WO2013103567A2 - Methods of blocking platelet activation during extracorporeal circulation using cangrelor - Google Patents
Methods of blocking platelet activation during extracorporeal circulation using cangrelor Download PDFInfo
- Publication number
- WO2013103567A2 WO2013103567A2 PCT/US2012/071666 US2012071666W WO2013103567A2 WO 2013103567 A2 WO2013103567 A2 WO 2013103567A2 US 2012071666 W US2012071666 W US 2012071666W WO 2013103567 A2 WO2013103567 A2 WO 2013103567A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cangrelor
- ecc
- subject
- administered
- medical procedure
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
- A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the invention relates to methods of blocking activation of platelets during medical procedures involving extracorporeal circulation (ECC) of blood, hypothermia, or both.
- ECC extracorporeal circulation
- Extracorporeal circulation is employed in many cardiac surgical procedures to maintain stable circulatory parameters of the patient.
- hypothermia ranging between 28°C and 32°C is widely employed as adjunct to ECC to increase the patient's ischemia tolerance.
- platelet activation is a potentially hazardous side effect that can result when either or both of the techniques are used during cardiac procedures.
- Fibrinogen is the main ligand of the platelet receptor glycoprotein (GP) Ilb/IIIa (CD41/CD61) and mediates binding of platelets in aggregates.
- GP platelet receptor glycoprotein
- CD41/CD61 platelet receptor glycoprotein
- platelets release their granule contents, form aggregates, adhere to ECC surfaces, and thereby become unavailable for adequate blood coagulation.
- ADP platelet agonist adenosine diphosphate
- ADP plays a central role in hypothermia-induced platelet activation and that pharmacological blockade of the platelet ADP receptor P2Y12 inhibits hypothermia-induced platelet activation. 13 ADP-mediated platelet activation is therefore of particular importance during ECC.
- Pharmacological inhibition of the GPIIb/IIIa receptor has been proposed to protect platelet function temporarily during ECC. 6 ' 7
- this approach which has been termed "platelet anaesthesia”
- the optimal agent for platelet protection would therefore be a short-acting substance to achieve safe therapy control during hypothermic ECC.
- the present invention is directed to a method of inhibiting activation of platelets in the blood of a subject undergoing an extracorporeal circulation (ECC)- based medical procedure, a hypothermia-based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting activation of platelets in the blood of the subject.
- ECC extracorporeal circulation
- the invention is directed to a method of inhibiting platelet granule release in the blood of a subject undergoing an ECC-based medical procedure, a hypothermia-based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting platelet granule release in the blood of the subject
- the invention is directed to a method of inhibiting platelet- leukocyte aggregation in the blood of a subject undergoing an ECC-based medical procedure, a hypothermia-based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting platelet- leukocyte aggregation in the blood of the subject.
- the invention is directed to a method of inhibiting platelet loss from the blood of a subject undergoing an ECC-based medical procedure, a hypothermia- based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting platelet loss from the blood of the subject.
- the ECC-based medical procedure is a medical procedure selected from the group consisting of surgery, hemodialysis, hemofiltration, apheresis, extracorporeal membrane oxygenation, and ventricular assist devices.
- the ECC-based medical procedure is cardiopulmonary bypass surgery.
- the methods of the present invention further comprise administering an anticoagulant to the subject.
- Suitable anticoagulants include heparin and bivalirudin.
- the anticoagulant may be administered to the subject prior to, concurrent with, or after the pharmaceutical composition comprising cangrelor is administered to the subject.
- the anticoagulant may be administered to the subject orally, as an intravenous bolus, as a continuous intravenous infusion, or as an intravenous bolus followed by a continuous intravenous infusion.
- the bolus may comprise between about 0.1 and 10 mg/kg bivalirudin, such as about 0.75 mg/kg bivalirudin, for example.
- the infusion may comprises between about 0.5 and 10 mg/kg/h bivalirudin, such as about 1.75 mg/kg/h bivalirudin, for example.
- the pharmaceutical composition further comprises a
- the pharmaceutical composition is administered to the subject in an oral dosage form, an intravenous dosage form, or both.
- the pharmaceutical composition is administered to the subject orally, as an intravenous bolus, as a continuous intravenous infusion, or as an intravenous bolus followed by a continuous intravenous infusion.
- the pharmaceutical composition is administered to the subject prior to beginning the medical procedure as an intravenous bolus and during the procedure as a continuous intravenous infusion.
- the pharmaceutical composition comprises between about 20 and 40 ⁇ g/kg. [0018] In particular aspects, the pharmaceutical composition comprises about 30 ⁇ g/kg cangrelor.
- the pharmaceutical composition comprising cangrelor when administered as an intravenous bolus, the bolus comprises between about 20 and 40 ⁇ g/kg cangrelor.
- the pharmaceutical composition comprising cangrelor when administered as an intravenous bolus, the bolus comprises about 30 ⁇ g/kg cangrelor.
- the infusion comprises between about 1 and 10 ⁇ g/kg/min cangrelor.
- the infusion comprises about 4 ⁇ g/kg/min cangrelor.
- FIG. 1 ECC- and hypothermia-induced platelet granule release, platelet- granulocyte binding and platelet loss inhibited by ADP-receptor blockade ex vivo.
- FIG. 2 Platelet interaction with the ECC surface during hypothermic ECC is not inhibited by ADP-receptor blockade ex vivo.
- A specialized ELISA
- Binding of an anti-CD42ba-PE mAb was measured using flow cytometry. Data are given as means and SEM; mean baseline values were transformed to 100% and data measured post-ECC are given as percentages of adjusted baseline values of each temperature group; groups were compared using RM- ANOVA with Bonferroni's multiple comparison test (*p ⁇ 0.05).
- FIG. 3 Timeline of hypothermic cardiopulmonary bypass (CPB) in pigs.
- Tl-6 indicate blood sampling time points: Tl: skin incision before median sternotomy; T2: 10 minutes after initiation of cangrelor or placebo infusion and heparin application directly before start of cardiopulmonary bypass (CPB); T3: 45 minutes after start of CPB; T4: directly before end of CPB; T5: 10 minutes after end of CPB; T6: 60 minutes after end of CPB.
- FIG. 4 Haematocrit and haemoglobin values as well as platelet counts. Prior to, during and following hypothermic CPB in vehicle ("placebo") and cangrelor-treated (0.075 ⁇ g kg "1 min "1 ) pigs changes in haematocrit (A) and haemoglobin concentration (B) were measured. Data are given as means and SEM; in both groups, baseline values (Tl) were compared to T2-T6 of the respective group using RM-ANOVA with Bonferroni's multiple comparison test
- Platelet counts were measured at all time points (Tl-6). Data are given as means and SEM. For platelet counts a haematocrit correction was performed for values measured after start of CPB (T2-6) to adjust for haemodilution caused by the priming volume of the heart lung machine. Mean baseline values were adjusted to 100% and data measured during and after CPB are given in relation to the adjusted baseline value in each treatment groups; groups were compared using RM-ANOVA with Bonferroni's multiple comparison test.
- Tl skin incision before median sternotomy
- T2 10 minutes after initiation of cangrelor or placebo infusion and heparin application directly before start of CPB
- T3 45 minutes after start of CPB
- T4 directly before end of CPB
- T5 10 minutes after end of CPB
- T6 60 minutes after end of CPB.
- FIG. 5 ADP-receptor blockade with cangrelor prevents an increase of platelet aggregation.
- Whole blood samples were taken at different time points prior to, during and after hypothermic CPB (Tl-6) from vehicle ("placebo") and cangrelor infused (0.075 ⁇ g kg "1 min "1 ) pigs.
- Platelet-rich plasma was prepared from all blood samples and ADP-induced (20 ⁇ ) platelet aggregation was analyzed. Data are given as means and SEM.
- Tl skin incision before median sternotomy
- T2 10 minutes after initiation of cangrelor or placebo infusion and heparin application directly before start of CPB
- T3 45 minutes after start of CPB
- T4 directly before end of CPB
- T5 10 minutes after end of CPB
- T6 60 minutes after end of CPB.
- Tl skin incision before median sternotomy
- T2 10 minutes after initiation of cangrelor or placebo infusion and heparin application directly before start of CPB
- T3 45 minutes after start of CPB
- T4 directly before end of CPB
- T5 10 minutes after end of CPB
- T6 60 minutes after end of CPB.
- the present invention is directed to methods of protecting platelet function during medical procedures that include ECC or hypothermia, or both, and that address these problems.
- the present invention is directed to methods that utilize the non- thienopyridine adenosine triphosphate analogue cangrelor, which reversibly binds to and inhibits the P 2 Y 12 ADP receptor.
- Cangrelor is direct- acting, reversible, and selective, and it has a short half-life. It is metabolized through dephosphorylation pathways and has a plasma half-life of 3-5 minutes; platelet function returns to normal within 30-60 minutes of drug termination. 23 When given as a bolus plus infusion, it quickly and consistently inhibits platelets to a high degree with normalization of platelet function shortly after discontinuation. A phase 2 trial in patients undergoing PCI demonstrated dose-dependent platelet inhibition similar to that achieved with abciximab, less bleeding time prolongation, and more rapid return to platelet function. 24
- the rapid on- and off- set of this agent allows targeted and short- term platelet protection in the setting of ECC and/or hypothermia.
- the data show that no influence of cangrelor on haemoglobin values as an indicator for blood loss.
- the invention is therefore directed to methods of protecting platelets during medical procedures that include ECC or hypothermia, or both.
- the methods comprise administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing a medical procedure that includes ECC or hypothermia, or both.
- the invention is directed to methods of protecting platelets in the blood of a subject undergoing an ECC -based medical procedure, a hypothermia-based medical procedure or a hypothermic ECC-based medical procedure, where the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby protecting platelets in the blood of the subject.
- the protection of platelets through the methods of the present invention includes, but is not limited to, inhibiting activation of platelets, inhibiting platelet granule release, inhibiting platelet-leukocyte aggregation (including platelet-granulocyte aggregation), inhibiting platelet aggregation and inhibiting platelet loss from the blood of the subject.
- the invention is directed to a method of inhibiting activation of platelets in the blood of a subject undergoing an ECC-based medical procedure, a hypothermia- based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting activation of platelets in the blood of the subject.
- the present invention is directed to a method of inhibiting platelet granule release in the blood of a subject undergoing an ECC-based medical procedure, a hypothermia-based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting platelet granule release in the blood of the subject.
- the present invention is directed to a method of inhibiting platelet-leukocyte aggregation in the blood of a subject undergoing an ECC-based medical procedure, a hypothermia-based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting platelet-leukocyte aggregation in the blood of the subject.
- the platelet-leukocyte aggregation is platelet-granulocyte aggregation.
- the present invention is directed to a method of inhibiting platelet loss from the blood of a subject undergoing an ECC-based medical procedure, a hypothermia-based medical procedure, or a hypothermic ECC-based medical procedure, wherein the method comprises administering an effective amount of a pharmaceutical composition comprising cangrelor to a subject undergoing such a procedure, thereby inhibiting platelet loss from the blood of the subject.
- compositions comprising them are well known in the art and set forth, for example, in U.S. Patent No. 5,721,219. Additional disclosure relevant to the production and use of cangrelor may be found in U.S. Patent Nos. 5,955,447, 6,130,208 and 6,114,313, as well as in U.S. Appln. Publication No. 2006/0270607.
- the medical procedure may be any which involve extracorporeal circulation (ECC), hypothermia or hypothermic ECC.
- ECC extracorporeal circulation
- Medical procedures involving ECC include, but are not limited to, surgery, such as cardiopulmonary bypass surgery, and hemodialysis, such as kidney dialysis.
- the medical procedures also include hemofiltration, apheresis (including plasmapheresis, erythrocytapheresis, plateletpheresis and leukapheresis), extracorporeal membrane oxygenation (ECMO), and ventricular assist devices.
- apheresis including plasmapheresis, erythrocytapheresis, plateletpheresis and leukapheresis
- ECMO extracorporeal membrane oxygenation
- an anticoagulant is administered to the subject.
- Each of the methods disclosed herein may therefore include the additional step of administering an anticoagulant in addition to the pharmaceutical composition comprising cangrelor.
- Suitable anticoagulants include heparin and bivalirudin.
- the manner and timing of anticoagulant administration will vary and depend on the medical procedure being performed on the subject. Thus, anticoagulant administration may be prior to, concurrent with, or after administration of cangrelor.
- the anticoagulant bivalirudin is a potent, reversible inhibitor of the serine protease thrombin. Thrombin is critical in the thrombotic process, cleaving fibrinogen into fibrin monomers and converting Factor XIII to Factor Xllla, thereby allowing fibrin to develop into a covalently cross-linked framework which leads to clot formation.
- the chemical structure of bivalirudin is shown in Formula II.
- bivalirudin encompasses the compound of Formula II as well as pharmaceutically acceptable salts thereof. Salts of bivalirudin, processes for the production of bivalirudin, and pharmaceutical
- compositions comprising bivalirudin are well known in the art and set forth, for example, in U.S. Patent No. 5,196,404.
- a hypothermic temperature means a temperature lower than the average core body temperature of the subject.
- a hypothermic temperature includes, but is not limited to, a temperature of less than about 37°C, 36°C, 35°C, 34°C, 33°C 5 32°C 5 31°C 5 30°C 5 29°C, 28°C, 27°C, 26°C, 25°C, 24°C, 23°C, 22°C, 21°C, 20°C, 19°C, 18°C, 17°C, 16°C, or 15°C.
- the hypothermic temperature may also be defined as a temperature of about 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, or 37°C.
- ECC can be conducted under conditions of normothermia, that is, where cooling is not applied to the subject or to the blood of the subject.
- ECC can be conducted under conditions of hyperthermia where the subject or to the blood of the subject is warmed to either maintain the core temperature of the subject or to elevate the core temperature of the subject.
- cangrelor is formulated and administered to a subject in the form of a pharmaceutical composition comprising the active agent and, optionally, a pharmaceutically acceptable carrier, diluent and/or excipient.
- a pharmaceutical composition comprising cangrelor, and optionally a pharmaceutically acceptable carrier, diluent and/or excipient.
- an anticoagulant such as heparin or bivalirudin, may be formulated and administered to a subject in the form of a pharmaceutical composition comprising the active agent and, optionally, a pharmaceutically acceptable carrier, diluent and/or excipient.
- the present invention also encompasses a pharmaceutical composition
- a pharmaceutical composition comprising an anticoagulant, such as heparin or bivalirudin, and optionally a pharmaceutically acceptable carrier, diluent and/or excipient.
- the invention also encompasses pharmaceutical compositions comprising both cangrelor and an anticoagulant, such as heparin or bivalirudin, in the same composition.
- the term “medicament” is synonymous with "pharmaceutical composition.”
- Suitable carriers and diluents are well known to those skilled in the art and include saline, such as 0.9% NaCl, buffered saline, dextrose (e.g., 5% dextrose in water), water, Water- for-Injection (WFI), glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80TM), 0.002% polysorbate 80 (Tween-80TM), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g.
- Cremophor EL poloxamer 407 and 188, a cyclodextrin or a cyclodextrin derivative (including HPCD ((2-hydroxypropyl)-cyclodextrin) and (2-hydroxyethyl)- cyclodextrin, hydrophilic and hydrophobic carriers, and combinations thereof.
- Hydrophobic carriers include, for example, fat emulsions, lipids, PEGylated phospholipids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes. The terms specifically exclude cell culture medium.
- Excipients included in the pharmaceutical compositions have different purposes depending, for example on the nature of the drugs, and the mode of administration.
- excipients include, without limitation: stabilizing agents, solubilizing agents and surfactants, buffers, antioxidants and preservatives, tonicity agents, bulking agents, lubricating agents, emulsifiers, suspending or viscosity agents, inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, antibacterials, chelating agents, sweeteners, perfuming agents, flavouring agents, coloring agents, administration aids, and combinations thereof.
- compositions may contain common carriers and excipients, such as cornstarch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, alginic acid, croscarmellose sodium, and sodium starch glycolate.
- common carriers and excipients such as cornstarch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, alginic acid, croscarmellose sodium, and sodium starch glycolate.
- compositions of the present invention may be formulated, for example, for oral, sublingual, intranasal, intraocular, rectal, transdermal, mucosal, topical or parenteral administration.
- Parenteral modes of administration include without limitation, intradermal, subcutaneous (s.c, s.q., sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.), intra-arterial, intramedulary, intracardiac, intra- articular (joint), intrasynovial (joint fluid area), intracranial, intraspinal, and intrathecal (spinal fluids). Any known device useful for parenteral injection or infusion of drug formulations can be used to effect such administration.
- administration of the pharmaceutical compositions is via parenteral administration, preferably intravenous administration, or oral administration.
- a sterile formulation of the pharmaceutical compositions of the present invention and optionally one or more additives, including solubilizers or surfactants, can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion.
- Intravenous fluids include, without limitation, physiological saline, 0.9% NaCl, phosphate buffered saline, 5% dextrose in water, 0.002% polysorbate 80 (Tween-80TM) in water or Ringer'sTM solution.
- a sterile formulation of the pharmaceutical compositions of the present invention can be dissolved and administered in a pharmaceutical diluent such as Water-for-Injection (WFI), physiological saline, 0.9% NaCl or 5% dextrose in water.
- WFI Water-for-Injection
- physiological saline 0.9% NaCl or 5% dextrose in water.
- compositions comprising cangrelor include pharmaceutical compositions comprising from about 0.1 to about 50 mg/ml of cangrelor.
- Particular examples of pharmaceutical compositions comprising cangrelor include the following: (i) cangrelor at a concentration of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/mL in 0.9% NaCl, and (ii) cangrelor at a concentration of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/mL in 5% dextrose.
- the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier or diluent.
- compositions comprising bivalirudin include pharmaceutical compositions comprising from about 0.1 to about 50 mg/ml of bivalirudin.
- Particular examples of pharmaceutical compositions comprising bivalirudin include the following: (i) bivalirudin at a concentration of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/mL in 0.9% NaCl, and (ii) bivalirudin at a concentration of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/mL in 5% dextrose.
- the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier or diluent.
- the pH of the pharmaceutical compositions of the present invention ranges from about 5 to about 8. In specific examples, the pH is about 5, 5.5, 6, 6.5, 7, 7.5, or 8.
- dose refers to physically discrete units that contain a predetermined quantity of cangrelor and/or an anticoagulant calculated to produce a desired protective or therapeutic effect. These terms are synonymous with
- compositions comprising cangrelor and/or anticoagulant of the present invention will vary depending upon the stated goals of the methods, the physical characteristics of the subject, existence of related or unrelated medical conditions, the composition of the formulation, the means used to administer the drug to the subject and the location of administration, whether directly to the subject or to equipment used during the medical procedure.
- the specific dose for a given subject will generally be set by the judgment of the attending physician.
- a pharmaceutical composition comprising cangrelor may be administered as a bolus, as a continuous infusion, or as a bolus followed by a continuous infusion.
- a bolus may be administered shortly before the start of the medical procedure, followed by continuous infusion during the procedure.
- a dose of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 ⁇ g/kg cangrelor, or more is administered to the subject.
- between about 20 and 40 ⁇ g/kg cangrelor is administered, more preferably about 30 ⁇ g/kg.
- cangrelor When administered as a continuous infusion, cangrelor may be administered at about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 ⁇ g/kg/min, or more, to the subject. In preferred embodiments, between about 1 and 10 ⁇ g/kg/min cangrelor is administered, more preferably about 4 ⁇ g/kg/min.
- cangrelor is administered at about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 ⁇ g/kg/min, or more, to the subject. In preferred embodiments, between about 1 and 10 ⁇ g/kg/min cangrelor is administered, more preferably about 4 ⁇ g/kg/min.
- different dosages may be
- a pharmaceutical composition comprising bivalirudin when administered as an intravenous (IV) formulation, may be administered as a bolus, as a continuous infusion, or as a bolus followed by a continuous infusion.
- IV intravenous
- a dose of about 0.05, 0.1, 0.25, 0.5, 0.75, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg/kg bivalirudin, or more is administered to the subject. In preferred embodiments, between about 0.1 and 10 mg/kg bivalirudin is administered, more preferably about 0.75 mg/kg.
- bivalirudin When administered as a continuous infusion, bivalirudin may be administered at about 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 mg/kg/h, or more, to the subject. In preferred embodiments, between about 0.5 and 10 mg/kg/h bivalirudin is administered, more preferably about 1.75 mg/kg/h. The skilled artisan will understand that different dosages may be administered during different points of the medical procedure being performed on the subject.
- IV formulations comprising both cangrelor and an anticoagulant, such as bivalirudin, may be prepared using the same guidelines above for IV formulations comprising either cangrelor or an anticoagulant alone.
- the infusion may continue for the duration of the medical procedure, or may continue for at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 320, 340 or 360 minutes, or more.
- the period of time over which the pharmaceutical composition is administered may be shorter or longer than the indicated times due to the particular characteristics of a subject or medical procedure.
- the bolus may be administered within about 360, 300, 240, 180, 120, 90, 60, 50, 40, 30, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 minute prior to the beginning of the medical procedure, such as before the beginning of ECC and/or hypothermia when the medical procedure includes either or both.
- the bolus may also be administered after the start of the medical procedure, or after the start of ECC or hypothermia.
- the course of treatment associated with the methods of the present invention will depend on the particular medical procedure being practiced. However, the course of treatment will generally begin prior to the start of the medical procedure and continue for the duration of the procedure. When the medical procedure is stopped, administration of the pharmaceutical composition comprising cangrelor will also generally cease.
- administration of the pharmaceutical composition comprising cangrelor and/or an anticoagulant to the subject may continue for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or more hours, for about 1, 2, 3, 4, 5, 6, 7 or more days, for about 1, 2, 3, 4 or more weeks, or for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months.
- a "subject" upon which the methods of the present invention may be practiced refers to an animal, such as a mammalian or an avian species, including a human, a non-human primate, a horse, a cow, a sheep, a goat, a dog, and a cat, or other animal of agricultural importance.
- HLM heart-lung machine
- Cardiopulmonary bypass was established using a heart-lung machine ("S3 System Slimline”; Stockert, Kunststoff, Germany) containing the following elements: 3/8 inch tubing ("Bioline coating", Jostra), bag reservoir (Medistad, Medemblik, Netherlands), and oxygenator (Quadrox, "Bioline coating", Jostra). Blood flow within the CPB circuit was maintained by a roller pump (Stockert). A suction device served to return any blood, which occurred during the procedure inside the pericardial cavity to the animal's circulation. The oxygenator was connected to a heat exchanger to establish desired blood temperatures in the range of 37-28 °C. The priming volume (1 liter) consisted to one third of isotonic saline
- CPB was performed with an average flow of 3 to 3.5 1 min "1 to establish a mean arterial blood pressure of 60 mmHg.
- Aortic clamping was not performed and the heart was left beating throughout the whole procedure.
- the animal was cooled down to 28°C using the CPB circuit.
- weaning from CPB was performed under administration of noradrenaline infusion (maximum value of 0.1 ⁇ g kg "1 min "1 ) to establish a minimal mean arterial blood pressure of 60 mmHg.
- protamine was administered in a dosage of 400 IE kg "1 .
- Cangrelor (The Medicines Company) was dissolved in aqua ad injectionem to achieve a final concentration of 0.05 mg ml "1 .
- Blood was sampled at skin incision before sternotomy (Tl), 10 minutes after initiation of cangrelor or placebo infusion and heparin application directly before start of CPB (T2), 45 minutes after start of CPB (T3), directly before end of CPB (T4), 10 minutes after the end of CPB (T5), and 60 minutes after end of CPB (T6).
- Human platelets were analyzed directly after blood sampling ("baseline”) and after 30 minutes of ex vivo ECC in baseline and circulated samples. Expression of P-selectin, CD42ba as well as activated GPIIb/IIIa on human platelets was analyzed according to previously described methods. 13 ' 15 For detection of platelet-granulocyte binding, 45 ⁇ of whole blood was incubated for 20 minutes with 10 ⁇ of an anti-CD41-FITC mAb (Beckman Coulter, Marseille, France) and 10 ⁇ of an anti-CD15-PE mAb (Beckman Coulter).
- samples were treated with FACS Lysing Solution (BD Biosciences, Heidelberg, Germany), centrifuged at 200 g for 5 minutes and washed with PBS (Invitrogen GmbH, Düsseldorf, Germany). Samples were fixed with CellFix® (BD Biosciences).
- Binding of the platelet- specific protein CD41 is a measure for the deposition of platelets to the ECC surface.
- CD41-ECC binding was detected as previously described using a specially designed ELISA method. 14 Briefly, ECC tubings were collected, washed and blocked after 30 min of circulation in the ECC-model. Surface-bound CD41 was detected using a primary anti-CD41 antibody (Sigma, Deisenhofen, Germany) and an alkaline phosphatase conjugated secondary antibody (Immunotech/Coulter, Marseille, France). The chromogenic reaction was stopped by addition of NaOH and light absorbance determined with an ELISA reader MR 5000 (Dynatech, Denkendorf, Germany) at 405 nm.
- ADP plasma levels were determined according to a previously described standard method (ATP bioluminescence assay kit CLS II; Roche, Mannheim, Germany). 13 ' 18
- ⁇ -TG ⁇ -thromboglobulin
- TAT thrombin-antithrombin
- Ex vivo platelet aggregation was measured as previously described 17 in porcine platelet-rich plasma at the indicated sampling time points.
- platelet-rich plasma was prepared and aggregation was induced by ADP (fc: 20 ⁇ ) and measured using a 4-channel aggregometer (PAP-4, Biodata Corp, Horsham, PA, USA).
- Tl Mean baseline (Tl) values of both treatment groups were adjusted to 100%, if indicated. In each group data measured at times points T2 to T6 are given in relation to these adjusted baseline values.
- Bonferroni's multiple comparison test was performed. A p-value of ⁇ 0.05 was defined as statistically significant.
- P 2 Y 12 receptor blockade inhibits platelet granule release, platelet-granulocyte binding, and platelet loss during ex vivo hypothermic ECC
- hypothermic ECC increased levels of the platelet activation markers P-selectin 5.9- fold and ⁇ -TG 43.9-fold (p ⁇ 0.0001; Figure 1A and B).
- Normothermic ECC caused a 16.2-fold increase of ⁇ -TG plasma levels (p ⁇ 0.01), whereas no significant increase in P-selectin expression was observed.
- treatment with the P 2 Y 12 antagonists cangrelor or 2- MeSAMP significantly decreased levels of the platelet activation markers P-selectin and ⁇ -TG, respectively (p ⁇ 0.0001; Figure 1A and B).
- P 2 Y 12 blockade decreased ⁇ -TG release during normothermic ECC, however without reaching statistical significance.
- ADP is continuously metabolized in plasma and whole blood. 13 ' 22 This phenomenon contributes to explain the observed tendency for lower ADP levels in P 2 Y 12 blocker- treated samples compared to baseline values.
- Platelet-granulocyte aggregate formation was significantly increased during hypothermic ECC (p ⁇ 0.01, Figure ID). Treatment with the P 2 Y 12 antagonists cangrelor significantly reduced this effect (p ⁇ 0.05).
- ECC resulted in a significant loss of circulating platelets (Figure IE; p ⁇ 0.0001) in vehicle (PBS) treated blood (control), which was further increased by hypothermia (p ⁇ 0.001). This effect was significantly reduced by both cangrelor (p ⁇ 0.001) and 2-MeSAMP (p ⁇ 0.0001).
- PBS circulating platelets
- cangrelor p ⁇ 0.001
- 2-MeSAMP p ⁇ 0.0001
- P 2 Y 12 blockade inhibits platelet-granulocyte binding and thereby loss of single platelets in cell aggregates, but does not prevent adhesion of platelets to the ECC surface.
- TAT complex formation was measured before and after ECC in all groups.
- hypothermic CPB was determined in preliminary experiments employing cangrelor in concentrations ranging from 0.025 to 2 ⁇ g kg "1 min "1 (data not shown). A concentration of 0.075 ⁇ g kg "1 per minute was found to sufficiently inhibit platelet function and allowing rapid reversibility of P 2 Y 12 blockade at the same time.
- a major concern in the setting of pharmacological platelet inhibition during CPB is the potential induction of platelet dysfunction and bleeding. Therefore, the duration of platelet inhibition during CPB was evaluated using the short-acting platelet P2Y12 inhibitor cangrelor.
- ADP-induced platelet aggregation was investigated at different time points prior to, during and after CPB ( Figure 5).
- Cangrelor infusion significantly inhibited ADP-induced platelet aggregation directly after start of infusion prior CPB (T2, p ⁇ 0.01), after 45 minutes of CPB (T3, p ⁇ 0.001), and before the end of CPB (T4, p ⁇ 0.05).
- T2, p ⁇ 0.01 start of infusion prior CPB
- T3, p ⁇ 0.001 after 45 minutes of CPB
- T4 p ⁇ 0.05 time after the end of CPB
- 10 minutes after cangrelor infusion was terminated, platelet function fully returned to values observed in placebo-treated controls.
- Platelet activation is associated with a conformational switch of the GPIIb/IIIa receptor allowing fibrinogen binding, which can be detected in flow cytometry. 17
- binding of fibrinogen to platelets was determined (Figure 6). In placebo-treated animals, an increase in platelet fibrinogen binding was observed during hypothermic CPB reaching statistical significance (p ⁇ 0.05) 60 minutes after
- hypothermia on blood loss and transfusion requirement Anesthesiology 2008; 108: 71-7.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR112014016764A BR112014016764A8 (en) | 2012-01-04 | 2012-12-26 | platelet activation blocking methods during cardiopulmonary bypass using cangrelor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261582994P | 2012-01-04 | 2012-01-04 | |
US61/582,994 | 2012-01-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013103567A2 true WO2013103567A2 (en) | 2013-07-11 |
Family
ID=48745531
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/071666 WO2013103567A2 (en) | 2012-01-04 | 2012-12-26 | Methods of blocking platelet activation during extracorporeal circulation using cangrelor |
Country Status (2)
Country | Link |
---|---|
BR (1) | BR112014016764A8 (en) |
WO (1) | WO2013103567A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016114818A1 (en) * | 2015-01-14 | 2016-07-21 | The Medicines Company | Pharmaceutical formulations comprising high purity cangrelor and methods for preparing and using the same |
-
2012
- 2012-12-26 WO PCT/US2012/071666 patent/WO2013103567A2/en active Application Filing
- 2012-12-26 BR BR112014016764A patent/BR112014016764A8/en not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016114818A1 (en) * | 2015-01-14 | 2016-07-21 | The Medicines Company | Pharmaceutical formulations comprising high purity cangrelor and methods for preparing and using the same |
US9700575B2 (en) | 2015-01-14 | 2017-07-11 | Chiesi Farmaceutici, S.P.A. | Pharmaceutical formulations comprising high purity cangrelor and methods for preparing and using the same |
US10039780B2 (en) | 2015-01-14 | 2018-08-07 | Chiesi Farmaceutici S.P.A. | Pharmaceutical formulations comprising high purity cangrelor and methods for preparing and using the same |
Also Published As
Publication number | Publication date |
---|---|
BR112014016764A8 (en) | 2017-07-04 |
BR112014016764A2 (en) | 2017-06-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2844931C (en) | Maintenance of platelet inhibition during antiplatelet therapy | |
Menasché et al. | Deferoxamine reduces neutrophil-mediated free radical production during cardiopulmonary bypass in man | |
Krajewski et al. | Short-acting P2Y12 blockade to reduce platelet dysfunction and coagulopathy during experimental extracorporeal circulation and hypothermia | |
Xu et al. | Activated platelets contribute importantly to myocardial reperfusion injury | |
Hu et al. | The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model | |
JP5653916B2 (en) | Von Willebrand factor or Factor VIII and von Willebrand factor for treating coagulopathy induced by inhibitors of platelets | |
Bonow et al. | Lack of effect of aspirin on myocardial infarct size in the dog | |
US9320754B2 (en) | Maintenance of platelet inhibition during antiplatelet therapy | |
WO2014163656A1 (en) | Maintenance of platelet inhibition during antiplatelet therapy | |
ES2253763T3 (en) | METHOD FOR THE STABILIZATION OF PLATES. | |
Chung et al. | Combined administration of nitric oxide gas and iloprost during cardiopulmonary bypass reduces platelet dysfunction: a pilot clinical study | |
KR20100037029A (en) | Unit dose formulations and methods of treating and preventing thrombosis with thromboxane receptor antagonists | |
BR112015002321A2 (en) | use of recombinant antithrombin | |
EP0181267B1 (en) | Fibrinolysis-enhancing agents | |
Montrucchio et al. | Role of platelet-activating factor in the reperfusion injury of rabbit ischemic heart. | |
WO2013103567A2 (en) | Methods of blocking platelet activation during extracorporeal circulation using cangrelor | |
Driessen et al. | Comparison of the standard roller pump and a pulsatile centrifugal pump for extracorporeal circulation during routine coronary artery bypass grafting | |
Sollevi et al. | Adenosine spares platelets during cardiopulmonary bypass in man without causing systemic vasodilatation | |
Stahl et al. | Role of granulocytes and C5a in myocardial response to zymosan-activated serum | |
GIERCKSKY et al. | Protection of rats by phospholipase C from Bacillus cereus against the effects of intravenous infusions of purified tissue thromboplastin | |
R Tuinman et al. | Coagulopathy as a therapeutic target for TRALI: rationale and possible sites of action | |
WO2020243612A1 (en) | Method of preventing and treating thrombosis | |
Brown et al. | The use of human antithrombin III concentrate for treatment of heparin resistance during cardiopulmonary bypass | |
Slichter et al. | Inhibition of the enzyme purine nucleoside phosphorylase (PNP) reduces refractoriness to transfused platelets in a dog model | |
SK51298A3 (en) | Pharmaceutical compositions containing platelet aggregation inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12864345 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase in: |
Ref document number: 2014551275 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112014016764 Country of ref document: BR |
|
NENP | Non-entry into the national phase in: |
Ref country code: JP |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 12864345 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase in: |
Ref document number: 112014016764 Country of ref document: BR Kind code of ref document: A2 Effective date: 20140707 |