazine (Cyclo His-Pro). The effects of these two putative neurotransmitters on the pancreatic B-cell function have been evaluated in vitro, with islets of normal or dysthyroid mice. TRH and Cyclo His-Pro (10(-11)-10(-6) M) were without effect on insulin release induced by 10-20 mM glucose in islets of normal mice. They transiently accelerated the slow waves of membrane potential triggered in B cells by 10 mM glucose, but did not cause any sustained change in overall electrical activity, and did not affect the rate of 86Rb+ efflux from islet cells. They were also ineffective when insulin release was stimulated by leucine or arginine, or was potentiated by forskolin, an activator of the adenylate cyclase. Hyperthyroidism (induced by injections of thyroxine) caused a fall in islet insulin content, but augmented the 2 phases of glucose-induced release. On the other hand, hypothyroidism (induced by a low iodine diet and propylthiouracil) caused an increase in islet insulin content, but depressed the second phase of release. TRH did not affect either phase of insulin release by islets of hyperthyroid or hypothyroid mice. These results show that pancreatic B cells are not a target for TRH and Cyclo His-Pro.