Comparison of drug-induced liver injury risk between propylthiouracil and methimazole: A quantitative systems toxicology approach.

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.

Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.

Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

Jagged/Notch proteins promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs.

This study tested the hypothesis that Jagged2/Notches promoted the endothelial-mesenchymal transition (endMT)-mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing the expression of GATA-binding factors which were inhibited by propylthiouracil (PTU) (i.e. 0.1% in water for daily drinking since Day 5 after PAH induction) in rodent. As compared with the control (i.e. HUVECs), the protein expressions of GATAs (3/4/6) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly reduced, whereas the endothelial-phenotype markers (CD31/E-cadherin) were significantly increased in silenced JAG2 gene or in silenced GATA3 gene of HUVECs (all p < 0.001). As compared with the control, the protein expressions of intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 and Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly upregulated in TGF-ß/monocrotaline-treated HUVECs that were significantly reversed by PTU treatment (all p < 0.001). By Day 42, the results of animal study demonstrated that the right-ventricular systolic-blood-pressure (RVSBP), RV weight (RVW) and lung injury/fibrotic scores were significantly increased in MCT group than sham-control (SC) that were reversed in MCT + PTU groups, whereas arterial oxygen saturation (%) and vasorelaxation/nitric oxide production of PA exhibited an opposite pattern of RVW among the groups (all p < 0.0001). The protein expressions of hypertrophic (ß-MHC)/pressure-overload (BNP)/oxidative-stress (NOX-1/NOX-2) biomarkers in RV and the protein expressions of intercellular signalling (GATAs3/4/6, Jagged1/2, notch1/2) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/TGF-ß/α-SMA/p-Smad2) in lung parenchyma displayed an identical pattern of RVW among the groups (all p < 0.0001). Jagged-Notch-GATAs signalling, endMT markers and RVSBP that were increased in PAH were suppressed by PTU.

Long-term outcomes of anti-thyroid drug treatment in childhood-onset Graves' disease.

OBJECTIVE: Outcomes of childhood-onset Graves' disease (GD) and suggested duration of anti-thyroid drug (ATD) therapy have been controversial. This study aimed to determine long-term outcomes following ATD therapy, including remission and relapse rates. DESIGN, PATIENTS AND MEASUREMENTS: A retrospective study of 265 paediatric patients with GD who were initially treated with ATD was conducted. Long-term outcomes were analysed. RESULTS: Median (IQR) age at diagnosis was 11.5 (9.4, 13.7) years. Duration of ATD treatment was 4.3 (2.3, 6.7) years and time since diagnosis to the enrolment was 7.1 (3.8, 10.9) years. There were 77, 93 and 95 patients who underwent definitive treatment, had ATD discontinuation, and were still being treated with ATD, respectively. The remission rate was 21% (56 out of 265 patients) and relapse rate was 40% (37 out of 93 patients). Cumulative incidence of first remission increased with the duration of ATD treatment with maximum remission rate at 5.3 years following ATD therapy. Among patients who experienced relapse, approximately 50% had disease relapse which occurred within 1 year after ATD discontinuation. Patients with goitre size of less than 3.5 cm, thyroid-stimulating hormone receptor antibody of less than 10 IU/L, no ophthalmopathy at diagnosis and methimazole dose requirement of less than 0.25 mg/kg/day at 1 year after treatment were more likely to achieve remission. CONCLUSIONS: Remission rate of childhood-onset GD was relatively low following ATD treatment. Longer-term ATD therapy was associated with increased remission rate. Approximately 50% of patients with relapse had disease relapse within 1 year following ATD discontinuation.

Combined levothyroxine and testosterone treatment for restoring erectile dysfunction in propylthiouracil-induced hypothyroid rats.

BACKGROUND: Sexual dysfunction may indicate severe endocrine diseases. Recent research has suggested a link between hypothyroidism, low testosterone (T) levels, and erectile dysfunction (ED); however, the exact cause is unknown. AIM: We sought to investigate possible beneficial effects of levothyroxine and T alone or in combination on ED in propylthiouracil (PTU)-induced hypothyroid rats. METHODS: Adult Wistar rats (n = 35) were divided into 5 groups: control, PTU-induced hypothyroidism, PTU + levothyroxine, PTU + Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, and decanoate) and PTU + levothyroxine + Sustanon. PTU was given in drinking water for 6 weeks. Four weeks after PTU administration, levothyroxine (20 µg microgram kg/day, oral) and Sustanon (10 mg/kg/week, intramuscular) were given for 2 weeks. Serum levels of total T, triiodothyronine (T3), and thyroxine (T4) were determined. In vivo erectile response and in vitro relaxant responses were measured. Localization of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), and phosphodiesterase type 5 (PDE5) were determined using immunohistochemical analysis. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. OUTCOMES: Outcome variables included in vivo erectile function, in vitro relaxant and contractile responses of corpus cavernosum (CC) strips; protein localization of eNOS, nNOS, and PDE5; and smooth muscle content in penile tissue. RESULTS: The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3, and T4. Levothyroxine increased T3 and T4 levels, whereas Sustanon normalized only total T levels. Combined treatment enhanced all hormone levels. Rats with hypothyroidism displayed the lowest erectile response (P < 0.001 vs controls). Combined treatment returned reduced responses, while partial amelioration was observed after levothyroxine and Sustanon treatment alone. Acetylcholine (P < 0.01 vs controls), electrical field stimulation (P < 0.001 vs controls), and sildenafil-induced relaxant responses (P < 0.05 vs controls) were decreased in the CC strips from hypothyroid rats. The combined treatment increased the reduction in relaxation responses. Levothyroxine and Sustanon restored decreases in eNOS and nNOS expression in the hypothyroid group. There was no significant difference in PDE5 expression among groups. Monotreatment partially enhanced reduced smooth muscle mass, while combined therapy completely recovered. CLINICAL IMPLICATIONS: The combination of thyroid hormones and T is likely to be a therapeutic approach for treatment of hypothyroidism-induced ED in men. STRENGTHS AND LIMITATIONS: Beneficial effects of levothyroxine and Sustanon treatment were shown in vitro and in vivo in PTU-induced hypothyroid rats. The main limitation of the study was the lack of measurement of androgen-sensitive organ weights and luteinizing hormone, follicle-stimulating hormone, and prolactin levels. CONCLUSION: These findings demonstrate that neurogenic and endothelium-dependent relaxation responses are reduced by hypothyroidism, which is detrimental to T levels and erectile responses. Levothyroxine and Sustanon combination medication was able to counteract this effect.

DRESS/DiHS syndrome induced by Propylthiouracil: a case report.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as Drug-induced hypersensitivity syndrome (DiHS), is a severe adverse drug reaction. Propylthiouracil, a member of thiouracils group, is widely used in medical treatment of hyperthyroidism. Propylthiouracil is associated with multiple adverse effects such as rash, agranulocytosis hepatitis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, but rarely triggers DRESS/DiHS syndrome. Here, we describe a severe case of propylthiouracil-induced DRESS/DiHS syndrome. CASE PRESENTATION: A 38-year-old female was treated with methimazole for hyperthyroidism at first. 4 weeks later, the patient developed elevated liver transaminase so methimazole was stopped. After liver function improved in 2 weeks, medication was switched to propylthiouracil therapy. The patient subsequently developed nausea and rash followed by a high fever, acute toxic hepatitis and multiple organ dysfunction (liver, lung and heart), which lasted for 1 month after propylthiouracil was started. According to the diagnostic criteria, the patient was diagnosed of DRESS/DiHS syndrome which was induced by propylthiouracil. As a result, propylthiouracil was immediately withdrawn. And patient was then treated with adalimumab, systematic corticosteroids and plasmapheresis in sequence. Symptoms were finally resolved 4 weeks later. CONCLUSIONS: Propylthiouracil is a rare cause of the DRESS/DiHS syndrome, which typically consists of severe dermatitis and various degrees of internal organ involvement. We want to emphasize through this severe case that DRESS/DiHS syndrome should be promptly recognized to hasten recovery.

Repositioning the existing drugs for neuroinflammation: a fusion of computational approach and biological validation to counter the Parkinson's disease progression.

Parkinson's disease is caused by the deficiency of striatal dopamine and the accumulation of aggregated α-synuclein in the substantia nigra pars compacta (SNpc). Neuroinflammation associated with oxidative stress is a key factor contributing to the death of dopaminergic neurons in SNpc and advancement of Parkinson's disease. Two molecular targets, i.e., nuclear factor kappa-light-chain-enhancer (NF-kB) and α-synuclein play a substantial role in neuroinflammation progression. Therefore, the compounds targeting these neuroinflammatory targets hold a great potential to combat Parkinson's disease. Thereby, in this study, molecular docking and Connectivity Map (CMap) based gene expression profiling was utilized to reposition the approved drugs as neuroprotective agents for Parkinson's disease. With in silico screening, two drugs namely theophylline and propylthiouracil were selected for anti-neuroinflammatory activity evaluation in in vivo models of chronic neuroinflammation. The neuroinflammatory effect of the identified compounds was confirmed by quantifying the expression of three important neuroinflammatory mediators, i.e. IL-6, TNF-alpha, and IL-1 beta on brain tissue using ELISA assay. The ELISA experiment demonstrated that both compounds significantly decreased the expression of neuroinflammatory mediators, highlighting the compounds' potential in neuroinflammation management. Furthermore, the drug and disease interaction network of the two identified drugs and diseases (neuroinflammation and Parkinson's disease) suggested that the two drugs might interact with various targets namely adenosine receptors, Poly [ADP-ribose] polymerase-1, myeloperoxidase (MPO) and thyroid peroxidase through multiple pathways associated with neuroinflammation and Parkinson's disease. Computational studies suggest that a particular drug may be effective in managing Parkinson's disease associated with neuroinflammation. However, further research is needed to confirm this in biological experiments.

Feasibility study for a downsized comparative thyroid assay with measurement of brain thyroid hormones and histopathology in rats: Case study with 6-propylthiouracil and sodium phenobarbital at high dose.

Concern has been raised that thyroid hormone disruptors (THDs) may potentially interfere with the developing brain, but effects of mild suppression of maternal THs by environmental contaminants on neonatal brain development are not fully understood. The comparative thyroid assay (CTA) is a screening test for offspring THDs, but it requires several animals and is criticized that reliance on serum THs alone as predictive markers of brain malfunction is inadequate. To verify feasibility of the downsized CTA but additional examination of brain THs levels and histopathology, we commenced internal-validation studies. This paper presents the data of the study where 6-propylthiouracil (6-PTU, 10 ppm) and sodium phenobarbital (NaPB, 1000 ppm) were dosed by feeding from gestational days (GD)6-20, and from GD6 to lactation day 21. The modified CTA detected 6-PTU-induced severe (>70%) suppression of serum THs in dams, with >50% suppressed serum/brain TH levels in offspring and brain heterotopia in postnatal day 21 pups. The modified CTA also detected NaPB-induced mild (<35%) suppression of serum THs in dams, with mild (<35%) reduction of serum/brain TH levels in fetuses but not in pups. These findings suggest that the modified CTA may have a potential as a screening test for offspring THDs.

A CASE REPORT OF HAND AND FOOT SKIN CHANGES RESEMBLING PTU-INDUCED VASCULITIS IN A YOUNG MALE WITH DIFFUSE TOXIC GOITRE.

Context: Propylthiouracil (PTU) could cause lupus or vasculitis-like hypersensitivities thus interfering with some other concomitant diseases. Objective: Clinicians must be aware of the side effects of medications, particularly after their introduction and long-term use. Some clinical manifestations may be similar to well-known drug side effects or hypersensitivity. Every unusual clinical scenario related to drug use must be evaluated individually and thoroughly. Subjects and Methods: Hands and feet skin changes were observed several days after PTU administration in a male patient with severe diffuse toxic goitre. A complete blood count, biochemistry analyses, thyroid function tests and antibodies, and immunology analyses were performed. Results: As the skin changes were distributed regionally, liver function tests were normal, and there were no signs of clinical deterioration, it was decided to continue PTU treatment and monitor the patient. The initial maculopapular rash quickly turned vesicular, then scaly. After two weeks, the skin changes were wholly restored, with no scarring. Hand, Foot, and Mouth disease (HFMD) was diagnosed after a thorough epidemiological survey and clinical workout. Conclusions: Our case study demonstrates that skin changes associated with HFMD may resemble those associated with PTU-induced vasculitis.

Adult-onset hypothyroidism causes mechanical hypersensitivity due to peripheral nerve hyperexcitability based on voltage-gated potassium channel downregulation in male mice.

Thyroid hormones play an important role in the central and peripheral nervous system functions. Approximately 50% of adult-onset hypothyroid patients have sensory symptoms including pain, possibly caused by peripheral neuropathy. However, the mechanism causing the pain has not been clarified. We generated an adult-onset hypothyroid model animal by administering 50 ppm propylthiouracil (PTU) for 5 weeks to male mice. Female mice were not tested in this study. Mechanical hypersensitivity, determined by the von Frey hair test, was observed during the PTU exposure and recovered after the exposure termination. The sciatic nerve compound action potential was also analyzed. Under single-pulse stimulation, no significant change in the threshold and conduction velocity was observed in the PTU-administered group. On the other hand, under train-pulse stimulation, the latency delay in the Aδ-fiber component was less in the PTU-administered group in Week 4 of PTU exposure, indicating relative hyperexcitability. Fluticasone, which is the anti-inflammatory agent with an ability to activate the voltage-gated potassium channel subfamily A (Kv1), restored the decrease in the latency change ratio by PTU exposure under the train-pulse stimulation supporting our hypothesis that Kv1 may be involved in the conductivity change. Kv1.1 protein level decreased significantly in the sciatic nerve of the PTU-administered group. These results indicate that adult-onset hypothyroidism causes mechanical hypersensitivity owing to hyperexcitability of the peripheral nerve and that reduction of Kv1.1 level may be involved in such alteration.

Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis.

OBJECTIVES: The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy. METHODS: We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity. RESULTS: We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01-1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14-1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up. CONCLUSIONS: ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.

A Spotlight on Drug-Induced Vasculitis.

PURPOSE OF REVIEW: Drug-induced vasculitis (DIV) is a rare form of vasculitis related to the use of various drugs. DIV primarily affects small to medium size vessels, but it can potentially involve vessels of any size. Differentiating between primary systemic vasculitis and DIV can be challenging; however, it is crucial, so that the offending agent can be discontinued promptly. RECENT FINDINGS: The clinical phenotype of DIV is protean and depends on the size of the affected vessels. It ranges from arthralgias, to an isolated cutaneous rash, to severe single or multi-organ involvement. While withdrawal of the offending drug is the most important step in management, a significant number of patients require immunosuppressive therapy for varying periods of time. DIV can affect any vascular bed size, leading to protean vasculitic syndromes. Increased awareness among general practitioners, specialty, and subspecialty physicians is crucial for early recognition, and withdrawal of drug for better outcomes.

Genetic taste sensitivity and dental caries in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: PROP test (6-n-propylthiouracil) for the identification of genetic sensitivity to caries in young individuals has emerged as a useful tool for caries risk assessment. AIM: To systematically appraise available evidence on the association between genetic taste sensitivity, as detected by (PROP), and caries. DESIGN: Seven databases, as of March 2020, were searched. Search terms included 'caries', 'taste predisposition', 'PROP'. Risk of bias assessment was performed using ROBINS-I tool, and the quality of evidence was assessed with GRADE. Random-effects meta-analyses were conducted to synthesize data, and pooled effects were estimated through standardized mean differences (SMDs) and associated confidence Intervals (95% CIs). RESULTS: Of 92 articles initially retrieved, 12 were eligible for inclusion. Seven contributed to the meta-analyses. All were cross-sectional studies, with moderate-to-serious risk of bias. The non-tasters of PROP exhibited a significantly higher value for the DMFT compared with tasters (SMD: 1.23; 95% CI: 0.90, 1.56; P < .001), whereas the association for the DMFS was SMD: 1.34; 95% CI: 0.66, 2.01; P < .001 (non-tasters versus super-tasters). The quality of evidence was very low overall. CONCLUSIONS: Within the limitations of this study, non-tasters to PROP exhibited higher caries experience, with subsequent clinical implications for follow-up and management of the 'high-susceptibility' individuals.

Antithyroid drug use during pregnancy and the risk of birth defects in offspring: systematic review and meta-analysis of observational studies with methodological considerations.

AIMS: Maternal antithyroid drug (ATD) use during pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this risk and how it compares to untreated hyperthyroidism due to methodological limitations of previous studies. METHODS: Systematic review of MEDLINE and EMBASE identifying observational studies examining ATD use during pregnancy and risk of birth defects by 28 August 2020. Data were extracted on study characteristics, effect estimates and comparator groups. Adjusted effect estimates were pooled using a random-effects generic inverse variance method and absolute risk calculated. RESULTS: Seven cohort studies and 1 case-control study involving 6 212 322 pregnancies and 388 976 birth defects were identified reporting regression effect estimates. Compared to an unexposed population comparison, the association between ATD use during pregnancy and birth defects in offspring was: adjusted risk ratio (aRR) 1.16 95% confidence interval (CI) 1.08-1.25 for propylthiouracil (PTU); aRR 1.28 95%CI 1.06-1.54 for methimazole/carbimazole (MMI/CMZ); aRR 1.51, 95%CI 1.16-1.97 for both MMI/CMZ and PTU; and aRR 1.15 95%CI 1.02-1.29 for untreated hyperthyroidism. The excess risk of any and major birth defects per 1000, respectively, was: 10.2 and 1.3 for PTU; 17.8 and 2.3 for MMI/CMZ; 32.5 and 4.1 for both MMI/CMZ and PTU; and 9.6 and 1.2 for untreated hyperthyroidism. CONCLUSIONS: When appropriately analysed the risk of birth defects associated with ATD use in pregnancy is attenuated. Although still elevated, the risk of birth defects is smallest with PTU compared to MMI/CMZ and may be similar to that of untreated hyperthyroidism.

Thyrotoxicosis and dilated cardiomyopathy in developing countries.

BACKGROUND: Thyrotoxicosis is the state of thyroid hormone excess. But, in sub-Saharan Africa (SSA), specifically Northern Ethiopia, scientific evidence about thyrotoxicosis and its cardiac complications like dilated cardiomyopathy is limited. Therefore, this study aimed to explore the thyrotoxicosis presentation and management and identify factors associated with dilated cardiomyopathy in a tertiary hospital in Northern Ethiopia. METHODS: An institution-based cross-sectional study was conducted in Ayder Comprehensive Specialized Hospital from 2017 to 2018. Data from 200 thyrotoxicosis cases were collected using a structured questionnaire. After describing variables, logistic regression was conducted to identify independent predictors of dilated cardiomyopathy. Statistical significance was declared at p < 0.05. RESULTS: Mean age at presentation of thyrotoxicosis was 45 years and females accounted for 89 % of the cases. The most frequent etiology was multinodular toxic goiter (51.5 %). As well, the most common symptoms and signs were palpitation and goiter respectively. Thyroid storm occurred in 6 % of the cases. Out of 89 patients subjected to echocardiography, 35 (39.3 %) of them had dilated cardiomyopathy. And, the odds of dilated cardiomyopathy were higher in patients who had atrial fibrillation (AOR = 15.95, 95 % CI:5.89-38.16, p = 0.001) and tachycardia (AOR = 2.73, 95 % CI:1.04-7.15, p = 0.040). All patients took propylthiouracil and 13.0 % of them experienced its side effects. Concerning ß-blockers, propranolol was the most commonly (78.5 % of the cases) used drug followed by atenolol (15.0 %). Six patients underwent surgery. CONCLUSIONS: In developing countries like Ethiopia, patients with thyrotoxicosis have no access to methimazole which is the first-line anti-thyroid drug. Besides, they greatly suffer from dilated cardiomyopathy (due to late presentation) and side effects of propylthiouracil. Therefore, we recommend that patients should get adequate health information about thyrotoxicosis and anti-thyroid drugs including their side effects. Additionally, hospitals and other concerned bodies should also avail of TSH tests and methimazole at an affordable cost. Furthermore, community awareness about iodized salt and iodine-rich foods should be enhanced.

Desensitization to Methimazole.

OBJECTIVE: Thionamides (methimazole and propylthiouracil) have been associated with common side effects, such as rash and pruritus, and rare but serious adverse effects, such as agranulocytosis and hepatotoxicity. Methimazole is usually the preferred thionamide for the treatment of hyperthyroidism if the patient is not planning to conceive or not in the first trimester of pregnancy, given the less frequent dosing and lower risk of hepatotoxicity. In patients who experience rash or itching when treated with methimazole, switching them to propylthiouracil is one treatment option. Here we report our experience regarding desensitization to methimazole to allow continued treatment with methimazole as an alternative management option. METHODS: We conducted a retrospective chart review of patients at a single institution who had side effects to methimazole and who were desensitized to methimazole under the supervision of an allergist. A total of 7 patients were included who experienced side effects to methimazole that did not include agranulocytosis or hepatotoxicity. RESULTS: All 7 patients were able to take methimazole for treatment of their hyperthyroidism, either for continued medical therapy or as a bridge to definitive therapy, with either surgery or radioactive iodine treatment. CONCLUSION: Under the supervision of an allergist, desensitization to methimazole is an option for treating patients who experience side effects to methimazole (excluding agranulocytosis and hepatotoxicity).

Thionamide-induced Agranulocytosis: A Retrospective Analysis of 36 Patients With Hyperthyroidism.

OBJECTIVE: Agranulocytosis is a rare but serious adverse drug reaction (ADR) of thionamide antithyroid drugs (ATDs). We explored the characteristics of ADRs in patients with hyperthyroidism. METHODS: This retrospective study included 3558 inpatients with Graves disease treated in a Class A Grade 3 hospital between 2015 and 2019. The clinical presentation and laboratory workup of patients with antithyroid drug (ATD)-induced agranulocytosis was analyzed. RESULTS: Agranulocytosis was thought to be caused by ATDs in 36 patients. The hospital length of stay was 12 (10-16) days, and hospitalization costs were approximately $2810.89 ($2156.50-$4164.67). The median duration of ATD therapy prior to agranulocytosis development was 30 (20-40) days. Fever (83.33%) and sore throat (75%) were the most common symptoms as early signs of agranulocytosis. The lowest neutrophil counts were 0.01 (0.00-0.03) × 109/L and 0.14 (0.02-0.29) × 109/L in the methimazole and propylthiouracil groups, respectively (P = .037). The recovery times of agranulocytosis were 9.32 ± 2.89 days and 5.60 ± 4.10 days in the methimazole and propylthiouracil groups, respectively (P = .016). Patients with severe agranulocytosis required a longer time to recover (P < .001) and had closer to normal serum thyroxine and triiodothyronine levels. The interval between the first symptom of agranulocytosis and ATD withdrawal was 1 (0-3) day. CONCLUSIONS: Patients with agranulocytosis needed a long hospital length of stay and incurred high costs. Methimazole was prone to causing a more serious agranulocytosis than propylthiouracil. High thyroid hormone was unlikely to play a role in adverse drug reactions. Patient education is important.

Inhibition of lysyl oxidase stimulates TGF-ß signaling and metalloproteinases-2 and -9 expression and contributes to the disruption of ascending aorta in rats: protection by propylthiouracil.

Mutations in lysyl oxidase (LOX) genes cause severe vascular anomalies in mice and humans. LOX activity can be irreversibly inhibited by the administration of ß-aminoproprionitrile (BAPN). We investigated the mechanisms underlying the damage to the ascending thoracic aorta induced by LOX deficiency and evaluated whether 6-propylthiouracil (PTU) can afford protection in rats. BAPN administration caused disruption of the ascending aortic wall, increased the number of apoptotic cells, stimulated TGF-ß signaling (increase of nuclear p-SMAD2 staining), and up-regulated the expression of metalloproteinases-2 and -9. In BAPN-treated animals, PTU reduced apoptosis, p-SMAD2 staining, MMP-2, and -9 expression, and markedly decreased the damage to the aortic wall. Our results suggest that, as in some heritable vascular diseases, enhanced TGF-ß signaling and upregulation of MMP-2 and -9 can contribute to the pathogenesis of ascending aorta damage caused by LOX deficiency. We have also shown that PTU, a drug already in clinical use, protects against the effects of LOX inhibition. MMP-2 and -9 might be potential targets of new therapeutic strategies for the treatment of vascular diseases caused by LOX deficiency.

Propylthiouracil-induced otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report and review of the literature.

Propylthiouracil (PTU)-induced otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is an extremely rare adverse event associated with anti-thyroid drugs and is not well recognized. A 42-year-old woman with Graves' disease undergoing PTU therapy for 8 years visited our hospital because of earache and congested feeling in her left ear. Blood tests, a computed tomography scan and pure tone audiometry revealed otitis media and moderate mixed hearing impairment. Antibiotics, ear drops with antibiotics and painkillers were administered. However, her earache and hearing loss gradually got worse and symptoms of facial nerve palsy appeared. At several weeks after initiation of the treatment, a high serum level of myeloperoxidase (MPO)-ANCA, 75.6 U/mL, was revealed. After excluding other causes, she was diagnosed with OMAAV. PTU was suspected as the cause of her OMAAV and was immediately discontinued, and prednisolone was started. Hearing impairment in her left ear gradually got better and showed substantial improvement. Facial nerve palsy disappeared. Although PTU-induced OMAAV is an extremely rare disease, it is important to recognize the disease, as delayed treatment can lead to irreversible hearing loss, hypertrophic pachymeningitis, and subarachnoid hemorrhage. When patients taking anti-thyroid drugs, especially PTU, are diagnosed with refractory otitis media or hearing loss, it is possible that OMAAV might be the cause and thus serum ANCA levels should be evaluated.

Pharmacological torpor prolongs rat survival in lethal normobaric hypoxia.

Resistance to hypoxia is one of the most prominent features of natural hibernation and is expected to be present in the pharmacological torpor (PT) that simulates hibernation. We studied resistance to lethal hypoxia (3.5% oxygen content) in rats under PT. To initiate PT, we used the previously developed pharmacological composition (PC) which, after a single intravenous injection, can induce a daily decrease in Tb by 7 °C-8 °C at the environmental temperature of 22 °C-23 °C. Half-survival (median) time of rats in lethal hypoxia was found to increase from 5 ± 0.8 min in anesthetized control rats to 150 ± 12 min in rats injected with PC, which is a 30-fold increase. Behavioral tests after PT and hypoxia, including the traveling distance, the number of rearing and grooming episodes, revealed that animal responses are significantly restored within a week. It is assumed that the discovered unprecedented resistance of artificially torpid rats to lethal hypoxia may open up broad prospects for the therapeutic use of PT for preconditioning to various damaging factors, treatment of diseases, and extend the so-called "golden hour" for lifesaving interventions.