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PubMed1984

Propylthiouracil-associated hemolytic anemia, thrombocytopenia, and antinuclear antibodies in cats with hyperthyroidism.

Nine of 105 cats with hyperthyroidism treated with propylthiouracil developed a serious immune-mediated drug reaction during treatment. Adverse clinical signs, which developed after 19 to 37 days (mean, 24.8 days) of propylthiouracil administration, included lethargy, weakness, anorexia, and bleeding diathesis. Physical examination revealed pale mucous membranes, and petechial hemorrhages of the skin and oral cavity. Results of hematologic testing revealed severe anemia and thrombocytopenia. The direct antiglobulin (Coombs') test was positive in all 7 cats evaluated, whereas the serum antinuclear antibody titer was greater than or equal to 1:10 in 5 of the 8 cats tested. In 4 of the cats, treatment included appropriate supportive therapy and cessation of propylthiouracil; in these cats, anemia and thrombocytopenia resolved and Coombs' and antinuclear antibody tests became negative within 2 weeks.

Anemia, Hemolytic↗
PubMed1982

Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats.

Hyperalphalipoproteinemia, characterized by increased plasma concentrations of apoA-I and of HDL lipid and protein, was observed in rats treated with triiodothyronine (T(3)) for 7 days. The increase in the plasma HDL apoproteins was general for apoC, apoE plus A-IV, and apoA-I, as determined by isoelectric focusing. Hypotriglyceridemia, characterized by decreased concentrations of VLDL and apoB, was also observed in the hyperthyroid state. Although in the mildly hypothyroid animals (propylthiouracil-treated), hepatic metabolism of free fatty acid is shifted toward esterification to triglyceride and VLDL formation, as we reported previously, plasma HDL and apoA-I concentrations were not different from control plasma values, while the d 1.006-1.063 g/ml (IDL + LDL) lipoprotein fraction tended to be increased. In general, the proportion of apoE in the (IDL + LDL) fraction of the hypothyroid rat was greater than in controls and hyperthyroid animals, while the proportion of apoE tended to be lower in VLDL from both hypo- and hyperthyroid rats than in VLDL from controls. An enhanced release of apoA-I by perfused livers isolated from rats treated with T(3) was also observed; this enhanced output of apoA-I may explain, in part, the hyperalphalipoproteinemia observed in these rats. The depressed net output of apoA-I in vitro by perfused livers from rats treated with propylthiouracil (PTU) was not expressed in a statistically significant diminished plasma concentration of HDL or apoA-I in the intact animals. Treatment with T(3) also resulted in modification of the content of essential fatty acids in various lipid classes. Linoleic acid residues were significantly reduced and arachidonic acid content was increased in plasma phospholipids and esterified cholesterol in T(3)-treated rats. However, the relative fatty acid composition of unesterified fatty acids and triglyceride fatty acids was not altered by T(3) treatment. PTU treatment had no effect on fatty acid distribution in any of the plasma lipids. Secretion of biliary lipids was increased in perfused livers from T(3)-treated rats, while treatment with PTU did not affect release of lipids in the bile. These observations suggest a regulatory role for thyroid hormones that determine concentration and composition of plasma HDL and other lipoproteins.-Wilcox, H. G., W. G. Keyes, T. A. Hale, R. Frank, D. W. Morgan, and M. Heimberg. Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats.

Animals↗
PubMed1993

[Major adverse reactions to propylthiouracil in 586 cases of hyperthyroidism].

Aiming to know the incidence and evolution of major adverse reactions to propylthiouracil in patients with hyperthyroidism, we performed a retrospective analysis of 586 patients treated between 1982 and 1992. All known complications associated to the use of propylthiouracil were considered major adverse reactions, when other causes were discarded. Eight patients (1.4% of the sample) had major adverse reactions: three had agranulocytosis, 3 hepatitis, 1 cholestasis and 1 vasculitis. All had a good evolution after discontinuing the drug. The patients with agranulocytosis were treated with antibiotics and the patient with cholestasis received prednisone. We conclude that major adverse reactions to propylthiouracil are infrequent, that they occur preferentially during the first months of treatment, earlier after reexposure and that there was no associated mortality.

Adolescent↗
PubMedDate not supplied

Effects of propylthiouracil on intestinal transit time and symptoms in hyperthyroid patients.

BACKGROUND/AIMS: Gastrointestinal disturbances such as diarrhea and malabsorption with steatorrhea may show up in hyperthyroid patients. The aim of our study was to evaluate oro-caecal transit time (OCTT) and gastrointestinal symptoms in hyperthyroid patients before and after propylthiouracil administration. MATERIALS AND METHODS: Twenty hyperthyroid patients (15 Females and 5 Males, mean age 47 years) were studied. Eight of them had diarrhea and 10 steatorrhea. The control group was composed of 20 healthy volunteers (13 F and 7 M, mean age 49 yrs). OCTT and fecal fat excretion were measured before and after propylthiouracil administration (300 mg/day for 10 day and then 200 mg/day for 30 days). RESULTS: Before the treatment in hyperthyroid patients had began the mean OCTT was significantly lower than in the control group (64 min. versus 107 min; p < 0.0001). After treatment mean OCTT became similar to the controls (p = ns); diarrhea disappeared in all affected patients and mean fecal fat excretion was reduced from 7.9 gr/24h to 3.4 gr/24h, with a statistically significantly difference (p < 0.0001). CONCLUSIONS: The treatment with propylthiouracil induces the normalization of thyroid hormone status and consequently of OCTT with the disappearance of gastrointestinal symptoms, such as diarrhea and steatorrhea, with a better efficacy if compared to other drugs utilized in the treatment of hyperthyroidism.

Administration, Oral↗
PubMed1984

Propylthiouracil and hepatitis. Two cases and a review of the literature.

Propylthiouracil-induced hepatitis is an uncommon entity. Two further cases are reported herein, and the clinical and laboratory features of the other six cases in the English literature are reviewed. The initial appearance of the disease is similar to that of viral hepatitis, characterized by nausea, vomiting, and jaundice. The biochemical pattern of injury is predominantly hepatocellular, with marked elevation of transaminase valves and less striking elevation of alkaline phosphatase values. Recovery is usually complete after withdrawal of the drug, but there have been at least two fatalities, including the first patient (to our knowledge) whose case is reported herein. Despite its rarity, the disease should be suspected in any patient receiving propylthiouracil in whom clinical or laboratory evidence of hepatocellular injury develops.

Adult↗
PubMed1978

Prospective randomized comparison of propylthiouracil.

Forty-nine patients with Graves' disease were randomly divided into two groups. One group received propylthiouracil, 150 mg every eight hours, and the other group received propylthiouracil, 450 mg as a single daily dose. All patients' conditions were evaluated clinically anc chemically at two-week intervals. The response to the divided dosage schedule was prompt and predictable, and by ten weeks all but one patient had achieved remission. The group that received the single daily dose regimen responded less favorably, and at ten weeks ten patients had failed to achieve remission (P less than .001). However, when these patients' regimens were switched to the every-eight-hour schedule, all but one patient became euthyroid in an additional four weeks.

Drug Evaluation↗
PubMed1975

Observations on the fine structure of propylthiouracil-induced "brown degeneration" in the zona reticularis of mouse adrenal cortex.

Propylthiouracil (6-propyl-2-thiouracil), an anti-thyroid agent, was fed to mice in a concentration equal to 0.1% of their diet for periods of 10 and 15 weeks. The cells of the inner zone of the adrenal cortex were examined with the electron microscope. In animals receiving propylthiouracil for ten weeks mitochondria were altered and the smooth endoplasmic reticulum (SER) showed a marked focal proliferation. In contrast to control animals rough endoplasmic reticulum was abundant and was frequently associated with the hyperplastic SER. After 15 weeks these alterations were no longer present but had been replaced by a spectrum of "brown degeneration." The less affected cells were characterized by increased numbers of liposomes and lysosomes and the more affected cells by liposomal and mitochondrial degeneration. These observations emphasize that "brown degeneration" is a true degenerative process and not a spontaneous proliferation of ceroid pigment. It is suggested that the changes described may be directly related to an alteration in cholesterol metabolism.

Adrenal Cortex↗
PubMed1975

Altered plasma half-lives of antipyrine, propylthiouracil, and methimazole in thyroid dysfunction.

In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half-lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half-liver plus or minus S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 plus or minus 1.4 hr, 6.7 plus or minus 1.0 hr, and 9.3 plus or minus 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 plus or minus 1.2 hr, 4.3 plus or minus 0.7 hr, and 6.9 plus or minus 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half-lives of these drugs were prolonged to 26.4 plus or minus 4.0 hr, 24.7 plus or minus 34.5 hr, and 13.6 plus or minus 4.8 hr, respectively. Return to the euthyroid state restored plasma half-lives to or toward normal. Alterations in plasma drug half-lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.

Adult↗
PubMedDate not supplied

Disposition of intravenous propylthiouracil.

Propylthiouracil was administered to 10 healty, male volunteers by a short intravenous infusion. Plasma and urinary drug concentrations were determined by a specific high-performance liquid chromatography assay, and protein binding was determined by equilibrium dialysis. After infusion, the plasma concentrations declined biexponentially, and the following median parameters (and ranges) were determined: clearance 273.5 ml/min (159.5-377.8 ml/min); free drug clearance, 1537.7 ml/min (985.9-1927.3 ml/min); apparent volume of distribution, 28.0 liters (22.7-44.4 liters); apparent elimination half-life, 1.28 hr (0.88-2.05 hr); k21, 3.12 hr-1 (1.06-5.36 hr-1): alpha 7.34 hr-1 (1.94-25.03 hr-1): Vc 9.40 liters (5.16-18.58 liters). In urine, only 1.28 per cent (0.03-2.01 per cent) of the administered dose was recovered over 24 hours as unchanged drug. The ratio (1.2 per cent) of urinary clearance (3.2 ml/min) to plasma clearance is far less (P less than 0.001) than the free fraction in plasma (median 18.2 percent, range 16.2-20.2 per cent) and this suggests that there is significant renal tubular reabsorption of propylthiouracil. In healthy subjects, both intraindividual and interindividual variation of protein binding is modest, and free drug clearance can be predicted from total drug clearance (y =- 257.6 + 4.56x, r = 0.95, P less than 0.001).

Adult↗
PubMed1984

Aldosterone and plasma renin activity in hyperthyroid rats: effects of propranolol and propylthiouracil.

Variations in renin- angiotensin-aldosterone system (RAAS) in experimentally induced hyperthyroidism were studied. The changes observed in the RAAS in these conditions, evaluated through the plasma renin activity (PRA), are parallel to serum aldosterone concentration (AC). An increase in PRA and AC is produced following the administration of triiodothyronine, possibly through elevated adrenergic activity: beta-blocker, propranolol, returned the PRA and AC to normal. The active hormone is seen to be triiodothyronine, confirmed by using the antithyroid preparation, propylthiouracil, to inhibit the conversion of thyroxine. Propylthiouracil administration to hyperthyroid animals lowers the PRA and AC.

Aldosterone↗
PubMed2006

HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway.

The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced activation of the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemistry showed an increased number of proliferating cell nuclear antigen (PCNA)-positive cells in the thyroid gland of PTU-treated rats. Moreover, the phosphorylation of ERK1 and ERK2 was increased in the extract from goiter tissue as compared with the thyroid tissue of untreated rats. To determine whether the inhibition of selected pro-survival pathways (i.e., p21ras-MAPK) was sufficient to affect goitrogenesis, thyroids from 12 PTU-treated rats were injected in vivo with an adenovirus transducing a dominant-negative ras gene (Rad-L61.S186) and another set of 12 rats were injected with a pharmacological inhibitor of MAPK (PD98059). Both Rad-L61.S186 and PD98059 were able to inhibit the PTU-induced goiter. It is interesting to note that lovastatin, when administered in drinking water, significantly prevented the thyroid gland enlargement. Therefore, lovastatin-treated thyroid glands were significantly smaller than those treated with PTU alone. In addition, the lovastatin-treated glands also showed a decreased expression of phosphorylated ERK1/2 and a number of PCNA-positive cells. Our data suggest that lovastatin is an efficient inhibitor of goitrogenesis and provide a rationale for innovative therapeutic strategies employing statins in the treatment of nodular goiter in humans.

Animals↗
PubMed2002

ANCA-positive glomerulonephritis and IgA nephropathy in a patient on propylthiouracil.

A 14-year-old girl developed acute renal failure after 3 years therapy with propylthiouracil (PTU) for Grave's disease. Serologic evaluation showed antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 and myeloperoxidase. Renal biopsy showed a crescentic glomerulonephritis (GN) as well as evidence of IgA nephropathy (IgAN). PTU was discontinued and the patient was treated with prednisone and cyclophosphamide. ANCA became negative and renal function improved, but did not normalize. A second biopsy showed evidence of IgA nephropathy only. Propylthiouracil use has been associated with ANCA positive pauci-immune glomerulonephritis, but not with IgA nephropathy. An overlap syndrome between IgAN and ANCA-positive GN, however, has been described. This patient may have had a preexisting IgAN, with acute pauci-immune GN secondary to PTU, or this may be the first description of an overlap syndrome of IgAN and ANCA vasculitis all caused by PTU therapy.

Acute Kidney Injury↗
PubMed1985

Effects of triiodothyronine and propylthiouracil on regeneration of catecholaminergic nerve terminals in the paraventricular hypothalamic nucleus of the adult rat.

Effects of triiodothyronine and the antithyroid drug, propylthiouracil, on regeneration of catecholaminergic nerve terminals in the paraventricular hypothalamic nucleus of adult rats were studied. Lesions were produced by 6-hydroxydopamine neurotoxin and then the animals were treated with triiodothyronine or propylthiouracil inducing hyperthyroidism or hypothyroidism, respectively, as determined by radioimmunoassay. Although catecholaminergic varicosities increased with time in the paraventricular hypothalamic nucleus of rats after lesion, fluorescent microscopic quantitation showed no statistical difference in their number between rats treated with triiodothyronine and the vehicle for as long as 56 days. Furthermore, electron microscopic quantitation at 56 days postlesion showed no significant difference between the triiodothyronine-treated and control rats in terms of the density, proportion, size, types of synapses, and synaptic frequency of catecholaminergic nerve terminals. There were growth cones in the paraventricular hypothalamic nucleus, suggesting growth activity after lesion. However, we found that exogenous administration of large doses of triiodothyronine at 25 micrograms/kg had little effect on the enhancement of regeneration of central catecholaminergic terminals after their destruction by 6-hydroxydopamine.

Animals↗
PubMed1986

Propylthiouracil, a selective inhibitor of NADH-cytochrome b5 reductase.

Propylthiouracil inhibited the activity of NADH-cytochrome b5 reductase of rat liver microsomes using potassium ferricyanide as electron acceptor. On the other hand, NADPH-cytochrome P-450 reductase activity was not affected by the compound. NADH-supported reduction of cytochrome b5 was also inhibited by propylthiouracil in the reconstituted system consisting of cytochrome b5 and partially purified NADH-cytochrome b5 reductase.

Animals↗
PubMed1993

Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy.

Vasculitis is a rare complication of propylthiouracil therapy. Antineutrophil cytoplasmic antibodies (ANCA) have been described in association with several vasculitic disorders. We report detection of ANCA against human neutrophil elastase, proteinase 3, and myeloperoxidase in serum from six patients who developed evidence of vasculitis during propylthiouracil treatment of hyperthyroidism. On withdrawal of the drug ANCA concentrations fell and clinical symptoms resolved completely.

Adult↗
PubMed1991

Selective liquid chromatographic assay for propylthiouracil in plasma.

A liquid chromatographic assay was developed to quantitate propylthiouracil in plasma using an internal standard, 5-propyl-2-thiouracil, of similar structure and physical properties. Caffeine, which coelutes with propylthiouracil, was removed by extraction from serum treated with base. No other compounds were found to interfere in the assay. The drug was extracted from plasma with chloroform with a recovery of 59.4% and the intra- and inter-assay coefficients of variation were 5.7 and 3.3%, respectively. The assay was linear to 3 micrograms/ml with a lower detection limit of 40 ng/ml for a sample volume of 1 ml.

Caffeine↗
PubMed2006

Serum thyroid hormones and performance of offspring in ewes receiving propylthiouracil with or without melatonin.

Two experiments were conducted during mid-gestation to examine effects in ewes of propylthiouracil (PTU) treatment alone or with melatonin on serum thyroid hormones, postpartum reproduction, and lamb performance. In the first experiment, beginning on day 0 (first day of treatment when all animals were 72.2+/-0.9 days of gestation), ewes received daily treatments (gavage) consisting of either 0mg (n=6) or 40 mg (n=6) PTU/kg body weight/day for 15 days. After 15 days, the 40 mg dosage was decreased to 20mg/kg body weight for an additional 20 days (35 days of PTU). Serum thyroxine (T4) did not differ (P>0.10) between groups through day 4; but on day 5, control females had a serum value of 67 ng/ml compared with 46 (+/-5)ng/ml for PTU-treated ewes (P=0.02). On the last day that 40 mg of PTU was administered, serum T4 averaged 67 and 7 (+/-5)ng/ml (P<0.001) in the two respective groups. Serum T4 remained low and was 80 and 1 ng/ml (P<0.001) in control and treated ewes on day 34. Serum T4 rose gradually after PTU but remained different from that observed in control ewes through day 48. Lambs from control and treated ewes had similar (P=0.46) T4 values at birth but lambs from PTU-treated ewes had lower (P=0.03) birth weights than did those from control ewes. Serum progesterone (P4) after parturition indicated a lack of cyclicity in all ewes. In the second experiment, beginning on day 0 (76.8+/-4.7 days of gestation), ewes received PTU as in Experiment 1. In addition, after 15 days of PTU, melatonin was given (i.m. injections at 5mg/day) for 30 days. Propylthiouracil decreased (P 0.60) for lambs born to control and treated ewes. Female offspring of PTU+melatonin-treated dams reached puberty, became anestrus, and returned to cyclicity at similar (P>0.10) times to contemporary ewe lambs. Results indicate that 40/20mg PTU alone or with melatonin does not induce cyclicity after lambing in spring lambing ewes and has little effect on offspring performance.

Animals↗
PubMed1988

Interaction of propylthiouracil and its precursors with horseradish peroxidase.

Interactions of horseradish peroxidase with propylthiouracil, thiouracil, propyluracil and uracil lead to the formation of complexes that exhibit different absorption spectra which can be attributed to the perturbation of peroxidase as the result of the drug-binding on a polar site in the protein. In this paper, by dilatometry and viscometry structural alterations in horseradish peroxidase were detected from its interaction with propylthiouracil and thiouracil only, and the physiological inhibition of peroxidase for these antithyroid drugs seems to be through structural alterations in the protein.

Horseradish Peroxidase↗