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PubMed1977

Hyperthyroidism during pregnancy treated with propylthiouracil. The significance of maternal and foetal parameters.

Hyperthyroidism during pregnancy may be dangerous to the infant. The major risks are prematurity and neonatal thyrotoxicosis. The latter may be due to placental transfer of thyroid stimulating immunoglobulins from mother to fetus. Of two siblings of a previously thyrotoxic mother the first had marked symptoms of neonatal thyrotoxicosis after a pregnancy where no antithyroid treatment was given. The second child had only minimal thyrotoxic symptoms but almost as high levels of thyroid hormones as the first. During the second pregnancy propylthiouracil was given to the mother from 26 weeks' gestation, because of increased fetal movements and fetal tachycardia. Fetal movements and fetal heart rate were considered to be most valuable indicators of thyroid function in the fetus. Intense control is necessary from the beginning of the second trimester.

Adult↗
PubMed1984

Enhancement of glutathione S-transferase activity in rat liver by repeated administration of propylthiouracil.

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.

Animals↗
PubMed1988

Oxidative metabolism of propylthiouracil by peroxidases from rat bone marrow.

1. Propylthiouracil (PTU) was degraded by myeloperoxidase (MPO) or eosinophil peroxidase (EPO), purified from rat bone marrow, in the presence of H2O2 and Cl-. In the absence of either H2O2 or Cl-, MPO and EPO do not degrade PTU. Optimum concentrations of KCl for MPO and EPO were 50 and 250 mM, respectively. 2. The characteristics of PTU degradation by MPO-H2O2-Cl- were similar to those of the chlorinating activity of the peroxidase. 3. Hypochlorous acid as well as MPO-H2O2-Cl- also degraded PTU. Metabolites of PTU degradation by MPO-H2O2-Cl-, which were separated by C18 reversed phase h.p.l.c., were the same as those produced by hypochlorous acid. 4. Of the metabolites of PTU formed by MPO-H2O2-Cl-, one was identified as PTU sulphonic acid (6-propyl-4-hydroxypyrimidine-2-sulphonate) and another seemed to be propyluracil.

Animals↗
PubMed1992

Intrathyroidal activated (Ia+) T-lymphocyte CD+ subsets and B cells in Graves' hyperthyroidism respond rapidly to propylthiouracil therapy: demonstration using fine needle aspirates and two-colour laser flow cytometry.

Using a rapid (whole blood lysis) single laser microfluorocytometric technique that permitted the simultaneous analysis of two monoclonal antibody surface markers tagged with different fluorescent dyes, the intrathyroidal (IT) and peripheral blood (PB) activated [Ia+ = DR+] T-lymphocyte CD3+ subsets and [F(ab')2+] B cells were studied in hyperthyroid patients with Graves' disease (GD) before and after 1-4 months of propylthiouracil (PTU) therapy. IT lymphocytes were obtained by serial fine needle aspiration. In untreated patients a marked quantitative (approximately < 10 fold) increase in activated (Ia+ CD3+) T-lymphocytes as well as CD4+ and CD8+ subsets, for IT compared to PB sites, was found. The percentages of Ia+ CD4+ and Ia+ CD8+ within Ia+ CD3+ were not significantly different between the two sources of T cells. F(ab')2+. B cells were significantly increased (approximately 2-3 fold) in IT compared to PB. In hyperthyroid GD patients, PTU therapy induced rapid and specific changes within the Ia+ CD3+ subsets, namely a reduction in the Ia+ CD4+ subset and an increase in the Ia+ CD8+ subset, resulting in a marked decrease in the Ia+ CD4+/Ia+ CD8+ ratio. These changes occurred in association with a reduction in serum T4 and T3 concentration. No significant changes could be detected within the total (predominantly non-activated) CD3+, CD4+ or CD8+ lymphocyte subsets within PB and only a small decrease in the CD4+/CD8+ ratio was demonstrated in IT, following PTU treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Increased lipid peroxidation in hyperthyroid patients: suppression by propylthiouracil treatment.

Plasma and urinary levels of thiobarbituric acid reactive substances (TBAR) were determined in 24 hyperthyroid patients, 19 hypothyroid subjects, 35 controls, and 17 hyperthyroid patients before and after propylthiouracil (PTU) treatment (400 mg/day for 2-3 months), as indexes of lipid peroxidation. These measurements were carried out together with t-butyl hydroperoxide (t-BHP)-induced oxygen uptake and visible chemiluminescence in erythrocytes as functional tests related to the antioxigenic capacity of cells. Hyperthyroid patients exhibited increased levels of plasma and urinary TBAR compared to controls. Erythrocyte suspensions from hyperthyroid patients showed, compared to controls, higher rates of oxygen consumption with shorter induction periods upon addition of t-BHP, together with 142% and 75% increases in basal and t-BHP-induced chemiluminescence, respectively. Levels of TBAR in untreated hyperthyroid patients in plasma (16.2 +/- 1.3 pmol/mg of protein) and urine (15.9 +/- 1.5 nmol/mg of creatinine) were decreased after PTU treatment (Plasma, 9.5 +/- 0.7, p less than 10(-4); urine, 7.8 +/- 0.9, P less than 10(-5) to values not significantly different from those of the control group (plasma, 10.3 +/- 0.6; urine, 7.9 +/- 0.7). Compared to control, elevated rates of oxygen uptake induced by t-BHP, basal and t-BHP-induced chemiluminescence in erythrocyte suspensions from untreated hyperthyroid patients were reverted to normal by PTU, while decreased induction period (T0) values were enhanced. Determination of these lipid peroxidative parameters in hypothyroid patients revealed no significant changes over control values, excepted t-BHP-induced chemiluminescence in erythrocytes that was diminished. These data indicate that hyperthyroidism is associated with a pro-oxidant condition characterized by an enhancement in circulating and urinary lipid peroxidative indexes, which is suppressed by PTU treatment. It is suggested that this condition might reflect an oxidative stress at cellular level in tissues which are target for thyroid hormone action with a calorigenic response.

Adult↗
PubMed1986

Propylthiouracil-induced cholestatic jaundice.

The typical propylthiouracil (PTU)-linked hepatotoxicity, is known to manifest itself by hepatocellular injury with greatly increased serum transaminase values and evidence of hepatic necrosis on liver biopsy. Herewith presented is a 33-year old, thyrotoxic woman who developed cholestatic jaundice two weeks after initiation of PTU therapy. The diagnosis was confirmed by liver biopsy. A causal link between PTU treatment and the cholestatic jaundice was suggested by: the time of onset, typical skin rash and a positive migration inhibition factor (MIF) test to PTU. Awareness of this rare complication of PTU treatment may prevent the performance of unnecessary, expensive and possibly harmful diagnostic procedures.

Adult↗
PubMed1991

Effect of beta agonist clenbuterol on the body composition of rats with hypothyroidism induced by oral administration of propylthiouracil.

The object of this experiment was to examine whether the administration of clenbuterol exerts clenbuterol's repartitioning effects in rats with hypothyroidism induced by the oral administration of propylthiouracil (PTU). Male Wistar rats aged 5 weeks were divided into 4 groups: control, PTU administrated (PTU), clenbuterol administrated (CL), and PTU plus clenbuterol administrated (PTU/CL) groups. Rats were raised for 7 weeks at 26 degrees C and given 13 g of diet every day. The PTU and PTU/CL groups were fed a basal diet containing PTU at the level of 30 mg/kg diet throughout the experimental period. Clenbuterol was added to the diet of the CL and PTU/CL groups at the dose of 0.1 ppm from the 3rd week. Serum thyroxine concentrations of rats were significantly lower in rats in the PTU and PTU/CL groups than those in the control and CL groups. Thus, the administration of PTU succeeded to induce hypothyroidism. The clenbuterol administration seemed to exert its repartitioning effects in euthyroid rats, while the administration neither increased body protein nor decreased body fat in hypothyroid rats. This result therefore suggests that the effects of clenbuterol on the alteration of body composition may vary with the level of thyroid activity in rats.

Adipose Tissue↗
PubMed1990

Lack of effect of propylthiouracil and methylmercaptoimidazole on thyroglobulin biosynthesis.

Experiments were performed both in vivo and in vitro to test a previous proposal that part of the antithyroid action of the thioureylene drugs, propylthiouracil (PTU) and methylmercaptoimidazole, can be attributed to inhibition of thyroglobulin (Tg) biosynthesis. Rat thyroid lobes were incubated in leucine-free Eagle's medium containing bovine thyroid-stimulating hormone and 0, 0.1-0.2, or 1 mM drug. After a 30-min preincubation, 5 mu Ci of [14C]leucine were added and the incubation was continued for 4 hr. The soluble fraction was analyzed by sucrose density gradient centrifugation, and the fractions corresponding to the 19S Tg peak were pooled and assayed for 14C. No inhibition of 14C incorporation into 19S Tg was observed, even in thyroid lobes incubated in the presence of 1 mM methylmercaptoimidazole or 2 mM PTU. At the same time, 14C incorporation into 19S Tg was completely inhibited when lobes were incubated in the presence of 0.1 mM puromycin. In vivo, rats received an injection of PTU (1 mumol/100 g body wt), followed 60 min later by an injection of 25 mu Ci of [14C]leucine. Blood samples and thyroids were taken 5 hr after the [14C]leucine injection. Serum thyroid-stimulating hormone was not significantly affected by the PTU injection. The thyroid-soluble fraction was analyzed by sucrose density gradient centrifugation. No significant differences between saline and PTU-injected groups were observed in [14C]leucine incorporation into 19S Tg. We conclude from both our in vitro and our in vivo studies that PTU and methylmercaptoimidazole have no inhibitory effect on thyroglobulin synthesis in rat thyroids and that such inhibition does not play a significant role in the antithyroid action of these drugs.

Animals↗
PubMed1990

Age dependency of triiodothyronine-induced thermogenesis in young chicks: inhibition by propylthiouracil.

Age dependency of triiodothyronine (T3)-induced thermogenesis of young chicks at 1 and 2 wk of age was investigated by dietary administration of .5% propylthiouracil (PTU), an inhibitor of thyroid hormone synthesis. Heat production measured by indirect calorimetry was increased by an intraperitoneal injection of T3, but the thermogenic effect was larger at 2 wk than at 1 wk of age. Heat production at 2 wk of age was decreased by PTU when the T3 was not administered, whereas the inhibitory effect of PTU was not found at 1 wk of age. It would appear, therefore, that little or no thermogenesis is responsive to exogenous T3 in young chicks at 1 wk of age even though the suppression of endogenous T3 is likely to occur by the PTU treatment.

Age Factors↗
PubMed1992

Effects of context on sweet and bitter tastes: unrelated to sensitivity to PROP (6-n-propylthiouracil).

In a double-shifting context paradigm, subjects gave magnitude estimates of the perceived intensity of qualitatively dissimilar taste substances (saccharin and quinine, sucrose and quinine) or qualitatively similar ones (saccharin and sucrose), with each pair of substances taking on different contextual sets of concentrations in different sessions. The dissimilar pairs produced substantial differential effects of context (e.g., a particular concentration of saccharin or sucrose was judged more intense than a particular quinine in one contextual setting, less intense in another), but the similar pair did not. This result accords with the hypothesis that differential context effects depend on qualitative similarity. Contrary to expectations, however, the magnitude of the context effect did not differ in tasters and nontasters of the bitter substance 6-n-propylthiouracil (PROP), groups previously shown to differ in sensitivity to bitterness in saccharin. Similarity judgments suggest that saccharin and sucrose were qualitatively alike for all subjects, regardless of sensitivity to PROP.

Attention↗
PubMed2006

Genetic sensitivity to the bitter taste of 6-n propylthiouracil: a new risk determinant for dental caries in children.

The aims of the present study were to contrast the prevalence of dental caries in children with different genetic sensitivity levels to the bitter taste of 6-n-propylthiouracil (PROP) and to determine the taste quality and taste intensity preferences of food products among the taster and nontaster groups. Overall caries experience (dmfs/DMFS) was significantly higher for nontasters than tasters. Caries experience on the available surfaces (dfs/DFS) was found to be significantly higher in nontasters than in medium tasters and in medium tasters than in supertasters (r=-0.41, P < 0.001). Majority of the nontasters were sweet likers and preferred strong tasting food products, while majority of the supertasters were sweet dislikers and preferred weak tastes. There was a significant increase in the overall caries experience in the population, as the genetic ability to detect PROP taste decreased ( P < 0.001). After all associated factors (age, gender, race, number of teeth and OHI-S) were controlled; multiple linear regression analyses revealed that taste was the only variable significantly related to overall caries experience.

Age Factors↗
PubMedDate not supplied

Propylthiouracil-induced sensorineural hearing loss associated with antineutrophil cytoplasmic antibodies.

OBJECTIVE: To report the case of a young woman with Graves' disease in whom ototoxicity developed because of propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We present the clinical findings, pertinent laboratory data, and follow-up course of a patient with Graves' disease and bilateral sensorineural hearing loss. We also provide a literature review regarding thionamide-induced ANCA-associated vasculitis. RESULTS: In a 22-year-old Thai woman with Graves' disease, tinnitus, hearing impairment in the left ear (with progression to the right ear), and vertigo developed after 3 years of therapy with PTU. Audiograms showed bilateral sensorineural hearing loss with cochlear lesions. She also had low-grade fever, intermittent chronic abdominal pain, weight loss, polyarthralgia, and conjunctivitis. An indirect immunofluorescence test for ANCA was positive. The hearing impairment and tinnitus were gradually reduced after PTU withdrawal and corticosteroid and azathioprine treatment. Definitive therapy by subtotal thyroidectomy was subsequently performed and yielded good results. CONCLUSION: This rare case of PTU-induced ANCA-associated vasculitis manifested with ototoxicity in combination with systemic involvement.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Rectal administration of propylthiouracil in suppository form in patients with thyrotoxicosis and critical illness: case report and review of literature.

OBJECTIVE: To report the successful management of thyrotoxicosis in a seriously ill 47-year-old man with a perforated gastric ulcer in whom oral intake was contraindicated. METHODS: Our patient was treated with 400 mg of propylthiouracil (PTU) every 6 hours in the form of specially prepared suppositories for rectal administration, together with intravenously infused esmolol. RESULTS: We were able to demonstrate substantial absorption of PTU administered by means of rectal suppositories. Serum levels of PTU were maintained within the high therapeutic range for 5 days until the patient was able to tolerate orally administered therapy. The patient improved clinically during this treatment. CONCLUSION: This case strongly supports the rectal administration of PTU in suppository form as an appropriate alternative route in any patient with thyrotoxicosis, including the critically ill patient, when oral administration is not possible.

Administration, Rectal↗
PubMed2001

Cerebellar parameters in developing 15 day old rat pups treated with propylthiouracil in comparison with 5 and 24 day old.

OBJECTIVE: To investigate and quantify structural parameters in the developing cerebellum during hypothyroidism in pre and postnatal stages in 15 day old rat pups in comparison with 5 and 24 day old. METHODS: Propylthiouracil (PTU) was fed to rat dams during mating, pregnancy and nursing and their pups in drinking water. Consequently hypothyroxinemia was induced in the dams and the developing foeti during prenatal period and maintained in the dams and pups. The number of treated and control dams was five in each group. The treated and control pups were eight and eleven respectively. The whole cerebellum was dissected out and routinely processed for histological and morphometric analysis. Structural changes in cerebellum were estimated using "design based" stereological methods. The total volume of cerebellum, intracerebellar nuclei and cerebellar compartments were estimated using Cavalieri Principle. Numerical density of cells was estimated using the disector method and the total cell number was then calculated. RESULTS: In the 15 day pups there was significant reduction (P<0.05) in the mean volumes of cerebellum, internal granular layer, molecular layer, cerebellar cortex, mean ratio of the total volume of intracerebellar nuclei to the cerebellar volume and increased mean volume of external granular layer in treated pup group compared with control. The mean volumes of intracerebellar nuclei and white matter and the mean numerical densities and total numbers of neurons and Purkinje cells in intracerebellar nuclei and cerebellum respectively were nearly equal in control and treated groups. Significant increase (P<0.05) in the mean numerical density and total number of glial cells in treated pups compared with control was observed. There was significant decrease (P<0.05) in the mean neuron/neuroglia ratio in the intracerebellar nuclei, mean numerical density and mean total number of granule cells and reduction in the mean ratio of total number of granule/Purkinje cells in the treated group compared with control. The linear regression comparison for the total volume of the intracerebellar nuclei to total volume of the cerebellum in 5, 15 and 24 day control and treated pups and for the total number of glial cells on the total volume of intracerebellar nuclei in the same were significantly different (P<0.05). Total numbers of neurons and glial cells in the intracerebellar nuclei showed peak values in 15 day pups. CONCLUSION: Thus PTU-induced hypothyroidism causes variation in quantitative structural parameters in developing cerebellum and disrupts progressive cellular developmental processes. Maintenance of normal T4 and T3 levels during growth and maturation of cerebellum is absolutely essential.

Aging↗
PubMed1998

Effect of propylthiouracil induced hypothyroidism in developing rat cerebellum: comparison of cerebellar parameters in five day old normal and treated rat pups.

The effect of pre and postnatal hypothyroid environment on the development of cerebellum in the rat pups was determined. Four groups of rat dams, namely control, Group I, II and III were treated with propylthiouracil (PTU) in water for different length of time during pregnancy and nursing periods. The pups born from these dam groups were subsequently named after the corresponding dam group, namely control, Group I, II and III. General quantitative results showed that pups from the treated dams had significantly lower (p < 0.05) body weights compared to control pups. Cerebella from five day old pups were taken and structural changes estimated using unbiased "design based" stereological methods, which have made it possible to investigate specific qualities in the organ. The total volumes of cerebellum and intracerebellar nuclei were estimated using Cavalieri Principle. The mean total volume of cerebellum and the mean total volume of intracerebellar nuclei were significantly lower (p < 0.05) in all the pup groups (I, II, III) from the treated dams compared to control pups from the control dams. The cerebellar volume decreased in relation to the duration of treatment. The mean ratio of the total volume of intracerebellar nuclei to volume of cerebellum was significantly increased (p < 0.05) in Group III pups compared to control and Group I pups. The mean numerical density of neurones in the intracerebellar nuclei was nearly equal in all the pup groups except in Group III pups whereby it was increased. The mean total number of neurones in Groups I and II pups was reduced, but did not reach statistical significance. The mean numerical density of neuroglia in the intracerebellar nuclei was nearly the same in all the pup groups, the mean total number of glial cells was significantly reduced (p < 0.05) in Groups I and II pups compared to control and the mean neuron/glial ratio was increased in Group III pups compared to control and other treated groups. Thus, the neuroglia appear to be more sensitive to hypothyroidism than neurons. The above results show that PTU-induced hypothyroidism causes reduction in structural parameters in developing cerebellum and confirm that growth and maturation of the foetal cerebellum is dependent on the maintenance of normal T4 and T3 levels in the pregnant dam and developing pups during pre and postnatal stages of development.

Animals↗
PubMed1976

Clinical study on early changes in thyroid function of hyperthyroidism treated with propylthiouracil and a relatively small dose of iodide.

In order to compare the acute effects of three kinds of antithyroid agents of iodide (I-), propylthiouracil (PTU) and PTU combined with iodide (PTU+I-) on thyroid function in hyperthyroid patients with diffuse goiter, serum concentrations of thyroxine (T4), triiodothyronine (T3), T3-resin sponge uptake (T3-RU) and free thyroxine index (FT4I) were employed as thyroid function parameters. In the group given iodine (1 mg/day) as iodinated-lecithine, the initial values of T4, T3, T3-RU and FT4I were 20.9 +/- 1.6 microng/100 ml (T4), greater than 740 ng/100 ml (T3), 49.5 +/- 2.3% (T3-RU) and 14.7 +/- 1.8 (FT4I). At the end of one week of therapy, they decreased clearly to 15.6 +/- 2.2 microng/100 ml, 457 +/- 87 ng/100 ml, 42.2 +/- 4.0% and 9.7 +/- 2.4. The so-called "escape phenomenon" from iodide inhibition was observed in serum T4, T3-RU and FT4I values at the end of two weeks of iodide therapy, while serum T3 continued to decrease but the value of T3 was far outside of the normal range. In the PTU group (300 mg/day), thyroid function parameters were 22.5 +/- 0.8 microng/100 ml (T4), greater than 592 ng/100 ml (T3), 54.9 +/- 1.0% (T3-RU) and 18.7 +/- 1.0 (FT4I) before treatment. They decreased continually week by week. At the end of four-week treatment with PTU, the value of each thyroid function parameter was 11.1 +/- 1.9 microng/100 ml, 229 +/- 56 ng/100 ml, 36.6 +/- 4.4% and 5.7 +/- 1.7. In the group of hyperthyroidism simultaneously given both PTU and iodide (300 mg/PTU and 1 mg/iodine), these thyroid function parameters decreased as well as in the group treated with PTU alone for more than two weeks. More rapid or significant decrease of T4, T3, T3-RU and ft4i in PTU+I- group than in PTU group was observed in the present study. These results suggested strongly that iodide alone was not an adequate therapy for hyperthyroidism as well known and they were also compatible with the idea that the concomitant administration of PTU and iodide was more effective in the early phase of therapy of hyperthyroidism than PTU alone.

Adolescent↗
PubMed1999

Propylthiouracil-induced hypothyroidism reduces xenograft tumor growth in athymic nude mice.

BACKGROUND: Thyroid hormones are endocrine modulators of several vital processes that are crucial to tumor growth and differentiation. Several anecdotal reports in the literature suggest that some histologic types of carcinoma may remain in a dormant state for prolonged periods of time in patients with hypothyroidism, with eventual progression of the disease once the decreased thyroid function is identified and corrected. METHODS: Oral propylthiouracil (PTU) was used to induce hypothyroidism in athymic nude mice that were subsequently inoculated with lung adenocarcinoma and prostate adenocarcinoma cells. Mice were also treated with a combination of PTU and thyroxine, which resulted in hyperthyroid levels of T(4). RESULTS: Subcutaneous lung and prostate xenografts grew significantly more slowly in hypothyroid mice treated with PTU than in euthyroid or hyperthyroid mice, regardless of treatment with PTU. Tumors grew well in groups of mice that were changed from a hypothyroid state to a euthyroid state by withdrawal of oral PTU. Administration of PTU 3 weeks after tumor inoculation also caused the tumor growth to slow significantly compared with tumors in mice that did not receive PTU. Mice that received PTU and thyroxine had tumors that grew as well as the tumors in euthyroid control animals. CONCLUSIONS: Our study indicates that human lung and prostate tumors do not grow well in hypothyroid nude mice, and that rendering these animals euthyroid has a significant impact on the growth rate of these tumors. Furthermore, in vitro and in vivo data indicated that this was not a result of an interaction of the tumor cells with PTU, but rather a result of the hypothyroid state.

Animals↗