HBI-3000 prevents secondary sudden cardiac death.

BACKGROUND: In postmyocardial infarction patients, transient episodes of ischemia are associated with a greater incidence of sudden cardiac death (SCD). Ventricular tachycardia and ventricular fibrillation (VF) are responsible for the majority of SCDs, but current pharmacological interventions for prevention of lethal ventricular arrhythmias are less than satisfactory. We investigated the efficacy of HBI-3000 (HBI), a novel antiarrhythmic agent, in preventing SCD in a conscious canine model. METHODS: After 3 to 7 days of a surgically induced myocardial infarction (ie, 90-minute occlusion of the left anterior descending coronary artery followed by 30 minutes of reperfusion), conscious animals were administered vehicle (0.9% NaCl solution for injection) or HBI (15 mg/kg) intravenously. An occlusive thrombus at a site remote from the previous myocardial infarction was induced by electrolytic injury to the intimal surface of the left circumflex coronary artery. RESULTS: Control animals developed premature ventricular complexes (PVCs) followed by ventricular tachycardia, which terminated in VF in 5 of the 8 dogs. HBI reduced the frequency of PVCs, and only 1 of the 9 HBI-treated animals developed VF (P < .05). In a separate group of postinfarcted animals, the electrical conversion threshold was assessed before and after the intravenous administration of HBI (5, 10, or 15 mg/kg) or flecainide (3 mg/kg), a class IC antiarrhythmic agent. The electrical conversion threshold was not altered by HBI, whereas the administration of flecainide increased the threshold (P < .01 vs baseline). CONCLUSIONS: The data indicate that HBI is an effective antiarrhythmic and antifibrillatory agent for the prevention of VF or sudden cardiac death.

Hirudin and s18886 maintain luminal patency after thrombolysis with alfimeprase.

BACKGROUND: An optimal strategy to improve reperfusion in patients with arterial occlusions is a recognized clinical need. We hypothesized that hirudin (thrombin inhibitor) and S18886 [S18, thromboxane A(2) receptor (TP) antagonist] would improve blood flow and reperfusion rates after thrombolysis with the direct-acting fibrinolytic enzyme alfimeprase. METHODS: In anesthetized beagles, carotid artery thrombosis was induced by electrolytic endothelial injury. After 30 minutes of occlusion, animals were administered vehicle, hirudin, and/or S18. Carotid artery blood flow was monitored for 90 minutes after the infusion of alfimeprase or recombinant tissue plasminogen activator (rt-PA). RESULTS: The onset to reperfusion was more rapid in animals treated with alfimeprase than in those treated with rt-PA. All the animals treated with hirudin + S18 + alfimeprase maintained vessel patency, and all vehicle-treated animals reoccluded. In animals treated with hirudin + S18 + alfimeprase, time to reocclusion and total reflow time after thrombolysis were longer compared with vehicle-treated animals. The quality and quantity of blood flow were most improved in animals treated with hirudin + S18 + alfimeprase. There were no significant differences in time to reocclusion, total reflow time, and quality and quantity of blood flow between vehicle + rt-PA-treated animals and hirudin + S18 + rt-PA-treated animals. CONCLUSIONS: Dual antithrombotic therapy with hirudin and S18 improves reperfusion after thrombolysis with alfimeprase but not rt-PA.

Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers.

Prostaglandin endoperoxide H synthases (PGHSs)-1 and -2 (also called cyclooxygenases (COXs)-1 and -2) catalyze the committed step in prostaglandin biosynthesis. Both isoforms are targets of nonsteroidal antiinflammatory drugs (NSAIDs). PGHSs are homodimers that exhibit half-of-sites COX activity; moreover, some NSAIDs cause enzyme inhibition by binding only one monomer. To learn more about the cross-talk that must be occurring between the monomers comprising each PGHS-1 dimer, we analyzed structures of PGHS-1 crystallized under five different conditions including in the absence of any tightly binding ligand and in the presence of nonspecific NSAIDs and of a COX-2 inhibitor. When crystallized with substoichiometric amounts of an NSAID, both monomers are often fully occupied with inhibitor; thus, the enzyme prefers to crystallize in a fully occupied form. In comparing the five structures, we only observe changes in the positions of residues 123-129 and residues 510-515. In cases where one monomer is fully occupied with an NSAID and the partner monomer is incompletely occupied, an alternate conformation of the loop involving residues 123-129 is seen in the partially occupied monomer. We propose, on the basis of this observation and previous cross-linking studies, that cross-talk between monomers involves this mobile 123-129 loop, which is located at the dimer interface. In ovine PGHS-1 crystallized in the absence of an NSAID, there is an alternative route for substrate entry into the COX site different than the well-known route through the membrane binding domain.

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A(2) formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.