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Margareta Nordlander - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacodynamic, pharmacokinetic and clinical effects of Clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control.
    Cardiovascular drug reviews, 2006
    Co-Authors: Margareta Nordlander, Per-ove Sjöquist, Hans Ericsson, Lars Rydén
    Abstract:

    Abstract Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of Clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, Clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, Clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery Clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, Clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, Clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with Clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that Clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.

  • comparison of Clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery
    European Journal of Anaesthesiology, 2005
    Co-Authors: A V V Powroznyk, Alain Vuylsteke, C Naughton, S L Misso, J Holloway, Ase Jolinmellgard, R D Latimer, Margareta Nordlander, R O Feneck
    Abstract:

    BACKGROUND AND OBJECTIVE We set out to compare the efficacy of Clevidipine and sodium nitroprusside infusions in the control of blood pressure and the haemodynamic changes they produce in hypertensive patients after operation for elective coronary bypass grafting. METHODS Thirty patients were randomly allocated to receive either Clevidipine or sodium nitroprusside after their mean arterial pressure (MAP) had reached > 90 mmHg for at least 10 min in the postoperative period. The MAP was continuously measured and related to time. Thus, the efficacy of the drugs in controlling arterial pressure could be inversely related to the total area under the MAP-time curve outside a target MAP range of 70-80 mmHg normalized per hour (AUC(MAP) mmHg min h(-1)). Haemodynamic variables and the number of dose-rate adjustments required to maintain MAP were also studied. RESULTS There was no statistically significant difference in the efficacy (AUC(MAP) mmHg min h(-1)) of Clevidipine (106 +/- 25 mmHg min h(-1)) compared with sodium nitroprusside (101 +/- 28 mmHg min h(-1)). Nor was any significant difference found in the total number of dose adjustments required to control MAP within the target range. The heart rate in patients receiving Clevidipine increased less than in those given sodium nitroprusside. Stroke volume, central venous pressure and pulmonary artery pressure were significantly reduced upon administration of sodium nitroprusside but not of Clevidipine. CONCLUSIONS There was no significant difference between Clevidipine and sodium nitroprusside in their efficacy in controlling MAP. The haemodynamic changes, including tachycardia, were less pronounced with Clevidipine than with sodium nitroprusside.

  • Clevidipine in adult cardiac surgical patients: a dose-finding study.
    Anesthesiology, 2002
    Co-Authors: James M. Bailey, Jerrold H. Levy, Åse Jolin-mellgård, James Ramsay, Linda Shore-lesserson, Richard C. Prielipp, Neil W. Brister, G. Roach, Margareta Nordlander
    Abstract:

    BACKGROUND Treatment of elevated blood pressure is frequently necessary after cardiac surgery to minimize postoperative bleeding and to attenuate afterload changes associated with hypertension. The purpose of this study was to investigate the pharmacodynamics and pharmacokinetics of a short-acting calcium channel antagonist, Clevidipine, in the treatment of hypertension in postoperative cardiac surgical patients. METHODS Postoperative cardiac surgical patients were randomized to receive placebo or one of six doses of Clevidipine. Hemodynamic parameters were recorded and blood samples were drawn for determination of Clevidipine plasma concentrations during infusion and after discontinuation of Clevidipine. The concentration-response relation was analyzed using logistic regression, and pharmacokinetic models were applied to the data using population analysis. RESULTS There were significant decreases in mean arterial blood pressure and systemic vascular resistance at doses greater than or equal to 1.37 microg. kg-1. min-1. There were no changes in heart rate, central venous pressure, pulmonary artery occlusion pressure, or cardiac index with increasing doses of Clevidipine. The Clevidipine C50 value for a 10% or greater decrease in mean arterial pressure was 9.7 microg/l and for a 20% or greater decrease in mean arterial pressure was 26.3 microg/l. The pharmacokinetics of Clevidipine were best described with a three-compartment model with a volume of distribution of 32.4 l and clearance of 4.3 l/min. The early phase of drug disposition had a half-life of 0.6 min. The context-sensitive half-time is less than 2 min for up to 12 h of administration. CONCLUSION Clevidipine is a calcium channel antagonist with a very short duration of action that effectively decreases systemic vascular resistance and mean arterial pressure without changing heart rate, cardiac index, or cardiac filling pressures.

  • pharmacokinetics and pulmonary extraction of Clevidipine a new vasodilating ultrashort acting dihydropyridine during cardiopulmonary bypass
    BJA: British Journal of Anaesthesia, 2000
    Co-Authors: Alain Vuylsteke, Ase Jolinmellgard, Margareta Nordlander, Hans Ericsson, Q. Milner, D. Mur, John Dunning, R D Latimer
    Abstract:

    Clevidipine is a new vascular-selective, calcium channel antagonist of the dihydropyridine type with an ester side chain susceptible to esterase metabolism. In healthy volunteers, it has high clearance (0.069 litres min −1 kg −1 ) with a small volume of distribution at steady state (0.19 litres kg −1 ). The half-lives of the two initial rapid phases, accounting for approximately 95% of the area under the curve after an i.v. bolus, are 0.7 and 2.3 min, respectively. The aims of this study were to determine the pharmacokinetics and the pulmonary extraction ratio of Clevidipine in patients undergoing cardiac surgery. Seventeen patients received Clevidipine as an i.v. infusion before cardiopulmonary bypass (CPB), and eight of these patients were also given Clevidipine during hypothermic CPB. Mixed venous and arterial blood samples were taken for pharmacokinetic analysis and calculation of pulmonary extraction ratio. A two-compartment pharmacokinetic model with zero-order input was used to describe the pharmacokinetics of Clevidipine before and during CPB. Virtually identical concentrations in mixed venous and arterial blood suggest negligible pulmonary metabolism of Clevidipine. The total blood clearance of Clevidipine is extremely high (0.055 litres min −1 kg −1 ). During CPB, clearance of Clevidipine was significantly reduced, to 0.03 litres min −1 kg −1 ( P

  • Pharmacokinetics and arteriovenous differences in Clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers.
    Anesthesiology, 2000
    Co-Authors: Hans Ericsson, Margareta Nordlander, Åse Jolin-mellgård, Ulf Bredberg, Ulf G. Eriksson, Carl Gunnar Regårdh
    Abstract:

    Background: Clevidipine is an ultra–short-acting calcium antagonist developed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of Clevidipine after 20-min and 24-h intravenous infusions, and to determine the relation between the arterial and venous concentrations and the hemodynamic responses to Clevidipine in healthy volunteers. Methods: Four volunteers received Clevidipine for 20 min, and eight subjects were administered Clevidipine intravenously for 24 h at two different dose rates. Arterial and venous blood samples were drawn for pharmacokinetic evaluation, and blood pressure and heart rate were recorded. Results: A triexponential disposition model described the pharmacokinetics of Clevidipine. The mean arterial blood clearance of Clevidipine was 0.069 l · kg−1 · min−1 and the mean volume of distribution at steady state was 0.19 l/kg. The duration of the infusion had negligible effect on the pharmacokinetic parameters, and the context-sensitive half-time for Clevidipine, simulated from the mean pharmacokinetic parameters derived after 24 h infusion at the highest dose, was less than 1 min. The arterial blood levels reached steady state within 2 min of the start of infusion and were about twice as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the peak arterial blood concentration. Conclusion: Clevidipine is a high clearance drug with a small volume of distribution, resulting in extremely short half-lives in healthy subjects. The initial rapid increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that Clevidipine can be rapidly titrated to the desired effect.

Lars Rydén - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacodynamic, pharmacokinetic and clinical effects of Clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control.
    Cardiovascular drug reviews, 2006
    Co-Authors: Margareta Nordlander, Per-ove Sjöquist, Hans Ericsson, Lars Rydén
    Abstract:

    Abstract Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of Clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, Clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, Clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery Clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, Clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, Clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with Clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that Clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.

  • Time-dependent cardioprotection with calcium antagonism and experimental studies with Clevidipine in ischemic-reperfused pig hearts: part I.
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Qing-dong Wang, Per-ove Sjöquist, Hans Ericsson, Daisuke Segawa, Lars Johansson, Lars Rydén
    Abstract:

    Clevidipine is a new ultrashort-acting dihydropyridine calcium antagonist developed for blood pressure regulation during cardiac surgery. When given locally to the ischemic and reperfused myocardium, Clevidipine exerts a cardioprotective effect that varies depending on the timing of administration during ischemia. The current study explored the pharmacokinetics of Clevidipine when administered locally into the coronary circulation. Pentobarbital-anesthetized pigs were randomly divided into four groups, of which three were subjected to myocardial ischemia through ligation of the left anterior descending coronary artery (LAD) for 15, 35, or 45 minutes (n = 4 in each group). The fourth group (n = 4) was not subjected to LAD occlusion and acted as nonischemic controls. Clevidipine (0.3 nmol/kg per minute) was infused over a period of 5 minutes through a catheter distal to the LAD ligation in the ischemic pigs, or at the corresponding site of the nonligated LAD in the nonischemic pigs. Following release of the LAD ligation, or in the nonligated group following the drug infusion, the pigs were subjected to 60 minutes of reperfusion. Simultaneous blood samples were obtained for analysis of Clevidipine from the femoral artery and the coronary vein during reperfusion and during drug infusion in the nonischemic pigs. Blood samples for estimating the in vitro hydrolysis rate both in whole blood and in plasma were also obtained. In nonischemic hearts, Clevidipine reached a steady state level in the coronary venous blood of about 30 nM during the infusion. The concentration declined almost to the detection limit (1 nM) within 3 minutes of the end of infusion. The mean blood clearance of Clevidipine was calculated to be 0.17 l/min per kilogram, and the estimated half-life was 0.5 minute. In animals subjected to different periods of ischemia, very low levels of Clevidipine were detected in the coronary venous blood only during the first 2 minutes of reperfusion. There were no detectable levels in the arterial blood at any time. Blood concentration profiles of Clevidipine did not differ with the length of myocardial ischemia. The in vitro half-life in pig blood was 13 minutes, and the corresponding half-life in plasma was 111 minutes. At a dose known to exert cardioprotection when given as an intracoronary injection, the systemic concentration of Clevidipine does not reach pharmacologically active levels. Clevidipine has an ultrashort blood half-life, and ischemic duration of up to 45 minutes does not seem to change the cardiac metabolism of this drug. Thus, it represents a pharmacological tool well suited for the study of time windows in cardioprotection. Moreover, considering the possibility of exerting myocardioprotection without any systemic effects, it could be an interesting compound to test in a clinical setting.

  • Time-dependent cardioprotection with calcium antagonism and experimental studies with Clevidipine in ischemic-reperfused pig hearts: part II.
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Daisuke Segawa, Per-ove Sjöquist, Adrian T. Gonon, Qing-dong Wang, Lars Rydén
    Abstract:

    The intracellular calcium level is increased during ischemia and early reperfusion. The aim of this study was to study the role of the calcium influx in the development of myocardial ischemic and reperfusion injury during the early and late phases of ischemia and during early reperfusion. An ultrashort-acting calcium antagonist, Clevidipine, was used as a tool for this investigation. Pentobarbital-anesthetized pigs were subjected to 45 minutes of LAD occlusion followed by 240 minutes of reperfusion. In the first set of experiments, Clevidipine (0.3 nmol/kg per minute) was infused over 5 minutes into the ischemic myocardium via a catheter in the LAD, starting at 5, 35, or 44 minutes following the onset of ischemia (n = 6 in each group). The area at risk and the infarct size were determined after 240 minutes of reperfusion by staining with Evans blue dye and triphenyl tetrazolium chloride (TTC), respectively. In a second set of experiments, two groups of animals (n = 6 in each) were subjected to the same periods of ischemia and reperfusion; one group received no infusion during ischemia, whereas the other group received vehicle infusion during a 5-minute period between 5 and 10 minutes of ischemia. In the first set of experiments, there were no significant differences between the groups with regard to hemodynamic variables. The area at risk expressed as a percentage of the left ventricle was of similar magnitude in all three Clevidipine-treated groups (about 18%). The infarct size, expressed as a percentage of the area at risk, was significantly smaller in pigs given Clevidipine after 5 minutes (58 +/- 17%; p < 0.01) and after 44 minutes (42 +/- 6%; p < 0.01) of ischemia than in pigs receiving Clevidipine after 35 minutes of ischemia (85 +/- 4%). The difference in infarct size between pigs given Clevidipine after 5 or 44 minutes of ischemia was not significant. In the second set of experiments, there was a similar area at risk and no significant difference in infarct size between the noninfusion group and the 5-minute vehicle infusion group, indicating that the LAD infusion per se did not affect infarct size. The present results demonstrate that blockade of calcium influx by the short-acting dihydropyridine calcium antagonist Clevidipine during the early phase of ischemia and at the time of reperfusion, but not during a late phase of ischemia, limits infarct size induced by ischemia and reperfusion. This indicates that the pathophysiological importance of calcium influx varies according to the different phases of myocardial ischemia and reperfusion.

  • Calcium antagonist protects the myocardium from reperfusion injury by interfering with mechanisms directly related to reperfusion: an experimental study with the ultrashort-acting calcium antagonist Clevidipine.
    Journal of cardiovascular pharmacology, 2000
    Co-Authors: Daisuke Segawa, Margareta Nordlander, Per-ove Sjöquist, Adrian T. Gonon, Qing-dong Wang, Lars Rydén
    Abstract:

    To test the hypothesis that calcium antagonists protect the myocardium from reperfusion-induced damage by local myocardial mechanisms just at the time of reperfusion, the myocardioprotective effects of the dihydropyridine Clevidipine were investigated, taking advantage of its ultrashort-acting effect. Pigs were subjected to 45 min of myocardial ischemia by occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Either Clevidipine (0.3 nmol/kg/min, n = 6) or the corresponding amount of vehicle (n = 6) was administered to the ischemic myocardium by retrograde coronary venous infusion over a 30-min period starting 10 min before reperfusion. Hemodynamic variables (heart rate, left ventricular systolic and end-diastolic pressure, max dP/dt, and mean arterial blood pressure) as well as coronary blood flow were measured throughout the experiment. At the end of reperfusion, the area at risk (percentage of left ventricle) was determined by infusion of Evans blue into the left atrium, and the infarct size, by triphenyl tetrazolium chloride (TTC) staining. The plasma level of endothelin-like immunoreactivity (ET-LI) was analyzed in blood from the aorta and the anterior coronary vein before ischemia and at different times during reperfusion. The area at risk was similar in the vehicle and the Clevidipine groups. The infarct size, expressed as a percentage of the area at risk, was 80 +/- 9.2 in the vehicle group, whereas it was significantly reduced to 51 +/- 9.2% in the Clevidipine group (p < 0.01). Clevidipine did not influence any of the hemodynamic variables measured throughout the study. A nonsignificant trend toward decreased total ET-LI overflow during 4-h reperfusion was observed in the Clevidipine-treated pigs compared with vehicle-treated ones (5.3 +/- 1.4 vs. 7.1 +/- 3.4 pmol). These results demonstrate that, in this model of ischemia/reperfusion-induced myocardial infarction, Clevidipine reduced the damage to the myocardium when given in association with reperfusion. The local administration of the compound together with its short blood half-life shows that Clevidipine reduces reperfusion-induced damage by local mechanisms within the ischemic tissue rather than by peripheral mechanisms.

  • cardiac inotropic vs chronotropic selectivity of isradipine nifedipine and Clevidipine a new ultrashort acting dihydropyridine
    European Journal of Pharmacology, 1999
    Co-Authors: Daisuke Segawa, Margareta Nordlander, Per-ove Sjöquist, Adrian T. Gonon, Qing-dong Wang, Lars Rydén
    Abstract:

    Cardiac effects of Clevidipine, a new ultrashort-acting dihydropyridine Ca2+ channel antagonist were investigated in Langendorff-perfused rat hearts and compared to those of nifedipine and isradipine. The aim was to determine and compare the negative inotropic vs. chronotropic potency of these drugs. The hearts were perfused with oxygenated Krebs-Henseleit buffer at a perfusion pressure of 90 cm H2O. After stabilization, one concentration of each drug was administered for 45 min followed by a higher concentration for an additional 45 min. The concentrations of each drug in this study were 10(-9), 3 x 10(-9), 10(-8), 10(-7), 10(-6.5) and 10(-6) M for Clevidipine and nifedipine, and 10(-10), 3 x 10(-10), 10(-9), 10(-8), 10(-7.5) and 10(-7) M for isradipine. Each concentration of each drug was tested in six hearts. Coronary flow, left ventricular dP/dt max, left ventricular systolic pressure and heart rate were recorded when the hearts were beating spontaneously and during pacing at a constant rate for 1 min. Spontaneous heart rate and atrio-ventricular conduction were not affected by Clevidipine at any of the concentrations studied, while nifedipine and isradipine caused a concentration-dependent decrease. These two drugs caused atrio-ventricular block at high concentrations. All three compounds reduced cardiac contractility in a concentration-dependent manner. When isradipine was administered, at a given concentration, heart rate and contractility decreased proportionately. When Clevidipine or nifedipine was given, at a given concentration, the proportionate reduction in left ventricular dP/dt max was greater than that in heart rate, resulting in a high inotropic vs. chronotropic selectivity. It is concluded that in contrast to nifedipine and isradipine, Clevidipine does not impair atrio-ventricular conduction. Like nifedipine, Clevidipine is selective for inotropic vs. chronotropic cardiac effects.

Hans Ericsson - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacodynamic, pharmacokinetic and clinical effects of Clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control.
    Cardiovascular drug reviews, 2006
    Co-Authors: Margareta Nordlander, Per-ove Sjöquist, Hans Ericsson, Lars Rydén
    Abstract:

    Abstract Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of Clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, Clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, Clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery Clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, Clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, Clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with Clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that Clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.

  • Time-dependent cardioprotection with calcium antagonism and experimental studies with Clevidipine in ischemic-reperfused pig hearts: part I.
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Qing-dong Wang, Per-ove Sjöquist, Hans Ericsson, Daisuke Segawa, Lars Johansson, Lars Rydén
    Abstract:

    Clevidipine is a new ultrashort-acting dihydropyridine calcium antagonist developed for blood pressure regulation during cardiac surgery. When given locally to the ischemic and reperfused myocardium, Clevidipine exerts a cardioprotective effect that varies depending on the timing of administration during ischemia. The current study explored the pharmacokinetics of Clevidipine when administered locally into the coronary circulation. Pentobarbital-anesthetized pigs were randomly divided into four groups, of which three were subjected to myocardial ischemia through ligation of the left anterior descending coronary artery (LAD) for 15, 35, or 45 minutes (n = 4 in each group). The fourth group (n = 4) was not subjected to LAD occlusion and acted as nonischemic controls. Clevidipine (0.3 nmol/kg per minute) was infused over a period of 5 minutes through a catheter distal to the LAD ligation in the ischemic pigs, or at the corresponding site of the nonligated LAD in the nonischemic pigs. Following release of the LAD ligation, or in the nonligated group following the drug infusion, the pigs were subjected to 60 minutes of reperfusion. Simultaneous blood samples were obtained for analysis of Clevidipine from the femoral artery and the coronary vein during reperfusion and during drug infusion in the nonischemic pigs. Blood samples for estimating the in vitro hydrolysis rate both in whole blood and in plasma were also obtained. In nonischemic hearts, Clevidipine reached a steady state level in the coronary venous blood of about 30 nM during the infusion. The concentration declined almost to the detection limit (1 nM) within 3 minutes of the end of infusion. The mean blood clearance of Clevidipine was calculated to be 0.17 l/min per kilogram, and the estimated half-life was 0.5 minute. In animals subjected to different periods of ischemia, very low levels of Clevidipine were detected in the coronary venous blood only during the first 2 minutes of reperfusion. There were no detectable levels in the arterial blood at any time. Blood concentration profiles of Clevidipine did not differ with the length of myocardial ischemia. The in vitro half-life in pig blood was 13 minutes, and the corresponding half-life in plasma was 111 minutes. At a dose known to exert cardioprotection when given as an intracoronary injection, the systemic concentration of Clevidipine does not reach pharmacologically active levels. Clevidipine has an ultrashort blood half-life, and ischemic duration of up to 45 minutes does not seem to change the cardiac metabolism of this drug. Thus, it represents a pharmacological tool well suited for the study of time windows in cardioprotection. Moreover, considering the possibility of exerting myocardioprotection without any systemic effects, it could be an interesting compound to test in a clinical setting.

  • Enantioselective pharmacokinetics of the enantiomers of Clevidipine following intravenous infusion of the racemate in essential hypertensive patients.
    Chirality, 2001
    Co-Authors: Hans Ericsson, Jonas Schwieler, Bo Lindmark, Per Löfdahl, Tomas Thulin, Carl‐gunnar Regårdh
    Abstract:

    The aim of the study was to characterize the individual pharmacokinetics of (−)-R- and (+)-S-Clevidipine following intravenous constant rate infusion of rac-Clevidipine to essential hypertensive patients. Twenty patients received three out of five randomized treatments with Clevidipine. The pharmacokinetics of the separate enantiomers were evaluated by compartmental analysis of blood concentrations vs. time curves using the population approach. The derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-Clevidipine. A two-compartment model was used to describe the dispositions of the enantiomers; there were only minor differences between the estimated pharmacokinetic parameters of the separate enantiomers. The mean blood clearance values of (−)-R- and (+)-S-Clevidipine were 0.103 and 0.096 l/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0.54 l/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concentration was achieved approximately 8 min postinfusion for (−)-R-Clevidipine and 11 min for (+)-S-Clevidipine, following clinically relevant infusion times with Clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution for the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a single enantiomer as an alternative to the racemic Clevidipine will not offer any clinical advantages. Chirality 13:130–134, 2001. © 2001 Wiley-Liss, Inc.

  • pharmacokinetics and pulmonary extraction of Clevidipine a new vasodilating ultrashort acting dihydropyridine during cardiopulmonary bypass
    BJA: British Journal of Anaesthesia, 2000
    Co-Authors: Alain Vuylsteke, Ase Jolinmellgard, Margareta Nordlander, Hans Ericsson, Q. Milner, D. Mur, John Dunning, R D Latimer
    Abstract:

    Clevidipine is a new vascular-selective, calcium channel antagonist of the dihydropyridine type with an ester side chain susceptible to esterase metabolism. In healthy volunteers, it has high clearance (0.069 litres min −1 kg −1 ) with a small volume of distribution at steady state (0.19 litres kg −1 ). The half-lives of the two initial rapid phases, accounting for approximately 95% of the area under the curve after an i.v. bolus, are 0.7 and 2.3 min, respectively. The aims of this study were to determine the pharmacokinetics and the pulmonary extraction ratio of Clevidipine in patients undergoing cardiac surgery. Seventeen patients received Clevidipine as an i.v. infusion before cardiopulmonary bypass (CPB), and eight of these patients were also given Clevidipine during hypothermic CPB. Mixed venous and arterial blood samples were taken for pharmacokinetic analysis and calculation of pulmonary extraction ratio. A two-compartment pharmacokinetic model with zero-order input was used to describe the pharmacokinetics of Clevidipine before and during CPB. Virtually identical concentrations in mixed venous and arterial blood suggest negligible pulmonary metabolism of Clevidipine. The total blood clearance of Clevidipine is extremely high (0.055 litres min −1 kg −1 ). During CPB, clearance of Clevidipine was significantly reduced, to 0.03 litres min −1 kg −1 ( P

  • Pharmacokinetics and arteriovenous differences in Clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers.
    Anesthesiology, 2000
    Co-Authors: Hans Ericsson, Margareta Nordlander, Åse Jolin-mellgård, Ulf Bredberg, Ulf G. Eriksson, Carl Gunnar Regårdh
    Abstract:

    Background: Clevidipine is an ultra–short-acting calcium antagonist developed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of Clevidipine after 20-min and 24-h intravenous infusions, and to determine the relation between the arterial and venous concentrations and the hemodynamic responses to Clevidipine in healthy volunteers. Methods: Four volunteers received Clevidipine for 20 min, and eight subjects were administered Clevidipine intravenously for 24 h at two different dose rates. Arterial and venous blood samples were drawn for pharmacokinetic evaluation, and blood pressure and heart rate were recorded. Results: A triexponential disposition model described the pharmacokinetics of Clevidipine. The mean arterial blood clearance of Clevidipine was 0.069 l · kg−1 · min−1 and the mean volume of distribution at steady state was 0.19 l/kg. The duration of the infusion had negligible effect on the pharmacokinetic parameters, and the context-sensitive half-time for Clevidipine, simulated from the mean pharmacokinetic parameters derived after 24 h infusion at the highest dose, was less than 1 min. The arterial blood levels reached steady state within 2 min of the start of infusion and were about twice as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the peak arterial blood concentration. Conclusion: Clevidipine is a high clearance drug with a small volume of distribution, resulting in extremely short half-lives in healthy subjects. The initial rapid increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that Clevidipine can be rapidly titrated to the desired effect.

Per-ove Sjöquist - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacodynamic, pharmacokinetic and clinical effects of Clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control.
    Cardiovascular drug reviews, 2006
    Co-Authors: Margareta Nordlander, Per-ove Sjöquist, Hans Ericsson, Lars Rydén
    Abstract:

    Abstract Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of Clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, Clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, Clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery Clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, Clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, Clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with Clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that Clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.

  • Calcium antagonist Clevidipine reduces myocardial reperfusion injury by a mechanism related to bradykinin and nitric oxide
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Andrey Gourine, John Pernow, Dmitry M Poputnikov, Per-ove Sjöquist
    Abstract:

    Certain calcium antagonists, in addition to their classic actions, can increase blood flow during ischemia via bradykinin- and nitric oxide (NO)-dependent mechanisms and protect the ischemic myocardium against reperfusion injury by enhancing NO bioavailability. The current study aimed to investigate the possible involvement of bradykinin and NO in the cardioprotective action of the short-acting calcium antagonist Clevidipine during late ischemia and reperfusion. Anesthetized pigs were subjected to 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Four groups were given vehicle, Clevidipine, Clevidipine in combination with the bradykinin B2 receptor antagonist HOE 140 or Clevidipine in combination with HOE 140 and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) into the LAD during the last 10 min of ischemia and the first 5 min of reperfusion. There were no significant differences in hemodynamics among the groups before ischemia or during ischemia-reperfusion. The infarct size (IS) was 87% +/- 2% of the area at risk in the vehicle group. Clevidipine reduced the IS to 60% +/- 3% (p < 0.001 vs vehicle). When Clevidipine was administered together with HOE 140, the protective effect of Clevidipine was abolished (IS, 80% +/- 3%; p < 0.001 vs Clevidipine), whereas addition of SNAP restored cardioprotection (IS, 62% +/- 5%; p < 0.001 vs vehicle). The increase in LAD blood flow by endothelium-dependent dilator substance P was significantly larger in the Clevidipine group than in the other groups. The results suggest that the cardioprotective effect of Clevidipine during late ischemia and early reperfusion is mediated via bradykinin- and NO-related mechanisms.

  • Time-dependent cardioprotection with calcium antagonism and experimental studies with Clevidipine in ischemic-reperfused pig hearts: part I.
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Qing-dong Wang, Per-ove Sjöquist, Hans Ericsson, Daisuke Segawa, Lars Johansson, Lars Rydén
    Abstract:

    Clevidipine is a new ultrashort-acting dihydropyridine calcium antagonist developed for blood pressure regulation during cardiac surgery. When given locally to the ischemic and reperfused myocardium, Clevidipine exerts a cardioprotective effect that varies depending on the timing of administration during ischemia. The current study explored the pharmacokinetics of Clevidipine when administered locally into the coronary circulation. Pentobarbital-anesthetized pigs were randomly divided into four groups, of which three were subjected to myocardial ischemia through ligation of the left anterior descending coronary artery (LAD) for 15, 35, or 45 minutes (n = 4 in each group). The fourth group (n = 4) was not subjected to LAD occlusion and acted as nonischemic controls. Clevidipine (0.3 nmol/kg per minute) was infused over a period of 5 minutes through a catheter distal to the LAD ligation in the ischemic pigs, or at the corresponding site of the nonligated LAD in the nonischemic pigs. Following release of the LAD ligation, or in the nonligated group following the drug infusion, the pigs were subjected to 60 minutes of reperfusion. Simultaneous blood samples were obtained for analysis of Clevidipine from the femoral artery and the coronary vein during reperfusion and during drug infusion in the nonischemic pigs. Blood samples for estimating the in vitro hydrolysis rate both in whole blood and in plasma were also obtained. In nonischemic hearts, Clevidipine reached a steady state level in the coronary venous blood of about 30 nM during the infusion. The concentration declined almost to the detection limit (1 nM) within 3 minutes of the end of infusion. The mean blood clearance of Clevidipine was calculated to be 0.17 l/min per kilogram, and the estimated half-life was 0.5 minute. In animals subjected to different periods of ischemia, very low levels of Clevidipine were detected in the coronary venous blood only during the first 2 minutes of reperfusion. There were no detectable levels in the arterial blood at any time. Blood concentration profiles of Clevidipine did not differ with the length of myocardial ischemia. The in vitro half-life in pig blood was 13 minutes, and the corresponding half-life in plasma was 111 minutes. At a dose known to exert cardioprotection when given as an intracoronary injection, the systemic concentration of Clevidipine does not reach pharmacologically active levels. Clevidipine has an ultrashort blood half-life, and ischemic duration of up to 45 minutes does not seem to change the cardiac metabolism of this drug. Thus, it represents a pharmacological tool well suited for the study of time windows in cardioprotection. Moreover, considering the possibility of exerting myocardioprotection without any systemic effects, it could be an interesting compound to test in a clinical setting.

  • Time-dependent cardioprotection with calcium antagonism and experimental studies with Clevidipine in ischemic-reperfused pig hearts: part II.
    Journal of cardiovascular pharmacology, 2002
    Co-Authors: Daisuke Segawa, Per-ove Sjöquist, Adrian T. Gonon, Qing-dong Wang, Lars Rydén
    Abstract:

    The intracellular calcium level is increased during ischemia and early reperfusion. The aim of this study was to study the role of the calcium influx in the development of myocardial ischemic and reperfusion injury during the early and late phases of ischemia and during early reperfusion. An ultrashort-acting calcium antagonist, Clevidipine, was used as a tool for this investigation. Pentobarbital-anesthetized pigs were subjected to 45 minutes of LAD occlusion followed by 240 minutes of reperfusion. In the first set of experiments, Clevidipine (0.3 nmol/kg per minute) was infused over 5 minutes into the ischemic myocardium via a catheter in the LAD, starting at 5, 35, or 44 minutes following the onset of ischemia (n = 6 in each group). The area at risk and the infarct size were determined after 240 minutes of reperfusion by staining with Evans blue dye and triphenyl tetrazolium chloride (TTC), respectively. In a second set of experiments, two groups of animals (n = 6 in each) were subjected to the same periods of ischemia and reperfusion; one group received no infusion during ischemia, whereas the other group received vehicle infusion during a 5-minute period between 5 and 10 minutes of ischemia. In the first set of experiments, there were no significant differences between the groups with regard to hemodynamic variables. The area at risk expressed as a percentage of the left ventricle was of similar magnitude in all three Clevidipine-treated groups (about 18%). The infarct size, expressed as a percentage of the area at risk, was significantly smaller in pigs given Clevidipine after 5 minutes (58 +/- 17%; p < 0.01) and after 44 minutes (42 +/- 6%; p < 0.01) of ischemia than in pigs receiving Clevidipine after 35 minutes of ischemia (85 +/- 4%). The difference in infarct size between pigs given Clevidipine after 5 or 44 minutes of ischemia was not significant. In the second set of experiments, there was a similar area at risk and no significant difference in infarct size between the noninfusion group and the 5-minute vehicle infusion group, indicating that the LAD infusion per se did not affect infarct size. The present results demonstrate that blockade of calcium influx by the short-acting dihydropyridine calcium antagonist Clevidipine during the early phase of ischemia and at the time of reperfusion, but not during a late phase of ischemia, limits infarct size induced by ischemia and reperfusion. This indicates that the pathophysiological importance of calcium influx varies according to the different phases of myocardial ischemia and reperfusion.

  • Short-acting calcium antagonist Clevidipine protects against reperfusion injury via local nitric oxide-related mechanisms in the jeopardised myocardium.
    Cardiovascular research, 2001
    Co-Authors: Andrey Gourine, Per-ove Sjöquist, Adrian T. Gonon, John Pernow
    Abstract:

    Background: Calcium antagonists may, in addition to their classical actions, release nitric oxide (NO) from coronary arteries. The aim of this study was to elucidate the possible interaction between the cardioprotective effect of a short-acting calcium antagonist and NO during myocardial ischaemia and reperfusion. Methods: Anaesthetised pigs were subjected to 45 min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Five groups were given vehicle (n59), Clevidipine (n58), the NO synthase inhibitor L-NMMA (n56), Clevidipine in combination with L-NMMA (n56) or Clevidipine in combination with L-NMMA and NO precursor L-arginine (n56) into the LAD during the last 10 min of ischaemia and the first 5 min of reperfusion. Results: There were no significant differences in LAD blood flow, mean arterial pressure, rate-pressure product or dP /d t between the groups before ischaemia or during reperfusion. The infarct size (IS) was 8662% of the area at risk in the vehicle group. Clevidipine reduced the IS to 59 63% (P,0.001). When Clevidipine was administered together with L-NMMA, the protective effect of Clevidipine was abolished (IS, 8763%; P,0.001 vs. Clevidipine), whereas addition of L-arginine restored its cardioprotective effect (IS 60 63%; P,0.001 vs. vehicle). L-NMMA did not affect IS per se (8865%). Endothelium-dependent coronary vasodilation induced by substance P was significantly larger in the Clevidipine group than in the other groups. Conclusion: Local administration of a calcium antagonist during the late ischaemia and early reperfusion reduces IS and preserves coronary endothelial function. The cardioprotective effect of Clevidipine is suggested to be dependent on maintained local bioavailability of NO. © 2001 Elsevier Science B.V. All rights reserved.

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  • comparison of Clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery
    European Journal of Anaesthesiology, 2005
    Co-Authors: A V V Powroznyk, Alain Vuylsteke, C Naughton, S L Misso, J Holloway, Ase Jolinmellgard, R D Latimer, Margareta Nordlander, R O Feneck
    Abstract:

    BACKGROUND AND OBJECTIVE We set out to compare the efficacy of Clevidipine and sodium nitroprusside infusions in the control of blood pressure and the haemodynamic changes they produce in hypertensive patients after operation for elective coronary bypass grafting. METHODS Thirty patients were randomly allocated to receive either Clevidipine or sodium nitroprusside after their mean arterial pressure (MAP) had reached > 90 mmHg for at least 10 min in the postoperative period. The MAP was continuously measured and related to time. Thus, the efficacy of the drugs in controlling arterial pressure could be inversely related to the total area under the MAP-time curve outside a target MAP range of 70-80 mmHg normalized per hour (AUC(MAP) mmHg min h(-1)). Haemodynamic variables and the number of dose-rate adjustments required to maintain MAP were also studied. RESULTS There was no statistically significant difference in the efficacy (AUC(MAP) mmHg min h(-1)) of Clevidipine (106 +/- 25 mmHg min h(-1)) compared with sodium nitroprusside (101 +/- 28 mmHg min h(-1)). Nor was any significant difference found in the total number of dose adjustments required to control MAP within the target range. The heart rate in patients receiving Clevidipine increased less than in those given sodium nitroprusside. Stroke volume, central venous pressure and pulmonary artery pressure were significantly reduced upon administration of sodium nitroprusside but not of Clevidipine. CONCLUSIONS There was no significant difference between Clevidipine and sodium nitroprusside in their efficacy in controlling MAP. The haemodynamic changes, including tachycardia, were less pronounced with Clevidipine than with sodium nitroprusside.

  • pharmacokinetics and pulmonary extraction of Clevidipine a new vasodilating ultrashort acting dihydropyridine during cardiopulmonary bypass
    BJA: British Journal of Anaesthesia, 2000
    Co-Authors: Alain Vuylsteke, Ase Jolinmellgard, Margareta Nordlander, Hans Ericsson, Q. Milner, D. Mur, John Dunning, R D Latimer
    Abstract:

    Clevidipine is a new vascular-selective, calcium channel antagonist of the dihydropyridine type with an ester side chain susceptible to esterase metabolism. In healthy volunteers, it has high clearance (0.069 litres min −1 kg −1 ) with a small volume of distribution at steady state (0.19 litres kg −1 ). The half-lives of the two initial rapid phases, accounting for approximately 95% of the area under the curve after an i.v. bolus, are 0.7 and 2.3 min, respectively. The aims of this study were to determine the pharmacokinetics and the pulmonary extraction ratio of Clevidipine in patients undergoing cardiac surgery. Seventeen patients received Clevidipine as an i.v. infusion before cardiopulmonary bypass (CPB), and eight of these patients were also given Clevidipine during hypothermic CPB. Mixed venous and arterial blood samples were taken for pharmacokinetic analysis and calculation of pulmonary extraction ratio. A two-compartment pharmacokinetic model with zero-order input was used to describe the pharmacokinetics of Clevidipine before and during CPB. Virtually identical concentrations in mixed venous and arterial blood suggest negligible pulmonary metabolism of Clevidipine. The total blood clearance of Clevidipine is extremely high (0.055 litres min −1 kg −1 ). During CPB, clearance of Clevidipine was significantly reduced, to 0.03 litres min −1 kg −1 ( P

  • Pharmacokinetics and pulmonary extraction of Clevidipine, a new vasodilating ultrashort‐acting dihydropyridine, during cardiopulmonary bypass†
    British journal of anaesthesia, 2000
    Co-Authors: Alain Vuylsteke, Margareta Nordlander, Hans Ericsson, Q. Milner, D. Mur, John Dunning, Åse Jolin-mellgård, R D Latimer
    Abstract:

    Clevidipine is a new vascular-selective, calcium channel antagonist of the dihydropyridine type with an ester side chain susceptible to esterase metabolism. In healthy volunteers, it has high clearance (0.069 litres min −1 kg −1 ) with a small volume of distribution at steady state (0.19 litres kg −1 ). The half-lives of the two initial rapid phases, accounting for approximately 95% of the area under the curve after an i.v. bolus, are 0.7 and 2.3 min, respectively. The aims of this study were to determine the pharmacokinetics and the pulmonary extraction ratio of Clevidipine in patients undergoing cardiac surgery. Seventeen patients received Clevidipine as an i.v. infusion before cardiopulmonary bypass (CPB), and eight of these patients were also given Clevidipine during hypothermic CPB. Mixed venous and arterial blood samples were taken for pharmacokinetic analysis and calculation of pulmonary extraction ratio. A two-compartment pharmacokinetic model with zero-order input was used to describe the pharmacokinetics of Clevidipine before and during CPB. Virtually identical concentrations in mixed venous and arterial blood suggest negligible pulmonary metabolism of Clevidipine. The total blood clearance of Clevidipine is extremely high (0.055 litres min −1 kg −1 ). During CPB, clearance of Clevidipine was significantly reduced, to 0.03 litres min −1 kg −1 ( P