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Comparative effects of anatomic infarct size of verapamil, ibuprofen, and morphine-promethazine-chlorpromazine combination
ABSTRACTS
COMPARATIVE EFFECTS OF ANATOMIC INFARCT SIZE OF VERAPAMIL, IBUPROFEN, AND MORPHINE-PROMETHAZINE-CHLORPROMAZINE COMBINATION Lair G.T. LRibeiro2 MD, Tsunehiro Yasuda, MD, Edward Lowenstein, MD, Eugene Braunwald, MD, FACC, Peter R. Maroko, MD, FACC, Harvard Med Sch/Peter B Brigham Hosp, Boston, MA The goal of this studywas to examine the effects of promising interventions on the anatomic infarct size (IS) after a permanent coronary artery occlusion in the dog model. Thus, i hr after left anterior coronary artery occlusion, 47 dogs were randomized into groups: i) untreated controls; 2) veramamil (V), a calcium antagonist, (0.2 mg/kg IV at i hr plus 0.6 mg/kg/hr for 7 hrs); 3) ibuprofen (Ib), a prostaglandin inhibitor, (12.5 mg/kg IV at 1,4 and 7 hrs); and 4) combination of morphinepromethazine-chlorpromazine (MPC, "lytic cocktail") (0.9/0.45/0.45 mg/kg/hr between 1-12 h r s ) After 24 hrs the hearts were excised, "breadloafed", and stained in triphenyl-tetrazolium-chloride. IS (as % of left ventricle) by planimetry of the slices and by weight of the dissected tissue were similar (r=0.92). IS, by weight, was 28.2 + 1.7% of left ventricle in controls (n=19), and was smaller in V [1.4.7 + 3.0% (n=10, p<0.01)], Ib [19.9 + 2.5% (n=9, p<0~05)], and MPC [12.9 + 3.2% (n=9, p<0.01)] groups. Heart rate, arterial pressure and hematocrit were similar at randomization, i.e., i hr after occlusion, for all groups as was the distance from aorta to site of occlusion. In conclusion, even after delaying their administrationby i hour, verapamil, ibuprofen and the "lytic cocktail", three interventions that act by completely diverse mechanisms, reduced IS, as evaluated by a direct anatomic measurement, by 48, 29 and 54% respectively, suggesting their potential usefulness.
INFARCT SIZE REDUCTION BY INTRAVENOUS IBUPROFEN AFTER CORONARY OCCLUSION IN CONSCIOUS DOGS. Bodh I. Jugdutt, MBChB, Grover M. Hutchins, MD, Bernadine H. Bulkley, MD, FAcC, Lewis C. Becker, MD, FACC. The Johns Hopkins Medical Institutions, Baltimore, Maryland. We studied the effect of ibuprofen, a non-steroldal anti-inflammatory and prostaglanclin-inh[biting drug, on myocardial infarct size relative to the size of the risk region 2 days after left circumflex coronary artery occlusion in conscious dogs. Intravenous infusions over 6 hours were given immediatelypost occlusion:saline to 12 control dogs and ibuprofen (6 mg/kg/hr) to 12 dogs.Coronary blood flow was measured pre and post occlusion by 9F radlbactive microspheres, and risk region was defined by post-mortem coronary angiography. Changes in arterial pressure, heart rate and left atrial pressure were similar in control and ibuprofen dogs. Collateral blood flow increased and resistance decreased over the 6 hours post occlusion in both groups, and these changes did not differ significantly. The massesof infarct and risk region were measured by planimetry of weighed r~ngs of the left ventricle (LbO. Infarct (g) Risk (g) LV (g) Infarct/Risk (%) CONTROL i 2 . 8 33.2 ~ 34.5 IBUPROFEN 7.0* 34.6 91.3 17.5"* *p < O. 1, **p < O.02 vs Control The relation between massesof infarct and risk region was altered (p ~: O. 001) by [buprofen so that dogs with similar risk regionshad smaller infarcts.Thus, ibuprofen infusion after coronary occlusion decreases infarct size relative to the regions at risk.This protection is not explained by changes in collateral flow, heart rate and blood pressure and may be due to beneficial metabolic and cellular properties of ibuprofen outweighing deleterious effects of prostaglandin inhibition.
396
February 1979
The American Journal of cARDIOLOGY
SULFINPYRAZONE INCREASES COLLATERAL BLOOD FLOW FOLLOWING ACUTE CORONARY OCCLUSION Nancy Davenport~ RN, PhD; Robert E. Goldstein, MD, FACC; NorineL. Capurro, PhD; N. Raphael Shulman, MD; Stephen E. Epstein, MD, FACC, NHLBI, Bethesda, Md. Recent studies suggest that daily administration of sulfinpyrazone (SPZ) decreases patient mortality during the first year following acute myocardial infarction (AMI). However, the effect of SPZ, a known platelet-inhibiting drug, immediately following acute coronary occlusion is unknown. Previous studies of two other platelet inhibit0rs, aspirin and indomethacin, demonstrated that myocardial collateral blood flow (CBF) is increased by aspirin but decreasedby indomethacin. To determine whether changes in CBF are induced by SPZ, 21 open-chest dogs were studied. Radioactive microspheres (15±5~) were injected 5 min after occlusion of left anterior descending (LAD) coronary artery. The occlusion was then released and SPZ 30 mg/kg administered to ii dogs; 10 control dogs received saline. One hr after release the LAD was permanently occluded and microspheres injected 5 min and 4 hrs thereafter. No significant changes in CBF tonormal or ischemic zones occurred in control dogs. In the ischemic zone epicardium of the SPZ treated group, CBF, which was 0.13 ml/min/g 5 min after first occlusion, rose to 0.20 (p~ 01) 5 sin after 2nd occlusion and to 0.31 (p~.02) 4 hrs after 2nd occlusion. Small changes occurred in the ischemic zone endocardium: CBF, 0.035 5 min after ist occlusion, rose to 0.084 (p!.01) 5 min after 2nd occlusion and remained elevated (0.076) 4 hrs after 2nd occlusion. The platelets of each SPZ-treated dog showed a completely inhibited response to ADP-induced aggregation. Thus SPZ, like aspirin, can increase CBF to ischemic epicardium. This favorable effect on CBF may play a role in the salutary action of SPZ in patients following AMI.
EVALUATION OF REVERSIBLE AND IRREVERSIBLE ISCHE C AREAS I N ACUPE MYOCARDIAL INFABL~fION Haruo Tamoda, FD, Sadatoshi Matmm~to, MD, Yutaka Suzuki, ND, Dept. Cardfol. & Radiol., Tokai University, Japan. To evaluate reversible and irreversible myocardial ischemic areas in patients(pts) with acute myocardial infarction(AMI) , we have developed the following methods: (I) 2 mCi Of 201-TIC1 was injected intravenously(i.v.) and left ventricular(LV) myocardial perfusion images were obtained; (2) inlnediately thereafter, 5 mg of isosorbide dinitrate (ISD) was administered s u b l ~ l l y ; and (3) 10 minutes after the administration, another bolus of 2 mCi of 201-TIC1 was given i.v. and LV myocardial perfusion imaging was repeated(double scan method). Ten pts with AMI (within 12 hours after onset) and i0 pts with healed MI (more than 1 m o n t h after onset) were studied by the double Scan method. In pts with healed MI, myocardial perfusion defect areas (average of three different projections) changed by 5.3 ~ 1.2% with ISD administration. On the other hand, in pts with AMI, perfusion defect areas decreased by 34.5 ± 4.5% with ISD administration indicating that there were reversible ischemic areas in AMI which could be transiently reduced with ISD. For clinical implications, 80 pts with AMI were divided into 2 Groups (Grp) at randam: Grp I - 40 pts treated with conventional methods, and Grp II - 40 pts treated with continuous ISD administration(every 3 hours for 3 days). There was no significant difference in prognostic indices a t the time of admission. Final MI sizes estimated by 201-TIC1 2 months after onset(per cent of perfusion defects to total LV) were significantly smaller in Grp II(19.8 ± 3.1%) than in Grp I(32.1 ± 3.7%) (pK0.02). Mortality was 25.0% in Grp i and i0.0% in grp I I . Thus, evaluation of reversible and irreversible ischemic areas in AMI by the double scan method is useful in attempt/rig aggressive treabment of AMI.
Volume 43
COMPARATIVE EFFECTS OF ANATOMIC INFARCT SIZE OF VERAPAMIL, IBUPROFEN, AND MORPHINE-PROMETHAZINE-CHLORPROMAZINE COMBINATION Lair G.T. LRibeiro2 MD, Tsunehiro Yasuda, MD, Edward Lowenstein, MD, Eugene Braunwald, MD, FACC, Peter R. Maroko, MD, FACC, Harvard Med Sch/Peter B Brigham Hosp, Boston, MA The goal of this studywas to examine the effects of promising interventions on the anatomic infarct size (IS) after a permanent coronary artery occlusion in the dog model. Thus, i hr after left anterior coronary artery occlusion, 47 dogs were randomized into groups: i) untreated controls; 2) veramamil (V), a calcium antagonist, (0.2 mg/kg IV at i hr plus 0.6 mg/kg/hr for 7 hrs); 3) ibuprofen (Ib), a prostaglandin inhibitor, (12.5 mg/kg IV at 1,4 and 7 hrs); and 4) combination of morphinepromethazine-chlorpromazine (MPC, "lytic cocktail") (0.9/0.45/0.45 mg/kg/hr between 1-12 h r s ) After 24 hrs the hearts were excised, "breadloafed", and stained in triphenyl-tetrazolium-chloride. IS (as % of left ventricle) by planimetry of the slices and by weight of the dissected tissue were similar (r=0.92). IS, by weight, was 28.2 + 1.7% of left ventricle in controls (n=19), and was smaller in V [1.4.7 + 3.0% (n=10, p<0.01)], Ib [19.9 + 2.5% (n=9, p<0~05)], and MPC [12.9 + 3.2% (n=9, p<0.01)] groups. Heart rate, arterial pressure and hematocrit were similar at randomization, i.e., i hr after occlusion, for all groups as was the distance from aorta to site of occlusion. In conclusion, even after delaying their administrationby i hour, verapamil, ibuprofen and the "lytic cocktail", three interventions that act by completely diverse mechanisms, reduced IS, as evaluated by a direct anatomic measurement, by 48, 29 and 54% respectively, suggesting their potential usefulness.
INFARCT SIZE REDUCTION BY INTRAVENOUS IBUPROFEN AFTER CORONARY OCCLUSION IN CONSCIOUS DOGS. Bodh I. Jugdutt, MBChB, Grover M. Hutchins, MD, Bernadine H. Bulkley, MD, FAcC, Lewis C. Becker, MD, FACC. The Johns Hopkins Medical Institutions, Baltimore, Maryland. We studied the effect of ibuprofen, a non-steroldal anti-inflammatory and prostaglanclin-inh[biting drug, on myocardial infarct size relative to the size of the risk region 2 days after left circumflex coronary artery occlusion in conscious dogs. Intravenous infusions over 6 hours were given immediatelypost occlusion:saline to 12 control dogs and ibuprofen (6 mg/kg/hr) to 12 dogs.Coronary blood flow was measured pre and post occlusion by 9F radlbactive microspheres, and risk region was defined by post-mortem coronary angiography. Changes in arterial pressure, heart rate and left atrial pressure were similar in control and ibuprofen dogs. Collateral blood flow increased and resistance decreased over the 6 hours post occlusion in both groups, and these changes did not differ significantly. The massesof infarct and risk region were measured by planimetry of weighed r~ngs of the left ventricle (LbO. Infarct (g) Risk (g) LV (g) Infarct/Risk (%) CONTROL i 2 . 8 33.2 ~ 34.5 IBUPROFEN 7.0* 34.6 91.3 17.5"* *p < O. 1, **p < O.02 vs Control The relation between massesof infarct and risk region was altered (p ~: O. 001) by [buprofen so that dogs with similar risk regionshad smaller infarcts.Thus, ibuprofen infusion after coronary occlusion decreases infarct size relative to the regions at risk.This protection is not explained by changes in collateral flow, heart rate and blood pressure and may be due to beneficial metabolic and cellular properties of ibuprofen outweighing deleterious effects of prostaglandin inhibition.
396
February 1979
The American Journal of cARDIOLOGY
SULFINPYRAZONE INCREASES COLLATERAL BLOOD FLOW FOLLOWING ACUTE CORONARY OCCLUSION Nancy Davenport~ RN, PhD; Robert E. Goldstein, MD, FACC; NorineL. Capurro, PhD; N. Raphael Shulman, MD; Stephen E. Epstein, MD, FACC, NHLBI, Bethesda, Md. Recent studies suggest that daily administration of sulfinpyrazone (SPZ) decreases patient mortality during the first year following acute myocardial infarction (AMI). However, the effect of SPZ, a known platelet-inhibiting drug, immediately following acute coronary occlusion is unknown. Previous studies of two other platelet inhibit0rs, aspirin and indomethacin, demonstrated that myocardial collateral blood flow (CBF) is increased by aspirin but decreasedby indomethacin. To determine whether changes in CBF are induced by SPZ, 21 open-chest dogs were studied. Radioactive microspheres (15±5~) were injected 5 min after occlusion of left anterior descending (LAD) coronary artery. The occlusion was then released and SPZ 30 mg/kg administered to ii dogs; 10 control dogs received saline. One hr after release the LAD was permanently occluded and microspheres injected 5 min and 4 hrs thereafter. No significant changes in CBF tonormal or ischemic zones occurred in control dogs. In the ischemic zone epicardium of the SPZ treated group, CBF, which was 0.13 ml/min/g 5 min after first occlusion, rose to 0.20 (p~ 01) 5 sin after 2nd occlusion and to 0.31 (p~.02) 4 hrs after 2nd occlusion. Small changes occurred in the ischemic zone endocardium: CBF, 0.035 5 min after ist occlusion, rose to 0.084 (p!.01) 5 min after 2nd occlusion and remained elevated (0.076) 4 hrs after 2nd occlusion. The platelets of each SPZ-treated dog showed a completely inhibited response to ADP-induced aggregation. Thus SPZ, like aspirin, can increase CBF to ischemic epicardium. This favorable effect on CBF may play a role in the salutary action of SPZ in patients following AMI.
EVALUATION OF REVERSIBLE AND IRREVERSIBLE ISCHE C AREAS I N ACUPE MYOCARDIAL INFABL~fION Haruo Tamoda, FD, Sadatoshi Matmm~to, MD, Yutaka Suzuki, ND, Dept. Cardfol. & Radiol., Tokai University, Japan. To evaluate reversible and irreversible myocardial ischemic areas in patients(pts) with acute myocardial infarction(AMI) , we have developed the following methods: (I) 2 mCi Of 201-TIC1 was injected intravenously(i.v.) and left ventricular(LV) myocardial perfusion images were obtained; (2) inlnediately thereafter, 5 mg of isosorbide dinitrate (ISD) was administered s u b l ~ l l y ; and (3) 10 minutes after the administration, another bolus of 2 mCi of 201-TIC1 was given i.v. and LV myocardial perfusion imaging was repeated(double scan method). Ten pts with AMI (within 12 hours after onset) and i0 pts with healed MI (more than 1 m o n t h after onset) were studied by the double Scan method. In pts with healed MI, myocardial perfusion defect areas (average of three different projections) changed by 5.3 ~ 1.2% with ISD administration. On the other hand, in pts with AMI, perfusion defect areas decreased by 34.5 ± 4.5% with ISD administration indicating that there were reversible ischemic areas in AMI which could be transiently reduced with ISD. For clinical implications, 80 pts with AMI were divided into 2 Groups (Grp) at randam: Grp I - 40 pts treated with conventional methods, and Grp II - 40 pts treated with continuous ISD administration(every 3 hours for 3 days). There was no significant difference in prognostic indices a t the time of admission. Final MI sizes estimated by 201-TIC1 2 months after onset(per cent of perfusion defects to total LV) were significantly smaller in Grp II(19.8 ± 3.1%) than in Grp I(32.1 ± 3.7%) (pK0.02). Mortality was 25.0% in Grp i and i0.0% in grp I I . Thus, evaluation of reversible and irreversible ischemic areas in AMI by the double scan method is useful in attempt/rig aggressive treabment of AMI.
Volume 43