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.

Antihistamines quality of life studies to assess the efficacy and safety in allergic rhinitis in Punjab, India

Allergic rhinitis impairs social life, but it is not known whether quality of life may be improved when patient are treated with H 1 blockers. The present study evaluated the comparative efficacy and safety of cetirizine, loratidine and astemizole in patients of allergic rhinitis. The design was open, randomized, parallel group comparison of three active treatment groups over a six week period. Sixty patients of either sex in the age group of 16 - 45 years, suffering from allergic rhinitis were selected randomly. The effect of cetirizine, loratidine and astemizole were observed on various parameters i.e., sneezing, nasal obstruction, watering of eyes, sedation and overall well being of the patients over a period of six weeks. The Visual Analogue Scale [VAS] was utilized as a quantitative measure of symptom relief. An improvement in patient's discomfort as assessed by VAS was observed in all treatment groups, with cetirizine 10mg daily being significantly more effective than loratidine 10mg and astemizole 10mg. Cetirizine resulted in a significant reduction in sneezing and nasal obstruction as compared to loratidine and astemizole [p<0.05]. Cetirizine and loratidine both were equally efficacious in relieving watering of eyes but cetirizine as well as loratidine were more efficacious as compared to astemizole [p<0.05]. Sedation was found to be maximum with cetirizine followed by astemizole and loratidine over six weeks of study period. Cetirizine has been found to be most effective in relieving the symptoms of allergic rhinitis followed by loratidine and astemizole and it can also improve quality of life for patients with allergic rhinitis

Riesgo de interacciones medicamentosas. Combinaciones de medicamentos asociados a arritmia ventricular / Risk of drug interactions. Combinations of drugs associated with ventricular arrhythmias

OBJECTIVE: To determine the frequency of concurrent use of cisapride, astemizole and terfenadine with macrolides and azole antimitotics, drug combinations that have been reported in the literature as producing a pharmacological interaction associated with potentially fatal ventricular arrhythmias. MATERIAL AND METHODS: A retrospective analysis of a total of 72,444 prescriptions generated by 611 physicians during a 6 months period for ambulatory patients, was performed. The database included a register of automatic alerts produced every time a predetermined drug combination was detected. RESULTS: 145 potentially risk situations were detected, with an incidence rate to 2.1 cases per 1,000 prescriptions, which increases to 6.2 when prescriptions for terfenadine, astemizole, and cisapride were included, with 12, 9 y 5, respectively. Only 36 physicians (6) wrote prescriptions producing alerts, and about half (45) were pediatricians. The same physician prescribed both drugs in 31 of the cases. CONCLUSION: The use of drug combinations associated with a high risk of potentially fatal ventricular arrhythmias is relatively high in Mexico. An electronic online detecting system showed to be useful in preventing this kind of potential pharmacological interactions.

Desarrollo de un método espectrofluorométrico para determinar astemizol / Development of a spectrometry fluorescence for determine astemizole

Se propone un nuevo método analítico para la valoración de astemizol (AZ) en materia prima basado en la fluorescencia natural de la molécula lambda (máx exc)= 28 lambda (máx em) = 425 nm. El método permitió determinar AZ en una solución buffer de ácido clorhídrico - cloruro de potasio (pH 1,3), en un rango de 100 - 1000 ng/mL respectivamente, con un límite de detección estimado de 17 ng/mL. El método propuesto es más simple, rápido y económico que el método oficial de la farmacopea estadounidense (USP XXIV), y no requiere tratamiento previo de la muestra para convertir el AZ en otra especie química, como ocurre con los métodos espectrofotométricos. Se propone su aplicación a la determinación de AZ en formas farmacéuticas sólidas y muestras biológicas debido a la sensibilidad y especificidad inherentes al método.

Aplicación de un sistema por inyección en flujo a la determinación cuantitativa de astemizol en formas farmacéuticas sólidas / Application of an injections system in flow to the quantitative determination of astemizole in solid pharmaceutical forms

Se desarrolló un método analítico para cuantificar astemizol en tabletas, mediante la aplicación de un sistema por inyección en flujo y detección espectrofotométrica (UV) directa. El astemizol se separó de los excipientes directamente con metanol. Las disoluciones se inyectaron en un flujo continuo constituido por una solución de ácido clorhídrico 0.1 M. El intervalo lineal, obtenido usando el método de adición estándar, resultó entre 20 y 100 µg/mL, con un límite de detección igual a 0,01 µg/mL. El sistema se automatizó para determinar soluciones muestras a una velocidad de 1/min con un coeficiente de variación menor que 1,5 por ciento (n=25). El método desarrollado resultó económico, rápido, reproducible y fácil de aplicar en aquellos laboratrios que realizan un elevado número de análisis de rutina.

Efecto inhibitorio del astemizol en pruebas cutáneas con histamina / The effect of the astemizol to inhibit the cutaneos response to the histamine

Objetivo. Determinar el efecto del astemizol para inhibir la respuesta cutánea a la histamina. Material y método. Se realizó un ensayo clínico en sujetos adultos sanos; se efectuaron pruebas cutáneas con histamina por prick (1 mg/ml) e intradérmicas (0.01 mg/ml) diarias, durante la toma de 10 mg de astemizol en ayunas en un periodo de siete días y otros tantos más después de suspenderlo, así como el día 14, 21, y 28. Se determinó la inhibición y la reaparición de la respuesta cutánea. Resultados. Se estudiaron 12 sujetos con edad promedio de 36 años ñ 11.2 DS. La inhibición completa se presentó a partir del cuarto día y la mayoría de los sujetos (79 por ciento) hasta el séptimo día. La reacción normal se recuperó en más de siete días pero menos de 14 en el 100 por ciento. Conclusiones. De acuerdo con estos resultados, el astemizol inhibe la reacción cutánea a la histamina desde el primer día en 50 por ciento de los sujetos y su mayor acción es al séptimo día, mientras que al suspenderlo la respuesta normal se recupera en más de siete días

Participación de receptores histaminérgicos involucrados en la permeabilidad vascular / Participation of histaminergic receptors involved in vascular permeability

La permeabilidad vascular puede ser modificada por la liberación de histamina endógena como resultado de la presencia de ciertos tiobarbitúricos (tiopental) en el organismo. Esta modificación en la permeabilidad es mediada por la activación del receptor histaminérgico H1, pero es incierta la participación del receptor H2. En este trabajo se evalúa la participación de receptores H1 y H2 durante los cambios de permeabilidad vascular inducidos por histamina, a través de la determinación de concentraciones séricas de albúmina, proteínas totales y globulinas, que indirectamente lo indican. Se formaron 5 grupos de organismos; un control y 4 experimentales denominados grupo A, B, C y D. A los organismos del grupo A se les aplicó histamina IV, 10 µg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso; al grupo C se le inyectó ranitidina IV, 0.13 mg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso y 0.13 mg/Kg de peso de astemizol y ranitidina IV, respectivamente. El grupo A mostró un decremento significativo en las concentraciones de albúmina, proteínas totales y globulinas. En los grupos B, C y D se observó una disminución en la concentración de proteínas totales y globulinas, pero no de albúmina. Estos resultados muestran que los receptores H1 y H2 están involucrados en el aumento de permeabilidad vascular a la albúmina, pero tal vez exista un proceso de permeabilidad diferencial en el cual el paso de globulinas desde la luz vascular hasta el intersticio esté regulado por otro mecanismo

Comparative study of cardiac safety profiles of loratadine and astemizole in rats

The second [non-sedating] generation antihistamines; terfenadine and astemizole have been reported to produce QTc prolongation and ventricular arrhythmias. With the withdrawal of terfenadine and the warnings for astemizole recommended by U.S.FDA, loratadine becomes one of the currently widely available non-sedating antihistamines. We examined and compared the effects of loratadine and astemizole on the electrocardiographic QT c interval and heart rate in adult albino rats.Two groups, each 6 anaesthetised adult albino rats; loratadine, and astemizole-treated groups were used. Each drug was given in 4 doses about 0.1, 1, 5 and 10 times its antihistaminic ED[50] in rats, with 30-minutes dosing interval. The heart rate and QT c interval [mean values over the dosing interval] were the electrocardiographic parameters measured. Loratadine doses about 0.1, 1 and 5 times the antihistaminic ED[50] produced insignificant changes in the HR and QTc interval, while the loratadine dose about 10 times the ED[50] produced significant minimal increases in the HR and QT c interval versus the control in rats. Astemizole doses about 0.1 and 1 times its ED[50] produced insignificant changes in the HR, while astemizole doses about 5 and 10 times its EDSO produced significant moderate decrease [opposite to loratadine effect] in the HR. All astemizole doses about 0.1, 1, 5 and 10 times its ED[50] produced significant moderate prolongations in the QT c interval versus the control which were much greater than loratadine effect with its dose 10 times the ED[50]. Loratadine has no or little effects on the HR and QTc interval with doses up to 10 times the ED[50] and is considered to have much better cardiac safety profile in comparison to astemizole doses from 0.1 up to 10 times its ED[50] which is cardiotoxic based on the greater QTc interval prolongations

Elección de un antihistamínico ideal desde una perspectiva actual / The ideal antihistamine. A current perspective

Las patologías alérgicas han aumentado su prevalencia en todo el mundo, lo que conlleva un aumento en la prescripción de antihistamínicos orales. Sin embargo, los efectos adversos de dichos medicamentos son muy frecuentes, especialmente en el sistema nervioso central, por lo que al prescribirlos se debe tener presente el clásico adagio de la Medicina: "primum non nocere" ("antes que nada no dañar"). El presente artículo describe las generalidades de la acción de la histamina en el organismo, así como los efectos terapéuticos y secundarios de los antihistamínicos de primera y segunda generación. Finalmente presenta una descripción detallada del nuevo antialérgico epínastina.

A Case of Hydroxyzine Induced Torsades de Pointes

Torsades de pointes is a polymorphic ventricular tachycardia associated with prolonged QT interval and increased U wave amplitude. It has been found to be induced by various drugs, electrolyte imbalances, and so on, but the mechanism of torsades de pointes has not been completely documented. Two hypotheses, early afterdepolarization and dispersion of repolarization have been known to be the possible mechanism. Terfenadine and astemizole are the antihistamines, known to be one of the etiologic agents of torsades de pointes, and factors associated with increased risk are significant liver disease, drug overdose, and concomitant administration of imidazole and macrolide antimicrobial drugs. There has been only one case reported that torsades de pointes had been induced by first-generation antihistamine, piprinhydrinate. We experienced a case of 43 year old male patient with torsades de pointes induced by first-generation antihistamine, hydroxyzine and treated successfully with drug cessation, MgSO

A Case of Torsade de Pointes after Treatment with Terfenadine and Ketoconazole

Torsade de pointes (TdP) is a form of polymorphic ventricular tachycardia that is associated with prolongation of the QT interval. Although it occurs in many clinical settings, torsade de pointes is most commonly caused by drugs. The second generation antihistamines, including terfenadine and astemizole, have little sedation or other adverse effects on the CNS. They have been used widely to treat various allergic diseases, but it has been reported that overdoses or combinations with antifungal agents or macrolide antibiotics may lead to TdP. We report a case of TdP that occured during com-bination therapy of terfenadine and ketoconazole.

A Case of Torsade de Pointes after Combined Use of Terfenadine and Itraconazole

Torsade de pointes is a life-threatening, polymorphic ventricular tachycardia associated with prolongation of the QTc interval. Although torsade de pointes is found in many clinical settings, it is mostly drug induced. Similar problems have been described with nonsedating H1-selective antihistamines like terfenadine and astemizole. The increased risks of both H1-antihistamines were associated with exposure to supratherapeutic doses or concomitant exposure to the cytochrome P-450 inhibitors, ketoconazole, erythromycin and cimetidine. We report a 51-year-old woman with torsade de pointes and a long QTc interval caused by the combined use of terfenadine and itraconazole. After discontinuation of these drugs and treatments with electrical cardioversion and magnesium sulfate, torsade de pointes and prolonged QTc interval were no longer observed and she was discharged in good condition with a normal ECG. In conclusion, physicians should be aware that terfenadine and astemizole can cause torsade de pointes in rare cases.

Otitis media serosa. Estudio comparativo de carbinoxamina-pseudoefedrina vs astemizol-pseudoefedrina / Otitis media serous. Compartive study of carbinoxamina-pseudoefedrina vs astemizol-pseudoefedrina

Se estudiaron 48 niños de 3 a 8 años de edad, de uno y otro sexo(30 varones y 18 mujeres), que asistieron a la consulta externa de otorrinolaringología del Hospital del ISSSTE de Nuevo Laredo, Tamaulipas y a la consulta privada de la Clínica de Alergia y Otorrinolaringología en Nuevo Laredo, Tamaulipas, del mes de noviembre de 1995 a abril de 1996. Algunos de los efectos secundarios observados en los pacientes tratados en el grupo A (carbinoxamina-P) fueron: sedación leve y en algunos casos hiperexcitabilidad e irritabilidad. Sin embargo, no fue necesario suspender la medicación o modificar la dosis. En el grupo B (astemizol-P) se observó solamente excitación e irritabilidad en algunos casos por hipersensibilidad a la pseudoefedrina. Es muy importante considerar que el tratamiento adecuado y oportuno en un paciente con otitis media serosa permitirá evitar secuelas que pueden causar, a largo plazo, un impacto significativo en el lenguaje y desarrollo intelectual del niño

Estado actual de antihistamínicos / Current state of antihistamine drugs

El aumento de la prevalencia mundial de las patologías respiratorias alérgicas conlleva un aumento simultáneo en la prescripción de antihistamínicos orales. Los efectos adversos que dichos medicamentos provocan en el sistema nervioso central son muy frecuentes(1), por lo que se presenta una revisión actualizada de los antihistamínicos sistémicos bajo el clásico adagio de la Medicina: "Primum non nocere" ("antes que nada no dañar"). En esta revisión se describe las generalidades de la acción de la histamina en el organismo. Los efectos terapéuticos y secundarios de los antihistamínicos de primera y segunda generación y finalmente se presenta una descripción acabada del nuevo antialérgico epinastina

Anti-histamínicos "näo clássicos" e cardiotoxidade / Non-classical antihistamines and cardiotoxicity

O desenvolvimento dos anti-histamínicos "nao-clásicos" tem sido considerado um significante avanço no tratamento dos pacientes alérgicos. Além de proporcionarem reduçao dos sintomas, sao medicamentos de uso oral que nao causam sedaçao ou prejuízo à atividade psicomotora do paciente. Entretanto, alguns relatos de casos com efeitos cardíacos adversos atribuídos à terfenadina e ao astemizol, administrados em altas doses e/ou associados ao cetoconazol ou a antibióticos macrolídeos, têm causado muita discussao. Neste trabalho revemos tais eventos, bem como suas possíveis explicaçoes.

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.

Evaluación comparativa del astemizol-pseudoefedrina y loratadina-pseudoefedrina en niños con rinitis alérgica / Evaluated comparative the effectiveness and safety of astemizole-pseudoephedrine to loratadine-pseudoephedrine in the treatment of allergic rhinitis

Se realizó un estudio con el propósito de evaluar la eficacia y la tolerancia de la solución astemizol-pseudoefedrina en comparación con el jarabe loratadina-pseudoefedrina en el tratamiento de la rinitis alérgica. Se incluyeron 50 niños de uno y otro sexo (34 varones y 16 mujeres) de edades entre 2 y 7 años que se asignaron al azar a cada grupo. Los pacientes se evaluaron antes, a los 3 y los 7 días de tratamiento. Los niños tratados con astemizol-pseudoefedrina obtuvieron mejores resultados, con efectividad promedio de 48 por ciento contra 64 por ciento de loratadina-pseudoefedrina. La diferencia fue significativa a favor de astemizol-pseudoefedrina para los síntomas oculares según las evaluaciones del médico y para la obstrucción y el prurito nasal y el estornudo según el diario del paciente. Ambos medicamentos comenzaron su acción antes de 30 minutos de administrados; a las 4 horas 38 por ciento de los pacientes del grupo tratado con astemizol-pseudoefedrina refirieron alivio contra 16 por ciento del grupo loratadina-pseudoefedrina. Un paciente del primer grupo y tres del segundo presentaron efectos secundarios