Bracketed Stability Evaluation of Methimazole USP in PLO Gel Mediflo™30 Pre-Mixed.

Extemporaneously compounded Methimazole 1% and 10% in PLO Gel Mediflo™30 Pre-Mixed were studied to assess physical, chemical and microbial stability over time. The formulations were stored at room temperature in tightly closed, light resistant plastic containers. Chemical stability was evaluated using a validated, stability indicating HPLC analysis and physical stability was evaluated through observation of organoleptic appearance and pH measurement at predetermined time points. Lastly, antimicrobial effectiveness testing was conducted per USP <51> guidelines. The results indicate that compounded Methimazole remained within the stability criteria for the duration of the study and can be assigned an extended beyond-use-date of 120 days under the studied conditions.

Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity.

Methimazole (MMI) is a widely used antithyroid drug, but it can cause hepatotoxicity by unknown mechanisms. Previous studies showed that the hepatic metabolism of MMI produces N-methylthiourea, leading to liver damage. However, the specific enzyme responsible for the production of the toxic metabolite N-methylthiourea is still unclear. In this study, we screened cytochromes P450 (CYPs) in N-methylthiourea production from MMI. CYP2A6 was identified as the key enzyme in catalyzing MMI metabolism to produce N-methylthiourea. When mice were pretreated with a CYP2A6 inhibitor, formation of N-methylthiourea from MMI was remarkably reduced. Consistently, the CYP2A6 inhibitor prevented MMI-induced hepatotoxicity. These results demonstrated that CYP2A6 is essential in MMI bioactivation and hepatotoxicity.

Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane.

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 21/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF4. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6, monoclinic, space group P 21/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 21/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.

Novel Hg (II) selective fluorescent green sensor based on carbon dots synthesized from starch and functionalized with methimazole.

We describe a green new method for the synthesis of water-soluble photoluminescent carbon dots (CDs) that were functionalized with methimazole (MTZ) and applied to determine Hg2+ based on the fluorescence extinction. Starch obtained from rice was used as a natural source for the production of CDs by hydrothermal treatment. Also, it was proposed a factorial design to optimize the parameters for CD synthesis and the results showed that the luminescence intensity is a function of temperature and not of the heating time in the hydrothermal process. The synthesized CDs were characterized using fluorescence techniques, Fourier transform infrared spectroscopy (FTIR), and UV-Vis spectroscopy. Through transmission electron microscopy (TEM) and dynamic light scattering (DLS), it was found the formation of CDs on a nanometer scale with an average size of 11 nm. The functionalization with MTZ, eliminated all interferences from other metals, indicating a selective response to Hg2+ ions. The method was applied to Hg2+ determination in waters. Under optimal conditions, was obtained a limit of detection of 1.8 × 10-7 mol L-1 with a linear range from 3.3 × 10-7 to 50.0 × 10-6 mol L-1. Therefore, the proposed method can be considered a simple, selective, and precise alternative that minimizes the number of reagents used for Hg2+ determination in natural waters, and can be applied on a large scale in environmental analyzes.

Unraveling diverse action of triton X-100 and methimazole on lysozyme fibrillation/aggregation: Physicochemical insights.

Identification of functionalities responsible for prevention of fibrillation in proteins is important to design effective drugs in addressing neurodegenerative diseases. We have used nonionic surfactant triton X-100 (TX-100) and antithyroid drug methimazole (MMI) to understand mechanistic aspects of action of these molecules having different functionalities on hen egg-white lysozyme at different stages of fibrillation. After establishing the nucleation, elongation and maturation stages of fibrillation of protein at 57 °C, energetics of interactions with these molecules have been determined by using isothermal titration calorimetry. Differential scanning calorimetry has permitted assessment of thermal stability of the protein at these stages, with or without these molecular entities. The enthalpies of interaction of TX-100 and MMI with protein fibrils suggest importance of hydrogen bonding and polar interactions in their effectiveness towards prevention of fibrils. TX-100, in spite of several polar centres, is unable to prevent fibrillation, rather it promotes. MMI is able to establish polar interactions with interacting strands of the protein and disintegrate fibrils. A rigorous comparison with inhibitors reported in literature highlights importance -OH and >CO functionalities in fibrillation prevention. Even though MMI has hydrogen bonding centres, its efficiency as inhibitor falls after the inhibited lysozyme fibrils further interact and form amorphous aggregates.

Binding of methimazole and NADP(H) to human FMO3: In vitro and in silico studies.

Human flavin-containing monooxygenase isoform 3 (hFMO3) is an important hepatic drug-metabolizing enzyme, catalyzing the monooxygenation of nucleophilic heteroatom-containing xenobiotics. Based on the structure of bacterial FMO, it is proposed that a conserved asparagine is involved in both NADP(H) and substrate binding. In order to explore the role of this amino acid in hFMO3, two mutants were constructed. In the case of N61Q, increasing the steric hindrance above the flavin N5-C4a causes poor NADP(H) binding, destabilizing the catalytic FAD intermediate, whereas the introduction of a negatively charged residue, N61D, interferes mainly with catalytic intermediate formation and its stability. To better understand the substrate-enzyme interaction, in vitro as well as in silico experiments were carried out with methimazole as substrate. Methimazole is a high-affinity substrate of hFMO3 and can competitively suppress the metabolism of other compounds. Our results demonstrate that methimazole Pi-stacks above the isoalloxazine ring of FAD in hFMO3, in a similar way to indole binding to the bacterial FMO. However, for hFMO3 indole is found to act as a non-substrate competitive inhibitor. Finally, understanding the binding mode of methimazole and indole could be advantageous for development of hFMO3 inhibitors, currently investigated as a possible treatment strategy for atherosclerosis.

Determination of methimazole based on electropolymerized-molecularly imprinted polypyrrole modified pencil graphite sensor.

Preparation of a molecularly imprinted polymer (MIP) film and its recognition property for methimazole (MMZ) was investigated. The polypyrrole (PPy) film was prepared by the cyclic voltammetric deposition of pyrrole in the presence of a supporting electrolyte (NaClO4·H2O) with and without MMZ through on a pencil graphite electrode (PGE). A computational study based on density functional theory was developed to evaluate the template-monomer geometry and interaction energy in the prepolymerization mixture. The performance of MIP sensor and non-imprinted polymer (NIP) film was evaluated by differential pulse voltammetry (DPV). The most important parameters controlling the performance of sensor were investigated and optimized. The prepared electrode was used for MMZ measurement by a three-step procedure, including analyte extraction in the electrode, electrode washing and electrochemical measurement of MMZ. The molecularly imprinted film exhibited a high selectivity and sensitivity toward methimazole in the experimental conditions. The calibration curve demonstrated linearity over a concentration range of 0.007-6mM with a correlation coefficient (r2) of 0.9808. The accuracy of the method was studied through spiking blank samples showed recovery of 98% with precision of 4%. Limit of detection based on S/N=3 was obtained 3×10-6M. The proposed sensor was applied successfully to determine MMZ in biological model samples and pharmaceuticals.

Design of anti-thyroid drugs: Binding studies and structure determination of the complex of lactoperoxidase with 2-mercaptoimidazole at 2.30 Å resolution.

Lactoperoxidase (LPO) belongs to mammalian heme peroxidase superfamily, which also includes myeloperoxidase (MPO), eosinophil peroxidase (EPO), and thyroid peroxidase (TPO). LPO catalyzes the oxidation of a number of substrates including thiocyanate while TPO catalyzes the biosynthesis of thyroid hormones. LPO is also been shown to catalyze the biosynthesis of thyroid hormones indicating similar functional and structural properties. The binding studies showed that 2-mercaptoimidazole (MZY) bound to LPO with a dissociation constant of 0.63 µM. The inhibition studies showed that the value of IC50 was 17 µM. The crystal structure of the complex of LPO with MZY showed that MZY bound to LPO in the substrate-binding site on the distal heme side. MZY was oriented in the substrate-binding site in such a way that the sulfur atom is at a distance of 2.58 Å from the heme iron. Previously, a similar compound, 3-amino-1,2,4-triazole (amitrole) was also shown to bind to LPO in the substrate-binding site on the distal heme side. The amino nitrogen atom of amitrole occupied the same position as that of sulfur atom in the present structure indicating a similar mode of binding. Recently, the structure of the complex of LPO with a potent antithyroid drug, 1-methylimidazole-2-thiol (methimazole, MMZ) was also determined. It showed that MMZ bound to LPO in the substrate-binding site on the distal heme side with 2 orientations. The position of methyl group was same in the 2 orientations while the positions of sulfur atom differed indicating a higher preference for a methyl group.

Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells.

Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity indicating that the IL-6 inhibition is not via a toxic effect. Flow cytometric analysis and QRT-PCR revealed that the TNBC cell lines do not express the IL-6 receptor (IL-6Rα). Trans-AM assays suggested that COB-141 exerts its inhibitory effect, at least in part, by reducing NF-κB (p65/p50) DNA binding. In summary, COB-141 is a potent inhibitor of TNBC cell expressed IL-6 and the inhibition does not appear to be due to non-specific toxicity. The TNBC cell lines do not have an intact classical IL-6 signaling pathway. COB-141's inhibitory effect may be due, at least in part, to reducing NF-κB (p65/p50) DNA binding.

Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder.

A near loss of smell may result from conductive and/or neural olfactory disorders. However, an olfactory test to selectively detect neural disorders has not been established. We investigated whether onset latency of sensory response to intravenous odor injection can detect neural disorders in humans and mice. We showed that longer preoperative onset latency of odor recognition to intravenous odor in patients with chronic rhinosinusitis predicted worse recovery of olfactory symptoms following sinus surgery. The onset latency of the olfactory sensory neuron (OSN) response to intravenous odor using synaptopHluorin signals from OSN axon terminals was delayed in mice with reduced numbers of OSNs (neural disorder) but not with increased mucus or blocked orthonasal pathways (conductive disorders). Moreover, the increase in onset latency correlated with the decrease in mature OSN numbers. Longer onset latency to intravenous odor injection is a useful biomarker for presence and severity of olfactory disorders with neural etiology.

Novel synthetic kojic acid-methimazole derivatives inhibit mushroom tyrosinase and melanogenesis.

In this study, two kojic acid-methimazole (2-mercapto-1-methylimidazole, MMI, 1) derivatives, 5-hydroxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 4) and 5-methoxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 5), were synthesized to examine their inhibitory kinetics on mushroom tyrosinase. Compound 4 exhibited a potent inhibitory effect on monophenolase activity in a dose-dependent manner, with an IC50 value of 0.03 mM. On diphenolase activity, compound 4 exhibited a less inhibitory effect (IC50 = 1.29 mM) but was stronger than kojic acid (IC50 = 1.80 mM). Kinetic analysis indicated that compound 4 was both as a noncompetitive monophenolase and diphenolase inhibitor. By contrast, compound 5 exhibited no inhibitory effects on mushroom tyrosinase activity. The IC50 value of compound 4 for the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was 4.09 mM, being much higher than the IC50 of compound 4 for inhibiting the tyrosinase activity. The results indicated that the antioxidant activity of compound 4 may be partly related to the potent inhibitory effect on mushroom tyrosinase. Compound 4 also exerted a potent inhibitory effect on intracellular melanin formation in B16/F10 murine melanoma cells, and caused no cytotoxicity. Furthermore, compound 4 induced no adverse effects on the Hen's egg test-chorioallantoic membrane (HET-CAM).

Kinetics and Mechanism of Oxidation of Methimazole by Chlorite in Slightly Acidic Media.

The kinetics and mechanism of the oxidation of methimazole (1-methyl-3H-imidazole), MMI, by chlorite in mildly acidic environments were studied. It is a complex reaction that gives oligo-oscillations in chlorine dioxide concentrations in excess chlorite conditions. The stoichiometry is strictly 2:1, with the sulfur center being oxidized to sulfate and the organic moiety being hydrolyzed to several indeterminate species. In excess MMI conditions over chlorite, the sulfinic acid and sulfonic acid were observed as major intermediates. The sulfenic acid, which was observed in the electrochemical oxidation of MMI, was not observed with chlorite oxidations. Initial reduction of chlorite produced HOCl, an autocatalytic species in chlorite oxidations. HOCl rapidly reacts with chlorite to produce chlorine dioxide, which, in turn, reacts rapidly with MMI to produce more chlorite. The reaction of chlorine dioxide with MMI is competitive, in rate, with the chlorite-MMI and HOCl-ClO2(-) reactions. This explains the oligo-oscillations in ClO2 concentrations.

Raman and DFT study of methimazole chemisorbed on gold colloidal nanoparticles.

The adsorption of methimazole on gold colloidal nanoparticles was investigated using a combination of surface-enhanced Raman scattering and density functional theory calculations, which allowed identifying the thiolate anion as the molecular species chemically interacting with the active sites of the gold surface, modeled as zero-charge metal adatoms, only through the sulfur atom. This result can be important for the use of these ligand/metal nanohybrids in the process of drug delivery. Moreover, functionalized gold nanoparticles are able to promote the Raman enhancement in the red-light region as well as in the near-infrared, where generally no fluorescence emission occurs. This paves the way for the use of these nanosystems in a biological environment, even in vivo experiments.

Evaluation of the Most Frequently Prescribed Extemporaneously Compounded Veterinary Medications at a Large Independent Community Pharmacy.

Extemporaneous drug formulation is essential to provide optimal pharmaceutical care to veterinary patients. The need for this is exacerbated by the fact that commercially produced veterinary-specific products, without a human indication, require specialty veterinary manufacturing facilities and a new animal drug application process to gain marketing approval. This study examined the prescription patterns of extemporaneously compounded veterinary preparations in the compounding department at a large independent community pharmacy. Data was obtained from a total of 1348 prescriptions requiring extemporaneous compounding over the course of a two-year period (2014-2015). A database was constructed and each compounded prescription was allocated to a therapeutic category based on the American Hospital Formulary Service Drug Information. Data analysis showed that the most commonly prescribed preparations belonged to the central nervous system (39%), anti-infective agents (21%), and hormones (12%) therapeutic categories. Overall, suspensions were the most dispensed (47%), extemporaneously compounded dosage forms followed by solutions (28%), and capsules (10%). The majority (88%) of compounded preparations were administered by the oral route. The top three drugs that are compounded for veterinary medicine were (1) potassium bromide oral solution for canine epilepsy, (2) methimazole solution used to treat hyperthyroidism in cats, and (3) metronidazole suspension, an antibiotic for the treatment of diarrhea and other infections in dogs and cats. Remarkably, our findings are in good agreement with previously published survey data on the top drugs that are compounded for veterinary medicine. In the era of personalized medicine, veterinary extemporaneous compounding for specialized needs will continue to play an important role providing optimum therapy for veterinary patients.

Anti-thyroid and antifungal activities, BSA interaction and acid phosphatase inhibition of methimazole copper(II) complexes.

It has been reported that various metal coordination compounds have improved some biological properties. A high activity of acid phosphatase (AcP) is associated to several diseases (osteoporosis, Alzheimer's, prostate cancer, among others) and makes it a target for the development of new potential inhibitors. Anti-thyroid agents have disadvantageous side effects and the scarcity of medicines in this area motivated many researchers to synthesize new ones. Several copper(II) complexes have shown antifungal activities. In this work we presented for a first time the inhibition of AcP and the anti-thyroid activity produced by methimazole-Cu(II) complexes. Cu-Met ([Cu(MeimzH)2(H2O)2](NO3)2·H2O) produces a weak inhibition action while Cu-Met-phen ([Cu(MeimzH)2(phen)(H2O)2]Cl2) shows a strong inhibition effect (IC50 = 300 µM) being more effective than the reported behavior of vanadium complexes. Cu-Met-phen also presented a fairly good anti-thyroid activity with a formation constant value, Kc=1.02 × 10(10)M(-1) being 10(6) times more active than methimazole (Kc = 4.16 × 10(4)M(-1)) in opposition to Cu-Met which presented activity (Kc=9.54 × 10(3)M(-1)) but in a lesser extent than that of the free ligand. None of the complexes show antifungal activity except Cu-phen (MIC = 11.71 µgmL(-1) on Candidaalbicans) which was tested for comparison. Besides, albumin interaction experiments denoted high affinity toward the complexes and the calculated binding constants indicate reversible binding to the protein.

Simple modifications to methimazole that enhance its inhibitory effect on tumor necrosis factor-α-induced vascular cell adhesion molecule-1 expression by human endothelial cells.

The expression of vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium can be increased by pro-inflammatory cytokines [e.g. tumor necrosis factor-α (TNF-α)]. VCAM-1 contributes to leukocyte adhesion to, and emigration from, the vasculature which is a key aspect of pathological inflammation. As such, a promising therapeutic approach for pathological inflammation is to inhibit the expression of VCAM-1. Methimazole [3-methyl-1, 3 imidazole-2 thione (MMI)] is routinely used for the treatment of Graves׳ disease and patients treated with MMI have decreased levels of circulating VCAM-1. In this study we used cultured human umbilical vein endothelial cells (HUVEC) to investigate the effect of MMI structural modifications on TNF-α induced VCAM-1 expression. We found that addition of a phenyl ring at the 4-nitrogen of MMI yields a compound that is significantly more potent than MMI at inhibiting 24h TNF-α-induced VCAM-1 protein expression. Addition of a para methoxy to the appended phenyl group increases the inhibition while substitution of a thiazole ring for an imidazole ring in the phenyl derivatives yields no clear difference in inhibition. Addition of the phenyl ring to MMI appears to increase toxicity as does substitution of a thiazole ring for an imidazole ring in the phenyl MMI derivatives. Each of the compounds reduced TNF-α-induced VCAM-1 mRNA expression and had a functional inhibitory effect, i.e. each inhibited monocytic cell adhesion to 24h TNF-α-activated HUVEC under fluid flow conditions. Combined, these studies provide important insights into the design of MMI-related anti-inflammatory compounds.

Inhibitory effects of novel synthetic methimazole derivatives on mushroom tyrosinase and melanogenesis.

In this study, we synthesized 4 methimazole (2-mercapto-1-methylimidazole, MMI) derivatives. The kinetics of inhibition on mushroom tyrosinase by methimazole and its derivatives were investigated. The results indicated that tert-butyl 3-methyl-2-sulfanylidene-2,3-dihydro-1H-imidazole-1-carboxylate (compound 3; 3), 2-mercaptoimidazole (MI; compound 1; 1) and MMI (compound 2; 2) significantly inhibited tyrosinase activity in a dose-dependent manner, exhibiting an IC50 value of 1.50mM, 4.11 mM, and 1.43 mM. However, compound 4 (4), compound 5 (5), and compound 6 (6) exerted no inhibitory effect on mushroom tyrosinase activity. Kinetic analysis indicated that 3 was a noncompetitive tyrosinase inhibitor, whereas both 1 and 2 were exhibited as mixed-type tyrosinase inhibitors. Furthermore, 3 exerted a potent inhibitory effect on intracellular melanin formation in the B16/F10 murine melanoma cells and did not cause cytotoxicity, as 1 and 2 did.

Development of a thyroperoxidase inhibition assay for high-throughput screening.

High-throughput screening (HTPS) assays to detect inhibitors of thyroperoxidase (TPO), the enzymatic catalyst for thyroid hormone (TH) synthesis, are not currently available. Herein, we describe the development of a HTPS TPO inhibition assay. Rat thyroid microsomes and a fluorescent peroxidase substrate, Amplex UltraRed (AUR), were employed in an end-point assay for comparison to the existing kinetic guaiacol (GUA) oxidation assay. Following optimization of assay metrics, including Z', dynamic range, and activity, using methimazole (MMI), the assay was tested with a 21-chemical training set. The potency of MMI-induced TPO inhibition was greater with AUR compared to GUA. The dynamic range and Z' score with MMI were as follows: 127-fold and 0.62 for the GUA assay, 18-fold and 0.86 for the 96-well AUR assay, and 11.5-fold and 0.93 for the 384-well AUR assay. The 384-well AUR assay drastically reduced animal use, requiring one-tenth of the rat thyroid microsomal protein needed for the GUA 96-well format assay. Fourteen chemicals inhibited TPO, with a relative potency ranking of MMI > ethylene thiourea > 6-propylthiouracil > 2,2',4,4'-tetrahydroxy-benzophenone > 2-mercaptobenzothiazole > 3-amino-1,2,4-triazole > genistein > 4-propoxyphenol > sulfamethazine > daidzein > 4-nonylphenol > triclosan > iopanoic acid > resorcinol. These data demonstrate the capacity of this assay to detect diverse TPO inhibitors. Seven chemicals acted as negatives: 2-hydroxy-4-methoxybenzophenone, dibutylphthalate, diethylhexylphthalate, diethylphthalate, 3,5-dimethylpyrazole-1-methanol, methyl 2-methyl-benzoate, and sodium perchlorate. This assay could be used to screen large numbers of chemicals as an integral component of a tiered TH-disruptor screening approach.

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.

The efficacy and safety of a novel lipophilic formulation of methimazole for the once daily transdermal treatment of cats with hyperthyroidism.

BACKGROUND: Previous studies on transdermal methimazole have used pluronic lecithin organogel as the vehicle. This might not be the most suitable vehicle for a lipophilic drug, such as methimazole. HYPOTHESIS/OBJECTIVES: Once daily transdermal administration of a novel lipophilic formulation of methimazole is as safe and effective as oral carbimazole in treating hyperthyroidism in cats. ANIMALS: Forty-five client-owned cats diagnosed with hyperthyroidism. METHODS: Prospective study. Cats with newly diagnosed, untreated hyperthyroidism were treated with carbimazole (5 mg p.o., q12h) or methimazole (10 mg) applied to the inner pinnae q24h. Cats were examined after 0, 1, 4, 8, and 12 weeks of treatment. Clinical signs, body weight, systolic blood pressure, hematologic, serum biochemical and urine parameters, total serum thyroxine concentrations (TT4), and serum methimazole concentrations were recorded. RESULTS: No significant differences between groups were detected at day 0. Both formulations were effective in treating hyperthyroidism. No significant differences were detected in thyroxine concentrations, body weight, blood pressure, heart rate, alkaline phosphatase, alanine aminotransferase, creatinine, urea, and urine specific gravity (USG) between groups. The serum methimazole concentrations correlated poorly with TT4-concentrations in both groups. CONCLUSIONS AND CLINICAL IMPORTANCE: In this 12-week trial, once daily application of a novel formulation of transdermal methimazole applied to the pinnae was as effective and safe as twice daily oral carbimazole in the treatment of cats with hyperthyroidism. This novel formulation and transdermal application could have practical advantages to some pet owners.