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PubMed1988

Altered disposition of propylthiouracil in cats with hyperthyroidism.

The oral and intravenous disposition of the anti-thyroid drug propylthiouracil (PTU) was determined in six clinically healthy cats and four cats with naturally occurring hyperthyroidism. Compared with the normal cats, the mean plasma elimination half-life of PTU was significantly (P less than 0.001) shorter in the hyperthyroid cats (77.5 +/- 5.8 minutes compared with 125.5 +/- 3.7 minutes) and the total body clearance of PTU was significantly (P less than 0.05) more rapid in the cats with hyperthyroidism (5.1 +/- 0.8 ml kg-1 min-1 compared with 2.7 +/- 0.2 ml kg-1 min-1). Following oral administration, both the bioavailability (59.7 +/- 4.9 per cent compared with 73.3 +/- 3.7 per cent) and peak plasma concentrations (14.5 +/- 1.6 micrograms ml-1 compared with 18.9 +/- 0.9 micrograms ml-1) of PTU were significantly (P less than 0.05) lower in the hyperthyroid cats than in the control cats. No difference was noted, however, between the apparent volume of distribution for PTU in the two groups of cats. Overall, results of this study indicate that the oral bioavailability of PTU is decreased and PTU disposition is accelerated in cats with hyperthyroidism.

Animals↗

PubMed1988

Recurrent agranulocytosis following carbimazole and propylthiouracil therapy.

Agranulocytosis is an infrequent but potentially fatal complication of anti-thyroid drugs. There is little information regarding the use of a second anti-thyroid drug when initial therapy results in agranulocytosis. This report summarises a case of recurrent agranulocytosis following the consecutive administration of carbimazole and propylthiouracil.

Agranulocytosis↗

PubMed1988

Differential immunosuppressive action of carbimazole and propylthiouracil.

Carbimazole and Propylthiouracil (PTU) are widely used in the treatment of Graves' disease, although controversy still exists as to whether or not they have any direct effect on the immune system. While many previous studies have investigated the possible effects of one or other of these drugs on the immune system only a few have directly compared the effects of equivalent doses of each drug. This study aimed to examine the effects of both drugs, during the initial 8 weeks of treatment, on various biochemical and immunological parameters. The results obtained showed that while thyroid hormone levels fell at similar rates in both treatment groups, TRAb levels and T cell subset abnormalities returned towards normal more rapidly in patients receiving Carbimazole compared to PTU. These results indicate that the effects of Carbimazole on TRAb levels and T cell subset abnormalities are not due solely to its action in controlling the biochemical features of Graves' disease and provide indirect evidence of an action on the immune system in vivo.

Adult↗

PubMed1988

Rectal absorption of propylthiouracil.

The rectal absorption of propylthiouracil (PTU) was studied and compared to oral absorption in normal volunteers. Plasma levels of PTU after administration of suppositories of PTU base and PTU diethanolamine were significantly lower compared to the oral route. Elevated plasma reverse T3 levels were demonstrated after each treatment, however, suggesting a desirable therapeutic effect at this dosage level for all preparations.

Administration, Rectal↗

PubMed1987

Effects of diethylstilbestrol and propylthiouracil on the rat pituitary. An immunohistochemical and ultrastructural study.

The effects of diethylstilbestrol [(DES) CAS: 56-53-1] and propylthiouracil [(PTU) CAS: 51-52-5] on the pituitary glands of female weanling F344 rats were studied by immunohistochemistry and electron microscopy. Six weeks of PTU treatment resulted in a significant increase in pituitary gland weight and in the percentage of pituitary prolactin (PRL) cells. The percentage of thyroid-stimulating hormone (TSH) cells was slightly increased in PTU-treated rats. DES treatment produced a thirteenfold increase in pituitary gland weight and a significant increase in the percentage of PRL cells as well as in serum PRL levels. Combined PTU-DES treatment increased pituitary gland weight and serum PRL levels, but this increase was less than that observed with only DES treatment. A relative decrease in the percentage of TSH cells was seen after both DES and PTU-DES treatment. Ultrastructural immunohistochemical studies showed two types of PRL cells in the pituitary of all groups. Classical PRL cells with granule diameters of 150-800 nm were most abundant in DES-treated groups, whereas cells with smaller granules, 100-350 nm in diameter, were equally prominent in control groups and after PTU treatment. The results of this study show that while PTU causes a slight increase in pituitary gland weight and in PRL cell numbers, it inhibits estrogen-induced PRL cell hyperplasia. This model can be used to study the effects of PTU on pituitary PRL cell morphology and on the regulation of PRL cell hyperplasia.

Animals↗

PubMed1987

Effect of nutritional status on propylthiouracil-induced protection against acetaminophen hepatotoxicity in the rat.

The effect of pair feeding of euthyroid rats compared with propylthiouracil (PTU) treated rats on acetaminophen (APAP)-induced hepatotoxicity was studied. Also, the effect of food deprivation of both the euthyroid and PTU-induced hypothyroid rats for 24 h, as well as forced feeding of the euthyroid rats after a toxic dose of APAP, was determined. Pair feeding decreased both protein and energy intake compared with ad libitum-fed controls and resulted in decreased growth rate similar to that for the PTU treated rats. In contrast to the protective effect of PTU pretreatment, decreased protein energy intake by the euthyroid rats either tended to make them more susceptible to acetaminophen-induced hepatotoxicity or had no effect as assessed by elevation of serum transaminases (SGOT,SGPT) and by hepatic necrotic score. Pair feeding also significantly altered drug disposition with an increase in the molar ratio of urinary APAP-mercapturic acid conjugate, but not the absolute amount, suggesting possible increased cytochrome P-450 dependent drug metabolizing enzyme activity. Compared with PTU-fed, in the pair-fed the molar ratio of glucuronide conjugate decreased and sulfate conjugate increased. Hepatic reduced glutathione (GSH) concentrations before and 4 h after a toxic dose of acetaminophen administration were higher in the PTU pretreated compared with euthyroid rats. Fasting of the PTU pretreated rats for 24 h after acetaminophen administration abolished the PTU-induced protective effect. Forced feeding of the euthyroid rats after a toxic dose of acetaminophen increased rather than decreased the toxicity when compared with euthyroid ad libitum-fed rats. Data suggest that higher concentrations of hepatic glutathione in the PTU pretreated compared with euthyroid rats before and 4 h after acetaminophen administration contribute to PTU-induced protection. Forced feeding of rats when the liver is severely damaged and its function compromised is harmful rather than protective. We conclude that the nutritional state of the animal significantly influences drug toxicity and should be taken into consideration in designing drug therapy and evaluation of drug toxicity.

Acetaminophen↗

PubMed1985

Propylthiouracil-induced immune-mediated disease in the cat.

An immune-mediated disease was produced in 9 of 17 (53%) normal healthy cats by daily p.o. administration of 150 mg of 6-propylthiouracil (PTU). This disease syndrome is characterized by lethargy, weight loss, lymphadenopathy, hemolytic anemia, a positive direct antiglobulin test (DAT) and antinuclear antibodies (ANA). The duration of drug administration before the development of a positive DAT and/or ANA ranged from 3 to 8 weeks (Mean +/- S.E.M. = 4.5 +/- 0.6), whereas the duration before the onset of clinical signs ranged from 4 to 8 weeks (6.1 +/- 0.6 weeks). On cessation of PTU administration, clinical signs resolved in all cats within 2 weeks, and the DAT and test for ANA were negative within 1 to 4 weeks (1.9 +/- 0.4 weeks). During nine PTU-rechallenge periods in four cats, both the mean time to develop a positive DAT and ANA (2.5 +/- 0.8 weeks) and the mean time to develop overt clinical signs (2.6 +/- 0.7 weeks) were shorter than similar mean times in the initial PTU treatment period (P less than .01). During nine episodes of PTU-induced disease in seven cats, PTU administration was discontinued and replaced with 150 mg of 6-propyluracil (PU), a nonsulfur analog of PTU. Resolution of both clinical and serologic signs of disease occurred in seven of the nine disease episodes within 1 to 3 weeks (2.1 +/- 0.4 weeks). In the two cats whose disease did not resolve on PU, one was sacrificed after 1 week of PU administration, without clinical or serologic resolution, because of the severity of the PTU-induced disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Hemolytic, Autoimmune↗

PubMed1975

Treatment of hyperthyroidism in pregnancy with propylthiouracil and methimazole.

Twenty-one women were studied who had received propylthiouracil or methimazole during 26 pregnancies. Four of the infants had a goiter at birth, and 3 of these had neonatal thyrotoxicosis. In 2 children neonatal thyrotoxicosis was not evident at birth because of maternal antithyroid therapy. Five children had congenital defects. Two mothers were responsible for 4 of the children with abnormalities, and both mothers had been treated with thiourea drugs for long periods, ranging from 7 to 11 years. The majority of children who are exposed to these drugs in utero appear to have no subsequent ill effects. However, prolonged therapy with these agents may be undesirable.

Abnormalities, Drug-Induced↗

PubMed1979

Morphological and biochemical changes in propylthiouracil-diet induced coronary atherosclerosis under a regression regimen.

Many of the morphologic and biochemical features of porcine coronary atherosclerosis produced by high cholesterol, high fat diet and propoylthiouracil returned to control values after cessation of the atherogenic regimen. These include disappearance of foam cells and a decrease in lipid content, DNA concentration, and DNA and protein synthesis. The morpholigic and biochemical features of te atherosclerotic lesions described herein were similar to those produced in swine and other species by a variety of inciting agents during both the progression and regression phase of the disease. These results indicate that the porcine propylthiouracil-diet model may be useful for the study of coronary lesions. Second, the similarities of response of arterial tissue in several experimental animals suggest the possibility that human coronary lesions by analogy may regress under therapeutic regimens.

Animals↗

PubMed1982

Effects of propylthiouracil on MHV-3 virus mouse hepatitis.

A study was undertaken to observe the effect of propylthiouracil (PTU) on MHV-3 virus mouse hepatitis. PTU-treatment adversely influenced the course of the hepatitis. This effect was reflected by a significantly higher mortality rate, in spite of the absence of any significant difference of the plasma transaminase activity increase and of the liver virus content.

Alanine Transaminase↗

PubMed1983

Effects of propylthiouracil on urinary metabolites of cyclophosphamide in rats.

Our previous studies have shown a protective effect of propylthiouracil (PTU) pretreatment against the toxicity of cyclophosphamide (CP). The present study was undertaken to investigate the mechanism of the PTU protection. CP is metabolized by the cytochrome P-450 drug-metabolizing enzyme system in the liver to alkylating metabolites, to active antineoplastic agents, and to acrolein, the most toxic and least antineoplastic metabolite. Measurements of CP metabolites in blood and urine during a 4-hr i.v. infusion of CP (50 mg/kg body weight/hr) showed urinary acrolein excretion to be 2.5 times higher in control rats as compared to PTU-treated rats. Since it has been reported that urinary acrolein levels are directly related to the frequency and severity of hemorrhagic cystitis, it is concluded from our observations that prevention of hemorrhagic cystitis is probably mediated by the PTU effect on lowering urinary acrolein concentration and excretion. Serum alkylating activity was significantly higher in the PTU-pretreated rats, which may enhance the antineoplastic potential of CP.

Animals↗

PubMedDate not supplied

Intellectual development in children whose mothers received propylthiouracil during pregnancy.

Standard intelligence tests were administered to twenty-eight children who had been exposed to PTU in utero and thirty-two non-exposed siblings. There was no significant difference in results between the two groups. The present study suggests that with careful attention, pregnant women with thyrotoxicosis can be treated with propylthiouracil without interfering with subsequent intellectual development in the offspring.

Adolescent↗

PubMed1983

Toxic effects of propylthiouracil in the rat.

Repeated intraperitoneal administration of propylthiouracil (PTU, 0.5-1.5 mmole/Kg) to rats caused a dose related decrease in body weight. A dose dependent increase in liver weight and a decrease in spleen weight were also seen. Leukocyte counts were markedly reduced in all PTU treated animals. Histopathological changes were observed. These consisted of congestion of red pulp of the spleen and vacuolization of the liver.

Animals↗

PubMed1980

Propylthiouracil-induced hepatic damage.

Two cases of propylthiouracil-induced liver damage have been observed. The first case is of an acute type of damage, proven by rechallenge; the second presents a clinical and histologic picture resembling chronic active hepatitis, with spontaneous remission.

Adult↗

PubMed1980

Effect of propylthiouracil on 125I-L-triiodothyronine binding to the nuclei and on malic enzyme activity in rat liver cytosol.

The effect of propylthiouracil (PTU), triiodothyronine (T3) and thyroxine (T4) on malic enzyme activity of rat liver cytosol and on the binding of 125I-L-triiodothyronine to nuclear fraction was examined. Significant decrease of in vitro binding of 125I-T3 to the liver nuclei was found in rats fed PTU for 12 h, 24 h and 120 h. Hepatic malic enzyme activity was unchanged after 12 h, but markedly decreased after 24 h and 120 h of PTU treatment. In 120 h PTU fed animals the effect of T3 on malic enzyme activity was five times higher in comparison to an equimolar dose of T4. Finally, the effect of T4 on malic enzyme activity was observed which might result from the intrinsic activity T4 under the conditions of decreased T4 to T3 conversion due to PTU feeding. The obtained results show that there is a certain correlation between nuclear T3 binding and cytosol malic enzyme activity which is presumably induced directly through m-RNA synthesis stimulated by thyroid hormones.

Animals↗

PubMed1980

Pharmacokinetics of propylthiouracil upon p.o. administration in man.

A pharmacokinetic analysis of propylthiouracil (PTU) plasma concentration versus time data for twelve euthyroid subjects was performed using the NONLIN computer program. The plasma concentration-time curves were best described by a one-compartment open model. PTU was administered to fasted subjects as a single 150-mg peroral dose. Venous blood samples were taken for a period of 8 hrs, and the concentration of unmetabolized PTU was determined by a new specific high-pressure liquid chromatographic procedure. Estimates of pharmacokinetic parameters generated in the study were compared with corresponding parameters reported in the literature.

Administration, Oral↗

PubMed1979

Effect of short-term therapy with propylthiouracil in patients with alcoholic liver disease.

The effect of propylthiouracil (PTU; 300 mg/day) on alcoholic liver disease was evaluated in 133 patients in a short-term randomized double-blind trial. Severity of the disease was assessed by a composite clinical and laboratory index (CCLI). A normalization rate (NR) representing the rate of improvement in CCLI was calculated. Patients with alcoholic hepatitis, with and without cirrhosis, showed a significantly higher NR on PTU (43.6 +/- 4.6) than on placebo (19.8 +/- 3.3; P less than 0.001). A similar effect was observed in patients with abnormal prothrombin (no biopsy): NR was 32.9 +/- 6.9 on PTU and 2.6 +/- 3.7 on placebo (P less than 0.005). The effect of PTU on each clinical and laboratory component of the CCLI was also compared in these two groups. In 38 patients with alcoholic hepatitis and in 25 with abnormal prothrombin, those on PTU showed a greater improvement in 15 of 15 items (P less than 0.001) and 14 of 15 (P less than 0.01), respectively. When patients were divided according to the severity of the disease into those in the lower and upper halves of the CCLI range (81 and 52 patients, respectively), PTU was shown to have a significant effect only in the latter: The NR was 41.4 +/- 3.8 on PTU and 22.5 +/- 4.2 on placebo (P less than 0.005). PTU was ineffective in patients with inactive cirrhosis.

Double-Blind Method↗

PubMed1979

Thyroid hormones in alcoholic liver disease. Effect of treatment with 6-n-propylthiouracil.

The relationship between alcoholic liver disease and circulating thyroid hormones was investigated in 124 hospitalized patients treated with placebo or propylthiouracil (PTU) for a maximum of 46 days in a double-blind study. Serum triiodothyronine (T3) levels on admission were significantly (P less than 10(-6) and inversely correlated with the severity of alcoholic liver disease. After hospitalization, changes in T3-levels in patients with low admission T3 significantly correlated (P less than 0.001) with the degree of spontaneous improvement of liver function (placebo group). Treatment with 300 mg of PTU daily (Orrego et al. Gastroenterology 76:105--115, 1979) markedly increased the rate of improvement in severely ill patients with low T3 on admission. In this group, serum T3-levels were also increased after PTU, but this increase did not correlate with the change in the patient's condition. It is suggested that the known inhibitory effect of PTU on peripheral deiodination of T4 to T3 is marked by a more marked improvement in liver function in this group. PTU treatment in this group reduced the free T4-index and increased TSH levels markedly (16%; P less than 0.02) toward levels found in hypothyroidism. PTU did not improve the condition of mildly ill patients with normal admission T3-levels, nor did it alter free T4-index or serum TSH levels in these patients. Serum T3-levels provide a sensitive indicator of the severity of alcoholic liver disease and of its response to conventional treatment. Serum T3-levels also distinguish between a group of patients, in whom low-dose PTU administration results in a beneficial effect, and another group, in whom no therapeutic effect of PTU is observed.

Humans↗