Neuroinflammation in the normal aging hippocampus.

A consequence of normal aging is a greater susceptibility to memory impairments following an immune challenge such as infection, surgery, or traumatic brain injury. The neuroinflammatory response, produced by these challenges results in increased and prolonged production of pro-inflammatory cytokines in the otherwise healthy aged brain. Here we discuss the mechanisms by which long-lasting elevations in pro-inflammatory cytokines in the hippocampus produce memory impairments. Sensitized microglia are a primary source of this exaggerated neuroinflammatory response and appear to be a hallmark of the normal aging brain. We review the current understanding of the causes and effects of normal aging-induced microglial sensitization, including dysregulations of the neuroendocrine system, potentiation of neuroinflammatory responses following an immune challenge, and the impairment of memories. We end with a discussion of therapeutic approaches to prevent these deleterious effects.

Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation.

Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT(4) receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6-day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T(1/2) after first dose. Secondary endpoints included gastric emptying (GE) T(1/2) and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T(1/2), and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T(1/2) at 15-50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted.

Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study).

This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 microg/kg bolus followed by a 0.75 microg/kg/min infusion; eptifibatide as a 180 microg/kg bolus with a 2.0 microg/kg/min infusion; or eptifibatide as a 250 microg/kg bolus with a 3.0 microg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 microM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 microg/kg bolus followed by a 2.0 microg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.

Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention.

BACKGROUND: Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. METHODS AND RESULTS: Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later. CONCLUSIONS: A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.

Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial.

CONTEXT: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial showed the efficacy of adjunctive, double-bolus eptifibatide therapy in reducing ischemic complications of nonurgent coronary stent implantation at 48 hours and at 30 days. OBJECTIVE: To determine whether the beneficial effects of eptifibatide persist at 6 months after treatment. DESIGN: Follow-up study of a randomized, double-blind, placebo-controlled, crossover-permitted trial conducted from June 1999 through February 2000. SETTING: Ninety-two tertiary care centers in the United States and Canada. PARTICIPANTS: A total of 2064 patients scheduled to undergo nonurgent percutaneous coronary intervention with stent implantation. INTERVENTION: Patients were randomly assigned to receive placebo or eptifibatide (two 180-microg/kg boluses 10 minutes apart and continuous infusion of 2.0 microg/kg per minute), started immediately before stent implantation and continued for 18 to 24 hours. Complete follow-up data were available for 988 (95.0%) of 1040 patients given eptifibatide and 977 (95.4%) of 1024 patients given placebo. MAIN OUTCOME MEASURES: Composite rates of death or myocardial infarction (MI); death, MI, or target vessel revascularization; and their individual components 6 months after enrollment, compared between the 2 groups. RESULTS: By 6 months, the composite end point of death or MI had occurred in 7.5% of eptifibatide-treated patients and in 11.5% of placebo-treated patients (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.84; P =.002). The composite of death, MI, or target vessel revascularization was 14.2% in eptifibatide-treated patients vs 18.3% in placebo-treated patients (HR, 0.75; 95% CI, 0.60-0.93; P =.008). Most of this benefit accrued early (<48 hours after initiation of therapy) and was maintained through 6 months. Six-month mortality in the eptifibatide group was 0.8% vs 1.4% in the placebo group (HR, 0.56; 95% CI, 0.24-1.34; P =.19) and target vessel revascularization occurred in 8.6% of the eptifibatide group vs 9.4% of the placebo group (HR, 0.91; 95% CI, 0.68-1.22; P =.51). CONCLUSION: Adjunctive eptifibatide therapy during coronary stent implantation provides benefit through 6-month follow-up.

Therapeutic value of eptifibatide at community hospitals transferring patients to tertiary referral centers early after admission for acute coronary syndromes. PURSUIT Investigators.

OBJECTIVES: We aimed to evaluate the benefits of the glycoprotein (GP) IIb/IIIa antagonist, eptifibatide, after patients with acute coronary syndromes (ACS) were admitted to hospitals that approach revascularization for ACS through early transfer to tertiary referral centers. BACKGROUND: Across a variety of hospital settings, GP IIb/IIIa inhibition, after patients were admitted to the hospital for non-ST segment elevation ACS, is associated with a reduction in death or myocardial infarction (MI) before and during a percutaneous coronary intervention. METHODS: The outcomes of 429 patients from 153 sites in the Platelet glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, who were transferred during study drug infusion ("transfer patients"), were compared with those of 1,987 patients who either remained in the hospital at those sites or were transferred after study drug termination ("nontransfer patients"). RESULTS: The baseline characteristics of transfer and nontransfer patients were similar. Patients receiving eptifibatide were transferred less frequently than those receiving placebo (16% vs. 20%, p = 0.014). Transfer patients underwent more procedures and experienced a greater 30-day incidence of death or MI, as compared with nontransfer patients (21% vs. 12%, p = 0.001). Eptifibatide was associated with a reduction in death or MI through 30 days, independent of transfer status (2.5% absolute reduction), as well as for those transferred (5.5% absolute reduction). CONCLUSIONS: For patients with ACS admitted to community hospitals, eptifibatide is associated with a reduced need for transfer and improved clinical outcomes.

Design and methodology of the ESPRIT trial: evaluating a novel dosing regimen of eptifibatide in percutaneous coronary intervention.

BACKGROUND: Clinical trials of the glycoprotein (GP) IIb/IIIa inhibitors have shown that these potent antiplatelet agents are effective in reducing the ischemic complications of percutaneous coronary interventions. However, even though stents are now implanted in >75% of percutaneous interventional procedures, only one study, a trial of the monoclonal antibody abciximab, has formally evaluated adjunctive GP IIb/IIIa inhibition in this setting. METHODS AND RESULTS: Eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has also undergone evaluation as an adjunct to coronary intervention. In clinical trials performed heretofore, however, it has appeared to have less relative clinical efficacy than the monoclonal antibody abciximab. Since the early seminal trials, it has been recognized that the doses of eptifibatide previously used achieved only 30% to 50% of maximal platelet GP IIb/IIIa integrin inhibition. This is considerably less than the 80% level of receptor inhibition that has been proposed to prevent coronary thrombus formation in animal models and that has been achieved in clinical trials with abciximab. CONCLUSIONS: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial was designed to test the safety and efficacy of a high-dose, "180/2.0/180" double-bolus regimen of eptifibatide (a 180-microg/kg bolus followed 10 minutes later by a second 180-microg/kg bolus of eptifibatide combined with a 2.0-microg/kg per minute infusion) as an adjunct to nonacute percutaneous coronary intervention with stent implantation. In this report, we review the rationale, design, and methods of this clinical investigation.

Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition. Insights from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial.

BACKGROUND: A multinational, randomized, placebo-controlled trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, PURSUIT) demonstrated that the platelet glycoprotein IIb/IIIa receptor antagonist eptifibatide reduced the incidence of death or myocardial infarction among patients with acute ischemic syndromes without ST-segment elevation. Because of expected differences in practice patterns, a prospectively planned analysis of outcomes as a function of regions of the world was performed. The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States. METHODS AND RESULTS: Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase-MB elevation were eligible for enrollment. Of the 10 948 patients randomized worldwide, 4035 were enrolled within the United States. Patients were allocated to placebo or eptifibatide infusion for up to 72 to 96 hours. Other medical therapies and revascularization strategies were at the discretion of the treating physician. Eptifibatide reduced the rate of the primary end point of death or myocardial infarction by 30 days from 15.4% to 11.9% (P=0.003) among patients in the United States. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%; P=0.004). Bleeding events were more common in patients receiving eptifibatide but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the United States than elsewhere in the world. CONCLUSIONS: Platelet glycoprotein IIb/IIIa receptor blockade with eptifibatide reduces the incidence of death or myocardial infarction among patients treated for acute ischemic syndromes without ST-segment elevation within the United States.

Clinical and therapeutic profile of patients presenting with acute coronary syndromes who do not have significant coronary artery disease.The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators.

BACKGROUND: A proportion of patients who present with suspected acute coronary syndrome (ACS) are found to have insignificant coronary artery disease (CAD) during coronary angiography, but these patients have not been well characterized. METHODS AND RESULTS: Of the 5767 patients with non-ST-segment elevation ACS who were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and who underwent in-hospital angiography, 88% had significant CAD (any stenosis >50%), 6% had mild CAD (any stenosis >0% to

Timing of and risk factors for myocardial ischemic events after percutaneous coronary intervention (IMPACT-II). Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.

We studied both the time course and risk factors for adverse clinical events after percutaneous coronary intervention (PCI). Such information is critical to clinical decision-making, but scant quantitative data exist to describe the time course of these adverse outcomes. Patients enrolled in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) trial were analyzed. Patients undergoing elective, urgent, or emergency PCI (n = 4,010) were randomized to receive either placebo or 1 of 2 eptifibatide regimens during intervention. We evaluated the time to the primary end point of the trial, the 30-day composite of death, myocardial infarction, repeat nonelective PCI, nonelective bypass surgery, or stenting for abrupt closure. Adverse events occurred in 407 patients (10.1%). Because the risk of events declined substantially between 6 and 9 hours (66% occurred within 6 hours), events were classified as occurring before or after 6 hours. Independent predictors of "early" events included dissection, pre- and postprocedural coronary blood flow, side-branch occlusion, procedural thrombolytic use, previous bypass, presentation with unstable angina, absence of diabetes, and hyperlipidemia. The predictors of "late" events included lower weight, increased baseline heart rate, coronary dissection, and procedural thrombolytic use. The risk of ischemic events were greatest immediately after PCI and rapidly declined, so that by 9 hours the hazard function plot was flat; 66% of events occurred within 6 hours of PCI. Knowledge of the risk factors for early and late events help risk-stratify patients before and after intervention for myocardial ischemic events.

Prior aspirin use predicts worse outcomes in patients with non-ST-elevation acute coronary syndromes. PURSUIT Investigators. Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy.

Aspirin is beneficial in the prevention and treatment of cardiovascular events, but patients who have events while taking aspirin may have worse outcomes than those not on aspirin. We investigated the association between prior aspirin use and clinical outcomes in 9,461 patients with non-ST-elevation acute coronary syndromes enrolled in the Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, before and after adjustment for baseline factors. We also examined whether eptifibatide has a differential treatment effect in prior aspirin users. Prior aspirin users were less likely to have an enrollment myocardial infarction (MI) (vs unstable angina) (43.9% vs 48.8%, p = 0.001) but more likely to have death or MI at 30 days (16.1% vs 13.0%, p = 0.001) and at 6 months (19.9% vs 15.9%, p = 0.001). After adjustment, prior aspirin users remained less likely to have an enrollment MI (odds ratio 0.88, 95% confidence interval 0.79 to 0.97) and more likely to have death or MI at 30 days (odds ratio 1.16, 95% confidence interval 1.00 to 1.33) but not at 6 months (odds ratio 1.14, 95% confidence interval 0.98 to 1.33). In a multivariable model, eptifibatide did not have a different treatment effect in prior aspirin users compared with nonusers (p = 0.534). Prior aspirin users had fewer enrollment MIs but worse long-term outcomes than nonusers. We found no evidence for a different treatment effect of eptifibatide in prior aspirin users.

Nonimmunogenicity of eptifibatide, a cyclic heptapeptide inhibitor of platelet glycoprotein IIb-IIIa.

Inhibitors of platelet glycoprotein (GP) IIb-IIIa have been demonstrated to be effective in controlling acute cardiac complications in patients presenting with acute ischemic coronary syndromes (AICS). Since patients with atherosclerotic coronary vascular disease may present with AICS on multiple occasions, it is important to have documented evidence that novel antithrombotic agents are nonimmunogenic and thus safe for repeated administration. Eptifibatide (Integrilin) is a cyclic heptapeptide inhibitor that contains a modified lysine-glycine-aspartic acid sequence that recognizes the binding site of platelet GP IIb-IIIa, resulting in potent and selective inhibition of its binding to fibrinogen. An enzyme-linked immunosorbent assay sensitive to all classes of immunoglobulins was developed to test the immunogenicity of eptifibatide in humans. In two clinical studies, Integrilin to Minimize and Prevent Acute Coronary Thrombosis (IMPACT) and IMPACT II, samples were obtained from 414 patients undergoing coronary angioplasty to determine anti-eptifibatide antibodies at baseline and 30 days after treatment. In a separate clinical pharmacology study, 28 healthy volunteers received 2 infusions of eptifibatide 28 days apart and were monitored at baseline (immediately before the first infusion), at 28 days (immediately before the second infusion), and at 42, 56, 84, and 112 days after enrollment to monitor for an anamnestic anti-eptifibatide response. Eptifibatide administration did not result in an antibody response in any of the 3 studies, even after repeated administration. Eptifibatide represents a potent, specific inhibitor of the platelet GP IIb-IIIa complex that has not been observed to be immunogenic in clinical studies and is thus safe for repeated administration. This finding suggests that small, peptide-based therapeutic agents, which are becoming increasingly common, may be used in humans without inciting an immune response.

Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. IMPACT-II Investigators. Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II.

OBJECTIVES: We examined the relations of elevated creatine kinase (CK) and its myocardial band isoenzyme (CK-MB) to clinical outcomes after percutaneous coronary intervention (PCI) in patients enrolled in Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II (trial) (IMPACT-II), a trial of the platelet glycoprotein IIb/IIIa inhibitor eptifibatide. BACKGROUND: Elevation of cardiac enzymes often occurs after PCI, but its clinical implications are uncertain. METHODS: Patients undergoing elective, scheduled PCI for any indication were analyzed. Parallel analyses investigated CK (n=3,535) and CK-MB (n=2,341) levels after PCI (within 4 to 20 h). Clinical outcomes at 30 days and 6 months were stratified by postprocedure CK and CK-MB (multiple of the site's upper normal limit). RESULTS: Overall, 1,779 patients (76%) had no CK-MB elevation; CK-MB levels were elevated to 1 to 3 times the upper normal limit in 323 patients (13.8%), to 3 to 5 times normal in 84 (3.6%), to 5 to 10 times normal in 86 (3.7%), and to >10 times normal in 69 patients (2.9%). Elevated CK-MB was associated with an increased risk of death, reinfarction, or emergency revascularization at 30 days, and of death, reinfarction, or surgical revascularization at 6 months. Elevated total CK to above three times normal was less frequent, but its prognostic significance paralleled that seen for CK-MB. The degree of risk correlated with the rise in CK or CK-MB, even for patients with successful procedures not complicated by abrupt closure. CONCLUSIONS: Elevations in cardiac enzymes, including small increases (between one and three times normal) often not considered an infarction, are associated with an increased risk for short-term adverse clinical outcomes after successful or unsuccessful PCI.

Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators.

BACKGROUND: Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase. METHODS AND RESULTS: We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P = .006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P = .05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively). CONCLUSIONS: The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.

Refining the treatment of women with unstable angina--a randomized, double-blind, comparative safety and efficacy evaluation of Integrelin versus aspirin in the management of unstable angina.

BACKGROUND: Although women typically develop coronary artery disease several years after men, once they have symptomatic disease their thromboembolic complications are worse than in men. The mechanism mediating this gender difference in outcome after thromboembolic events is unknown. We previously studied platelet functions in siblings from patients with premature coronary artery disease. We observed that platelets from women are responsive than their male counterparts. In particular, platelets from women stimulated ex vivo with various agonists bind more fibrinogen molecules than platelets from men. HYPOTHESIS: We hypothesized that in patients with acute coronary events, the control of platelet activity might require stronger antagonists in women than in men. METHODS: To test this hypothesis, we investigated retrospectively the results of a trial on Integrelin in unstable angina. RESULTS: We report that platelet aggregation and Holter-detected ischemic episodes are significantly reduced in women with unstable angina treated with the specific GPIIb-IIIa inhibitor, Integrelin, compared with the standard platelet inhibitor aspirin. In contrast, both platelet aggregation and Holter-detected ischemic events are well controlled in men with unstable angina treated with standard therapy including aspirin. CONCLUSION: Integrelin does provide protection in men, but, in contrast with women, not beyond what can be achieved with aspirin. Our data are consistent with the concept that the platelets from women require stronger and more specific inhibitors to limit their activity, and that platelets may play a more important role in women with acute coronary syndromes than in men. Most important, specific GPIIb-IIIa inhibitors may represent a therapeutic option which provides as much suppression of ischemic events in women as they do in men with coronary artery disease.

Effects of integrelin, a platelet glycoprotein IIb/IIIa receptor antagonist, in unstable angina. A randomized multicenter trial.

BACKGROUND: Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina. METHODS AND RESULTS: Patients received intravenous heparin and standard ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin. 45 micrograms/kg bolus followed by a 0.5 microgram.kg-1. min-1 continuous infusion; or placebo aspirin and high-dose Integrelin, 90 micrograms/kg bolus followed by a 1.0-microgram.kg-1, min-1 constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24 +/- 0.11 ischemic episodes (mean +/- SEM) on Holter lasting 8.41 +/- 5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0 +/- 0.33, P < .05) and longer duration (26.2 +/- 9.8 minutes, P = .01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms. CONCLUSIONS: Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.

Early clinical experience with integrelin, an inhibitor of the platelet glycoprotein IIb/IIIa integrin receptor.

Aggregation of platelets leading to thrombosis is one of the hallmarks of unstable angina, acute myocardial infarction, and ischaemic complications following coronary angioplasty. Activated platelets bind to fibrinogen through the glycoprotein IIb/IIIa integrin receptor. New agents have been developed to bind this receptor and thus prevent aggregation of platelets. One such compound (integrelin) is a cyclical peptide that has been shown to be a potent inhibitor of the glycoprotein IIb/IIIa receptor in man. A number of phase I and phase II clinical trials have been completed to evaluate this agent for the indications of unstable angina, acute myocardial infarction, as well as an adjunct to coronary angioplasty. This article will focus on the clinical investigation of integrelin with particular emphasis on its use during angioplasty. It has been consistently shown across different trials that integrelin can inhibit between 70% and 95% of platelet aggregation responses to 20 mumols of ADP at a variety of dosages used in the phase II trials. Preliminaray data also suggest that a more clinically unstable patient may require a higher dose of integrelin to cause a near complete inhibition of the platelet aggregation response to ADP. Future studies will need to explore more definitely the relationship between dose of glycoprotein IIb/IIIa receptor blockers and clinical instability.

A multiclinic trial evaluating arbaprostil [15(R)-15-methyl prostaglandin E2] as a therapeutic agent for gastric ulcer.

A randomized, double-blind, placebo-controlled, multiclinic trial evaluated arbaprostil [15(R)-15 methyl prostaglandin E2] for the treatment of acute gastric ulcer, achieving an overall enrollment of 124 patients (of which 113 were considered evaluable). This 6-wk trial used an arbaprostil dose of 10 micrograms q.i.d., which has little gastric acid antisecretory activity. Endoscopies were performed after 21 and 42 days of treatment, at which times the arbaprostil and placebo healing rates, respectively, were 6/59 (10.2%) and 4/53 (7.6%) on day 21 and 25/59 (42.4%) and 16/50 (32.0%) on day 42. No significant differences between the treatment groups were found for pain relief, antacid consumption, and mucosal healing. This trial documents that a 10-micrograms dose of arbaprostil (which may be considered cytoprotective because of its small effect on gastric acid secretion), although safe and associated with no side effects, is not efficacious in healing acute gastric ulcers.

In vitro activity of menogaril and N-demethylmenogaril in a human tumor cloning assay.

The activity of menogaril and its major metabolite in animals and humans, N-demethylmenogaril, has been investigated in the human stem cell assay as developed by Salmon et al. Among 31 evaluable samples, four were sensitive to menogaril, including one which responded to N-demethylmenogaril. Three samples resistant to menogaril responded to N-demethylmenogaril. None was sensitive to doxorubicin. Overall, one out of seven ovarian samples and one out of three breast samples responded to menogaril. Our data confirm the in vitro activity of menogaril in ovarian and breast cancer; in addition, they suggest incomplete cross-resistance between doxorubicin and menogaril and, considering the concentrations of N-demethylmenogaril in animals and humans, a minor role for this metabolite in the overall antitumor activity of the parent compound.