BACKGROUND: Methimazole, an oral antithyroid drug, has recently gained attention for its skin-brightening effects when applied topically to treat melasma. This study aims to develop, optimize, and characterize a methimazole microemulsion as a novel, safe approach for local melasma treatment.
METHODS: We prepared microemulsion formulations containing 3% methimazole by combining appropriate amounts of surfactants (Tween 80 and Span 20), propylene glycol cosurfactant, and an oil phase (oleic acid-transcutol p at a 1:10 ratio). We then assessed droplet size, stability, viscosity, and skin permeation using rat skin models.
RESULTS: The microemulsions\' droplet sizes ranged from 7.06 to 28.13 nm, with viscosities between 120 and 254 centipoises. Our analysis identified droplet size, viscosity, and membrane release as significant independent variables. We determined the permeability parameters of the optimal formulation through rat skin, including steady-state permeability rate (Jss), permeability coefficient (p), lag time (Tlag), and apparent diffusion coefficient (Dapp).
CONCLUSIONS: We found that the microemulsions\' characteristics, physicochemical properties, and in vitro release depended on the surfactant-to-cosurfactant ratio, water content, and oil content. We developed an optimal formulation with a high surfactant-to-cosurfactant ratio and low water and oil percentages. This formulation shows potential for commercialization and manufacturing of final products.

With the help of electrochemical methods, including CV and EIS, the influence of methimazole, carbimazole, and the concentration of the supporting electrolyte on the kinetics and mechanism of zinc electroreduction on a mercury electrode was compared and analyzed. Moreover, molecular dynamics simulations of zinc/carbimazole and zinc/methimazole solutions were carried out to determine the effect of drugs on the hydration sphere of Zn2+ ions. It was shown that the electroreduction of Zn2+ in the presence of methimazole and carbimazole occurs in two steps and the first one determines the kinetics of the entire process. The presence of both drugs in the solution and the increase in the concentration of the supporting electrolyte reduce the degree of hydration of the depolarizer ions and the hydration of the electrode surface, what is a factor favoring the rate of electroreduction. Based on theoretical studies, the formation of stable complexes between Zn2+ and the molecules of both drugs in a solution was considered unlikely. However, active complexes can be formed between depolarizer ions and molecules adsorbed at the electrode surface. They constitute a bridge facilitating charge exchange during the electrode reaction, revealing the catalytic abilities of methimazole and carbimazole. In the range of cdrug ≤ 1 × 10-3 mol dm-3, carbimazole is a better catalyst, whereas in the range of cdrug ≥ 5 × 10-3 mol dm-3, it is methimazole. The effectiveness of both compounds in catalyzing the first stage of the electrode reaction increases with the increase in the NaClO4 concentration.

Propylthiouracil (PTU) and methimazole (MMI), two classical antithyroid agents possess risk of drug-induced liver injury (DILI) with unknown mechanism of action. This study aimed to examine and compare their hepatic toxicity using a quantitative system toxicology approach. The impact of PTU and MMI on hepatocyte survival, oxidative stress, mitochondrial function and bile acid transporters were assessed in vitro. The physiologically based pharmacokinetic (PBPK) models of PTU and MMI were constructed while their risk of DILI was calculated by DILIsym, a quantitative systems toxicology (QST) model by integrating the results from in vitro toxicological studies and PBPK models. The simulated DILI (ALT >2 × ULN) incidence for PTU (300 mg/d) was 21.2%, which was within the range observed in clinical practice. Moreover, a threshold dose of 200 mg/d was predicted with oxidative stress proposed as an important toxic mechanism. However, DILIsym predicted a 0% incidence of hepatoxicity caused by MMI (30 mg/d), suggesting that the toxicity of MMI was not mediated through mechanism incorporated into DILIsym. In conclusion, DILIsym appears to be a practical tool to unveil hepatoxicity mechanism and predict clinical risk of DILI.

BACKGROUND: Methimazole is an antithyroid drug known to cause hematological toxicity, including agranulocytosis and, very rarely, pancytopenia. We herein present a case of a patient with Graves\' Disease (GD) who developed methimazole-induced pancytopenia.
METHODS: A 53-year-old Peruvian woman with GD, initially treated with methimazole 20 mg BID, experienced odynophagia, fever, and malaise after 37 days of treatment. The initial diagnosis was agranulocytosis, leading to the discontinuation of methimazole and initiation of antibiotics. Due to persistent neutropenia, a Granulocyte Colony-stimulating Factor (G-CSF) was administered. Eight days later, she developed pancytopenia and was managed with hematopoietic agents and platelet transfusions. The patient recovered with normalization of the blood count, eliminating the need for Bone Marrow (BM) examination. Radioiodine therapy was chosen as the definitive treatment, resulting in hypothyroidism. Currently, the patient is thyroidal and hematologically stable.
CONCLUSIONS: Methimazole-induced pancytopenia is a rare and serious complication; however, with appropriate treatment, complete recovery can be achieved.

Amiodarone is a class III anti-arrhythmic drug found to be effective in treating multiple life-threatening arrhythmias, including paroxysmal atrial fibrillation. Despite its effectiveness, amiodarone has been found to result in thyroid dysfunction. Amiodarone-induced thyrotoxicosis (AIT) is classified as type 1, which often develops in those with autoimmune hyperthyroid conditions, or type 2, which occurs because of destructive thyroiditis in an apparently normal thyroid. Differentiating between both types often poses a clinical and therapeutic dilemma, as AIT 1 is treated with thionamides, whereas AIT 2 requires steroids for treatment. We present a case of a patient with AIT who was treated empirically for both subtypes with methimazole and prednisone without clinical improvement. Methimazole was later stopped due to concern for agranulocytosis, and the patient was then treated with cholestyramine, metoprolol, and prednisone. Given persistent thyrotoxicosis, the decision was made to proceed with surgical intervention. The patient underwent a successful total thyroidectomy without complications. The patient\'s condition clinically improved post-surgery and was discharged home on post-operative day 2 in stable condition. Prednisone was tapered over two weeks, and he was started on a weight-based dose of levothyroxine. He continues to follow up in our clinic for postoperative hypothyroidism and is clinically and biochemically euthyroid.

We describe the clinical presentation and evaluation of a 10-year-old boy who presented to our medical center with years of progressive proximal muscle weakness, muscle atrophy, and weight loss. In addition to a myopathic phenotype, he was found to have tachycardia, tremor, and learning difficulties. Electromyography revealed chronic myopathic changes and laboratory screening was notable for undetectable thyroid stimulating hormone. Follow-up testing revealed elevated thyroid peroxidase antibodies and thyroid stimulating immunoglobulins. Ultrasound examination revealed an enlarged heterogeneous thyroid gland. Four weeks after treatment with atenolol and methimazole, his strength and cognition began to improve. This case highlights the importance of evaluating for potentially reversible toxic-metabolic etiologies in children presenting with any progressive neurologic symptoms.

Lifelong neurogenesis endows the mouse olfactory system with a capacity for regeneration that is unique in the mammalian nervous system. Throughout life, olfactory sensory neurons (OSNs) are generated from olfactory epithelium (OE) stem cells in the nose, while the subventricular zone generates neuroblasts that migrate to the olfactory bulb (OB) and differentiate into multiple populations of inhibitory interneurons. Methimazole (MMZ) selectively ablates OSNs, but OE neurogenesis enables OSN repopulation and gradual recovery of OSN input to the OB within 6 weeks. However, it is not known how OB interneurons are affected by this loss and subsequent regeneration of OSN input following MMZ treatment. We found that dopaminergic neuron density was significantly reduced 7-14 days post-MMZ but recovered substantially at 35 days. The density of parvalbumin-expressing interneurons was unaffected by MMZ; however, their soma size was significantly reduced at 7-14 days post-MMZ, recovering by 35 days. Surprisingly, we found a transient increase in the density of calretinin-expressing neurons in the glomerular and external plexiform layers, but not the granule cell layer, 7 days post-MMZ. This could not be accounted for by increased neurogenesis but may result from increased calretinin expression. Together, our data demonstrate cell type- and layer-specific changes in OB interneuron density and morphology after MMZ treatment, providing new insight into the range of plasticity mechanisms employed by OB circuits during loss and regeneration of sensory input.

UNASSIGNED: Pseudo-orthostatic tremor is a hyperkinetic movement disorder usually associated with other neurological comorbidities, mainly Parkinson\'s disease.
UNASSIGNED: A 65-year-old male presented with unsteadiness and leg tremor while standing. Electrophysiological evaluation confirmed the presence of pseudo-orthostatic tremor. Blood test showed an undiagnosed Graves\' disease. A complete remission of tremor was achieved with methimazole. Dopamine transporter scintigraphy showed a mild reduction of the striatal binding, bilaterally.
UNASSIGNED: Graves\' disease can be associated with pseudo-orthostatic tremor. Thyroid function should be assessed in patients complaining of unsteadiness. The causative role of hyperthyroidism in determining dopaminergic degeneration and uncovering subclinical parkinsonism warrants further investigations.

Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.

Graves\' disease (GD), an autoimmune thyroid disease, is one of the main autoimmune diseases in the general population. It is known that the pathophysiology of this disease may be related to immunological mechanisms dysregulation. These mechanisms can be influenced by GD therapies, such as iodide or antithyroid drugs (ATD).
OBJECTIVE: Verify relation between clinical, biochemical and treatment modalities used prior to surgery and histopathological characteristics observed in total thyroidectomy products from patients previously diagnosed with Graves\' disease. Furthermore, these data were related to composition of lymphocytic infiltrate in terms of proportions of lymphocytes CD4+, CD8+, CD25+ and CD20+. We aim to contribute to the understanding of the evolution pattern of GD, whose pathophysiology is not yet completely understood.
METHODS: Cross-sectional study assessing thyroidectomy products for the presence of lymphocytic infiltrate, as well as the proportion and intensity of CD4+, CD8+, CD25+ and CD20+ markers. We selected 50 patients who underwent total or partial thyroidectomy in a tertiary service between 1996 and 2013 due to GD with histopathological confirmation. The control group (non-autoimmune disease group) consisted of 12 patients with histopathological data compatible with normal perilesional thyroid parenchyma. The intensity of lymphocytic infiltrate and immunohistochemical expression of the markers CD4+ (helper T lymphocytes), CD8+ (cytotoxic T lymphocytes), CD25+ (regulatory T lymphocytes) and CD20+ (B lymphocytes) were retrospectively evaluated and relationship with ultrasound, laboratory and clinical data was assessed.
RESULTS: No differences were found in intensity, presence of lymphoid follicles, and expression of CD4+/CD8+/CD25+ in patients with GD who did or did not use ATD or iodide. In the group that did not use ATD, a higher proportion of CD20+ expression was found. The GD group was associated with hyperplastic epithelium and the control group was associated with simple epithelium. There was no difference in ultrasound thyroid volume between the groups. In GD patients with mild lymphocytic infiltrate, higher free thyroxin (FT4) levels were observed than those in patients with no infiltrate or moderate infiltrate.
CONCLUSIONS: We found a lower proportion of intrathyroidal CD20+ B lymphocytes in patients under use of methimazole. However, no difference was observed in intrathyroidal lymphocyte subpopulations related to the short-term use of iodide. The understanding of thyroid autoimmunity, as well as identifying points of pharmacological modulation, are very important for advancement and improvement in treatments for these diseases.