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PubMed1988

Effect of thyroid status on beta-adrenoceptors and calcium channels in rat cardiac and vascular tissue.

To determine the influence of thyroid hormone on beta-adrenoceptors and Ca2+ channels, rats were treated with thyroxine (75 micrograms/100 g sc daily for 5 days) or propylthiouracil (0.05% in drinking water for 30 days). beta-Adrenoceptor density in ventricular tissue, measured by [125I]iodocyanopindolol binding, was significantly increased and decreased respectively, following thyroxine or propylthiouracil treatment to 124.7 +/- 7.11 fmol/mg protein and 71.98 +/- 5.37 fmol/mg protein from euthyroid (control) levels of 93.7 +/- 4.58 fmol/mg protein. Ca2+ channel density, measured by [3H]nitrendipine binding, was altered in the opposite direction; it was significantly decreased and increased to 324 +/- 24 fmol/mg protein and 691 +/- 31 fmol/mg protein from 562 +/- 35 fmol/mg protein after thyroxine or propylthiouracil treatment, respectively. No changes in affinity of either ligand were observed. Responses of isolated papillary muscles from propylthiouracil-treated animals accorded with changes seen in the binding studies. The geometric mean EC50 of isoproterenol increased from 9.5 x 10(-9) mol/l to 5.5 x 10(-8) mol/l, and the EC50 for calcium decreased from 3.16 x 10(-3) mol/l to 1.36 x 10(-3) mol/l; moreover, the responsiveness to the Ca2+ channel activator Bay K 8644 was increased. The corresponding responses in thyroxine-treated animals could not be examined because of prominent arrhythmic activity. As with papillary muscles the sensitivity of left atria to isoproterenol was decreased after treatment with propylthiouracil, with geometric mean EC50 values increasing from 3.21 x 10(-9) mol/l to 89.4 x 10(-9) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2000

Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies.

OBJECTIVE: The triggers that induce antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis (APV) are largely unknown. However, there have been reports suggesting that hydralazine, propylthiouracil, and several other drugs may cause some cases of APV, and the majority of these cases have been associated with antimyeloperoxidase (anti-MPO) ANCA. Our experience led us to hypothesize that cases of high titers of anti-MPO antibodies are often drug-associated. METHODS: In this study, we determined the prevalence of exposure to hydralazine, propylthiouracil, and other drugs previously implicated in APV among 30 patients with vasculitis and the highest titers of anti-MPO antibodies newly detected in our laboratory between 1994 and 1998. The clinical, histologic, and other serologic features of these 30 patients were also examined. RESULTS: The 30 study patients accounted for 12% of the 250 new patients with APV and anti-MPO who were tested during the study period. All 30 study subjects had anti-MPO titers that were more than 12 times the median titer of the 250 patients. Ten (33%) of the 30 patients had been exposed to hydralazine and 3 (10%) had been exposed to propylthiouracil. An additional 5 patients (17%) had been exposed to 1 of the other previously reported candidate drugs: 2 to penicillamine, 2 to allopurinol, and 1 to sulfasalazine. One of the patients exposed to hydralazine had also been exposed to allopurinol. In all cases, the clinical and histologic findings were typical of APV. There was a strong association between the presence of antielastase and/ or antilactoferrin antibodies and exposure to candidate drugs. CONCLUSION: These data suggest that a sizable proportion of cases of APV with high titers of anti-MPO antibodies are drug-associated, especially following exposure to hydralazine or propylthiouracil. We recommend that the use of these drugs should be sought in cases of anti-MPO-positive vasculitis, particularly among patients with high titers of these antibodies.

Adolescent↗

PubMed1996

Cardiac alpha-adrenergic receptor expression is regulated by thyroid hormone during a critical developmental period.

Although thyroid hormone is obligatory for the development of cardiac beta-adrenergic receptors, it is difficult to assign a specific role for the hormone in receptor ontogeny because beta-receptor expression is affected similarly in the adult. We have determined whether thyroid hormone plays a role in receptor development by evaluating alpha 1-adrenergic receptors, which in the adult are downregulated by thyroid hormone. Propylthiouracil given from gestational day 17 through postnatal day 5 caused significant deficits in the number of alpha 1-receptors and values resolved to normal in parallel with hormone level recovery. When propylthiouracil was administered later (postnatal days 11 through 15) only a transient deficit in alpha 1-receptor binding was seen; hyperthyroidism (triiodothyronine) could still evoke stimulation of receptor expression at this stage. The effects on receptor expression were distinguished from general effects on cell differentiation by examining alpha 2-receptors, which disappear over the first three postnatal weeks; delayed differentiation caused by propylthiouracil would slow the decline in alpha 2-receptors, whereas accelerated differentiation caused by triiodothyronine would hasten the decline. Instead, the effects were similar to those on alpha 1-receptors: perinatal propylthiouracil administration reduced, and neonatal triiodothyronine administration enhanced, alpha 2-receptor binding sites. Thus, thyroid hormone plays a role in the control of cardiac adrenergic receptor expression during a critical development period, with conjoint regulation of the multiple receptor subtypes present within the tissue. As adrenergic stimulation is important in maintaining cardiac function in the perinatal period, alterations of thyroid status during this period can be expected to result in abnormal reactivity and increased perinatal risk.

Animals↗

PubMed1993

Usefulness of difference spectroscopy in the study of the binding of uracil derivatives to human serum albumin.

Propylthiouracil is an antithyroid drug which is carried by the blood, thanks to its binding with human seroalbumin (HSA), and induces a structural alteration in HSA that changes the binding capability of other ligands. Then, with the aim of fixing the functional group in propylthiouracil involved in the interactions with HSA, the binding parameters for several uracil derivatives bound on HSA have been estimated. Interaction of propyluracil, thiouracil and propylthiouracil with HSA leads to the formation of complexes that show spectral shifts. These spectral shifts are a measure of the fraction of chromophoric groups, which is perturbed in the interaction with HSA, and thus can be used in the ligand binding estimate. The difference spectroscopy results correspond to the binding on a single centre in HSA. The difference spectra of propyluracils in seroalbumin coincide with those of propyluracils in a perturbant solvent (ethanol). On the other hand, propylthiouracil and propyluracil bind to seroalbumin on a larger scale than uracil and thiouracil. Thus, we can conclude that this binding is strengthened by hydrophobic interactions between the propyl group in propyluracils and apolar substituents on HSA.

Humans↗

PubMed1989

Regulation of liver angiotensinogen mRNA by glucocorticoids and thyroxine.

This study examines the immediate and longer-term changes in angiotensinogen mRNA and in plasma angiotensinogen which follow the withdrawal and replacement of glucocorticoids or thyroxine. RNA from rat liver was analysed by Northern blot and dot-blot hybridization with a 40-mer oligodeoxynucleotide probe specific for angiotensinogen mRNA. Adrenalectomy decreased plasma angiotensinogen and angiotensinogen mRNA to 55 and 50% of control values respectively over a period of 16 days. Similar decreases were obtained after propylthiouracil (1 mg/kg for 16 days) treatment, except when injected simultaneously with T3 (3 micrograms/kg/day). Over the same period plasma renin activity increased in adrenalectomized rats from 4.1 +/- 0.8 to 7.0 +/- 1.5 pmol angiotensin I (AI)/ml/h, and decreased in propylthiouracil-treated rats from 3.8 +/- 0.4 to 1.6 +/- 0.4 pmol AI/ml/h. Approximate half-times of 2-3 days were calculated for both plasma angiotensinogen and angiotensinogen mRNA post-adrenalectomy or after propylthiouracil treatment. Dexamethasone (400 micrograms/kg, i.m.) given to intact rats rapidly increased angiotensinogen mRNA to a maximum of 250% of control by 8 h and with a half-maximal response of 2.8 h. Plasma angiotensinogen responded similarly, apart from an initial delay of 2 h. Treatment with different doses of propylthiouracil and dexamethasone showed that responses were dose-related. We conclude that changes in plasma angiotensinogen and angiotensinogen mRNA are closely correlated, and that under various physiological circumstances angiotensinogen mRNA has a rapid rate of accumulation but a slow rate of decay.

Adrenalectomy↗

PubMed1978

Hormone action at the membrane level. VIII. Adrenergic receptors in rat heart and adipocytes and their modulation by thyroxine.

The regulation of adrenergic receptors in rat heart was measured in rats made hyperthyroid by injection with thyroxine and made hypothyroid by addition of propylthiouracil to the drinking water. Hyperthyroid rats display cardiac hypertrophy and a decrease in epididymal fat pad weight. The maximal beta-receptor level of ventricular membranes, as determined by (-)-[3H]dihydroalprenolol binding, was increased 60% by thyroxine treatment and decreased about 30% by propylthiouracil treatment. The affinity of the beta receptor was unchanged after thyroxine or propylthiouracil treatment. The maximal activity of the isoproterenol-stimulated adenylate cyclase (EC 4.6.1.1) varied with thyroid state in a manner parallel to the increase in beta-adrenergic binding sites. Thyroxine treatment also increases by 2-fold the beta receptors in isolated rat fat cells. Propylthiouracil treatment lowered the level of alpha receptors in heart by 30% as measured by [3H]dihydroergocryptine binding, but increased the affinity about 2.5-fold. The highest level of alpha receptors was seen in control hearts. These studies indicate that thyroxine may control the turnover of beta-adrenergic receptors in heart and fat cells and regulate physiological responses in these tissues via a hormone-hormone interplay system. Thyroxine treatment reduced the activity of the membrane-bound Mg2+-ATPase (EC 3.6.1.3) and 5'-mononucleotidase (EC 3.1.3.5) but appears to increase the activity of the (Na+ + K+)ATPase (EC 3.6.1.4).

Adenosine Triphosphatases↗

PubMed1997

Anti-thyroid drugs decrease mucosal damage in a rat model of experimental colitis.

BACKGROUND: Methimazole, an anti-thyroid drug, was recently found to be useful in the treatment of systemic lupus erythematosus and other autoimmune diseases. Moreover, decreased thyroid hormone production is associated with a variety of immunological manifestations, such as reduced activation of CD4+ cells, increased CD8+ cell activity and reduced soluble IL-2 receptors. In the present study we examined the effects of methimazole and propylthiouracil on a rat model of experimental colitis. METHODS: Colitis was induced by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB). Two weeks prior to induction of colitis, rats were treated by either methimaziole (0.04%) or propylthiouracil (0.01%) in drinking water after a week of free access to water. Rats were sacrificed 48 h or 7 days after induction of colitis. The colon was isolated, rinsed with ice-cold water and weighed. Damage was assessed both macroscopically and microscopically and myeloperoxidase (MPO) activity determined. RESULTS: All treated rats were hypothyroid as manifested by a significant elevation of thyroid stimulating hormone (TSH), by comparison with the control groups (mean -1.82 +/- 0.40 versus 0.11 +/- 0.02 mmol/L, respectively). The inflammatory response elicited by TNB resulted in severe mucosal damage 48 h after damage induction, which persisted for 7 days. Pre-treatment with either methimazole 0.04% or propylthiouracil 0.01% significantly decreased mucosal damage macroscopically (lesion area, lesion score and segmental weight) microscopically and also significantly decreased MPO level at both time points (P < 0.01). CONCLUSIONS: Methimazole and propylthiouracil significantly reduce mucosal damage and colonic weight in a rat model of colitis. The mode by which they do so remains to be studied.

Animals↗

PubMed1991

Subcellular distribution of thyroxine 5'-monodeiodinase activity in rabbit kidney.

Thyroxine 5'-monodeiodinase is located in the proximal tubules of the rabbit kidney. To estimate the subcellular distribution of 5'-monodeiodinase activity, we prepared subcellular fractions, a basolateral membrane fraction and a brush border membrane fraction, from kidneys of Japanese white rabbits. Each fraction (0.5 mg protein) was incubated at 37 degrees C for 60 min with 0.5 micrograms T4 in the presence of 5 mM DTT. The T3 generated in the reaction mixture was extracted with cold ethanol and measured by RIA. For analysis of propylthiouracil-insensitive thyroxine 5'-monodeiodinase, we examined its kinetic behavior at nanomolar concentrations of the substrate, T4, in the presence of 100 microM propylthiouracil. In order of decreasing activity, basolateral membrane, microsomal fraction, mitochondrial fraction, cytosolic fraction, brush border membrane and nuclear fraction were capable of converting T4 to T3. Upon addition of 10(-5) M propylthiouracil to the reaction mixture, 5'-monodeiodinase activities of basolateral membrane and brush border membrane were inhibited by more than 90%, but that of microsomes was inhibited by only about 50%. In addition, kinetic analysis of microsomal 5'-monodeiodinase activity at nanomolar T4 concentrations in the presence of 10(-4) M propylthiouracil suggested on apparent Km of 3.8 nmol. These results indicate that there is high-Km 5'-monodeiodinase activity (PTU-sensitive) in the basolateral and brush border membranes and also high-Km and low-Km 5'-monodeiodinase (PTU-insensitive) in the microsomes of rabbit kidney.

Animals↗

PubMed1976

Control of cell growth. II. Requirement of thyroid hormones for the in vivo estrogen-dependent growth of rat pituitary tumor cells.

Further examination of rat pituitary cell line GH3/C14 showed that at least the physiologic concentration of L-thyroxine was required for estrogen-dependent growth in vivo. Two L-thyroxine synthesis inhibitors, 6-n-propyl-2-thiouracil (propylthiouracil) and 1-methylimidazole-2-thiol (methimazole), were administered concurrently with estrogen to GH3/C14-inoculated hosts. Propylthiouracil administration to estrogen-treated males, intact females, and estrogen-treated ovariectomized females inhibited tumor formation by 93, greater than 95, and 68%, respectively, as compared to tumor formation in controls not treated with propylthiouracil. Methimazole treatment of estrogen-primed males and intact females inhibited tumor formation by 78 and 95%, respectively. Concentrations of total L-thyroxine and free L-thyroixine in sera from normal and inhibitor-treated hosts were depressed 70-80% by propylthiouracil and 60-70% by methimazole. Administration of either drug caused greater inhibition of tumor growth than of total body weight gain. In addition, the administration of a combination of L-thyroxine and L-triiodothyronine to male rats promoted tumor formation even in the absence of exogenous estrogen.

Animals↗

PubMed1985

Hepatotoxicity from antithyroid drugs.

We review the cases of hepatic injury from propylthiouracil, methimazole and carbimazole in the English language literature and compare them to cases of agranulocytosis in a recent review. The data on hepatotoxicity confirm the findings for agranulocytosis that low-dose methimazole is safer than propylthiouracil and that methimazole toxicity is more common over 40 years old. In contrast, propylthiouracil hepatotoxicity often occurs in younger patients. Most cases of hepatic injury occur in the first few months of drug therapy as with agranulocytosis. The reason that methimazole typically causes cholestatic hepatitis while propylthiouracil causes cytotoxic hepatitis remains unknown.

Adolescent↗

PubMed1985

Studies of the regulation of mouse renin genes by measurement of renin messenger ribonucleic acid.

The transcriptional activity of renin genes in the mouse kidney and submandibular gland (SMG) was examined by measurement of renin messenger RNA (mRNA) (nanograms per g tissue) and compared with renin activity (micromoles angiotensin I per h/g tissue). In control adult mice renin mRNA and renin activity (in parentheses) were 1.8 +/- 0.24 (11 +/- 1.1) in male kidney, 3.6 +/- 0.66 (18 +/- 2.8) in female kidney, 230 +/- 34 (903 +/- 59) in male SMG, and 31 +/- 6 (188 +/- 47) in female SMG (mean +/- SE, n = 6). The ratio of renin mRNA among these four tissues was similar to that of renin activity (1:2:100:17, respectively). Although the values in male kidney were one one-hundredth those in SMG, 1000 to 10000 times more SMG cells are involved per gram of tissue so that, per renin-synthesizing cell, kidney values would be 10 to 100 times SMG values. Expression of renin gene(s) in a renal juxtaglomerular cell may thus be higher than in a SMG granular duct cell. Values in adult male SMG were a consequence of a 40-fold rise at puberty, were decreased to 16% (+/- 3.8) by castration, but were not significantly influenced by treatment with testosterone, T4, propylthiouracil, sodium depletion, or spironolactone. Renin mRNA in adult female SMG was 18-fold higher than juvenile values, was increased 10-fold (+/- 1.6) by testosterone (to adult male levels) and 5.5-fold (+/- 0.81) by T4 (P less than 0.005), but was decreased to 42% (+/- 29) of normal by propylthiouracil (P less than 0.05). Propylthiouracil caused a small but significant decrease in testosterone-treated female values. In the kidney renin mRNA was increased 3.0-fold (+/- 0.30) by captopril, 2.3-fold (+/- 0.23) by a low sodium diet, and 1.7-fold (+/- 0.13) by spironolactone after 1 week, whereas T4, testosterone, or propylthiouracil had little or no effect. Sialoadenectomy increased renin mRNA and renin in male but not in female kidney, suggesting that a SMG factor, possibly renin, may have a role in suppression of renin synthesis in male kidney. In conclusion, measurement of renin mRNA suggests that testosterone regulates renin gene expression by a direct effect in male mouse SMG, whereas in the female regulation is by thyroid hormone. In the kidney conditions which increase renin content are accompanied by parallel (5-fold higher) increases in renin mRNA, suggesting enhanced expression of renin gene(s) in renal juxtaglomerular cells in chronic low sodium states.

Animals↗

PubMed1998

Effect of antithyroid drugs on hydroxyl radical formation and alpha-1-proteinase inhibitor inactivation by neutrophils: therapeutic implications.

The release of proteolytic enzymes and generation of strong oxidants such as the hydroxyl radical by activated neutrophils has been proposed to play an important role in mediating toxin-induced liver injury. The antithyroid drug propylthiouracil protects against liver injury induced by many hepatotoxic agents and markedly reduces mortality in patients with alcoholic liver disease. However, the mechanism(s) by which propylthiouracil protects against liver injury is not well understood. The present studies investigate the effect of antithyroid drugs on proteolytic enzyme activity and on hydroxyl radical generation from activated neutrophils. In the presence of hydrogen peroxide and chloride, neutrophil myeloperoxidase, an enzyme from the same gene superfamily as thyroid peroxidase, generates hypochlorous acid which inactivates alpha-1-proteinase inhibitor (A1PI) present in serum. This inactivation allows neutrophil-released proteolytic enzymes to attack cells. In the present study myeloperoxidase activity was inhibited fully at therapeutic concentrations by antithyroid drugs (propylthiouracil and methimazole). Antithyroid drugs fully prevented hypochlorous acid formation, and prevented neutrophil-mediated inactivation of A1PI, with concomitant blockage of proteolytic activity. Conversely, generation of both superoxide and hydroxyl radicals by activated neutrophils was unaffected by propylthiouracil. The production of these oxygen radicals was fully inhibited by the NADPH oxidase inhibitor diphenylene iodonium chloride, however. These studies indicate that antithyroid drugs are unlikely to prevent cell injury by inhibiting hydroxyl radical generation or by scavenging hydroxyl radicals, but are likely to exert their hepatoprotective anti-inflammatory action by inhibiting neutrophil myeloperoxidase, an enzyme akin to thyroid peroxidase.

Animals↗

PubMed1987

Effects of dietary cholesterol and hypothyroidism on rat apolipoprotein mRNA metabolism.

The effects of dietary cholesterol and hypothyroidism on the mRNA levels of rat apolipoproteins A-I, A-IV, and E were measured in extracts of rat liver and rat intestine by hybridization to specific cDNA. Four groups, each comprised of six rats, were fed diets consisting of normal laboratory rat chow and either no supplements (control); 5% lard, 1% cholesterol, and 0.3% taurocholic acid (CF); 5% lard, 1% cholesterol, 0.3% taurocholic acid, and 0.1% propylthiouracil (CF-PTU); or 0.1% propylthiouracil (PTU) for 32 days. At the conclusion of the diets, serum cholesterol, triiodothyronine, and thyroxine levels were measured. The average serum cholesterol concentrations for the four groups were 50.4 +/- 3.7, 75.6 +/- 15.3, 135.3 +/- 41.5, and 73.3 +/- 16.4 mg/dl, respectively. The presence of propylthiouracil in the diets significantly lowered triiodothyronine and thyroxine levels in the serum. The mRNA levels for apolipoproteins A-I and A-IV in rat liver decreased significantly after the feeding of the CF-PTU diet (31 +/- 4% and 32 +/- 3% of normal, respectively) and the PTU diet (34 +/- 8% and 43 +/- 12% of normal, respectively), but showed little change after the CF diet (88 +/- 16% and 108 +/- 15% of normal, respectively). The effects of dietary propylthiouracil on the hepatic mRNA levels for apolipoproteins A-I and A-IV imply a role for thyroid hormones in regulating the mRNA levels for these apolipoproteins in rat liver. ApoE mRNA levels in the rat liver decreased slightly after the CF-PTU diet (74 +/- 12% of normal) and after the PTU diet (73 +/- 10% of normal).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Which anti-thyroid drug?

Anti-thyroid drugs are widely used to treat diffuse toxic goiter (Graves' disease). Of the two drugs currently available in the United States, propylthiouracil is prescribed far more often than is methimazole (Tapazole). However, compared with propylthiouracil, methimazole can be given as a single daily dose, is cheaper, and, at low doses, is associated with less major toxicity; for these reasons, methimazole should be used for the routine management of Graves' disease when anti-thyroid drugs are selected as primary therapy. On the other hand, because of certain pharmacologic factors, propylthiouracil should be used in selected situations, particularly in patients with "thyroid storm" and in pregnant or lactating women.

Drug Administration Schedule↗

PubMed1989

Effects of experimental hypothyroidism on the distribution of lipids and lipoproteins in the plasma of rats.

Male Sprague-Dawley rats were treated for up to 4 weeks with propylthiouracil in a study designed to determine the effects of experimental hypothyroidism on plasma lipoproteins. The distribution of lipid constituents across the plasma lipoprotein spectrum was assessed by size exclusion chromatography and the lipoprotein particle size was assessed by gradient gel electrophoresis. A reduction in the concentration of thyroid hormones was accompanied by changes to plasma lipoproteins within 1 week of commencing treatment with propylthiouracil. These changes progressed for a further week, after which the pattern remained relatively stable for up to 4 weeks of treatment. In the animals treated with propylthiouracil, there was a marked reduction in the concentration of all constituents of very-low-density lipoproteins (VLDL). There was a coincident increase in concentration of all constituents of low-density lipoproteins (LDL), with an increase in LDL triacylglycerol being particularly obvious. There was also a marked and sustained increase in the concentration of cholesterol in high-density lipoproteins (HDL), but in this case, there were no sustained increases in the concentrations of other HDL constituents. There was, however, an appearance of new populations of very large HDL particles comparable to the HDLc which accumulate in the plasma of cholesterol-fed animals.

Animals↗

PubMed1995

Myeloperoxidase-antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis complicating the course of Graves' disease: report of three adult cases.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has been recently recognized in Graves' disease patients treated with propylthiouracil. We have experienced three adult cases of Graves' disease with main features being renal derangements. All three patients, who were between the ages of 22 and 82 years, had been treated with propylthiouracil for 2 to 5 years after a diagnosis of Graves' disease. After several weeks of upper respiratory tract infection or flu-like symptoms, they abruptly began to manifest proteinuria and hematuria concomitant with severe anemia. Their serum creatinine increased from normal levels to 1.2 to 3.6 mg/dL. Renal biopsy revealed crescentic glomerulonephritis without deposition of immune complexes (ie, pauci-immune type). Crescent formations were observed in 40% to 60% of the glomeruli in all three cases. The serum from the patients revealed positive perinuclear-ANCA and negative cytoplasmic-ANCA (C-ANCA) pattern, and myeloperoxidase (MPO)-ANCA titers were 120 to 502 ELISA Units/mL (normal, < 10 ELISA Units/mL). A withdrawal of propylthiouracil with or without immunosuppressive therapy ameliorated their renal derangements. Graves' disease patients should be placed under vigilant observation by monitoring their urinalysis and serum creatinine, especially when being treated with antithyroid drugs and when suffering from flu-like symptoms.

Adult↗

PubMed2004

Anti-thyroid thioureylenes in the treatment of psoriasis.

Psoriasis is a common skin disorder associated with significant morbidity. Many agents are used in the medical management of this debilitating condition with the newer anti-cytokine agents being the most recent addition to the pharmacological armamentarium to battle the disorder. Cost concerns are very important with the newer "biologic" treatments costing in excess of 10,000 US dollars annually. The need for cheaper, orally administered agents is therefore imperative. This paper addresses the potential role of anti-thyroid thioureylenes, propylthiouracil and methimazole, in the treatment of psoriasis and reviews the possible mechanism of action of these drugs in this disorder. It is hypothesized that the beneficial effect of anti-thyroid thioureylenes in psoriasis is linked to their effect as anti-proliferative agents as reflected by significant decrease in markers of cellular proliferation such as proliferative cell nuclear antigen in biopsy specimens after treatment with these drugs. Propylthiouracil has been shown to bind to the hepatic T 3 receptor and it is possible that propylthiouracil (6-n-propyl-2-thiouracil) binding to the ligand-binding site normally occupied by T 3 impairs transcription by inactivating the effect of T 3 as well as by squelching retinoic X receptor heterodimer formation with other receptors of the steroid receptor superfamily such as the peroxisome proliferator-activated receptor, retinoic acid receptor and vitamin D receptors.

Antithyroid Agents↗

PubMed2003

Detection of endocrine-modulating effects of the antithyroid acting drug 6-propyl-2-thiouracil in rats, based on the "Enhanced OECD Test Guideline 407".

The antithyroid acting drug propylthiouracil (PTU) was administered to male and female Wistar rats at 0, 0.1, 1, or 10mg/kg body weight for 4 weeks according to the draft protocol of the "Enhanced OECD Test Guideline 407" (enhanced TG 407) in order to investigate its suitability to detect endocrine-mediated effects. The study was conducted with two identical subsets of five animals per sex and dose each to provide data on sensitivity. The modified protocol includes the investigation of additional organ weights, pathology, and histopathology, of thyroid hormones, of spermatozoa, and of estrus cycle. At time of sacrifice, all females were in the diestrus stage as prescribed. Adverse effects were observed in the thyroid gland (hypertrophy/ hyperplasia) and the pituitary gland (hyperplasia of basophilic cells, hypoplasia of acidophilic cells) together with dose-related decreased serum triiodothyronine (T3) and thyroxine (T4) levels and increased thyroid stimulating hormone (TSH) levels. Other effects of PTU included decrease of organ weights, anaemia, impaired blood coagulation, and reduced activity of enzymes. Hence, some of the additional examined endpoints of the enhanced TG 407, e.g., examination of pituitary gland and thyroid hormones, were suitable to detect endocrine-modulating effects of propylthiouracil. Treatment of five animals provides sufficient sensitivity to detect the described adverse effects of propylthiouracil. The enhanced TG is currently under investigation in several laboratories, evaluation of all the results will allow determining its practicability as well as the most suitable additional endpoints.

Administration, Oral↗