Resolution of propylthiouracil-induced hepatic failure after treatment of thyrotoxicosis.
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Adult↗
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Reactivity of the pituitary--thyroid system to exogenic thyroxine and propylthiouracil during the peri- and neonatal period in the pig.
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Animals↗
Preparation and in vitro evaluation of propylthiouracil microspheres made of Eudragit RL 100 and cellulose acetate butyrate polymers using the emulsion-solvent evaporation method.
The objectives of this investigation are to evaluate the encapsulation efficiency of the anti-thyroid agent 6-n-propyl-2-thiouracil using two polymers of different characteristics (cellulose acetate butyrate polymer, (CAB-551-0.01) and ammonio methacrylate copolymer (Eudragit RL 100) and to study the effect of this encapsulation on the drug release properties. Polymers were used separately and in combination to prepare different microspheres. Also, the effect of polymer solution phase viscosity was studied for each of the polymers and for their combinations. An Ostwald viscometer was used to evaluate the relative viscosities of polymer solution phases and their combinations. Microspheres with 25% theoretical drug loading of 6-n-propyl-2-thiouracil core material were prepared by the emulsion solvent evaporation method. Microspheres prepared from CAB-551-0.01, which has higher relative polymer phase viscosity than Eudragit RL 100, showed significantly lower drug release rates and a noticeable lag time. Polymer combinations of CAB-551-0.01 and Eudragit RL 100 (1:1) showed an interesting synergistic increase in relative polymer solution viscosities at all concentrations. Unlike microspheres prepared from the two polymers separately which follow Higuchi spherical matrix release kinetics, microspheres prepared using a combination (1:1) of the two polymers showed near zero order with faster rates compared to those prepared using CAB-551-0.01 equivalent polymer concentrations. The results of this study suggest that 6-n-propyl-2-thiouracil was successfully and efficiently encapsulated and release rates of matrix microspheres are related to polymer solution phase viscosity, but when polymer combinations were used other factors such as structural effects must be considered.
Cellulose↗
Taste sensitivity to 6-n-propylthiouracil predicts acceptance of bitter-tasting spinach in 3-6-y-old children.
BACKGROUND: Understanding what motivates the preference for and selection of foods has important health implications. Research suggests that the phytochemicals present in green leafy vegetables contain anticarcinogenic properties. As a result of the bitter taste of phytochemical compounds, however, foods containing these are often not well accepted, particularly by children. OBJECTIVE: We aimed to study the relation between sensitivity to the bitter taste of 6-n-propylthiocuracil (PROP) and acceptance of bitter- and strong-tasting foods in 3-6-y-old children. DESIGN: Two independent procedures, a threshold detection and a suprathreshold intensity task, were used to measure individual sensitivity to PROP, and 3 independent tasks were used to assess food acceptance. RESULTS: Sensitivity to the bitter taste of PROP was positively correlated with dislike of the taste of raw spinach (P < 0.05). CONCLUSIONS: The acceptance of spinach may to some extent be mediated by individual taste perception and be predictable via both threshold and suprathreshold measures of PROP taste sensitivity. Furthermore, children as young as 3 y of age can partake in direct investigations of taste, reliably comply with test procedures, and accurately communicate taste perceptions and preferences under study conditions.
Child, Preschool↗
Identification of 3,3'-diiodothyroacetic acid sulfate: a major metabolite of 3,3',5-triiodothyronine in propylthiouracil-treated rats.
The sulfate conjugate 3, [3'-125I] diiodothyroacetic acid (3,3'-TA2S) was discovered in plasma, and occasionally in bile, of 6-propyl-2-thiouracil-treated rats after administration of [125I]T3. The identification of this T3 metabolite was based on the following evidence: 1) the compound co-eluted in two different HPLC systems with synthetic 3,3'-TA2S; 2) its chromatographic behavior on Sephadex LH-20 was characteristic for a conjugated iodothyronine derivative; and 3) the metabolite was hydrolyzed by arylsulfatase and the liberated product comigrated with synthetic 3,3'-TA2 on HPLC. Marked accumulation of 3,3'-TA2S was observed only in rats with impaired type I deidodinase activity but not in controls. Furthermore, plasma and biliary 3,3'-TA2S levels varied with the experimental conditions such as anesthesia, i.e. both were increased in ketamine-anesthetized over pentobarbital-anesthetized animals. It was not possible to indicate the exact pathway through which 3,3'-TA2S is generated from T3; neither is it known how much of T3 is actually metabolized via 3,3'-TA2S. However, the significant plasma 3,3'-TA2S levels, even in unanesthetized animals, illustrate the physiological relevance of this T3 metabolite.
Anesthesia↗
Effects of hypophysectomy and short- and long-term propylthiouracil treatment on the rat thyroid.
The morphology and histology of the post-pharyngeal part of the gastrointestinal tract of the ferret were studied. The oesophagus was a distensible muscular tube. Its mucosa was lined by keratinizing stratified squamous epithelium. The muscle coat was striated throughout except mear the cardia. A cardiac sphincter was present. The stomach was morphologically and histologically very similar to that of man. The duodenum appeared C-shaped and had a mesoduodenum. The bile and pancreatic ducts formed a common duct in the wall of the duodenum. The sphincter of Oddi was present. Brunner's glands were present in the pyloric part of the stomach, and up to the common opening of the bile and pancreatic ducts in the duodenum. The intestine could be differentiated macroscopically and microscopically into small and large intestines. The small intestine distal to the duodenum formed coiled tubes suspended by a mesentery. It was not possible morphologically to differentiate jejunum and ileum. Histologically, however, the distal portion was identifiable as ileum by increasing numbers of goblet cells, and Peyer's patches in the submucosa. Villi were present in the mucosa throughout but there was no spiral or circular fold. The large intestine was a straight dilated tube lying in the left flank and extending from the splenic flexure to the anus in the median plane. It was suspended by a short mesocolon except for the rectal portion in the pelvis. The ileo-colic junction was differentiated morphologically and histologically. There was no caecum, appendix, taeniae coli or appendices epiploicae. The large intestine was not differentiated topographically into ascending, transverse and des
Animals↗
Pyrimidine and purine salvage deoxyribonucleoside metabolism in hepatic and renal homogenates from rats pretreated with propylthiouracil or L-thyroxine.
OBJECTIVES: In vitro activities of thymidine kinase (TK, EC 2.7.1.21), adenosine kinase (AK, EC 2.7.1.20) and deoxycytidine kinase (dCK, EC 2.7.1.74) enzymes involved in the salvage pathway of DNA precursor synthesis, in homogenates of the rat liver and kidney, were examined. Type I iodothyronine-5'-deiodinase (5'D-I) is the main enzyme responsible for peripheral metabolism of thyroid hormones. This occurs especially in the liver, kidney and muscle. The activity of 5'D-I is inhibited bypropylthiouracil (PTU), an antithyroid drug. METHODS: The liver and kidney were collected from rats pretreated in vivo with either a 0.1% solution of PTU in drinking water for 2 weeks or injected with levothyroxine (L-T(4), 50 &mgr;g/kg BW, daily) for 2 weeks. The enzyme activities were measured by ascending chromatography and expressed asthe amounts of radioactive reaction products of the phosphorylation of dThd (for TK), ofdAdo (for AK and dCK) and of dGuo (for dCK). RESULTS: In liver homogenates, PTU-pretreatment decreased the activities of the three enzymes when compared to control values and those of L-T(4)-treated animals; also L-T(4) injections decreased the AK and dCK activities in the liver homogenates. PTU-pretreatment increased TK activity and the rate of dGuo phosphorylation in kidney homogenates, when compared to controls and to the L-T(4)-pretreated animals. Conversely, both PTU- and L-T(4)-pretreatment reduced the rate of dAdo phosphorylation in kidney homogenates. CONCLUSION: Changes in the activities of examined enzymes which participate inpyrimidine orpurine metabolism of the salvage pathway of DNA synthesis in the liver afterPTU-pretreatment (as shown herein) are similar to the changes of the 5'D-I activity after PTU-treatment (as reported by others). Thus, the observations suggest a role of the salvage pathway of DNA synthesis in the peripheral metabolism of thyroid hormones.
Journal Article↗
Effects of hypothyroidism induced by 6-n-propylthiouracil and its reversal by T3 on rat heart superoxide dismutase, catalase and lipid peroxidation.
The present study critically evaluates the effects of hypothyroid and hyperthyroid states on lipid peroxidation and two enzymes of active oxygen metabolism, namely superoxide dismutase (SOD) and catalase (CAT) in the rat heart mitochondrial and post-mitochondrial fractions. Lipid peroxidation, an index of oxidative stress, was elevated in the heart tissue in hypothyroid state but reduced upon T3 supplementation. Hyperthyroidism registered increased SOD activity in post-mitochondrial fraction. Mitochondrial SOD activity was reduced in hypothyroid state, which was further reduced by T3 administration. In contrast, different thyroid states had no effect on catalase activity in the mitochondrial fraction. The hypothyroid state however, significantly augmented catalase activity in post-mitochondrial fraction. The results suggest that the antioxidant defence status of cardiac tissue is well modulated by thyroid hormone.
Animals↗
[Case of thyroid storm during administration of propylthiouracil in hyperthyroidism].
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Adult↗
Oxidative stress and serum paraoxonase activity in experimental hypothyroidism: effect of vitamin E supplementation.
Thyroid hormones are associated with the oxidative and antioxidative status of the organism. Since data on the oxidative status of hypothyroidism are limited and controversial, we investigated the oxidant and antioxidant status and serum paraoxonase/arylesterase activities in propylthiouracil-induced hypothyroidism and examined the effect of vitamin E supplementation on this experimental model. Forty male Sprague Dawley rats were randomly divided into four groups (group 1, control; group 2, control + vitamin E; group 3, propylthiouracil; group 4, propylthiouracil + vitamin E). Plasma, red blood cell, liver, heart and skeletal muscle malondialdehyde levels were increased in the propylthiouracil-treated group compared with the control rats and were decreased in propylthiouracil + vitamin E group compared with the propylthiouracil-treated group. Vitamin E supplementation also significantly increased liver and kidney reduced glutathione levels in propylthiouracil treated animals. Serum paraoxonase and arylesterase activities were decreased in propylthiouracil treated group and vitamin E supplementation caused significant increase in serum paraoxonase activity compared with the propylthiouracil-treated rats. These findings suggest that hypothyroidism is accompanied with increased oxidative stress and vitamin E supplementation exerts beneficial effects on this situation.
Animals↗
Comparison of standardized initial doses of two antithyroid drugs in the treatment of Graves' disease.
OBJECTIVES: To obtain a simple standard regimen, suitable for general practice, and based upon the addition of antithyroid drug plus thyroxine for attaining euthyroidism in patients with Graves' disease. DESIGN: Prospective, randomized trial of patients with Graves' disease followed for 3 months after the initiation of therapy with an antithyroid drug and combined with the later addition of triiodothyronine to keep the patient euthyroid. The patients were randomized, according to birth date, between methimazole and propylthiouracil. Three dose schemes were tested for each antithyroid drug. SETTING: The study was performed at the thyroid outpatient units of two general hospitals, with the patients having been referred from primary care. SUBJECTS: Ninety-four patients with Graves' disease who were suitable for treatment with antithyroid drugs. INTERVENTIONS: The patients were allocated into six groups. Three groups received methimazole (10 mg every 6th, 8th or 12th h) and three received propylthiouracil (100 mg every 6th, 8th or 12th h). Twenty micrograms of triiodothyronine was added when the patients were euthyroid to avoid hypothyroidism. MAIN OUTCOME MEASURES: The lowest serum free thyroxine level within 3 months of the initiation of the antithyroid treatment. RESULTS: Fourteen per cent of the patients on methimazole 10 mg every 12th h and 29% on propylthiouracil 100 mg every 12th h did not achieve euthyroidism within the 3-month observation period. All but one patient on methimazole 10 mg every 8th h or propylthiouracil 100 mg every 8th h reduced the free serum thyroxine levels to the normal or hypothyroid range within the observation period. All of the patients on methimazole 10 mg every 6th h and 56% on propylthiouracil 100 mg every 6th h reduced the serum T4 values into the hypothyroid range within the period. CONCLUSION: A standard regimen, based upon the addition of methimazole 10 mg every 8th or 6th h or propylthiouracil 100 mg every 8th or 6th h and followed by the addition of thyroxine or triiodothyronine when euthyroid to avoid hypothyroidism, seems to be suitable for attaining euthyroidism within 3 months in patients with Graves' disease. A dose scheme based on methimazole 10 mg every 12th h or propylthiouracil 100 mg every 12th h were found to be unsuitable due to an unacceptably high incidence of failure to attain euthyroidism or hypothyroidism within 3 months.
Adolescent↗
The economy of isometric force development, myosin isoenzyme pattern and myofibrillar ATPase activity in normal and hypothyroid rat myocardium.
Hypothyroidism was induced in Wistar-Kyoto rats by adding propylthiouracil to the drinking water (0.8 mg/ml). Initial heat, total activity-related heat, and resting heat rate were measured in left ventricular papillary muscle preparations of propylthiouracil-treated and control rats contracting isometrically at 12 beats/min (21 degrees C), using Hill type, planar vacuum-deposited bismuth and antimony thermopiles. In the propylthiouracil preparations, relative to control, time-to-peak tension increased from 288 +/- 27 (mean +/- SD) to 411 +/- 25 msec (P less than 0.001), dp/dtmax decreased from 38.3 +/- 9.5 to 20.4 +/- 3.5 g X mm-2/sec (P less than 0.001), and peak developed tension decreased from 6.11 +/- 1.75 to 4.64 +/- 0.89 g X mm-2 (P less than 0.05). In the propylthiouracil preparations, initial heat was significantly (P less than 0.001) reduced by 27 or 43% when normalized to peak twitch tension or tension-time integral, respectively. In experiments where the papillary muscles were tetanized, the slope of the linear function of total activity-related heat versus tension-time integral was decreased by 43% (P less than 0.001) in the propylthiouracil preparations, indicating an improved economy of isometric tension maintenance. The predominant myosin isoenzyme of the left ventricular wall, as well as the papillary muscle myocardium, was the V3 variety in the propylthiouracil animals, in contrast to V1 in the controls. Myofibrillar actomyosin calcium-magnesium-stimulated adenosine triphosphatase activity was significantly (P less than 0.02) decreased from 55 +/- 18 (control) to 31 +/- 8 nmol inorganic phosphate ion/mg X min (propylthiouracil).(ABSTRACT TRUNCATED AT 250 WORDS)
Actomyosin↗
Antithyroid drugs interact with renal medullary prostaglandin H synthase.
The antithyroid drugs propylthiouracil and methimazole exert their effects on the thyroid gland by inhibiting thyroid peroxidase. In addition to this effect, these drugs have been reported to inhibit prostaglandin production in both the thyroid gland and the kidney. The purpose of our studies was to evaluate the mechanism of the effects of these drugs on prostaglandin production. Both propylthiouracil and methimazole reversibly inhibited prostaglandin E2 production in both inner medullary slices and isolated renal papillary collecting tubule cells. The inhibition of arachidonic acid-induced increases in PGE2 production indicated that the effects of methimazole and propylthiouracil were on the enzyme complex prostaglandin H synthase, and not on the phospholipase mechanisms responsible for the release of arachidonic acid from tissue phospholipids. Propylthiouracil inhibited both arachidonic acid and hydrogen peroxide-dependent binding of 14C-N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide to protein, indicating that the effect of propylthiouracil is on the hydroperoxidase and not on the cyclooxygenase component of prostaglandin H synthase. Our data also indicate the potential of the antithyroid drugs for inhibition of metabolism of drugs and xenobiotics by prostaglandin H synthase. Metabolism of both methimazole and propylthiouracil by the hydroperoxidase component of prostaglandin H synthase was demonstrated. It is proposed that this interaction with the hydroperoxidase component of prostaglandin H synthase is at least in part the mechanism by which propylthiouracil and methimazole inhibit prostaglandin production. The inhibition of tissue peroxidase provides these agents with the capability to prevent the peroxidatic metabolism of drugs and xenobiotics.
Animals↗
Clinical pharmacokinetics of antithyroid drugs.
Organic antithyroid drugs used today include propylthiouracil and the mercaptoimidazolines, carbimazole and methimazole. They can be measured with accuracy and in small quantities in serum by gas-liquid chromatography, high performance liquid chromatography and radio-immunoassay. Bioavailability of these drugs varies from 80 to 95%. During absorption carbimazole, which itself is inactive, is completely converted to methimazole. The total volume of distribution is about 40L for methimazole and around 30L for propylthiouracil, which is about 80% protein-bound, while methimazole is virtually non-protein-bound. Drug transfer across the placenta and into breast milk is also higher for the more lipid-soluble methimazole than for propylthiouracil, which is excreted into breast milk only in small quantities so that no harmful effect to the suckling infant is to be expected. Both drugs are concentrated in the thyroid gland, exerting an effect on intrathyroidal iodine metabolism for periods exceeding those in which serum concentrations can be measured. Less than 10% of both drugs is excreted unchanged in the urine, but detailed metabolic pathways are unknown. The half-life of methimazole is 3 to 5 hours with a total clearance of about 200ml/minute. Propylthiouracil has a half-life of 1 to 2 hours with a clearance of around 120ml/min/m2. Some studies have shown an increased rate of metabolism of anti-thyroid drugs in hyperthyroidism, in particular for methimazole. No reliable information exists regarding pharmacokinetics of these agents in renal and hepatic failure or in children. The clearance of propylthiouracil is unchanged in the elderly. Several mechanisms for the inhibiting effect of these agents on intrathyroidal hormone metabolism have been suggested. In contrast to methimazole, propylthiouracil inhibits the peripheral conversion of thyroxine to triiodothyronine. Preliminary dose-response studies with propylthiouracil suggest a peak therapeutic serum concentration of above 4 micrograms/ml in the treatment of thyrotoxicosis. The choice between the antithyroid drugs is based more upon personal preference and experience than on strict pharmacological principles, as no important differences exist between these drugs with regard to the rate of remission or frequency of occurrence of serious adverse reactions.
Antithyroid Agents↗
Immunomodulatory effect of the treatment of Graves' disease on antigen-specific monocyte procoagulant activity production.
The monocyte procoagulant activity (PCA) production assay has been shown to be a good parameter of cell-mediated immunity. We have studied antigen-specific PCA production in peripheral blood mononuclear cells from patients with Graves' disease to determine the effect of the treatment on the cell-mediated immune response. Peripheral blood mononuclear cells from patients with untreated or relapsed Graves' disease produced significantly greater PCA with thyroid antigen stimulation than those from normal subjects. Patients both on antithyroid drugs in the hyperthyroid state and within 3 months post-131I therapy also produced significantly larger amount of PCA than normal subjects. However, there was no significant difference in PCA production with thyroid antigen stimulation between normal subjects and patients on anti-thyroid drugs in the euthyroid state, or patients over 3 months post-131I therapy. The ratio of positive to negative PCA production in patients on anti-thyroid drugs in the euthyroid state or over 3 months post-131I therapy was significantly lower than in untreated or relapsed Graves' disease patients. Mononuclear cells from patients on propylthiouracil responded to propylthiouracil in vitro by production of PCA. Cells from normal subjects, untreated Graves' disease patients, or patients with Hashimoto's thyroiditis did not produce PCA with propylthiouracil stimulation. Mononuclear cells from patients who were on propylthiouracil for more than 3 months produced greater PCA than those on the drug for less than 3 months, suggesting sensitization of lymphocytes to propylthiouracil during the course of treatment. However, after 131I therapy, they gradually became unresponsive to propylthiouracil. This study has shown that the activity of the antigen-specific response assessed by PCA production in mononuclear cells from Graves' disease patients declined after treatment, suggesting that the treatment exerted immunomodulatory effects.
Adolescent↗
Effect on exophthalmos of various methods of treatment of Graves' disease.
Patients with both exophthalmos and hyperthyroidism were treated with different modes of therapy for their hyperthyroidism. Propylthiouracil followed by surgery, propylthiouracil followed by radioactive iodine, propylthiouracil alone, and radioactive iodine alone were used. Some of the patients became hypothyroid and were made euthyroid with levothyroxine sodium. Based on the mode of therapy and whether or not hypothyroidism occurred, each patient was assigned to one of seven groups and followed up for 18 months or longer. Careful exophthalmometry was performed at six-week intervals in all patients. Though progression of exophthalmos was noted in all groups, the group that received propylthiouracil demonstrated the greatest progression of exophthalmos. In the group receiving sodium iodide l 131 therapy and in the group treated surgically, the rate of progression of exophthalmos was lessened with the development of hypothyroidism. Since these hypothyroid patients were made euthyroid with supplemental levothyroxine, it appeared that loss of thyroid tissue, rather than the hypothyroidism per se, was responsible for the decrease in progression of the exophthalmos. The continued progression of exophthalmos in the propylthiouracil-treated group may be related to effects of propylthiouracil on the immune system.
Exophthalmos↗
Potentiation of glucose-induced insulin release by thiourea and thiourea derivatives.
The effect of thiourea and its derivatives, including methyl- and propylthiouracil as well as the imidazole derivative thiamazole on glucose-induced insulin secretion from incubated rat pancreatic islets was studied. Additionally, the effect of a single oral dose of propylthiouracil on plasma insulin and glucose tolerance was tested in anaesthetized rats. In the presence of 2.8 mM glucose, neither thiourea nor methylthiouracil, propylthiouracil or thiamazole stimulated the secretion of insulin from pancreatic islets. However, in the presence of 11.1 mM glucose all of the above compounds augmented the insulin-releasing properties of glucose in a concentration-related manner-propylthiouracil being the most potent drug. Propylthiouracil (100 and 200 mg/kg body weight) significantly augmented insulin secretion in vivo in response to i.v. glucose (0.5 g/kg). Accordingly, the rate constant of glucose elimination (K-value) was increased. The data suggest that thiourea-containing chemical compounds sensitize pancreatic islets to the insulin-triggering action of glucose.
Animals↗
Graves' disease in pregnancy years after hypothyroidism with recurrent passive-transfer neonatal Graves' disease in offspring. Therapeutic considerations.
Symptoms and signs of severe hypothyroidism developed in a young woman at age 15. These symptoms progressed for a year; at age 16, she was found to have a firm goiter, thyroid autoantibodies, very low serum thyroxine and high thyrotropin values, indicating autoimmune thyroiditis with hypothyroidism. She received L-thyroxine, 0.20 mg per day, and was well until age 24 when she became pregnant. In the first trimester, manifestations indicative of hyperthyroidism developed; these were only ultimately recognized immediately after delivery of a 32-week still-born goitrous baby. Despite the discontinuation of thyroxine therapy, the hyperthyroidism persisted and was confirmed as Graves' disease by elevated thyroxine, triiodothyronine, and radioactive iodine uptake values, a diffuse scanning result, and the presence of thyroid-stimulating antibody. The patient was treated with propylthiouracil and became pregnant while receiving that regimen. Later, several months after delivery, the patient was treated with radioactive iodine, ultimately became hypothyroid, and has been treated ever since with thyroxine. She became pregnant again and, because of the continuing high titers of thyroid-stimulating antibody, received propylthiouracil, 100 mg daily, commencing in the third trimester of pregnancy, to avoid probable fetal hyperthyroidism due to the transplacental transfer of thyroid-stimulating antibody. In each of the last two pregnancies, when the infants were born, they seemed normal (because of the transplacental effect of propylthiouracil), but passive-transfer neonatal hyperthyroidism developed in each within 10 days after delivery, ultimately requiring treatment by conventional means. This case illustrates the following points: (1) Hyperthyroidism occasionally develops years after hypothyroidism. (2) In young women, high titers of thyroid-stimulating antibody may produce fetal and neonatal passive-transfer hyperthyroidism even at a time when the mother herself is no longer hyperthyroid; 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. (3) Because the infants had been protected in utero by the placental transfer of propylthiouracil, neonatal hyperthyroidism did not develop until several days after delivery.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗