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La Clinica Terapeutica 2019Type-1 helper (Th1) dependent chemokines, such as monokine induced by interferon (IFN)-γ (MIG) seem to contribute to the Graves' disease (GD) pathogenesis. The... (Review)
Review
Type-1 helper (Th1) dependent chemokines, such as monokine induced by interferon (IFN)-γ (MIG) seem to contribute to the Graves' disease (GD) pathogenesis. The thyrocytes secrete the chemokine (C-X-C motif) ligand (CXCL)10 under the IFN-γ influence. Therefore, high levels of MIG in peripheral liquids indicate a Th1 orientated immune response and are associated with the active phase of GD in hyperthyroid patients (newly diagnosed and relapsing). Methimazole (MMI), used for the hyperthyroidism treatment, causes a reduction of the MIG secretion by isolated thyrocytes, a decrease of serum MIG levels and leads to a shift from a Th1 to Th2 response in patients with GD in the active phase. The Th1 lymphocytes recruited in the tissues enhance the IFN-γ and tumor necrosis factor (TNF)-α production, that in turn stimulate MIG secretion from these cells; this mechanism originates an amplification feedback loop, causing a perpetuation of the autoimmune process. It has been seen that peroxisome proliferator-activated receptors (PPAR)-γ and PPAR-α activators can modulate the IFN-γ induced MIG secretion in vitro, in GD thyrocytes. More studies are needed to examine the interactions between cytokines and chemokines in the GD pathogenesis and to evaluate the role of MIG as a new therapeutic target.
Topics: Antithyroid Agents; Antiviral Agents; Chemokine CXCL10; Chemokine CXCL9; Graves Disease; Humans; Methimazole; Th1 Cells
PubMed: 31304517
DOI: 10.7417/CT.2019.2149 -
Frontiers in Endocrinology 2023The use of iodinated contrast media (ICM) can lead to thyrotoxicosis, especially in patients with risk factors, such as Graves' disease, multinodular goiter, older age,...
INTRODUCTION
The use of iodinated contrast media (ICM) can lead to thyrotoxicosis, especially in patients with risk factors, such as Graves' disease, multinodular goiter, older age, and iodine deficiency. Although hyperthyroidism may have clinically relevant effects, whether high-risk patients should receive prophylactic treatment before they are administered ICM is still debated.
AIM OF THE STUDY
We aimed to demonstrate the safety and efficacy of prophylactic treatment with sodium perchlorate and/or methimazole to prevent ICM-induced hyperthyroidism (ICMIH) in a population of high-risk cardiac patients. We ran a cost analysis to ascertain the most cost-effective prophylactic treatment protocol. We also aimed to identify possible risk factors for the onset of ICMIH.
MATERIALS AND METHODS
We performed a longitudinal retrospective study on 61 patients admitted to a tertiary-level cardiology unit for diagnostic and/or therapeutic ICM-procedures. We included patients with available records of thyroid function tests performed before and after ICM were administered, who were at high risk of developing ICMIH. Patients were given one of two different prophylactic treatments (methimazole alone or both methimazole and sodium perchlorate) or no prophylactic treatment. The difference between their thyroid function at the baseline and 11-30 days after the ICM-related procedure was considered the principal endpoint.
RESULTS
Twenty-three (38%) of the 61 patients were given a prophylactic treatment. Thyroid function deteriorated after the administration of ICM in 9/61 patients (15%). These cases were associated with higher plasma creatinine levels at admission, higher baseline TSH levels, lower baseline FT4 levels, and no use of prophylactic treatment. The type of prophylaxis provided did not influence any onset of ICMIH. A cost-benefit analysis showed that prophylactic treatment with methimazole alone was less costly per person than the combination protocol. On multivariate analysis, only the use of a prophylactic treatment was independently associated with a reduction in the risk of ICMIH. Patients not given any prophylactic treatment had a nearly five-fold higher relative risk of developing ICMIH.
CONCLUSION
Prophylactic treatment can prevent the onset of ICMIH in high-risk populations administered ICM. Prophylaxis is safe and effective in this setting, especially in cardiopathic patients. Prophylaxis with methimazole alone seems to be the most cost-effective option.
Topics: Humans; Contrast Media; Methimazole; Retrospective Studies; Hyperthyroidism; Graves Disease; Risk Factors
PubMed: 37255974
DOI: 10.3389/fendo.2023.1154251 -
Diabetes Therapy : Research, Treatment... Dec 2019Diabetes mellitus (DM) and thyroid dysfunction (TD) often tend to coexist in patients. Both hypothyroidism and hyperthyroidism are more common in type 2 diabetes... (Review)
Review
Diabetes mellitus (DM) and thyroid dysfunction (TD) often tend to coexist in patients. Both hypothyroidism and hyperthyroidism are more common in type 2 diabetes mellitus (T2DM) patients than in their nondiabetic counterparts. Current guidelines are neither clear nor specific about the frequency of thyroid function monitoring in T2DM patients. Circulating thyroid hormones affect several different organs and cells, have a major impact on glucose, lipid, and protein metabolism, and can worsen glycaemic control in T2DM. Hyperthyroidism and thyrotoxicosis can worsen subclinical DM and cause hyperglycaemia in T2DM patients, increasing the risk of diabetic complications. T2DM reduces thyroid-stimulating hormone levels and impairs the conversion of thyroxine (T4) to triiodothyronine (T3) in the peripheral tissues. Poorly managed T2DM can lead to insulin resistance and hyperinsulinaemia, which causes thyroid tissue proliferation and increases nodule formation and goitre size. In addition, while metformin can be beneficial in both T2DM and TD patients, other antidiabetics such as sulfonylureas, pioglitazone, and thiazolidinediones can negatively impact TD. Antithyroid drugs such as methimazole can impair glycaemic control in T2DM patients. Thyrovigilance in T2DM patients and diabetovigilance in TD patients may therefore be necessary to facilitate individualized care and management.Funding: Abbott India Ltd.
PubMed: 31583645
DOI: 10.1007/s13300-019-00700-4 -
Proceedings (Baylor University. Medical... 2022Thyrotoxic periodic paralysis is a life-threatening complication characterized by acute paralysis of proximal muscles with severe hypokalemia in patients with a known or...
Thyrotoxic periodic paralysis is a life-threatening complication characterized by acute paralysis of proximal muscles with severe hypokalemia in patients with a known or undiagnosed history of thyrotoxicosis. A 24-year-old man was brought to the emergency room with 1 month of progressively worsening lower-extremity weakness followed by urinary retention. He demonstrated severe motor weakness in proximal muscles with absent reflexes. Laboratory testing showed a dangerously low potassium of 1.3 mmol/L. Further testing to establish an etiology revealed a new diagnosis of thyrotoxicosis, and the patient was also started on the antithyroid medication methimazole and propranolol. Immediate oral and intravenous potassium supplementation was initiated to normalize the serum potassium levels to 4.7 mmol/L; that was followed by the gradual recovery of his motor function. This case report highlights the need for early consideration of endocrine and metabolic causes of acute flaccid paralysis.
PubMed: 36304593
DOI: 10.1080/08998280.2022.2095144 -
International Journal of Biological... Oct 2018Human flavin-containing monooxygenase isoform 3 (hFMO3) is an important hepatic drug-metabolizing enzyme, catalyzing the monooxygenation of nucleophilic...
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.
Topics: Amino Acids; Atherosclerosis; Catalysis; Computer Simulation; Flavins; Humans; Indoles; Methimazole; NADP; Oxygenases; Protein Binding; Substrate Specificity
PubMed: 29959003
DOI: 10.1016/j.ijbiomac.2018.06.104 -
Annals of Pediatric Endocrinology &... Sep 2021The first-line antithyroid drug for children and adolescents with Graves' disease (GD) is methimazole (MMI). This study evaluated the relationship between the initial...
PURPOSE
The first-line antithyroid drug for children and adolescents with Graves' disease (GD) is methimazole (MMI). This study evaluated the relationship between the initial MMI dose and the clinical course of GD after treatment.
METHODS
We studied the efficacy of the initial MMI dose and the relationship between the initial MMI dose and adverse events (AEs). We retrospectively enrolled 22 males and 77 females and divided those subjects into 3 groups according to the initial dose of MMI: <0.4 mg/kg/day (group A; n=32); 0.4-0.7 mg/kg/day (group B; n=39); and >0.7 mg/kg/day (group C; n=28).
RESULTS
The mean time to the normalization of free thyroxine (fT4) levels upon initial treatment was 5.64, 8.61, and 7.98 weeks in groups A, B, and C, respectively (P=0.116). The incidence of liver dysfunction, neutropenia, and skin rash was 12.5%, 20.5%, and 42.9% in groups A, B, and C, respectively (P=0.018). Neutropenia, as a severe AE, was absent in group A, but its prevalence was 7.7% in group B and 21.4% in group C (P=0.015). When comparing only groups B and C, the incidences of liver dysfunction and neutropenia were higher in group C (P=0.04 and P=0.021, respectively).
CONCLUSION
The mean time to the normalization of fT4 levels did not differ among the 3 groups, but the incidence of AEs was higher in the groups that received high MMI doses. High doses of MMI (>0.7 mg/kg/day) should be reconsidered as an initial treatment for children and adolescents with GD.
PubMed: 34610704
DOI: 10.6065/apem.2142046.023 -
Journal of Cachexia, Sarcopenia and... Feb 2022Thyroid hormone excess induces protein energy wasting, which in turn promotes muscle weakness and bone loss in patients with Graves' disease. Although most studies have...
BACKGROUND
Thyroid hormone excess induces protein energy wasting, which in turn promotes muscle weakness and bone loss in patients with Graves' disease. Although most studies have confirmed a relationship between thyrotoxicosis and muscle dysfunction, few have measured changes in plasma metabolites and immune cells during the development and recovery from thyrotoxic myopathy. The aim of this study was to identify specific plasma metabolites and T-cell subsets that predict thyrotoxic myopathy recovery in patients with Graves' disease.
METHODS
One hundred patients (mean age, 40.0 ± 14.2 years; 67.0% female), with newly diagnosed or relapsed Graves' disease were enrolled at the start of methimazole treatment. Handgrip strength and Five Times Sit to Stand Test performance time were measured at Weeks 0, 12, and 24. In an additional 35 patients (mean age, 38.9 ± 13.5 years; 65.7% female), plasma metabolites and immunophenotypes of peripheral blood were evaluated at Weeks 0 and 12, and the results of a short physical performance battery assessment were recorded at the same time.
RESULTS
In both patient groups, methimazole-induced euthyroidism was associated with improved handgrip strength and lower limb muscle function at 12 weeks. Elevated plasma metabolites including acylcarnitines were restored to normal levels at Week 12 regardless of gender, body mass index, or age (P trend <0.01). Senescent CD8 CD28 CD57 T-cell levels in peripheral blood were positively correlated with acylcarnitine levels (P < 0.05) and decreased during thyrotoxicosis recovery (P < 0.05). High levels of senescent CD8 T cells at Week 0 were significantly associated with small increases in handgrip strength after 12 weeks of methimazole treatment (P < 0.05), but not statistically associated with Five Times Sit to Stand Test performance.
CONCLUSIONS
Restoring euthyroidism in Graves' disease patients was associated with improved skeletal muscle function and performance, while thyroid hormone-associated changes in plasma acylcarnitines levels correlated with muscle dysfunction recovery. T-cell senescence-related systemic inflammation correlated with plasma acylcarnitine levels and was also associated with small increases in handgrip strength.
Topics: Adult; CD8-Positive T-Lymphocytes; Female; Graves Disease; Hand Strength; Humans; Male; Methimazole; Middle Aged; Muscular Diseases
PubMed: 34970859
DOI: 10.1002/jcsm.12889 -
Frontiers in Immunology 2023A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use...
Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells.
A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer's Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1β and IL-6 mRNA in the brain´s prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APP Alzheimer´s mouse model. In all cases, the improvement in learning capacity was associated with a downregulation of IL-1β mRNA. Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimer´s disease. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNS-related diseases.
Topics: Mice; Animals; Alzheimer Disease; Menthol; Amyloid beta-Protein Precursor; T-Lymphocytes, Regulatory; Mice, Transgenic; Cognition; Immunity
PubMed: 37187754
DOI: 10.3389/fimmu.2023.1130044 -
JCEM Case Reports Mar 2023A 30-year-old man presented with 3-year history of Graves disease. He was initially diagnosed after he developed unilateral proptosis and was initiated on methimazole...
A 30-year-old man presented with 3-year history of Graves disease. He was initially diagnosed after he developed unilateral proptosis and was initiated on methimazole 5 mg, on which he was currently euthyroid. Visible right-sided thyromegaly and trouble swallowing developed 2 months after presentation to our practice. Biochemical evaluation revealed suppressed TSH, normal free T4 and total T3, and elevated thyroid stimulating immunoglobulin with normal thyroid receptor antibody. An ultrasound of the thyroid demonstrated left-sided small nodules with right-sided thyromegaly. A nuclear medicine uptake scan revealed significantly greater uptake in the right thyroid lobe, with overall minimal uptake in the left lobe. The need for definitive therapy that would not exacerbate orbitopathy was discussed, and the patient elected for a right-sided hemithyroidectomy. Postoperative biochemical evaluation demonstrated biochemical euthyroidism despite continued elevation in thyroid stimulating immunoglobulin and newly elevated thyroid receptor antibody while remaining off methimazole. Graves disease can rarely involve a single thyroid lobe. Given the rarity, further investigation is needed to determine the natural course of this form of Graves disease.
PubMed: 37908479
DOI: 10.1210/jcemcr/luad023 -
Biomedicine & Pharmacotherapy =... Aug 20233,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug, however over 200 studies demonstrate that acute (e.g. hyperthermia, rhabdomyolysis) and chronic...
3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug, however over 200 studies demonstrate that acute (e.g. hyperthermia, rhabdomyolysis) and chronic (e.g. neurotoxicity) toxicity effects of MDMA were observed in different animals. Methimazole (MMI), an inhibitor of thyroid hormone synthesis, was found to significantly reduce the HSP72 expression of heat stress induced in fibroblasts. Hence, we attempted to understand the effects of MMI on MDMA induced changes in vivo. Male SD rats were randomly divided into four groups as follows:(a) water-saline (b) water-MDMA (c) MMI-saline and (d) MMI-MDMA group. In the temperature analysis test, MMI was found to alleviate MDMA-induced hyperthermia and increase the heat loss index (HLI), revealing its peripheral vasodilation effect. PET experiment suggested that MDMA induced elevated glucose uptake by skeletal muscles, which was resolved by MMI pretreatment. IHC staining (serotonin transporter, SERT) showed the evidence of neurotoxicity caused by MDMA (serotonin fiber loss), which was alleviated by MMI. Furthermore, the animal behaviour test (forced swimming test, FST) showed higher swimming time but lower immobility time in MMI-MDMA and MMI-saline groups. Taken together, treatment of MMI shows benefits such as lowered body temperature, alleviation of neurotoxicity and excited behaviour. However, further investigations should be conducted in the future to provide in-depth evidence for its clinical use.
Topics: Rats; Male; Animals; N-Methyl-3,4-methylenedioxyamphetamine; Methimazole; Rats, Sprague-Dawley; Body Temperature; Neurotoxicity Syndromes; Hyperthermia, Induced
PubMed: 37224751
DOI: 10.1016/j.biopha.2023.114880