Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 59
Filter
Add more filters










Publication year range
1.
Thromb Res ; 103(4): 309-24, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11562341

ABSTRACT

FXV673 is a novel, potent, and selective factor Xa (FXa) inhibitor. FXV673 inhibited human, dog, and rabbit FXa with a K(i) of 0.52, 1.41, and 0.27 nM, respectively. FXV673 also displayed excellent specificity toward FXa relative to other serine proteases. It showed selectivity of more than 1000-fold over thrombin, activated protein C (aPC), plasmin, and tissue-plasminogen activator (t-PA). FXV673 prolonged plasma activated partial thromboplastin time (APTT) and prothrombin time (PT) in a dose-dependent fashion. In the APTT assays, the concentrations (microM) required for doubling coagulation time were 0.41 (human), 0.65 (monkey), 1.12 (dog), 0.25 (rabbit), and 0.80 (rat). The concentrations (microM) required in the PT assays were 1.1 (human), 1.32 (monkey), 2.31 (dog), 0.92 (rabbit), and 1.69 (rat). A coupled-enzyme assay was performed to measure thrombin activity following prothrombinase conversion of prothrombin to thrombin. FXV673 showed IC(50)s of 1.38 and 2.55 nM, respectively, when artificial phosphatidylserine/phosphatidylcholine (PS/PC) liposomes or fresh platelets were used as the phospholipid source for prothrombinase complex formation. It was demonstrated that FXV673 could inhibit further thrombin generation in the prothrombinase complex using PS/PC liposomes. FXV673 dose-dependently prolonged the time to vessel occlusion and inhibited thrombus formation in well-characterized canine models of thrombosis. Interspecies extrapolation (approximately 2.5-fold higher sensitivity for FXa inhibition in human than in dog) suggested that 100 ng/ml of FXV673 would be an effective plasma concentration for clinical studies. Currently FXV673 is undergoing clinical studies to be developed as an antithrombotic agent.


Subject(s)
Cyclic N-Oxides/pharmacology , Factor Xa Inhibitors , Fibrinolytic Agents/pharmacology , Pyridines/pharmacology , Thrombosis/drug therapy , Animals , Blood Coagulation Tests , Carotid Arteries , Cyclic N-Oxides/administration & dosage , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Factor V/antagonists & inhibitors , Factor Xa , Fibrinolytic Agents/administration & dosage , Haplorhini , Humans , Jugular Veins , Kinetics , Membranes, Artificial , Pyridines/administration & dosage , Rats , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/pharmacology
2.
Br J Pharmacol ; 133(7): 1190-8, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11487531

ABSTRACT

We compared the antithrombotic efficacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt-PA-induced coronary thrombolysis. Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8), FXV673 (10, 30 or 100 microg kg(-1)+1, 3, or 10 microg kg(-1) min(-1), respectively; n=8 per dose), heparin (60 u kg(-1)+0.7 u kg(-1) min(-1), n=8), or RPR109891 (30 microg kg(-1)+0.45 microg kg(-1) min(-1), n=8), was initiated. Aspirin (5 mg kg(-1), i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt-PA was administered (100 microg kg(-1)+20 microg kg(-1) min(-1) for 60 min). The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was significantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23+/-5 min for FXV673 versus 41+/-11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P<0.05). Throughout the protocol, blood flow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose-dependent manner. Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively. In conclusion, FXV673 is more effective than heparin and at least as effective as RPR109891 when used as an adjunct during rt-PA-induced coronary thrombolysis.


Subject(s)
Coronary Thrombosis/drug therapy , Cyclic N-Oxides/therapeutic use , Factor Xa Inhibitors , Fibrinolytic Agents/therapeutic use , Pyridines/therapeutic use , Thrombolytic Therapy , Animals , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Coronary Circulation/drug effects , Coronary Thrombosis/physiopathology , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Female , Heparin/therapeutic use , Male , Partial Thromboplastin Time , Peptides/therapeutic use , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Prothrombin/antagonists & inhibitors , Prothrombin Time , Recombinant Proteins/therapeutic use , Time Factors , Tissue Plasminogen Activator/therapeutic use , Treatment Outcome , Vascular Patency/drug effects
3.
J Cardiovasc Pharmacol ; 38(2): 288-97, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11483879

ABSTRACT

Factor Xa (fXa) plays a pivotal role in the activation of the coagulation system during thrombosis, but, unlike GPIIb/IIIa receptor antagonists, the role of fXa inhibition in arterial passivation is not well defined. We compared the long-term antithrombotic efficacy of a direct fXa inhibitor, FXV673, and heparin after short-term infusion in conscious dogs. Dogs were instrumented surgically to induce carotid artery thrombosis by electrolytic injury. On day 1, dogs received a 3-h infusion of placebo (n = 10), FXV673 (100 microg/kg + 10 microg/kg/min, n = 7), or heparin (60 U/kg + 0.7 U/kg/min, n 7). Injury (100 microA) was initiated concomitantly for 1 h. The procedure was repeated on day 2 with injury of 200 microA for 3 h. Carotid artery blood flow (CBF) and coagulation parameters were monitored continuously for 3 h on days 1 and 2 and for 30 min on days 3, 4, and 5. On day 1 at 3 h, CBF in the placebo-treated group was 26% of baseline with 70% incidence of occlusion. None of the vessels occluded in the heparin and FXV673 groups; however, the CBF was significantly higher in the FXV673 group (92+/-8 ml/min versus 39+/-12 ml/min). Before injury on day 2, CBF recovered in all groups to 71-89% of baseline. After the second injury, all vessels in the placebo-treated group progressed to complete occlusion by 3 h. CBF was significantly higher in FXV673 group compared with heparin throughout the 3-h period. On days 3, 4, and 5 the placebo-treated vessels remained occluded, but the CBF in the heparin group was 33+/-20 ml/min, 55+/-11 ml/min and 68+/-12 ml/min, respectively, compared with 84+/-10 ml/min, 98+/-7 ml/min, and 99+/-10 ml/min in the FXV673 group. The arterial thrombus mass was significantly lower in FXV673 group (13+/-4 mg) compared with placebo (103+/-10 mg) and heparin (44+/-11 mg). In summary, these data demonstrate that short-term infusion of FXV673 was associated with long-term efficacy that was superior to standard heparin and underscore the role of direct fXa inhibition in arterial passivation.


Subject(s)
Carotid Artery Thrombosis/blood , Carotid Artery Thrombosis/physiopathology , Cyclic N-Oxides/pharmacology , Disease Models, Animal , Factor Xa Inhibitors , Fibrinolytic Agents/pharmacology , Pyridines/pharmacology , Animals , Carotid Artery Thrombosis/drug therapy , Consciousness/drug effects , Consciousness/physiology , Cyclic N-Oxides/chemistry , Cyclic N-Oxides/therapeutic use , Dogs , Female , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/therapeutic use , Male , Pyridines/chemistry , Pyridines/therapeutic use , Regional Blood Flow/drug effects , Regional Blood Flow/physiology
4.
Thromb Res ; 102(3): 261-71, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11369420

ABSTRACT

It is known that a low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin in unstable angina/non-Q-wave myocardial infarction (UA/NQMI) and the platelet GPIIb/IIIa receptors play an important role in acute myocardial infarction (AMI). Therefore, enoxaparin might have a similar advantage over heparin when used with a GPIIb/IIIa antagonist (RPR109891) in coronary thrombolysis. After induction of coronary thrombosis in anesthetized dogs, infusion of saline, enoxaparin, heparin, RPR109891, enoxaparin+RPR109891, or heparin+RPR109891 was initiated followed 15 min later by recombinant tissue plasminogen activator (rt-PA). The incidence of reperfusion in the enoxaparin+RPR109891- and the heparin+RPR109891-treated groups was similar, but time to reperfusion tended to be shorter for enoxaparin versus heparin. Only 43% of the vessels reoccluded in the enoxaparin+RPR109891 group, compared to 100% vessels in the heparin+RPR109891 group. Enoxaparin+RPR109891 maintained flow for a significantly longer time compared to saline, enoxaparin, heparin, and heparin+RPR109891. Enoxaparin+RPR109891 and heparin+RPR109891 increased the template bleeding time by 2- and 3-fold and activated partial thromboplastin time (APTT) by 1.3- and 3-fold, respectively. These data suggest that enoxaparin is more effective and potentially safer than heparin when combined with a GPIIb/IIIa receptor antagonist during rt-PA-induced coronary thrombolysis.


Subject(s)
Coronary Thrombosis/drug therapy , Enoxaparin/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Thrombolytic Therapy/methods , Animals , Blood Flow Velocity/drug effects , Disease Models, Animal , Dogs , Drug Therapy, Combination , Enoxaparin/administration & dosage , Enoxaparin/standards , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/pharmacology , Heparin/administration & dosage , Heparin/pharmacology , Heparin/standards , Male , Oligopeptides/administration & dosage , Oligopeptides/pharmacology , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Therapeutic Equivalency , Time Factors , Tissue Plasminogen Activator/administration & dosage , Tissue Plasminogen Activator/pharmacology , Vascular Patency/drug effects
5.
Thromb Res ; 99(1): 71-82, 2000 Jul 01.
Article in English | MEDLINE | ID: mdl-11012377

ABSTRACT

RPR 130737 inhibited factor Xa (FXa) with a Ki of 2.4 nM and also displayed excellent specificity toward FXa relative to other serine proteases. It showed selectivity of more than 1000-fold over thrombin, activated protein C, plasmin, tissue-plasminogen activator and trypsin. RPR 130737 prolonged plasma activated partial thromboplastin time and prothrombin time in a dose-dependent fashion. In the activated partial thromboplastin time assay, the concentrations required for doubling coagulation time were 0.32 microM (human), 0.61 microM (monkey), 0.44 microM (dog), 0.15 microM (rabbit), and 0.82 microM (rat). The concentrations required to double prothrombin time were 0.86 microM (human), and 1.26 microM (monkey), 1.15 microM (dog), 0.39 microM (rabbit) and 7.31 microM (rat). Kinetic studies revealed that RPR 130737 was a fast binding, reversible and competitive inhibitor for FXa when Spectrozyme FXa, a chromogenic substrate, was used. A coupled-enzyme assay measuring thrombin activity following prothrombinase conversion of prothrombin to thrombin indicated that RPR 130737 was a potent inhibitor for prothrombinase-bound FXa. In this assay, RPR 130737 showed IC50s of 17 nM and 35.9 nM, respectively when artificial phosphatidylserine/phosphatidylcholine (PS/PC) liposomes or gel-filtered platelets were used as the phospholipid source. An FX-deficient plasma clotting-time correction assay further demonstrated that RPR 130737 was a specific inhibitor of FXa. RPR 130737 showed no effect on platelet aggregation in vitro. These results indicate that RPR 130737 has the potential to be developed as an antithrombotic agent based on its potent and selective inhibitory effect against FXa.


Subject(s)
Amidines/pharmacology , Factor Xa Inhibitors , Sulfones/pharmacology , Anticoagulants/pharmacology , Blood Coagulation Tests , Dose-Response Relationship, Drug , Factor X Deficiency/blood , Humans , Kinetics , Platelet Aggregation/drug effects , Protein Binding , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , Thrombin/antagonists & inhibitors , Thromboplastin/metabolism
6.
J Cardiovasc Pharmacol ; 34(6): 791-9, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10598121

ABSTRACT

These studies were designed to examine the pharmacodynamic profile and antithrombotic efficacy of RPR120844, a competitive inhibitor of coagulation factor Xa, with a K(i) of 7 nM against human factor Xa. In vitro, RPR120844 doubled activated partial thromboplastin time (APTT) at concentrations of 1.54, 1.48, and 0.74 microM in plasma obtained from humans, dogs, and rats, respectively. Intravenous bolus administration of RPR 120844 at 0.3, 1, and 3 mg/kg to rats resulted in maximal increases in APTT of 1.8-, 2.6-, and 8.4-fold over baseline, respectively. The effect on prothrombin time (PT) was less pronounced, resulting in a 4.4-fold increase at 3 mg/kg. These effects were rapidly reversible; APTT and PT returned to control values by 30 min after dosing. Intragastric administration to rats at 50, 100, and 200 mg/kg resulted in modest increases in APTT and PT of 1.5- and 1.3-fold over baseline at the highest dose. Plasma levels were estimated by anti-Xa activity by using an amidolytic, chromogenic assay. Plasma levels were 0.65, 1.29, and 2.45 microM at 30 min after dosing at 50, 100, and 200 mg/kg, respectively. Intravenous administration to dogs at 0.1 and 0.3 mg/kg produced maximal increases in APTT of 1.7- and 2.4-fold over baseline, respectively. Intragastric administration to dogs at 50 mg/kg resulted in maximal increases in APTT and PT of 1.7- and 1.1-fold over baseline, with peak plasma levels of 3.9 microM observed at 15 min after dosing. In a rat model of FeCl2-induced carotid artery thrombosis, RPR120844 (3 mg/kg, i.v. bolus + 300 microg/kg/min constant infusion; n = 4) significantly increased time-to-occlusion from 18+/-1 min (vehicle, n = 4) to 60 min (maximal observation time) and reduced thrombus mass from 5.5 +/- 0.2 mg (vehicle) to 1.4 +/- 0.2 mg. These results indicate that RPR120844 is a potent, selective inhibitor of Xa that exhibits oral activity and is efficacious in a standard model of arterial thrombosis.


Subject(s)
Carotid Artery Thrombosis/drug therapy , Factor Xa Inhibitors , Fibrinolytic Agents/pharmacology , Sulfonamides/pharmacology , Thiophenes/pharmacology , Animals , Blood Coagulation Tests , Carotid Artery Thrombosis/chemically induced , Carotid Artery Thrombosis/physiopathology , Chlorides , Dogs , Female , Ferric Compounds/pharmacology , Fibrinolytic Agents/administration & dosage , Half-Life , Heparin/pharmacology , Injections, Intravenous , Intubation, Gastrointestinal , Macaca mulatta , Male , Rabbits , Rats , Rats, Sprague-Dawley , Sulfonamides/administration & dosage , Thiophenes/administration & dosage
7.
J Med Chem ; 42(18): 3557-71, 1999 Sep 09.
Article in English | MEDLINE | ID: mdl-10479288

ABSTRACT

The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (K(i) = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl(2)-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.


Subject(s)
Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Pyrrolidinones/chemical synthesis , Sulfonamides/chemical synthesis , Thiophenes/chemical synthesis , Animals , Anticoagulants/pharmacology , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Pyrrolidinones/pharmacology , Rabbits , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacology , Thiophenes/pharmacology , Thrombosis/drug therapy
8.
J Cardiovasc Pharmacol ; 33(5): 703-10, 1999 May.
Article in English | MEDLINE | ID: mdl-10226856

ABSTRACT

The hemodynamic and cardioprotective properties of the novel adenosine A1/A2 receptor agonist AMP 579 (IS-[1a,2b,3b,4a(S*)]-4-[7-[[1-[(3-chloro-2-thienyl)methyl]propylamino]- 3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxy cyclopentanecarboxamide) were studied in two canine models designed to simulate (a) mild single-vessel coronary artery disease, and (b) myocardial ischemia/reperfusion injury. In the first model, a moderate stenosis was placed on the left circumflex coronary artery (LCCA), and the effects of AMP 579 on regional myocardial blood flow were assessed. AMP 579, 10 micrograms/kg/min, i.v., for 10 min, induced coronary dilation without causing endocardial steal. In the model of ischemia/reperfusion injury (60 min LCCA occlusion/5 h reperfusion), AMP 579, 10 micrograms/kg/min, i.v., administered for 15 min before ischemia significantly decreased myocardial infarct size. Control infarct size to area at risk (IS/AAR) equaled 34 +/- 3% (n = 9); IS/AAR for AMP 579-treated dogs equaled 16 +/- 4% (n = 9). Preconditioning (5 min LCCA occlusion + 10 min reperfusion) immediately before the 60-min LCCA occlusion also resulted in a marked decrease in IS/AAR: 9 +/- 3% (n = 6). The selective A1 agonist CPA reduced infarct size when administered at 3 micrograms/kg/min, i.v., for 15 min before LCCA occlusion: IS/AAR = 11 +/- 3% (n = 5). Pretreatment of animals with the adenosine-receptor antagonist 8-SPT, 10 mg/kg, i.v., attenuated the myocardial protective effects associated with preconditioning, CPA, and AMP 579, resulting in IS/AAR values of 28 +/- 7% (n = 7), 28 +/- 4% (n = 8), and 26 +/- 3% (n = 8), respectively. The ability of 8-SPT to block the cardioprotective effects suggests that these effects were mediated through an interaction with adenosine receptors. These experimental results indicate that AMP 579 is an effective coronary vasodilator, which also can protect the heart from ischemic injury. Thus AMP 579 has the potential to be useful in cardiovascular therapeutics.


Subject(s)
Coronary Circulation/drug effects , Heart/drug effects , Imidazoles/pharmacology , Purinergic P1 Receptor Agonists , Pyridines/pharmacology , Animals , Coronary Disease/physiopathology , Dogs , Heart/physiopathology , Ischemic Preconditioning, Myocardial , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Ischemia/pathology , Myocardial Ischemia/physiopathology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Regional Blood Flow/drug effects
9.
Thromb Haemost ; 81(1): 157-60, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10348709

ABSTRACT

The in vivo antithrombotic activity of RPR 20844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, measured at the end of a 50 min infusion, was significantly reduced (p<0.05 vs. saline-treated animals) by RPR120844 at 30 and 100 microg/kg/min. At doses of 10, 30 and 100 microg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8+/-0.3, 1.5+/-0.9 and 2.4+/-0.6 microM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR 120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.


Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/pharmacology , Sulfonamides/pharmacology , Thiophenes/pharmacology , Venous Thrombosis/drug therapy , Animals , Dose-Response Relationship, Drug , Fibrinolytic Agents/chemistry , Partial Thromboplastin Time , Rabbits , Sulfonamides/chemistry , Thiophenes/chemistry , Venous Thrombosis/blood
10.
Gen Pharmacol ; 32(1): 41-5, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9888252

ABSTRACT

1. This study examined the potential role of tumor necrosis factor-alpha (TNF-alpha) in myocardial ischemia-reperfusion injury using an anesthetized rat model of myocardial infarction. 2. The key endpoints were infarct size and serum TNF-alpha levels (measured by a specific ELISA technique). 3. Three groups of rats were studied: vehicle controls (n=6); positive controls for infarct size reduction (ischemic preconditioning; n=6); and a group treated with the selective inhibitor of PDE-IV and TNF-alpha production, rolipram (1 mg/kg i.v. 10-min prereperfusion + 1 microg/kg per minute through 1-hr reperfusion, n=6). 4. Baseline preischemia levels of serum TNF-alpha were low (approximately 0.1 nM) and showed a trend for further reduction in all treatment groups at 1 min and 3 hr into the postischemia reperfusion period. 5. Infarct size (68+/-2% of the ischemic area in controls) was significantly reduced (41% decrease) by preconditioning, but was unchanged in rolipram-treated animals. 6. Collectively, these data argue against an important role for TNF-alpha in lethal reperfusion injury in this rat model of myocardial infarction.


Subject(s)
Myocardial Reperfusion Injury/etiology , Tumor Necrosis Factor-alpha/physiology , Anesthesia , Animals , Blood Pressure , Enzyme-Linked Immunosorbent Assay , Heart Rate , Male , Myocardial Infarction/complications , Pyrrolidinones/pharmacology , Rats , Rats, Sprague-Dawley , Rolipram , Tumor Necrosis Factor-alpha/analysis
11.
J Pharmacol Exp Ther ; 286(2): 611-8, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9694911

ABSTRACT

This study examined the cardioprotective effects and pharmacology of the novel adenosine A1/A2 receptor agonist ([1S-[1a,2b,3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-3H-imida zo[4,5-b] pyridyl-3-yl] cyclopentane carboxamide) (AMP 579), in a model of myocardial infarction. Experiments were performed in pentobarbital-anesthetized pigs in which myocardial infarction was induced by a 40-min occlusion of the left anterior descending coronary artery, followed by 3 hr of reperfusion. This procedure resulted in approximately 20% of the left ventricle being made ischemic in all test groups. In untreated animals, an infarct size equal to 56 +/- 5% of the ischemic area was observed. Preconditioning, with two cycles of 5 min of ischemia followed by 10-min reperfusion, resulted in a 70% reduction in infarct size (17 +/- 5%) relative to risk area. Administration of AMP 579 30 min before ischemia (3 microg/kg i.v. followed by 0.3 microg/kg/min i.v. through 1 hr of reperfusion) did not change blood pressure, HR or coronary blood flow but resulted in marked cardioprotection: a 98% reduction in infarct size (1 +/- 1%) relative to risk area. Moreover, whereas approximately 90% of control pigs suffered ventricular fibrillation during ischemia, no fibrillation was observed in animals treated with AMP 579. Further experiments determined the effects of AMP 579 when administered 30 min after the onset of myocardial ischemia, 10 min before reperfusion. Two doses were studied: a low hemodynamically silent dose (3 microg/kg + 0.3 microg/kg/min through 1 hr of reperfusion) and a 10-fold higher dose that did cause reductions in blood pressure and HR. Both doses of AMP 579 produced a comparable cardioprotective effect, reducing infarct size to approximately 50% of that observed in control animals. The cardioprotective effect of AMP 579 was a consequence of adenosine receptor stimulation, because it was completely inhibited by pretreatment with the specific adenosine receptor antagonist CGS 15943 (1 mg/kg i.v.). However, the selective A1 receptor agonist GR 79236 (3 microg/kg + 0.3 microg/kg/min i.v.) did not reduce infarct size, which suggests that under these experimental conditions, stimulation of adenosine A2 receptors is important for the cardioprotective effect of AMP 579. The adenosine-regulating agent acadesine (5 mg/kg + 0.5 mg/kg/min i.v.) also failed to reduce infarct size. In conclusion, the novel adenosine A1/A2 receptor agonist AMP 579 produces marked cardioprotection whether administered before myocardial ischemia or reperfusion. Cardioprotection is not dependent on changes in afterload or myocardial oxygen demand and is a consequence of adenosine receptor stimulation. The pharmacological profile of AMP 579 in this model is consistent with its potential utility in the treatment of acute myocardial infarction.


Subject(s)
Imidazoles/therapeutic use , Myocardial Infarction/prevention & control , Purinergic P1 Receptor Agonists , Pyridines/therapeutic use , Acute Disease , Animals , Female , Ischemic Preconditioning , Male , Myocardial Infarction/pathology , Myocardial Ischemia/pathology , Myocardial Ischemia/prevention & control , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/prevention & control , Myocardium/pathology , Swine , Swine, Miniature
12.
Arterioscler Thromb Vasc Biol ; 18(6): 908-14, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9633930

ABSTRACT

Experiments were designed to compare the antithrombotic efficacy of enoxaparin and unfractionated heparin (UH) in a model of platelet-dependent cyclic flow reductions (CFRs) in the stenosed canine circumflex coronary artery. Low-molecular-weight heparins (LMWHs) are safe and effective in the prevention and treatment of venous thromboembolism. The present experiments were designed to evaluate the potential use of LMWHs in arterial thrombotic indications by comparing the antithrombotic effect of an LMWH with that of UH in an animal model of unstable angina. After establishment of consistent CFRs by experimentally induced vascular stenosis and damage, vehicle (saline), enoxaparin, or UH was administered intravenously as a loading dose plus a continuous infusion for 1 hour. The inhibition of CFRs was taken as an indicator of antithrombotic efficacy. Enoxaparin inhibited repetitive platelet thrombus formation in a dose-dependent manner, with significant inhibition of CFRs achieved at 0.5 mg/kg + 5 microg/kg per minute. This dose of enoxaparin resulted in anti-Xa levels of 0.9 to 1.0 IU/mL, anti-IIa levels of 0.2 to 0.3 IU/mL, activated partial thromboplastin time (APTT) of 1.3-fold over baseline, and a 1.4-fold increase (NS) in template bleeding time. Near-complete abolishment of CFRs was achieved with enoxaparin at 1.0 mg/kg + 10 microg/kg per minute. This dose of enoxaparin produced anti-Xa levels of 2 to 2.2 IU/mL, anti-IIa levels of 0.5 to 0.6 IU/mL, an increase in APTT of 1.4- to 1.5-fold over baseline, and a 1.9-fold increase (P<0.05) in template bleeding time. In contrast, UH had no significant effect on CFRs at a dose (100 U/kg + 10 U/kg per minute) that resulted in anti-Xa levels of 1.2 to 1.6 IU/mL, anti-IIa levels of 1.8 to 2.4 IU/mL, an increase in APTT greater than 10-fold over baseline, and a 2.5-fold increase (P<0.05) in template bleeding time. Compared with the vehicle group, circulating platelet count and hematocrit were not changed significantly by any dose of enoxaparin or UH tested. Enoxaparin, unlike UH, prevented repetitive platelet-dependent thrombus formation in the dog, thereby supporting the potential use of enoxaparin as a replacement for heparin in the treatment of arterial thrombotic disorders such as unstable angina.


Subject(s)
Anticoagulants/therapeutic use , Coronary Thrombosis/prevention & control , Enoxaparin/therapeutic use , Heparin/therapeutic use , Animals , Coronary Thrombosis/blood , Coronary Thrombosis/physiopathology , Coronary Vessels , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Factor Xa/metabolism , Female , Hemodynamics , Male , Partial Thromboplastin Time , Prothrombin/metabolism , Prothrombin Time , Recurrence
13.
J Med Chem ; 41(4): 437-50, 1998 Feb 12.
Article in English | MEDLINE | ID: mdl-9484495

ABSTRACT

The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized beta-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted beta-alanines was also developed.


Subject(s)
Factor Xa Inhibitors , beta-Alanine/analogs & derivatives , beta-Alanine/chemical synthesis , Animals , Binding Sites , Cattle , Drug Design , Factor Xa/chemistry , Humans , Hydrogen Bonding , Indicators and Reagents , Infant, Newborn , Models, Molecular , Molecular Conformation , Protein Conformation , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacology , beta-Alanine/chemistry , beta-Alanine/pharmacology
14.
Thromb Haemost ; 78(4): 1278-85, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9364998

ABSTRACT

A canine model of electrolytic injury-induced coronary artery thrombosis and rtPA-induced thrombolysis was used to evaluate the relative antithrombotic efficacy of enoxaparin (a low molecular weight heparin), conventional therapy (heparin or heparin plus aspirin), and hirulog (a direct thrombin inhibitor), when used as adjunctive therapy during thrombolysis. After 60 min of clot aging, adjunctive therapy was begun at doses which elevated APTT approximately 2-fold over baseline. Fifteen minutes after the start of adjunctive therapy, recombinant tissue plasminogen activator (rtPA) was administered (100 microg/kg i.v. bolus + 20 microg/kg/min for 60 min). Adjunctive therapy continued for 1 h after termination of rtPA and blood flow was monitored for two additional hours. Enoxaparin (1 mg/kg i.v. bolus + 30 microg/kg/min, n = 10 for each treatment group) was the only adjunctive treatment that significantly increased the total minutes of flow (143 +/- 25 min out of a possible 240 min, vs 54 +/- 25 min for vehicle, p <0.05) and decreased thrombus mass (6.0 +/- 1.3 mg vs 11.8 +/- 3.2 mg for vehicle). Although hirulog (2 mg/kg i.v. bolus + 40 microg/kg/min) did not significantly increase the minutes of flow (120 +/- 27 min, p <0.06) or decrease thrombus mass (8.7 +/- 1.7 mg) compared to vehicle, these values were not significantly different than those measured in the enoxaparin group. However, the results with hirulog were achieved at the expense of a significantly greater increase in template bleeding time than that measured during enoxaparin treatment. Minutes of flow for heparin (50 U/kg i.v. bolus + 0.6 U/kg/min) and heparin plus aspirin (5 mg/kg i.v. bolus) were 69 +/- 20 and 60 +/- 23 min, respectively; thrombus masses were 8.2 +/- 1.3 and 7.3 +/- 1.0 mg, respectively. In summary, enoxaparin was more effective than conventional therapy in this model in terms of vessel patency and thrombus mass, and was as effective as hirulog, at least at a dose of hirulog that only modestly impaired hemostasis. Therefore, enoxaparin may prove to be a safe and effective alternative agent for adjunctive therapy during thrombolysis with rtPA.


Subject(s)
Coronary Thrombosis/drug therapy , Enoxaparin/therapeutic use , Fibrinolytic Agents/therapeutic use , Heparin/therapeutic use , Hirudins/analogs & derivatives , Peptide Fragments/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Thrombolytic Therapy , Tissue Plasminogen Activator/therapeutic use , Adenosine Diphosphate/pharmacology , Animals , Aspirin/administration & dosage , Aspirin/pharmacology , Aspirin/therapeutic use , Aspirin/toxicity , Bleeding Time , Collagen/pharmacology , Dogs , Drug Evaluation, Preclinical , Drug Synergism , Drug Therapy, Combination , Enoxaparin/administration & dosage , Enoxaparin/pharmacology , Enoxaparin/toxicity , Factor Xa Inhibitors , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/toxicity , Hemorrhage/chemically induced , Hemostasis/drug effects , Heparin/administration & dosage , Heparin/pharmacology , Heparin/toxicity , Hirudin Therapy , Hirudins/administration & dosage , Hirudins/pharmacology , Hirudins/toxicity , Male , Partial Thromboplastin Time , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacology , Peptide Fragments/toxicity , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/administration & dosage , Platelet Count/drug effects , Prothrombin/antagonists & inhibitors , Prothrombin Time , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Recombinant Proteins/toxicity , Recurrence , Safety , Thrombin/pharmacology , Tissue Plasminogen Activator/administration & dosage , Tissue Plasminogen Activator/pharmacology , Tissue Plasminogen Activator/toxicity
15.
J Pharmacol Exp Ther ; 281(2): 746-52, 1997 May.
Article in English | MEDLINE | ID: mdl-9152381

ABSTRACT

Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 [3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride] and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo [14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of [14C]farnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by < or = 51%. In the same paradigm, the HMG-CoA reductase inhibitor lovastatin failed to lower serum cholesterol in rats. In marmosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.


Subject(s)
Anticholesteremic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lovastatin/pharmacology , Quinolines/pharmacology , Animals , Callithrix , Cholesterol/biosynthesis , Cholestyramine Resin/pharmacology , Drug Synergism , Mevalonic Acid/metabolism , Rats , Rats, Sprague-Dawley
16.
J Cardiovasc Pharmacol ; 29(3): 417-26, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9125682

ABSTRACT

Because one manifestation of diabetes is an enhancement of the lipolytic process, we evaluated the antilipolytic effects of adenosine A1 agonists in vitro and in vivo in streptozotocin (STZ)-treated diabetic rats. In vitro, we examined the responses to norepinephrine (NE) and adenosine deaminase (ADA), as well as several adenosine A1 agonists, in isolated adipocytes from normal and diabetic rats. Both NE and ADA caused dose-dependent stimulation of lipolysis, elevating glycerol release twofold to threefold over baseline. The sensitivity to both NE and ADA was significantly enhanced in adipocytes from STZ-treated as compared with normal rats. N-5'-ethyl-N(6)(cyclopentyl) adenosine-5'-uronamide (RG14202) was by far the most potent A agonist in inhibiting NE-stimulated lipolysis [50% effective concentration (EC50): 0.014 +/- 0.0008 nM), approximately 1 and 2 log units more potent than N(6)-cyclopentyladenosine (CPA) and N(6)-cyclohexyl-2'-O-methyladenosine (SDZ WAG 994), respectively. In vivo we established a model for evaluating the therapeutic utility of adenosine A1 agonists, emphasizing duration of action. In STZ rats instrumented with telemetry transmitters, the metabolic effects of CPA, RG14202, and SDZ WAG 994 were assessed 6 h after oral administration. Under those conditions, RG14202 and SDZ WAG 994, but not CPA, significantly reduced triglycerides (TRIs) and TRI/free fatty acids (FFAs), respectively. However, all three A1 agonists dose-dependently reduced mean arterial pressure (MAP) and heart rate (HR) concurrently. Thus adenosine A1 agonists can inhibit lipolysis in vitro and in vivo; however, oral administration produces long-lasting beneficial metabolic effects only at doses that also produce a significant bradycardia.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Purinergic P1 Receptor Agonists , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine Deaminase/pharmacology , Adipocytes/drug effects , Adipocytes/metabolism , Animals , Blood Glucose/metabolism , Blood Pressure/drug effects , Cyclopentanes/pharmacology , Diabetes Mellitus, Experimental/physiopathology , Fatty Acids, Nonesterified/blood , Glycerol/blood , Heart Rate/drug effects , Lipolysis/drug effects , Male , Norepinephrine/pharmacology , Rats , Rats, Sprague-Dawley , Triglycerides/blood
17.
J Cardiovasc Pharmacol ; 29(1): 49-56, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9007670

ABSTRACT

Studies were undertaken to establish the regional hemodynamic profile and dose-response relation of the adenosine triphosphate (ATP)-dependent potassium channel activator lemakalim in anesthetized rats. In addition, the ability of the sulphonylurea potassium channel blocker glybenclamide to reverse the hemodynamic effects of an infusion of lemakalim was determined. Studies were performed in anesthetized rats instrumented to measure arterial pressure, heart rate, and hemodynamics in the coronary, mesenteric, renal, and hindquarters vascular beds. One group of rats (n = 5) received increasing intravenous infusion rates of the potassium channel activator lemakalim. The doses administered were 0.1, 0.3, 1.0, 3.0, and 10 micrograms/kg/min, and each dose was infused until steady-stateresponses were achieved. Dose-related decreases in mean arterial pressure were observed with the first significant effect occurring at 1 microgram/kg/min. The hindquarters bed was the most sensitive of the four beds measured. Vascular resistance was significantly decreased in this bed with an infusion of 0.3 microgram/kg/min i.v. lemakalim. In addition, this vascular bed was the only one to demonstrate significant increases in blood flow over baseline. Significant reductions in vascular resistance were observed over the dose range of 1-10 micrograms/kg/min for both the coronary and renal vascular beds. The mesenteric bed was less sensitive in that the first significant reduction in resistance was not observed until the infusion dose was increased to 3 micrograms/kg/min. The other group of rats (n = 5) was used to determine the dose-response relation of glybenclamide. These rats received an intravenous infusion of lemakalim at 1 microgram/kg/min to establish a moderate cardiovascular effect. Ascending cumulative intravenous injections of glybenclamide from 0.3 to 30 mg/kg were then administered. The lowest dose, 0.3 mg/kg, significantly attenuated the depressor response to the lemakalim infusion, but the response was not fully reversed until the dose of glybenclamide reached 10 mg/kg i.v.. Doses > 10 mg/kg i.v. of glybenclamide were required for complete reversal of the hemodynamic responses to this dose of lemakalim. Therefore lemakalim exerts vasodilatory properties in each of the beds measured but demonstrates a selectivity for the hindquarters. The results with glybenclamide demonstrate also that the responses to lemakalim are the result of activation of the ATP-dependent potassium channel. Last, doses > 10 mg/kg of glybenclamide are required to ensure that ATP-dependent potassium channels are blocked in the circulatory system in rats.


Subject(s)
Benzopyrans/pharmacology , Blood Circulation/drug effects , Glyburide/pharmacology , Potassium Channels/drug effects , Pyrroles/pharmacology , Adenosine Triphosphate/physiology , Anesthesia , Animals , Blood Pressure/drug effects , Coronary Circulation/drug effects , Cromakalim , Dose-Response Relationship, Drug , Hindlimb/blood supply , Male , Potassium Channels/metabolism , Rats , Rats, Sprague-Dawley , Renal Circulation/drug effects , Splanchnic Circulation/drug effects , Vascular Resistance/drug effects
18.
Arzneimittelforschung ; 46(8): 759-62, 1996 Aug.
Article in English | MEDLINE | ID: mdl-9125274

ABSTRACT

Squalene synthase, the first committed enzyme for sterol synthesis, converts farnesyl pyrophosphate to squalene with presqualene pyrophosphate as an intermediate. It was discovered that BM 21.0955 (1-hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphon ic acid), in development for the treatment of bone disorders, inhibited rat liver microsomal squalene synthase (K(i) = nmol/l). BM 21.0955 also inhibited sterol biosynthesis from mevalonate (IC50 = 42 nmol/l), and cholesterol biosynthesis in J774 cells (IC50 = mumol/l). Structural modifications on this molecule to make it more lipophilic may result in a new class of cholesterol-lowering agents.


Subject(s)
Cholesterol/biosynthesis , Diphosphonates/pharmacology , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Animals , Bone Resorption/prevention & control , Caprylates/metabolism , Cell Line , Cell-Free System , Ibandronic Acid , Lanosterol/biosynthesis , Mevalonic Acid/metabolism , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Rats
19.
Thromb Res ; 82(6): 495-507, 1996 Jun 15.
Article in English | MEDLINE | ID: mdl-8794522

ABSTRACT

RG13965, a pseudotetrapeptide analogue of Arg-Gly-Asp (RGD), inhibited collagen-induced dog, monkey, human, hamster, mouse, and pig platelet aggregation in vitro with IC50 values of 3.7, 4.6, 6.3, 126, 136 and 1600 microM, respectively. RG13965 (3, 10, and 30 mg/kg, i.v.) decreased the incidence of collagen/epinephrine-induced thrombosis in mice from 90% in untreated animals to 63, 37, and 0%, respectively. In hamsters, RG13965 (10 and 30 mg/kg, i.v.) prolonged the time required for formation of a hemostatic plug in severed mesenteric arteries by 1.6- and 3.6-fold, respectively. In a canine model of repetitive platelet thrombus formation in the coronary artery, RG13965 (0.1, 0.3, and 1 mg/kg, i.v.) reversibly inhibited cyclic flow reductions (CFRs) and inhibited ADP-induced ex vivo platelet aggregation by 29, 57, and 77%, respectively. RG13965 (1 mg/kg) completely inhibited CFRs for at least 40 min. Platelet count was not altered at any dose and template bleeding time was prolonged modestly (1.8-fold) at only the highest dose. RG13965 dose-dependently and reversibly inhibited thrombus formation at doses which did not completely inhibit ex vivo platelet aggregation and only modestly prolonged template bleeding time.


Subject(s)
Blood Platelets/metabolism , Oligopeptides/pharmacology , Platelet Adhesiveness/drug effects , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Animals , Binding, Competitive , Blood Platelets/cytology , Cells, Cultured , Cricetinae , Dogs , Fibrinogen/metabolism , Haplorhini , Humans , Mice , Oligopeptides/metabolism , Platelet Aggregation Inhibitors/metabolism , Swine
20.
Naunyn Schmiedebergs Arch Pharmacol ; 353(2): 233-40, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8717165

ABSTRACT

RPR 101821 (trans-2-[4-(benzoxazol-2-yl)-phenylmethoxy] amino cyclohexane hydrochloride) is a potent cholesterol-lowering agent in rodents and marmoset. The compound inhibited rat liver microsomal squalene synthase (IC50 = 1 nM) and 7-dehydrocholesterol (7DHC) reductase (IC50 = 1 microM; Lewis et al. 1995). When RPR 101821 (10 mg/kg), the 7DHC reductase inhibitor BM 15.766 (4[2-[4-(4-chlorocinnamyl)piperazine-1-yl]ethyl] benzoic acid; 10 mg/kg) or the HMG-CoA reductase inhibitor lovastatin (30 mg/kg) was given orally to rats at -29 h, -21 h and -5 h, serum cholesterol was reduced by 56%, 46% or 15%, respectively. The reduction in cholesterol with RPR 101821 was associated with an accumulation of 7DHC in serum, suggesting an inhibition of 7DHC reductase. In the presence of BM 15.766, RPR 101821 reduced the serum accumulation of 7DHC in a dose-dependent manner, with complete inhibition at 30 mg/kg, p.o. In Balb-cJ mice, RPR 101821 and lovastatin (50 mg/kg, b.i.d., p.o., for 14 days) lowered serum cholesterol by 67% and 2%, respectively. In marmosets, RPR 101821 and lovastatin (both at a dose of 10 mg/kg, p.o., b.i.d., for 7 days) reduced cholesterol by 28% and 19%, respectively. In summary, RPR 101821 is an orally effective potent cholesterol-lowering agent in rodents and a small primate species. The suggested mechanism of hypocholesterolemic effect is the inhibition of squalene synthase and 7DHC reductase.


Subject(s)
Benzoxazoles/pharmacology , Cyclohexylamines/pharmacology , Enzyme Inhibitors/pharmacology , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/drug effects , Animals , Callithrix , Cholesterol/blood , Lovastatin/pharmacology , Male , Mice , Mice, Inbred Strains , Rats , Rats, Sprague-Dawley
SELECTION OF CITATIONS
SEARCH DETAIL
...