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Diane K Jorkasky - One of the best experts on this subject based on the ideXlab platform.

  • effect of age and gender on the pharmacokinetics of Eprosartan
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Steven C Boike, Ann K Miller, Nevine Zariffa, Diane K Jorkasky
    Abstract:

    AIMS: To compare the pharmacokinetics of Eprosartan between young (18-45 years) and elderly (65 years) men and between young men and young, premenopausal women (18-45 years). METHODS: Twenty-four subjects (eight subjects/group) received a single 200 mg Eprosartan oral dose followed by serial blood sampling over 24 h. RESULTS: Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of Eprosartan between young females and young males or in the plasma protein binding of Eprosartan (98%) for the three groups. On average, AUC (0,infinity) and Cmax values were approximately 2-fold higher in elderly men than young men [AUC (0,infinity) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.001. Similarly, unbound AUC (0,infinity) and Cmax values were, on average, approximately 2-fold higher in elderly men than young men [unbound AUC (0,infinity) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h). CONCLUSIONS: No gender differences were observed in the pharmacokinetics of Eprosartan. There were approximately two fold higher AUC and Cmax values for Eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of Eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg Eprosartan) Eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of Eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.

  • pharmacokinetics and protein binding of Eprosartan in hemodialysis dependent patients with end stage renal disease
    Pharmacotherapy, 1999
    Co-Authors: Steven J Kovacs, David Tenero, David E Martin, Bernard E Ilson, Diane K Jorkasky
    Abstract:

    Study Objectives. To compare Eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values. Design. Open-label, parallel-group, single-dose study. Setting. Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit. Patients. Ten healthy volunteers and nine hemodialysis patients. Intervention. A single oral dose of Eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis. Measurements and Main Results. Concentrations of Eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC0–t was increased approximately 60% (95% CI −22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI −40, 71). Mean percent fraction unbound (%fu) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC0–t and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI −1, 199) greater, respectively, in patients. After hemodialysis, the mean %fu decreased from 3.19–2.01%. Mean recovery of Eprosartan in dialysate was 6.8 mg (range 0–23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance. Conclusions. Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of Eprosartan after hemodialysis are unnecessary.

  • pharmacokinetics of intravenously and orally administered Eprosartan in healthy males absolute bioavailability and effect of food
    Biopharmaceutics & Drug Disposition, 1998
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Duane Boyle, Nevine Zariffa, John Jushchyshyn, Steve Boike, David Lundberg, Diane K Jorkasky
    Abstract:

    Eighteen healthy males received a single 300 mg oral dose of Eprosartan as the commercial wet granulation formulation under fasting conditions and following a high-fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. Eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min−1) and a small steady-state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH-dependent aqueous solubility of Eprosartan is one factor which limits absorption. Eprosartan terminal half-life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate-limited elimination following oral administration. Oral administration of Eprosartan following a high-fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when Eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, Eprosartan may be administered without regard to meal times. © 1998 John Wiley & Sons, Ltd.

  • Eprosartan does not affect the pharmacodynamics of warfarin
    The Journal of Clinical Pharmacology, 1998
    Co-Authors: David J Kazierad, David E Martin, Bernard E Ilson, Steven C Boike, Nevine Zariffa, Alan Forrest, Diane K Jorkasky
    Abstract:

    Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of Eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either Eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with Eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of Eprosartan and warfarin. As measured by the INR, there is no apparent effect of Eprosartan on the anticoagulant effect of warfarin.

  • the effects of Eprosartan an angiotensin ii at1 receptor antagonist on uric acid excretion in patients with mild to moderate essential hypertension
    The Journal of Clinical Pharmacology, 1998
    Co-Authors: Bernard E Ilson, David E Martin, Steven C Boike, Diane K Jorkasky
    Abstract:

    The effects of antihypertensive agents, including angiotensin II receptor antagonists, on urine uric acid excretion may have important clinical consequences. Therefore, the effects of single and repeated doses of Eprosartan on uric acid excretion were evaluated in 57 male patients with mild-to-moderate essential hypertension in a double-blind, randomized, placebo-controlled, repeated dose, dose-rising, two-period, period-balanced, crossover study conducted in two parts. In part 1 (n = 33), the effects of Eprosartan dose regimens of of 50 mg, 100 mg, and 350 mg once daily and 150 mg every 12 hours on uric acid excretion were assessed. In part 2 (n = 24), the effects of Eprosartan dose regimens of 600 mg, 800 mg, and 1,200 mg once daily on uric acid excretion were assessed. Eprosartan was well tolerated. There were no appreciable changes from predose values in fractional excretion of uric acid (FE ua ), urine uric acid excretion, urine uric acid to creatinine (U ua /U cr ) ratios, or serum uric acid concentrations after single or repeated doses of Eprosartan. Mean U ua /U cr ratios for Eprosartan doses of 50 mg, 100 mg, or 350 mg daily or 150 mg every 12 hours were comparable to those for placebo. Mean FE ua values and U ua /U cr ratios for Eprosartan doses of 600 mg, 800 mg, or 1,200 mg daily also were comparable to those for placebo. Single and repeated oral doses of Eprosartan ranging from 50 mg to 1,200 mg daily had no effect on serum uric acid concentrations or urine uric acid excretion in patients with mild-to-moderate essential hypertension.

Bernard E Ilson - One of the best experts on this subject based on the ideXlab platform.

  • effect of age and gender on the pharmacokinetics of Eprosartan
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Steven C Boike, Ann K Miller, Nevine Zariffa, Diane K Jorkasky
    Abstract:

    AIMS: To compare the pharmacokinetics of Eprosartan between young (18-45 years) and elderly (65 years) men and between young men and young, premenopausal women (18-45 years). METHODS: Twenty-four subjects (eight subjects/group) received a single 200 mg Eprosartan oral dose followed by serial blood sampling over 24 h. RESULTS: Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of Eprosartan between young females and young males or in the plasma protein binding of Eprosartan (98%) for the three groups. On average, AUC (0,infinity) and Cmax values were approximately 2-fold higher in elderly men than young men [AUC (0,infinity) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.001. Similarly, unbound AUC (0,infinity) and Cmax values were, on average, approximately 2-fold higher in elderly men than young men [unbound AUC (0,infinity) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h). CONCLUSIONS: No gender differences were observed in the pharmacokinetics of Eprosartan. There were approximately two fold higher AUC and Cmax values for Eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of Eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg Eprosartan) Eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of Eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.

  • pharmacokinetics and protein binding of Eprosartan in hemodialysis dependent patients with end stage renal disease
    Pharmacotherapy, 1999
    Co-Authors: Steven J Kovacs, David Tenero, David E Martin, Bernard E Ilson, Diane K Jorkasky
    Abstract:

    Study Objectives. To compare Eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values. Design. Open-label, parallel-group, single-dose study. Setting. Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit. Patients. Ten healthy volunteers and nine hemodialysis patients. Intervention. A single oral dose of Eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis. Measurements and Main Results. Concentrations of Eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC0–t was increased approximately 60% (95% CI −22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI −40, 71). Mean percent fraction unbound (%fu) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC0–t and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI −1, 199) greater, respectively, in patients. After hemodialysis, the mean %fu decreased from 3.19–2.01%. Mean recovery of Eprosartan in dialysate was 6.8 mg (range 0–23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance. Conclusions. Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of Eprosartan after hemodialysis are unnecessary.

  • pharmacokinetics of intravenously and orally administered Eprosartan in healthy males absolute bioavailability and effect of food
    Biopharmaceutics & Drug Disposition, 1998
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Duane Boyle, Nevine Zariffa, John Jushchyshyn, Steve Boike, David Lundberg, Diane K Jorkasky
    Abstract:

    Eighteen healthy males received a single 300 mg oral dose of Eprosartan as the commercial wet granulation formulation under fasting conditions and following a high-fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. Eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min−1) and a small steady-state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH-dependent aqueous solubility of Eprosartan is one factor which limits absorption. Eprosartan terminal half-life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate-limited elimination following oral administration. Oral administration of Eprosartan following a high-fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when Eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, Eprosartan may be administered without regard to meal times. © 1998 John Wiley & Sons, Ltd.

  • Eprosartan does not affect the pharmacodynamics of warfarin
    The Journal of Clinical Pharmacology, 1998
    Co-Authors: David J Kazierad, David E Martin, Bernard E Ilson, Steven C Boike, Nevine Zariffa, Alan Forrest, Diane K Jorkasky
    Abstract:

    Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of Eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either Eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with Eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of Eprosartan and warfarin. As measured by the INR, there is no apparent effect of Eprosartan on the anticoagulant effect of warfarin.

  • the effects of Eprosartan an angiotensin ii at1 receptor antagonist on uric acid excretion in patients with mild to moderate essential hypertension
    The Journal of Clinical Pharmacology, 1998
    Co-Authors: Bernard E Ilson, David E Martin, Steven C Boike, Diane K Jorkasky
    Abstract:

    The effects of antihypertensive agents, including angiotensin II receptor antagonists, on urine uric acid excretion may have important clinical consequences. Therefore, the effects of single and repeated doses of Eprosartan on uric acid excretion were evaluated in 57 male patients with mild-to-moderate essential hypertension in a double-blind, randomized, placebo-controlled, repeated dose, dose-rising, two-period, period-balanced, crossover study conducted in two parts. In part 1 (n = 33), the effects of Eprosartan dose regimens of of 50 mg, 100 mg, and 350 mg once daily and 150 mg every 12 hours on uric acid excretion were assessed. In part 2 (n = 24), the effects of Eprosartan dose regimens of 600 mg, 800 mg, and 1,200 mg once daily on uric acid excretion were assessed. Eprosartan was well tolerated. There were no appreciable changes from predose values in fractional excretion of uric acid (FE ua ), urine uric acid excretion, urine uric acid to creatinine (U ua /U cr ) ratios, or serum uric acid concentrations after single or repeated doses of Eprosartan. Mean U ua /U cr ratios for Eprosartan doses of 50 mg, 100 mg, or 350 mg daily or 150 mg every 12 hours were comparable to those for placebo. Mean FE ua values and U ua /U cr ratios for Eprosartan doses of 600 mg, 800 mg, or 1,200 mg daily also were comparable to those for placebo. Single and repeated oral doses of Eprosartan ranging from 50 mg to 1,200 mg daily had no effect on serum uric acid concentrations or urine uric acid excretion in patients with mild-to-moderate essential hypertension.

David E Martin - One of the best experts on this subject based on the ideXlab platform.

  • effect of age and gender on the pharmacokinetics of Eprosartan
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Steven C Boike, Ann K Miller, Nevine Zariffa, Diane K Jorkasky
    Abstract:

    AIMS: To compare the pharmacokinetics of Eprosartan between young (18-45 years) and elderly (65 years) men and between young men and young, premenopausal women (18-45 years). METHODS: Twenty-four subjects (eight subjects/group) received a single 200 mg Eprosartan oral dose followed by serial blood sampling over 24 h. RESULTS: Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of Eprosartan between young females and young males or in the plasma protein binding of Eprosartan (98%) for the three groups. On average, AUC (0,infinity) and Cmax values were approximately 2-fold higher in elderly men than young men [AUC (0,infinity) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.001. Similarly, unbound AUC (0,infinity) and Cmax values were, on average, approximately 2-fold higher in elderly men than young men [unbound AUC (0,infinity) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h). CONCLUSIONS: No gender differences were observed in the pharmacokinetics of Eprosartan. There were approximately two fold higher AUC and Cmax values for Eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of Eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg Eprosartan) Eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of Eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.

  • pharmacokinetics and protein binding of Eprosartan in hemodialysis dependent patients with end stage renal disease
    Pharmacotherapy, 1999
    Co-Authors: Steven J Kovacs, David Tenero, David E Martin, Bernard E Ilson, Diane K Jorkasky
    Abstract:

    Study Objectives. To compare Eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values. Design. Open-label, parallel-group, single-dose study. Setting. Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit. Patients. Ten healthy volunteers and nine hemodialysis patients. Intervention. A single oral dose of Eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis. Measurements and Main Results. Concentrations of Eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC0–t was increased approximately 60% (95% CI −22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI −40, 71). Mean percent fraction unbound (%fu) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC0–t and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI −1, 199) greater, respectively, in patients. After hemodialysis, the mean %fu decreased from 3.19–2.01%. Mean recovery of Eprosartan in dialysate was 6.8 mg (range 0–23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance. Conclusions. Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of Eprosartan after hemodialysis are unnecessary.

  • pharmacokinetics of intravenously and orally administered Eprosartan in healthy males absolute bioavailability and effect of food
    Biopharmaceutics & Drug Disposition, 1998
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Duane Boyle, Nevine Zariffa, John Jushchyshyn, Steve Boike, David Lundberg, Diane K Jorkasky
    Abstract:

    Eighteen healthy males received a single 300 mg oral dose of Eprosartan as the commercial wet granulation formulation under fasting conditions and following a high-fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. Eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min−1) and a small steady-state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH-dependent aqueous solubility of Eprosartan is one factor which limits absorption. Eprosartan terminal half-life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate-limited elimination following oral administration. Oral administration of Eprosartan following a high-fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when Eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, Eprosartan may be administered without regard to meal times. © 1998 John Wiley & Sons, Ltd.

  • Eprosartan does not affect the pharmacodynamics of warfarin
    The Journal of Clinical Pharmacology, 1998
    Co-Authors: David J Kazierad, David E Martin, Bernard E Ilson, Steven C Boike, Nevine Zariffa, Alan Forrest, Diane K Jorkasky
    Abstract:

    Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of Eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either Eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with Eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of Eprosartan and warfarin. As measured by the INR, there is no apparent effect of Eprosartan on the anticoagulant effect of warfarin.

  • the effects of Eprosartan an angiotensin ii at1 receptor antagonist on uric acid excretion in patients with mild to moderate essential hypertension
    The Journal of Clinical Pharmacology, 1998
    Co-Authors: Bernard E Ilson, David E Martin, Steven C Boike, Diane K Jorkasky
    Abstract:

    The effects of antihypertensive agents, including angiotensin II receptor antagonists, on urine uric acid excretion may have important clinical consequences. Therefore, the effects of single and repeated doses of Eprosartan on uric acid excretion were evaluated in 57 male patients with mild-to-moderate essential hypertension in a double-blind, randomized, placebo-controlled, repeated dose, dose-rising, two-period, period-balanced, crossover study conducted in two parts. In part 1 (n = 33), the effects of Eprosartan dose regimens of of 50 mg, 100 mg, and 350 mg once daily and 150 mg every 12 hours on uric acid excretion were assessed. In part 2 (n = 24), the effects of Eprosartan dose regimens of 600 mg, 800 mg, and 1,200 mg once daily on uric acid excretion were assessed. Eprosartan was well tolerated. There were no appreciable changes from predose values in fractional excretion of uric acid (FE ua ), urine uric acid excretion, urine uric acid to creatinine (U ua /U cr ) ratios, or serum uric acid concentrations after single or repeated doses of Eprosartan. Mean U ua /U cr ratios for Eprosartan doses of 50 mg, 100 mg, or 350 mg daily or 150 mg every 12 hours were comparable to those for placebo. Mean FE ua values and U ua /U cr ratios for Eprosartan doses of 600 mg, 800 mg, or 1,200 mg daily also were comparable to those for placebo. Single and repeated oral doses of Eprosartan ranging from 50 mg to 1,200 mg daily had no effect on serum uric acid concentrations or urine uric acid excretion in patients with mild-to-moderate essential hypertension.

David P Brooks - One of the best experts on this subject based on the ideXlab platform.

  • the angiotensin type 1 receptor antagonist Eprosartan attenuates the progression of renal disease in spontaneously hypertensive stroke prone rats with accelerated hypertension
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Christian T Abrahamsen, Richard M. Edwards, Frank C Barone, Allen H Nelson, Lisa C Contino, Wallace G Campbell, Mark Pullen, Eugene T Grygielko, Nicholas J Laping, David P Brooks
    Abstract:

    The effects of the angiotensin type 1 (AT 1 ) receptor antagonist, Eprosartan, were studied in a model of severe, chronic hypertension. Treatment of male spontaneously hypertensive stroke prone rats (SHR-SP) fed a high-fat, high-salt diet with Eprosartan (60 mg/kg/day i.p.) for 12 weeks resulted in a lowering of blood pressure (250 ± 9 versus 284 ± 8 mm Hg), renal expression of transforming growth factor-β mRNA (1.5 ± 0.2 versus 5.4 ± 1.4) and the matrix components: plasminogen activator inhibitor-1 (5.2 ± 1.4 versus 31.4 ± 10.7), fibronectin (2.2 ± 0.6 versus 8.2 ± 2.2), collagen I-α1 (5.6 ± 2.0 versus 23.8 ± 7.3), and collagen III (2.7 ± 0.9 versus 7.6 ± 2.1). Data were corrected for rpL32 mRNA expression and expressed relative to Wistar Kyoto (WKY) rats [=1.0]. Expression of fibronectin protein was also lowered by Eprosartan (0.8 ± 0.1 versus 1.9 ± 0.5), relative to WKY rats. Eprosartan provided significant renoprotection to SHR-SP rats as measured by decreased proteinuria (22 ± 2 versus 127 ± 13 mg/day) and histological evidence of active renal damage (5 ± 2 versus 195 ± 6) and renal fibrosis (5.9 ± 0.7 versus 16.4 ± 1.9) in vehicle- versus Eprosartan-treated rats, respectively. Our results demonstrated that AT 1 receptor blockade with Eprosartan can reduce blood pressure and preserve renal structure and function in this model of severe, chronic hypertension. These effects were accompanied by a decreased renal expression of transforming growth factor-β1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.

  • Eprosartan reduces cardiac hypertrophy protects heart and kidney and prevents early mortality in severely hypertensive stroke prone rats
    Cardiovascular Research, 2001
    Co-Authors: Frank C Barone, David P Brooks, Robert W Coatney, Sudeep Chandra, Susanta K Sarkar, Allen H Nelson, Lisa C Contino, Wallace G Campbell, Eliot H Ohlstein, Robert N Willette
    Abstract:

    Objective: Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, Eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP). Methods: SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) ( n =25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats ( n =25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups. Results : Eprosartan decreased the severely elevated arterial pressure (−12%; P <0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (−13%; P <0.05) and marked mortality (50% by week 6 and 95% by week 9; P <0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion ( P <0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (−15.9%), chamber volume (−32.7%), stroke volume (−48.7%) and ejection fraction (−22.3%), and a remarkable decrease in cardiac output (−59.3%) compared to controls (all P <0.05). These same parameters in Eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P <0.05). Cardiac-gated MRI data confirmed the ability of Eprosartan to prevent cardiac pathology/remodeling ( P <0.05). Histopathological analysis of hearts and kidneys indicated that Eprosartan treatment significantly reduced end-organ damage ( P <0.01) and provided corroborative evidence that Eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by Eprosartan ( P <0.05). Conclusion : These data demonstrate that Eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

  • pharmacology of Eprosartan an angiotensin ii receptor antagonist exploring hypotheses from clinical data
    American Heart Journal, 1999
    Co-Authors: David P Brooks, Eliot H Ohlstein, Robert R. Ruffolo
    Abstract:

    Abstract Selective blockade of the angiotensin II AT1 receptor represents a novel mechanism for interrupting the renin-angiotensin system without altering the potential benefits of AT2 receptor stimulation. This selective inhibition produces none of the disadvantages associated with reduced bradykinin metabolism and angiotensin II generated by non–angiotensin-converting enzyme pathways. Eprosartan is a potent (1.4 nmol/L) AT1 receptor antagonist that competitively blocks angiotensin II–induced vascular contraction. In various animal models of disease, including hypertension and stroke, Eprosartan is effective in reducing disease progression. Eprosartan also has sympathoinhibitory activity, as demonstrated by an inhibition of the pressor responses induced by activation of sympathetic outflow through spinal cord stimulation in pithed rats. In contrast, some of the other angiotensin II receptor antagonists, such as losartan, at equivalent angiotensin II blocking doses, have no effect on sympathetic nervous system activity. Because Eprosartan can inhibit both the direct effects of angiotensin II as well as the indirect effects that are mediated by enhanced sympathetic neurotransmission, this may represent an important advance in the treatment of elevated systolic blood pressure. (Am Heart J 1999;138:S246-S251.)

  • effects of Eprosartan on glomerular injury in rats with reduced renal mass
    Pharmacology, 1999
    Co-Authors: Mehul M Gandhi, Timothy W Meyer, David P Brooks
    Abstract:

    The effects of the selective angiotensin AT1 receptor antagonist, Eprosartan, were evaluated in experimental renal disease. Five-sixth nephrectomy in male Munich-Wistar rats led to the development of hypertension, proteinuria and remnant glomerulosclerosis. Administration of the AT1 receptor antagonist, Eprosartan, for 4 weeks resulted in inhibition of angiotensin II activity as confirmed by a reduced blood pressure response to exogenous angiotensin II challenge. Compared to vehicle treatment, Eprosartan normalized blood pressure, reduced proteinuria and limited remnant glomerulosclerosis. These data suggest that Eprosartan may provide a new tool in the treatment of progressive renal disease.

  • Pharmacology of the angiotensin II receptor antagonist, Eprosartan.
    Expert Opinion on Investigational Drugs, 1998
    Co-Authors: Richard M. Edwards, Robert R. Ruffolo, David P Brooks
    Abstract:

    The non-peptide angiotensin II receptor antagonists represent a new class of drugs with demonstrated efficacy in the treatment of hypertension. Eprosartan is a potent, orally active AT1 receptor antagonist which is chemically distinct from losartan and other non-peptide angiotensin II receptor antagonists. Eprosartan has a high affinity for the angiotensin II AT1 receptor, but does not interact with the AT2 receptor, adrenergic receptors or other receptors involved in cardiovascular regulation. In contrast to most other angiotensin II antagonists, Eprosartan is a true competitive antagonist of the AT1 receptor. Eprosartan is effective in antagonising the cardiovascular and renal effects of exogenous angiotensin II in both experimental animals and humans. Furthermore, it is an effective antihypertensive agent when administered to renin-dependent hypertension animal models, and in patients with mild to severe hypertension. The antihypertensive effect of Eprosartan is maintained over a 24-h interval followin...

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  • effect of age and gender on the pharmacokinetics of Eprosartan
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Steven C Boike, Ann K Miller, Nevine Zariffa, Diane K Jorkasky
    Abstract:

    AIMS: To compare the pharmacokinetics of Eprosartan between young (18-45 years) and elderly (65 years) men and between young men and young, premenopausal women (18-45 years). METHODS: Twenty-four subjects (eight subjects/group) received a single 200 mg Eprosartan oral dose followed by serial blood sampling over 24 h. RESULTS: Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of Eprosartan between young females and young males or in the plasma protein binding of Eprosartan (98%) for the three groups. On average, AUC (0,infinity) and Cmax values were approximately 2-fold higher in elderly men than young men [AUC (0,infinity) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.001. Similarly, unbound AUC (0,infinity) and Cmax values were, on average, approximately 2-fold higher in elderly men than young men [unbound AUC (0,infinity) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h). CONCLUSIONS: No gender differences were observed in the pharmacokinetics of Eprosartan. There were approximately two fold higher AUC and Cmax values for Eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of Eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg Eprosartan) Eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of Eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.

  • pharmacokinetics and protein binding of Eprosartan in hemodialysis dependent patients with end stage renal disease
    Pharmacotherapy, 1999
    Co-Authors: Steven J Kovacs, David Tenero, David E Martin, Bernard E Ilson, Diane K Jorkasky
    Abstract:

    Study Objectives. To compare Eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values. Design. Open-label, parallel-group, single-dose study. Setting. Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit. Patients. Ten healthy volunteers and nine hemodialysis patients. Intervention. A single oral dose of Eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis. Measurements and Main Results. Concentrations of Eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC0–t was increased approximately 60% (95% CI −22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI −40, 71). Mean percent fraction unbound (%fu) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC0–t and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI −1, 199) greater, respectively, in patients. After hemodialysis, the mean %fu decreased from 3.19–2.01%. Mean recovery of Eprosartan in dialysate was 6.8 mg (range 0–23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance. Conclusions. Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of Eprosartan after hemodialysis are unnecessary.

  • a review of Eprosartan pharmacokinetic and pharmacodynamic drug interaction studies
    Pharmacotherapy, 1999
    Co-Authors: Robert A Blum, David J Kazierad, David Tenero
    Abstract:

    A series of clinical pharmacology studies was conducted to characterize potential interactions between Eprosartan and other commonly prescribed drugs. Separate studies assessed the effect of Eprosartan on the pharmacokinetics of digoxin and hydrochlorothiazide (HCTZ) and the pharmacodynamics of warfarin and glyburide (glibenclamide), as well as the effects of ranitidine, HCTZ, fluconazole, and ketoconazole on Eprosartan pharmacokinetics. Eprosartan had no significant effect on the pharmacokinetics of digoxin and HCTZ and the pharmacodynamics of warfarin and glyburide. Thus, no dosing adjustments are necessary during concomitant therapy with these agents. Ranitidine, HCTZ, ketoconazole, and fluconazole had no effect on Eprosartan pharmacokinetics. Single or multiple oral doses of Eprosartan were safe and well tolerated when coadministered with these agents.

  • pharmacokinetics of intravenously and orally administered Eprosartan in healthy males absolute bioavailability and effect of food
    Biopharmaceutics & Drug Disposition, 1998
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Duane Boyle, Nevine Zariffa, John Jushchyshyn, Steve Boike, David Lundberg, Diane K Jorkasky
    Abstract:

    Eighteen healthy males received a single 300 mg oral dose of Eprosartan as the commercial wet granulation formulation under fasting conditions and following a high-fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. Eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min−1) and a small steady-state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH-dependent aqueous solubility of Eprosartan is one factor which limits absorption. Eprosartan terminal half-life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate-limited elimination following oral administration. Oral administration of Eprosartan following a high-fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when Eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, Eprosartan may be administered without regard to meal times. © 1998 John Wiley & Sons, Ltd.

  • effect of ranitidine on the pharmacokinetics of orally administered Eprosartan an angiotensin ii antagonist in healthy male volunteers
    Annals of Pharmacotherapy, 1998
    Co-Authors: David Tenero, David E Martin, Bernard E Ilson, Duane Boyle, Steven C Boike, Alison M Carr, David E Lundberg, Diane K Jorkasky
    Abstract:

    OBJECTIVE:To assess the effect of ranitidine on the pharmacokinetics of Eprosartan in healthy male volunteers.DESIGN:Single-center, randomized, open-label, two-period, period-balanced, crossover study.PATIENTS:Seventeen healthy men aged 19 to 43 years.INTERVENTION:In each period (separated by a ≥7 d washout), subjects received a single 400-mg oral dose of Eprosartan alone, or a single oral dose of Eprosartan 400 mg and ranitidine 150 mg on day 4 after 3 days of ranitidine 150 mg twice daily. Serial pharmacokinetic samples were obtained for up to 24 hours following Eprosartan dosing.MAIN OUTCOME MEASURES:Plasma and urine Eprosartan concentrations during each treatment session.RESULTS:Eprosartan maximum concentration (Cmax), the AUC from time zero to the last quantifiable concentration (AUC0-t), and renal clearance (Clr) values were approximately 7%, 11%, and 4% lower, respectively, when administered with ranitidine compared with Eprosartan alone. The 95% CIs for the ratio of Eprosartan plus ranitidine comp...