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PubMed2005

Colonic ulcers in propylthiouracil induced vasculitis with secondary antiphospholipid syndrome.

A 48 year old white woman was admitted to the hospital because of several bouts of migratory polyarthritis, weight loss, fever, and abdominal pain over a period of 15 months. She had been taking propylthiouracil 100 mg daily for three years for hyperthyroidism treatment. A test for antineutrophil cytoplasmic autoantibodies (ANCA) was positive with a perinuclear pattern of staining. Antiphospholipid antibodies were also detected. Colonoscopy showed several ulcers on intestinal mucosa and the biopsy specimen showed intense microscopic vasculitis. The patient is well after methylprednisolone pulse therapy and eight months of oral azathioprine. A surveillance colonoscopy showed complete healing of intestinal ulcers. No recurrence of symptoms has occurred and autoantibodies are negative, 10 months after treatment finished. The sequence of events suggests a propylthiouracil induced vasculitis p-ANCA positive and an antiphospholipid syndrome. This is the first report of colonic ulcers diagnosed and successfully treated in such circumstances.

Antiphospholipid Syndrome↗
PubMed2004

A case of propylthiouracil-induced pyoderma gangrenosum associated with antineutrophil cytoplasmic antibody.

A 27-year-old woman who had been receiving propylthiouracil for 2 years for Graves' disease presented with painful ulceration on the lower limbs which had first appeared 2 weeks previously. Well-circumscribed hemorrhagic ulcerations with ragged borders were noted on both legs. Skin biopsy demonstrated a florid neutrophilic infiltrate and evidence of leukocytoclasis around small blood vessels in the papillary dermis compatible with the diagnosis of pyoderma gangrenosum. A highly positive perinuclear pattern of antineutrophil cytoplasmic antibody with specificities for IgM myeloperoxidase was observed. The authors think that propylthiouracil is associated with the occurrence of pyoderma gangrenosum in this patient.

Adult↗
PubMed1991

Propylthiouracil hypersensitivity with circumstantial evidence for drug-induced reversible sensorineural deafness: a case report.

Severe adverse reactions to propylthiouracil occur in 1-5% of patients. Three major side effects, namely agranulocytosis, hepatotoxicity and drug-induced hypersensitivity, have been described though these syndromes are not distinct entities and there can be overlaps in the clinical manifestations. The drug-induced hypersensitivity may be an immune-mediated reaction with multiorgan involvement in which a combination of polyarthritis, cutaneous vasculitis and fever is common. We report a patient with propylthiouracil-induced hypersensitivity with an unusual combination of high spiking fever, migratory polyarthritis, reversible sensorineural deafness, normochromic normocytic anaemia, leucocytosis and hepatotoxicity associated with polyclonal activation of multiple autoantibodies. This case illustrates the highly variable clinical manifestations of the syndrome. The prompt recovery upon withdrawal of the drug indicates the importance of early diagnosis.

Adult↗
PubMed1989

Effect of low-iodine diet and propylthiouracil on glycolytic enzymes in brain areas of adult rats.

Glycolytic activity of five brain areas in the rat was studied under two hypothyroid states: (1) induced by low-iodine diet from weaning, and (2) induced by propylthiouracil. The areas studied were the anterior cortex, amygdala, hypothalamus, septum and hippocampus. A low-iodine diet induced a decrease of pyruvate kinase activity in three region and of phosphofructokinase in the hippocampus, while hexokinase increased in both the amygdala and septum. Propylthiouracil treatment produced an increase in hexokinase activity in the hypothalamus and septum, and a decrease in the anterior cortex, while phosphofructokinase decreased significantly in the hippocampus. No significant changes of lactate dehydrogenase activity were observed. The correlation between the results and type of hypothyroidism is discussed.

Animals↗
PubMed1978

The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings.

A reinvestigation of the mechanism of action of methylmercaptoimidazole, propylthiouracil, and thiouracil on thyroid peroxidase (TPO) was undertaken. A preliminary incubation of TPO and H2O2 with methylmercaptoimidazole, propylthiouracil, or thiouracil was carried out in the absence of oxidizable substrates (i.e. I- or guaiacol). This incubation resulted in irreversible inactivation of TPO. The extent of inactivation could be determined after removal of the drug by gel filtration or by dilution into the assay mixture. Preincubation, as above, in the presence of iodide or thiocyanate prevented the irreversible inactivation of TPO. Rats receiving doses of these drugs which completely inhibited protein-bound iodine formation showed normal levels of TPO in their thyroid glands 30 min after drug administration. These findings suggest that the initial in vivo action of these drugs is to block iodination by trapping oxidized iodide, not by acting as "general inhibitors" of the TPO.

Animals↗
PubMed1984

The effects of propylthiouracil, iodothyronines, and other agents on thyroid hormone metabolism in human placenta.

Human and rat placental homogenates contain inner ring deiodinase activity (PT4ase) towards T4 and T3. This activity may decrease the transfer of T4 and T3 across the placenta and influence thyroid hormone disposal in the fetal circulation. Data are now presented on human PT4ase in subcellular fractions, the Km of human PT4ase, and the effects of drugs and other compounds on human and rat PT4ase. The specific activity (nanograms of rT3 produced per min/mg protein) of each fraction of human placenta was as follows: nuclear, 0.07; mitochondrial, 0.15; lysosomal, 0.19; microsomal, 1.30; and cytosol, 0.01. The apparent Michaelis-Menton (Km) for PT4ase in human placental microsomes was 1.2 X 10(-7) M. T3, 3,3'-diiodothyronine, iopanoic acid, iodoacetic acid, diamide, and propranolol all exhibited dose-dependent inhibition of human and rat PT4ase when tested in the presence of 10 mM dithiothreitol (DTT). Propylthiouracil did not inhibit PT4ase at 10 mM DTT, but when the DTT concentration was lowered to 0.25 mM, up to 71% inhibition was noted. Many drugs, as noted in other organs with respect to outer and inner ring iodothyronine deiodinases, inhibited human PT4ase. These studies may be relevant to the practice of administering propylthiouracil, propranolol, and iopanoic acid to pregnant women.

Animals↗
PubMed1998

Biochemical evaluation of oxidative stress in propylthiouracil treated hyperthyroid patients. Effects of vitamin C supplementation.

In this study the impact of vitamin C supplementation on oxidative damage as assessed by thiobarbituric acid reactive substances and markers of antioxidant status: namely Cu/Zn superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione were investigated in 24 hyperthyroid patients under propylthiouracil therapy (3x100 mg/day) for five days and in 15 healthy controls. Ascorbic acid (1000 mg/day) was given as a supplement for 1 month to both the patients and controls during the study period. Heparinised blood samples were taken at the beginning and the end of one month ascorbic acid supplementation. Comparison of the hyperthyroid patients with the controls revealed higher lipid peroxidation (p<0.001), higher Cu/Zn superoxide dismutase activity (p<0.001), higher glutathione level (p<0.001) and lower glutathione reductase activity (p<0.001). Vitamin C supplementation to hyperthyroid patients caused significant increases in glutathione concentration (p<0.001) and glutathione peroxidase activity (p<0.001), whereas there were significant decreases in glutathione reductase (p<0.001) and Cu/Zn superoxide dismutase activities (p<0.01). Thiobarbituric acid reactive substances and thiobarbituric acid reactive substances/glutathione ratio were significantly decreased (p<0.01). Vitamin C supplementation to euthyroid controls caused significant increases in glutathione concentration (p<0.001) and glutathione peroxidase and Cu/Zn superoxide dismutase activities (p<0.001), whereas there was a significant decrease in glutathione reductase (p<0.001). The thiobarbituric acid reactive substances/glutathione ratio was significantly decreased (p<0.05). Our findings reveal the potentiation of antioxidant status and a relief in oxidative stress in both propylthiouracil treated hyperthyroid patients and controls in response to vitamin C supplementation.

Adult↗
PubMed1995

Serum levels of interleukin 6 and tumor necrosis factor-alpha in hyperthyroid patients before and after propylthiouracil treatment.

Contrary to the usual inhibitory role of tumor necrosis factor-alpha (TNF-alpha) in thyroid metabolism, it also has specific stimulatory effects in autoimmune thyroid disorders, including induction of HLA class II antigen-presenting cell-T cell interaction. Despite high intrathyroidal concentrations, various studies were not able to demonstrate high serum levels of TNF-alpha in patients with Graves' disease. To investigate this discrepancy we determined TNF-alpha and interleukin 6 (IL-6) levels in 25 hyperthyroid patients who responded to propylthiouracil treatment (16 with Graves' disease and nine with toxic multinodular goiter) and compared them with the levels found in euthyroid patients with simple diffuse goiter (n = 15) and normal healthy controls (n = 15). Median IL-6 levels were high in both Graves' disease and toxic multinodular goiter patients before propylthiouracil treatment (23 and 26.5 pg/ml, respectively). After restoring euthyroidism there was a statistically significant decline to near-normal levels (3 and 10 pg/ml, respectively). On the other hand, median serum TNF-alpha levels were high only in Graves' disease patients (20 pg/ml) and could not be normalized with antithyroid medication (20 pg/ml) compared to that of controls (5 pg/ml). Tumor necrosis factor-alpha, but not IL-6, was found to be high in the sera of Graves' disease patients when euthyroid, which may be due to an ongoing antigen-antibody interaction, a feature of autoimmune attack. It remains to be determined whether the degree of TNF-alpha and/or IL-6 elevation will be a predictor of disease recurrence.

Adult↗
PubMedDate not supplied

Ampicillin and propylthiouracil pharmacokinetics in intestinal bypass patients followed up to a year after operation.

The pharmacokinetics of ampicillin and prophylthiouracil were studied in 6 and 9 patients, respectively, before and several times up to a year after a shunt operation for extreme obesity. The drugs were given intravenously and orally making it possible to estimate the absolute bioavailability. The bioavailability of propylthiouracil (about 80%) was unchanged by the surgical procedure but the fraction of ampicillin (given as pivampicillin) absorbed decreased from a preoperative value of 109 +/- 44% to 44 +/- 30% 12 months after the bypass operation. Volumes of distribution transiently decreased in the postoperative period for ampicillin. Clearance was initially reduced for both ampicillin and propylthiouracil after operation but returned to normal values a year later. Half-lives of both drugs were unchanged. These results are compared with previous data on pharmacokinetics in intestinal shunt patients and a tabular review is presented. Although no general rules presently emerge from the data available, it seems prudent to closely monitor intestinal shunt patients on drug therapy by both laboratory and clinical methods.

Adult↗
PubMed2003

Effects of propylthiouracil and bromocryptine on serum concentrations of thyrotrophin and thyroid hormones in normal female horses.

REASONS FOR PERFORMING STUDY: There exists a need for better diagnostic tests to characterise thyroid disease in horses. Currently available diagnostic tests fail to differentiate between thyroid gland disorders and thyroid abnormalities resulting from pituitary or hypothalamic problems. OBJECTIVES: To evaluate the effects of treatment with propylthiouracil (PTU) and bromocryptine (BROM) on serum concentrations of triiodothyronine (T3), thyroxine (T4), reverse T3 (rT3) and equine thyroid-stimulating hormone (e-TSH, thyrotrophin) in mature horses. METHODS: Healthy mature horses were treated using either PTU or BROM for 28 days. The effect of treatment on the thyroid axis was assessed by measuring T3, T4, rT3 and e-TSH before and at +14 and +28 days. The effect of PTU and BROM on the response of T3, T4, rT3 and e-TSH to thyrotrophin-release hormone (TRH) administration was also assessed before and at +14 and +28 days of treatment. RESULTS: Treatment with PTU led to a significant reduction in serum concentrations of T3, T4 and rT3 on Day 28 and increase of e-TSH on Day 28 (P < 0.05). Treatment with BROM did not cause any measurable effect on serum concentrations of T3, T4, rT3 or e-TSH. The percentage increment by which serum concentration of T4, T3 and e-TSH increased following stimulation with TRH was decreased by treatment with PTU for 28 days (P < 0.05) but were not affected by treatment with BROM for 28 days. CONCLUSIONS: These results suggest that 1) treatment with PTU may be used in horses as a model of primary hypothyroidism; 2) the use of BROM as a model of secondary hypothyroidism in horses is not supported; and 3) e-TSH assay deserves further investigation for the clinical diagnosis of thyroid axis dysfunction in horses. POTENTIAL RELEVANCE: Propylthiouracil effectively causes primary hypothyroidism. There is substantial variability between horses with respect to their sensitivity to this substance when administered orally. Further studies pertaining to the characterisation of equine thyroid disorders are warranted and the use of both PTU for the experimental induction of primary hypothyroidism and e-TSH for the diagnostic characterisation of thyroid disorders in horses should be considered.

Animals↗
PubMed2005

Management of a pregnant patient with Graves' disease complicated by propylthiouracil induced agranulocytosis.

Relapse and exacerbation of Graves' disease during pregnancy is rare, and thionamide induced agranulocytosis is an uncommon side effect. We report a case of a pregnant woman in her 24th week of gestation that experienced a relapse of Graves' disease that was complicated by propylthiouracil induced agranulocytosis. Following the discontinuation of propylthiouracil and administration of a broad-spectrum of antibiotics, agranulocytosis subsided within 10 days. A total thyroidectomy to avoid any future relapse was planned and a short course of a beta-adrenergic blocker and Lugol solution were prescribed before the operation. At the 28th week of gestation, a total thyroidectomy was performed without complications and thyroxine replacement therapy was commenced. At the 40th week of gestation, labor was induced and a 3,370 g healthy male infant was born without clinical features of thyrotoxicosis. We report herein on the patient and the treatment options for this rare and complicated case.

Adult↗
PubMedDate not supplied

The use of recombinant human G-CSF in the treatment of propylthiouracil-induced agranulocytosis.

A 43-year-old female patient with Basedow-Graves' disease developed agranulocytosis in the eighth month of propylthiouracil therapy. After discontinuing the drug, a broad spectrum antibiotic regimen plus recombinant human granulocyte colony-stimulating factor (G-CSF), a human haematopoietic growth factor, were started. Her granulocyte count returned to normal with the second dose of G-CSF, and ulcerating pharyngitis improved rapidly. We think that in patients with propylthiouracil-induced agranulocytosis, G-CSF will reduce the risk and severity of infection, and should be accepted as a part of the standard therapy.

Adult↗
PubMed2000

Anti-goitrous effect of lecithin-bound iodine in propylthiouracil treated rats.

OBJECTIVE: Excess iodine and some iodine-containing compounds are known to affect various parameters of thyroid function. Lecithin-bound iodine (LBI) is a compound which induces involution of an enlarged thyroid. LBI was tested for its ability to affect thyroid ornithine decarboxylase (ODC) activity and apoptosis. METHODS: LBI was given orally to propylthiouracil-pretreated rats and the changes in ODC activity and apoptosis were observed. The thyroid apoptosis was detected by DNA laddering and flow cytometry. RESULTS: LBI suppressed the thyroid ODC activity within one hour after its administration and lowered slightly but significantly the thyroid putrescine levels at 3 h. The DNA cleavage ladder was evident at 3-6 h after LBI treatment. Propylthiouracil induced thyroid enlargement was reduced significantly at 3 days after chronic treatment with LBI. The thyroidal content of putrescine was also decreased after chronic treatment. These effects of LBI were essentially the same as those of excess iodide, while other iodinated compounds including amiodarone, iopanoic acid and erythrosine had no effect on the thyroid ODC activity. CONCLUSIONS: These results suggest that LBI may exert its anti-goitrous effects, consisting of the inhibition of ODC activity and apoptosis, in the form of inorganic iodide in vivo.

Animals↗
PubMed2002

[Clinicopathological characteristics of propylthiouracil-induced antineutrophil cytoplasmic antibodies-positive vasculitis and their target antigens: a report of 4 cases and literature review].

OBJECTIVE: To study the clinicopathological manifestations and target antigens of propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA) positive vasculitis. METHODS: Four hospitalized patients with PTU-induced ANCA positive vasculitis in recent two years were studied. Target antigens and antibody titers were investigated with ELISA using seven highly purified known ANCA antigens as solid phase ligands. The known antigens included proteinase 3 (PR3), myeloperoxidase (MPO), human leukocyte elastase (HLE), lactoferrin (LF), cathepsinG (CG), bactericidal/permeability-increasing protein (BPI) and azurocidin (AZU). RESULTS: Four patients with Grave's disease, 2 female and 2 male with a mean age of 30 (11 approximately 57) years who had been treated with PTU for 7 approximately 60 months suffered from ANCA positive vasculitis. All the 4 patients had renal, lung, skin, joint, muscle and hematological involvement. Sera from all the 4 patients were ANCA positive and recognized MPO, LF and CG. Sera from 3 patients recognized HLE and AZU and 2 recognized PR3. None of the sera recognized BPI. The majority of the autoantibodies had high titers >/= 1:25 600. All the sera from 30 patients with Grave's disease and PTU treatment but without vasculitis were ANCA negative. All the 4 patients had pauci- immune glomerular lesions in renal biopsy; 2 had crescentic glomerulonephritis and the remaining 2 had minor glomerular abnormalities. All the 4 patients responded to withdrawal of propylthiouracil; 3 patients were treated with immunosuppressive agents. All the patients achieved clinical remission. However, one patient with crescentic glomerulonephritis was dialysis dependent. After withdrawal of PTU and administration of immunosuppressants, ANCA titres declined, but did not turn to negative in 1-6 months in most of the patients. CONCLUSIONS: PTU can induce ANCA positive vasculitis. The autoantibodies were polyclonal and recognized multiple target antigens of neutrophil cytoplasm. Early withdrawal of PTU and administration of immunosuppressive agents might improve the prognosis.

Adolescent↗
PubMedDate not supplied

Caries experience in children with various genetic sensitivity levels to the bitter taste of 6-n-propylthiouracil (PROP): a pilot study.

PURPOSE: The objective of this pilot study was to determine the prevalence of coronal dental caries among children with different genetic sensitivity levels of taste, as determined by 6-n-propylthiouracil (PROP). METHODS: Coronal caries and restorations in permanent and primary dentition were evaluated in 150 healthy school-aged children aged 6 to 12 years. A filter paper containing 6-n-propylthiouracil was used to determine each subject's genetic ability to taste bitter and sweet substances. Supertasters perceived stronger tastes from a variety of bitter and sweet substances than both medium tasters and nontasters. The data were analyzed by ANOVA with Duncan's multiple range test, Mantel-Haenszel chi-square, multiple linear regression analyses, and Pearson's coefficient of correlation. RESULTS: The nontasters had more mean decayed, missing, and filled surfaces (dfs/DMFS) than tasters. The values of mean decayed and filled surfaces of primary dentition and mean decayed, missing, and filled surfaces of permanent dentition (dfs/DMFS) and mean decayed surfaces of primary dentition and permanent dentition (ds/DS) were significantly higher in nontasters than in medium tasters, and in medium tasters compared with supertasters. After adjusting for missing teeth, the data were expressed as a percentage of the available surfaces, and the significant differences in dfs/DMFS and ds/DS persisted (r = -0.49, P < .001 and r = -0.51, P < .0001 respectively). CONCLUSIONS: After all associated factors were controlled, taste was the only independent variable significantly related to overall caries experience. The results of this study suggested an increased prevalence of overall caries experience in nontaster children.

Analysis of Variance↗
PubMedDate not supplied

Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study.

BACKGROUND: High-dose tamoxifen has had disappointing results as a palliative therapy in recurrent glioma. Insulin-like growth factor 1 (IGF-1) is a thyroid hormone modulated naturally occurring antagonist of tamoxifen-induced cytotoxicity. Thyroid function was suppressed to reduce IGF-1 levels in glioma patients and high-dose tamoxifen administered. MATERIALS AND METHODS: Propylthiouracil was used to induce chemical hypothyroidism in 22 patients with recurrent glioma. Tamoxifen was started within one month and given in escalating doses from 40 mg twice a day up to 80 mg 3 times a day. No significant toxicity developed. RESULTS: Eleven out of 22 patients became hypothyroid. No patients experienced symptoms of clinical hypothyroidism. Median survival was significantly longer in the hypothyroid group (10.1 months versus 3.1 months); p = 0.03. There was a significant decrease in blood levels of IGF-1 (p = 0.02). in hypothyroid patients. CONCLUSION: Patients treated for recurrent high-grade gliomas with high-dose tamoxifen had significantly longer survival when chemical hypothyroidism was induced with propylthiouracil.

Adult↗
PubMed1992

Effect of propylthiouracil on liver regeneration in rats after partial hepatectomy.

The effect of propylthiouracil (PTU) on the growth activity of intact liver and liver regenerating after partial (65-70%) hepatectomy (PH) was studied in rats. PTU (Propycil, Kali-Chemie, FRG) was dissolved in drinking water (1 g PTU per litre) and this was given to the rats, as their sole source of fluids, three days before PH and then up to the end of the experiment. In rats given PTU, marked inhibition of liver DNA synthesis and the mitotic activity of hepatocytes was found after PH. This effect was potentiated to some extent by partial inanition of the experimental animals given PTU, as demonstrated in a paired feeding test in control rats. PTU inhibition of DNA synthesis in intact and regenerating liver also took effect in thyroidectomized rats, even with substitution (thyroid hormone) therapy. The experiments demonstrated that the effect of propylthiouracil on DNA synthesis in the liver is mediated primarily by way of its direct effect on the liver.

Animals↗
PubMed1992

Thyroid hormone regulates ontogeny of beta adrenergic receptors and adenylate cyclase in rat heart and kidney: effects of propylthiouracil-induced perinatal hypothyroidism.

In mature animals, thyroid hormone is permissive for beta adrenergic receptor expression and adrenergic control of adenylate cyclase. To determine if endogenous thyroid hormones play a similar role in the development of receptors and transduction mechanisms, we administered propylthiouracil perinatally to rat dams and pups from gestational day 17 through postnatal day 5. Circulating thyroid hormones were completely suppressed through postnatal day 10 and then rose to only slightly subnormal values by the 3rd to 4th postnatal week. In the heart, hypothyroidism completely suppressed the initial development of beta adrenergic receptor binding sites, with recovery paralleling the return of thyroid hormone levels. In contrast, development of basal and isoproterenol-stimulated adenylate cyclase activity showed more lasting deficiencies with a delayed onset corresponding to general growth impairment; however, forskolin-stimulated adenylate cyclase developed in a nearly normal pattern. Effects on development of renal beta receptors and adenylate cyclase were of smaller magnitude and comprised only the delayed onset phase; receptor deficiencies appeared after 10 days and adverse effects on adenylate cyclase were limited to the isoproterenol-sensitive component, consisting of a shift of the ontogenetic peak to later ages. Endogenous thyroid hormones thus contribute two distinct factors to beta receptor/adenylate cyclase development: they are obligatory for cardiac beta receptor development, but also, in parallel with general effects on growth and development, serve to program the ontogeny of transduction factors linking the receptors to adenylate cyclase. The predominance of propylthiouracil effects on isoproterenol-stimulated adenylate cyclase but not on enzymatic responses to forskolin suggests that thyroid hormones may be controlling the development of regulatory G-proteins.

Adenylyl Cyclases↗