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.

Rapid determination of propylthiouracil and methimazole by surface-enhanced Raman scattering based on sodium alginate-protected silver nanoparticles.

A rapid, ultrasensitive and selective method has been established to determine antithyroid drugs [propylthiouracil (PTU) and methimazole (MTZ)] by surface-enhanced Raman scattering (SERS). Silver nanoparticles (AgNPs) were synthesized by reduction of silver nitrate (AgNO3) with sodium alginate (SA) and were used as SERS substrates. Through optimization of the SERS conditions, including the volume of SA-protected AgNPs solution, pH of Britton-Robinson (BR) buffer solution and concentration of NaCl solution, linear responses were obtained for PTU and MTZ in the concentration ranges of 3.02 × 10-9-1.06 × 10-5 mol L-1 and 1.21 × 10-9-1.21 × 10-5 mol L-1, respectively. By the present method, the limits of detection (LODs) for the determination of PTU and MTZ were as low as 1.58 × 10-10 mol L-1 and 2.97 × 10-11 mol L-1. The method was successfully applied for the determination of PTU and MTZ in real samples. The recovery of PTU and MTZ from actual samples ranged between 97.20 and 104.80%, with relative standard deviations (RSDs) less than 3.63%.

Extrapolating In Vitro Screening Assay Data for Thyroperoxidase Inhibition to Predict Serum Thyroid Hormones in the Rat.

Thyroperoxidase (TPO) is an enzyme essential for thyroid hormone (TH) synthesis and a target site for a number of xenobiotics that disrupt TH homeostasis. An in vitro high-throughput screening assay for TPO inhibition, the Amplex UltraRed-TPO (AUR-TPO), has been used to screen the ToxCast chemical libraries for this action. Output from this assay would be most useful if it could be readily translated into an in vivo response, namely a reduction of TH in serum. To this end, the relationship between TPO inhibition in vitro and serum TH decreases was examined in rats exposed to 2 classic TPO inhibitors, propylthiouracil (PTU) and methimazole (MMI). Serum and gland PTU, MMI, and TH levels were quantified using tandem liquid chromatography mass spectrometry. Thyroperoxidase activity was determined in thyroid gland microsomes treated with PTU or MMI in vitro and ex vivo from thyroid gland microsomes prepared from exposed animals. A quantitative model was constructed by contrasting in vitro and ex vivo AUR-TPO results and the in vivo time-course and dose-response analysis. In vitro:ex vivo correlations of AUR-TPO outputs indicated that less than 30% inhibition of TPO in vitro was sufficient to reduce serum T4 by 20%, a degree of regulatory significance. Although further testing of model estimates using other TPO inhibitors is essential for verification of these initial findings, the results of this study provide a means to translate in vitro screening assay results into predictions of in vivo serum T4 changes to inform risk assessment.

Hollow molecularly imprinted polymer based quartz crystal microbalance sensor for rapid detection of methimazole in food samples.

In this study, a novel detection method of methimazole was proposed based on the hollow molecularly imprinted quartz crystal microbalance (QCM) sensor, in which the hollow imprinted polymers (H-MIPs) were firstly prepared through the surface imprinted techniques, using hollow silica spheres as matrix supporting material and methimazole as template molecule. The characterizations of H-MIPs were carefully studied. Compared with traditional MIPs, H-MIPs exhibited faster mass transfer rate and higher adsorption capacity. After coating onto the surface of Au chip, the H-MIPs QCM sensor was fabricated. Based on the frequency shift, good linear behavior in the range of 5-70 µg L-1, limit of detection of 3 µg L-1, and good recoveries of 88.32%-107.96% in the spiked pork, beef and milk were obtained. The analysis process could complete within 8 min. The developed sensor provided an effective, fast and accurate method for the methimazole detection in food samples.

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.

Analysis of thyreostats in bovine feces using ultra high performance liquid chromatography with tandem mass spectrometry.

A method based on ultra-high performance liquid chromatography was developed and validated to detect six thyreostatic compounds: tapazole, thiouracil, methylthiouracil, dimethylthiouracil, propylthiouracil, and phenylthiouracil in faeces of bovine. Thyreostats were extracted from the matrix with a mixture of methanol and buffer (pH = 8). Next step was derivatization of analytes with 3-iodobenzylbromide. The liquid chromatographic separation of derivatives was obtained on a SB-C18 column (50 × 2.1 mm; 1.8 µm, Agilent) with gradient elution using a mobile phase consisting of acetonitrile/0.1% acetic acid within 7.5 min. The analysis was performed on a Shimadzu NEXERA X2 ultra-high performance liquid chromatograph with triple quadrupole MS 8050 instrument operating in positive electrospray ionization mode. Depending on the target compound, two or three diagnostic signals (selected reaction monitoring transitions) were monitored. The procedure was validated according to the Commission Decision 2002/657/EC. Recovery and repeatability met the performance criteria specified by this document for banned compounds. The recovery ranged from 97.5 to 110.5%, and repeatability did not exceed 14.1%. Decision limits and detection capabilities were below 10 µg/kg. The highest decision limits and detection capabilities concentrations were observed for phenylthiouracil of 3.48 and 6.96 µg/kg, respectively.

Sensitive amperometric determination of methimazole based on the electrocatalytic effect of rutin/multi-walled carbon nanotube film.

Electrochemical deposition was used to prepare a glassy carbon electrode modified with multi-walled carbon nanotubes and the glycosidic compound, rutin (R/MWCNTs/GCE). Cyclic voltammetry of the modified electrode in aqueous solution (pH8) showed a pair of well-defined, stable and reversible redox peaks with surface confined characteristics. The catechol moiety of rutin produced the voltammetric peaks via a 2 electron, 2 proton mechanism in the range of 0.0-0.4V (vs. Ag/AgCl). The transfer coefficient (α), heterogeneous electron transfer rate constant (ks), and surface concentration (Γ) for R/MWCNTs/GCE were calculated by using the cyclic voltammetric data. The modified electrode showed excellent catalytic activity toward oxidation of methimazole. Fixed-potential amperometry was used for sub-micromolar determination of methimazole at pH8. Linear dependence of anodic current to methimazole concentration was obtained in the range of 0.1-26µM of the drug with a limit of detection at 18nM. The modified electrode retained its initial response for at least 2weeks if stored in dry ambient conditions. The electrode was used for the amperometric determination of methimazole in formulations and spiked blood serum samples, successfully.

Flow injection analysis of thiamazole based on strong Ru(bpy)3 (2+) co-reactant electrochemiluminescence.

Based on the strong electrochemiluminescence (ECL) reaction between thiamazole and tris(2,2'-bipyridine)ruthenium(II) (Ru(bpy)3 (2+) ), a sensitive, simple and rapid flow injection analysis method for the determination of thiamazole was developed. When a Pt working electrode was maintained at a potential of +1.50 V (vs Ag/AgCl) in pH 12.0 H3 PO4 -NaOH solution containing thiamazole and Ru(bpy)3 (2+) at a flow rate of 1.0 mL/min, a linear range of 2.0 × 10(-7) -1.0 × 10(-4) mol/L with a detection limit of 5.0 × 10(-8) mol/L was obtained for the detection of thiamazole. The method showed good reproducibility with a relative standard deviation (RSD) of 0.75%. The method has been successfully applied to the determination of thiamazole in spiked animal feeds. In addition, a co-reactant ECL mechanism was proposed for the thiamazole-Ru(bpy)3 (2+) system.

A new Methimazole sensor based on nanocomposite of CdS NPs-RGO/IL-carbon paste electrode using differential FFT continuous linear sweep voltammetry.

A Methimazole sensor was designed and constructed based on nanocomposite of carbon, ionic liquid, reduced graphene oxide (RGO) and CdS nanoparticles. The sensor signal was obtained by Differential FFT continuous linear sweep voltammetry (DFFTCLSV) technique. The potential waveform contains two sections, preconcentration potential and potential ramp. In this detection technique, after subtracting the background current from noise, the electrode response was calculated, based on partial and total charge exchanges at the electrode surface. The combination of RGO and CdS nanoparticles can catalyze the electron transfer, which outcomes of the amplification of the sensor signal. The result showed that the sensor response was proportional to the concentrations of Methimazole in the range of 2.0 to 300 nM, with a detection limit of 5.5×10(-10) M. The sensor showed good reproducibility, long-term of usage stability and accuracy. The characterization of the sensor surface was studied by atomic force Microscopy and Electrochemical Impedance Spectroscopy. Moreover, the proposed sensor exhibited good accuracy, and R.S.D value of 2.82%, and the response time of less than 7 s.

A method for the determination of total and reduced methimazole in various biological samples.

A simple, rapid, reproducible and sensitive method based on HPLC with ultraviolet detection was developed for the determination of methimazole (MMI) in animal tissues and plasma samples. Under the optimum experimental conditions, the calibration curves for MMI were linear in the tested range 0.5-20 mg kg(-1) tissue sample (mg l(-1) plasma) with correlation coefficients better than 0.99. The performance of the proposed method was tested for the determination of MMI levels in brain, liver, thyroid gland and plasma of MMI-treated hens, as well as in their eggs and embryos. The proposed method reduces time and simplifies the sample preparation procedure.

Optimization of ion-pair based hollow fiber liquid phase microextraction combined with HPLC-UV for the determination of methimazole in biological samples and animal feed.

Ion-pair based hollow fiber liquid phase microextraction (IP-HFLPME) coupled with high performance liquid chromatography-ultraviolet detection was applied for the preconcentration and determination of methimazole in biological samples and animal feed. Optimization of the conditions for the high extraction efficiency was studied simultaneously using the experimental design. For the first step, the Plackett-Burman design was applied to screen the significant factors on the extraction efficiency. Central composite design (CCD) was then used for the optimization of important factors and the response surface equations were obtained. The optimum experimental conditions were donor phase pH, 12.2; extraction temperature, 45°C; extraction time, 50 min; sodium perchlorate concentration, 1.5 M; cetyltrimethylammonium bromide concentration, 0.65 mM, and without salt addition in donor phase. The limit of detection and the dynamic linear range were in the range of 0.1-0.7 µg L(-1) and 0.5-1000 µg L(-1), respectively. Preconcentration factors were obtained in the range of 93-155 in different matrices. Finally, the performance of the proposed method was tested for the determination of trace amounts of methimazole in plasma, urine, bovine milk, and animal feed samples, and satisfactory results were obtained (RSDs < 7.1%).

Determination of thiamazole in pharmaceutical samples by phosphorus molybdenum blue spectrophotometry.

A novel method is established to determine thiamazole by phosphorus molybdenum blue spectrophotometry. The experiment indicates that PO(4)(3-) reacts with Mo(7)O(24)(6-) in 0.30mol/L H(2)SO(4) solution to form a product with phosphorus-molybdenum heteropoly acid ([H(2)PMo(12)O(40)](-)). Then [H(2)PMo(12)O(40)](-) is deoxidized to form phosphorus molybdenum blue (H(3)PO(4)·10MoO(3)·Mo(2)O(5)) by thiamazole. The amount of thiamazole can be determined based on the absorbance of phosphorus molybdenum blue (λ(max)=710nm). A good linear relationship is obtained between the absorbance and the concentration of thiamazole in the range of 0.035-70µg/mL. The equation of the linear regression is A=0.03384+0.00834c (µg/mL), with a linear correlation coefficient of 0.9990. The apparent molar absorption coefficient is 1.0×10(3)L/(molcm). The method has been successfully applied to the determination of thiamazole in pharmaceutical samples with satisfactory results, and recoveries are in the range of 99.6-100.6%.

Electrochemical determination of methimazole based on the acetylene black/chitosan film electrode and its application to rat serum samples.

A novel method has been developed for the determination of methimazole, which was based on the enhanced electrochemical response of methimazole at the acetylene black/chitosan composite film modified glassy carbon electrode. The electrochemical behavior of methimazole was studied at this film electrode by cyclic voltammetry and differential pulse voltammetry. The experimental results showed that methimazole exhibited a remarkable oxidation peak at 0.63V at the film electrode. Compared with the bare glassy carbon electrode, the oxidation peak current increased greatly, and the peak potential shifted negatively, which indicated that the acetylene black/chitosan film electrode had good catalysis to the electrochemical oxidation of methimazole. The enhanced oxidation current of methimazole was indebted to the nano-porus structure of the composite film and the enlarged effective electrode area. The influences of some experimental conditions on the oxidation of methimazole were tested and the calibration plot was examined. The results indicated that the differential pulse response of methimazole was linear with its concentration in the range of 1.0×10(-7) to 2.0×10(-5)mol/L with a linear coefficient of 0.998, and in the range of 4.0×10(-5) to 3.0×10(-4)mol/L with a linear coefficient of 0.993. The detection limit was 2.0×10(-8)mol/L (S/N=3). The film electrode was used to detect the content of methimazole in rat serum samples by the standard addition method with satisfactory results.

A novel method for sensing of methimazole using gold nanoparticle-catalyzed chemiluminescent reaction.

Based on the inhibition effect of methimazole (MMI) on the reaction of luminol-H(2)O(2) catalyzed by gold nanoparticles, a novel chemiluminescence (CL) method was developed for the determination of MMI. Under the optimum conditions, the relative CL intensity was linearly related to MMI concentration in the range from 5.0 × 10(-8) to 5.0 × 10(-5) mol L(-1). The detection limit was 1.6 × 10(-8) mol L(-1) (S/N=3), and the RSD for 6.0 × 10(-6) mol L(-1) MMI was 4.83 (n=11). This method has high sensitivity, wide linear range, inexpensive instrumentation and has been applied to detect MMI in pharmaceutical tablets and pig serum samples. Furthermore, a possible reaction mechanism is discussed.

Synthesis and characterization of a molecularly imprinted polymer and its application as SPE enrichment sorbent for determination of trace methimazole in pig samples using HPLC-UV.

A novel molecularly imprinted polymer that could be applied as enrichment sorbent was prepared using methimazole (MMZ) as the template molecule, methacrylic acid as functional monomer, ethylene glycol dimethacrylate as cross-linker. Though evaluated by static, kinetic and competitive adsorption tests, the polymer exhibited high adsorption capacity, fast kinetics and good selective ability. A method for determination of trace MMZ was developed using this polymer as enrichment sorbent coupled with high performance liquid chromatography focusing on complex biological matrices. Under the optimum experimental conditions, the MMZ standard is linear within the concentration range studied, that is, from 0.5 microg L(-1) to 150 microg L(-1) (r2=0.9941). Lower limits of detection (LOD, at S/N=3) and quantification (LOQ, at S/N=10) in pig samples were 0.63 microg kg(-1) and 2.10 microg kg(-1) for kidney, 0.51 microg kg(-1) and 1.70 microg kg(-1) for liver, 0.56 microg kg(-1) and 1.86 microg kg(-1) for muscle, respectively. Recoveries and relative standard deviation (RSD, n=9) values for precision in the developed method were from 71.14% to 88.41% and from 2.53% to 6.18%.

Determination of thyreostatics in animal feeds by CE with electrochemical detector.

A simple, rapid, reproducible and sensitive method based on CE with electrochemical detector was developed for the simultaneous determination of five thyreostatics including 2-thiouracil (TU), 6-methyl-2-thiouracil (MTU), 6-propyl-2-thiouracil (PTU), 6-phenyl-2-thiouracil (PhTU) and methimazole (TAP) in animal feeds. A home-made wall-jet electrochemical detector with a 300 microm diameter platinum-disk-working electrode was equipped at the end of separation capillary and used to detect oxidation currents of these thyreostatics. Under the optimum experimental conditions, TU, MTU, PTU, PhTU and TAP could be well separated within 15 min at the separation voltage of 16 kV in 20 mmol/L sodium borate buffer (pH 9.2). The detection limits (S/N=3) of the five thyreostatics in animal feeds were found to be 7.6 microg/kg for TAP, 25 microg/kg for PTU, 15 microg/kg for PhTU, 18 microg/kg for TU and 20 microg/kg for MTU by the developed CE with electrochemical detector method coupled with solid-phase extraction sample pretreatment technique.

Pharmacologic treatment of hyperthyroidism during lactation.

QUESTION: I have a patient who has hyperthyroidism due to Graves disease. She was taking methimazole but discontinued when she found out she was pregnant. She is currently close to delivery and might require antithyroid therapy in the postpartum period. Can methimazole cross into human milk, and is breastfeeding safe for her infant? ANSWER: The exposure of infants to methimazole or propylthiouracil through breast milk is minimal and not clinically significant. Women with hyperthyroidism using methimazole or propylthiouracil should not be discouraged from breastfeeding, as the benefits of breastfeeding largely outweigh the theoretical minimal risks.

Assessment of povidone-iodine disinfectant compatibility with antimicrobial incise drape and adhesion inhibition on the skin using a gas chromatography/mass spectrometry approach.

According to orthopedists' reports, substitution of the original for a generic povidone-iodine (PVP-I) disinfectant could have led to some adhesion problems of antimicrobial incise drapes on the field of operation with the consequence of increasing the infection risk. Three methods have been used to assess the case: (a) a gas chromatography/mass spectrometry (GC-MS) approach quantifying methimazole formation from carbimazole, (b) in vitro adhesion experiments on a smooth glass plate surface and (c) the analysis of intrasurgical procedures. GC-MS results confirmed the higher potency of the original compared to the generic PVP-I. In vitro comparison of the adhesion on a PVP-I-pretreated glass surface showed no difference between the disinfectants and no significant destruction of the adhesive layer. However, due to different surgery preparation procedures, the remaining free skin surface granting sufficient adhesion differed if the intervening surgeon himself or his assistant prepared the field of operation. As a conclusion, the original PVP-I disinfectant is confirmed as the first-choice disinfectant for the field of operation. Adhesion problems were arising with new surgical staff and thus different preparation procedures. Exchanging PVP-I disinfectants cannot explain the adhesion problems of drapes and antimicrobial incise foils on the skin.

MMSPE-RP-HPLC method for the simultaneous determination of methimazole and selected metabolites in fish homogenates.

A simple and rapid high-performance liquid chromatography method with ultraviolet detection was developed for the determination of the thyreostatic compound methimazole (1-methyl-2-mercaptoimidazole, MET) and metabolites 2-mercaptoimidazol (SHMET), N-methylthiourea (MTU) and N-methylhydantoin (MEH) from zebrafish (D. rerio) whole body homogenates using mixed mode solid phase extraction technique for sample pre-treatment. The highly polar compounds were separated on a difunctionally bonded silica based reverse phase column using gradient elution. Retention factors ranged between 1.53 and 5.66. The method was linear between 0.1 and 30 microg/ml, the detection limits were 0.4 ng for MET and SHMET, 0.6 ng for MTU and 2.6 ng for MEH. Extraction method was exhibited average recovery rates of 85.2-97.6%.

Potentiometric and voltammetric determination of methimazole.

The determination of methimazole was investigated by potentiometric titration in an alkaline medium involving its reaction with iodine and square wave voltammetry (SWV) in 0.1 mol/l Tris-HCl buffer at pH 7.2. In potentiometric titration, the range of determination was 10-500 micromol. A stoichiometric reaction was obtained within the concentration range 0.75-1.25 mol/l of sodium hydroxide by potentiometric titration. A linear calibration graph was obtained over the concentration range 1-700 micromol/l by SWV. The lowest concentration of methimazole detected was 0.5 micromol/l. The relative standard deviations (R.S.D.) were 0.81% in potentiometric titration and 2.89% in square wave voltammetric analysis of thyromazol tablets. The data showed that potentiometric titration using iodine in sodium hydroxide can be used for the determination of methimazole in drug samples without prior separation.