Bioavailability of propylthiouracil from two formulation tablets.

Bioavailability studies were performed for 50 mg propylthiouracil tablets (Jelfa, Poland) versus 50 mg propycil tablets (Solvay, Germany). An open-label, two-phase, crossover study was conducted with 15 healthy subjects. All subjects were randomly assigned a drug assignment number from I to XV, which was used throughout the experimental period. Dosing periods for both formulation tablets: Propylthiouracil, Jelfa vs. Propycil, Solvay were separated by at least 7 days washout period. Following single dose drug administration, venous blood samples were obtained at the required times for 12 h and the drug serum levels were determined by HPLC and used for PK analysis. PK parameters were calculated by the computer program TopFit 2.0. HPLC chromatograms show retention times for propylthiouracil and methylthiouracil (internal standard) of 5.97 and 2.75 min, respectively at 20 °C, providing adequate separation from each other and from endogenous serum components. Pharmacokinetic parameters for both tablets were not significantly different. Serum concentration-time profiles are superimposed for the above tablets according to an open one-compartment body model. EBA for Propythiouracil Jelfa tablets vs. Propycil tablets was 96.8%, and not significantly different. Some authors applied a two-compartment body model for the calculation of propylthiouracil pharmacokinetic parameters, which approach is not rational according to our data.

Regional variations in percutaneous absorption of methimazole: an in vitro study on cat skin.

The use of transdermal gel medications in cats has become popular in veterinary medicine due to the ease of administration compared to oral medication. The research to support systemic absorption of drugs after transdermal gel administration and the preferred skin region to apply these drugs in cats is limited. The aim of this study was to characterize the effect of different skin regions on the percutaneous absorption pharmacokinetics of a commercially available transdermal methimazole after a finite dose was applied to feline skin in vitro. A commercial formulation of methimazole (10 mg) was applied to four skin regions (the inner stratum corneum of the ear, groin, neck, and thorax regions) from six cats. The receptor medium was sampled up to 36 h postapplication, and methimazole concentrations were measured using high-performance liquid chromatography. Methimazole was absorbed more completely across the pinnal skin, compared to the groin, neck, and thorax (P < 0.001), which justifies application to the pinna to maximize efficacy and also to minimize the effects of grooming.

Percutaneous absorption of methimazole: an in vitro study of the absorption pharmacokinetics for two different vehicles.

The use of transdermal medications in cats has become popular in veterinary medicine due to the ease of administration compared to oral medication. However, the research to support systemic absorption of drugs applied to the pinna after transdermal administration in cats is limited. The aim of this study was to characterize the percutaneous absorption pharmacokinetics of methimazole in a lipophilic vehicle compared to methimazole in Pluronic(®) lecithin organogel (PLO) using a finite dose applied to feline ear skin in an in vitro Franz cell model. The two formulations of methimazole (10 mg) were applied to the inner stratum corneum of six pairs of feline ears. The receptor medium was sampled up to 30 h post-administration, and methimazole concentrations were measured using high-performance liquid chromatography (HPLC). Histological examination of all ears was undertaken as small differences in the thickness of ear skin may have contributed to inter-individual differences in methimazole absorption between six cats. Methimazole was absorbed more completely across the pinnal skin when administered in the lipophilic vehicle compared to administration in the PLO gel (P < 0.001).

Pathogenesis of propylthiouracil-related hepatotoxicity in children: present concepts.

Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are the most common drugs used today in cases of adolescent thyrotoxicosis. Skepticism has been growing regarding the use of PTU in childhood and its association with severe liver failure. The aim of this review is to present all the recent data regarding pathogenesis of PTU hepatotoxicity in children and adolescents. Specifically, reactive drug metabolites and increased oxidative stress can directly activate inflammatory and immunological pathways. Drugs are not only immunogenic because of their chemical reactivity but also because they may bind through electrostatic forces to available T-cell receptors. Redox modulation is also a key regulatory strategy in the adaptive immune system. Subtle changes in the extracellular redox status may cause profound functional changes in redox-sensitive proteins. Genetic factors that affect drug biotransformation could also be implicated in this mechanistic model of PTU-related hepatotoxicity. Further studies are needed to fully understand the pathophysiology of PTU-induced liver damage.

The tissue-specific toxicity of methimazole in the mouse olfactory mucosa is partly mediated through target-tissue metabolic activation by CYP2A5.

The antithyroid drug methimazole (MMZ) can cause severe, tissue-specific toxicity in mouse olfactory mucosa (OM), presumably through a sequential metabolic activation of MMZ by cytochrome P450 (P450) and flavin monooxygenases (FMO). The aims of this study were to determine whether CYP2A5, one of the most abundant P450 enzymes in the mouse OM, is involved in MMZ metabolic activation, by comparing Cyp2a5-null with wild-type (WT) mice, and whether hepatic microsomal P450 enzymes, including CYP2A5, are essential for MMZ-induced OM toxicity, by comparing liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, with WT mice. We showed that the loss of CYP2A5 expression did not alter systemic clearance of MMZ (at 50 mg/kg, i.p.); but it did significantly decrease the rates of MMZ metabolism in the OM, whereas FMO expression in the OM was not reduced. MMZ induced depletion of nonprotein thiols, as well as pathological changes, in the OM of WT mice; the extent of these changes was much reduced in the Cyp2a5-null mice. Thus, CYP2A5 plays an important role in mediating MMZ toxicity in the OM. In contrast, the rate of systemic clearance of MMZ was significantly reduced in the LCN mice, compared to WT mice, whereas the MMZ-induced OM toxicity was not prevented. Therefore, hepatic P450 enzymes are essential for systemic MMZ clearance, but they are not required for MMZ-induced OM toxicity. We conclude that the tissue-specific toxicity of MMZ is mediated by target tissue metabolic activation, and the reaction is partly catalyzed by CYP2A5 in the OM.

Post-ablative hypothyroidism.

OBJECTIVE: To determine the incidence of hypothyroidism following radioactive iodine (RAI) treatment for hyperthyroidism and to study the relationship between pretreatment RAI uptake and treatment dose and the subsequent development of hypothyroidism. METHODS: Retrospective chart review of patients treated with RAI for hyperthyroidism between 1995 and 2000. 180 charts were reviewed; 41 met the inclusion criteria. Data were collected regarding the cause of hyperthyroidism, initial RAI uptake, initial dose of RAI, number of RAI treatments, and post treatment thyroid status. RESULTS: Patients in toxic nodular goiter group had significantly lower 24-hour RAI-123 uptake as compared to those with Graves' disease. However patients with Graves' disease received significantly lower RAI dose in comparison to those with toxic nodular goiters. Cure rates following RAI administration were similar in both groups. 70% of patients with Graves' disease developed post-ablative hypothyroidism as compared to 42% in toxic nodular goiter group (p = 0.086). There was no relationship between the dose of RAI or pretreatment RAI uptake and the likelihood of developing hypothyroidism. CONCLUSION: We found that, within our study population, post-ablative hypothyroidism tended to be more prevalent in patients with Graves' disease as compared to those with toxic nodular goiter. However cure rates following RAI administration were similar in both groups. We also found that neither the magnitude of the administered RAI dose nor the pre-treatment RAI uptake predicted the development of subsequent hypothyroidism.

Serum concentrations of methimazole in cats after a single oral dose of controlled-release carbimazole or sugar-coated methimazole (thiamazole).

Methimazole (thiamazole) is an antithyroid drug commonly used to treat feline hyperthyroidism. It is routinely given twice daily. Carbimazole is a methimazole derivative that is rapidly metabolized to methimazole in vivo. A controlled-release tablet for once-daily carbimazole therapy has recently been developed in an attempt to improve compliance during medical management of feline hyperthyroidism. The results of a crossover study in six cats suggest that the pharmacokinetics of methimazole with a single dose of this controlled-release tablet may be similar to those with a single dose of a sugar-coated methimazole tablet when the two drugs are given at an equimolar dose. The mean half-lives were nearly identical (3.12 hours, sugar-coated methimazole tablets; 3.28 hours, controlled-release carbimazole tablets). The serum concentrations of methimazole at 24 hours were 21.7 ± 28.9 ng/mL in the cats treated with 5-mg sugar-coated methimazole tablets and 28.7 ± 37 ng/mL in the cats treated with 10-mg carbimazole tablets (which provide approximately 25% more methimazole after conversion to the active metabolite).

Epididymis expresses the highest 5'-deiodinase activity in the male reproductive system: kinetic characterization, distribution, and hormonal regulation.

We characterized the enzymes that catalyze the deiodination of T(4) to T(3) in the male reproductive tract. Testis, epididymis (EPI), seminal vesicles, prostate, bulbourethral glands, spermatozoa, and semen were taken from sexually mature rats (300 g). Iodothyronine 5'-deiodinase (5'-D) activity was quantified by the radiolabeled-iodide-release method. 5'-D activity was 10-fold higher in EPI and semen than in the rest of the tissues. In EPI, semen, and prostate, the enzymatic activity was completely inhibited by 1 mm 6-n-propyl-2-thiouracil, whereas in the other tissues the inhibition was partial (50%). The high susceptibility to 6-n-propyl-2-thiouracil inhibition, a ping-pong kinetic pattern, and low cofactor (Michaelis Menten constant for dithiothreitol=0.7 mm) and high substrate (Michaelis Menten constant for reverse T(3)=0.4 microm) requirements indicate that EPI 5'-D corresponds to type 1 deiodinase (D1). Real-time RT-PCR amplification of D1 mRNA in this tissue confirms this conclusion. The highest EPI D1 expression occurred at the onset of puberty and sexual maturity, and in the adult, this activity was more abundant in corpus and caput than in the caudal region. EPI D1 expression was elevated under conditions of hyperthyroidism and with addition of 17beta-estradiol. Our data also showed a direct association between D1 and a functional epididymis marker, the neutral alpha-glucosidase enzyme, suggesting that local generation of T(3) could be associated with the development and function of EPI and/or spermatozoa maturation. Further studies are necessary to analyze the possible physiological relevance of 5'-D in the male reproductive system.

Safety of topical methimazole for the treatment of melasma. Transdermal absorption, the effect on thyroid function and cutaneous adverse effects.

Methimazole is an oral antithyroid compound that exhibits a skin-depigmenting effect when used topically. However, the effect of topical methimazole on thyroid function has not been reported. This study was aimed at assessing the safety of topical methimazole used to treat pigmented lesions, without affecting thyroid hormones due to systemic delivery. The pharmacokinetics of methimazole, either applied in the form of a 5% topical formulation to facial skin or taken orally in the form of a 5-mg tablet by 6 volunteers, were determined. In addition, the effect of long-term topical applications of 5% methimazole on the function of the thyroid gland in 20 patients with epidermal melasma was determined following 6 weeks of once-daily application. Cutaneous adverse effects of topical methimazole were determined. From 15 min up to 24 h after application, methimazole was undetectable in the serum of the individuals receiving single topical methimazole dosing. Methimazole, however, was detected in serum after 15 min of oral administration and remained detectable in serum up to 24 h after administration. Long-term topical methimazole applications in melasma patients did not induce any significant changes in serum TSH, free thyroxine and free triiodothyronine levels. Topical methimazole was well tolerated by the patients and did not induce any significant cutaneous side effects. Present data together with the previously shown non-cytotoxic and non-mutagenic characteristics of methimazole indicate that this agent could be considered as a safe skin-depigmenting compound for topical treatment of skin hyperpigmentary disorders in humans.

Pharmacokinetics of controlled-release carbimazole tablets support once daily dosing in cats.

Carbimazole, a prodrug of methimazole, is used in the treatment of hyperthyroidism in cats. The pharmacokinetics of methimazole was investigated in healthy cats following oral administration of 15 mg of carbimazole as a controlled-release tablet (Vidalta), Intervet). The controlled-release tablet did not produce a pronounced concentration peak and methimazole was present in the circulation for a sustained period, compared with a conventional tablet formulation. The time to reach peak concentrations after carbimazole administration was quite long (t(max) 6 h). The absolute bioavailability of carbimazole was around 88 +/- 11%. Repeated oral administration daily for 13 consecutive days did not lead to accumulation of methimazole in plasma. The extent of absorption of carbimazole was about 40% higher when administered to cats that had been fed compared to fasted cats. The relative oral bioavailability of methimazole following administration of the controlled-release tablets was similar to that of a conventional release formulation (83 +/- 21%). The pharmacokinetics of this controlled-release formulation of carbimazole supports its use as a once daily treatment (both as a starting dose and for maintenance therapy) for cats with hyperthyroidism.

Thermoresponsive drug delivery using liquid crystal-embedded cellulose nitrate membranes.

The aim of this study was to investigate the use of thermotropic liquid crystalline (TLC) blends of 4-pentyl-4'-cyanobiphenyl (K15) and 4-heptyl-4'-cyanobiphenyl (K21) with appropriate nematic to isotropic phase temperature (Tn - i) just above body temperature as a temperature-modulated drug permeation system. Using differential scanning calorimetry (DSC) we showed that the phase transition temperature (Tn - i) of K15 and K21 were 34.2 degrees C and 41.5 degrees C respectively. However, the thermogram of K15 and K21 blends with different ratios was shown to be a single endothermic peak similar to that of pure TLCs. K15 and K21 blends did not behave as a physical blend of two thermotropic liquid crystals with different Tn - i. However, they are rather mixed together in such ways that behave like a single unit TLC. The Tn - i of these TLC mixtures was linearly proportionate to the ratio of K15:K21. Using appropriate ratio of K15:K21 TLC, a mixture with desirable phase transition temperature was obtained. A triple layer of cellulose nitrate membranes containing a 50:50 mixture of K15 and K21 was used for drug permeation studies. This composite membrane showed good pulsatile permeation of drug molecules in response to temperature changes below and above the Tn - i of the K15 and K21 blends in a reproducible and reversible manner. Paracetamol and methimazole were chosen as hydrophobic and hydrophilic drug models, respectively. Methimazole permeability through the TLC membrane was much higher (36.0 x 10(-5) cm/s) at temperatures above the phase transition temperature of liquid crystal blends than that (7.2 x 10(-5) cm/s) at temperatures below the phase transition temperature of liquid crystal blends (38.1 degrees C).

[Current problems in the treatment of Graves' disease in pregnancy and in lactation].

In Graves' patients complicated by pregnancy, both maternal and fetal problems related to the disease can be reduced or avoided by controlling hyperthyroidism. However, optimal treatment for mothers may exert detrimental effects on fetuses. Methimazole may cause "methimazole embryopathy". Antithyroid drug doses that maintain mothers in euthyroid status are sometimes excessive fetuses. Furthermore, successful treatment with surgery or radioiodine occasionally may result in fetal hyperthyroidism due to TSH receptor antibody(TRAb). There are approaches to manage these problems. Propylthiouracil is chosen in treating Graves' disease in early pregnancy. In later pregnancy, maternal free thyroxine is maintained near or somewhat above normal. Ablative therapy is not recommended in women whose TRAb levels are extremely high from the standpoint of fetal thyroid state.

Oral drug therapy following bariatric surgery: an overview of fundamentals, literature and clinical recommendations.

Bariatric surgery is the most effective solution for severe obesity and obesity with comorbidities, and the number of patients going through bariatric surgery is rapidly and constantly growing. The modified gastrointestinal anatomy of the patient may lead to significant pharmacokinetic alterations in the oral absorption of drugs after the surgery; however, because of insufficient available literature and inadequate awareness of the medical team, bariatric surgery patients may be discharged from the hospital with insufficient instructions regarding their medication therapy. In this article, we aim to present the various mechanisms by which bariatric surgery may influence oral drug absorption, to provide an overview of the currently available literature on the subject, and to draw guidelines for the recommendations bariatric surgery patients should be instructed before leaving the hospital. To date, and until more robust data are published, it is essential to follow and monitor patients closely for safety and efficacy of their medication therapies, both in the immediate and distant time post-surgery.

Liquid chromatographic assay of abouthiouzine in plasma and its application to pharmacokinetic studies.

Abouthiouzine is a newly synthesized antithyroid agent with a proposed less adverse effects profile than other currently used drugs. A simple and rapid reversed phase high performance liquid chromatography assay was developed to determine the concentration of abouthiouzine in human plasma. The procedure involved extraction of the drug and propranolol (internal standard) from the plasma using ethylacetate. The extract was evaporated under nitrogen and the residue was constituted with the mobile phase and injected onto micro-Bondapack phenyl column (10 microm, 3.9 mm x 150 mm). The mobile phase consisted of 10 mM potassium dihydrogen phosphate buffer, acetonitrile, and methanol in the ratio of 60:25:15 (v/v/v, pH=3.0), which was delivered at a rate of 1.5 ml/min. Abouthiouzine and the internal standard were monitored using UV detection at 240 nm; the run time was less than 5 min. The detection limit of abouthiouzine is 0.5 microg/ml. The within- and between-day coefficients of variation were less than 7%. Our method has been successfully used to measure abouthiouzine plasma concentrations in a rabbit model following an intravenous administration of the drug.

Radioiodine uptake and thyroid hormone levels on or off simultaneous carbimazole medication: a prospective paired comparison.

AIM: To allow radioiodine (RAI) treatment in patients with need for anti-thyroid drug medication and low RAI uptakes we investigated the feasibility of discontinuing carbimazole for 3 days to enhance the RAI uptake without concurrent exacerbation of hyperthyroidism. METHODS: We prospectively investigated RAI dynamics and thyroid hormone concentration in 12 patients with low RAI uptake (<30%) under simultaneous carbimazole medication and 3 days after discontinuation. At both time points fT(4), T(3) and TSH were monitored. RESULTS: Discontinuation of carbimazole for 3 days led to a significant increase of RAI uptake in all patients. We found an enhancement up to 4.9-fold compared to the measurement on carbimazole. The mean RAI uptake increased from 15.2 +/- 4.4% to 50.1 +/- 15.5% (p<0.001). The intrapersonal radioiodine half-life increased from 4.2 +/- 1.6 days to 5.4 +/- 0.7 days (p = 0.13). Mean thyroid hormone concentration was not affected by the three day withdrawal of anti-thyroid drugs and no patient suffered from an aggravation of biochemical hyperthyroidism. CONCLUSION: A withdrawal of carbimazole for 3 days is long enough to provide sufficiently high RAI uptakes for RAI treatment in patients with low RAI uptakes and short enough to avoid the risk of exacerbation of hyperthyroidism.

Trans-pinnal movement of methimazole: an in vitro study showing that methimazole can cross from the inner to outer pinna of cats.

OBJECTIVES: The aim of the study was to determine if methimazole applied in a transdermal formulation to the internal pinna will cross to the external pinna in an in vitro Franz cell model. METHODS: The ears from six cats were harvested soon after death. Whole ears were mounted onto Franz-type diffusion cells with the stratum corneum of the inner pinnae uppermost. A commercial transdermal preparation containing methimazole (0.1 ml/10 mg) was applied to the inner pinnae. At 1, 2, 4, 6, 8, 12, 18, 24 and 30 h, a 200 µl sample of reservoir solution was removed to determine the methimazole concentration by high-performance liquid chromatography. The ears were then dissected, separating the internal pinna from the cartilage and the external pinna, before the methimazole concentration was measured at each site. The thickness of the different regions of the ear was measured on paraffin histology sections. RESULTS: Mean ± SD methimazole concentrations at 30 h for the right and left ear, respectively, were: inner ear, 1.25 ± 0.53 mg/g, 0.39 ± 0.26 mg/g; cartilage, 1.36 ± 0.47 mg/g, 0.33 ± 0.20 mg/g; and outer ear, 1.0 ± 0.32 mg/g, 0.33 ± 0.14 mg/g. There was a difference between the left and right ears (P <0.001). Minimal methimazole concentrations were detected in the receptor fluid. The mean methimazole concentration absorbed by the skin after application of 10 mg was, for the right ear, 3.65 ± 1.27 mg/g and, for the left, 1.08 ± 0.27 mg/g. There was no correlation between methimazole concentrations and thickness of each region of the ear. CONCLUSIONS AND RELEVANCE: Methimazole in a lipophilic vehicle applied to the inner pinna will penetrate to the outer pinna of cats in an in vitro model, which may have safety implications for humans associated with cats treated with transdermal methimazole. Substantial inter-individual variation was found. Further research is required in the area of transdermal penetration of drugs in cats.

Methimazole and propylthiouracil equally cross the perfused human term placental lobule.

Propylthiouracil (PTU) is widely believed to cross the placenta less freely than methimazole (MMI) and is therefore regarded as the preferred drug for treatment of hyperthyroidism in pregnancy. Clinical studies comparing the two drugs show, however, no differences in maternal or fetal thyroid function. We investigated transfer from the maternal to the fetal circuit in the isolated perfused term human placental lobule of low and high doses of PTU (4 micrograms/mL and 40 micrograms/mL) and MMI (1.5 micrograms/mL and 15 micrograms/mL) in protein-free perfusate and low doses of both drugs with addition of 40 g/L of bovine albumin. Both drugs readily crossed the placenta, reaching equilibrium in all experiments in about 2 h. Drug concentrations in the two circuits fitted a two compartmental model. Transfer kinetics for the two drugs were similar, nonsaturable, and unaffected by addition of albumin. Clearances (mL.min-1.g-1, means +/- SD) of PTU from maternal to fetal circuits were: 0.229 +/- 0.110, 0.216 +/- 0.065, and 0.170 +/- 0.032; and for transfer of MMI: 0.165 +/- 0.025, 0.232 +/- 0.153, and 0.174 +/- 0.009 (for low doses without, low doses with, and high doses without albumin, respectively). Clearances of PTU from fetal to maternal circuits were: 0.147 +/- 0.072, 0.109 +/- 0.014, and 0.116 +/- 0.028; and for transfer of MMI: 0.095 +/- 0.029, 0.122 +/- 0.088, and 0.12 +/- 0.005 (in the same experiments). There was no significant difference between drugs or drug doses and no effect of addition of albumin. We conclude that PTU and MMI have similar placental transfer kinetics.

Thyroid function and intellectual development of infants nursed by mothers taking methimazole.

For many years, breast-feeding was forbidden if antithyroid drugs were being used. Recently, limited studies have shown the relative safety of propylthiouracil and methimazole (MMI). It is not known whether MMI therapy of lactating mothers for 1 yr is safe for breast-fed infants and does not cause alterations in thyroid function and intellectual development. Between 1988 and 1998, 139 thyrotoxic lactating mothers and their infants were studied. Fifty-one thyrotoxic lactating mothers were treated with MMI during pregnancy, and MMI was continued during breast-feeding. Eighty-eight mothers were given 10 mg MMI (n 46) or 20 mg MMI (n = 42) daily for 1 month, 10 mg daily for the second month, and 5-10 mg daily thereafter. Serum T4, T3, and TSH concentrations were measured in thyrotoxic lactating mothers and their infants, before and at 1, 2, 4, 8, and 12 months. Serum MMI was measured in the infants of thyrotoxic lactating mothers taking 20 mg MMI. Thyroid function, urinary iodine, thyroid antibodies, intelligence quotient (IQ), verbal and functional components (Wechsler and Goodenough tests) were performed on 14 children of thyrotoxic lactating mothers between 48 and 74 months of age and on 17 controls. Mean +/- SD of FT4I in thyrotoxic lactating mothers treated with 10 mg MMI for 1 month decreased from 19.4 +/- 4.1 to 11.6 +/- 4.4 and from 20.5 +/- 4.7 to 9.8 +/- 1.5 when treated with 20 mg MMI. Values for FT3I decreased from 462 +/- 52 to 194 +/- 52 with 10 mg MMI and from 481 +/- 92 to 171 +/- 38 with 20 mg MMI. FT4I and FT3I were normal from the third to the twelfth months. In all infants FT4I, FT3I, and TSH concentrations were normal before and up to 12 months of MMI therapy in their lactating mothers. The lowest T4 and T3 values were 108 and 1.87 nmol/L, and the highest TSH value was 4.0 mU/L. Serum MMI levels in infants were less than 0.03 microg/mL. Six mothers receiving 20 mg MMI had increased serum TSH concentrations ranging from 26-135 mU/L after 1 month of treatment. Their infants were euthyroid with serum TSH values less than 2.6 mU/L. At 48-74 months of age, height, weight, FT4I, FT3I, TSH, and antithyroid antibody titers were not different than controls. The mean IQ was 107 +/- 14 vs. 106 +/- 16 (Goodenough test) and 103 +/- 10 vs. 103 +/- 16 (Wechsler test) for infants of thyrotoxic lactating mothers and control infants, respectively. Similarly, there was no difference in verbal and performance IQ and their components between infants of thyrotoxic lactating mothers and control children. No deleterious effects occur in thyroid function and physical and intellectual development of breast-fed infants whose lactating mothers were treated with doses of MMI up to 20 mg daily.

Enhancement of radioiodine treatment of small-pool hyperthyroidism with antithyroid drugs: kinetics and dosimetry.

UNLABELLED: (131)I-Iodide is the treatment of choice in most cases of hyperthyroidism, with a standard 7,000-cGy (rad) thyroid absorbed dose generally resulting in an incidental blood absorbed dose of less than 10 cGy (rad). However, in approximately 15% of patients there is a small, rapidly secreted thyroid iodine pool (small-pool patients) and, based on theoretic calculations, an incidental blood absorbed dose of up to 150 cGy (rad) could result. In such small-pool patients, continuing antithyroid drugs (ATDs) at a reduced dosage during (131)I therapy should inhibit the formation of (131)I-labeled levothyroxine and triiodothyronine and thereby reduce the protein-bound (131)I-iodine concentration in blood and the blood absorbed dose. METHODS: To test this hypothesis, thyroid and blood time-activity data were measured and absorbed doses were calculated for an (131)I tracer administered to small-pool hyperthyroid patients (n = 9) not receiving ATDs (off ATDs) and then receiving ATDs (on ATDs). RESULTS: The blood absorbed dose (cGy/37 MBq [rad/mCi] administered) was reduced from 2.54 +/- 0.91 (mean +/- SD) without ATDs to 1.27 +/- 0.54 with ATDs (P < 0.0001), whereas the thyroid absorbed dose was unchanged (1,870 +/- 700 vs. 2,080 +/- 1,080). The blood absorbed dose for an administered (131)I activity required to deliver a standard prescribed absorbed dose of 7,000 cGy (rad) to the thyroid therefore was reduced by over 50% with ATDs, from 11.3 +/- 6.5 to 4.9 +/- 2.8 cGy (rad) (P < 0.001). CONCLUSION: Continued administration of ATDs during (131)I therapy thus can effectively reduce extrathyroid radiation in small-pool patients without significantly reducing the target tissue (i.e., thyroid) dose.

Hyperthyroidism. Current treatment guidelines.

Hyperthyroidism is common and affects approximately 2% of women and 0.2% of men. The most common cause of hyperthyroidism is Graves' disease, an autoimmune disorder associated with circulating immunoglobulins that bind to and stimulate the thyrotropin (TSH) receptor, resulting in sustained thyroid overactivity. Toxic nodular goitres cause hyperthyroidism due to autonomous hyperfunctioning of localised areas of the thyroid. There are 3 recognised modalities of treatment for hyperthyroidism: antithyroid drugs, surgery and radioiodine. All are effective but no single method offers an absolute cure. Patients with Graves' disease may be prescribed antithyroid drugs over a period of 12 to 18 months with a view to inducing a long term remission. These drugs are also often given for a short period to render the patient euthyroid before definitive therapy with radioiodine or thyroidectomy. However, antithyroid drugs will not 'cure' hyperthyroidism associated with a toxic nodular goitre. The use of radioiodine as a first-line therapy for hyperthyroidism is growing. It is well tolerated, with the only long term sequelae being the risk of developing radioiodine-induced hypothyroidism. Radioiodine can be used in all age groups other than children, although it should also be avoided in pregnancy and during lactation. Pregnancy should be avoided for 4 months following its administration. Radioiodine may cause a deterioration in Graves' ophthalmopathy and corticosteroid cover may reduce the risk of this complication. The treatment of choice for toxic nodular goitre hyperthyroidism is radioiodine. Surgery, either subtotal or near-total thyroidectomy, has limited but specific roles to play in the treatment of hyperthyroidism: this approach is rarely used in patients with Graves' disease unless radioiodine has been refused or there is a large goitre causing symptoms of compression in the neck. The goal of surgery is to cure the underlying pathology while leaving residual thyroid tissue to maintain postoperative euthyroidism.