The Experts below are selected from a list of 96 Experts worldwide ranked by ideXlab platform
John J. Murray - One of the best experts on this subject based on the ideXlab platform.
-
923-3 Fluosol Reduces Myocardial Reperfusion Injury by Prolonged Suppression of Neutrophils by its Detergent Component (RheothRx) and not by Enhancing O2Delivery
Journal of the American College of Cardiology, 1995Co-Authors: João V. Vitola, David A. Ingram, Mervyn B. Forman, John P. Holsinger, James B. Atkinson, John J. MurrayAbstract:Fluosol, a complex mixture of O2carrying perfluorocarbons (PFCs) emulsified by the detergent pluronic F-68 and a variety of lipids, significantly reduces myocardial reperfusion injury (RI) in animals and humans as shown in some initial clinical trials. Potential mechanisms for Fluosol include enhanced O2delivery to the reperfused tissue and modulation of various neutrophil (PMNs) functions. Recent studies in dogs and man demonstrate the same beneficial effect for treatment of Rl with the detergent component alone, RheothRx, which is currently undergoing clinical trials. We have shown that the effect of Fluosol on PMNs is related to this detergent. However, prolonged infusion (48 hrs) of detergent is required to reduce Rl to the same extent as Fluosol given over only 1 hr. Possible mechanisms for the beneficial effects of Fluosol (O2delivery vs effects on PMNs) were investigated in a model of regional ischemia utilizing rabbits undergoing 30mins of circumflex occlusion and 48 hrs of reperfusion. Infarct size (area of necrosis, AN) was determined histologically and expressed as percent of risk region (area at risk, AR). Animals received Fluosol (30cc/kg) with or without O2or saline over the first 60mins of reperfusion. AR was similar in all groups. (Mean±SEM of AN/AR (%), n=11 for all groups). The treatment with Fluosol with or without O2(44±3 and 40;±3, respectively) was significantly (p<0.05) reduced compared to control (63±4). Another group received F-I08, a larger size pluronic detergent found to be 2.5-fold more potent in suppressing PMN function in vitrocompared to F-68, during the first 3 hrs of reperfusion. This treatment did not alter the infarct size (63±5). RheothRx was found to form 4 nm micelles in solution whereas Fluosol formed particles approximately 100 times larger. Similar sized particles were formed by substituting the perfluorocarbons with mineral oil. The in vitroactivity of this pluronic/mineral oil micelle on PMN function was similar to Fluosol. Infusion of these larger oil micelles was tolerated by rabbits and used in further infarct studies.ConclusionsThese studies suggest that (1) reduction of RI by Fluosol is not due to enhanced O2delivery by the PFCs to reperfused myocardium and (2) since the Fluosol emulsion markedly reduces the clearance of the detergent F-68 (t½: Fluosol ≅ 8 hrs vs RheothRx ≅ 1.5 hrs). prolonged PMN suppression rather than potency of suppression is the mechanism whereby Fluosol ameliorates RI. Fluosol's clinical efficacy may be enhanced by prolonging its infusion to ensure an adequate blood level to suppress PMN function beyond the time of reperfusion injury. RheothRx's clinical usefulness may be facilitated by decreasing its renal clearance by delivering larger micelles of the detergent in order to produce prolonged PMN suppression with a shorter infusion time
-
Activation of complement by Fluosol attributable to the pluronic detergent micelle structure.
Journal of cardiovascular pharmacology, 1993Co-Authors: David A. Ingram, Mervyn B. Forman, John J. MurrayAbstract:Fluosol, a complex mixture of perfluorocarbons with a high oxygen-carrying capacity emulsified with the detergent pluronic F-68 and various lipids, recently was approved for adjuvant therapy to reduce myocardial ischemia during coronary angioplasty. Anaphylactoid reactions after Fluosol infusion through activation of the complement pathway have been reported in some patients. We examined the mechanism of complement activation by Fluosol. In vitro, incubation of both dog and human plasma with Fluosol for 1 h caused a significant reduction in total hemolytic complement levels (CH50). None of the individual components of Fluosol tested activated complement. A reduction in CH50 levels similar to that observed with Fluosol was obtained after incubation of dog or human plasma with the detergent pluronic F-68 in combination with either perfluorocarbon. In vivo, a bolus injection of the detergent and perfluorocarbon fully mimicked the anaphylactoid reaction of Fluosol previously observed in dogs, with transient profound hypotension, tachycardia, and reduction in CH50 levels occurring < or = 5 min. To investigate further the mechanism by which the pluronic/perfluorocarbon combination activates complement, an inert dense liquid (mineral oil or silicon oil) substituted for the perfluorocarbons produced comparable complement activation both in vitro and in vivo. These observations suggest that creation of a larger pluronic micelle around a core of perfluorocarbons or any inert dense substance, causes formation of a specific surface configuration, resulting in activation of the complement cascade.
-
Phagocytic activation of human neutrophils by the detergent component of Fluosol.
The American journal of pathology, 1992Co-Authors: David A. Ingram, Mervyn B. Forman, John J. MurrayAbstract:Fluosol (Alpha Therapeutic Corporation, Los Angeles, CA) an emulsion of perfluorocarbons with a high oxygen-carrying capacity, was approved as an adjunct to alleviate myocardial ischemia during coronary angioplasty. This drug also significantly enhances myocardial salvage presumably related to an action on the neutrophil. The mechanism by which Fluosol and its individual components, including the detergent Pluronic F-68, affected neutrophil function was examined. During the incubation of neutrophils with Fluosol, a rapid stimulation of superoxide anion production and degranulation which progressively increased over a 30-minute period was detected. Neutrophils incubated with only Pluronic F-68 produced similar amounts of superoxide anion. Cytochalasin B, an inhibitor of phagocytosis, significantly inhibited this superoxide anion generation. As shown previously, neutrophils incubated with Fluosol for 30 minutes and then subsequently stimulated manifested a reduction in lysozyme release as compared with untreated cells. Results of an electron microscopic examination confirmed the cellular uptake of the Fluosol within phagocytic vacuoles. Neutrophil viability determined by trypan blue was unaffected after Fluosol treatment. These observations show that the Fluosol emulsion, primarily through micelles formed by the detergent Pluronic F-68, activates human neutrophils by serving as a phagocytic stimulus, which produces a cell refractory to subsequent stimulation.
-
Pharmacologic perturbation of neutrophils by Fluosol results in a sustained reduction in infarct size in the canine model of reperfusion
Journal of the American College of Cardiology, 1992Co-Authors: Mervyn B. Forman, David A. Ingram, Christos J. Pitarys, Harry D. Vildibill, Thomas L. Lambert, Renu Virmani, John J. MurrayAbstract:Abstract Previous studies have demonstrated that intravenous administration of large doses of Fluosol, a perfluorochemical preparation, reduced infarct size 24 h after reperfusion, an effect that was associated with reduced neutrophil infiltration. The effect of a clinically tolerable dose of Fluosol on infarct size after a prolonged period of reperfusion and its mechanism of action on neutrophils remain unknown. Twenty-one anesthetized closed chest dogs were subjected to 90 min of proximal left anterior descending coronary artery occlusion and 72 h of reperfusion. An additional five dogs that did not undergo regional myocardial ischemia were utilized to explore the mechanism of action of Fluosol on neutrophil function. In the infarct study, animals were randomized to receive either intravenous Fluosol (n = 10) or an equivalent volume of Ringer's lactate solution (control; n = 11) at 15 ml/kg body weight during the last 30 min of occlusion and for the 1st 30 min of reperfusion Fluosol significantly reduced infarct size when expressed as percent area at risk 72 h aller reperfusion (13.7 ± 2.7% vs. 38.3 ± 4.5%, respectively, p These data demonstrate that low dose intravenous Fluosol produces a sustained reduction in infarct size in the canine model. The beneficial effect may be in part due to the suppression of various neutrophil functions in the reperfused myocardium subsequent to peripheral activation by Fluosol. Such interventions may offer a novel therapy to enhance myocardial salvage by sequestration of circulating neutrophils during the critical early reperfusion period.
Mervyn B. Forman - One of the best experts on this subject based on the ideXlab platform.
-
923-3 Fluosol Reduces Myocardial Reperfusion Injury by Prolonged Suppression of Neutrophils by its Detergent Component (RheothRx) and not by Enhancing O2Delivery
Journal of the American College of Cardiology, 1995Co-Authors: João V. Vitola, David A. Ingram, Mervyn B. Forman, John P. Holsinger, James B. Atkinson, John J. MurrayAbstract:Fluosol, a complex mixture of O2carrying perfluorocarbons (PFCs) emulsified by the detergent pluronic F-68 and a variety of lipids, significantly reduces myocardial reperfusion injury (RI) in animals and humans as shown in some initial clinical trials. Potential mechanisms for Fluosol include enhanced O2delivery to the reperfused tissue and modulation of various neutrophil (PMNs) functions. Recent studies in dogs and man demonstrate the same beneficial effect for treatment of Rl with the detergent component alone, RheothRx, which is currently undergoing clinical trials. We have shown that the effect of Fluosol on PMNs is related to this detergent. However, prolonged infusion (48 hrs) of detergent is required to reduce Rl to the same extent as Fluosol given over only 1 hr. Possible mechanisms for the beneficial effects of Fluosol (O2delivery vs effects on PMNs) were investigated in a model of regional ischemia utilizing rabbits undergoing 30mins of circumflex occlusion and 48 hrs of reperfusion. Infarct size (area of necrosis, AN) was determined histologically and expressed as percent of risk region (area at risk, AR). Animals received Fluosol (30cc/kg) with or without O2or saline over the first 60mins of reperfusion. AR was similar in all groups. (Mean±SEM of AN/AR (%), n=11 for all groups). The treatment with Fluosol with or without O2(44±3 and 40;±3, respectively) was significantly (p<0.05) reduced compared to control (63±4). Another group received F-I08, a larger size pluronic detergent found to be 2.5-fold more potent in suppressing PMN function in vitrocompared to F-68, during the first 3 hrs of reperfusion. This treatment did not alter the infarct size (63±5). RheothRx was found to form 4 nm micelles in solution whereas Fluosol formed particles approximately 100 times larger. Similar sized particles were formed by substituting the perfluorocarbons with mineral oil. The in vitroactivity of this pluronic/mineral oil micelle on PMN function was similar to Fluosol. Infusion of these larger oil micelles was tolerated by rabbits and used in further infarct studies.ConclusionsThese studies suggest that (1) reduction of RI by Fluosol is not due to enhanced O2delivery by the PFCs to reperfused myocardium and (2) since the Fluosol emulsion markedly reduces the clearance of the detergent F-68 (t½: Fluosol ≅ 8 hrs vs RheothRx ≅ 1.5 hrs). prolonged PMN suppression rather than potency of suppression is the mechanism whereby Fluosol ameliorates RI. Fluosol's clinical efficacy may be enhanced by prolonging its infusion to ensure an adequate blood level to suppress PMN function beyond the time of reperfusion injury. RheothRx's clinical usefulness may be facilitated by decreasing its renal clearance by delivering larger micelles of the detergent in order to produce prolonged PMN suppression with a shorter infusion time
-
Activation of complement by Fluosol attributable to the pluronic detergent micelle structure.
Journal of cardiovascular pharmacology, 1993Co-Authors: David A. Ingram, Mervyn B. Forman, John J. MurrayAbstract:Fluosol, a complex mixture of perfluorocarbons with a high oxygen-carrying capacity emulsified with the detergent pluronic F-68 and various lipids, recently was approved for adjuvant therapy to reduce myocardial ischemia during coronary angioplasty. Anaphylactoid reactions after Fluosol infusion through activation of the complement pathway have been reported in some patients. We examined the mechanism of complement activation by Fluosol. In vitro, incubation of both dog and human plasma with Fluosol for 1 h caused a significant reduction in total hemolytic complement levels (CH50). None of the individual components of Fluosol tested activated complement. A reduction in CH50 levels similar to that observed with Fluosol was obtained after incubation of dog or human plasma with the detergent pluronic F-68 in combination with either perfluorocarbon. In vivo, a bolus injection of the detergent and perfluorocarbon fully mimicked the anaphylactoid reaction of Fluosol previously observed in dogs, with transient profound hypotension, tachycardia, and reduction in CH50 levels occurring < or = 5 min. To investigate further the mechanism by which the pluronic/perfluorocarbon combination activates complement, an inert dense liquid (mineral oil or silicon oil) substituted for the perfluorocarbons produced comparable complement activation both in vitro and in vivo. These observations suggest that creation of a larger pluronic micelle around a core of perfluorocarbons or any inert dense substance, causes formation of a specific surface configuration, resulting in activation of the complement cascade.
-
Phagocytic activation of human neutrophils by the detergent component of Fluosol.
The American journal of pathology, 1992Co-Authors: David A. Ingram, Mervyn B. Forman, John J. MurrayAbstract:Fluosol (Alpha Therapeutic Corporation, Los Angeles, CA) an emulsion of perfluorocarbons with a high oxygen-carrying capacity, was approved as an adjunct to alleviate myocardial ischemia during coronary angioplasty. This drug also significantly enhances myocardial salvage presumably related to an action on the neutrophil. The mechanism by which Fluosol and its individual components, including the detergent Pluronic F-68, affected neutrophil function was examined. During the incubation of neutrophils with Fluosol, a rapid stimulation of superoxide anion production and degranulation which progressively increased over a 30-minute period was detected. Neutrophils incubated with only Pluronic F-68 produced similar amounts of superoxide anion. Cytochalasin B, an inhibitor of phagocytosis, significantly inhibited this superoxide anion generation. As shown previously, neutrophils incubated with Fluosol for 30 minutes and then subsequently stimulated manifested a reduction in lysozyme release as compared with untreated cells. Results of an electron microscopic examination confirmed the cellular uptake of the Fluosol within phagocytic vacuoles. Neutrophil viability determined by trypan blue was unaffected after Fluosol treatment. These observations show that the Fluosol emulsion, primarily through micelles formed by the detergent Pluronic F-68, activates human neutrophils by serving as a phagocytic stimulus, which produces a cell refractory to subsequent stimulation.
-
Pharmacologic perturbation of neutrophils by Fluosol results in a sustained reduction in infarct size in the canine model of reperfusion
Journal of the American College of Cardiology, 1992Co-Authors: Mervyn B. Forman, David A. Ingram, Christos J. Pitarys, Harry D. Vildibill, Thomas L. Lambert, Renu Virmani, John J. MurrayAbstract:Abstract Previous studies have demonstrated that intravenous administration of large doses of Fluosol, a perfluorochemical preparation, reduced infarct size 24 h after reperfusion, an effect that was associated with reduced neutrophil infiltration. The effect of a clinically tolerable dose of Fluosol on infarct size after a prolonged period of reperfusion and its mechanism of action on neutrophils remain unknown. Twenty-one anesthetized closed chest dogs were subjected to 90 min of proximal left anterior descending coronary artery occlusion and 72 h of reperfusion. An additional five dogs that did not undergo regional myocardial ischemia were utilized to explore the mechanism of action of Fluosol on neutrophil function. In the infarct study, animals were randomized to receive either intravenous Fluosol (n = 10) or an equivalent volume of Ringer's lactate solution (control; n = 11) at 15 ml/kg body weight during the last 30 min of occlusion and for the 1st 30 min of reperfusion Fluosol significantly reduced infarct size when expressed as percent area at risk 72 h aller reperfusion (13.7 ± 2.7% vs. 38.3 ± 4.5%, respectively, p These data demonstrate that low dose intravenous Fluosol produces a sustained reduction in infarct size in the canine model. The beneficial effect may be in part due to the suppression of various neutrophil functions in the reperfused myocardium subsequent to peripheral activation by Fluosol. Such interventions may offer a novel therapy to enhance myocardial salvage by sequestration of circulating neutrophils during the critical early reperfusion period.
Sharon R. Oliver - One of the best experts on this subject based on the ideXlab platform.
-
influence of moderate haemodilution with Fluosol or normal saline on carbaryl disposition in sprague dawley rats
Journal of Pharmacy and Pharmacology, 1997Co-Authors: Robert P. Shrewsbury, L. W. Johnson, Sharon R. OliverAbstract:In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg−1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL). These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.
-
Influence of Moderate Haemodilution with Fluosol or Normal Saline on Carbaryl Disposition in Sprague‐Dawley Rats
The Journal of pharmacy and pharmacology, 1997Co-Authors: Robert P. Shrewsbury, L. W. Johnson, Sharon R. OliverAbstract:In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg−1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL). These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.
-
The effect of moderate hemodilution with Fluosol on cytochrome P4502D6 activity in the rat.
Artificial cells blood substitutes and immobilization biotechnology, 1994Co-Authors: Robert P. Shrewsbury, Sharon R. Oliver, Lisa G. WhiteAbstract:Desmethylimipramine (desipramine, DMI) is predominantly 2-hydroxylated to 2-hydroxydesipramine, and the remainder is N-demethylated to didesmethylimipramine (DDM1) in both rats and man. DMI 2-hydroxylation is mediated by the same cytochrome P-450 isoenzyme (P4502D6) in rats and man. Fluosol hemodilution has previously been shown to influence the activity of P4502B1 and P4502B2, the cytochrome P-450 isoenzymes induced by phenobarbital in rats. In this study, DMI was used as a model substrate to investigate the influence of moderate Fluosol hemodilution on P4502D6 activity in rats. DMI total body clearance was not influenced by Fluosol hemodilution. This was an anticipated outcome since phenobarbital had a negligible effect on DMI metabolism, and Fluosol and phenobarbital affect the same isoenzymes. DMI Vdss was increased at 0.5 hour after hemodilution, but decreased from 24-72 hours. The decreased Vdss is most likely due to increased concentrations of alpha-1-acid-glycoprotein. Thus, Fluosol hemodilution i...
Robert P. Shrewsbury - One of the best experts on this subject based on the ideXlab platform.
-
influence of moderate haemodilution with Fluosol or normal saline on carbaryl disposition in sprague dawley rats
Journal of Pharmacy and Pharmacology, 1997Co-Authors: Robert P. Shrewsbury, L. W. Johnson, Sharon R. OliverAbstract:In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg−1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL). These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.
-
Influence of Moderate Haemodilution with Fluosol or Normal Saline on Carbaryl Disposition in Sprague‐Dawley Rats
The Journal of pharmacy and pharmacology, 1997Co-Authors: Robert P. Shrewsbury, L. W. Johnson, Sharon R. OliverAbstract:In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg−1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL). These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.
-
The effect of moderate hemodilution with Fluosol on cytochrome P4502D6 activity in the rat.
Artificial cells blood substitutes and immobilization biotechnology, 1994Co-Authors: Robert P. Shrewsbury, Sharon R. Oliver, Lisa G. WhiteAbstract:Desmethylimipramine (desipramine, DMI) is predominantly 2-hydroxylated to 2-hydroxydesipramine, and the remainder is N-demethylated to didesmethylimipramine (DDM1) in both rats and man. DMI 2-hydroxylation is mediated by the same cytochrome P-450 isoenzyme (P4502D6) in rats and man. Fluosol hemodilution has previously been shown to influence the activity of P4502B1 and P4502B2, the cytochrome P-450 isoenzymes induced by phenobarbital in rats. In this study, DMI was used as a model substrate to investigate the influence of moderate Fluosol hemodilution on P4502D6 activity in rats. DMI total body clearance was not influenced by Fluosol hemodilution. This was an anticipated outcome since phenobarbital had a negligible effect on DMI metabolism, and Fluosol and phenobarbital affect the same isoenzymes. DMI Vdss was increased at 0.5 hour after hemodilution, but decreased from 24-72 hours. The decreased Vdss is most likely due to increased concentrations of alpha-1-acid-glycoprotein. Thus, Fluosol hemodilution i...
-
The Effect of Moderate Haemodilution with Fluosol-DA or Hespan on the Nonmicrosomal Acetylation of Sulphadimidine in the Rat
The Journal of pharmacy and pharmacology, 1992Co-Authors: Robert P. Shrewsbury, Lisa G. White, Donald D. Hong, Teressa R. GordonAbstract:The effects of Fluosol-DA (Fluosol) and Hespan haemodilution on the nonmicrosomal acetylation of sulphadimidine were studied in male rats. Fluosol increased the acetylsulphadimidine percent excreted in urine, the metabolic formation rate constant (kf), and the formation clearance (CLF) for 72 h after haemodilution without any significant changes in the sulphadimidine apparent volume of distribution (Vd) or total body clearance (CL). Hespan haemodilution increased the acetylsulphadimidine percent excreted in urine only at 48 h while significantly decreasing the sulphadimidine clearance, urinary excretion rate constant (ku), and renal clearance (CLR) for 72 h. The enhanced N-acetyltransferase activity after Fluosol haemodilution may have therapeutic consequences for concomitantly given drugs metabolized by this enzyme.
Renu Virmani - One of the best experts on this subject based on the ideXlab platform.
-
hyperoxic reperfusion is required to reduce infarct size after intravenous therapy with perfluorochemical Fluosol da 20 or its detergent component poloxamer 188 in a poorly collateralized animal model absence of a role of polymorphonuclear leukocytes
Journal of the American College of Cardiology, 1994Co-Authors: Frank D. Kolodgie, Andrew Farb, Greg C Carlson, Patricia S Wilson, Renu VirmaniAbstract:Abstract Objectives . The aim of this study was to assess whether hyperoxic reperfusion contributes to the efficacy of Fluosol 20% or poloxamer 188 for infarct size reduction and whether suppression of polymorphonuclear leukocyte function is responsible for cardioprotection. Background . The perfluorochemical Fluosol and its detergent component poloxamer 188 limit myocardial reperfusion-induced injury; however, the underlying mechanism(s) are uncertain. Methods . A series of in vivo and ex vivo studies were performed in a 30-min temporary coronary occlusion rabbit model. Before reperfusion, rabbits received a 25-ml/kg infusion of 1) Fluosol; 2) poloxamer 188 (equivalent % w/v to Fluosol, 675 mg/kg body weight); or 3) 5% dextrose (control). In protocol A, animals were subjected to either normoxic or hyperoxic reperfusion; in protocols B and C, hyperoxic reperfusion was studied. In protocol B, myocardial blood flow was assessed. In protocol C, polymorphonuclear leukocyte function and myocardial myeloperoxidase were determined. Results . In rabbits subjected to normoxic reperfusion, infarct size (normalized to risk region weight) was not significantly different among groups. In rabbits subjected to hyperoxic reperfusion, infarcts were significantly reduced with both poloxamer 188 and Fluosol treatment compared with control animals (p = 0.05 and p = 0.0004, respectively). Blood flow at 3 h of reperfusion within the ischemic endocardium was greater in the Fluosol and poloxamer 188 groups than in the control group (p = 0.001 and p = 0.08, respectively). Myeloperoxidase activity was not affected by treatment, nor was there suppression of polymorphonuclear leukocyte function. Conclusions . Fluosol and poloxamer 188 reduce infarct size in rabbits subjected to hyperoxic reperfusion. Suppression of polymorphonuclear leukocyte function was not demonstrated, suggesting a greater role for increased arterial oxygen delivery in salvaging ischemic myocardium.
-
Pharmacologic perturbation of neutrophils by Fluosol results in a sustained reduction in infarct size in the canine model of reperfusion
Journal of the American College of Cardiology, 1992Co-Authors: Mervyn B. Forman, David A. Ingram, Christos J. Pitarys, Harry D. Vildibill, Thomas L. Lambert, Renu Virmani, John J. MurrayAbstract:Abstract Previous studies have demonstrated that intravenous administration of large doses of Fluosol, a perfluorochemical preparation, reduced infarct size 24 h after reperfusion, an effect that was associated with reduced neutrophil infiltration. The effect of a clinically tolerable dose of Fluosol on infarct size after a prolonged period of reperfusion and its mechanism of action on neutrophils remain unknown. Twenty-one anesthetized closed chest dogs were subjected to 90 min of proximal left anterior descending coronary artery occlusion and 72 h of reperfusion. An additional five dogs that did not undergo regional myocardial ischemia were utilized to explore the mechanism of action of Fluosol on neutrophil function. In the infarct study, animals were randomized to receive either intravenous Fluosol (n = 10) or an equivalent volume of Ringer's lactate solution (control; n = 11) at 15 ml/kg body weight during the last 30 min of occlusion and for the 1st 30 min of reperfusion Fluosol significantly reduced infarct size when expressed as percent area at risk 72 h aller reperfusion (13.7 ± 2.7% vs. 38.3 ± 4.5%, respectively, p These data demonstrate that low dose intravenous Fluosol produces a sustained reduction in infarct size in the canine model. The beneficial effect may be in part due to the suppression of various neutrophil functions in the reperfused myocardium subsequent to peripheral activation by Fluosol. Such interventions may offer a novel therapy to enhance myocardial salvage by sequestration of circulating neutrophils during the critical early reperfusion period.