Heparin attenuates the Hypotensive Effect associated with Heparin by nikeborome

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									                                                                         Heparin attenuates the Hypotensive Effect associated with
                                                                                      Heparin-Antagonist PMX-60056
                                                            R. E. McAllister MD DPhil, R. Scott PhD, B. Korczak PhD, Mark Stafford-Smith MD, CM, FRCPC†
                                          PolyMedix, Inc., Radnor, PA 19087, USA, Department of Anesthesiology†, Duke University Medical Center, Durham, NC 27710, USA

                                                                                                              Background                                                                       PMX-60056           Max. BP Drop                Placebo            Max. BP drop
                                                                                                                                                                                                                   %       mmHg                                   %       mmHg
                               ABSTRACT
                                                                              • PMX-60056 is a new small molecule developed from first principles to                                                 Systolic     8.90%   10.5
                                                                                                                                                                                                                                   [95%CI]
                                                                                                                                                                                                                                  [1.4,19.6]        Systolic    -0.80%    -1.0
                                                                                                                                                                                                                                                                                  [95%CI]
                                                                                                                                                                                                                                                                                 [-5.1,3.1]
Background: PMX-60056 is a new small molecule developed from first              antagonize the anticoagulant effect of heparin                                                                       Diastolic   14.70%    11     [1.9,20.0]        Diastolic   1.90%     1.5    [-0.7,3.7]
principles to antagonize the anticoagulant effect of heparin. Initial
studies in man were limited by dose-related hypotension that was              • Initial studies in man were limited by dose-related hypotension that was
transient but undesirable; average systolic (sbp) and diastolic (dbp) blood     transient but undesirable; average systolic (sbp) and diastolic (dbp) blood
pressure reductions of 35% and 45% that were observed with 0.5mg/kg
recovered over 30 minutes. However doses of 0.1 and 0.2mg/kg did not
                                                                                pressure reductions of 35% and 45% that were observed with 0.5mg/kg                                            A.                                              B.
result in clinically relevant hypotension. Since PMX-60056 combines             recovered over 30 minutes. However doses of 0.1 and 0.2mg/kg did not
rapidly and irreversibly with heparin, hypotensive effects associated with      result in clinically relevant hypotension.
unopposed drug may not accurately reflect the clinical safety profile of
PMX-60056 in the presence of heparin. Therefore we tested the                 • Since PMX-60056 combines rapidly and irreversibly with heparin, hypotensive
hypothesis that 0.3mg/kg PMX-60056 in heparin-anticoagulated subjects           effects associated with unopposed drug may not accurately reflect the
would not be associated with hypotensive responses seen with unopposed
agent.
                                                                                clinical safety profile of PMX-60056 in the presence of heparin.

Methods: With IRB approval and informed consent, six volunteer male
subjects participated in this double-blind randomized placebo-controlled
                                                                                                              Hypothesis
crossover trial. Subjects received 70U/kg heparin by intravenous bolus
then, after 20 minutes, a 10 minute infusion of either PMX-60056 or           In heparin-anticoagulated human subjects 0.3mg/kg PMX-60056 is not
placebo. Point of care anticoagulation testing and hemodynamic data,          associated with hypotensive responses seen with unopposed agent.                  Figure 1                      Figure 2
including heart rate, sbp and dbp (by automated brachial arm cuff) were
obtained prior to drug infusion, at 2, 5, and 9 mins during, and 2, 5, 10,                                                                                                                                       Results
20, 60, and 240 mins after the infusion. After a 2-day washout the                                              Methods                                         • Mean sbp and dbp values are depicted (Figures 1 & 2).
second arm of the protocol was performed in a similar fashion. All
subjects were observed from the day prior to the day after completion of      • With IRB approval and informed consent, six volunteer male subjects
the protocol. The nadir sbp/dbp values following completion of study            participated in this double-blind randomized placebo-controlled crossover       • Nadir sbp/dbp were not significantly different from baseline for placebo, while nadir
drug for each subject were averaged for comparison with values
immediately preceding the study drug, using a 2-sample paired t-test,           trial.                                                                            sbp/dbp values of 10.5 and 11.0mmHg respectively reflected a modest but significant blood
p<0.05 was considered significant.                                                                                                                                pressure drop with PMX-60056 (8.9 and 14.7%, respectively) (Table).
                                                                              • Subjects received 70U/kg heparin by intravenous bolus then, after 20
Results: Mean sbp and dbp values are depicted (Figure). Nadir sbp/dbp           minutes, a 10 minute infusion of either PMX-60056 or placebo.
were not significantly different from baseline for placebo, while nadir
                                                                                                                                                                • The table shows the maximum mean reductions in %, and in mmHg with 95% confidence
sbp/dbp values of 10.5 and 11.0mmHg respectively reflected a modest           • Point of care anticoagulation testing and hemodynamic data, including             intervals (CI) for the absolute reductions.
but significant blood pressure drop with PMX-60056 (8.9 and 14.7%,              heart rate, sbp and dbp (by automated brachial arm cuff) were obtained
respectively) (Table). The table shows the maximum mean reductions in
%, and in mmHg with 95% confidence intervals (CI) for the absolute              prior to drug infusion, at 2, 5, and 9 mins during, and 2, 5, 10, 20, 60, and   • No subjects had symptomatic hypotension at any time.
reductions. No subjects had symptomatic hypotension at any time.                240 mins after the infusion.
Conclusions: Blood pressure declines observed after heparin-                  • After a 2-day washout the second arm of the protocol was performed in a                                                  Conclusions
anticoagulated individuals receive 0.3mg/kg PMX-60056 are modest                similar fashion. All subjects were observed from the day prior to the day       • Blood pressure declines observed after heparin-anticoagulated individuals receive 0.3mg/kg
compared to placebo, and attenuated compared to those observed in non-
anticoagulated individuals receiving (unopposed) 0.5mg/kg PMX-60056.
                                                                                after completion of the protocol.                                                 PMX-60056 are modest compared to placebo, and attenuated compared to those observed in
Preliminary point of care anticoagulation assessments indicate that 0.3
                                                                              • The nadir sbp/dbp values following completion of study drug for each              non-anticoagulated individuals receiving (unopposed) 0.5mg/kg PMX-60056.
mg/kg PMX-60056 exceeds that required to reverse the 70 U/kg heparin
involved in the study protocol.                                                 subject were averaged for comparison with values immediately preceding          • Preliminary point of care anticoagulation assessments indicate that 0.3 mg/kg PMX-60056
                                                                                the study drug, using a 2-sample paired t-test, p<0.05 was considered             exceeds that required to reverse the 70 U/kg heparin involved in the study protocol.
                                                                                significant.
                                                                                                                                          DUKE
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