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PubMed1990

High-performance liquid chromatographic determination of propylthiouracil in plasma.

A high-performance liquid chromatographic method for the determination of the antithyroid drug propylthiouracil in dog plasma has been developed. Propylthiouracil and the internal standard, methylthiouracil, are extracted from plasma with methylene chloride at pH 6 and the organic layer is evaporated to dryness. The residue is chromatographed on a Chromspher C18 reversed-phase column using Pic B-7 (0.005 M 1-heptanesulphonic acid in water)-1% acetic acid-methanol (40:45:15, v/v/v) as the mobile phase. Quantification is achieved by monitoring the UV absorbance at 300 nm. The response is linear (0.1-15 micrograms/ml) and using 100 microliters of plasma the detection limit is 50 ng/ml. The within-run coefficient of variation is less than or equal to 5% and the accuracy is within 10% of the theoretical value at concentrations between 0.1 and 15 micrograms/ml plasma.

Animals↗
PubMed1994

Antineutrophil cytoplasmic autoantibody-positive crescentic glomerulonephritis as a complication of treatment with propylthiouracil in children.

Propylthiouracil, which is commonly used in the treatment of hyperthyroidism, has been associated in adults with antineutrophil cytoplasmic autoantibody, a serologic marker of vasculitis. Severe renal disease has not been reported as a complication of therapy with this drug. We report severe antineutrophil cytoplasmic autoantibody-positive vasculitis in children receiving propylthiouracil, as well as rapidly progressive crescentic glomerulonephritis after administration of this drug.

Adolescent↗
PubMed1994

Acute interstitial nephritis with renal failure associated with propylthiouracil therapy.

Propylthiouracil therapy is associated with a variety of adverse reactions. Renal involvement, although rare, has occurred, but neither acute interstitial nephritis nor severe acute renal failure has been reported previously. We report a case of fulminant acute interstitial nephritis with renal failure following treatment with propylthiouracil.

Acute Disease↗
PubMed1994

In vitro and in vivo evaluation in dogs and pigs of a hydrophilic matrix containing propylthiouracil.

A hydrophilic matrix tablet containing 300 mg of propylthiouracil was formulated with several types of hydroxypropylmethylcellulose. The influence of polymer and drug granule particle size, polymer concentration, crystallinity and geometry of the polymer particles, the polymer incorporation outside or inside the granule, addition of a filler and tablet hardness were studied. Polymer concentration, polymer particle size and geometry, filler addition and type of the filler used had a major influence on in vitro drug dissolution profiles. The bioavailability of propylthiouracil in dogs from the hydrophilic matrices investigated was low, because of the short gastro-intestinal transit times of the matrix tablets in the dogs. The matrix tablets reached the colon in fasted dogs within 2-3 hours after administration. The results indicated the poor predictability of bioavailability experiments in dogs with hydrophilic matrices. Although the bioavailability data in pigs seemed promising, a transit time study revealed a long stomach residence time of the matrix tablets in pigs. These data suggested that pigs are an inappropriate animal model for bioavailability studies of erodible matrix tablets.

Animals↗
PubMed1998

Induction of an ATPase inhibitor protein by propylthiouracil and protection against paracetamol (acetaminophen) hepatotoxicity in the rat.

1. The purpose of the present study was to test the following hypothesis: propylthiouracil (PTU) treatments of rats induces an increase in the concentration and activity of the mitochondrial ATPase (m-ATPase) inhibitor protein (IF1). The PTU-induced elevated baseline levels of this inhibitor protein inactivated m-ATPase, and prevented hepatotoxicity by a toxic dose of acetaminophen (AAP) (paracetamol), by maintaining hepatic adenosine 5'-triphosphate (ATP) levels. 2. Male Wistar rats were either gavaged with a toxic dose of AAP alone, or after pretreatment with PTU for periods of 3 and 12 days. 3. Twenty four hours after acetaminophen treatment alone, toxicity was manifested by: an approximately 10 fold increase in serum transaminase levels (serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase); depletion of hepatic reduced glutathione (GSH) and ATP levels; loss of inhibitor protein activity, and extensive pericentral necrosis of the hepatocytes. Propylthiouracil pretreatment for 12 days enhanced the concentration of the following metabolites in the liver: ATP (1.5 fold), ATPase inhibitor protein (IF1) (4.5 fold), and reduced glutathione (1.3 fold), while the activity of the inhibitor protein increased 2 fold. When the PTU treated rats were challenged with AAP, transaminases were not elevated, and only sporadic areas of necrosis were detected by histological examination of the liver tissue. In contrast to the 12 day treatment with PTU the 3 day treatment had no protection against AAP. No histological evidence of protection was manifested and the transaminases were not different from AAP treated controls. Most of the protective metabolites were depleted. 4. Our findings suggest that PTU-induced increased concentration of inhibitor protein and GSH, are contributing factors in the prevention of hepatotoxicity by maintaining hepatic m-ATP levels and reducing the harmful effect of the toxic metabolite of AAP.

Acetaminophen↗
PubMed2000

Thyroid function in wholly breast-feeding infants whose mothers take high doses of propylthiouracil.

BACKGROUND: Propylthiouracil (PTU) might theoretically be preferred over methimazole (MMI) during breast-feeding because of its lower milk/serum concentration ratio (0.1 vs. 1.0). The problem is that Graves' disease often relapses during the postpartum period, and high doses of PTU are sometimes needed to control maternal hyperthyroidism) during breast-feeding. However, there are virtually no data on the effects of maternal PTU on thyroid status of infants whose mothers take more than 300 mg PTU daily and who are wholly breast-feeding. OBJECTIVES: To investigate whether mothers can breast-feed without adverse effects on infants' thyroid status while taking 300 mg or more daily of PTU. SUBJECTS AND DESIGN: Eleven infants who were wholly breast-fed while their mothers took PTU 300-750 mg daily for Graves' hyperthyroidism were included in this study. In one of the 11 infants, the mother also took iodine 6 mg daily for a limited period. Thyroid status in these infants was evaluated. MEASUREMENTS: Free T4 (FT4), thyrotrophin (TSH), and TSH binding inhibiting antibody (TBIAb) concentrations were examined at least once in the age range 6 days to 9 months. Maternal blood was also examined for FT4 and TBIAb on the same day, or within a week, of the infants' blood tests. FT4, TSH and TBIAb concentrations at birth were examined, using cord blood, in cases where antithyroid drugs had been continued through delivery. RESULTS: Three of the 11 infants had TSH concentrations higher than the normal range for adults. In one of the three infants, the TSH concentration, which was determined 19 weeks after birth, was just above the normal range. In the remaining two infants whose mothers had taken PTU through delivery, TSH concentrations, determined within 7 days after birth, were distinctly high, but they became normal while maternal PTU doses were the same as or higher than those at the initial examination. Maternal PTU doses or FT4 concentrations were not significantly correlated with infants' TSH concentrations. CONCLUSION: Mothers can breast-feed while taking propylthiouracil at doses as high as 750 mg daily without adverse effects on thyroid status in their infants.

Adult↗
PubMed1999

Pyoderma gangrenosum with secondary pyarthrosis following propylthiouracil.

The association of pyoderma gangrenosum and arthritic symptoms is well documented. We present a rarely reported variant of this in a 44-year-old woman with pyoderma gangrenosum and bilateral large purulent effusions of her knees. She had no evidence of underlying rheumatoid arthritis or a specific seronegative spondyloarthropathy. Of note she had a history of Graves' disease for which she had been treated with propylthiouracil for 3 years and on investigation at this presentation had a markedly elevated perinuclear antineutrophil cytoplasm antibody (P-ANCA) level with specificities for IgM myeloperoxidase, IgG elastase and IgG lactoferrin. We believe this patient had pyoderma gangrenosum with secondary sterile pyarthrosis and a P-ANCA precipitated by propylthiouracil.

Adult↗
PubMedDate not supplied

An anti-neutrophil antibody associated with a propylthiouracil-induced lupus-like syndrome.

A 15-year-old woman with thyrotoxicosis controlled by propylthiouracil presented with chills, fever, splenomegaly, anemia, thrombocytopenia, leukopenia, hypergammaglobulinemia, immune complexes, a positive anti-nuclear antibody test, and a cellular marrow with normal maturation. Anti-neutrophil antibody was detected by cytotoxicity testing. The activity was restricted to the IgM fraction and was absorbed optimally at 4 degrees C. The antibody activity was recovered in both heat and ether eluates made from granulocytes. Lymphocytes, platelets, and red blood cells failed to absorb reactivity. The antibody did not inhibit superoxide production or bacterial killing. Propylthiouracil was discontinued and all signs and symptoms resolved.

Adolescent↗
PubMed2005

Synergistic effect of phospholipid-based liposomes and propylthiouracil on U-937 cell growth.

Scientific evidence indicates that exogenous phospholipids in the form of liposomes can affect cell growth. Effects of liposomes on cell growth depend on several factors including composition of liposomes, lipid concentration, and type of cells studied. Because phagocytic cells such as monocytes and macrophages are natural targets of liposomes, intracellular delivery of drugs to modulate cellular activity of these cells is of interest. We explored the effects of phospholipid-based liposomes composed of soy bean phosphatidylcholine (PC) as the main lipid component on U-937 cell growth. Effects of charge-imposing lipids and cholesterol were also studied. In addition, we investigated whether phospholipid-based liposomes would exert any interaction on cell growth with propylthiouracil, a drug with known antiproliferative activity. We found that PC in the form of extruded liposomes had intrinsic antiproliferative activity on U-937 cells at concentrations of 200 microM and up without any appreciable cytotoxicity. Phosphatidylserine and phosphatidylglycerol, but not dicetlylphosphate, at 10 mol% increased growth retardation activity of PC liposomes. Cholesterol at 30 mol% did not have any effect on cell growth, except for liposomes composed of PC and phosphatidylserine, where growth retardation was negated in the presence of cholesterol. Synergistic effect on cell growth was seen with certain liposome compositions when 5.5 microg/mL of propylthiouracil was coincubated. The results of this study suggest that the effects of exogenous lipids on cell growth should be taken into consideration when PC-based liposomes are to be used as drug delivery systems, especially when the targets are cells with phagocytic activity.

Animals↗
PubMed1995

Rectal administration of iodide and propylthiouracil in the treatment of thyroid storm.

We administered potassium iodide and propylthiouracil per rectum, in conjunction with intravenous dexamethasone and propranolol, for emergent treatment of a patient in thyroid storm with small bowel obstruction. Shortly after initiation of this treatment, the patient successfully underwent two emergent surgical procedures for resection of an intestinal volvulus with advanced peritonitis. Serum levels of iodide and propylthiouracil showed substantial absorption of these drugs via the rectal route. Measurement of 24-h urinary-free iodide indicated that the bioavailability of potassium iodide delivered by retention enema was at least 40%. Parenteral iodide preparations have been unavailable in the past, and continue to be difficult to obtain emergently. Rectal administration of inorganic iodide is an effective, readily available and less expensive alternative to parenteral sodium iodide for patients in thyroid storm with upper gastrointestinal tract dysfunction.

Administration, Rectal↗
PubMed2005

Central nervous system vasculitis caused by propylthiouracil therapy: a case report and literature review.

Antineutrophil cytoplasmic antibodies (ANCA) are associated with vasculitis, including vasculitis induced by drugs such as the thionamides. The affected organ systems in thionamide-induced vasculitis have been primarily renal, musculoskeletal, and dermatologic. We describe the first case of thionamide-induced central nervous system vasculitis presenting as confusion, with complete resolution after discontinuation of propylthiouracil. We review the literature and summarize 42 additional cases of thionamide-induced ANCA-positive vasculitis since 1992. Propylthiouracil was responsible in 93% of cases and the predominant ANCA pattern on immunofluorescent staining was perinuclear (p-ANCA). Clinical improvement occurred after drug discontinuation in 93%, steroid therapy was used in some cases. The mean duration of treatment with thionamides was 35 months prior to presentation. Long-term medical treatment with thionamides for hyperthyroidism may increase the risk of this severe side effect.

Central Nervous System Diseases↗
PubMed1994

Hepatotoxicity from propylthiouracil.

Propylthiouracil is a drug used commonly to treat hyperthyroidism. Among its side effects, hepatotoxicity is one of the rarest but one of the most serious. This complication may be due to an immune mechanism. However, particular risk factors associated with the development of hepatotoxicity are not known, and its occurrence is unpredictable. I report a case of acute hepatitis developing during propylthiouracil therapy for Graves' disease and review the literature related to this problem.

Acute Disease↗
PubMedDate not supplied

Palmar skin lesions reversed by propylthiouracil therapy.

Antithyroid thioureylene compounds such as propylthiouracil, methimazole, and thiamazole have been shown to have some beneficial effect in the treatment of plaque psoriasis in small clinical trials. An incidental finding is reported here on a patient with autoimmune polyendocrine syndrome type II who had dermatitis-like palmar skin lesions on the right palm, which was reversed with propylthiouracil therapy.

Adult↗
PubMed1979

Kinetics of propylthiouracil in the elderly.

The pharmakokinetics of propylthiouracil was evaluated in 9 elderly patients and compared to previous results from 6 younger subjects. By giving the drug both by the intravenous and oral route of administration it was possible to estimate the rate and extent of bioavailability. The various kinetic parameters were calculated according to a two-compartment model by use of two different methods: a graphical hand drawn one and by a special developed computer program based on a least squares minimalisation. While no significant differences could be demonstrated between the two age groups concerning volumes of distribution, clearance and extent of absorption, a large difference was found with regard to the absorption rate constant ka, which was about 3 times higher in the younger than in the elderly subjects, presumably due a reduced gastric emptying time. Considering the comparison between the two methods of calculations all the kinetics parameters were similar except ka and the slow disposition rate constant betw which were underestimated by the graphical method. It is concluded that no-age dependent changes exist concerning the kinetics of propylthiouracil except for a decreased rate of absorption. Graphical methods in pharmacokinetics are useful in obtaining distribution and elimination data but seem often biased for the evaluation of absorption rate constants.

Age Factors↗
PubMed1994

Lupus erythematosus-like syndrome induced by thiamazole and propylthiouracil.

A 17-year-old Japanese woman developed a lupus erythematosus-like syndrome during treatment for Graves' disease with thiamazole and propylthiouracil. Erythema, arthralgia, and low grade fever developed during therapy with thiamazole; purplish-red erythema developed during therapy with propylthiouracil. Antinuclear antibodies, anti-single-stranded DNA antibodies, and anti-double-stranded DNA antibodies were positive throughout the administration of these two drugs. Eruptions and other symptoms improved after their discontinuation. The titers of autoantibodies also decreased two months after withdrawal. The patient had HLA DR4.

Adolescent↗
PubMed1993

Effect of propylthiouracil and methimazole on serum levels of interleukin-2 receptors in patients with psoriasis.

BACKGROUND: We have previously reported clinical improvement in patients with psoriasis who received orally administered antithyroid thioureylenes, propylthiouracil (PTU), and methimazole (MMI). The antithyroid drugs are believed to exert immunomodulatory effects based on the results of studies in patients with Graves' disease, the only disease in which they are clinically used. The potential of these drugs to mediate clinical improvement in patients with psoriasis by reducing expression of the interleukin-2 receptor (IL2R), a marker of early T and B cell activation, was addressed in the present study. METHODS: Baseline serum concentrations of IL2R were measured by an enzyme-linked immunosorbant assay (ELISA) in 15 patients with stable plaque psoriasis and in the same patients after 8 weeks of oral therapy with either 300 mg of propylthiouracil (n = 7) or 40 mg methimazole (n = 8) given daily. Baseline values were compared with normal controls. RESULTS: Serum IL2R concentrations in the psoriatic patients were significantly higher than in normal controls. After treatment with PTU or MMI, IL2R serum concentrations were not significantly reduced either in the group as a whole or separately in the PTU and MMI treated patients. CONCLUSIONS: Since elevated serum concentrations of IL2R often reflect T and B cell activation, and elevated IL2R serum levels are seen in several autoimmune diseases, it is speculated that the beneficial effect of thioureylenes in patients with psoriasis is mediated by some mechanism(s) other than reduction of IL2R expression in activated lymphocytes.

Adult↗
PubMed2004

p16 expression in psoriatic lesions following therapy with propylthiouracil, an antithyroid thioureylene.

Plaque formation is a characteristic finding in patients with psoriasis and reflects cytokine-induced keratinocyte proliferation and/or impaired apoptosis of keratinocytes. Antithyroid thioureylenes such as propylthiouracil (PTU) and methimazole (MMI) are effective in the treatment of plaque psoriasis. Following PTU and MMI treatment, proliferative cell nuclear antigen (PCNA) expression is significantly reduced, suggesting that these medications have an antiproliferative effect. p16 is an antiapoptotic protein that is present in relative abundance in psoriatic plaques and is believed to play a potential role in the persistent senescence and impaired apoptosis of the keratinocytes in the plaque. This study examined p16 expression in biopsy samples of eight patients with plaque psoriasis given 300 mg of propylthiouracil in divided doses for 3 months. Despite significant clinical and histological improvement with PTU treatment, p16 expression was essentially unchanged, suggesting that the beneficial effect of PTU in psoriasis is not mediated through a decrease in p16 expression. The effect of PTU on other antiapoptotic proteins such as bcl-xL remains to be determined.

Adult↗
PubMed1982

Thyroid stimulating antibodies, thyroglobulin antibodies and serum proteins during treatment of Graves' disease with radioiodine or propylthiouracil.

The relation between serum concentrations of thyroglobulin antibodies (TgAb), thyroid-stimulating antibodies (TSAb) and serum immunoglobulins during treatment of Graves' disease was studied in 36 consecutive patients treated randomly with 131-iodine (n = 16) or propylthiouracil (n = 20). The patients were investigated before treatment was started and on seven occasions within the following year. In the entire patient group 78% were positive for TSAb and 47% for TgAb. There was a significant correlation between TSAb and TgAb in 15 patients concomitantly positive. There were no significant changes in serum immunoglobulins during treatment in either group of patients. In the radioiodine-treated group of patients TgAb was reduced after 1 week, whereas TSAb showed insignificant variations. After 5-10 weeks both antibodies increased, for TgAb with a median peak level 3 time above the initial concentration. Of 16 patients treated with radioiodine five developed myxoedema and four of these were positive for TgAb. There was a relation between the development of myxoedema and the ratio between increases of TSAb and TgAb. Increase in TSAb was not related to serum thyroglobulin (Tg) measured in TgAb-negative patients. Propylthiouracil showed minor effects on the studied variables, but with lower mean values of Tg, TgAb and TSAb at the end of the observation period. The results indicate an immunological relation between TSAb and TgAb, although differences between their course exist in some situations.

Adult↗