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© 2000 International Anesthesia Research Society
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Abstract |
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Previous perfluorocarbon (PFC) emulsions have been associated with transient adverse events (i.e., platelet activation, decreased platelet count, febrile responses, changes in hemodynamic function). The Phase I studies described in this report were parallel, randomized, double-blinded, placebo-controlled studies conducted in 48 healthy volunteers (n = 24 per study) with perflubron emulsion (OxygentTM; Alliance Pharmaceutical Corp., San Diego, CA). Because of the decreased platelet counts observed with previous PFC emulsions and the intended use of perflubron emulsion in surgical patients, these studies assessed postdosing coagulation responses and hemostasis. PFC pharmacokinetic variables were also evaluated. The primary endpoint for examination of coagulation effects was prospectively defined as bleeding time. Subjects received either saline (3 mL/kg) control, or perflubron emulsion at 1.2 g PFC/kg or 1.8 g PFC/kg, and were evaluated for a 14-day period. No postinfusion changes in bleeding time or differences in ex vivo agonist-induced platelet aggregation were observed. A 17% reduction in platelet count was observed 3 days after dosing in the 1.8-g PFC/kg group; levels recovered to baseline by Day 7. The intravascular half-life of perflubron for the first 24 h was dose dependent: 9.4 ± 2.2 h and 6.1 ± 1.9 h in the 1.8- and 1.2-g PFC/kg groups, respectively. Results indicate that this perflubron emulsion did not affect coagulation function in healthy volunteers.
Implications: In major surgical procedures, perfluorocarbon-based temporary oxygen carriers are potentially important alternatives to blood transfusion. Newer, second-generation perfluorocarbon-based oxygen carriers have been developed to improve on the short-term side effects observed with earlier formulations. This report summarizes Phase I clinical safety data in healthy volunteers receiving the oxygen carrier, perflubron emulsion.
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Introduction |
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Avoiding allogeneic blood transfusion during surgical procedures that have a large expected blood loss is an important surgical outcome. Perfluorocarbons (PFCs) have an oxygen (O2)-carrying capacity that is a linear function of ambient O2 tension. Consequently, when administered in the presence of high levels of inspired oxygen, PFC emulsions are loaded (primed) with O2, which then is released readily on encountering low tissue O2 tension (1–3). The ability to transport O2 and thereby increase the amount of O2 available to the tissues has prompted investigations of the use of PFC emulsions as temporary O2 carriers for a number of clinical applications, including their use as a substitute for allogeneic blood transfusions during major elective surgery.
PFCs are inert synthetic molecules, consisting of a cyclic or linear carbon backbone with fluorine atoms substituted for hydrogen (4). Because PFCs are highly hydrophobic, they require emulsification with a surfactant to generate a biocompatible formulation for IV administration. First-generation PFC emulsions, such as Fluosol® (Green Cross Corp., Osaka, Japan), were limited by their physicochemical properties and clinical side effects. Nevertheless, Fluosol® is the only PFC emulsion to gain United States regulatory approval for supplementing O2 transport during a surgical procedure (i.e., high-risk coronary balloon angioplasty) (5,6). The commercial success of Fluosol® was limited, however, because of its short intravascular half-life, small PFC concentration (20% PFC wt/vol and, therefore, low O2-carrying capacity), and emulsion instability, hence, the need for frozen storage and mixing of components just before use (6,7). Furthermore, the agent used to emulsify the PFC, Pluronic-F68, was associated with complement-mediated adverse effects and accompanying decreases in platelet count (8–10).
Perflubron-based emulsions provide several advantages over the first-generation PFC emulsions because of their improved physicochemical properties: larger PFC concentrations (up to 100% PFC wt/vol; i.e., 100 g/100 mL) for higher O2-carrying capacity, stability at room temperature, and the use of egg yolk phospholipids as emulsifiers (8,11–13). In a pilot clinical study, a single dose of 0.9 g PFC/kg of a 90% wt/vol perflubron emulsion formulation increased O2 tension in mixed venous blood during continuous blood loss, in the absence of any untoward effects attributable to the emulsion (14). However, in preclinical and early clinical studies, dosing with 90% or 100% wt/vol perflubron emulsions formulations was associated with moderate reductions in circulating platelet count (11,15; Cernaianu et al., unpublished observations, 1994). In addition, these formulations were associated with a febrile, flu-like response within the first 24 h after infusion. To overcome these effects and improve particle stability, a second-generation perflubron emulsion (60% wt/vol PFC) was formulated with a smaller particle size (median, 0.16 to 0.18 µm; versus 0.27 to 0.30 µm for earlier formulations). This was associated with reduced febrile responses and improved intravascular retention times in rats (16).
Because perflubron emulsion is targeted for major elective surgery applications, and previous PFC emulsions have been associated with reductions in platelet count, it was necessary to evaluate fully the effect of this emulsion on platelet function. Thus, two Phase I studies were conducted to determine whether perflubron-based emulsion (60% wt/vol PFC formulation) affects coagulation and hemostasis. The two studies assessed overall safety, hemostasis and coagulation responses, blood cell counts, and perflubron blood levels after dosing. Although these variables were assessed with identical schedules in the two studies, one study (OXHT-007) also examined fibrin degradation products and elimination of PFC in expired air, whereas the other (OXHT-008) included a detailed evaluation of the effect of perflubron emulsion on immune function, which is described in the accompanying article (17). The coagulation aspects and perflubron pharmacokinetic and elimination data for the two studies are described in this report.
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Methods |
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Forty-eight healthy volunteers were enrolled in the studies (24 per study) between February and May 1995. Adults between 18 and 45 yr old were eligible if found healthy by medical history and physical examination: absence of liver, renal, cardiovascular, or immune dysfunction; and no history of alcohol or drug abuse. Exclusion criteria included any history of bleeding disorders, template bleeding time (BT) > 8 min, prothrombin time (PT) > 12.9 s, activated partial thromboplastin time (PTT) > 36 s, platelet count < 200,000/µL, white blood cell count or hemoglobin levels outside the normal clinical range before study entry, or recent infection. In addition, subjects were required to show normal ex vivo platelet aggregation responses to the agonists adenosine diphosphate (ADP) and collagen. Women were required to use an accepted method of birth control and to have a negative serum ß-human chorionic gonadotropin test result at baseline. Use of aspirin-containing medication within 14 days before study drug infusion was prohibited and confirmed by measuring platelet aggregation in response to arachidonic acid on the day subjects began their clinic stay. Medications other than chemical contraceptives were excluded beginning 10 days before dosing.
The two studies were prospective, randomized, double-blinded, parallel-group, placebo-controlled, and single-dose in design. One study (OXHT-007) was conducted at Innovex Inc. (Lenexa, KS) and the other (OXHT-008) (17) at the Clinical Research Center (New Orleans, LA). Both studies were approved by each institution’s respective institutional review board. Written, informed consent was obtained from all subjects before protocol initiation.
The studies consisted of a screening visit, a 10-day inpatient period (from Day –3 to Day 7), with a follow-up visit on Day 14. On Day 0, subjects were randomized, equally by sex, to one of three groups (16 subjects per group): 3 mL/kg 0.9% saline (Control), 1.2 g PFC/kg perflubron emulsion (P1.2), or 1.8 g PFC/kg perflubron emulsion (P1.8). The study drug (OxygentTM, Alliance Pharmaceutical Corp., San Diego, CA) was administered by the pharmacist (all other study personnel as well as the subjects were blinded to treatment) via an IV infusion at a rate of 15 mL/min. The perflubron emulsion used in these studies was a 60% wt/vol perflubron-based emulsion containing perfluorooctyl bromide (C8F17Br; 58%) and perfluorodecyl bromide (2%) emulsified with egg yolk phospholipid in phosphate-buffered saline.
Coagulation and hemostasis variables were measured before (baseline) and after dosing according to the schedule of tests listed below. The primary endpoint for determining whether dosing with perflubron emulsion induced any abnormal coagulation response was a prolongation in template BT, which was assessed by using the Surgicutt® instrument (International Technidyne Corp., Edison, NJ). The normal range for BT after a horizontal incision with this instrument is 2 to 8 min; the critical limit for a prolonged BT response was defined a priori as 
16 min, i.e., 2 times greater than the upper limit of normal. BT was measured at 2, 24, and 72 h and at 7 days after dosing. Ex vivo platelet aggregation responses to 10 µM ADP (Bio-Data Corp., Horsham, PA) and 10 µg/mL collagen (Chronolog, Havertown, PA) were assessed in platelet-rich plasma (PRP) from blood samples obtained at the same time points as the BT measurements. Platelet aggregation was measured as an increase in optical density (turbidity) by using a Model PAP-4 Aggregometer (Bio-Data Corp.). PT, PTT, and fibrinogen levels were measured by using standard clinical laboratory methods in both studies at 2 h and at 1, 3, 5, 7, and 14 days after dosing. Fibrin degradation products were assessed only in the OXHT-007 study.
To determine if the optical properties of the emulsion could interfere with turbidity-based measurement of platelet aggregation, a post hoc comparison of the turbidity method with an electrical impedance assay (Model 560CA Lumi-Aggregometer, Chronolog) was performed. For this comparison, whole blood samples were obtained from four volunteers and divided into three aliquots: one was used as control and the other two were supplemented with perflubron emulsion to give PFC concentrations of 11 and 23 mg PFC/mL. These PFC concentrations are equivalent to those measured in the circulating blood of volunteers 2 h after the infusion of 1.2 or 1.8 g PFC/kg perflubron emulsion, respectively. PRP samples (220,000/µL) were then prepared and the aggregation assays performed as described above for the turbidity assay and following the standard procedure provided by the manufacturer for the electrical impedance assay.
Pharmacokinetic evaluations of the rate of clearance of perflubron from the blood were performed in all 16 subjects from each perflubron emulsion treatment group (P1.2 and P1.8). Blood samples were drawn at 0.5, 1, 2, 4, 8, 12, 18, and 24 h and at 2, 4, 7, and 14 days after the infusion. In the OXHT-007 study, expired air samples were collected at 24-h intervals after the infusion through Day 7 and on Day 14. Air samples were measured directly for PFC content by using a gas chromatography electron capture detection procedure. Before gas chromatography analysis, blood samples were extracted twice with iso-octane. In addition to comparing clearance rates for each treatment group overall, data were analyzed according to actual dose administered (body weight x per-kilogram dose). The primary pharmacokinetic variables included maximum PFC concentration, time to maximum PFC concentration, blood t1/2, and elimination rate (estimated from expired air concentrations).
Subjects were monitored continuously throughout the study for occurrence of adverse events. Vital signs, including heart rate, systolic and diastolic blood pressures, respiratory rate, and oral body temperature, were monitored hourly after infusion on Day 0, daily through Day 7, and on Day 14. Laboratory variables were measured at baseline, daily through Day 7, and on Day 14.
Data were calculated and presented as the mean ± SD or SEM, or they were tabulated by frequency for each group. Descriptive statistics were calculated for each group at each time point and for changes from baseline at postinfusion time points. Differences between groups were determined by using analysis of variance (with Fisher’s least significant difference method) by using StatView IITM software (Abacus Concepts, Inc., Berkeley, CA). For all statistical comparisons, a P value < 0.05 was considered significant.
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Results |
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Patient Demographic and Baseline Variables
All 48 subjects (24 volunteers per study) completed the studies. Demographic and baseline characteristics are summarized by treatment group in Table 1. By design, each treatment group was evenly divided between sexes. There were no notable between-group differences in demographic variables, such as age, weight, or height, or in any of the baseline measures of coagulation function.
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Coagulation Function
BT was defined a priori as the primary endpoint for assessing coagulation function in vivo. Baseline BT values were similar among groups, both within the two studies and combined by groups across studies, and ranged from 3.0 to 3.6 min (Table 1). As shown in Figure 1A, no significant changes in BT were observed for the control or either PFC group after the infusion of perflubron emulsion: BT remained within the normal range of 2 to 8 min at all evaluation points. A postdosing increase in BT to a value above the upper limit of normal was observed for one subject in the saline control group, who had a BT of 8.75 min on Day 7 postinfusion.
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Mean platelet counts for the three treatment groups are shown in Figure 1B. Platelet counts were similar among treatment groups at baseline, and no notable changes occurred for the Control and P1.2 groups after infusion. A small decrease in platelet count was observed on Day 3 for the P1.8 group, with a nadir 17% below baseline (P < 0.001); however, platelet count returned to a value that was similar to baseline by Day 7. At no time during the studies did the mean platelet count in any group occur outside the normal clinical range (130,000 to 400,000/µL). One subject experienced a platelet count decrease below the lower limit of the normal range: a female subject in the P1.8 group, whose platelet count decreased to 117,000/µL on Day 3 from a baseline value of 220,000/µL but recovered to above 200,000/µL at the next time point (Day 7).
Ex vivo platelet aggregation responses to ADP and collagen were similar among groups at baseline (Figure 2). There appeared to be a dose-related reduction in agonist-induced platelet aggregation in blood samples collected 2 h after infusion: a 33.3% (with ADP) and 34.2% (with collagen) reduction from baseline values in the P1.2 group, and a 56.4% (ADP) and 58.9% (collagen) reduction in the P1.8 group, compared with a 7.3% (ADP) and 7.7% (collagen) reduction in the Control group. In the perflubron emulsion groups, agonist-induced platelet aggregation was near baseline levels at the next time point, Day 1, and remained stable for the duration of the studies. However, the plasma was cloudy at the 2 h time point because of the presence of emulsion particles. This raised concerns that, given the inherent turbidity of the emulsion, the high levels of emulsion particles present at that time point could be expected to interfere with the turbidity assay by causing excessive light scattering.
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Therefore a post hoc laboratory investigation was conducted to compare the results of agonist-induced ex vivo platelet aggregation obtained by using the turbidity with the impedance assay technique. For this, human blood was spiked with 11 or 23 mg PFC/mL, which was equivalent to the amount that was found in the circulation at 2 h after dosing in the volunteers enrolled. The results showed a clear difference for identical samples assayed by the two techniques (Figure 3). When aggregation was monitored as a change in turbidity, apparent dose-dependent reductions in platelet aggregation (defined by relative change in turbidity from baseline after addition of agonists) were observed in the emulsion-supplemented PRP samples. For each perflubron emulsion concentration, the apparent magnitude of platelet aggregation reduction was similar for the two agonists: in 11 mg PFC/mL PRP samples the reduction averaged 39.5% ± 11.7% (ADP) and 41.9% ± 4.0% (collagen); in the 23 mg PFC/mL PRP samples, the reduction averaged 67.6% ± 7.8% (ADP) and 67.3% ± 3.4% (collagen). In contrast, when platelet aggregation was measured by the electrical impedance assay, no perflubron emulsion-mediated effects on agonist-induced ex vivo platelet aggregation were observed in either the whole blood or PRP samples.
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No between-group differences were observed in baseline values of the remaining coagulation factors measured in the clinical studies, including PT, PTT, and fibrinogen levels (Table 2). No clinically relevant changes in PT, PTT, or fibrin degradation products values were observed in the course of the study. Fibrinogen levels increased moderately between Days 1 and 3, but returned to baseline levels by Day 7.
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Overall Safety
Overall safety findings have been pooled from both studies and are described in more detail in the companion report (17). There were no changes of clinical significance in systolic and diastolic blood pressure, heart rate, or respiratory rate. Mean body temperature values for all groups remained near 37°C throughout the study (17). Five of the 32 PFC-treated subjects (all in the P1.8 group) had an increase in body temperature >1°C above baseline. In each of these cases, temperature peaked at 8 h after dosing but returned to baseline values between 12 and 16 h after dosing; however, the highest individual increase was to 39°C (this subject had a 2°C-increase from 37°C at baseline). Flu-like side effects within the first day of dosing were reported for PFC-treated subjects; however, these typically were resolved by 24 h after dosing (17).
Perflubron Emulsion Pharmacokinetic Variables
Blood perflubron concentration data from both studies were combined for each dose group. Peak perflubron concentrations at 20 min after the start of dosing (a time point chosen to approximate the end of dosing while standardizing the timing of blood draws across treatment groups to maintain the blinded nature of the study) were 13,475 ± 1,392 and 22,400 ± 3,369 mg/L for the P1.2 and P1.8 groups, respectively. After an initial distribution phase within the first hour after infusion, there was an initial rapid rate of perflubron clearance from the circulation over the first 24 h followed by a much slower terminal phase. The initial half-life (t1/2) during the first 24 h after administration of perflubron emulsion was dose-dependent: t1/2 was 9.4 ± 2.2 h in the P1.8 group and 6.1 ± 1.9 h in the P1.2 group (Figure 4). This phase is thought to represent the saturable mononuclear phagocytic system (MPS) uptake of emulsion particles (16,17). Analysis of the data by dose administered, to account for differences in body weight, indicated that there was a rank order correlation between the mean half-life at 12 h after infusion (t1/2,12h) and the absolute PFC dose administered (Table 3). Thus, the t1/2,12h ranged from 4.62 ± 0.32 h for the lightest subjects, who received a total of 50 to 70 g PFC, to 10.8 ± 2.9 h for heavier subjects administered 151 to 171 g PFC. There was also a relationship between the area under the curve for perflubron with body weight (data not shown). Overall, however, the concentration-time profiles indicated that blood perflubron concentrations within the first 12 h after infusion depended more on the per-kilogram dose than on the absolute dose.
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The terminal half-life of perflubron in the circulation was 190.7 ± 15.3 h for the P1.2 group and 257.9 ± 20.7 h for the P1.8 group. This slow terminal rate is considered to represent elimination of nonemulsified perflubron in the circulation, as emulsion particles are broken down within the MPS and the PFC redistributes to lipid compartments within the body (5,16,17). The slow clearance rate of this terminal phase indicates a longer persistence of PFCs in body tissue lipids.
The rate of perflubron elimination via exhaled air appeared to be constant over the 14-day postinfusion period. The half-life appeared to parallel the terminal clearance rate from the blood, rather than the rapid initial rate of emulsion particle clearance (Figure 4).
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Discussion |
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Annual allogeneic red blood cell transfusion in the United States now exceeds 13 million units, of which approximately two thirds are used because of surgical blood loss (18). Although the safety of the blood supply has improved in recent years with more rigorous screening and testing (19), avoiding allogeneic transfusion remains a preferred outcome in surgery because of the continued risks of disease transmission, transfusion reactions, and immunosuppression (19–21). Hence, there is a search for blood management options that support tissue oxygenation during surgical procedures and reduce the need for allogeneic blood transfusion.
The O2-carrying properties of the perflubron-based PFC emulsions, and the ease with which perflubron emulsion can be used in the surgical setting, make them well suited to support tissue oxygenation during surgical procedures in which significant blood loss is anticipated. Earlier perflubron-based formulations caused a transient reduction in platelet count (approximately 30% relative to baseline) (22,23; Cernaianu et al., unpublished results, 1994), and flu-like symptoms in conscious subjects (22,23). The perflubron-based emulsion formulation currently under investigation (OxygentTM) was designed to have a much smaller particle size (median particle diameter from 0.16 to 0.18 µm) to minimize these effects. Therefore, the clinical studies reported here were designed to evaluate the overall safety of this current formulation, with particular attention to its effects on coagulation function.
BT was chosen as the most direct method to assess effects on coagulation responses in vivo. The studies presented here clearly demonstrated that infusion of perflubron emulsion had no effect on BT, either within the initial hours after infusion (relevant for proposed use in surgery) or in the days after infusion, including the Day 3 postdosing time point when decreases in platelet count have been observed in studies with earlier formulations. Although slight decreases in mean platelet count on Day 3 also were observed in this study, a statistically significant decrease was observed only for the large-dose (P1.8) group (17% relative to baseline), but this still remained within the normal range. The decrease in platelet count observed in these studies was considerably smaller than the changes observed in studies with the earlier perflubron emulsions (14,15). Only one subject (P1.8 group) had a decrease in platelet count on Day 3 to a value below the lower limit of normal; however, the decrease was not accompanied by any prolongation of BT or changes in ex vivo platelet aggregation for this subject. Likewise, there were no changes for the P1.8 group as a whole for either of these assays after dosing, confirming that any minor changes in platelet count induced by the large-dose (1.8 g PFC/kg) had no functional consequences for this study group. Subsequent to these Phase I studies, a Phase II efficacy study was conducted in anesthetized surgical patients. The 36 patients treated with 1.8g/kg PFC showed no decrease relative to colloid controls, rather all groups showed very similar thrombocytosis between 7 and 14 days after dosing (24). Major surgery is typically associated with postoperative increases in platelet counts that may, in part, explain the differences between the healthy conscious volunteers and the targeted surgical patient population.
Although the results of the turbidity assay appeared to demonstrate a transient effect of perflubron emulsion on platelet aggregation at the two-hour time point, post hoc studies demonstrated that this effect was most likely an artifact caused by the large concentration of emulsion particles present in the circulation at this time point. The emulsion particles appeared to interfere with light transmittance through the PRP sample, thereby confounding interpretation of the platelet aggregation response. The absence of an effect when the same samples were assessed by using a standard electrical impedance assay confirmed the confounding light-scattering effect of the emulsion at the early postdosing time point. Taken together, the data indicate that this 60% wt/vol perflubron emulsion does not affect platelet function ex vivo. Although "fluorocrit" was not formally monitored in these studies, the plasma samples obtained at two hours after infusion from perflubron-treated subjects had a cloudy appearance. This observation is consistent with other reports that perflubron emulsion-containing plasma samples have a lipemic, more turbid appearance (25).
A dependence of particle clearance from the circulation on particle size has been observed with various PFC and liposomal formulations (6,13,16,26–28). Particles 0.3 µm appear to be cleared much more rapidly by the MPS than particles 
0.2 µm. Therefore, it was expected that developing a perflubron emulsion with relatively smaller mean particle size would increase intravascular persistence (13,28,29). Preclinical studies in rats confirmed that the 60% wt/vol PFC emulsion formulation had a longer circulation half-life (16). In the clinical studies presented here, the pharmacokinetic properties of perflubron emulsion were assessed in humans administered clinically relevant doses. The intravascular blood half-life of perflubron emulsion was dose and body-weight dependent. There also appeared to be a relationship between the perflubron area under the curve and body weight for subjects within each per-kilogram dose group (data not shown), confirming that the absolute dose of perflubron (in grams) is related to the rate of perflubron clearance from the blood.
Despite the correlation between t1/2,12h and body weight, examination of the concentration-time profiles indicated that blood concentrations of perflubron within the first 12 hours postinfusion depended more on the per-kilogram dose than on the absolute dose. Regardless, it is clear that the intravascular half-life of perflubron emulsion is sufficiently long to support systemic oxygenation during elective surgical procedures.
Another important aspect of the pharmacokinetic properties of perflubron emulsion relates to how these variables correlate with the overall safety of this 60% PFC emulsion. As described in the accompanying report (17), perflubron emulsion dosing was associated with minor flu-like symptoms. A transient febrile response was observed eight hours after dosing in the large-dose group. Both perflubron emulsion-treated groups experienced flu-like symptoms, such as headache and dizziness, which typically resolved between 12 and 24 hours after dosing. The timing correlated with the first phase of PFC clearance from the blood, that is, MPS uptake of the emulsion particles. Anesthesia is known to suppress leukocyte activation, so it is likely that such effects will be minimized in surgical patients. Additionally, the postinfusion responses were short-lived, suggesting that there would be limited effects observed in the postoperative recovery period compared with an untreated patient. Indeed, in a Phase II trial, initiated after these Phase I studies were completed, involving 147 orthopedic surgical patients, 38 of whom were treated with 0.9 g PFC/kg and 36 were treated with 1.8 g PFC/kg of perflubron emulsion, no adverse flu-like or febrile responses were reported (24).
In summary, the results of these two double-blinded, placebo-controlled Phase I studies in conscious, healthy subjects indicate that perflubron emulsion, administered in doses of up to 1.8 g PFC/kg, appears to be safe for further evaluation in surgical patients. Importantly, while IV administered perflubron emulsion was associated with a transient reduction in platelet count, no adverse effects on coagulation or BT were observed. These results suggest that perflubron emulsion administration would not pose a risk for perioperative bleeding in surgical patients. The efficacy of small-dose perflubron emulsion (i.e., 0.9 g PFC/kg) for support of systemic oxygenation in hemodiluted patients has been demonstrated in a pilot Phase II study in seven surgical patients (14). Additionally, in a subsequent Phase II trial in orthopedic surgical patients (initiated after the completion of the safety studies reported here), perflubron emulsion administered in a dose up to 1.8 g PFC/kg was effective at reversing physiologic transfusion triggers and delaying the need for subsequent transfusion (24). Thus, the safety profile of perflubron emulsion, when administered at doses shown to enhance systemic oxygenation, supports its continued clinical evaluation as a temporary O2 carrier and as a substitute for allogeneic blood transfusion to prevent tissue hypoxia.
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Acknowledgments |
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The authors gratefully acknowledge contributions from the following individuals: Glenn Luena (PFC analysis of blood samples), Gerald Neslund, PhD, and Elizabeth Kornbrust (impedance platelet aggregation studies), and Dianne Uphoff (CRA) from Alliance Pharmaceutical Corp.; Linda Zech (Study Coordinator) and Sean Davenport (platelet aggregations) from Innovex Inc.; and Tom Osgood (platelet aggregations), Cheryl Cunningham (Study Coordinator), and Terry Abdun (Study Coordinator) from the Clinical Research Center in New Orleans, LA.
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