Showing papers on "Propylthiouracil published in 1984"
TL;DR: Results indicate that endogenous thyroid hormone induces the synthesis of ventricular heavy chain alpha, which as a dimer forms the V1 isomyosin, or plays a permissive role for the continued synthesis of heavy chainalpha in ventricles of fetal and neonatal rats.
170 citations
TL;DR: A sensitive, specific, and practical bioassay for thyroid-stimulating immunoglobulin (TSI) is now available for clinical use and correlated well with relapse or remission after antithyroid drug therapy.
Abstract: A sensitive, specific, and practical bioassay for thyroid-stimulating immunoglobulin (TSI) is now available for clinical use. Fifty-seven of 61 patients with untreated hyperthyroid Graves’ disease were TSI positive (sensitivity, 93%). TSI was undetectable in all normal subjects and in patients with Hashimoto’s thyroiditis (without concurrent Graves’ ophthalmopathy), nontoxic goiter, and toxic nodular goiter (specificity, 100%). The prevalence of TSI in serum declined after therapy, particularly during methimazole or propylthiouracil treatment. TSI correlated well with relapse or remission after antithyroid drug therapy. All 12 patients who were TSI negative at the time of discontinuing antithyroid drug therapy remained in remission (average follow-up of 10 months). TSI values in Graves’ disease correlated better with thyroid dysfunction than with ophthalmopathy. Prenatal TSI activity tended to be higher in mothers of infants who developed neonatal Graves’ disease than in atrisk mothers who delivered norma...
121 citations
TL;DR: The similar patterns of change in TSI during treatment with TD and PC are strong evidence against an immunosuppressive effect of TD and provide indirect evidence for the theory that the restoration of the euthyroid state is the cause of decreasing TSI levels and normalization of the immune regulation in many patients duringreatment with antithyroid drugs.
Abstract: Previous studies have shown that serum titers of thyroid-specific antibodies such as thyroid-stimulating immunoglobulins (TSI), TSH-displacing antibodies (TDA), or microsomal antibodies (MAb) decrease in patients with Graves’ disease during therapy with thionamide drugs (TD). In keeping with some in vitro results it was postulated that TD have an immunosuppressive action which may be partly responsible for the beneficial effects. To further elucidate this theory, we compared the changes in TSI during treatment with TD such as methimazole (MMI) and propylthiouracil (PTU) as well as with perchlorate (PC), an unrelated compound with a different mode of therapeutic action. Of 69 patients with hyperthyroidism due to Graves' disease, serum from 62 (90%) was positive for TSI, as measured by cAMP accumulation in a thyroid tissue culture assay. Six patients had to be excluded due to noncompliance. Of the remaining 56 patients, those 41 subjects (73%)with good control of the disease were followed up to 24 months du...
110 citations
TL;DR: It is suggested that normal TSH levels induce close to maximal expression of the thyroglobulin gene but that continuous presence of TSH is required in order to maintain the gene in an activated state.
Abstract: The availability of rat thyroglobulin cDNA clones was exploited to study the regulation of thyroglobulin gene transcription by thyrotropin (TSH). Groups of rats were subjected to treatments leading to reduction or increase in the rat serum TSH (rTSH) levels. Thyroid gland nuclei were isolated, incubated in vitro in the presence of 32P-labeled uridine triphosphate, and thyroglobulin transcripts were quantitated by hybridization to immobilized rat thyroglobulin cDNA clones. Transcription of the thyroglobulin gene was found to be very active in thyroid nuclei from control animals. It represented about 10% of total RNA polymerase II activity. Chronic hyperstimulation of the thyroid glands with endogenous rTSH was achieved in rats treated with the goitrogen propylthiouracil. No significant increase of thyroglobulin gene transcription could be measured in thyroid nuclei from these animals. On the contrary, a dramatic decrease in thyroglobulin gene transcription was observed in those animals in which endogenous rTSH levels had been suppressed by hypophysectomy or by the administration of triiodothyronine. Injection of exogenous bovine TSH in such animals readily restored transcriptional activity of the gene. Our results identify transcription as an important regulatory step involved in TSH action. They suggest that normal TSH levels induce close to maximal expression of the thyroglobulin gene but that continuous presence of TSH is required in order to maintain the gene in an activated state.
103 citations
TL;DR: The results suggest that there may be major changes in the distribution and metabolism of T3 or that an alternative enzymatic pathway is the predominant source of extrathyroidally produced T3 in these rats.
Abstract: Earlier studies have shown larger increments in serum T3 in 2-week-old congenitally hypothyroid rats than in euthyroid controls after injections of small doses of T4. Since hepatic and renal 5′-deiodination of T4 to T3 in vitro (5′D-I) is reduced during the neonatal period and in hypothyroidism, those results suggest that there may be major changes in the distribution and metabolism of T3 or that an alternative enzymatic pathway is the predominant source of extrathyroidally produced T3 in these rats. The alternative pathway, 5′D-II, is a relatively minor source of serum T3 in adult euthyroid rats, but the contribution of this pathway to the extrathyroid T3 pool during the neonatal period and in hypothyroxinemia is not known. Consequently, we studied [125I]T4 and [131I]T3 kinetics and fractional T4 to T3 conversion in 2-week-old euthyroid and hypothyroid rats and then explored the source of circulating T3 by manipulating 5′D-I activity with propylthiouracil and that of 5′D-II with thyroid hormone. The plas...
74 citations
TL;DR: It is concluded that patients with Graves' disease may be prone to develop this complication of antithyroid drug therapy because of underlying immunological abnormalities.
Abstract: Studies of in vitro immunoreactivity to propylthiouracil (PTU), methimazole (MMI), and carbimazole (CARB), as assessed by peripheral blood lymphocyte transformation and 2 antibody tests, were carried out in 12 patients with Graves' hyperthyroidism who had developed agranulocytosis during treatment with PTU (11 patients) or CARB (1 patient) from 1 week to 10 yr earlier Significant lymphocyte transformation responses to antithyroid drugs (stimulation indices greater than mean +/- 2 SD for normal subjects) were found in 5 of 6 patients tested, in 1 patient to PTU only, in 3 patients to MMI only, and in 1 patient to both PTU and MMI, but in none of 10 patients currently being treated with PTU who did not develop agranulocytosis Circulating antibodies causing neutrophil agglutination in the presence of antithyroid drugs were demonstrated, using the indirect Coombs test, in 5 of 7 patients tested, in 2 patients to PTU only, in 3 patients to CARB only and in 1 patient (the only one tested with MMI) to PTU and MMI Lymphocyte transformation and antibody tests to PTU were both carried out in 6 patients Of these, both tests were positive in one patient, both negative in 3 patients, and 1 negative and 1 positive in 2 patients In the 1 patient in whom both tests were carried out with CARB (patient 3), tests were negative, whereas in the 1 patient in whom both tests were carried out with MMI (patient 3), 1 test was positive, whereas the other was negative Thus, in patients in whom both tests were carried out using the same drug, correlation between lymphocyte transformation responses and the detection of neutrophil antibodies was found in 5 of 6 cases Antibodies reactive with neutrophils were also detected in 2 of the 5 patients tested using an enzyme-linked immunosorbent assay In this test antibodies to PTU or MMI were not demonstrated Possible mechanisms for the neutrophil depression in relation to these findings are discussed It is concluded that patients with Graves' disease may be prone to develop this complication of antithyroid drug therapy because of underlying immunological abnormalities
68 citations
Journal Article•
TL;DR: Nine of 105 cats with hyperthyroidism treated with propylthiouracil developed a serious immune-mediated drug reaction during treatment; in these cats, anemia and thrombocytopenia resolved and Coombs' and antinuclear antibody tests became negative within 2 weeks.
Abstract: Nine of 105 cats with hyperthyroidism treated with propylthiouracil developed a serious immune-mediated drug reaction during treatment. Adverse clinical signs, which developed after 19 to 37 days (mean, 24.8 days) of propylthiouracil administration, included lethargy, weakness, anorexia, and bleeding diathesis. Physical examination revealed pale mucous membranes, and petechial hemorrhages of the skin and oral cavity. Results of hematologic testing revealed severe anemia and thrombocytopenia. The direct antiglobulin (Coombs') test was positive in all 7 cats evaluated, whereas the serum antinuclear antibody titer was greater than or equal to 1:10 in 5 of the 8 cats tested. In 4 of the cats, treatment included appropriate supportive therapy and cessation of propylthiouracil; in these cats, anemia and thrombocytopenia resolved and Coombs' and antinuclear antibody tests became negative within 2 weeks.
66 citations
Journal Article•
TL;DR: The potential for toxicity is discussed in relationship to the cellular mechanisms of action of thyroid hormones and the following therapy is recommended to decrease further the toxic potential.
Abstract: Although thyroid medications are commonly prescribed, there are only nine case reports describing the consequences of acute excessive ingestion of thyroid hormones Two additional cases are presented and the prior nine cases are reviewed The potential for toxicity is discussed in relationship to the cellular mechanisms of action of thyroid hormones Although the potential for toxicity is low, the following therapy is recommended to decrease further the toxic potential: (1) lavage and activated charcoal to decrease absorption, (2) cholestyramine to decrease enterohepatic circulation (3) prednisone and/or propylthiouracil to decrease conversion of thyroxine to triiodothyronine, and (4) propranolol to block metabolic effects If symptoms of toxicity develop, then attempts to remove thyroid hormones should be undertaken using exchange transfusion
50 citations
Journal Article•
TL;DR: An overall evaluation of central catecholaminergic pathways in whole brain indicated a much smaller effect of hypothyroidism, with no (norepinephrine) or only minor (dopamine) deficits in transmitter content and smaller, transient reductions in turnover.
Abstract: Thyroid status is thought to play a major role in establishing the time course of development of sympathetic nerve pathways. Hypothyroidism induced by perinatal administration of propylthiouracil to developing rats resulted in substantial deficits in cardiac norepinephrine levels that persisted into adulthood. This shortfall was not accompanied by compensatory receptor supersensitivity or by increased utilization of remaining transmitter. Indeed neonatal hypothyroidism is known to result in end-organ subsensitivity and the norepinephrine turnover rate, an index of spontaneous activity of the neuron, was found to be markedly subnormal. The ability of cardiac sympathetic neurons to release transmitter upon pharmacological challenge was also compromised by hypothyroidism: in control neonates, administration of tyramine resulted in displacement of norepinephrine from nerve terminals, a response which was present very early in development. Hypothyroid rats did not develop the ability to release transmitter in response to tyramine until 10 days postnatally and a fully mature response was not apparent until weeks later. Ontogeny of the capability to release norepinephrine in response to hypotension (baroreflex) also was assessed through administration of hydralazine, a direct arteriolar vasodilator; control rats showed a characteristic development of this response at the end of the 2nd postnatal week, whereas hypothyroid rats did not show any potential for norepinephrine release until young adulthood (41 days). In comparison to cardiac sympathetic neurons, an overall evaluation of central catecholaminergic pathways in whole brain indicated a much smaller effect of hypothyroidism, with no (norepinephrine) or only minor (dopamine) deficits in transmitter content and smaller, transient reductions in turnover.(ABSTRACT TRUNCATED AT 250 WORDS)
41 citations
TL;DR: This case illustrates the following points: Hyperthyroidism occasionally develops years after hypothyroidism; transplacental treatment of the fetus by maternal propylthiouracil ingestion may thus be necessary during the last trimester, but only when there is a high degree of probability that the fetus is at risk.
37 citations
TL;DR: Thyroid hyperplasia was induced in C3H mice by a low iodine diet feeding supplemented with propylthiouracil and the cellular proliferation was studied by autoradiography after a pulse labelling with [3H]thymidine.
Abstract: Thyroid hyperplasia was induced in C3H mice by a low iodine diet feeding supplemented with propylthiouracil. The morphological modifications associated to the development of hyperplasia were analyzed at light microscopical level and the cellular proliferation was studied by autoradiography after a pulse labelling with [3H]thymidine. The initial modification during the course of hyperplasia is the development of the vascularization. It includes the dilatation of the capillaries, which occurs before any extended modification of the follicular cells and any change of the thyroid weight, and the proliferation of endothelial cells which starts earlier than that of follicular cells.
TL;DR: These studies may be relevant to the practice of administering propylthiouracil, propranolol, and iopanoic acid to pregnant women and the effects of drugs and other compounds on human and rat PT4ase.
Abstract: Human and rat placental homogenates contain inner ring deiodinase activity (PT4ase) towards T4 and T3. This activity may decrease the transfer of T4 and T3 across the placenta and influence thyroid hormone disposal in the fetal circulation. Data are now presented on human PT4ase in subcellular fractions, the Km of human PT4ase, and the effects of drugs and other compounds on human and rat PT4ase. The specific activity (nanograms of rT3 produced per min/ mg protein) of each fraction of human placenta was as follows: nuclear, 0.07; mitochondrial, 0.15; lysosomal, 0.19; microsomal, 1.30; and cytosol, 0.01. The apparent Michaelis-Menton (Km) for PT4ase in human placental microsomes was 1.2 × 10-7 M. T3, 3,3′-diiodothyronine, iopanoic acid, iodoacetic acid, diamide, and propranolol all exhibited dose-dependent inhibition of human and rat PT4ase when tested in the presence of 10 mM dithiothreitol (DTT). Propylthiouracil did not inhibit PT4ase at 10 mM DTT, but when the DTT concentration was lowered to 0.25 mM, ...
TL;DR: Agranulocytosis developed in a patient who was receiving propylthiouracil and Cytotoxicity was shown to be mediated by a complement-dependent IgM antibody.
Abstract: Agranulocytosis developed in a patient who was receiving propylthiouracil. Using a microgranulocytotoxicity assay, serum taken from the patient was shown to be strongly granulocytotoxic when tested against the patients granulocytes and those obtained from two of eight normal subjects. Tests for granulocyte agglutinins and for lymphocytotoxicity were negative. Granulocytotoxic activity decreased as the patient's peripheral granulocyte count recovered. Cytotoxicity was shown to be mediated by a complement-dependent IgM antibody.
TL;DR: It is suggested that reduction in hypothalamic dopaminergic tone may have contributed to the inappropriately increased TSH secretion in the patient and regression of the clinical manifestations of hyperthyroidism occurred during bromocriptine drug therapy.
Abstract: We describe a patient with TSH-induced hyperthyroidism successfully treated with bromocriptine. A 25-yr-old woman was found to have hyperthyroidism due to excessive TSH secretion; no pituitary tumor was found. Her serum T4 level ranged between 21.9 and 25.9 micrograms/dl and that of T3 between 283 and 314 ng/dl. Serum TSH was between 5 and 9 microU/ml with an exaggerated response to TRH. Basal metabolic rate was +26 to +38%. Serum PRL was also elevated (79 ng/ml). Administration of bromocriptine for 4 months decreased serum TSH and PRL levels to normal with a concomitant fall in levels of serum T3 and T4. Regression of the clinical manifestations of hyperthyroidism occurred during bromocriptine drug therapy. These results suggest that reduction in hypothalamic dopaminergic tone may have contributed to the inappropriately increased TSH secretion in the patient.
TL;DR: It seems prudent to closely monitor intestinal shunt patients on drug therapy by both laboratory and clinical methods, as no general rules presently emerge from the data available.
Abstract: The pharmacokinetics of ampicillin and propylthiouracil were studied in 6 and 9 patients, respectively, before and several times up to a year after a shunt operation for extreme obesity. The drugs were given intravenously and orally making it possible to estimate the absolute bioavailability. The bioavailability of propylthiouracil (about 80%) was unchanged by the surgical procedure but the fraction of ampicillin (given as pivampicillin) absorbed decreased from a preoperative value of 109 ± 44% to 44 ± 30% 12 months after the bypass operation. Volumes of distribution transiently decreased in the postoperative period for ampicillin. Clearance was initially reduced for both ampicillin and propylthiouracil after operation but returned to normal values a year later. Half-lives of both drugs were unchanged.
TL;DR: Cough productive of sputum, exertional dyspnea, and hypoxemia developed in two patients with Graves' disease after six months (patient 1) or three weeks (patient 2) of treatment with propylthiouracil, 300 mg/day.
Abstract: • Cough productive of sputum, exertional dyspnea, and hypoxemia developed in two patients with Graves' disease after six months (patient 1) or three weeks (patient 2) of treatment with propylthiouracil, 300 mg/day. Chest roentgenograms and transbronchial lung biopsy specimens revealed diffuse interstitial pneumonitis. Lymphocyte transformation by phytohemagglutinin was highly stimulated by propylthiouracil. Symptoms and signs improved after cessation of the drug therapy and administration of prednisolone acetate. These cases represent the first report of a complication of diffuse interstitial pneumonitis induced by propylthiouracil. (Arch Intern Med1984;144:1764-1765)
TL;DR: Thyro glands with Hashimoto's thyroiditis had activities of T4 to T3 conversion similar to the normal thyroid glands, and these values were greater than that of the normal thyroids but did not differ significantly when compared with each other.
Abstract: To investigate the activity of the thyroid gland to convert T4 to T3, we measured the activity of thyroid T4 5'-deiodinase in the following human thyroid glands: 9 normal glands, 5 Hashimoto's thyroiditis, 13 follicular adenomas, 11 methimazole (MMI)-treated Graves' disease (GD), 11 propranolol iodide-treated GD, and 8 propylthiouracil (PTU)-treated GD. The enzyme activity was determined by the ability of 100,000 X g pellet of the thyroid homogenate to convert T4 to T3 in vitro. Normal thyroids showed the enzyme activity of 1.59 +/- 0.18 (mean +/- SEM) pmol T3/mg protein/min. Euthyroid Hashimoto's thyroiditis displayed the enzyme activity of 1.01 +/- 0.15 pmol T3/mg protein/min, which was similar to the normal thyroid enzyme activity. The hypothyroid gland of Hashimoto's thyroiditis showed the enzyme activity of 1.8 pmol T3/mg protein/min. Follicular adenomas showed a wide range of enzyme activity with the mean level of 3.24 +/- 0.82 pmol T3/mg protein/min that did not differ significantly from that of the normal thyroids. Interestingly, one adenoma, despite TSH suppression that ordinarily decreases enzyme activity, showed the greatest activity of 11.0 pmol T3/mg protein/min. Graves' thyroids following treatment with MMI, PTU, and propranolol-iodide showed enzyme activities of 4.61 +/- 0.53, 3.95 +/- 0.43, and 3.51 +/- 0.46 pmol T3/mg protein/min, respectively; all these values were greater than that of the normal thyroids (P less than 0.01), but did not differ significantly when compared with each other. In summary, thyroid glands with Hashimoto's thyroiditis had activities of T4 to T3 conversion similar to the normal thyroid glands.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The results suggest that the high serum rT3 level nearly always seen in "the low T3 syndrome" in humans is merely a coincidental character of the human species, and that it has little importance for in vivo homeostasis.
Abstract: Fasting or administration of propylthiouracil (PTU), ipodate, or dexamethasone are all known to induce a pattern of low serum triiodothyronine (T3) concentrations and high serum reverse T3 (rT3) concentrations in humans. In the present study it was found that this is not a universal phenomenon. In normal dogs exposed to fasting or these various pharmacologic agents, the serum T3 level was always depressed as in humans. However, different variations in serum rT3 levels were observed. Fasting and PTU administration were accompanied by slight decreases in the serum rT3 concentration. A single dose of ipodate did not alter serum rT3 levels, but serum thyroxine (T4) levels increased by more than 50%. Dexamethasone induced a considerable increase in serum rT3 levels, while serum T4 levels were unaltered. The results suggest that the high serum rT3 level nearly always seen in "the low T3 syndrome" in humans is merely a coincidental character of the human species, and that it has little importance for in vivo homeostasis.
TL;DR: It is suggested that thyroid status modulates P-TRH concentrations, which may be due to the disappearance of the TRH-DA in response to hypothyroidism.
Abstract: The effect of hypothyroidism on pancreatic TRH (P-TRH) and P-TRH-degrading activity (P-TRH-DA) was studied in adult rats. Hypothyroidism was induced in three groups during 4, 6, or 9 weeks by propylthiouracil (PTU) in drinking water and a low iodine diet (LID). Another group received PTU-LID for 6 weeks, followed by 5 weeks on a normal diet to restore euthyroidism. A possible toxic effect of PTU per se was eliminated by treating one control group with PTU and T3. P-TRH and TRH-DA were measured by specific RIA. In the hypothyroid groups, P-TRH concentrations (mean +/- SEM) were increased 10-fold (6.95 +/- 2.09; 5.51 +/- 1.3; 9.79 +/- 3.3 pg/(mg X 100 g BW), respectively, with a control value of 0.55 +/- 0.39, P less than 0.01). This increase was reversible, as shown by the group on PTU-LID followed by a normal diet (0.58 +/- 0.39, NS). P-TRH-DA present in the control group was decreased after 4 weeks of PTU-LID treatment and totally abolished after 6 and 9 weeks of PTU-LID treatment. In conclusion, these results suggest that thyroid status modulates P-TRH concentrations. This effect may be due to the disappearance of the TRH-DA in response to hypothyroidism. P-TRH stores may be regulated by the enzyme(s) involved in P-TRH-DA.
TL;DR: The results suggest that two different mechanisms were involved in renin release, one activated in T rats and the other in pharmacological hypothyroidism.
Abstract: Kinetic studies of the renin-angiotensin system (RAS) were carried out by measuring plasma renin activity (PRA), plasma renin concentration (PRC) and plasma renin substrate (PRS). Changes in this system were studied during hypothyroidism, after administration of propylthiouracil (PTU), and in thyroidectomized rats. A significant decrease in PRA and PRC was observed in those animals previously treated with PTU. However, a significant increase in PRC, and a decrease in PRS, were found in T animals, but no changes in PRA were observed. In these animals, after daily administration of potassium iodide for 1 week (T + KI), no changes in RAS were observed in comparison with T rats. Nevertheless, administration of daily doses of triiodo-L-thyronine (T + T3) induced a significant increase in PRA, leaving PRC unaltered. In this case the changes in PRA were related to the increase in PRS after T3 treatment. These results suggest that two different mechanisms were involved in renin release, one activated in T rats and the other in pharmacological hypothyroidism.
TL;DR: Variations in renin- angiotensin-aldosterone system (RAAS) in experimentally induced hyperthyroidism were studied and the active hormone is seen to be triiodothyronine, confirmed by using the antithyroid preparation, propylthiouracil, to inhibit the conversion of thyroxine.
Abstract: Variations in renin- angiotensin-aldosterone system (RAAS) in experimentally induced hyperthyroidism were studied. The changes observed in the RAAS in these conditions, evaluated through the plasma renin activity (PRA), are parallel to serum aldosterone concentration (AC). An increase in PRA and AC is produced following the administration of triiodothyronine, possibly through elevated adrenergic activity: beta-blocker, propranolol, returned the PRA and AC to normal. The active hormone is seen to be triiodothyronine, confirmed by using the antithyroid preparation, propylthiouracil, to inhibit the conversion of thyroxine. Propylthiouracil administration to hyperthyroid animals lowers the PRA and AC.
TL;DR: The results support the views that: (1) endogenous thyroid hormones contribute to the maintenance of normal developmental patterns of ODC and the polyamines, and (2) the ODC/polyamine system participates in events modulating subsequent tissue growth.
TL;DR: Treatment of rats with propylthiouracil for one to two weeks caused an increase in glutathione S-transferase (GST) activity of the liver cytosol, but not of the particulate fraction, and enzyme activity towards chlorodinitrobenzene was the highest.
Abstract: Treatment of rats with propylthiouracil for one to two weeks caused an increase in glutathione S-transferase (GST) activity of the liver cytosol, but not of the particulate fraction. Increased GST activity was reversed two weeks after discontinuing PTU administration. Activation of the enzyme was inversely proportional to the decrease in leukocytes. Repeated administration of PTU increased the Vmax of the enzyme without affecting the Km value for the substrate 1-chloro-2,4-dinitrobenzene, whereas both the Km and Vmax for glutathione (GSH) were increased by PTU treatment. GSH content and GSH peroxidase activity were not affected by PTU, but this resulted in an increase in glucose 6-phosphate dehydrogenase activity. PTU treatment caused increase in GST activity using 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene, p-nitrobenzyl chloride, and benzalacetone as substrates; enzyme activity towards chlorodinitrobenzene was the highest.
Journal Article•
TL;DR: Evidence is discussed regarding whether the increase in type II 5'-deiodinating activity in hypothyroidism and the decrease in hyperthyroidism, are beneficial defense mechanisms; this is likely to be so in some parts of the body, but may ot be in the thyrotrophic cells of the anterior pituitary.
Abstract: There are two iodothyronine 5'-deiodinases in the rat anterior pituitary gland. The type II 5'-deiodinase is responsible for the observable T4 to T3 conversion in pituitary tissue, both in vivo and in vitro. This type II enzyme has kinetic characteristics which distinguish it from type I activity, and it is also insensitive to inhibition by propylthiouracil. Iopanoic acid is both a substrate for, and an inhibitor of, the pituitary type II 5'-deiodinase. Studies in the rat and in man using iopanoic acid as a probe indicate that conversion of T4 to T3 within the anterior pituitary is a necessary step in the expression of thyroid hormone effects on the thyrotrophic and somatotrophic cells after T4 administration. Amiodarone, which has effects on the human pituitary-thyroid axis similar to those of iopanoic acid, has little inhibitory activity on T4 5'-deiodination in rat pituitary homogenate. Phenytoin, which lowers the serum T4 after chronic administration without inducing an increase in thyrotropin, could theoretically act by enhancing intrapituitary T3 production. In actuality, phenytoin shows only inhibitory activity in vitro on type II 5'-deiodination in rat pituitary and brain homogenates and on type I activity in rat liver homogenates. Phenytoin treatment in vivo has no significant effect on T4 5'-deiodination in pituitary or liver homogenates either. Evidence is discussed regarding whether the increase in type II 5'-deiodinating activity in hypothyroidism, and the decrease in hyperthyroidism, are beneficial defense mechanisms; this is likely to be so in some parts of the body, but may ot be in the thyrotrophic cells of the anterior pituitary.
TL;DR: The results suggest that the mechanism of inhibition of myeloperoxidase activity by PTU given in vivo or incubated with the enzyme in vitro may be the same.
TL;DR: Thyrotoxicosis is a relatively common complication of amiodarone treatment, probably caused by its high iodine content, and the complication should be considered whenever tachyarrhythmias worsen on treatment with amodarone.
TL;DR: Assessment of the contribution of the major intracellular changes to the adaptive hypertrophic process in various heart models finds the economy of the metabolic recovery process was unchanged in the pressure overload and Goldblatt preparations and in the propylthiouracil preparation the recovery processes became uneconomical.
Abstract: Myocardial hypertrophy, with high morbidity and mortality, is a natural outcome of hypertensive heart disease. The increase in myocardial mass is associated with a cellular and subcellular reorganization of the myocytes. The following study uses rapid myothermal techniques to assess the contribution of the major intracellular changes to the adaptive hypertrophic process in various heart models. Pressure overload and thyrotoxic hypertrophy were produced in the rabbit. In the rat, hypertrophy was produced by constricting the renal artery (Goldblatt hypertensive rat) or by using the spontaneously hypertensive rat strain. Atrophy was produced by administration of propylthiouracil in the drinking water. The V1/V3 myosin isoenzyme ratio was decreased in the pressure overload, Goldblatt, and propylthiouracil animals. This was associated with a decrease in total activity-related heat, initial heat, and tension-dependent heat per tension time integral. The tension-independent heat was decreased in the pressure overload, while the time to peak tension was increased. The economy of the metabolic recovery process was unchanged in the pressure overload and Goldblatt preparations. In the propylthiouracil preparation the recovery processes became uneconomical. The spontaneously hypertensive rat exhibited mild cardiac hypertrophy but in all other respects the heart was unchanged from the normal animals. The thyrotoxic hearts had a high V1/V3 myosin isoenzyme ratio, which was associated with a high total activity-related heat, initial heat, and tension-dependent heat per tension time integral. The tension-independent heat was reduced in the thyrotoxic preparations. The appropriateness of each of the intracellular changes is evaluated in terms of the demands made on the heart.
Journal Article•
TL;DR: The data indicate the potential of the antithyroid drugs for inhibition of metabolism of drugs and xenobiotics by prostaglandin H synthase, and proposes that this interaction with the hydroperoxidase component of prostag landinh synthase is at least in part the mechanism by which propylthiouracil and methimazole inhibit prostaglandsin production.
TL;DR: Thyroid-stimulating hormone (TSH) stimulated Tg release in vitro from enzymatically dispersed normal rat thyroid cells in a dose-dependent manner and this system provides a means of studying the control of Tg secretion in vitro.
Abstract: Serum thyroglobulin (Tg), measured by radioimmunoassay, was high in 6-propylthiouracil (PTU)-treated rats but low in thyroxine (T4)-treated animals compared with euthyroid controls. Thyroid-stimulating hormone (TSH) stimulated Tg release in vitro from enzymatically dispersed normal rat thyroid cells in a dose-dependent manner. Thyroid cells prepared from T4-treated animals behaved similarly to cells from control rats, whereas in vitro basal release of Tg from thyroid cells prepared from PTU-treated animals was high and the response to TSH was lost. Our data confirm the TSH dependency of Tg release in vivo and in vitro and our system provides a means of studying the control of Tg secretion in vitro.
TL;DR: Most of the laboratory findings argue against the presence of a TSH producing pituitary tumour and the most likely cause for inappropriate TSH secretion in this patient is selective resistance of the thyrotroph to thyroid hormones.
Abstract: A patient with inappropriate thyrotrophin (TSH) secretion is described. She initially presented with classical hyperthyroidism during pregnancy, responded to propylthiouracil and, subsequently, had a normal delivery. Hyperthyroidism persisted and 7.5 months later a subtotal thyroidectomy was performed. After a further 16 months, mild symptoms of hyperthyroidism recurred. She again responded to propylthiouracil, but developed galactorrhoea. At that stage, it was noted that she had persistently elevated circulating TSH in the presence of elevated T4 and T3 levels. Her symptomatology was mild, although objective indices of thyroid activity, including pulse rate, BMR, sex hormone binding globulin and cholesterol, were indicative of hyperthyroidism. CT scan and tomography of the sella were normal. She had a markedly exaggerated TSH response to thyrotrophin releasing hormone (TRH). Basal TSH and responsiveness to TRH was suppressed by high dose dexamethasone. The TSH response to TRH was partially suppressed by exogenous T3, but there was no effect on basal TSH levels. TSH also decreased slightly with L-dopa and bromocriptine. Circulating TSH rose markedly during methimazole administration. TSH alpha and beta subunits were elevated and appropriate for the high TSH. In addition, both subunits increased following TRH. The patient had basal hyperprolactinaemia with an impaired prolactin (PRL) response to TRH and metoclopramide. PRL suppressed with L-dopa and bromocriptine. The remaining anterior pituitary function was intact. Most of the laboratory findings argue against the presence of a TSH producing pituitary tumour and the most likely cause for inappropriate TSH secretion in this patient is selective resistance of the thyrotroph to thyroid hormones. A mild element of peripheral resistance might also be present. The hyperprolactinaemia could be related to lactotroph resistance to thyroid hormone. The complexities of treatment in this patient are stressed. Therapy was initially attempted with low dose dexamethasone, but this had no effect. T3 treatment produced an exacerbation of her symptomatology and did not influence basal TSH, thyroid hormones, or 131I uptake. Bromocriptine administration for 11 months partially suppressed basal TSH without influencing T3 and there was an increase in T4. Methimazole did decrease her T4 and T3, but TSH and PRL rose to even greater levels. Her hyperthyroidism was eventually controlled with an ablative dose of 131I. Thyroid hormone will be given in an attempt to suppress her TSH.