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PubMed1987

The perchlorate discharge test for examining thyroid function in rats.

A perchlorate discharge test was developed for rats to detect changes in the thyroidal iodide accumulation and organification mechanisms. Rats were pretreated with compounds that alter thyroid function by different mechanisms: SK&F 93479 (an H2-antagonist that enhances pituitary thyroid stimulating hormone drive by increasing thyroid hormone clearance) and propylthiouracil (an inhibitor of iodide organification). Six hours following administration of 125I, either potassium perchlorate (10 mg/kg x 2.5 min) or saline was given i.p. Perchlorate significantly reduced the thyroid: blood 125I ratio in propylthiouracil-treated rats but had no effect in those pretreated with SK&F 93479, indicating an iodide organification block in the former. At the same time thyroidal radioiodide accumulation in SK&F 93479-treated rats (no perchlorate) was enhanced, whereas that in propylthiouracil-treated animals (no perchlorate) was depressed.

Animals↗

PubMed1996

NGF prevents further atrophy of cholinergic cells of the nucleus basalis due to cortical infarction in adult post-hypothyroid rats but does not restore cell size compared to euthyroid [correction of euthroid] rats.

We have tested the hypotheses that nerve growth factor treatment in adult post-hypothyroid rats can: (1) restore cross-sectional area of cholinergic cells of the nucleus basalis and (2) prevent further atrophy of these neurons following cortical infarction. In addition, we assessed the expression of p75NGFR and p140trkA mRNAs in the nucleus basalis cells of post-hypothyroid rats. Rats were rendered hypothyroid by the addition of propylthiouracil to their diet beginning on embryonic day 19 until the age of 1 month. At this time both the pups and their dams continued to receive 0.05% propylthiouracil in their diet and the pups were thyroidectomized. At 60 days, propylthiouracil treatment was interrupted and thyroxine levels were restored to normal by daily subcutaneous administration of physiological levels of thyroxine. Morphometric analysis identified atrophied nucleus basalis magnocellularis cholinergic cells at two ages, days 75 and 105, identified by in situ hybridization for p75NGFR and p140trkA mRNAs in methylene blue stained cells (day 75) and choline acetyltransferase immunostaining (day 105). The mean number of silver grains (pixels) per microns2 (mean +/- S.E.M.) of cell body cross-sectional area for p75NGFR mRNA in the nucleus basalis magnocellularis of euthyroid rats was 3.43 +/- 0.89, which was not statistically different from post-hypothyroid animals (4.02 +/- 1.07). A similar finding was noted for p140trkA mRNA: mean number of grains in the euthyroid group was 5.54 +/- 0.96 and was not statistically different from the post-hypothyroid group (6.32 +/- 1.45). Nerve growth factor treatment in adulthood (between days 75 and 82) did not restore cross-sectional area from early thyroid deprivation. However, it prevented further atrophy of nucleus basalis magnocellularis neurons following cortical devascularization inflicted in adulthood (day 75).

Acetylcholine↗

PubMed1998

Antineutrophil cytoplasmic antibody (ANCA)-positive cutaneous leucocytoclastic vasculitis associated with antithyroid therapy in Graves' disease.

Presented is a case of a 27-year-old male with Graves' disease on long-term propylthiouracil treatment who, when changed to carbimazole, rapidly developed a petechial and purpuric eruption on the legs, which subsequently flared on treatment with radioiodine. The clinical diagnosis of leucocytoclastic vasculitis was confirmed on skin biopsy. High-titre antineutrophil cytoplasmic antibodies in a perinuclear pattern (P-ANCA) were identified. No anti-myeloperoxidase activity was noted; therefore, the P-ANCA were classified in the atypical group. The target antigens, as determined by enzyme-linked immunosorbent assay, were lysozyme, lactoferrin and bactericidal/permeability increasing protein. Propylthiouracil and carbimazole are chemically related antithyroid drugs. There are reports of typical and atypical P-ANCA-positive cutaneous vasculitis due to propylthiouracil. Cutaneous vasculitis associated with atypical P-ANCA has not been noted previously to be temporally related to carbimazole use. The consideration of thionamides as possible aetiological agents in cases of P-ANCA-positive drug-induced vasculitis is suggested.

Adult↗

PubMed1996

Inhibitory effects of (+/-)-tetrahydropalmatine on thyrotropin-stimulating hormone concentration in hyperthyroid rats.

The effects of (+/-)-tetrahydropalmatine ((+/-)-THP) on the hypothalamus-pituitary-thyroid system in rats were investigated. Thyroid function experiments indicated that (+/-)-THP produces significant decreases in thyroid function in hyperthyroid rats after 14 days of treatment. These effects were the same as those of propylthiouracil. However, propylthiouracil also decreased thyroid function in normal rats. Measurements of thyrotropin-stimulating hormone (TSH) demonstrated that (+/-)-THP decreased TSH in hyperthyroid rats after 14 days of treatment; however, propylthiouracil increased TSH in hyperthyroid rats. (+/-)-THP had no influence on TSH, or thyroid and pituitary weight in normal and hyperthyroid rats. We conclude that (+/-)-THP has an antithyroid function and the mechanism of action may be related to the inhibition of TSH in the pituitary.

Animals↗

PubMed1985

cAMP-independent stimulation of glycogen phosphorylase in newborn rat hepatocytes.

Postnatal development of glycogen phosphorylase activation by the cAMP-independent pathway was examined in isolated rat hepatocytes from control and propylthiouracil-treated congenital hypothyroid rat pups. At 5 days postnatum there was complete phosphorylase activation by beta-adrenergic stimulation, glucagon, and the calcium ionophore A23187, but no activation by alpha-adrenergic stimulation. Activation of phosphorylase by angiotensin or vasopressin was less than in hepatocytes from adult rats (P less than 0.01). At 28 days postnatum activation by all of these hormones was complete. In the propylthiouracil-treated group hormone responsiveness was similar to the control at 5 days postnatum. However, alpha-adrenergic (P less than 0.025), angiotensin, and vasopressin (P less than 0.05) activation was decreased at 28 days postnatum, and beta-adrenergic, glucagon, and A23187 activation was complete. The attenuated responses were restored by thyroxine replacement from 15 days postnatum. [32P]Pi incorporation into phosphatidylinositol by epinephrine and vasopressin in 28-day propylthiouracil-treated rats was lower than the control (P less than 0.01). We speculate that the diminished phosphorylase response of hepatocytes to alpha-adrenergic, vasopressin, or angiotensin stimuli in the early neonatal period could be related to low receptor numbers and the weaker phosphoinositide response during this period. Also, the depressed phosphorylase response to alpha-adrenergic, vasopressin, and angiotensin stimulation in congenital hypothyroidism at 28 days postnatum could be related to a decrease in number of plasma membrane receptors for these agonists.

Angiotensin II↗

PubMedDate not supplied

The inhomogeneity and appropriateness of the myocardial response to stress.

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.

Adaptation, Physiological↗

PubMed1982

Treatment of lymphocytic thyroiditis with spontaneously resolving hyperthyroidism (silent thyroiditis).

The duration of the hyperthyroidism associated with lymphocytic thyroiditis (LT) with spontaneously resolving hyperthyroidism (SRH) was serially monitored in groups of patients who were not given any treatment (control subjects) or treated with propylthiouracil and/or propranolol hydrochloride and prednisone. The length of time for the thyroxine tests from diagnosis to the normal range was 57 +/- 17, 45 +/- 13, and 15 +/- 7 days (mean +/- SD) indicating a dramatic response to prednisone therapy but none to propylthiouracil and/or propranolol therapy. Five patients were found who had seven episodes of SRH while receiving thyroid hormone suppression therapy after having verified chronic LT (two patients) and LT-SRH (three patients). This indicates that thyroid suppression with thyroid hormone may be ineffective in preventing this disease. Two patients were treated by subtotal thyroidectomy because of recurrent or prolonged episodes of SRH. From this experience, the therapeutic alternatives available to the clinician are reviewed.

Humans↗

PubMedDate not supplied

Preliminary validation of a short-term morphological assay to evaluate adverse effects on amphibian metamorphosis and thyroid function using Xenopus laevis.

Short-term static-renewal studies were performed on Xenopus laevis embryos with 16 selected test materials from day 50 (stage 60) to day 64 (stage 66) (14-day test) to evaluate effects on tail resorption and thyroid function. Of the 16 test materials, nine were found to inhibit significantly the rate of tail resorption, four were found to stimulate metamorphosis and three had no appreciable effect on the rate of metamorphosis. In an effort to determine if the morphological effects observed were related to alteration in thyroid activity, measurement of triiodothyronine (T3) in the test organisms and coadministration studies using thyroxine (agonist) or propylthiouracil (antagonist) were performed based on the morphological response noted during tail resorption. Of the nine compounds found to inhibit the rate of tail resorption, six were found to reduce the levels of T3. In each case, the inhibitory response could be at least partially alleviated by the co-administration of thyroxine. Larvae exposed to the four stimulatory agents had somewhat elevated levels of T3 and were responsive to propylthiouracil antagonism. These results suggest that 12 of the 14 compounds tested in this study that altered the rate of tail resorption did so via the thyroid axis. Overall, the X. laevis model appeared to be a suitable system for evaluating the impact of environmental agents and chemical products on thyroid function.

Animals↗

PubMed2006

Evaluation of the antithyroid, antioxidative and antihyperglycemic activity of scopoletin from Aegle marmelos leaves in hyperthyroid rats.

Scopoletin (7-hydroxy-6-methoxy coumarin) was isolated from the leaves of Aegle marmelos and evaluated for its potential to regulate hyperthyroidism, lipid peroxidation and hyperglycemia in levo-thyroxine-induced hyperthyroid rats. Scopoletin (1.00 mg/kg, p.o.) administered daily for 7 days to levo-thyroxine-treated animals decreased the levels of serum thyroid hormones and glucose as well as hepatic glucose-6-phosphatase activity, demonstrating its potential to regulate hyperthyroidism and hyperglycemia. Scopoletin also inhibited hepatic lipid peroxidation and increased the activity of antioxidants, superoxide dismutase and catalase. Compared with the standard antithyroid drug, propylthiouracil, scopoletin exhibited a superior therapeutic activity, since unlike propylthiouracil, it also inhibited hepatic lipid peroxidation. These findings indicate that scopoletin has the potential to inhibit thyroid function and hyperglycemia without hepatotoxicity.

Aegle↗

PubMed1996

Significant reversal of thyrotoxicosis-associated dilated cardiomyopathy with induction of the euthyroid state.

Thyrotoxicosis rarely precipitates heart failure. Older patients and those with underlying cardiac disease are at greater risk of experiencing this complication of thyrotoxicosis. A 43 year old male who presented with subclinical thyrotoxicosis, atrial fibrillation, and a dilated cardiomyopathy is discussed. There was no evidence of clinically significant underlying cardiac disease. At admission, the patient had an ejection fraction of 25%. Thyrotoxicosis was treated with propylthiouracil. At 14 weeks after hospitalization, the patient had an ejection fraction of 50% with significant reduction in cardiac chamber sizes and left ventricular mass index. He was biochemically euthyroid at that time. After ten months of propylthiouracil therapy, he had progressive improvement in cardiac function and decrease in left ventricular mass index. Thyrotoxicosis-associated cardiomyopathy may reverse significantly with treatment of thyrotoxicosis alone; this complication of thyrotoxicosis should be considered in any young individual with a dilated cardiomyopathy of unknown etiology.

Adult↗

PubMed1992

The evolution of Graves' ophthalmopathy during treatment with antithyroid drug alone and combined with triiodothyronine.

We analyzed the evolution of the ophthalmopathy associated with Graves' hyperthyroidism in 45 patients treated with two different antithyroid drug regimens. Group A patients (n = 31) received either methimazole (40-100 mg daily) or propylthiouracil (400-900 mg daily) combined with T3 daily throughout treatment. Group B patients (n = 14) were treated with conventional regimen with lower doses of either methimazole (5-25 mg daily) or propylthiouracil (50-300 mg daily) and no T3 addition. Eye signs and proptosis measurement were evaluated just before the beginning of the treatment and compared with the results after antithyroid drug withdrawal. Improvement of the eye signs considered on grounds of the NOSPECS classification was greater in group A than group B (p less than 0.01). Also, the decrease in proptosis measurement was greater (p less than 0.01) in patients treated with combined regimen (21.5 +/- 2.4 mm to 20.4 +/- 2.3 mm) than in patients receiving conventional therapy (20.4 +/- 1.6 mm to 20.0 +/- 1.7 mm). Serum thyroglobulin concentrations did not correlate with either the severity or the evolution of the ophthalmopathy. Negative serum antithyroglobulin antibody (TgAb) was associated with the improvement of the ophthalmopathy that was noted in 24 out of 27 patients (Chi-Square = 5.84; p less than 0.001). Thus, serum TgAb levels might have some connection with progression of eye signs but serum Tg concentration does not. Our study suggests that in most patients the transition from hyperthyroidism to euthyroidism induced by antithyroid drug therapy is associated with the improvement of the Graves' ophthalmopathy. However, no marked difference can be drawn between the two treatment regimens.

Adolescent↗

PubMed1999

Systemic adverse effect of antithyroid drugs.

Antithyroid drugs adverse effects are varied and rare. Autoimmune disorders (vasculitis, lupus erythematosus, polyarthritis...) are unusual and serious complications of antithyroid drugs. Since 1945, fewer than 100 cases of systemic manifestations related to antithyroid drugs have been reported in the literature, most frequently with propylthiouracil. The outcome is usually good after drug discontinuation, but some fatal cases have been reported. Because possible cross-sensitivity with other antithyroid drugs, the appropriate treatment for hyperthyroidism relapse if a patient has had an antithyroid drug adverse reaction, should be 131I-Iodine or surgery. We report four new cases of systemic manifestations during propylthiouracil therapy.

Adult↗

PubMed1988

Effect of thyroxine replacement therapy on the growth patterns of body, brain, and cerebellum in the neonatal hypothyroid rat.

The reversibility of the effects of propylthiouracil induced neonatal hypothyroidism by daily subcutaneous injections of L-thyroxine (T4) was investigated in the rat. Four groups of rat pups were used in this experiment: Group I (control) received equivalent amounts of saline subcutaneously; Group II (hypothyroid) received propylthiouracil injections daily; Group III (T4-14) are hypothyroid rats who received daily T4 replacement therapy (2.5 micrograms/day) subcutaneously starting on Day 14; Group IV (T4-21) are also hypothyroid rats whose T4 replacement therapy (2.5 micrograms/day) was started on Day 21. The four parameters studied were body length, body weight, brain weight, and cerebellar weight in these four groups of animals at 4, 7, 10, 14, 21, 28, 35, and 42 postnatal days. A minimum of eight animals were studied for each time sequence. The present study clearly indicated the beneficial effect of T4 therapy on the length and body weight of the hypothyroid animals, whether therapy was started at Postnatal Day 14 or 21. In addition, a more important finding of this study was the significant increase in brain and cerebellar weights of T4-treated animals compared to the hypothyroid animals, this beneficial effect being more striking in the T4-14 group when compared to that in the T4-14 animals.

Animals↗

PubMed1982

Modulation of estrogen-induced peroxidase activity in the rat uterus by thyroid hormones.

The effect of thyroid hormones, iodide, propylthiouracil and other thyroid-active agents on estrogen receptor concentration and on the induction of peroxidase in the immature rat uterus by estradiol (E2) was examined T3 (0.5 mg/Kg) given daily for 6 days produced a large decrease in E2-induced uterine peroxidase but lowered only slightly the concentration of cytosolic or nuclear receptors in this organ. T4 also decreased the effect of E2 on uterine peroxidase induction and the inhibitory action of T3 was observed in thyroidectomized rats. The administration of iodide (10 mM) in the drinking water for 6 days caused a 2-fold increase in estrogen-induced peroxidase in both normal and thyroidectomized immature animals without influencing the estrogen receptor concentration in the uterus. The effect of other thyroid-active agents on serum T3 and T4 levels was also determined. Treatment for 6 days with propylthiouracil (6 mM) increased the concentration of estrogen receptors in the uterus and decreased serum T3 and T4 levels without any effect on uterine peroxidase activity while bromide and perchlorate did not influence these parameters. Possible mechanisms for the inhibitory effects of thyroid hormones on uterine peroxidase induction by E2 are discussed.

Animals↗

PubMed1984

Reduction of increased levels of blood glycerol and ketone bodies by propranolol in human hyperthyroidism: role of the fall of the triiodothyronine level.

Hyperthyroid patients in the postabsorptive state have elevated levels of blood glycerol and ketone bodies (KB): this is believed to be due to increased lipolysis and ketogenesis. These increased glycerol and KB levels return toward normal after oral propranolol administration. In order to investigate the mechanism of action of propranolol in hyperthyroid patients, we compared the effects of the oral administration of propranolol with those of timolol, propylthiouracil (PTU), and a placebo. The placebo had no effect. The free thyroxine index, immunoreactive insulin level and glucagon level were not modified by propranolol, timolol, or PTU. Propranolol decreased the pulse rate (P less than 0.01) and the levels of serum triiodothyronine (T3; P less than 0.05), blood glycerol (P less than 0.01), and KB (P less than 0.01). Like propranolol, timolol decreased the pulse rate (P less than 0.01) but had no effect on the T3, glycerol, or KB levels. Propylthiouracil did not modify the pulse rate, but like propranolol, it decreased the T3 (P less than 0.05), glycerol (P less than 0.01) and KB (P less than 0.01) levels. These results suggest that the metabolic actions of propranolol are not caused by its hemodynamic effects nor its beta-blocking properties but are mediated by the decrease of the T3 level.

Adolescent↗

PubMed1993

5' Deiodinase activity in brain regions of adult rats: modifications in different situations of experimental hypothyroidism.

In the central nervous system, type II 5' deiodinase (5'D-II) is highly regulated, as judged by the dramatic changes in enzyme levels observed after abrupt alterations in thyroid status. In this work, the 5'-DII activity has been studied in different situations of experimental hypothyroidism (propylthiouracil, methimazole, thyroidectomy, and low iodine diet), in various brain regions (pituitary, cerebellum, brain stem, hypothalamus, cortex, and whole brain) in adult rats. Propylthiouracil and methimazole significantly increase the activity in all brain regions. These increases are higher in rats treated with methimazole. Thyroidectomy significantly increases the activity in cortex and pituitary. A low iodine diet significantly increases in all brain regions except in the hypothalamus. The concentration of triiodothyronine (T3) studied in the major brain regions remained unchanged. The results obtained show a compensatory mechanism in pituitary and other brain regions in order to maintain the T3 levels in brain tissue.

Animals↗

PubMed2002

Drug-induced neutropenia associated with anti-neutrophil cytoplasmic antibodies (ANCA): possible involvement of complement in granulocyte cytotoxicity.

Although antineutrophil antibodies are thought to be involved in drug-induced neutropenia, neither the precise mechanisms nor the particular antigens on the neutrophil surface have yet been clarified. Recently, we examined a patient with Graves' disease who developed antineutrophil cytoplasmic antibodies (ANCA) after propylthiouracil treatment and exhibited neutropenia. Because several target antigens of ANCA are expressed on the surface of neutrophils, it was suggested that ANCA might contribute to neutropenia. The patient's serum bound specifically to neutrophils and HL-60 cells differentiated into granulocytes, and lysed the HL-60 cells via a complement-mediated mechanism. Furthermore, two representative ANCA antigens, proteinase 3 and myeloperoxidase, significantly inhibited both the binding and cytotoxicity of the serum. Finally, tumour necrosis factor-alpha, which is known to up-regulate cell surface expression of several ANCA antigens, enhanced both the binding and cytotoxicity of the serum. These findings suggest that ANCA induced by propylthiouracil contributed to leucopenia through a complement-mediated mechanism.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed1981

Correlation between plasma thyroxine levels and corticosterone-binding activity in intact, ovariectomized, and ovariectomized estrogen-treated rats.

Plasma levels of total thyroxine (T4) and corticosteroid-binding activity (CBA) were determined in intact, ovariectomized, or ovariectomized, estrogen-treated rats during treatment with propylthiouracil (PTU) and following recovery from PTU. Propylthiouracil treatment reduced the mean plasma T4 concentration to 9 ng/ml and the mean plasma CBA to 39% of normal, while following recovery from PTU, the mean values for plasma T4 and CBA were 56 ng/ml and 108%, respectively. There was a strong (r equals plus +0.89) relationship between plasma levels of T4 and CBA as determined by linear regression analysis. Ovariectomy had no effect on either plasma T4 or CBA in euthyroid animals but significantly decreased CBA in PTU-treated, hypothyroid animals. The results indicate a robust influence of thyroid activity on plasma CBA and suggest a possible interaction between the thyroid and ovary in control of CBA.

Animals↗