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Edward M Gilbert - One of the best experts on this subject based on the ideXlab platform.
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COMPARE: comparison of the effects of Carvedilol CR and Carvedilol IR on left ventricular ejection fraction in patients with heart failure.
The American journal of cardiology, 2006Co-Authors: Barry H Greenberg, Mandeep Mehra, John R Teerlink, Paul Ordronneau, David Mccollum, Edward M GilbertAbstract:Left ventricular ejection fraction (LVEF) is an important measure of ventricular function in the evaluation of heart failure. Immediate-release (IR) Carvedilol twice daily has been shown to improve LVEF in subjects with ischemic and nonischemic chronic heart failure. A once-daily formulation, controlled-release (CR) Carvedilol, is expected to improve quality of care through improved adherence as a result of the reduced frequency of dosing. This multicenter, randomized, double-blind study in subjects with stable chronic heart failure will compare the change in LVEF in patients receiving Carvedilol IR with those receiving Carvedilol CR. LVEF will be measured by 2-dimensional echocardiography at 6 months after entry into the maintenance period of the study drug. The secondary objectives of this study are to assess changes in left ventricular remodeling and function, to evaluate changes in brain natriuretic peptide levels, and to determine the incidence of all-cause and heart failure-related hospitalizations and all-cause mortality after treatment with Carvedilol CR or Carvedilol IR.
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race and the response to adrenergic blockade with Carvedilol in patients with chronic heart failure
The New England Journal of Medicine, 2001Co-Authors: Clyde W Yancy, Jay N Cohn, Edward M Gilbert, Michael R Bristow, Mary Ann Lukas, Michael Fowler, Wilson S Colucci, Sarah T Young, Milton PackerAbstract:Background The benefits of angiotensin-converting–enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to Carvedilol in patients with chronic heart failure. Methods In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or Carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of Carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. Results As compared with placebo, Carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leadi...
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comparative hemodynamic left ventricular functional and antiadrenergic effects of chronic treatment with metoprolol versus Carvedilol in the failing heart
Circulation, 1996Co-Authors: Edward M Gilbert, S L Olsen, William T Abraham, Brack G Hattler, Michel White, Patrice Mealy, Patti Larrabee, Michael R BristowAbstract:Background The basic pharmacology of the third-generation β-blocking agent Carvedilol differs considerably from second-generation compounds such as metoprolol. Moreover, Carvedilol may produce different, ie, more favorable, clinical effects in chronic heart failure. For these reasons, we compared the effects of Carvedilol and metoprolol on adrenergic activity, receptor expression, degree of clinical β-blockade, hemodynamics, and left ventricular function in patients with mild or moderate chronic heart failure. Methods and Results The effects of Carvedilol versus metoprolol were compared in two concurrent placebo-controlled trials with Carvedilol or metoprolol that had common substudies focused on adrenergic, hemodynamic, and left ventricular functional measurements. All subjects in the substudies had chronic heart failure resulting from idiopathic dilated cardiomyopathy. Carvedilol at 50 to 100 mg/d produced reductions in exercise heart rate that were similar to metoprolol at 125 to 150 mg/d, indicating c...
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Carvedilol produces dose related improvements in left ventricular function and survival in subjects with chronic heart failure
Circulation, 1996Co-Authors: Michael R Bristow, Edward M Gilbert, Michael B. Fowler, William T Abraham, Kirkwood F Adams, Ray E Hershberger, Spencer H Kubo, Kenneth A Narahara, Henry Ingersoll, Steven K KruegerAbstract:Background We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of Carvedilol, a “third-generation” β-blocking agent with vasodilator properties, in chronic heart failure. Methods and Results Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID Carvedilol (low-dose group), 12.5 mg BID Carvedilol (medium-dose group), or 25 mg BID Carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, Carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, ...
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Carvedilol improves left ventricular function and symptoms in chronic heart failure a double blind randomized study
Journal of the American College of Cardiology, 1995Co-Authors: S L Olsen, Edward M Gilbert, Dale G Renlund, David O Taylor, Frank D Yanowitz, Michael R BristowAbstract:Objectives. This study assessed the safety and efficacy of Carvedilol in patients with heart failure caused by idiopathic or ischemic cardiomyopathy. Background. Carvedilol is a mildly beta 1 -selective betaadrenergic blocking agent with vasodilator properties. Beta-blockade may be beneficial in patients with heart failure, but the effects of Carvedilol are not known. Methods. Sixty patients with heart failure (New York Heart Association functional classes II to IV) and left ventricular ejection fraction ≤ 0.35 were enrolled in the study. All patients tolerated challenge with Carvedilol, 3.125 mg twice a day, and were randomized to receive Carvedilol (n = 36) versus placebo (n = 24). Study medication was titrated over 1 month from 6.25 to 25 mg twice a day ( 75 kg) and continued for 3 months. One placebo-treated and two Carvedilol-treated patients did not complete the study. Results. Carvedilol therapy resulted in a significant reduction in heart rate and mean pulmonary artery and pulmonary capillary wedge pressures and a significant increase in stroke volume and left ventricular stroke work. Left ventricular ejection fraction increased 52% in the Carvedilol group (from 0.21 to 0.32, p Conclusions. Long-term Carvedilol therapy improves rest cardiac function and lessens symptoms in patients with heart failure.
Milton Packer - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic profile of controlled release Carvedilol in patients with left ventricular dysfunction associated with chronic heart failure or after myocardial infarction
American Journal of Cardiology, 2006Co-Authors: Milton Packer, Charlotte A Baidoo, David Tenero, Mary Ann Lukas, Barry H GreenbergAbstract:We compared the pharmacokinetic (PK) profiles of repeated dosing with the currently available immediate-release (IR) Carvedilol (given twice daily) and a newly developed controlled-release (CR) formulation (given once daily) in patients with left ventricular dysfunction (LVD). We enrolled 188 patients with stable mild, moderate, or severe heart failure as well as survivors of a recent acute myocardial infarction (MI) with asymptomatic LVD (left ventricular ejection fraction ≤0.40) in a crossover study. PK variables were initially assessed after patients had received Carvedilol IR 3.125, 6.25, 12.5, or 25 mg twice daily for ≥2 weeks. Patients were then switched to the corresponding dose of Carvedilol CR (10, 20, 40, or 80 mg once daily), and PK variables were reassessed after an additional 2 weeks. The primary measures included trough plasma concentration (C τ ), maximum plasma concentration (C max ), and area under the concentration-time curve (AUC [0–t] ) for both enantiomers of Carvedilol of each formulation of the drug. The AUC (0–t) and the trough and maximum Carvedilol concentrations for both the R(+) and S(−) enantiomers were similar when Carvedilol IR was compared with Carvedilol CR as follows: 3.125 mg twice daily versus 10 mg once daily, 6.25 mg twice daily versus 20 mg once daily, 12.5 mg twice daily versus 40 mg once daily, and 25 mg twice daily versus 80 mg once daily, respectively. Based on a pooled analysis, the AUC (0–t) , C max , and C τ for both R(+) and S(−) were equivalent for the CR and IR formulations, with point estimates and 90% confidence intervals within the bioequivalence limits of 80%–125%. The fluctuation index (the CR–IR ratio for [C max − C min ]/C ss where C min is the minimum observed concentration over the dosing interval and C ss is the concentration at steady state) for both R(+)- and S(−)-Carvedilol was approximately 1, indicating that the peak-to-trough fluctuation in plasma concentration for Carvedilol after use of Carvedilol CR once daily was similar to that for Carvedilol IR given twice daily. The median time to maximum observed plasma concentration (t max ) was approximately 3 hours longer for both enantiomers after administration of Carvedilol CR as compared with Carvedilol IR. These data demonstrate that the new Carvedilol CR formulation given once daily is equivalent to the currently available Carvedilol IR formulation given twice daily in patients with heart failure and asymptomatic post-MI LVD.
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Carvedilol reduces the costs of medical care in severe heart failure an economic analysis of the copernicus study applied to the united kingdom
International Journal of Cardiology, 2005Co-Authors: Simon Stewart, Andrew J S Coats, John J V Mcmurray, Ansgar Hebborn, Milton PackerAbstract:Abstract Background The aim of this study was to determine the effects of Carvedilol on the costs related to the treatment of severe chronic heart failure (CHF). Methods Costs for the treatment for heart failure within the National Health Service (NHS) in the United Kingdom (UK) were applied to resource utilisation data prospectively collected in all patients randomized into the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Unit-specific, per diem (hospital bed day) costs were used to calculate expenditures due to hospitalizations. We also included costs of Carvedilol treatment, general practitioner surgery/office visits, hospital out-patient clinic visits and nursing home care based on estimates derived from validated patterns of clinical practice in the UK. Results The estimated cost of Carvedilol therapy and related ambulatory care for the 1156 patients assigned to active treatment was £530,771 (£44.89 per patient/month of follow-up). However, patients assigned to Carvedilol were hospitalised less often and accumulated fewer and less expensive days of admission. Consequently, the total estimated cost of hospital care was £3.49 million in the Carvedilol group compared with £4.24 million for the 1133 patients in the placebo arm. The cost of post-discharge care was also less in the Carvedilol than in the placebo group (£479,200 vs. £548,300). Overall, the cost per patient treated in the Carvedilol group was £3948 compared to £4279 in the placebo group. This equated to a cost of £385.98 vs. £434.18, respectively, per patient/month of follow-up: an 11.1% reduction in health care costs in favour of Carvedilol. Conclusions These findings suggest that not only can Carvedilol treatment increase survival and reduce hospital admissions in patients with severe CHF but that it can also cut costs in the process.
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comparative effects of Carvedilol and metoprolol on left ventricular ejection fraction in heart failure results of a meta analysis
American Heart Journal, 2001Co-Authors: Milton Packer, George V Antonopoulos, Jesse A Berlin, Jesse Chittams, Marvin A Konstam, James E UdelsonAbstract:Abstract Background Both metoprolol and Carvedilol improve cardiac function and prolong survival in patients with heart failure. Carvedilol has broader antiadrenergic effects than metoprolol, but it is not clear whether this characteristic is associated with greater benefits on cardiac function during long-term treatment. Study Design We performed a meta-analysis of all 19 randomized controlled trials of Carvedilol or metoprolol that measured left ventricular ejection fraction before and after an average of 8.3 ± 0.1 months of treatment in 2184 patients with chronic heart failure. The mean daily doses were 58 ± 1 mg of Carvedilol and the equivalent of 162 ± 1 mg of extended-release metoprolol. In the 15 placebo-controlled trials, the mean ejection fraction increased more in the trials of Carvedilol than in the trials of metoprolol (placebo-corrected increases of +0.065 and +0.038, respectively), P = .0002. In the 4 active-controlled trials that compared metoprolol directly with Carvedilol, the mean ejection fraction also increased more in the Carvedilol groups than in the metoprolol groups (+0.084 on Carvedilol and +0.057 on metoprolol, respectively), P = .009. The difference in favor of Carvedilol in the active-controlled trials was nearly identical to the difference observed in the placebo-controlled trials and was apparent in patients with and without coronary artery disease. Conclusion Long-term treatment with Carvedilol produces greater effects on left ventricular ejection fraction than metoprolol when both drugs are prescribed in doses similar to those that have been shown to prolong life. (Am Heart J 2001;141:899-907.)
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race and the response to adrenergic blockade with Carvedilol in patients with chronic heart failure
The New England Journal of Medicine, 2001Co-Authors: Clyde W Yancy, Jay N Cohn, Edward M Gilbert, Michael R Bristow, Mary Ann Lukas, Michael Fowler, Wilson S Colucci, Sarah T Young, Milton PackerAbstract:Background The benefits of angiotensin-converting–enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to Carvedilol in patients with chronic heart failure. Methods In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or Carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of Carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. Results As compared with placebo, Carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leadi...
Michael R Bristow - One of the best experts on this subject based on the ideXlab platform.
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race and the response to adrenergic blockade with Carvedilol in patients with chronic heart failure
The New England Journal of Medicine, 2001Co-Authors: Clyde W Yancy, Jay N Cohn, Edward M Gilbert, Michael R Bristow, Mary Ann Lukas, Michael Fowler, Wilson S Colucci, Sarah T Young, Milton PackerAbstract:Background The benefits of angiotensin-converting–enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to Carvedilol in patients with chronic heart failure. Methods In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or Carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of Carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. Results As compared with placebo, Carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leadi...
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comparative hemodynamic left ventricular functional and antiadrenergic effects of chronic treatment with metoprolol versus Carvedilol in the failing heart
Circulation, 1996Co-Authors: Edward M Gilbert, S L Olsen, William T Abraham, Brack G Hattler, Michel White, Patrice Mealy, Patti Larrabee, Michael R BristowAbstract:Background The basic pharmacology of the third-generation β-blocking agent Carvedilol differs considerably from second-generation compounds such as metoprolol. Moreover, Carvedilol may produce different, ie, more favorable, clinical effects in chronic heart failure. For these reasons, we compared the effects of Carvedilol and metoprolol on adrenergic activity, receptor expression, degree of clinical β-blockade, hemodynamics, and left ventricular function in patients with mild or moderate chronic heart failure. Methods and Results The effects of Carvedilol versus metoprolol were compared in two concurrent placebo-controlled trials with Carvedilol or metoprolol that had common substudies focused on adrenergic, hemodynamic, and left ventricular functional measurements. All subjects in the substudies had chronic heart failure resulting from idiopathic dilated cardiomyopathy. Carvedilol at 50 to 100 mg/d produced reductions in exercise heart rate that were similar to metoprolol at 125 to 150 mg/d, indicating c...
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Carvedilol produces dose related improvements in left ventricular function and survival in subjects with chronic heart failure
Circulation, 1996Co-Authors: Michael R Bristow, Edward M Gilbert, Michael B. Fowler, William T Abraham, Kirkwood F Adams, Ray E Hershberger, Spencer H Kubo, Kenneth A Narahara, Henry Ingersoll, Steven K KruegerAbstract:Background We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of Carvedilol, a “third-generation” β-blocking agent with vasodilator properties, in chronic heart failure. Methods and Results Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID Carvedilol (low-dose group), 12.5 mg BID Carvedilol (medium-dose group), or 25 mg BID Carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, Carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, ...
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Carvedilol improves left ventricular function and symptoms in chronic heart failure a double blind randomized study
Journal of the American College of Cardiology, 1995Co-Authors: S L Olsen, Edward M Gilbert, Dale G Renlund, David O Taylor, Frank D Yanowitz, Michael R BristowAbstract:Objectives. This study assessed the safety and efficacy of Carvedilol in patients with heart failure caused by idiopathic or ischemic cardiomyopathy. Background. Carvedilol is a mildly beta 1 -selective betaadrenergic blocking agent with vasodilator properties. Beta-blockade may be beneficial in patients with heart failure, but the effects of Carvedilol are not known. Methods. Sixty patients with heart failure (New York Heart Association functional classes II to IV) and left ventricular ejection fraction ≤ 0.35 were enrolled in the study. All patients tolerated challenge with Carvedilol, 3.125 mg twice a day, and were randomized to receive Carvedilol (n = 36) versus placebo (n = 24). Study medication was titrated over 1 month from 6.25 to 25 mg twice a day ( 75 kg) and continued for 3 months. One placebo-treated and two Carvedilol-treated patients did not complete the study. Results. Carvedilol therapy resulted in a significant reduction in heart rate and mean pulmonary artery and pulmonary capillary wedge pressures and a significant increase in stroke volume and left ventricular stroke work. Left ventricular ejection fraction increased 52% in the Carvedilol group (from 0.21 to 0.32, p Conclusions. Long-term Carvedilol therapy improves rest cardiac function and lessens symptoms in patients with heart failure.
Christian Höcht - One of the best experts on this subject based on the ideXlab platform.
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is urethane chloralose anaesthesia appropriate for pharmacokinetic pharmacodynamic assessment studies with Carvedilol
Journal of Pharmacological and Toxicological Methods, 2009Co-Authors: Facundo Martín Bertera, Carla Andrea Di Verniero, Marcos A. Mayer, Guillermo F. Bramuglia, Carlos A. Taira, Christian HöchtAbstract:Abstract Introduction The aim of the work was to establish the impact of urethane–chloralose anaesthesia on pharmacokinetic–pharmacodynamic (PK–PD) properties of Carvedilol in control rats and l -NAME hypertensive animals. Methods Male Wistar Rats were randomly divided into: control ( n = 12) with tap water to drink and L -NAME rats ( n = 12) with L -NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of Carvedilol (1 mg kg − 1 , i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg − 1 , i.p.) – chloralose (50 mg kg − 1 , i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK–PD modeling of Carvedilol was made by means of an effect compartment model. Results Neither urethane–chloralose nor L -NAME modified estimation of pharmacokinetic parameters of Carvedilol. Although urethane–chloralose did not modify potency of Carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L -NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to Carvedilol in control rats. Whilst no differences were found in the estimated potency of Carvedilol hypotensive response comparing control and L -NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of Carvedilol was significantly greater in anaesthetized control and L -NAME animals in comparison to conscious rats. L -NAME rats showed a greater maximal hypotensive response comparing to control group. Discussion Urethane–chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK–PD properties of Carvedilol, considering that it does not affect the potency of Carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane–chloralose anaesthetized animals, regarding the impact of l -NAME treatment on PK–PD properties of Carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of Carvedilol in both normotensive and L -NAME hypertensive rats.
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Is urethane–chloralose anaesthesia appropriate for pharmacokinetic–pharmacodynamic assessment? Studies with Carvedilol
Journal of pharmacological and toxicological methods, 2008Co-Authors: Facundo Martín Bertera, Carla Andrea Di Verniero, Marcos A. Mayer, Guillermo F. Bramuglia, Carlos A. Taira, Christian HöchtAbstract:Abstract Introduction The aim of the work was to establish the impact of urethane–chloralose anaesthesia on pharmacokinetic–pharmacodynamic (PK–PD) properties of Carvedilol in control rats and l -NAME hypertensive animals. Methods Male Wistar Rats were randomly divided into: control ( n = 12) with tap water to drink and L -NAME rats ( n = 12) with L -NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of Carvedilol (1 mg kg − 1 , i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg − 1 , i.p.) – chloralose (50 mg kg − 1 , i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK–PD modeling of Carvedilol was made by means of an effect compartment model. Results Neither urethane–chloralose nor L -NAME modified estimation of pharmacokinetic parameters of Carvedilol. Although urethane–chloralose did not modify potency of Carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L -NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to Carvedilol in control rats. Whilst no differences were found in the estimated potency of Carvedilol hypotensive response comparing control and L -NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of Carvedilol was significantly greater in anaesthetized control and L -NAME animals in comparison to conscious rats. L -NAME rats showed a greater maximal hypotensive response comparing to control group. Discussion Urethane–chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK–PD properties of Carvedilol, considering that it does not affect the potency of Carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane–chloralose anaesthetized animals, regarding the impact of l -NAME treatment on PK–PD properties of Carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of Carvedilol in both normotensive and L -NAME hypertensive rats.
Facundo Martín Bertera - One of the best experts on this subject based on the ideXlab platform.
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is urethane chloralose anaesthesia appropriate for pharmacokinetic pharmacodynamic assessment studies with Carvedilol
Journal of Pharmacological and Toxicological Methods, 2009Co-Authors: Facundo Martín Bertera, Carla Andrea Di Verniero, Marcos A. Mayer, Guillermo F. Bramuglia, Carlos A. Taira, Christian HöchtAbstract:Abstract Introduction The aim of the work was to establish the impact of urethane–chloralose anaesthesia on pharmacokinetic–pharmacodynamic (PK–PD) properties of Carvedilol in control rats and l -NAME hypertensive animals. Methods Male Wistar Rats were randomly divided into: control ( n = 12) with tap water to drink and L -NAME rats ( n = 12) with L -NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of Carvedilol (1 mg kg − 1 , i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg − 1 , i.p.) – chloralose (50 mg kg − 1 , i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK–PD modeling of Carvedilol was made by means of an effect compartment model. Results Neither urethane–chloralose nor L -NAME modified estimation of pharmacokinetic parameters of Carvedilol. Although urethane–chloralose did not modify potency of Carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L -NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to Carvedilol in control rats. Whilst no differences were found in the estimated potency of Carvedilol hypotensive response comparing control and L -NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of Carvedilol was significantly greater in anaesthetized control and L -NAME animals in comparison to conscious rats. L -NAME rats showed a greater maximal hypotensive response comparing to control group. Discussion Urethane–chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK–PD properties of Carvedilol, considering that it does not affect the potency of Carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane–chloralose anaesthetized animals, regarding the impact of l -NAME treatment on PK–PD properties of Carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of Carvedilol in both normotensive and L -NAME hypertensive rats.
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Is urethane–chloralose anaesthesia appropriate for pharmacokinetic–pharmacodynamic assessment? Studies with Carvedilol
Journal of pharmacological and toxicological methods, 2008Co-Authors: Facundo Martín Bertera, Carla Andrea Di Verniero, Marcos A. Mayer, Guillermo F. Bramuglia, Carlos A. Taira, Christian HöchtAbstract:Abstract Introduction The aim of the work was to establish the impact of urethane–chloralose anaesthesia on pharmacokinetic–pharmacodynamic (PK–PD) properties of Carvedilol in control rats and l -NAME hypertensive animals. Methods Male Wistar Rats were randomly divided into: control ( n = 12) with tap water to drink and L -NAME rats ( n = 12) with L -NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of Carvedilol (1 mg kg − 1 , i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg − 1 , i.p.) – chloralose (50 mg kg − 1 , i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK–PD modeling of Carvedilol was made by means of an effect compartment model. Results Neither urethane–chloralose nor L -NAME modified estimation of pharmacokinetic parameters of Carvedilol. Although urethane–chloralose did not modify potency of Carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L -NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to Carvedilol in control rats. Whilst no differences were found in the estimated potency of Carvedilol hypotensive response comparing control and L -NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of Carvedilol was significantly greater in anaesthetized control and L -NAME animals in comparison to conscious rats. L -NAME rats showed a greater maximal hypotensive response comparing to control group. Discussion Urethane–chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK–PD properties of Carvedilol, considering that it does not affect the potency of Carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane–chloralose anaesthetized animals, regarding the impact of l -NAME treatment on PK–PD properties of Carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of Carvedilol in both normotensive and L -NAME hypertensive rats.