methimazole and Drug-Related-Side-Effects-and-Adverse-Reactions

To compare the therapeutic effect and side effect of the treatments on hyperthyroid exophthalmos with the combination of acupuncture and medication and with medication only.. Fifty-two cases were randomly divided into an acupuncture and medication group (27 cases) and a medication group (25 cases). Acupuncture in combination of oral taking of Thiamazole and Euthyrox were adopted for the acupuncture and medication group. And acupoints such as Jingming (BL 1), Chengqi (ST 1) and Sizhukong (TE 23) etc. were selected. Western medication for oral taking was applied as the only treatment for the medication group. Objective eye syndrome marks, side effects and accidents were compared between two groups before and after treatment.. The improvement of the objective marks of eye syndrome in the acupuncture and medication group was better than that in the medication group (P < 0.01). There were 4 cases with hypoleucocytosis, 3 cases with rash and 3 cases with aggravated symptom of exophthalmos in the medication group during the treatment, while no case with side effects was observed in the acupuncture and medication group. However, 8 cases were found with hemorrhage and 8 with hematoma in the acupuncture and medication group.. Treatment with the combination of acupuncture and medication may not only enhance the therapeutic effect, but also reduce the side effects.

Topics: Acupuncture Points; Acupuncture Therapy; Adult; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Exophthalmos; Female; Graves Ophthalmopathy; Humans; Male; Methimazole; Middle Aged; Thyroxine; Treatment Outcome; Young Adult

Topics: Antithyroid Agents; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; East Asian People; Female; Humans; Hyperthyroidism; Methimazole; Propylthiouracil

The most common cause of hyperthyroidism is Graves' disease. Propylthiouracil (PTU) is one of the drugs used to treat this disease. Leukocytoclastic vasculitis is described among dermatologic adverse effects of PTU.. A 18-year-old woman, allergic to methimazole, developed a vasculitis associated to ANCAs with characteristics of leukocytoclastic vasculitis, associated to PTU treatment. She did not present systemic involvement. PTU treatment was suspended. Two months later, the skin lesions had almost completely resolved.. Leukocytoclastic vasculitis should be considered in the spectrum of complications caused by the consumption of propylthiouracil. The lesions can manifest over time, from a few weeks to years after taking the drug. When there is no systemic involvement, propylthiouracil suspension is sufficient to cure the disease.. La causa más frecuente de hipertiroidismo es la enfermedad de Graves. El propiltiouracilo es uno de los medicamentos más prescritos para esta enfermedad. Uno de los efectos adversos dermatológicos del propiltiouracilo es la vasculitis leucocitoclástica.. Paciente femenina de 18 años, alérgica al metamizol, con vasculitis asociada a ANCAs, con características de vasculitis leucocitoclástica provocada por el consumo de propiltiouracilo. No se observó afectación sistémica. Dos meses después de suspender el propiltiouracilo desaparecieron casi por completo las lesiones en la piel.. La vasculitis leucocitoclástica debe considerarse en el espectro de complicaciones provocadas por el consumo de propiltiouracilo. Las lesiones pueden manifestarse con el paso del tiempo, desde unas semanas hasta años después de consumir el fármaco. Cuando no existe afectación sistémica, la suspensión del propiltiouracilo es suficiente para detener la enfermedad.

Topics: Adolescent; Antithyroid Agents; Drug-Related Side Effects and Adverse Reactions; Female; Graves Disease; Humans; Methimazole; Propylthiouracil; Vasculitis, Leukocytoclastic, Cutaneous

Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins play an essential role in the adaptive immune response for the presentation of self and non-self peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug induced agranulocytosis (severe lower white blood cell count) in patients with B*27:05, B*38:02 and DRB1*08:03 alleles in different populations: Taiwanese, Vietnamese, Han Chinese and Caucasian.. In this study, informatics methods were used to investigate if any sequence or structural similarities exist between the two associated HLA-B alleles, compared with a set of "control" alleles assumed not be associated, which could help explain the molecular basis of the adverse drug reaction. We demonstrated using MHC Motif Viewer and MHCcluster that the two alleles do not have a propensity to bind similar peptides, and thus at a gross level the structure of the antigen presentation region of the two alleles are not similar. We also performed multiple sequence alignment to identify polymorphisms shared by the risk but not by the control alleles and molecular docking to compare the predicted binding poses of the drug-allele combinations.. Two residues, Cys67 and Thr80, were identified from the multiple sequence alignments to be unique to these risk alleles alone. The molecular docking showed the poses of the risk alleles to favour the F-pocket of the peptide binding groove, close to the Thr80 residue, with the control alleles generally favouring a different pocket. The data are thus suggestive that Thr80 may be a critical residue in HLA-mediated anti-thyroid drug induced agranulocytosis, and thus can guide future research and risk assessment.

Topics: Adaptive Immunity; Agranulocytosis; Alleles; Amino Acid Sequence; Antithyroid Agents; Asian People; Binding Sites; Drug-Related Side Effects and Adverse Reactions; Genetic Predisposition to Disease; HLA-B Antigens; Humans; Medical Informatics; Methimazole; Propylthiouracil; Protein Binding; White People

Vasculogenesis and angiogenesis are the processes by which new blood vessels are formed. We have developed a serum-free human adipose stromal cell and umbilical cord vein endothelial cell based vasculogenesis/angiogenesis test. In this study, the test was validated in our GLP laboratory following the OECD Guidance Document 34 [1] using erlotinib, acetylic salicylic acid, levamisole, 2-methoxyestradiol, anti-VEGF, methimazole, and D-mannitol to show its reproducibility, repeatability, and predictivity for humans. The results were obtained from immunostained tubule structures and cytotoxicity assessment. The performance of the test was evaluated using 26 suspected teratogens and non-teratogens. The positive predictive value was 71.4% and the negative predictive value was 50.0%, indicating that inhibition of vasculogenesis is a significant mechanism behind teratogenesis. In conclusion, this test has great potential to be a screening test for prioritization purposes of chemicals and to be a test in a battery to predict developmental hazards in a regulatory context.

Topics: 2-Methoxyestradiol; Adipose Tissue; Aspirin; Cells, Cultured; Culture Media; Drug-Related Side Effects and Adverse Reactions; Erlotinib Hydrochloride; Estradiol; Human Umbilical Vein Endothelial Cells; Humans; Laboratories; Levamisole; Mannitol; Methimazole; Neovascularization, Physiologic; Reproducibility of Results; Serum; Stromal Cells; Teratogens; Toxicity Tests; Umbilical Cord; Vascular Endothelial Growth Factor A

Methimazole is commonly prescribed for patients who are thyrotoxic. Cholestatic hepatitis is a rare but serious adverse event which may be associated with interventional therapy. In this case report, we present two Chinese women with cholestatic jaundice due to methimazole treatment. Both patients had a history of hyperthyroidism; initial laboratory studies of liver function were normal and cholestatic hepatitis occurred after treatment with methimazole. Concomitant liver disease, such as viral hepatitis (A, B, C, D, E), autoimmune hepatitis, primary biliary cirrhosis and calculus of bile duct, were excluded. Liver enzyme levels in both patients returned to normal after stopping methimazole therapy and taking hepatoprotective drugs. It is essential that patients are informed about the earliest symptoms of serious adverse effects of antithyroid drugs, such as hepatic toxicity, and that they are advised to stop taking the drug immediately and contact their physician if such symptoms occur.

Topics: Adult; Anti-Inflammatory Agents; Antithyroid Agents; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis; Humans; Hyperthyroidism; Jaundice, Obstructive; Methimazole; Methylprednisolone; Middle Aged; Prognosis

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Insecta; Rats; Risk Factors

Agranulocytosis is a rare adverse effect of methimazole. The usual duration of treatment prior to the onset of agranulocytosis is approximately 1 to 4 months, and can be as long as 1 year. Agranulocytosis together with hepatotoxicity is an extremely rare idiosyncratic side effect of methimazole treatment. We present an unprecedented case of a Grave's disease patient who showed a strong reaction to methimazole with obvious agranulocytosis and hepatotoxicity which developed only six days after administration. This case, along with a literature review, is offered with the aim to increase the awareness of physicians of sudden onset agranulocytosis and hepatotoxicity from methimazole.

Topics: Adult; Agranulocytosis; Antithyroid Agents; Bone Marrow; Drug-Related Side Effects and Adverse Reactions; Female; Graves Disease; Humans; Liver; Methimazole; Time Factors

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests