Showing papers on "Propylthiouracil published in 1975"

Experimental alcohol-induced hepatic necrosis: suppression by propylthiouracil.

Abstract: We have previously reported that a hypermetabolic state, resembling that produced by thryoid hormones, exists in the livers of animals treated chronically with ethanol. We propose that this alteration produces a relative hypoxia in the centrilobular zone of the liver which, if severe enough, leads to cellular death and to the production of hepatitis. Rats consuming ethanol for 30 days, given with a nutritionally adequate diet, and exposed to reduced oxygen tensions for only 6 hr, developed histological and biochemical evidence of hepatocellular necrosis and inflammatory lesions confined to the centrilobular zone. The severity was proportional to the degree of hypoxia. Pair-fed (nonalcohol) controls showed no such lesions. Treatment of the animals with propylthiouracil for 3-10 days abolished the hypermetabolic state of the liver in ethanol-consuming animals, and drastically reduced the histological and biochemical effects of hypoxia in them. These findings may have implications for pathogenesis and treatment of alcoholic hepatitis in man.

Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of "inappropriate secretion of TSH".

Abstract: An 18-yr-old woman with clinical and laboratory features of hyperthyroidism had persistently elevated serum levels of immunoreative thyrotropin (TSH). During 11 yr of follow-up there had been no evidence of a pituitary tumor. After thyrotropin-releasing hormone (TRH), there was a marked increase in TSH and secondarily in triiodothyronine (T3), the latter observation confirming the biologic activity of the TSH. Exogenous T3 raised serum T3 and several measurements of peripheral thyroid hormone effect, while decreasing serum TSH, thyroxine (T4), and thyroidal radioiodine uptake. After T3, the TRH-stimulated TSH response was decreased but was still inappropriate for the elevated serum T3 levels. Dexamethasone reduced serum TSH but did not inhibit TRH stimulation of TSH. Propylthiouracil reduced serum T4 and T3 and raised TSH. This patient represents a new syndrome of TSH-induced hyperthyroidism, differing from previous reports in the absence of an obvious pituitary tumor and in the responsiveness of the TSH to TRH stimulation and thyroid hormone suppression. This syndrome appears to be caused by a selective, partial resistance of the pituitary to the action of thyroid hormone. This case is also compared with previous reports in the literature of patients with elevated serum levels of immunoreactive TSH in the presence of elevated total and free thyroid hormones. A classification of these cases, termed "inappropriate secretion of TSH," is proposed.

Inhibition by iodide of the activation of the thyroid cyclic 3',5' AMP system

Abstract: The action of iodide on the cyclic AMP system of dog thryoid slices has been studied. Iodide inhibits the enhancement of cyclic AMP accumulation in the presence of TSH. Such an effect is also observed in horse, beef and sheep thyroid slices, but not in dog kidney slices stimulated by parathyroid hormone or in rat parotid slices stimulated by isoproterenol. The effect in dog thyroid slices is suppressed by iniM NaClO4, lm M methimazole and lmM propylthiouracil. Similar data have been obtained for prostaglandin Ei stimulation. Effects of thyrotropin mediated by cyclic AMP, i.e., activation of iodothyronine secretion, l-14C-glucose oxidation, and lactate formation, were also inhibited by iodide but not by iodide and methimazole. Similar activations when caused by dbcAMP were not inhibited by iodide. The data suggest a. model in which an intracellular agent resulting from the oxidation of iodide acts on the thyroid cyclic AMP system. (Endocrinology 96: 781, 1975)

Altered plasma half-lives of antipyrine, propylthiouracil, and methimazole in thyroid dysfunction.

Abstract: In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half-lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half-liver plus or minus S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 plus or minus 1.4 hr, 6.7 plus or minus 1.0 hr, and 9.3 plus or minus 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 plus or minus 1.2 hr, 4.3 plus or minus 0.7 hr, and 6.9 plus or minus 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half-lives of these drugs were prolonged to 26.4 plus or minus 4.0 hr, 24.7 plus or minus 34.5 hr, and 13.6 plus or minus 4.8 hr, respectively. Return to the euthyroid state restored plasma half-lives to or toward normal. Alterations in plasma drug half-lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.

Liver disease caused by propylthiouracil.

Abstract: Chronicctive hepatitis consists of a group of chronic liver diseases with continuous or episodic acute inflammation. Long-incubation serum hepatitis virus (HBAg type B) has been implicated as a major causative factor; 1 Wilson disease is another that is considerably less common. 2 Cases of drug-induced chronic active hepatitis are rare; laxatives containing oxyphenisatin 3,4 and methyldopa (Aldomet) 5 are the only known examples. There are only two references in the literature associating propylthiouracil with liver abnormalities 6,7 ; in these cases, however, other possible causes of liver disease were not excluded. This report describes the clinical and light and electron microscopic findings of our first case of liver disease and possible chronic active hepatitis associated with propylthiouracil. Patient Summary A 56-year-old white man entered Duke Hospital with a two-year history of weakness, a 22.7-kg (50-lb) weight loss despite an increased appetite, insomnia, hyperdefecation (five formed stools per day), heat intolerance, and

Correlation of serum triiodothyronine (T3) and thyroxine (T4) with biologic effects of thyroid hormone replacement in propylthiouracil-treated rats.

Abstract: To study the role of T4 to T3 conversion in the biologic action of T4, thyroidectomized, hypothyroid rats were given subcutaneous T4 (08 or 16 μg/100g/day) with or without intraperitoneal propylthiouracil (PTU) (1 mg/100g/day) Rats were killed after 5, 10, 12, or 15 days of treatment and serum T3 and T4 levels were correlated with serum TSH, liver mitochondrial αGPD activity and weight gain In rats killed at 5 days, PTU treatment resulted in higher serum T4, lower serum T3, and a markedly elevated serum T4:T3 ratio, demonstrating that PTU inhibits peripheral conversion of T4 to T3 in the rat Despite higher T4 levels, mean serum TSH was higher in the two groups receiving PTU as well as T4 In rats receiving 08 μg T4, growth rate was also slower with concomitant PTU administration In other groups of rats treated with 08 μg T4 for 10 and 15 days, PTU treatment resulted in similar differences in T3, T4, and T4:T3 ratios and serum TSH At 15 days, rats treated with 08 μg T4 + PTU had significantly lower αGPD activity than rats receiving 08 μg T4 alone PTU treatment had no effect on αGPD activity in rats maintained on 01 μg T3/100g/day indicating that there was no inhibition of this biologic response to T3 by this agent PTU without T4 had no significant effect on TSH, weight gain, or αGPD activity In addition, the dialyzable fraction of T3 and T4 in serum was not altered by this agent These data show that in animals treated with T4, with and without PTU, TSH suppression, αGPD activity and growth correlate better with serum T3 concentrations than with serum T4 This suggests that for maximum biologic activity, T4 must be converted to T3

Pharmacokinetics of Propylthiouracil in Man After a Single Oral Dose

Abstract: A specific method for the analysis ofpropylthiouracil by high pressureion exchange chromatography is presented Preliminary pharmacokinetic data in 6 normal subjects following the administration of 200 mg per os of propylthiouracil indicated a half-life of 11 hr

Pituitary unresponsiveness to thyrotropin-releasing hormone in thyrotoxic patients during chronic anti-thyroid drug therapy and in rats previously treated with excess thyroid hormone.

Abstract: In an attempt to study pituitarythyroid feedback control in thyrotoxic patients, TRH tests were performed in 10 thyrotoxic patients who were treated for varying intervals with propylthiouracil. Plasma TSH was undetectable before and after administration of 500 μg TRH in 7 patients (euthyroid or hypothyroid) after therapy for 1 to 4 months. Also, plasma TSH was undetectable before and after TRH in 3 patients who had been euthyroid for at least 6 months. To explore this abnormality, rats were made thyrotoxic by administering large doses of thyroxine or desiccated thyroid for 3 to 28 days. Discontinuation of thyroid hormone administration was followed by a significant but temporary fall of plasma thyroxine and triiodothyronine concentration below control levels. Duration of the low plasma thyroxine and triiodothyronine concentrations was longer with the prolonged administration of thyroid hormone. Despite low plasma thyroxine and triiodothyronine concentrations, plasma TSH was below normabefore and after adm...

Hepatitis and Propylthiouracil

Abstract: Excerpt Drugs of the thioamide type, introduced during the 1940s for the treatment of thyrotoxicosis, were occasionally noted to produce jaundice. This effect was noted mostly with thiouracil, meth...

Pharmacodynamics of Propylthiouracil in Normal and Hyperthyroid Subjects After a Single Oral Dose

Abstract: Serum levels of propylthiouracil were measured in 8 normal persons and in 7 patients with hyperthyroidism after a single, 300 mg, oral dose of 6-n-propyl-2-thiouracil (PTU). The patients with hyperthyroidism were restudied after 3, 6, and 9 weeks of individualized treatment with PTU. The serum half-life of the drug in normal subjects was 1.65 h. In patients with hyperthyroidism the serum half-life was similar, and it did not change significantly as the euthyroid state was achieved.

Stimulation by propylthiouracil of the hexose monophosphate shunt in human polymorphonuclear leucocytes during phagocytosis.

Abstract: Summary. The effect of propylthiouracil on glucose metabolism in human polymorphonuclear leucocytes was studied. At a therapeutically achievable concentration (0.1 mm), propylthiouracil stimulated hexose monophosphate shunt activity in normal leucocytes during phagocytosis but not in resting cells. However, in the presence of hydrogen peroxide it stimulated hexose monophosphate shunt activity in resting cells, and in the soluble fraction when reduced glutathione and reduced nictotinamide adenine dinucleotide phosphate (NADPH) were also present. Propylthiouracil had no effect on glucose-1-C oxidation in either phagocytosing or resting leucocytes obtained from two male patients with chronic granulomatous disease. Stimulation of the hexose monophosphate shunt activity in normal leucocytes during phagocytosis also was demonstrated with methimazole, thiouracil and thiourea, but not with adenine, uracil or urea. There was an apparent minimal common structure requirement in thiourea. Propylthiouracil had no effect on phagocytosis, formate oxidation, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase or catalase activities. Thus, the stimulation of the hexose monophosphate shunt activity by propylthiouracil is dependent on hydrogen peroxide and is best explained by its stimulation or participation in the glutathione cycle.

Thyroid hormone control of serotonin in developing rat brain.

Abstract: The influence of thyroid hormone on serotonin was studied in different regions of the rat brain. Surgical thyroidectomy of adult male rats led to significant increases in the level of serotonin in the hypothalamus but had no effect on this biogenic amine in the brain stem and basal ganglia. Experimental cretinism, induced by daily propylthiouracil treatment starting at birth, caused increased serotonin levels in all brain regions studied. In contrast. neonatal hyperthyroidism, produced by daily administration of L-triiodothyronine from birth, had no effect on the ontogenic patterns of serotonin. The turnover of serotonin, estimated by determining the rate of increase of the amine following administration of the monoamine oxidase inhibitor, pargyline, was decreased in the brains of 30-day-old cretinous rats when compared to their control littermates. The data suggest that thyroid hormone may exert an important regulatory influence on serotonin metabolism in the developing brain.

Observations on the fine structure of propylthiouracil‐induced “brown degeneration” in the zona reticularis of mouse adrenal cortex

Abstract: Propylthiouracil (6-propyl-2-thiouracil), an anti-thyroid agent, was fed to mice in a concentration equal to 0.1% of their diet for periods of 10 and 15 weeks. The cells of the inner zone of the adrenal cortex were examined with the electron microscope. In animals receiving propylthiouracil for ten weeks mitochondria were altered and the smooth endoplasmic reticulum (SER) showed a marked focal proliferation. In contrast to control animals rough endoplasmic reticulum was abundant and was frequently associated with the hyperplastic SER. After 15 weeks these alterations were no longer present but had been replaced by a spectrum of "brown degeneration." The less affected cells were characterized by increased numbers of liposomes and lysosomes and the more affected cells by liposomal and mitochondrial degeneration. These observations emphasize that "brown degeneration" is a true degenerative process and not a spontaneous proliferation of ceroid pigment. It is suggested that the changes described may be directly related to an alteration in cholesterol metabolism.

Cyclic AMP in the thyroid of the rat fed prophylthiouracil: in vitro unresponsiveness to thyrotropin.

Abstract: Fragments of thyroid from rats fed Purina +0.1% propylthiouracil were incubated in vitro and the concentration of cyclic AMP measured. The normal gland showed a 3-fold increase in cyclic AMP with 50 mU thyrotropin per ml or 10(-4) M prostaglandin E1; tissue from rats fed propylthiouracil for 10 days to 6 months responded to prostaglandin E1 but not to thyrotropin. Feeding Purina without propylthiouracil for 1 month after 5 months of goitrogen restored thyrotropin-responsiveness, as did, to a lesser extent, injection of triiodothyronine, 50 mug twice daily for 5 days.

Effect of Frequency of Administration on the Accumulation and Metabolism of [35S]Propylthiouracil by the Rat Thyroid

Abstract: Repeated administration (every 8 h) of [35S]Propylthiouracil (PTU) resulted in gradual accumulation of unmetabolised PTU by the thyroid gland until the 9th dose was given. Subsequently a plateau-level was attained which was proportional to dose with the two dose levels used. During repeated administration once daily the intrathyroid concentration of free PTU varied markedly in the course of each 24-h period. Chromatographic analysis showed four compounds: PTU, sulphate and two unidentified compounds as well as origin material. The proportions of these compounds were different in the different dose studies. Thus, the ratio of compound Y⁄compound X was found to be inversely related to dose. The plasma 35Sradioactivity increased throughout the studies and was proportional to dose. (Endocrinology 96: 1324, 1975)

Binding of the 35-s of 35-s-propylthiouracil by follicular thyroglobulin in vivo and in vitro.

Abstract: Radioactivity was found bound to follicular thyroglobulin after administration of 35-S-propylthiouracil (PTU) to rats. Denaturation of the thyroglobulin using various procedures could not separate the 35-S from the protein; it was concluded that the 35-S is bound to thyroglobulin covalently. Fractionation of saline-soluble thyroid proteins was performed by ultracentrifugation on sucrose gradients. The PTU-sulphur/thyroglobulin (S/Tg) molar ratio was calculated in all fractions. One hour after the injection of PTU the S/Tg molar ratio was the same for 19S thyroglobulin from rats on stock diet and 18S thyroglobulin from rats on low iodine diet. Injection of KI to the animals before administration of 35-S-PTU significantly reduced the ratio. The highest S/Tg ratio 1.10 was noted at 19S thyroglobulin, 17 h after a single injection of PTU. Daily injection of PTU for six days increased the S/Tg ratio to 3.3. Inverse relationship between dose of PTU and S/Tg ratio was noted at one hour. In animals injected with large dose of 35-S-PTU and sacrificed several hours later the S/Tg was higher at the 12S subunits than at the 19S protein. The amount of PTU bound to 3-8S subunits was minimal. Sulphite liberated 64 percent of the 35-S bound to thyroglobulin which appeared as four compounds on thin layer chromatography plates. The main 35-S compound liberated by sulphite was sulphate.

Role of growth hormone in the enhancement of the propylthiouracil-induced goitrogenesis by small doses of thyroxine.

Abstract: The potentiation of the propylthiouracil (PTU)-induced goitrogenesis after chronic administration of small doses of thyroid hormone has been attributed to the high circulating level of thyrotrophin (TSH) or to the re-instatement of insulin. In re-examining this problem radioimmunoassayable concentrations of TSH, thyroxine (T4), insulin, and growth hormone (GH) were observed in sera of rats at sequential intervals after surgical or chemical thyroidectomy and after thyroidectomy and replacement therapy with GH or T4. In addition, TSH, GH or a combination of both hormones were injected into hypophysectomized recipients in a further attempt to delineate the effect of either hormone on the thyroid. As expected, the rate of body growth was inversely proportional to the apparent severity of the hypothyroidism achieved in the several experimental groups. Goitrogenesis was enhanced after T4 treatment but evidently was not the exclusive result of increased blood levels of TSH or insulin. Evidence is presented that suggest the enhancement of goitrogenesis may be a growth phenomenon involving the additive or synergistic action of GH and TSH and possible of other hormones.

A new syndrome of "inappropriate secretion of tsh"

Abstract: A B S T R A C T An 18-yr-old woman with clinical and laboratory features of hyperthyroidism had persistently elevated serum levels of immunoreactive thyrotropin (TSH). During 11 yr of follow-up there had been no evidence of a pituitary tumor. After thyrotropin-releasing hormone (TRH), there was a marked increase in TSH and secondarily in triiodothyronine (T3), the latter observation confirming the biologic activity of the TSH. Exogenous T3 raised serum Ts and several measurements of peripheral thyroid hormone effect, while decreasing serum TSH, thyroxine (T4), and thyroidal radioiodine uptake. After T3, the TRH-stimulated TSH response was decreased but was still inappropriate for the elevated serum Ta levels. Dexamethasone reduced serum TSH but did not inhibit TRH stimulation of TSH. Propylthiouracil reduced serum T4 and Ts and raised TSH. This patient represents a new syndrome of TSH-induced hyperthyroidism, differing from previous reports in the absence of an obvious pituitary tumor and in the responsiveness of the TSH to TRH stimulation and thyroid hormone suppression. This syndrome appears to be caused by a selective, partial resistance of the pituitary to the action of thyroid hormone. This case is also compared with previous reports in the literature of patients with elevated serum levels of immunoreactive TSH in the presence of elevated total and free thyroid hormones. A classification of these cases, termed "inappropriate secretion of TSH," is proposed.

Influence of age on the development of hypothyroidism by propylthiouracil feeding in the chick (Gallus domesticus)

Abstract: 1. 1. Propylthiouracil (0·15 per cent) was fed in mash to chicks aged 16 and 37 days for a period of 27 days and then were taken off propylthiouracil (PTU). 2. 2. Body weight, liver weight, liver glycogen, thyroid weight, plasma cholesterol and serum glutamic pyruvic transaminase (SGPT) were determined at various time intervals after initiation of PTU feeding and then when taken off PTU. 3. 3. On initiation of PTU feeding the hypothyroid changes mostly occurred earlier and were more severe in the younger chicks than in the older ones. 4. 4. Reverse changes (i.e. towards normal values) after taking chicks off PTU were faster in the older birds compared to the younger ones. 5. 5. Irrespective of the age at the start of PTU feeding, it took one week before normal growth rate was resumed after taking chicks off PTU. 6. 6. Results of these studies suggest that younger birds show more severe symptoms to the hypothyroid effect of PTU. However, given enough time after taking chicks off PTU, except for body weight, all the biochemical changes of hypothyroidism disappear, at least under the conditions of present study.

Studies on the heterogeneity of labeled iodoprotein from iodine-replete and iodine-deficient rats as determined by susceptibility to proteolysis.

Abstract: Thyroid iodoprotein from rats fed a high-iodine diet (HID) or a low-iodine diet (LID) were labeled with radioiodine in vivo for periods ranging from 4 hr to several days. Standardized aliquots of thyroid homogenate from rats with various treatments were digested for 4 hr with 1% pancreatin or with 0.003% pancreatin after 30 min pretreatment with beta-mercaptoethanol (ME-P). Four-hr labeled iodoprotein from both LID and HID rats was equally susceptible to digestion with 1% pancreatin; however, such iodoprotein from LID rats was more susceptible to digestion with ME-P than that from HID rats. With increasing intervals up to 7 days between administering radioiodine and removing the thyroids, there was a progressive rise in the resistance to digestion in iodoprotein from LID rats, but only a slight increase in resistance in iodoprotein from HID rats. If propylthiouracil was added to the diet beginning 24 hr after radioiodine administration, there was a marked increase in the rate of development of resistance of iodoprotein to digestion. Radioautographs showed that the radioiodine was localized primarily in the peripheral follicles after 2 days PTU. Similar differences in susceptibility to digestion were found in purified thyrogobulin prepared from HID and LID rats. No change in susceptibility to digestion of thyroid iodoprotein with time after labeling was seen in hypophysectomized LID rats in which thyroid secretion and thyroglobulin turnover is known to proceed at an extremely slow rate. The data indicate that there are at least two types of iodinated thyroglobulin in the rat thyroid. One is readily susceptible to digestion and has a rapid turnover in the thyroid. The other is more resistant to digestion, has a slow rate of turnover and is located primarily in the peripheral follicles.

Inhibition of multiplication of Mycobacterium leprae by several antithyroid drugs.

Abstract: Multiplication of Mycobacterium leprae in the mouse footpad was inhibited when mice were fed, mixed in their diet, 0.05 per cent methimazole, 0.066 per cent USP thyroid powder, methimazole plus thyroid powder, 0.15 per cent 5-n-heptyl-2-thioxo-4-thiazolidinone, 0.1 per cent propylthiouracil, and 0.1 per cent thambutosine for 154 days, beginning on the day of inoculation. All of the treatment regimens, except for the 2 containing thyroid powder, decreased the plasma concentrations of thyroxine and protein-bound iodine. It is suggested that the 2 antithyroid drugs, methiomazole and propylthiouracil, and the 2 antimicrobial agents, heptylthioxothiazolidinone and thiambutosine, all of which possess structural features in common, may exert the antithyroid and antimicrobial effects through a common mechanisms.

Influence of hypothyroidism on the lacticodehydrogenase isoenzymes during the cerebral cortex maturation in the rat

Abstract: The isoenzymes of lacticdehydrogenase of cerebral cortex, investigated by starch gel electrophoresis, are changed during pre and neonatal thyroidectomies in relation to these factors: a) dose of the drug (131I or Propylthiouracil), b) date of gestation, c) the age of the animal (with a maximal modification at the 17th-18th day). They retain an enzymatic pattern like the fetal pattern, showing the retardation of the developing central nervous system.

Rational therapy for thyroid storm.

Abstract: An approach to the management of patients with thyroid storm is described. The treatment regimen, which is directed against the abnormalities as they are presently understood, incorporates: (a) Propranolol to inhibit the catecholamine-mediated peripheral effects of the circulating thyronines; (b) Propylthiouracil to inhibit thyroid hormone synthesis and to inhibit peripheral conversion of thyroxine to triiodothyronine (T3), the predominant source of T3 production; (c) Iodine to block the glandular release of thyroid hormones; (d) Dexamethasone along with general supportive therapy. The regimen has been used for a 13 year old schoolgirl with thyroid storm, and the induced rapid fall in serum T3 levels is illustrated. It has also been used in patients with florid thyrotoxicosis undergoing emergency surgery and has resulted in marked clinical improvement associated with rapid decreases in serum T3 levels. It is a simple and efficient regimen, rendering cumbersome forms of therapy such as plasmapheresis and peritoneal dialysis unnecessary.

Synthesis and antiperoxidase activity of propylthiouracil derivatives and metabolites

Abstract: Some metabolites and potential metabolites of the antithyroid drug propylthiouracil (6-n-propyl-2-thiouracil) were synthesized and examined for antithyroid peroxidase activity. The compounds positively identified as metabolites of propylthiouracil or implicated in its metabolism were, at the concentrations examined, either completely inactive as thyroid peroxidase inhibitors or only weakly active. Propylthiouracil glucuronide was the most active metabolite, with a potency slightly more than 10% of that of the parent compound. All derivatives in which the sulfur was replaced by oxygen were completely inactive. Assays of propylthiouracil derivatives not implicated in metabolism demonstrated that 1-acetyl-6-n-propyl-2-thiouracil and 5-hydroxy-6-n-propyl-2-thiouracil were equally as potent as propylthiouracil and that 2-thiouracil-6-propanol and 2-thiouracil-6-propionic acid were weakly active. The data presented demonstrate that biotransformation of propylthiouracil, which occurs primarily at the S group, results in a substantial loss in antiperoxidase activity.