RESUMEN
Little is known about the effect of the recently developed calcimimetic evocalcet (Evo) on parathyroid calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression. We examined the effects of Evo and cinacalcet (Cina) on CaSR and VDR expression in 5/6 nephrectomized Sprague-Dawley rats fed a high-phosphorus diet for 4 weeks to develop secondary hyperparathyroidism (SHPT). These uremic rats were divided into 4 groups-baseline control (Nx4W) and groups with additional treatment with either the Vehicle, Evo, or Cina for 2 weeks; normal rats were used as normal controls (NC). Blood parameters and parathyroid tissue were analyzed. CaSR and VDR expression levels were determined using immunohistochemistry. The degree of kidney injury and hyperphosphatemia was similar in the uremic groups (Nx4W, Vehicle, Cina, and Evo). Serum parathyroid hormone levels were significantly higher in the Nx4W and Vehicle groups than in the NC group. This increase was significantly suppressed in the Cina and Evo groups compared with that in the Vehicle group. Serum calcium levels were significantly and equally lower in the Cina and Evo groups relative to those in the Vehicle group. CaSR expression was significantly lower in the Nx4W and Vehicle groups than in the NC group. This downregulation was of an equally lesser magnitude in the Cina and Evo groups. A similar trend was observed for VDR expression. These results indicate that Evo and Cina treatment can increase parathyroid CaSR and VDR expression in uremic rats with SHPT, which could provide better control of mineral and bone disorder markers.
Asunto(s)
Hiperparatiroidismo Secundario , Receptores de Calcitriol , Ratas , Animales , Receptores de Calcitriol/metabolismo , Receptores Sensibles al Calcio/metabolismo , Ratas Sprague-Dawley , Glándulas Paratiroides/metabolismo , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/complicaciones , Hiperparatiroidismo Secundario/metabolismo , Hormona Paratiroidea/metabolismo , Cinacalcet/farmacología , Cinacalcet/metabolismoRESUMEN
Mitochondrial dysfunction plays a critical role in the pathogenesis of kidney diseases via ATP depletion and reactive oxygen species overproduction. Nonetheless, few studies have reported the renal mitochondrial status clinical settings, partly due to a paucity of methodologies. Recently, a positron emission tomography probe, 18F-BCPP-BF, was developed to non-invasively visualize and quantitate the renal mitochondrial status in vivo. Here, 18F-BCPP-BF positron emission tomography was applied to three mechanistic kidney disease models in rats: kidney ischemia-reperfusion, 5/6 nephrectomy and anti-glomerular basement membrane glomerulonephritis. In rats with ischemia-reperfusion, a slight decrease in the kidney uptake of 18F-BCPP-BF was accompanied by morphological abnormality of the mitochondria in the proximal tubular cells after three hours of reperfusion, when the kidney function was slightly declined. In 5/6 nephrectomy and rats with anti-glomerular basement membrane glomerulonephritis, the kidney uptake of 18F-BCPP-BF cumulatively decreased with impairment of the kidney function, which was accompanied by a reduction of mitochondrial protein and a pathological tubulointerstitial exacerbation rather than glomerular injury. The 18F-BCPP-BF uptake in the injured kidney was suggested to represent the volume of healthy tubular epithelial cells with normally functioning mitochondria. Thus, this positron emission tomography probe can be a powerful tool for studying the pathophysiological meanings of the mitochondrial status in kidney disease.
Asunto(s)
Enfermedades Renales , Daño por Reperfusión , Animales , Riñón/diagnóstico por imagen , Mitocondrias , Tomografía de Emisión de Positrones , Ratas , Especies Reactivas de Oxígeno , Daño por Reperfusión/diagnóstico por imagenRESUMEN
Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4.
Asunto(s)
Adamantano/análogos & derivados , Dipéptidos/farmacología , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Glomérulos Renales/enzimología , Túbulos Renales/enzimología , Adamantano/metabolismo , Adamantano/farmacología , Animales , Células Cultivadas , Dipéptidos/metabolismo , Dipeptidil Peptidasa 4/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Humanos , Masculino , Unión Proteica , Ratas Sprague-Dawley , Fosfato de Sitagliptina/farmacologíaRESUMEN
Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure.
Asunto(s)
Adamantano/análogos & derivados , Dipéptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Corazón/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Adamantano/farmacología , Animales , Diástole , Dipeptidil Peptidasa 4/sangre , Ecocardiografía , Corazón/diagnóstico por imagen , Corazón/fisiopatología , Isoproterenol , Masculino , Miocardio/metabolismo , Miocardio/patología , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Elevated parathyroid hormone (PTH) levels in secondary hyperparathyroidism (SHPT) lead to vascular calcification, which is associated with cardiovascular events and mortality. Increased PTH production is caused by the excessive proliferation of parathyroid gland cells, which is accelerated by abnormal mineral homeostasis. Evocalcet, an oral calcimimetic agent, inhibits the secretion of PTH from parathyroid gland cells and has been used for the management of SHPT in dialysis patients. We observed the effects of evocalcet on ectopic calcification and parathyroid hyperplasia using chronic kidney disease (CKD) rats with SHPT. METHODS: CKD rats with SHPT induced by adenine received evocalcet orally for 5 weeks. The calcium and inorganic phosphorus content in the aorta, heart and kidney was measured. Ectopic calcified tissues were also assessed histologically. To observe the effects on the proliferation of parathyroid gland cells, parathyroid glands were histologically assessed in CKD rats with SHPT induced by 5/6 nephrectomy (Nx) after receiving evocalcet orally for 4 weeks. RESULTS: Evocalcet prevented the increase in calcium and inorganic phosphorus content in the ectopic tissues and suppressed calcification of the aorta, heart and kidney in CKD rats with SHPT by reducing the serum PTH and calcium levels. Evocalcet suppressed the parathyroid gland cell proliferation and reduced the sizes of parathyroid cells in CKD rats with SHPT. CONCLUSIONS: These findings suggest that evocalcet would prevent ectopic calcification and suppress parathyroid hyperplasia in patients with SHPT.
Asunto(s)
Hiperparatiroidismo Secundario/complicaciones , Naftalenos/uso terapéutico , Glándulas Paratiroides/patología , Pirrolidinas/uso terapéutico , Calcificación Vascular/prevención & control , Animales , Calcimiméticos/uso terapéutico , Hiperplasia/etiología , Hiperplasia/prevención & control , Masculino , Ratas , Ratas Sprague-Dawley , Calcificación Vascular/etiologíaRESUMEN
Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels.
Asunto(s)
Corteza Suprarrenal/efectos de los fármacos , Aldosterona/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Dihidropiridinas/farmacología , Corteza Suprarrenal/enzimología , Corteza Suprarrenal/metabolismo , Angiotensina II/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Calcio/metabolismo , Canales de Calcio Tipo L/efectos de los fármacos , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo T/metabolismo , Línea Celular , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Potenciales de la Membrana , Técnicas de Placa-Clamp , Cloruro de Potasio/farmacología , ARN Mensajero/metabolismo , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 11-beta-Hidroxilasa/metabolismo , Tetrazoles/farmacología , Valina/análogos & derivados , Valina/farmacología , ValsartánRESUMEN
Although previous studies have shown an important role of renal dipeptidyl peptidase-4 (DPP-4) inhibition in ameliorating kidney injury in hypertensive rats, the renal distribution of DPP-4 and mechanisms of renoprotective action of DPP-4 inhibition remain unclear. In this study, we examined the effects of the DPP-4 inhibitor saxagliptin on DPP-4 activity in renal cells (using in situ DPP-4 staining) and on renal gene expression related to inflammation and fibrosis in the renal injury in hypertensive Dahl salt-sensitive (Dahl-S) rats. Male rats fed a high-salt (8% NaCl) diet received vehicle (water) or saxagliptin (12.7mg/kg/day) for 4 weeks. Blood pressure (BP), serum glucose and 24-h urinary albumin and sodium excretions were measured, and renal histopathology was performed. High salt-diet increased BP and urinary albumin excretion, consequently resulting in glomerular sclerosis and tubulointerstitial fibrosis. Although saxagliptin did not affect BP and blood glucose levels, it significantly ameliorated urinary albumin excretion. In situ staining showed DPP-4 activity in glomerular and tubular cells. Saxagliptin significantly suppressed DPP-4 activity in renal tissue extracts and in glomerular and tubular cells. Saxagliptin also significantly attenuated the increase in inflammation and fibrosis-related gene expressions in the kidney. Our results demonstrate that saxagliptin inhibited the development of renal injury independent of its glucose-lowering effect. Glomerular and tubular DPP-4 inhibition by saxagliptin was associated with improvements in albuminuria and the suppression of inflammation and fibrosis-related genes. Thus, local glomerular and tubular DPP-4 inhibition by saxagliptin may play an important role in its renoprotective effects in Dahl-S rats.
Asunto(s)
Adamantano/análogos & derivados , Citoprotección/efectos de los fármacos , Dipéptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipertensión/tratamiento farmacológico , Riñón/efectos de los fármacos , Adamantano/farmacología , Adamantano/uso terapéutico , Animales , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Creatinina/sangre , Dipéptidos/uso terapéutico , Dipeptidil Peptidasa 4/sangre , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Fibrosis , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/metabolismo , Hipertensión/patología , Hipertensión/fisiopatología , Riñón/metabolismo , Riñón/patología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas Dahl , Sodio/orinaRESUMEN
Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury.
Asunto(s)
Adamantano/análogos & derivados , Dipéptidos/farmacología , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipertensión/tratamiento farmacológico , Enfermedades Renales/prevención & control , Glomérulos Renales/efectos de los fármacos , Adamantano/farmacología , Albuminuria/enzimología , Albuminuria/prevención & control , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Citoprotección , Dipeptidil Peptidasa 4/sangre , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipertensión/enzimología , Hipertensión/patología , Hipertensión/fisiopatología , Enfermedades Renales/enzimología , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Glomérulos Renales/enzimología , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Masculino , Ratas Endogámicas Dahl , Fosfato de Sitagliptina/farmacologíaRESUMEN
Aldosterone-induced activation of mineralocorticoid receptor, a member of the nuclear receptor family, results in increased tissue damage such as vascular inflammation and cardiac and perivascular fibrosis. Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for hypertension and angina. Benidipine exhibits pleiotropic pharmacological features such as renoprotective and cardioprotective effects through triple blockade of L-, N-, and T-type calcium channels. However, the mechanism of additional beneficial effects on end-organ damage is poorly understood. Here, we examined the effects of benidipine and other calcium channel blockers on aldosterone-induced mineralocorticoid receptor activation using luciferase reporter assay system. Benidipine showed more potent activity than efonidipine, amlodipine, or azelnidipine. Benidipine depressed the response to higher concentrations of aldosterone, whereas pretreatment of eplerenone, a steroidal mineralocorticoid receptor antagonist, did not. Binding studies using [(3)H] aldosterone indicated that benidipine and other calcium channel blockers competed for binding to mineralocorticoid receptor. Benidipine and other calcium channel blockers showed antagonistic activity on Ser810 to Leu mutant mineralocorticoid receptor, which is identified in patients with early-onset hypertension. On the other hand, eplerenone partially activated the mutant. Results of analysis using optical isomers of benidipine indicated that inhibitory effect of aldosterone-induced mineralocorticoid receptor activation was independent of its primary blockade of calcium channels. These results suggested that benidipine directly inhibits aldosterone-induced mineralocorticoid receptor activation, and the antagonistic activity might contribute to the drug's pleiotropic pharmacological features.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Antagonistas de Receptores de Mineralocorticoides , Aldosterona/farmacología , Sitios de Unión , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/metabolismo , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo N/metabolismo , Canales de Calcio Tipo T/metabolismo , Línea Celular , Dihidropiridinas/química , Dihidropiridinas/metabolismo , Eplerenona , Humanos , Modelos Moleculares , Conformación Molecular , Mutación , Piridinas/química , Piridinas/farmacología , Receptores de Mineralocorticoides/química , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Espironolactona/análogos & derivados , Espironolactona/farmacología , EstereoisomerismoRESUMEN
The purpose of this investigation was to define the sensitivity and specificity of the canine telemetry assay for detecting drug-induced QT interval prolongation. Data from twelve studies generated in the QT PRODACT project were used in this investigation. The study design was a 4x4 Latin square cross-over design and included the following drugs: MK-499, E-4031, terfenadine, haloperidol, cisapride, bepridil, propranolol, diphenhydramine, captopril, verapamil, amoxicillin, and ciprofloxacin. The estimated root squared error of the model, which estimated the slope of the QT-RR relationships for each animal, for all dogs during the pre-dosing period was 5.45%. Using the QT-RR model, the sensitivity and specificity in each cutoff value that judges QT prolongation were estimated based on the experiment errors and measurement errors in the 12 studies. When the cutoff value was 5%, the sensitivity in 10% prolongation was 0.978 and the specificity in 0% was 0.996. In conclusion, it was judged that a 5% cutoff value for changes in heart rate corrected QT interval using the canine telemetry assay is practical, and the sensitivity and specificity of the telemetry assay are very high when using the analytical method presented here. Based upon this information, the canine telemetry assay using the individual subject heart rate correction model is recommended as a sensitive test system for the in vivo assessment of risk for QT interval prolongation.
Asunto(s)
Electrocardiografía/métodos , Frecuencia Cardíaca , Síndrome de QT Prolongado/inducido químicamente , Modelos Estadísticos , Telemetría/métodos , Animales , Bases de Datos Factuales , Perros , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Sensibilidad y EspecificidadRESUMEN
The goal of the present study was to examine the utility of the conscious dog model by assessing the QT-interval-prolonging potential of ten positive compounds that have been reported to induce QT interval prolongation in clinical use and seven negative compounds considered not to have such an effect. Three doses of test compounds or vehicle were administered orally to male beagle dogs (n=4), and telemetry signals were recorded for 24 h after administration. All positive compounds (astemizole, bepridil, cisapride, E-4031, haloperidol, MK-499, pimozide, quinidine, terfenadine, and thioridazine) caused a significant increase in the corrected QT (QTc) interval, with a greater than 10% increase achieved at high doses. In contrast, administration of negative compounds (amoxicillin, captopril, ciprofloxacin, diphenhydramine, nifedipine, propranolol, and verapamil) did not produce any significant change in the QTc interval, with the exception of nifedipine that may have produced an overcorrection of the QTc interval due to increased heart rate. The estimated plasma concentrations of the positive compounds that caused a 10% increase in the QTc interval were in good agreement with the plasma/serum concentrations achieved in humans who developed prolonged QT interval or torsade de pointes (TdP). Although careful consideration should be given to the interpretation of QT data with marked heart rate change, these data suggest that an in vivo QT assay using the conscious dog is a useful model for the assessment of QT interval prolongation by human pharmaceuticals.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Síndrome de QT Prolongado/inducido químicamente , Modelos Animales , Animales , Bases de Datos Factuales , Perros , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Preparaciones Farmacéuticas/sangre , Farmacocinética , TelemetríaRESUMEN
In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n=3-4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and/or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation.