Ex-vivo study of the percutaneous absorption of a tramadol formulation through feline inner pinna skin.

OBJECTIVES: Oral medication of small animals, particularly cats, is often challenging. The transdermal route may provide an easier option for owners to administer chronic treatment. Tramadol is an analgesic mainly used in humans; it is also commonly used in dogs, despite some controversy over its clinical efficacy. Recent studies have suggested that tramadol is efficacious for pain management in cats. In cats, the inner pinna is the most commonly used site for transdermal drug therapy; the use of this site has been validated in experimental studies of methimazole and mirtazapine treatment. This ex vivo study aimed to characterise the percutaneous absorption pharmacokinetics of a formulation of tramadol in Pentravan through feline inner pinna skin. METHODS: High-performance liquid chromatography was used to assess the stability of the tramadol formulation (100 mg/ml in Pentravan) over three months at room temperature. Forced degradation was also assessed in neutral, acidic, alkaline, and oxidative conditions. A Franz cell system was employed to evaluate percutaneous absorption of a finite dose of tramadol. RESULTS: The tramadol formulation was stable for three months at room temperature. Tramadol penetrated through ex vivo feline inner pinna skin, but considerable intra- and inter-individual variability in kinetics was observed. Comparison with another vehicle, Lipoderm, revealed no significant difference in the percutaneous absorption of tramadol. CONCLUSIONS AND RELEVANCE: The Pentravan formulation assessed in this study supported tramadol absorption across the feline inner ear skin. In vivo studies are necessary to evaluate the pharmacokinetics and efficacy of this formulation.

Development of a high-performance liquid chromatography-tandem mass spectrometric method for the determination of Methimazole in human blood matrices.

Methimazole (MMI, 1-methyl-2-mercaptoimidazole) is widely used for the treatment of hyperthyroidisms. There are methods available for the measurement of MMI concentration in human serum or plasma from the past, but none meet the current regulatory standards for bioanalytical method validations. In this paper, we developed and validated a total MMI measurement method using liquid chromatography-tandem mass spectrometry (LC-MS/MS), a technique that conforms to current bioanalytical method validation. To form a free sulfhydryl group on MMI, sodium bisulfite was added to 50 µl of plasma or serum samples containing MMI before the derivatization step. The internal standard (MMI-D3) was spiked into samples, then these samples were derivatized with 4-chloro-7-nitro-2,1,3-benzoxadiazole. After derivatization, these samples were extracted by supported liquid extraction. Then, the organic solvent was evaporated and the residue was dissolved in 50% methanol and injected into the LC-MS/MS system. A calibration curve was plotted over the concentration range 1-1000 ng/mL (r2 = 0.999). The intra-day and inter-day precisions were less than 10.2% and 9.8%, respectively. The intra-day and inter-day accuracies were between 89.5% and 101.1%, and 96.0% and 99.7%, respectively. The long-term stability of samples showed good precision and accuracy. The validated method was successfully applied to determine serum total MMI concentration in Graves' disease patients after oral administration of 5, 10 or 15 mg MMI. The range of circulating total MMI concentrations was found to be between 2.69 and 304.27 ng/mL in this study. It was shown that the measured serum total MMI concentrations changed in a dose-dependent manner.

Physiologically Based Pharmacokinetic Modeling Approach to Predict Drug-Drug Interactions With Ethionamide Involving Impact of Genetic Polymorphism on FMO3.

The widely used second-line antituberculosis drug ethionamide shows wide interindividual variability in its disposition; however, the relevant factors affecting this phenomenon have not been characterized. We previously reported the major contribution of flavin-containing monooxygenase 3 (FMO3) in the reductive elimination pathway of ethionamide. In this study, ethionamide metabolism was potentially inhibited by methimazole in vitro. The drug-drug interaction leading to methimazole affecting the disposition of ethionamide mediated by FMO3 was then quantitated using a bottom-up approach with a physiologically based pharmacokinetic framework. The maximum concentration (Cmax ) and area under the curve (AUC) of ethionamide were estimated to increase by 13% and 16%, respectively, when coadministered with methimazole. Subsequently, we explored the effect of FMO3 genetic polymorphism on metabolic capacity, by constructing 2 common functional variants, Lys158 -FMO3 and Gly308 -FMO3. Compared to the wild type, recombinant Lys158 -FMO3 and Gly308 -FMO3 variants significantly decreased the intrinsic clearance of ethionamide by 2% and 24%, respectively. Two prevalent functional variants of FMO3 were predicted to affect ethionamide disposition, with mean ratios of Cmax and AUC of up to 1.5 and 1.7, respectively, in comparison with the wild type. In comparing single ethionamide administration with the wild type, simulations of the combined effects of comedications and FMO3 genetic polymorphism estimated that the Cmax and AUC ratios of ethionamide increased up to 1.7 and 2.0, respectively. These findings suggested that FMO3-mediated drug-drug interaction and genetic polymorphism could be important determinants of interindividual heterogeneity in ethionamide disposition that need to be considered comprehensively to optimize the personalized dosing of ethionamide.

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).

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.

Toxicities associated with 1-month treatment with propylthiouracil (PTU) and methimazole (MMI) in male rats.

Thionamides such as propylthiouracil (PTU) and methimazole (MMI) have been used for more than 50 years to treat the more common causes of thyrotoxicosis/hyperthyroidism such as Graves' disease. Serious adverse effects associated with thionamides in humans include idiosyncratic liver damage, agranulocytosis, aplastic anemia, and vasculitis. Both prospective and retrospective clinical studies with these drugs have failed to identify predictive biomarker for these adverse effects. To assess whether rat is a good model for predicting drug-related adverse events in the liver and in the bone marrow, we conducted a comprehensive study in male rats with multiple doses of PTU and MMI. As expected, euthyroid animals became hypothyroid along with several secondary changes associated with hypothyroidism. There were slight reductions in red blood cell parameters along with some marginal effects on the bone marrow elements. However, there was no evidence of significant neutropenia and liver injury in both PTU-treated and MMI-treated cohorts. MMI-related effects were noted in the seminiferous tubules of the testes. Overall, 1-month daily treatment of euthyroid rats with PTU or MMI resulted in hypothyroidism, minor bone marrow effects, and several secondary effects associated with hypothyroidism, but without any evidence of adverse effects reported in humans including liver injury and agranulocytosis.

The pharmacokinetics of methimazole in a novel lipophilic formulation administered transdermally to healthy cats.

AIM: To determine the pharmacokinetics of a novel lipophilic formulation of transdermal methimazole compared to oral carbimazole. METHODS: Healthy cats received 5 mg carbimazole orally every 12 hours for 13 treatments (n=6), then received transdermal methimazole (n=5) at a dose of 5 mg, then 10 mg, once daily on the pinna for 7 days, with 21 days between treatments. Concentrations of methimazole in serum over 24 hours and at 148 hours were determined by high performance liquid chromatography. RESULTS: Concentrations of methimazole in serum for the first 24 hours were not reliably detected in all cats treated with 5 mg methimazole transdermally, while for those receiving 5 mg carbimazole orally and 10 mg methimazole transdermally all cats had detectable concentrations of methimazole in serum. The maximum concentration and area under the curve were lower in cats receiving 10 mg methimazole transdermally (108 (SD 25) ng/mL and 2544 (SD 216) mg-hour/mL, respectively) than those receiving 5 mg oral carbimazole (355 (SD 113) ng/mL and 31,866 (SD 439) ng-hour/mL, respectively) (p<0.05). The time at maximal concentration and elimination half-life were longer for 10 mg transdermal methimazole (5.2 (SD 1.1) hours and 13 (SD 3) hours, respectively) compared to 5 mg oral carbimazole (2.1 (SD 1.6) hours and 5.1 (SD 1.2) hours, respectively). At 148 hours, mean concentrations of methimazole in serum were higher in cats receiving 10 mg methimazole transdermally (506 (SD 165) ng/mL) than for 5 mg oral carbimazole (255 (SD 28) ng/mL) or 5 mg transdermally (204 (SD 76) ng/mL). The mean relative bioavailability of 10 mg transdermal methimazole compared to oral carbimazole was 48 (min 43, max 55)%. CONCLUSION: Transdermal methimazole at a dose of 10 mg administered to the pinnae of healthy cats once daily in a novel lipophilic formulation has half the relative bioavailablity compared to 5 mg oral carbimazole. CLINICAL RELEVANCE: Transdermal methimazole can be absorbed from the skin of healthy cats.

Maternal transfer of methimazole and effects on thyroid hormone availability in embryonic tissues.

Methimazole (MMI) is an anti-thyroid drug used in the treatment of chronic hyperthyroidism. There is, however, some debate about its use during pregnancy as MMI is known to cross the mammalian placenta and reach the developing foetus. A similar problem occurs in birds, where MMI is deposited in the egg and taken up by the developing embryo. To investigate whether maternally derived MMI can have detrimental effects on embryonic development, we treated laying hens with MMI (0.03% in drinking water) and measured total and reduced MMI contents in the tissues of hens and embryos at different stages of development. In hens, MMI was selectively increased in the thyroid gland, while its levels in the liver and especially brain remained relatively low. Long-term MMI treatment induced a pronounced goitre with a decrease in thyroxine (T4) content but an increase in thyroidal 3,5,3'-triiodothyronine (T3) content. This resulted in normal T3 levels in tissues except in the brain. In chicken embryos, MMI levels were similar in the liver and brain. They gradually decreased during development but always remained above those in the corresponding maternal tissues. Contrary to the situation in hens, T4 availability was only moderately affected in embryos. Peripheral T3 levels were reduced in 14-day-old embryos but normal in 18-day-old embryos, while brain T3 content was decreased at all embryonic stages tested. We conclude that all embryonic tissues are exposed to relatively high doses of MMI and its oxidised metabolites. The effect of maternal MMI treatment on embryonic thyroid hormone availability is most pronounced for brain T3 content, which is reduced throughout the embryonic development period.

Buccal delivery of methimazole as an alternative means for improvement of drug bioavailability: permeation studies and matrix system design.

The aim of this study was to investigate the potential for systemic administration of Methimazole (MMI) through the buccal mucosa as an alternative route for drug delivery. Considering that the most important restriction in buccal drug delivery could be the low permeability of the mucosa, the ability of MMI to cross the mucosal barrier was assessed. Permeation of MMI through porcine buccal mucosa was investigated ex vivo using Franz type diffusion cells, buffer solution simulating saliva or natural human saliva as donor phase. The collected data suggested that buccal mucosa does not hinder MMI diffusion and the drug crosses the membrane (J(s) = 0.068 mg cm(-2) h(-1) and K(p) = 0.065 cm h(-1)). Matrix tablets, suitable for administration on buccal mucosa, were then designed and prepared by direct compression of MMI loaded matrices (70% w/w) using Eudragit(®) RS 100 as a matrixing, low permeable, pH-independent, mucoadhesive and insoluble agent. The matrix tablets were evaluated in vitro for dissolution; however, the drug was discharged too rapidly from tablets. To obtain drug release rate suitable to maintain constant drug levels in the central compartment the tablets were coated with lipophilic material (glycerol tristearate). In ex vivo permeation experiments, therapeutically MMI plasma levels were obtained when matrix tablets were coated with 0.10 mm thick lipophilic coating film. Coated tablets placed on buccal porcine mucosa provide optimal drug release rate. Coated buccal matrix tablets may represent a potential alternative dosage form for systemic delivery of MMI in hyperthyroidism management.

Tracking multiplex drugs and their dynamics in living cells using the label-free surface-enhanced Raman scattering technique.

Label free and real time detection of nonfluorescent drugs inside living cells has been realized by using surface-enhanced Raman scattering (SERS). For the first time, the characteristics of 6-mercapotopurine and methimazole, two different drugs, were monitored simultaneously by SERS in living cells. Particularly, the processes of diffusion and metabolism of drugs occurring in the intracellular matrix were investigated. The results indicate that the metabolism speed of 6-mercapotopurine in living HeLa cells is much faster than that of methimazole. Moreover, the detection sensitivity of intracellular drugs has also been checked and a low detection limit of 1 nM was obtained of drug 6-mercapotopurine in a single HeLa cell.

Management of hyperthyroidism during pregnancy and lactation.

INTRODUCTION: Poorly treated or untreated maternal overt hyperthyroidism may affect pregnancy outcome. Fetal and neonatal hypo- or hyper-thyroidism and neonatal central hypothyroidism may complicate health issues during intrauterine and neonatal periods. AIM: To review articles related to appropriate management of hyperthyroidism during pregnancy and lactation. METHODS: A literature review was performed using MEDLINE with the terms 'hyperthyroidism and pregnancy', 'antithyroid drugs and pregnancy', 'radioiodine and pregnancy', 'hyperthyroidism and lactation', and 'antithyroid drugs and lactation', both separately and in conjunction with the terms 'fetus' and 'maternal.' RESULTS: Antithyroid drugs are the main therapy for maternal hyperthyroidism. Both methimazole (MMI) and propylthiouracil (PTU) may be used during pregnancy; however, PTU is preferred in the first trimester and should be replaced by MMI after this trimester. Choanal and esophageal atresia of fetus in MMI-treated and maternal hepatotoxicity in PTU-treated pregnancies are of utmost concern. Maintaining free thyroxine concentration in the upper one-third of each trimester-specific reference interval denotes success of therapy. MMI is the mainstay of the treatment of post partum hyperthyroidism, in particular during lactation. CONCLUSION: Management of hyperthyroidism during pregnancy and lactation requires special considerations and should be carefully implemented to avoid any adverse effects on the mother, fetus, and neonate.

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.

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).

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.

[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.

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).

Pharmacokinetics and pharmacotherapy of thionamides in pregnancy.

Hyperthyroidism occurs in approximately 1 in every 1000 to 2000 pregnancies. Although the signs and symptoms of the disease are similar in the pregnant and nonpregnant patient, the complications of hyperthyroidism can have even more profound consequences for the mother and fetus during gestation. These include maternal heart failure, preeclampsia, miscarriage, and preterm labor; as well as fetal loss and low birth weight. Furthermore, thyroid function and laboratory testing for hyperthyroidism are altered in pregnancy. The gestational increase in thyroid size, increased thyroid-binding globulin levels, increased serum total T4 and total T3 levels, and decreased thyroid stimulating hormone levels often confuses the evaluation of the thyroid status in pregnancy. Worldwide, the thionamides-propylthiouracil, methimazole, and carbimazole-have been used in pregnancy for the treatment of hyperthyroidism. However, propylthiouracil has been the drug of choice in the United States because it is believed to have less potential to induce fetal/neonatal hypothyrodism, to cross the placenta and into breast milk to a lesser degree, and to be less teratogenic than methimazole or carbimazole. None of the above have been substantiated in more recent studies. The pharmacokinetics of the thionamides in the pregnant and nonpregnant states, as well as the pharmacotherapeutic recommendation for hyperthyroidism will be reviewed.