King Of Prussia, PA, United States

Prism Pharmaceuticals

www.prismpharma.com
King Of Prussia, PA, United States
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Cushing D.J.,Prism Pharmaceuticals | Cooper W.D.,Prism Pharmaceuticals | Cohen M.L.,Creative Pharmacology Solutions | McVoy J.R.S.,Commonwealth Biotechnologies Inc. | And 2 more authors.
European Journal of Pharmacology | Year: 2010

Protamine is the only agent approved to reverse heparin-induced anticoagulation. Due to the significant adverse effects of protamine there is an important need for an alternative agent with an improved safety profile. The pharmacodynamics of PM102, a novel peptide-based heparin antagonist, was evaluated and compared to protamine in a rat model. Rats were dosed with intravenous heparin (50U/kg) and 4min later with protamine (0.25, 0.75mg/kg single intravenous bolus) or PM102 (0.1, 0.3, 1, 3, 30mg/kg single intravenous bolus). Blood samples were collected though 60min for assessment of activated partial thromboplastin time (aPTT) and plasma concentration of PM102. Both doses of protamine markedly lowered the elevated aPTT to baseline values within 1 to 5min after administration. PM102 (0.3-30mg/kg) also rapidly and completely reversed heparin-induced increases in aPTT within 1 to 5min. The effects of PM102 administered as an infusion over 10min also reversed aPTT with similar potency to that observed for bolus administration. The onset of reversal with infusion was delayed relative to the same total dose given as a bolus; however, the maximum effect was similar. PM102 rapidly (Tmax 1-2.6min) appeared in plasma after dosing. Concentrations of PM102 generally declined rapidly after reaching Tmax with a mean T1/2 of 4 to 31min. PM102 is a novel synthetic peptide that effectively reverses the anticoagulant effect of heparin. It's utility as a bolus injection as well as infusion, its rapid efficacy and its rapid clearance make this an ideal candidate for clinical development. © 2010 Elsevier B.V.


Cushing D.J.,Prism Pharmaceuticals | Adams M.P.,Prism Pharmaceuticals | Cooper W.D.,Prism Pharmaceuticals | Agha B.,Prism Pharmaceuticals | Souney P.F.,Prism Pharmaceuticals
Journal of Clinical Pharmacology | Year: 2012

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 Premixed Injection is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight subjects were enrolled in this randomized, single-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 Premixed Injection and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The geometric ratio of the area under the concentration-time curve for time 0-72 hours (AUC0-72hr) for amiodarone was 0.96 (95% confidence interval [CI], 0.94-0.99). The geometric ratio of the maximum concentration (Cmax) for amiodarone was 0.87 (95% CI, 0.84-0.91). Because these ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to the PM101 Premixed Injection, ready-to-use formulation were identified. © 2012 American College of Clinical Pharmacology, Inc.


Souney P.F.,Prism Pharmaceuticals | Cooper W.D.,Prism Pharmaceuticals | Cushing D.J.,Prism Pharmaceuticals
Expert Opinion on Drug Safety | Year: 2010

Importance of the field: Intravenous amiodarone (A-IV) is used to manage ventricular and atrial arrhythmias. The current formulation uses polysorbate 80 and benzyl alcohol to maintain amiodarone in solution, and these co-solvents are linked with clinically-important adverse events and pharmaceutical incompatibilities. PM101 is a recently FDA-approved intravenous formulation of amiodarone that uses a cyclodextrin to solubilize amiodarone. Areas covered in this review: This review describes the clinical and pharmaceutical development of formulations of amiodarone for intravenous administration. The medical and pharmaceutical literature was searched for papers discussing A-IV, PM101 and their formulation components. Relevant literature was identified starting from 1948 to the present. What the reader will gain: The reader will learn about the important medical and pharmaceutical issues complicating A-IV administration, including an understanding of related hypotension and compatibility with commonly used infusion materials and how these issues may impact drug safety. PM101 has been developed to address several of these important issues. Take home message: PM101 is a new formulation of A-IV that is stable in commonly used infusion materials and avoids co-solvent related toxicities. © 2010 Informa UK Ltd.


Cushing D.J.,Prism Pharmaceuticals | Cooper W.D.,Prism Pharmaceuticals | Gralinski M.R.,CorDynamics
Clinical and Experimental Pharmacology and Physiology | Year: 2010

Hypotension frequently occurs with use of intravenous amiodarone and is managed by slowing the rate of administration. This response has been attributed to the cosolvents in the formulation and is believed to be solely related to the initial loading dose. The present study was performed to determine whether intravenous amiodarone-induced hypotension persists beyond the loading dose and into the maintenance infusion period and also whether hypotension occurs with maintenance level dosing alone. 2. Anaesthetized beagle dogs (n = 7/group) were instrumented to assess haemodynamics. Animals were treated with the human-equivalent dosing regimen (loading dose followed by maintenance infusion) of intravenous amiodarone or control (5% dextrose in water). 3. No haemodynamic changes were observed in the control group during the 6 h study. In contrast, administration of the standard intravenous amiodarone regimen produced rapid and significant decreases in mean aortic pressure, cardiac output and maximum rate of change of left ventricular pressure that persisted throughout the 6 h maintenance infusion period. Administration of amiodarone as the maintenance infusion dose alone produced haemodynamic changes that were similar in magnitude to those observed with administration of the full dosing regimen, but were delayed in onset by approximately 60 min. 4. Dosing with a cosolvent-free formulation of amiodarone (PM101) caused no haemodynamic effects during the 6 h dosing period, indicating that the cardiodepressant effects of intravenous amiodarone were due to its cosolvents. 5. These data suggest that consideration should be given to intravenous amiodarone as a potential cause for sustained hypotension during prolonged infusion. © 2010 Blackwell Publishing Asia Pty Ltd.


PubMed | Prism Pharmaceuticals
Type: Journal Article | Journal: Expert opinion on drug safety | Year: 2010

Intravenous amiodarone (A-IV) is used to manage ventricular and atrial arrhythmias. The current formulation uses polysorbate 80 and benzyl alcohol to maintain amiodarone in solution, and these co-solvents are linked with clinically-important adverse events and pharmaceutical incompatibilities. PM101 is a recently FDA-approved intravenous formulation of amiodarone that uses a cyclodextrin to solubilize amiodarone.This review describes the clinical and pharmaceutical development of formulations of amiodarone for intravenous administration. The medical and pharmaceutical literature was searched for papers discussing A-IV, PM101 and their formulation components. Relevant literature was identified starting from 1948 to the present.The reader will learn about the important medical and pharmaceutical issues complicating A-IV administration, including an understanding of related hypotension and compatibility with commonly used infusion materials and how these issues may impact drug safety. PM101 has been developed to address several of these important issues.PM101 is a new formulation of A-IV that is stable in commonly used infusion materials and avoids co-solvent related toxicities.


PubMed | Prism Pharmaceuticals
Type: Journal Article | Journal: Journal of clinical pharmacology | Year: 2014

Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 Premixed Injection is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight subjects were enrolled in this randomized, single-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 Premixed Injection and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The geometric ratio of the area under the concentration-time curve for time 0-72 hours (AUC0-72hr ) for amiodarone was 0.96 (95% confidence interval [CI], 0.94-0.99). The geometric ratio of the maximum concentration (Cmax ) for amiodarone was 0.87 (95% CI, 0.84-0.91). Because these ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to the PM101 Premixed Injection, ready-to-use formulation were identified.


PubMed | Prism Pharmaceuticals
Type: Journal Article | Journal: Clinical and experimental pharmacology & physiology | Year: 2012

1. PM103 is an intravenous formulation of clopidogrel being developed as an alternative to oral clopidogrel to provide for dosing flexibility in the emergent clinical setting. The present first-in-human study assessed the pharmacokinetic and pharmacodynamic effects of PM103 and its safety in 144 healthy human subjects. 2. The present was a randomized open-label parallel-group trial. Single intravenous doses of PM103 (0.1, 1.0, 10, 30, 100 or 300 mg) were administered to each group (n = 24 subjects per group). Platelet aggregation was assessed at baseline and then 15 and 30 min and 2, 5 and 24 h after drug administration. Determination of plasma concentrations of clopidogrel, clopidogrel carboxylic acid metabolite and the clopidogrel thiol metabolite were assessed at baseline and at 1, 5, 10, 20 and 30 min and 1, 2, 3, 4, 6, 8, 12 and 24 h after drug administration. 3. PM103 produced a rapid, persistent and dose-related inhibition of platelet aggregation. The onset of the ant platelet effect paralleled the appearance in plasma of the clopidogrel thiol active metabolite. PM103 was well tolerated and no subjects discontinued treatment because of adverse events. 4. These data suggest that PM103 may be a suitable alternative to oral clopidogrel for patients in whom the desired clinical management would include administration of clopidogrel after coronary angiography but prior to percutaneous coronary intervention.


PubMed | Prism Pharmaceuticals
Type: Comparative Study | Journal: Clinical and experimental pharmacology & physiology | Year: 2010

1. Hypotension frequently occurs with use of intravenous amiodarone and is managed by slowing the rate of administration. This response has been attributed to the cosolvents in the formulation and is believed to be solely related to the initial loading dose. The present study was performed to determine whether intravenous amiodarone-induced hypotension persists beyond the loading dose and into the maintenance infusion period and also whether hypotension occurs with maintenance level dosing alone. 2. Anaesthetized beagle dogs (n = 7/group) were instrumented to assess haemodynamics. Animals were treated with the human-equivalent dosing regimen (loading dose followed by maintenance infusion) of intravenous amiodarone or control (5% dextrose in water). 3. No haemodynamic changes were observed in the control group during the 6 h study. In contrast, administration of the standard intravenous amiodarone regimen produced rapid and significant decreases in mean aortic pressure, cardiac output and maximum rate of change of left ventricular pressure that persisted throughout the 6 h maintenance infusion period. Administration of amiodarone as the maintenance infusion dose alone produced haemodynamic changes that were similar in magnitude to those observed with administration of the full dosing regimen, but were delayed in onset by approximately 60 min. 4. Dosing with a cosolvent-free formulation of amiodarone (PM101) caused no haemodynamic effects during the 6 h dosing period, indicating that the cardiodepressant effects of intravenous amiodarone were due to its cosolvents. 5. These data suggest that consideration should be given to intravenous amiodarone as a potential cause for sustained hypotension during prolonged infusion.


Cushing D.J.,Prism Pharmaceuticals | Souney P.F.,Prism Pharmaceuticals | Cooper W.D.,Prism Pharmaceuticals | Mosher G.L.,CyDex Pharmaceuticals | And 3 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2012

1.PM103 is an intravenous formulation of clopidogrel being developed as an alternative to oral clopidogrel to provide for dosing flexibility in the emergent clinical setting. The present first-in-human study assessed the pharmacokinetic and pharmacodynamic effects of PM103 and its safety in 144 healthy human subjects. 2.The present was a randomized open-label parallel-group trial. Single intravenous doses of PM103 (0.1, 1.0, 10, 30, 100 or 300mg) were administered to each group (n=24 subjects per group). Platelet aggregation was assessed at baseline and then 15 and 30min and 2, 5 and 24h after drug administration. Determination of plasma concentrations of clopidogrel, clopidogrel carboxylic acid metabolite and the clopidogrel thiol metabolite were assessed at baseline and at 1, 5, 10, 20 and 30min and 1, 2, 3, 4, 6, 8, 12 and 24h after drug administration. 3.PM103 produced a rapid, persistent and dose-related inhibition of platelet aggregation. The onset of the ant platelet effect paralleled the appearance in plasma of the clopidogrel thiol active metabolite. PM103 was well tolerated and no subjects discontinued treatment because of adverse events. 4.These data suggest that PM103 may be a suitable alternative to oral clopidogrel for patients in whom the desired clinical management would include administration of clopidogrel after coronary angiography but prior to percutaneous coronary intervention. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

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