Acebutolol, a Cardioselective Beta Blocker, Promotes Glucose Uptake in Diabetic Model Cells by Inhibiting JNK-JIP1 Interaction

The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.

A Case of carbamazepine induced bronchiolitis obliterans organizing pneumonia / 결핵

BOOP(Bronchiolitis Obliterans Organizing Pneumonia) is an inflammatory reaction that follows damage to the bronchiolar epithelium of the small conducting airways. BOOP is characterized by the pathologic finding of excessive proliferation of granulation tissue within the respiratory bronchioles, alveolar duct and spaces, accompanied by organizing pneumonia. BOOP may result from diverse causes such as toxic fumes, connective tissue disorders, infections, organ transplantation and drugs or appear idiopathically. Drug induced BOOP has been described in association with acebutolol, amiodarone, cephalosporin, bleomycine, tryptophan, gold salts, barbiturates, sulfasalazine, and carbamazepine. Carbamazepine is an iminostilbene derivative that is used as both and anticonvulasnt and pain reliever for pains associated with trigeminal neuralgia. It is structually related to the tricyclic antidepressants. To our knowledge, there have been no previously reported case that has described development of BOOP during carbamazepine treatment in Korea, and only two cases have been reported in the world. We report a case of carbamazepine-induce BOOP with a brief review of literature.

experimental study of the possible alterantion in the lung collagen concentration in rats treated with either acebutolol or atenolol

To study the role of beta-adrenergic system in the regulation of collagen production, this work was carried out as a trial to clarify the effect of acebutolol, beta 1-adrenergic receptor selective blocker possessing partial agonist activity or intrinsic sympathomimetic activity, and atenolol, another beta 1-adrenergic receptor selective blocker lacking such an intrinsic sympathomimetic activity, on the collagen concentration of the lung. Total collagen concentrations were determined in the lungs of rats at the end of continuous daily treatment with the above-mentioned drugs for three, six and nine weeks, respectively. The comparison of their values with that of the control group revealed no statistically significant effect of these drugs on the lung total collagen concentrations. It was concluded that both drugs could be considered as relatively safe, at least from the viewpoint of their effect, on the lung tissue

High performance liquid chromatography assay of atenolol and acebutolol

High performance liquid chromatographic method for determination of the beta-adrenergic blockers, atenolol and acebutolol was described. The method involved separation on a C[18] column, using propyl paraben as internal standard and a mixture of water, methanol, acetonitrile and phosphoric acid as eluent in different ratios for each drug. They have been detected at 235 nm. The mean percentage recoveries of atenolol [20-120 ug ml-1] and acebutolol [10-100 ug ml-1] were 99.63 +/- SD 1.041 and 100.43 +/- SD 0.78, respectively. The method has been applied for the determination of the two drugs in their dosage forms

Randomised two way crossover comparison of the effects of six weeks propranolol and acebutolol therapy on plasma lipid profiles in patients with hypertension or ischaemic heart disease.

The effect of propranolol and acebutolol therapy on serum lipoproteins was studied in thirty patients (mean age 43.9 +/- 8.7 years) with essential hypertension and/or stable myocardial ischaemia. Patients received six weeks therapy with propranolol (80-160 mg per day) and acebutolol (400-800 mg per day) each in random order and were changed over from one to the other beta-blocker after 6 weeks therapy. On propranolol treatment there was no significant effect on total cholesterol and LDL-cholesterol but the concentration of serum triglycerides (94.2 +/- 37.7 to 129.1 +/- 41.2 mg/dl) and VLDL cholesterol (18.9 +/- 7.8 to 26.1 +/- 8.1 mg/dl) significantly increased, concentration of HDL cholesterol (49.5 +/- 9.4 to 42.4 +/- 8.7 mg/dl) significantly decreased (p less than 0.01). Atherogenic index also worsened from 4.17 +/- 0.48 to 5.15 +/- 0.54 (p less than 0.05) on propranolol therapy. Acebutolol therapy, on the other hand, produced no significant change in the concentration of total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol and VLDL cholesterol.

A cross-over trial comparing the effects of acebutolol and propranolol on the serum lipids and hypertension.

A two-way cross-over trial comparing the effects of acebutolol and propranolol on the lipid profile was conducted. 50 patients were evaluated. The primary objective was to determine whether treatment by certain classes of beta-blockers induced deleterious effects on the serum lipids which could partially or wholly negate the beneficial effect of controlling hypertension. Each patient served as his/her own control, and received 6 weeks of therapy with acebutolol and 6 weeks of therapy with propranolol. The analysis of the results revealed that acebutolol did not have any adverse effect on the lipid profile in contrast to reports which implicate other beta-blockers in inducing pro-atherogenic changes in the serum lipid profile; but acebutolol and propranolol were equi-effective in controlling hypertension.

The effect of beta-adrenoceptor antagonists alone and in combination with a GABA-elevating agent on isoniazid-induced convulsions in rats.

A delay in the onset of isoniazid-induced convulsions was found in rats pretreated with the beta 2-adrenoceptor blocker, butoxamine and the nonspecific beta-blocker, propranolol. In these animals the convulsive responses were inhibited in a dose dependent manner. These compounds were found to be effective even after the induction of convulsions. The beta 1-blocker, acebutolol was able to protect rats only when injected prior to the challenge. The anticonvulsant effect of acebutolol and propranolol but not that of butoxamine was found to be enhanced in animals pretreated with a gamma-aminobutyric acid (GABA) elevating agent, aminooxyacetic acid (AOAA). The findings indicate that the GABA-mediated anticonvulsant action of AOAA seems to be additive with that resulting from beta 1 but not beta 2-blockade.

Membrane stabilizing action of cardio-selective Beta-adrenergic blocking agent [acebutolol] on the electrically stimulated diaphragmatic tissue of the rat

Isolated diaphragm of albino rats was prepared and effect of electric stimulation was observed before and after treatment of the tissue with the cardioselective beta-adrenergic blocking agent, acebutolol. Acebutolol did not produce no Significant effect on the response of tissue to electric stimulation in small doses. But in high dose, there was marked pression of the contractile effect of tissue to electric stimulation. It is concluded that this effect of acebutolol in high uses is due to the membrane stabilizing action of the drug

Respuesta tensional al ejercicio dinámico e isométrico en hipertensos tratados con labetolol o acebutolol / Arterial pressure response to dynamic exercise in hypertensives treated with labetalol or acebutolol

En el presente estudio de diseño simple-ciego, placebo-control, cruzado y randomizado, evaluamos la respuesta tensional y las modificaciones hemodinámicas causadas por el tratamiento oral y durante dos semanas con un agente bloqueador beta-adrenérgico selectivo con efecto simpático-mimético intríseco (Acebutolol, 400 mg/día) o con un agente bloqueador alfa y beta-adrenérgico (Labetalol, 400 mg/día). A tal efecto, 25 pacientes hipertensos leves fueron sometidos a ejercicio isométrico al 30% de su capacidad máxima y a ejercicio dinámico hasta un máximo de 75W, bajo monitoreo con electrograma de impedancia y durante ciclos de tratamiento con placebo, Acebutolol o Labetalol en forma cruzada, La efectividad terapéutica de ambas drogas fue similar en reposo, pero el Labetalol indujo una menor respuesta hipertensiva al ejercicio isométrico que el Acebutolol, la cual parece deberse a un menor incremento de las resistencias periféricas. Durante el ejercicio dinámico se observó una atención de la respuesta hipertensiva similar con ambos medicamentos; el labetalol, sin embargo, permitió un incremento del gasto cardíaco mayor que el tratamiento con Acebutolol. Estos efectos diferenciales del Labetalol se atribuyen a su efecto bloqueador alfa-adrenérgico, y lo hacen particularmente útil en pacientes hipertensos con actividad física moderada o intensa

Antihypertensive effect of nifedipine-retard and acebutolol in patients with hypertension: a randomized double-blind study

A randomized double-blind, comparative study, with a new slow release preparation of nifedipine (nifedipine-retard), was undertaken in patients with mild, moderate and severe essential hypertensión WHO (stage I-II). After a two-week placebo period, patients were divided into three groups: 1) group I received nifedipine-retard 20 mg orally twice daily; 2) group II received acebutolol 200 mg orally twice daily; and 3) group III received nifedipine-retard 20 mg once daily plus acebutolol 200 mg orally once daily. All three dosage regimens were administered for six weeks. Nifedipine-retard (group I) reduced supine blood pressure from 162 ñ 4.2/105 ñ 1.4 mmHg (21.6 ñ 0.5/14.0 ñ 0.2 Pa) to 139 ñ 4.2/92 ñ 2.6 mmHg (18.5 ñ 0.5/12.3 ñ 0.3 kPa) and slighrly increased the heart rate. Acebutolol (group I) reduced supine blood pressure from 163 ñ 5.3/107 ñ 2.8 mmHg (21.7-0.7/14.2 ñ 0.4 kPa) to 144 ñ 5.0/93 ñ 3.7 mmHg (192 ñ 0.7/12.4 ñ 0.5 kPa) and decreased the heart rate. Nifedipine retard plus acebutolol (group III) reduced supine blood presure from 144 ñ 3.0/101 ñ 1.3 mmHg (19.2 ñ 0.4/13.4 ñ 012 kPa) to 123 ñ 3.4/84 ñ 2.8 mmHg (16.4 ñ 0.5/11.2 ñ 0.4 kPa) and did not significantly alter the heart the heart rate. There was a significant correlation (r = 0.65, p < 0.03) betwee baseline blood pressure and diastolic blood pressure after six weeks of therapy nifedipine-retard. There was a no significant trend between the age of patients and decrease of diastolic blood pressure, positive for nifedipine-retard, and negative for acebutolol. There was a low incidence of side effects with all dosage regimens..

Ensayo abierto y multicentrico de la asociación acebutolol-hidroclorotiazida en la hipertensión arterial leve / Open and multicenter assay of the association acebutolol-hydrochlorotiazide in light arterial hypertension

Se efectuó un ensayo abierto multicéntrico para determinar la eficacia de una combinación fija de acebutololol e hidroclotitiazida para el tratamiento de la hipertensión arterial leve (según OMS). Se trataron 306 pacientes, 110 del sexo masculino y 196 de sexo femenino con edad promedio de 55 años (19 a 84). La dosis administrada fue 400 mg de acebutolol y 25 mg de hidroclorotiazida en un comprimido. La presión arterial descendió durante el tratamiento de 189 + ou - 22.06/109 + ou - 12.18 mmHg a 145.73 + ou - 13.95/21 + ou - 10.92 mmHg. Ambos descensos fueron estadísticamente significativos (p<0.001). Las presiones descendieron significativamente hasta la séptima semana siguiendo una hipérbole con asíntota a los 135 mmHg. El 90% de los pacientes normalizaron la presión arterial. Se comprobaron efectos adversos en 35 pacientes (9.54%) pero fue necesario interrumpir el tratamiento sólo en 6(1.63%). Se considera que la combinación acebutolol/hidroclorotiazida es un agente seguro y confiable para el tratamiento de la hipertensión arterial asintomática

Effect of Combination Therapy of Acebutolol with Hydrochlrothiazide(Sectrazide(R)) on the Serum Lipids of Patients with Essential Hypertension

Serial changes of serum lipids were observed in 28 patients with essential hypertension, administered combination regimen of acebutolo 400mg and hydrochlorothiazide 25mf for up to 24 weeks. The results were as follows. 1) Serum total cholesterol and triglyceride level were varied within -6-5 and -2-7% change respectively which were not significant clinically. 2) High density lipoprotein-cholesterol decreased 5% at 6 weeks, 16% and 17% decrease in 12 and 24 weeks respecitively. The changes were more remarkable in the hyperlipidemic patients. 3) Pretreatment average blood pressure of 174/104mmHg lowered to 144/88 at 6 weeks and normalized to 135/86 at 12 weeks. 4) No adverse reaction were observed except mild weakness and indigestion which did not force the discontinuation of drugs. In summary, the fixed-ratio combination of acebutolol and hydrochlorothiazide was excellent in antihypertensive efficacy and patient's compliance, although decrease in high density lipoprotein-cholesterol demand the physician alert to exert vigilance especially in young hypertensives and hyperlipidemic patient to check serum lipids before and during medication, and to change regimen if metabolic derangement is detected in the view point of primary prevention of coronary heart disease.

Comparação dos efeitos anti-hipertensivos das associações da nifedipina retard com acebutolol ou com atenolol / Comparison of the anti-hypertensive effects of the combinations of nifedipine retard with acebutolol or with atenolol

Foram estudados, em ambulatorio, 42 pacientes com pressao arterial sistolica entre 160 e 230 mm Hg e diastolica entre 106 e 130 mm Hg divididos em 2 grupos, tratados com nifedipina retard (comprimidos de 20 mg, administrados de 12 em 12 horas) associada a 400 mg de acebutolol ou associada a 10 mg de atenolol, em dose matinal unica. O estudo foi aberto e "randomizado" e durou 10 semanas, 4 semanas de "wash out" inicial com placebo e 6 semanas de tratamento com as referidas associacoes.As caracteristicas dos 2 grupos eram comparaveis. Observou-se reducao estatisticamente significante da frequencia cardiaca (p < 0,01), da pressao sistolica (p <0,01) e da pressao diastolica (p < 0,01) em ambos os grupos, porem, o efeito anti-hipertensivo da nifedipina associada ao acebutolol foi mais precoce, e, em relacao a diastolica, significativamente (p < 0,05) superior as da outra associacao. Alem disso, esta associacao foi melhor tolerada e apresentando resultados clinicos significativamente (p < 0,05) melhores. Concluimos que estas associacoes, alem de sua eficacia antihipertensiva e boa tolerancia, por sua simplicidade, podem aumentar a adesao dos hipertensos a terapeutica

Ensayo doble ciego con acebutolol en pacientes hipertensos esenciales. / Double blind trial with acebutolol in patients with essential hypertension

Mediante el empleo de tecnica doble ciego se ensaya los efectos hipotensores de acebutolol en 49 hipertensos esenciales, 26 casos recibieron droga y 23 placebo. Se pudo comprobar que ambos grupos presentaron descenso de la presion sistolica y diastolica, pero que solo el grupo en que se utilizo la droga evidencio un descenso significativo y progresivo de ambas presiones, en el 88,5% de los casos. No se observaron efectos colaterales, la droga tiene la ventaja de poder utilizar-se en una sola dosis diaria; tampoco posee efectos bradicardisante de otros betabloqueadores, lo que puede ampliar el rango de indicaciones en comparacion a otros farmacos de la misma familia