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PubMed1978

The formation of tri-iodothyronine and reverse tri-iodothyronine from thyroxine in isolated rat renal tubules.

1. Conversion of thyroxine into tri-iodothyronine and reverse tri-iodothyronine in intact cells was studied with isolated renal tubules prepared by collagenase digestion. 2. Conversion of thyroxine into tri-iodothyronine and reverse tri-iodothyronine increased progressively for at least 90 min. 3. Studies of tri-iodothyronine production from increasing amounts of thyroxine revealed that the thyroxine to tri-iodothyronine conversion is saturable. 4. Iodine and carbimazole had no effect on the thyroxine to tri-iodothyronine conversion. 5. 6-Propyl-2-thiouracil had a direct non-competitive inhibitory effect on the conversion of thyroxine into tri-iodothyronine with a 75% inhibition of the conversion at a propylthiouracil concentration within the therapeutic range in vivo. Propylthiouracil also inhibited the net formation of reverse tri-iodothyronine from thyroxine at a similar propylthiouracil concentration, as well as inhibiting the subsequent degradation of reverse tri-iodothyronine.

Animals↗

PubMed1996

The effect of diltiazem on the manifestations of hyperthyroidism and thyroid function tests.

The aim of this study is to evaluate the effect of diltiazem on the symptoms and signs of hyperthyroidism and thyroid function tests and to assess whether diltiazem can be used associated with an anti-thyroid drug, propylthiouracil. Twenty-two patients with hyperthyroidism were included in a prospective, randomized and placebo controlled study. Group 1 (n:12) patients received diltiazem, 60 mg twice a day, for 30 days. Group 2 (n:10) patients received placebo for 30 days. The patients in both groups were given propylthiouracil, 100 mg three times a day, for the last 20 days of the study period. The patients remained in the hospital during the first 10 days. A standardized hyperthyroid symptom score (HSS) and thyroid function tests including thyroid-stimulating hormone (TSH), free thyroxine (free T4), free triiodothyronine (free T3), total thyroxine (T4) and total triiodothyronine (T3) were evaluated before and after 10 and 30 days of the study period. HSS decreased from 27.80 +/- 4.54 to 22.51 +/- 4.04 after 10 days of diltiazem therapy in Group 1 (p < 0.01). But there was no change in HSS in Group 2 (p > 0.01). No significant changes in thyroid function tests have occurred in both groups after 10 days of treatment. Diltiazem can be used in patients with hyperthyroidism to alleviate adrenergic manifestations. It can also be safely combined with propylthiouracil.

Antithyroid Agents↗

PubMed1975

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

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.

Administration, Oral↗

PubMed1980

Comparison of antithyroid drug metabolism in the rat and guinea pig.

The thyroid accumulation, metabolism and urine excretion of (35S) propylthiouracil was compared in the guinea pig and the rat. Per gram thyroid tissue, the guinea pig thyroid took up much less drug than the rat, metabolised it faster and had a shorter t 1/2 for total 35S and free (35S) propylthiouracil. Liver metabolism, clearance of the drug from the serum and excretion in the urine were also considerably faster in the guinea pig. It is likely that a much larger dose of propylthiouracil would need to be administered to induce goitre in the guinea pig than is necessary in the rat.

Animals↗

PubMed1973

Degradation of thyroid hormones by phagocytosing human leukocytes.

Thyroxine (T(4)) and triiodothyronine (T(9)) are rapidly degraded by a purified preparation of myeloperoxidase (MPO) and H(2)O(2) with the formation of iodide and material which remains at the origin on paper chromatography. Deiodination by MPO and H(2)O(2) occurs more readily at pH 7.0 than at pH 5.0 in contrast to iodination by this system which is known to occur more readily at pH 5.0 than at pH 7.0. Degradation is inhibited by azide, cyanide, ascorbic acid, and propylthiouracil. Methimazole stimulates deiodination by MPO and H(2)O(2) but inhibits this reaction when MPO is replaced by lactoperoxidase or horseradish peroxidase.Intact human leukocytes, in the resting state, degrade T(4) and T(3) slowly: degradation, however, is increased markedly during phagocytosis of preopsonized particles. Serum inhibits this reaction. T(3) can be detected as a minor product of T(4) degradation. Proteolytic digestion of the reaction products increases the recovery of monoiodotyrosine. The fixation of iodine in the cytoplasm of leukocytes which contain ingested bacteria was detected radioautographically. Chronic granulomatous disease leukocytes, which are deficient in H(2)O(2) formation, degrade T(4) and T(3) poorly during phagocytosis. MPO-deficient leukocytes degrade the thyroid hormones at a slower rate than do normal leukocytes although considerable degradation is still observed. Azide, cyanide, ascorbic acid, and propylthiouracil which inhibit certain peroxidasecatalyzed reactions inhibit degradation by normal leukocytes; however, inhibition is incomplete. Formation of iodinated origin material is inhibited to a greater degree by azide, cyanide, and propylthiouracil than is deiodination. Methimazole inhibits the formation of iodinated origin material by both normal and MPO-deficient leukocytes. However, deiodination by normal leukocytes is stimulated and that of MPO-deficient leukocytes is unaffected by methimazole. Hypoxia inhibits the degradation of T(4) and T(3) by untreated normal or MPO-deficient leukocytes and by normal leukocytes treated with azide or methimazole. These data suggest that both MPO-dependent and MPO-independent systems are involved in the degradation of T(4) and T(3) by phagocytosing leukocytes. The role of leukocytic degradation of T(4) and T(3) in thyroid hormone economy and in leukocytic microbicidal activity is considered.

Ascorbic Acid↗

PubMed1984

Iodothyronine 5'-deiodinase in rat kidney microsomes. Kinetic behavior at low substrate concentrations.

The thiol-activated enzymatic outer-ring monodeiodination of iodothyronines by rat kidney microsomes at low (nanomolar) substrate concentrations shows an apparently sequential reaction mechanism and is further characterized by insensitivity to inhibition by dicoumarol, a moderate sensitivity to inhibition by propylthiouracil (Ki = 100 microM) and iopanoic acid (Ki = 0.9 mM), responsiveness to 5 mM glutathione (GSH), and a thermal activation profile that is concave downward with a Td of approximately 20 degrees C. In contrast, the activity at high (micromolar) substrate concentrations shows a ping-pong reaction mechanism, is inhibited by micromolar concentrations of propylthiouracil, iopanoic acid and dicoumarol, is unresponsive to 5 mM GSH, and shows a concave upward thermal activation profile. Analysis of the microsomal deiodinase reaction over a wide range of 3,3',5'-triiodothyronine (rT3) concentrations (0.1 nM to 10 microM) suggested the presence of two enzymatic activities, with apparent Michaelis constants (Km) of 0.5 microM and 2.5 nM. Lineweaver-Burk plots of reaction velocities at nanomolar substrate concentrations in presence of 100 microM propylthiouracil also revealed an operationally distinct enzymatic activity with Km's of 2.5 and 0.63 nM and maximum velocities (Vmax's) of 16 and 0.58 pmol/mg protein per h for rT3 and thyroxine (T4), respectively. These findings are consistent with the presence of a low Km iodothyronine 5'-deiodinase in rat kidney microsomes distinct from the well characterized high Km enzyme and suggest that at circulating levels of free T4 the postulated low Km enzyme could be physiologically important.

Animals↗

PubMed1980

Thyrotropin binding to rat thyroid membranes: reduced capacity associated with goitrogenesis.

To investigate a possible role of TSH in the regulation of its own receptor, a sensitive assay of [125I]TSH tropin binding to rat thyroid membranes was used. With 1 mM MgCl2 in the buffer, Scatchard analysis of displacement of TSH gave a curvilinear plot with a high affinity, low capacity (K1, 3.4 nM; Q1, 3.1 pmol/microgram) and a low affinity, high capacity binding site (K2, 0.54 microM; Q2, 1.2 X 0.1 nmol/microgram). Feeding rats propylthiouracil led to a decrease in [125I]TSH binding (expressed either per U protein or per wet wt of tissue) that was related to the duration of treatment. Evaluation by Scatchard analysis showed that this was due to a loss of binding sites, e.g. a 50-60% decrease after 1 month of propylthiouracil treatment; affinity was actually slightly increased in the goitrous tissue. This change in the number of TSH-binding sites was readily reversed in association with the suppression of TSH in vivo either by injections of T3 for 3 days or more by feeding a normal diet for 1 month. Thus, the data are compatible with TSH, that is in high concentration in the serum of rats fed propylthiouracil, exerting a downregulatory influence on its own receptors.

Adenylyl Cyclases↗

PubMed1982

[The adverse effects of thioureylene antithyroid drugs (author's transl)].

The aims of the present study were to investigate the incidence of adverse effects of thioureylene antithyroid drugs and to see if there were any factors related to the development of the adverse effects. Methimazole or propylthiouracil was administered to 151 patients with Graves disease; 76 untreated cases and 75 treated cases. The overall incidence was 22.4% among the 76 untreated cases. The incidences were 26.7% (13/45 cases) for methimazole and 16.1% (5/31 cases) for propylthiouracil, respectively, which were significantly higher than those previously reported. Fourteen out of 17 cases with the adverse effects were given the other thioureylene. The successive incidence of the adverse effects was 28.6% (4 cases), which was not significantly different from that under the drug of first choice. The result suggests that methimazole and propylthiouracil may not have cross-reaction each other. On the other hand, antinuclear antibody and anti-DNA antibody became positive in 2 out of the 4 cases. It would be a significant phenomenon, since antinuclear antibody was positive in only 3% of cases before the drug treatment. Thus, an immunological mechanism seemed to be involved in the problems, although there was no correlation between antithyroid autoantibodies and the development of the adverse effects. The adverse effects were observed within 2 months of administration of less than 250 tablets in total in most of the cases. The results imply that allergic mechanism rather than accumulating or toxic effect may concern the development of adverse effects of the thioureylenes.

Adult↗

PubMed1983

[Side effects of antithyroid drugs].

In order to investigate the incidence of side effects of antithyroid drugs and to study if there were any factors related to the onset of the side effects, clinical and laboratory findings were examined in 71 untreated Graves' patients. The overall incidence was 28.2% among 71 cases who were initially administered methimazole or propylthiouracil. The incidences were 23.2% (13 of 56 cases) for methimazole and 46.7% (7 of 15 cases) for propylthiouracil, respectively, which were significantly higher than those previously reported. Seventeen of 20 cases with side effects under the drug of first choice were administered the another antithyroid drug. Four of 17 (23.5%) cases successively had side effects. The side effects were observed within 1.5 months of administration of less than 150 tablets in total in most of the cases. The serum concentration of Ig-E and peripheral eosinophils(/mm3) at the onset of the side effects were significantly higher than those before treatment. These results suggest that allergic mechanism rather than accumulating may concern the onset of side effects. Since in cases without the side effects the peripheral eosinophils at 3 to 4 weeks after administration were significantly higher than those before treatment and 19 of 51 (38.0%) cases without side effects had a high concentration of Ig-E of more than 500 u/ml, it is suggested that allergic mechanism may be triggered in most of Graves' patients who were administered methimazole or propylthiouracil. Thus, immunological disturbances in Graves' disease seems to be the cause of the side effects of antithyroid drugs, although there was no correlation between antithyroid autoantibodies and development of the side effects.

Adolescent↗

PubMed1983

Recurrent agranulocytosis induced by two different antithyroid agents.

A 45-year-old woman with thyrotoxicosis developed agranulocytosis after treatment with propylthiouracil. When the thyrotoxicosis recurred, accompanied by a severe psychotic reaction, administration of antithyroid medication was recommenced. The patient was given methimazole instead of propylthiouracil but, 10 weeks later, agranulocytosis again occurred. This is, to the best of our knowledge, the first report of a case in which agranulocytosis followed treatment with both propylthiouracil and methimazole in the same patient.

Agranulocytosis↗

PubMed2003

Effect of PTU on IL-12 and IL-10 in psoriasis.

Propylthiouracil (PTU), an antithyroid thioureylene with immunomodulatory properties, has been shown to be effective in the therapy of patients with plaque psoriasis. The mechanism of action of antithyroid thioureylenes in psoriasis remains unknown. Propylthiouracil is a commonly used agent in the treatment of patients with Graves' hyperthyroidism, a condition associated with elevated levels of interleukin-12 (IL-12), which fall significantly after propylthiouracil treatment. IL-12 is believed to play a pivotal role in the development of psoriasis. Production of IL-12 is modulated by the anti-inflammatory cytokine IL-10. The effect of PTU on IL-12 and IL-10 levels was, therefore, studied in twelve patients with plaque psoriasis. Treatment with 300 mg of PTU daily in divided doses for three months produced significant improvement of the PASI and histological scores in the patients. Serum IL-12 concentrations were undetectable at baseline and did not change with treatment. IL-10 concentrations were 1.39 +/- 1.49 pg/ml (mean +/- SD) at baseline, and showed no significant change after 2 weeks (1.63 +/- 1.61 pg/ml and 12 weeks 1.15 +/- 1.58 pg/ml of treatment with PTU. The data suggest that the clinical improvement with patients with psoriasis treated with PTU is not due to a fall in circulating IL-12 or a rise in IL-10 concentrations. Although the drug may have effects on lesional production of these cytokines this is not reflected in the circulating levels. It is speculated that the beneficial effect is likely mediated by an inhibitory effect on keratinocyte proliferation or promotion of apoptosis in these proliferated keratinocytes.

Administration, Oral↗

PubMed2004

Effects of antithyroid medication on the flow-volume loop in patients with hyperthyroidism.

This prospective study was designed to evaluate the effects of hyperthyroidism on flow-volume loops in nonasthmatic 20 patients with hyperthyroidism. Thyroid related hormones (Total T3, Total T4 and TSH), thyroid gland volumes with ultrasonography, circumference of neck values and flow-volume loops were obtained at the beginning and after three months of antithyroid treatment. Propylthiouracil treatment was followed by a statistically significant decrease in thyroid gland volume and circumference of neck (p< 0.001 and p< 0.001, respectively). The most significant result was improvement of maximum midexpiratory flow rate (MMEFR) after propylthiouracil therapy for three months (p= 0.003). Increases in mean forced expiratory flow after 25% of FVC has been exhaled (FEF25), mean forced expiratory flow after 75% of FVC has been exhaled (FEF75) values were found consistent with the overall improvement in expiratory flow parameters (p= 0.044, p= 0.012 respectively). In conclusion, we speculated that improvement of expiratory flow parameters might be the earlier changes in flow volume loops of patients who were treated with propylthiouracil for hyperthyroidism.

Administration, Oral↗

PubMed2006

Recurrent episodes of arthritis in a hyperthyroid patient.

Antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis is a potentially life-threatening adverse effect of antithyroid medications. We present a 22-year-old woman with Graves' disease who developed recurrent episodes of arthritis while on treatment with propylthiouracil. A diagnosis of propylthiouracil-induced ANCA-associated vasculitis was established only after exhaustive rheumatological investigations failed to establish a cause for her arthritis. Anti-myeloperoxidase antibody (anti-MPO) titres were grossly elevated at 172.7 RU/mL (0-20). Her arthritis resolved promptly following the withdrawal of propylthiouracil and the anti-MPO titres declined over 16 months to 66.8 RU/mL. While she did not develop the life-threatening renal or respiratory tract complications, there was a delay in establishing the correct diagnosis with its attendant morbidity. This case highlights the need for greater awareness of this relatively rare adverse effect of antithyroid medications so as to allow its early detection, leading to the prompt cessation of the offending medication.

Adult↗

PubMed1985

Effects of altered thyroid status on beta-adrenergic actions on skeletal muscle glycogen metabolism.

The effects of hypothyroidism on glycogen metabolism in rat skeletal muscle were studied using the perfused rat hindlimb preparation. Three weeks after propylthiouracil treatment, serum thyroxine was undetectable and muscle glycogen and Glc-6-P were decreased. Basal and epinephrine-stimulated phosphorylase a and phosphorylase b kinase activities were also significantly reduced, as were epinephrine-stimulated cAMP accumulation and cAMP-dependent protein kinase activity. Conversely, basal and epinephrine-stimulated glycogen synthase I activities were significantly higher while the Ka of the enzyme for Glc-6-P was lower in hypothyroid animals. Propylthiouracil-treated rats also had increased phosphoprotein phosphatase activities towards phosphorylase and glycogen synthase and decreased activity of phosphatase inhibitor 1. beta-Adrenergic receptor binding and basal and epinephrine-stimulated adenylate cyclase activities were reduced in muscle particulate fractions from hypothyroid rats. Administration of triiodothyronine to rats for 3 days after 3 weeks of propylthiouracil treatment restored the altered metabolic parameters to normal. It is proposed that the decreased beta-adrenergic responsiveness of the enzymes of glycogen metabolism in hypothyroid rat skeletal muscle is due to increased activity of phosphoprotein phosphatases and to reduced beta-adrenergic receptors and adenylate cyclase activity.

Animals↗

PubMed1980

Effects of thyroid hormone deficiency on pre- and postsynaptic noradrenergic mechanisms in the rat cerebral cortex.

Thyroid hormones are known to influence the noradrenergic neurotransmission in several peripheral organs. In order to find out whether similar changes exist in the central nervous system, we investigated adrenoceptor-mediated responses in the rat brain cortex during propylthiouracil-induced hypothyroidism. In contrast to unchanged basal cAMP levels, the cAMP accumulation following (-)noradrenaline incubation (3 X 10(-6)--3 X 10(-5) M) was significantly reduced in brain slices from hypothyroid animals. The difference between controls and propylthiouracil-fed rats became more pronounced when (-) isoprenaline (3 X 10(-6)--3 X 10(-5) M) was used for selective stimulation of beta-adrenoceptors. Since the cAMP increase mediated via alpha-adrenoceptors was not affected, it may be concluded that thyroid hormone deficiency only impairs the beta-adrenergic transmission. Phosphodiesterase activity remained unaltered suggesting that thyroid hormones influence the beta-adrenoceptors or the adenylate cyclase coupled to it. The sensitivity of presynaptic alpha-adrenoceptors modulating the release of noradrenaline was evaluated using occipital cortical slices preincubated in 3H-noradrenaline. Clonidine inhibited whereas phentolamine enhanced the 3H-overflow induced by electrical stimulation in a dose-dependent manner. No differences could be detected between control- and propylthiouracil-treated animals. Thus presynaptic alpha-adrenoceptors are not affected by hypothyroidism.

Animals↗

PubMed1994

Therapeutic 131I dose in hyperthyroidism: role of pretreatment with thionamide.

Radioiodine therapy has become a cornerstone of treatment of hyperthyroidism. However, the timing of its administration varies between 1) the time of initial diagnosis with concurrent therapy with beta adrenergic blocking drugs or 2) following induction of euthyroidism with thioamide, Propylthiouracil or Methimazole. This study assessed 24-HR 131I uptake values and the thyroid scan in 24 subjects with hyperthyroidism at the time of diagnosis and again after attaining the euthyroid state with Propylthiouracil or Methimazole. Propylthiouracil of Methimazole was withdrawn seven days prior to the second 24-HR 131I uptake and scan. In all subjects, as a group, 24-HR 131I uptake increased following antithyroid therapy as compared to the time of initial of diagnosis [76 + 5% Vs. 54 + 4%; p < 0.01]. The thyroid gland size decreased in nine of twenty-four subjects, but remained unchanged in the remaining subjects. Since 24-HR 131I uptake and the gland size are the major factors influencing the therapeutic radioiodine dosage, it is possible that initial therapy with thioamide drugs may reduce the therapeutic dose of 131I in subjects with hyperthyroidism belonging to both groups, i.e., Graves' disease and Multinodular toxic goiter by inducing a rise in 24-HR 131I uptake. Furthermore, the shrinkage of thyroid glands may further decrease the radioiodine dosage in patients with Graves' disease.

Adult↗

PubMed1990

Maturation of the corpus callosum of the rat: I. Influence of thyroid hormones on the topography of callosal projections.

The normal adult rat corpus callosum contains numerous axonal profiles that are immunoreactive for the high molecular weight subunit of the neurofilament triplet (NF-H). NF-H immunoreactivity develops gradually during the first 2 postnatal weeks. The expression of NF-H immunoreactivity is almost completely suppressed in rats rendered hypothyroid by neonatal treatment with propylthiouracil. To ensure that the cytoskeletal deficit was due to a shortage of thyroid hormones rather than to unspecific, toxic effects of propylthiouracil, hypothyroid animals kept on the propylthiouracil diet were given restorative thyroxine injections daily. Such animals express NF-H at normal levels. This suggests that the callosal axons may be arrested at an immature stage of development. The immaturity of the hypothyroid corpus callosum can also be revealed by a comparison of the myelin content in the corpus callosum between normal rats, hypothyroid rats, and hypothyroid rats under thyroxine therapy. Hypothyroid rats are severely deficient in myelin, and again this deficit can be corrected by postnatal thyroxine treatment. During normal callosal development, there is a progressive spatial restriction of the transcallosal projection that creates in the adult patches of callosally projecting cortex interposed by acallosal regions. Given the structural immaturity of the hypothyroid callosal axons, it was interesting to investigate the state of development of their topography. For this purpose, multiple injections of wheat germ agglutinin-horseradish peroxidase were made into the occipital and parietal cortices of adult hypothyroid animals. In normal rats, the majority of visual callosally projecting cells are located in three groups--in area 18b, at the boundary of area 17 and 18a, and in the lateral portion of area 18a. Within these areas projecting cells are concentrated in layers II-III, Va, and Vc-VIa. The callosal axon terminals are concentrated in these same regions, with a laminar distribution as far as the somata plus layer I. In the midportion of areas 17 and 18a, fewer callosal cells are found, and they occupy mainly layers Vc-VIa, as in the case for terminals in these same areas. In the parietal cortex, callosal cells and terminals are disposed in vertical arrays alternating with almost empty zones. Most are concentrated in layers III and V. The topography of the callosal axon terminal fields is unaffected by hypothyroidism. However, there is a dramatic redistribution of the callosally projecting cell somata.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Effect of dietary cholesterol on biliary cholesterol content and bile flow in the hypothyroid rat.

The hypothyroid rat model was used to investigate the effect of dietary-induced hypercholesterolemia on biliary cholesterol content and bile flow. Rats were divided into four dietary groups--diet A: Rat Chow; diet B: Rat Chow plus 0.1% propylthiouracil; diet C: Rat Chow plus 0.1% propylthiouracil, 0.3% taurocholate, 5% lard; diet D: Rat Chow plus 0.1% propylthiouracil, 0.3% taurocholate, 5% lard, and 1% cholesterol. After 6 wk, bile was collected and livers were excised for the preparation of membranes. In cholesterol-fed animals, biliary cholesterol content was increased. However, because of a significant decrease in the rate of bile flow that occurred in these animals, biliary cholesterol output was unchanged from the cholesterol output observed in control animals. Dietary cholesterol also caused a threefold increase in liver membrane cholesterol content and a 64% decrease in the activity of sodium-potassium-stimulated adenosine triphosphatase (Na+,K+-ATPase). In a separate group of animals, microsomes prepared from livers of control rats were incubated with phosphatidylserine liposomes, liposomes containing cholesterol, or buffer. The activity of Na+,K+-ATPase was increased in microsomes incubated with phosphatidylserine liposomes. However, when the cholesterol content of the microsomes was increased twofold by incubating the membranes with liposomes containing cholesterol, the stimulation of Na+,K+-ATPase activity was significantly decreased. The data suggest that in the cholesterol-fed hypothyroid rat, biliary cholesterol content is significantly increased; however, because of a decrease in the rate of bile flow, biliary cholesterol output is not changed. The decrease in bile flow is associated with an accumulation of cholesterol and a decrease in the activity of Na+,K+-ATPase in hepatic membranes.

Animals↗