propylthiouracil and Leukopenia

Thyroid hormone preparations, especially thyroxine, are widely used either at replacement doses to correct hypothyroidism or at suppressive doses to abolish thyrotropin (thyroid-stimulating hormone) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse/ nodular nontoxic goitre. In order to suppress thyrotropin secretion, it is necessary to administer slightly supraphysiological doses of thyroxine. Possible adverse effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats and, possibly, left ventricular hypertrophy) and bone changes (reduced bone density and bone mass), but the risk of these adverse effects can be minimised by carefully monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and adjusting the dosage accordingly. Thionamides [thiamazole (methimazole), carbimazole, propylthiouracil] are the most widely used antithyroid drugs. They are given for long periods of time and cause adverse effects in 3 to 5% of patients. In most cases, adverse effects are minor and transient (e.g. skin rash, itching, mild leucopenia). The most dangerous effect is agranulocytosis, which occurs in 0.1 to 0.5% of patients. This life-threatening condition can now be effectively treated by granulocyte colony-stimulating factor administration. Other major adverse effects (aplastic anaemia, thrombocytopenia, lupus erythematosus-like syndrome, vasculitis) are exceedingly rare.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Bone and Bones; Carbimazole; Cardiovascular System; Child; Collagen Diseases; Humans; Leukopenia; Liver; Methimazole; Propylthiouracil; Skin; Thyroid Hormones; Thyroxine

Over the past four decades, a great deal has been learned about the pharmacology and mechanisms of action of antithyroid drugs. Their ability to inhibit hormone biosynthesis involves complex interactions with thyroid peroxidase and thyroglobulin, many of which are still poorly understood. Their spectrum of activity is much wider than previously thought, and a number of clinically important extrathyroidal actions have been identified. Despite a greater appreciation for the intricacies of antithyroid-drug pharmacology, controversies still surround the use of these agents in the treatment of thyrotoxicosis. These controversies are apt to continue until the pathophysiology of Graves' disease is fully elucidated.

Topics: Adult; Agranulocytosis; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Child; Female; Fetus; Graves Disease; Humans; Hyperthyroidism; Immunity; Immunoglobulins; Infant, Newborn; Insulin Antibodies; Leukopenia; Lupus Vulgaris; Methimazole; Milk, Human; Pregnancy; Pregnancy Complications; Propylthiouracil; Vascular Diseases

The relationship between the toxic effect of propylthiouracil (PTU) and myeloperoxidase activity of rat bone marrow was examined. The administration of PTU for 1 or 2 weeks caused a decrease in leukocyte count with the concomitant inhibition of the activity of myeloperoxidase in the bone marrow. The decreases in both leukocyte counts and myeloperoxidase activity were restored to control levels at 2 weeks after the discontinuation of the administration. PTU treatment did not affect the affinity of H2O2 for the enzyme; however, an increase in the Km value for guaiacol was seen. PTU, incubated with bone marrow peroxidase in vitro increased the Km value of the enzyme for guaiacol, but had no effect on the Km value for H2O2. The results suggest that the mechanism of inhibition of myeloperoxidase activity by PTU given in vivo or incubated with the enzyme in vitro may be the same. The activity of bone marrow glutathione peroxidase was not influenced by PTU treatment.

Topics: Animals; Azides; Bone Marrow; Cyanides; Erythrocytes; Glutathione Peroxidase; In Vitro Techniques; Kinetics; Leukopenia; Male; Peroxidase; Peroxidases; Propylthiouracil; Rats; Rats, Inbred Strains; Time Factors

Treatment of rats with propylthiouracil for one to two weeks caused an increase in glutathione S-transferase (GST) activity of the liver cytosol, but not of the particulate fraction. Increased GST activity was reversed two weeks after discontinuing PTU administration. Activation of the enzyme was inversely proportional to the decrease in leukocytes. Repeated administration of PTU increased the Vmax of the enzyme without affecting the Km value for the substrate 1-chloro-2,4-dinitrobenzene, whereas both the Km and Vmax for glutathione (GSH) were increased by PTU treatment. GSH content and GSH peroxidase activity were not affected by PTU, but this resulted in an increase in glucose 6-phosphate dehydrogenase activity. PTU treatment caused increase in GST activity using 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene, p-nitrobenzyl chloride, and benzalacetone as substrates; enzyme activity towards chlorodinitrobenzene was the highest.

Topics: Animals; Cytosol; Enzyme Activation; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Kinetics; Leukopenia; Liver; Male; Propylthiouracil; Rats; Rats, Inbred Strains

Topics: Adult; Arthritis; Female; Humans; Hyperthyroidism; Leukopenia; Propylthiouracil; Skin; Vasculitis, Leukocytoclastic, Cutaneous

A patient had cutaneous vasculitis, leukopenia, and splenomegaly caused by the antithyroid drug, propylthiouracil. Histopathologic changes of acute vasculitis of the superficial and deep dermal blood vessels accompanied by fibrin thrombi formation were found in biopsy specimens of the cutaneous lesions. Direct immunofluorescence studies demonstrated IgM and C3 of the vessel walls suggesting immune complex deposition. The literature disclosed five cases with similar features associated with propylthiouracil therapy. Characteristic cutaneous findings include a recurrent, self-limited, symmetrical purpuric eruption that can involve the face or earlobes. Clinicians should recognize these changes as a cutaneous sign of a vasculitis associated with propylthiouracil therapy.

Topics: Adult; Biopsy; Blood Vessels; Complement C3; Female; Graves Disease; Humans; Immunoglobulin M; Leukopenia; Propylthiouracil; Skin; Splenomegaly; Vasculitis, Leukocytoclastic, Cutaneous

A method has previously been described which detected xenogeneic and allogeneic antibodies to human granulocytes by their inhibition of the normal phagocytosis-associated hexose monophosphate shunt (HMS) activity. This method was used to study three patients with acute agranulocytosis secondary to antithyroid drug administration. Two patients with methimazole and one patient with propylthiouracil induced agranulocytosis were studied. Serum samples from each of these three patients taken during the acute phase of agranulocytosis had inhibitory effects on phagocytosis-associated HMS activity in leukocytes from both normal donors and the patients after their full recovery from agranulocytosis. IgM but not IgG prepared from acute sera in two patients was also inhibitory. Disruption of IgM disulfide bonds by dithiothreitol destroyed its inhibitory activity. The possibility of drug-dependent immune destruction of leukocytes in these patients is discussed.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Drug Hypersensitivity; Female; Granulocytes; Graves Disease; Humans; Immunoglobulin M; Leukopenia; Methimazole; Phagocytosis; Propylthiouracil; Remission, Spontaneous

Topics: Adolescent; Agranulocytosis; Child; Child, Preschool; Drug Hypersensitivity; Female; Fever; Humans; Hyperthyroidism; Kidney Glomerulus; Leukocyte Count; Leukopenia; Lupus Erythematosus, Systemic; Male; Propylthiouracil; Urticaria

Topics: Autoimmune Diseases; Drug Hypersensitivity; Humans; Hypersensitivity; Hyperthyroidism; Leukopenia; Propylthiouracil

Topics: Adolescent; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperthyroidism; Leukocyte Count; Leukocyte Disorders; Leukocytes; Leukopenia; Propylthiouracil; Thiourea; Thyroid Gland

Topics: Humans; Leukocyte Disorders; Leukopenia; Propylthiouracil