Astemizole, an inhibitor of ether-à-go-go-1 potassium channel, increases the activity of the tyrosine kinase inhibitor gefitinib in breast cancer cells

Abstract Background Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression. Objective We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells. Materials and Methods The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using dose-response curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cytometry. Results Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle. Conclusions Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.

Endogenous metabolites investigation of cadiotoxicity induced by astemizole on zebrafish using GC-MS metabonomics / 中国药学杂志

OBJECTIVE: To analysis metabolic changes of zebrafish treated by astemizole, and to find potential cardiotoxicity related biomarkers. METHODS: Forty-eight hpf zebrafish was treated by astemizole and cardiac toxicity was denoted with heart rate, sinus venous (SV) -bulbus arteriosus (BA) distance and heart phenotype. Meanwhile, zebrafish tissue samples were obtained and subjected to GC-MS analysis to find potential biomarkers of cardiotoxicity. RESULTS: Heart rate of zebrafish treated by astemizole decreased significantly compared with the control groups accompanied with apparent atrioventricular block and cardiac morphological changes. Metabonomics analysis show that the metabolic profiling distinguished astemizole group from the control group and 12 potential biomarkers, glucose, glycine, lactic acid, creatinine, glutamine, N-acetyl-L-lysine, L-proline, citric acid, L-tyrosine, phosphate, cholesterol, palmitic acid, are identified. CONCLUSION: These results showed that metabonomics based on new model organism, zebrafish, can be used to express the astemizole-induced cardiotoxicity. The biomarkers found contribute to the early warning for drug-induced cardiotoxicity.

Two Cases of Torsade de Pointes after Astemizole Overdose

A 52-year-old women, suffering from generalized pruritus due to intrahepatic and common hepatic duct stones, was treated with astemizole, 30mg daily. Sixty one days later, convulsions and syncope developed suddenly during hospitalization. She had no history of arrhythmia, heart disease, electrolytes imbalance, or CNS disorders. As another case, a 44-year-old man suffering from pruritus due to liver cirrhosis, was treated with astemizole, 30mg daily. Thirty two days later, palpitations and syncope also developed suddenly during hospitalization. He was diagnosed liver cirrhosis, 3 years ago and there was no history of arrhythmia, heart disease, electrolytes imbalance, or CNS disorders. Administration of astemizole was stopped immediately. The laboratory investigations revealed the normal range of serum potassium, calcium and magnesium in both cases. The ECG finding showed the prolongation of QTc interval, frequent VPCs and intermittent polymorphic drugs. On 1st and 3rd day, after discontinue of astemisole, the ECG abnormalities disappeard. It is suggested that astemizole overdose can induce prolongation of QTc interval and torsade de pointes, especially in the patient with liver disease.

The efficacy and safety of loratadine versus astemizole in the treatment of perennial allergic rhinitis.

To compare the efficacy and safety of the new non-sedating H1 antagonist, Loratadine, with Astemizole, we conducted a double-blind, randomized parallel-group study in 40 allergic rhinitis Thai patients. Following a one-week run-in period, patients who had a mean daily total symptom score of at least 6 were randomized to study treatment. Twenty received Loratadine, the other 20 received Astemizole in the same dosage i.e., 10 mg tablet once a day for two weeks. The daily symptom scores recorded by the patients and the weekly symptom scores recorded by the physicians showed similar significant reductions in all symptoms. Both treatments were well-tolerated and no major adverse events were reported. However, drowsiness happened more frequently in the Astemizole group and the onset of relief in the Loratadine group was more rapid. Patients’ ratings for treatment efficacy in both groups were not significantly different. We conclude that both Loratadine and Astemizole taken 10 mg once a day are equally effective in reducing allergic rhinitis symptoms. But Loratadine appears to cause less sedation and to offer more rapid onset of relief.