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WO2011006169A1 - Méthodes de diagnostic et de traitement de troubles thrombotiques médiés par cyp2c19*2 - Google Patents

Méthodes de diagnostic et de traitement de troubles thrombotiques médiés par cyp2c19*2 Download PDF

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Publication number
WO2011006169A1
WO2011006169A1 PCT/US2010/041749 US2010041749W WO2011006169A1 WO 2011006169 A1 WO2011006169 A1 WO 2011006169A1 US 2010041749 W US2010041749 W US 2010041749W WO 2011006169 A1 WO2011006169 A1 WO 2011006169A1
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WIPO (PCT)
Prior art keywords
receptor inhibitor
reversible
elinogrel
direct
acting
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PCT/US2010/041749
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English (en)
Inventor
Paul A. Gurbel
Pamela B. Conley
Patrick Andre
Daniel D. Gretler
Marzena Jurek
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Portola Pharmaceuticals, Inc.
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Publication of WO2011006169A1 publication Critical patent/WO2011006169A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • This invention relates generally to analytical testing, and more particularly to the analysis of gene expression or hematology profiles as biomarkers for predicting the effectiveness of P2Yi 2 inhibitors in treating coronary artery disease or other ischemic events.
  • the present invention relates to methods of treatment of coronary artery disease or ischemic events as well as kits for use in identifying patients with coronary artery disease at risk for high platelet reactivity or increased bleeding.
  • Coronary artery disease is the principal cause of death in the United States, Europe and most of Asia.
  • P2Y ]2 receptor inhibition together with aspirin therapy, is a major treatment strategy in patients with high risk coronary artery disease.
  • P2Yi 2 inhibitors are the thienopyridines, clopidogrel and ticlopidine (Schomig et al. N Engl J Med. Apr 25 1996;334(17): 1084-1089; Bertrand et al. Circulation. Oct 20
  • Clopidogrel is routinely administered as a daily 75 mg dose along with 81 -325 mg aspirin in patients treated with coronary artery stents and after acute coronary syndromes.
  • Clopidogrel is also administered in stable patients with prior myocardial infarction or established peripheral arterial disease. However, the recurrence of ischemic events in these patients is still high (Tantry et al. Future Cardiology. 2006;2:343-346). Pharmacodynamic studies have demonstrated wide response variability to clopidogrel therapy and a substantial percentage of patients exhibit non-responsiveness or high on-treatment platelet reactivity (HPR) to ADP as measured by ex-vivo methods. (Gurbel et al. Circulation 2003; 107:2908- 13; Gurbel et al Rev. Cardiovasc. Med. 2006;7 Suppl 4:S20-8). Translational research has demonstrated that clopidogrel nonresponsiveness or HPR is associated with increased risk for recurrent ischemic events including stent thrombosis (Gurbel et al. J Am Coll Cardiol.
  • Prasugrel a newer thienopyridine that exhibited better platelet inhibition than clopidogrel in phase II studies, was also associated with lower ischemic event occurrence in a Phase III acute coronary syndrome trial.
  • prasugrel therapy is still associated with a recurrent ischemic event rate and an increased bleeding risk.
  • patient response to prasugrel is also related to cytochrome P450 genetic polymorphisms (Mega et al. Circulation May 4, 2009).
  • Elinogrel (Portola Pharmaceuticals Inc, South San Francisco, CA) is a new reversible, direct acting P2Yj 2 receptor inhibitor, that is being developed for several indications, including treatment of thrombosis, see, U.S. Pat. Application No. 11/556,490.
  • the present invention solves these problems by providing methods for determining subjects who are at risk for HPR or developing HPR or excessive bleeding associated with thienopyridine treatment in patients with cytochrome P450 (CYP) gene polymorphisms.
  • CYP cytochrome P450
  • the invention provides methods for determining subjects who are at risk for developing HPR or increased bleeding or who would be non-responsive to thienopyridine therapy based upon analysis of biomarkers present in the subject to be treated.
  • the invention provides for the use of thienopyridine therapy to identify patients at risk for experiencing HPR during thienopyridine therapy for a cardiovascular disorder.
  • the diagnosis involves the determination of gene expression profiles from the subject to be treated.
  • the invention provides methods for determining optimal treatment strategies for these patients. The prediction could therefore provide means of safer treatment regimens for the patient by helping the clinician to either (1) alter the dose of the drug, (2) provide additional or alternative concomitant medication or (3) choosing not to prescribe that drug for that patient.
  • the invention provides methods for diagnosing an increased risk for high platelet reactivity or increased bleeding in a subject suffering from a cardiovascular disorder, comprising (a) obtaining the genotype of a subject to be treated for CYP2C19*2, (b) determining whether the subject is at risk for high platelet reactivity or increased bleeding following administration of a irreversible, non-direct acting P2Yn receptor inhibitor.
  • the invention provides methods for diagnosing an increased risk for high platelet reactivity or increased bleeding in a subject suffering from a condition or disorder mediated at least in part by ADP-induced platelet aggregation, comprising (a) obtaining the genotype of a subject to be treated for CYP2C19*2, (b) determining whether the subject is at risk for high platelet reactivity or increased bleeding following administration of a irreversible, non-direct acting P2Y] 2 receptor inhibitor.
  • the invention provides methods of identifying a subject that is susceptible to developing an cardiovascular complication during a course of treatment comprising administering a irreversible, non-direct acting P2Yi 2 receptor inhibitor (a) providing a biological sample from a subject; (b) determining platelet reactivity in the biological sample; and (c) comparing platelet reactivity in the biological sample to a standard reactivity, wherein 43% or more platelet aggregation compared to the standard indicates that the subject is susceptible to developing a ischemic event during a course of treatment with a irreversible, non-direct acting P2Yi 2 receptor inhibitor.
  • the invention provides methods for preventing or treating thrombosis and thrombosis related conditions in a subject with a P2Y] 2 receptor inhibitor, comprising (a) obtaining the genotype of a subject to be treated for CYP2C19*2, (b) administering a therapeutically effective amount of reversible, direct acting P2Yi 2 receptor inhibitor to the subject having a CYP2C19*2 polymorphism.
  • the invention provides methods for treating a
  • cardiovascular disease in a patient resistant or non-responsive to a daily dose of irreversible, non-direct acting P2Yi 2 receptor inhibitor comprising: providing a therapeutic amount of a direct-acting, reversible P2Yj 2 receptor inhibitor; and administering the resistance- surmounting quantity of the direct-acting, reversible P2Y i2 receptor inhibitor to the patient.
  • the invention provides for the use of reversible, direct acting P2Yj 2 receptor inhibitor in the manufacture of a medicament for the; treatment of thrombotic conditions in a selected patient population non-responsive to irreversible, non- direct acting P2Yi 2 inhibitor, where in the patient population is selected on the basis of the genotype of the patients at a 2C19*2 genetic locus predictive of antiplatelet activity.
  • the invention also provides clinical assays, kits and reagents for predicting increased risk of HPR or increased bleeding prior to taking a drug.
  • the kits contain reagents for determining the gene expression of certain genes, where the expression profile of the genes is a biomarker for the risk of the subject for experiencing HPR or increased bleeding.
  • the invention provides for a kit for use in diagnosing an increased risk for high platelet reactivity in a subject suffering from a cardiovascular disorder, comprising: (a) a reagent for detecting a genetic polymorphism in CYP2C19*2 that is biomarker of an irreversible, non-direct acting P2Yi 2 receptor inhibitor- mediated high platelet reactivity; (b) a container for the reagent; and (c) a written product on or in the container describing the use of the biomarker in predicting an irreversible, non- direct acting P2Yi 2 receptor inhibitor-mediated high platelet reactivity in subjects
  • FIG. 1 Illustrates the study design.
  • HPR high platelet reactivity.
  • ASA aspirin.
  • FIG. 2 illustrates Individual patients' response to elinogrel as measured by 5 ⁇ M ADP-induced aggregation.
  • the gray line indicates the mean and dotted line represent the 43% cutoff value used for HPR.
  • FIG. 3 illustrates the pharmacodynamic response to a single oral 60 mg elinogrel dose in patients with high-platelet reactivity as measured by light transmittance aggregometry (5 ⁇ M ADP-induced aggregation).
  • FIG. 4 illustrates the pharmacodynamic response to a single oral 60 mg elinogrel dose in patients with high-platelet reactivity as measured by light transmittance aggregometry (20 ⁇ M ADP-induced aggregation).
  • FIG. 5 illustrates the pharmacodynamic response to a single oral 60 mg elinogrel dose in patients with high-platelet reactivity as measured by light transmittance aggregometry (10 ⁇ M ADP-induced aggregation).
  • FIG. 6 illustrates the pharmacodynamic response to a single oral 60mg elinogrel dose in patients with high-platelet reactivity as measured by light transmittance aggregometry (4 ⁇ g/ml collagen-induced aggregation).
  • FIG. 7 illustrates the pharmacodynamic response to a single oral 60mg elinogrel dose in patients with high-platelet reactivity as measured by light transmittance aggregometry (ADP-induced platelet-fibrin clot strength, MA-ADP).
  • FIG. 8 illustrates the pharmacodynamic response to a single oral 60mg elinogrel dose in patients with high-platelet reactivity as measured by light transmittance aggregometry (VerifyNow P2Yi 2 assay).
  • FIG. 9 illustrates the pharmacodynamic response to a single oral 60mg elinogrel dose in patients with high-platelet reactivity as measured by light transmittance aggregometry (vasodilator stimulated phosphoprotein phosphorylation assay, VASP-Platelet Reactivity Index).
  • FIG. 10- Illustrates the pharmacodynamic response to a single oral 60mg elinogrel dose in patients with high-platelet reactivity as measured by real time thrombosis profiler assay.
  • FIG. 13 illustrates the response to single oral 60mg elinogrel dose in a patient with high-platelet reactivity (on 75 or 150 mg clopidogrel) as measured by RTTP assay. This plot represents the change in thrombotic profile achieved at 4, 6 and 24 hrs after dosing with elinogrel.
  • FIG. 14 illustrates the determination of doses of elinogrel, clopidogrel and prasugrel in the mouse providing equivalent inhibition on arterial thrombosis.
  • Doses of elinogrel 7.5, 20 and 60 mg/kg
  • clopidogrel 1.5, 15 and 50 mg/kg
  • prasugrel 7.5, 3 and 10 mg/kg
  • FIG 14 illustrates A) the pharmacokinetic profile of elinogrel following oral dosing in mice.
  • Elinogrel significantly inhibited thrombus stability (vascular occlusion) at concentrations > 1 ⁇ g/ml in vivo.
  • FIG. 16 illustrates doses of elinogrel, clopidogrel and prasugrel providing equivalent antithrombotic activities differentially affect bleeding frequency over the 15 min period. Solid lines indicate bleeding period, gap (white bars) period of cessation of blood loss.
  • FIG. 17 illustrates how clopidogrel and prasugrel increase the volume of blood lost beyond levels attributed to P2Yi 2 inhibition.
  • FIG. 18 illustrates how clopidogrel and prasugrel increase the volume of blood lost in P2Yi2' mice. Effects of maximum doses of elinogrel, clopidogrel and prasugrel on blood loss measurement in P2Yi2' mice. Clopidogrel and prasugrel increased volume of blood loss in P2Yi2' mice.
  • FIG. 19 illustrates differential effects of elinogrel, clopidogrel and prasugrel on bleeding time frequency vs genetic targeting (micropunture model in mesenteric veins).
  • Thienopyridine-treated mice have a delayed occlusion of the vascular wound compared with P2Yi2 ' mice, while elinogrel-treated animals displayed a faster rate of closure than 20 either thienopyridine-treated or P2Yi2 ' mice that paralleled an increased amount of platelet deposition (D).
  • FIG. 20 illustrates differential effects of ADP concentration on anti-aggregatory activity of reversible (elinogrel) vs irreversible (clopidogrel and prasugrel) antagonists of P2Yi2.
  • High shear platelet thrombosis (1500/sec, ⁇ 1 mJVl) Folie BJ, Mclntire LV. Biophys J. 1989. 56: 1121-1141.
  • Low shear venous thrombosis 100/sec, ⁇ 5 mM
  • Hemostasis -10 niM Born et al. J Physiol 1984. 354:419-429.
  • FIGS. 21 A-D illustrate how thienopyri dines block vasoconstriction of mesenteric veins.
  • administering refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject.
  • Adminsitration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • ADP -mediated disease or condition refers to a disease or condition characterized by less than or greater than normal, ADP activity.
  • a ADP -mediated disease or condition is one in which modulation of ADP results in some effect on the underlying condition or disease (e.g., a ADP inhibitor or antagonist results in some improvement in patient well-being in at least some patients).
  • allele shall mean a particular form of a gene or DNA sequence at a specific chromosomal location (locus).
  • an "antagonist” or “inhibitor” refers to an agent or molecule that inhibits or binds to, partially or totally blocks stimulation or activity, decreases, closes, prevents, delays activation or enzymatic activity, inactivates, desensitizes, or down regulates the activity of a receptor of the invention.
  • antagonist also includes a reverse or inverse agonist.
  • blood sample refers to whole blood taken from a subject, or any fractions of blood including plasma or serum.
  • condition refers to a disease state for which the compounds, compositions and methods of the present invention are being used against.
  • clinical response means any or all of the following: a quantitative measure of the response, no response, and adverse response (i.e., side effects).
  • clinical trial means any research study designed to collect clinical data on responses to a particular treatment, and includes but is not limited to phase I, phase II and phase III clinical trials. Standard methods are used to define the patient population and to enroll subjects.
  • expression includes but is not limited to one or more of the following: transcription of the gene into precursor mRNA; splicing and other processing of the precursor mRNA to produce mature mRNA; mRNA stability; translation of the mature mRNA into protein (including codon usage and tRNA availability); and glycosylation and/or other modifications of the translation product, if required for proper expression and function.
  • RNA Ribonucleic acid
  • gene shall mean a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.
  • genotype shall mean an unphased 5' to 3' sequence of nucleotide pair(s) found at one or more polymorphic sites in a locus on a pair of homologous chromosomes in an individual.
  • genotype includes a full-genotype and/or a sub-genotype.
  • HPR high platelet reactivity
  • locus shall mean a location on a chromosome or DNA molecule corresponding to a gene or a physical or phenotypic feature.
  • mammal includes, without limitation, humans, domestic animals (e.g., dogs or cats), farm animals (cows, horses, or pigs), monkeys, rabbits, mice, and laboratory animals.
  • nucleotide pair shall mean the nucleotides found at a polymorphic site on the two copies of a chromosome from an individual.
  • "Patient” refers to human and non-human animals, especially mammals. Examples of patients include, but are not limited to, humans, cows, dogs, cats, goats, sheep, pigs and rabbits.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from
  • pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, NJN'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, trie
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
  • dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M.
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • AU isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • pharmaceutically effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • therapeutically effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.
  • the therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
  • platelet refers to a minute, nonnucleated, disklike cell found in the blood plasma of mammals that functions to promote blood clotting.
  • polymorphism shall mean any sequence variant present at a frequency of >1% in a population.
  • the sequence variant may be present at a frequency significantly greater than 1 % such as 5% or 10% or more.
  • the term may be used to refer to the sequence variation observed in an individual at a polymorphic site.
  • Polymorphisms include nucleotide substitutions, insertions, deletions and microsatellites and may, but need not, result in detectable differences in gene expression or protein function.
  • polymorphic site shall mean a position within a locus at which at least two alternative sequences are found in a population, the most frequent of which has a frequency of no more than 99%.
  • polynucleotide shall mean any RNA or DNA, which may be unmodified or modified RNA or DNA.
  • Polynucleotides include, without limitation, single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions.
  • polynucleotide refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA.
  • the term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons.
  • polypeptide shall mean any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
  • Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
  • Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
  • Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
  • the term "preventing” refers to the prophylactic treatment of a patient in need thereof.
  • the prophylactic treatment can be accomplished by providing an appropriate dose of a therapeutic agent to a subject at risk of suffering from an ailment, thereby substantially averting onset of the ailment.
  • a "SNP nucleic acid” is a nucleic acid sequence, which comprises a nucleotide that is variable within an otherwise identical nucleotide sequence between individuals or groups of individuals, thus, existing as alleles. Such SNP nucleic acids are preferably from about 15 to about 500 nucleotides in length.
  • the SNP nucleic acids may be part of a chromosome, or they may be an exact copy of a part of a chromosome, e.g., by amplification of such a part of a chromosome through PCR or through cloning.
  • the SNP nucleic acids are referred to hereafter simply as "SNPs”.
  • the SNP probes according to the invention are oligonucleotides that are complementary to a SNP nucleic acid.
  • treating refers to providing an appropriate dose of a therapeutic agent to a subject suffering from an ailment.
  • therapeutically effective amount refers to an amount of a therapeutic agent that is sufficient to affect the treatment of a subject suffering from an ailment.
  • recanalization refers to the process of restoring flow to or reuniting an interrupted channel of the body, such as a blood vessel.
  • restenosis refers to a re-narrowing or blockage of an artery at the same site where treatment, such as an angioplasty or a stent procedure, has been performed.
  • the phrase "selectively" or “specifically” when referring to binding to a receptor refers to a binding reaction that is determinative of the presence of the receptor, often in a heterogeneous population of receptors and other biologies.
  • the compounds bind to a particular receptor at least two times the background and more typically more than 10 to 100 times background.
  • Specific binding of a compound under such conditions requires a compound that is selected for its specificity for a particular receptor.
  • small organic molecules can be screened to obtain only those compounds that specifically or selectively bind to a selected receptor and not with other receptors or proteins.
  • a variety of assay formats may be used to select compounds that are selective for a particular receptor. For example, High-throughput screening assays are routinely used to select compounds that are selective for a particular a receptor.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • thrombosis refers to the blockage or clotting of a blood vessel caused by a clumping of cells, resulting in the obstruction of blood flow.
  • thrombosis refers to the clot that is formed within the blood vessel.
  • the terms “treat”, “treating”, “treatment” and grammatical variations thereof as used herein, includes partially or completely delaying, alleviating , mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.
  • the term "vessel” refers to any channel for carrying a fluid, such as an artery or vein.
  • a "blood vessel” refers to any of the vessels through which blood circulates in the body.
  • the lumen of a blood vessel refers to the inner open space or cavity of the blood vessel.
  • the invention advantageously provides a way to determine whether a patient will experience high platelet reactivity during drug treatment, prior to actually taking the drugs.
  • the invention thus provides safer treatment regimens for patients by helping clinicians to (1) provide additional or alternative concomitant medication, (2) alter the dose of the drug or (3) choose not to prescribe that drug for that patient.
  • CYP2C19 encodes cytochrome P450 2Cl 9 that plays a pivotal role in metabolizing thienopyridines (see also U.S. Patent No. 5,912,120).
  • a polymorphism in the CYP 2C19*2 genetic locus is "predictive" of a "high” risk of HPR when genetic polymorphism correlates significantly with the development of drug-induced HPR, see, Example 1. Determinations of significance (p values) can be determined by analysis of variance (ANOVA) or Fisher's Exact tests.
  • results can reasonably be extrapolated to the prediction of HPR in patients following the administration of any thienopyridine, based upon the structural similarity and modes of action of these compounds.
  • these thienopyrimidine compounds are chlopidogrel, prasugrel and ticagrelor.
  • results can be extrapolated to the prediction of HPR in patients who are being treated for diseases other than coronary artery disease.
  • the method of the invention is applicable to vertebrate subjects, particularly to mammalian subjects, more particularly to human subjects.
  • the administration of an agent or drug to a subject or patient includes self-administration and the administration by another.
  • the diagnosis of HPR can be accomplished using assays of platelet activity. Serum assays of platelet activity are well-known to those of skill in the medical arts and routine in hospital laboratories and are illustrated in the EXAMPLES.
  • the maximum tolerated dose (MTD) for a compound is determined using methods and materials known in the medical and pharmacological arts, for example through dose- escalation experiments.
  • One or more patients is first treated with a low dose of the compound, typically 10% of the dose anticipated to be therapeutic based on results of in vitro cell culture experiments.
  • the patients are observed for a period of time to determine the occurrence of toxicity.
  • Toxicity is typically evidenced as the observation of one or more of the following symptoms: vomiting, diarrhoea, peripheral neuropathy, ataxia, neutropaenia, or elevation of liver enzymes. If no toxicity is observed, the dose is increased 2-fold, and the patients are again observed for evidence of toxicity. This cycle is repeated until a dose producing evidence of toxicity is reached.
  • the dose immediately preceding the onset of unacceptable toxicity is taken as the MID.
  • a determination of the MTD for epothilone B is provided above.
  • Individuals carrying polymorphic CYP 2Cl 9 alleles may be detected at the DNA, the RNA, or the protein level using a variety of techniques that are well known in the art. Strategies for identification and detection are described in e.g. EP 730,663, EP 717,113, and PCT US97/02102.
  • the identification of alleles containing single nucleotide polymorphisms may involve the amplification of DNA from target samples. This can be accomplished by e.g., PCR. See generally PCR Technology: Principles and Applications for DNA
  • polymorphisms in specific DNA sequences can be accomplished by a variety of methods including, but not limited to, restriction-fragment-length-polymorphism detection based on allele- specific restriction-endonuclease cleavage (Kan & Dozy, Lancet 11:910-912 (1978)), hybridization with allele-specific oligonucleotide probes (Wallace et al, Nucl. Acids Res.
  • DGGE denaturing-gradient gel electrophoresis
  • DGGE denaturing-gradient gel electrophoresis
  • Single-strand-conformation- polymorphism detection Orita et al., Genomics 5:874-879 (1983)
  • RNAse cleavage at mismatched base-pairs Myers et al., Science 230: 1242 (1985)
  • chemical Cotton et al., Proc. Natl. Acad. Sci. U.S.A., 8Z:4397-4401 (1988)
  • enzymatic Youil et al., Proc.
  • the technique for detecting gene expression includes the use of a gene chip.
  • the construction and use of gene chips are well known in the art. See, U.S. Pat. Nos. 5,202,231; 5,445,934; 5,525,464; 5,695,940; 5,744,305; 5,795,716 and 5,800,992. See also, Johnston, M. Curr Biol 8:R171-174 (1998); Iyer V R et al., Science 283:83-87 (1999) and Elias P, "New human genome "chip” is a revolution in the offing" Los Angeles Daily News (Oct. 3, 2003).
  • polymorphism can be accomplished by means of so called TAQMAN ® SNP genotyping assays (available from Applied Biosystems, Foster City, CA).
  • the individuals included in the clinical population have been graded for the existence of the medical condition of interest.
  • This grading of potential patients could employ a standard physical exam or one or more lab tests.
  • grading of patients could use gene expression pattern for situations where there is a strong correlation between gene expression pattern and disease susceptibility or severity.
  • the therapeutic treatment of interest is administered to each individual in the trial population and each individual's response to the treatment is measured using one or more predetermined criteria. It is contemplated that in many cases, the trial population will exhibit a range of responses and that the investigator will choose the number of responder groups (e.g., low, medium, high) made up by the various responses. [0090] After both the clinical and polymorphism data have been obtained, correlations between individual response and genotype or haplotype content are created. Correlations may be produced in several ways.
  • individuals are grouped by their genotype or haplotype (or haplotype pair) (also referred to as a polymorphism group), and then the averages and standard deviations of clinical responses exhibited by the members of each polymorphism group are calculated.
  • haplotype or haplotype pair
  • Results are analyzed to determine if any observed variation in clinical response between polymorphism groups is statistically significant.
  • Statistical analysis methods which may be used are described in L. D. Fisher & G. vanBelle, Biostatistics: A Methodology for the Health Sciences (Wiley-Interscience, New York, 1993). This analysis may also include a regression calculation of which polymorphic sites in the gene give the most significant contribution to the differences in phenotype.
  • a second method for finding correlations between gene expression pattern and clinical responses uses predictive models based on error-minimizing optimization algorithms.
  • One of many possible optimization algorithms is a genetic algorithm (R. Judson, "Genetic Algorithms and Their Uses in Chemistry” in Reviews in Computational Chemistry, Vol. 10, pp. 1-73, K. B. Lipkowitz and D. B. Boyd, eds. (VCH Publishers, New York, 1997).
  • Correlations may also be analyzed using analysis of variation (ANOVA) techniques to determine how much of the variation in the clinical data is explained by different subsets of the polymorphic sites in the gene.
  • ANOVA is used to test hypotheses about whether a response variable is caused by or correlated with one or more traits or variables that can be measured (Fisher & vanBelle, supra, Ch. 10).
  • ANOVA is used to test hypotheses about whether a response variable is caused by or correlated with one or more traits or variables that can be measured (Fisher & vanBelle, supra, Ch. 10).
  • a mathematical model may be readily constructed by the skilled artisan that predicts clinical response as a function of gene expression pattern.
  • the identification of an association between a clinical response and a genotype or haplotype (or haplotype pair) for the gene may be the basis for designing a diagnostic method to determine those individuals who will or will not respond to the treatment, or alternatively, will respond at a lower level and thus may require more treatment, i.e., a greater dose of a drug.
  • the diagnostic method may take one of several forms: for example, a direct DNA test (i.e., of gene expression pattern), a serological test, or a physical exam measurement. The only requirement is that there be a good correlation between the diagnostic test results and the underlying genotype or haplotype that is in turn correlated with the clinical response. In a preferred embodiment, this diagnostic method uses the predictive haplotyping method described above.
  • a computer may implement any or all analytical and mathematical operations involved in practicing the methods of the present invention.
  • the computer may execute a program that generates views (or screens) displayed on a display device and with which the user can interact to view and analyze large amounts of information relating to the gene and its genomic variation, including chromosome location, gene structure, and gene family, gene expression data, polymorphism data, genetic sequence data, and clinical data population data (e.g., data on ethnogeographic origin, clinical responses, genotypes, and haplotypes for one or more populations).
  • the polymorphism data described herein may be stored as part of a relational database (e.g., an instance of an Oracle database or a set of ASCII flat files).
  • polymorphism data may be stored on the computer's hard drive or may, for example, be stored on a CD-ROM or on one or more other storage devices accessible by the computer.
  • the data may be stored on one or more databases in communication with the computer via a network.
  • the invention provides methods, compositions, and kits for haplotyping and/or genotyping the gene in an individual.
  • the compositions contain oligonucleotide probes and primers designed to specifically hybridize to one or more target regions containing, or that are adjacent to, a polymorphic site.
  • the methods and compositions for establishing the genotype or haplotype of an individual at the novel polymorphic sites described herein are useful for studying the effect of the polymorphisms in the etiology of diseases affected by the expression and function of the protein, studying the efficacy of drugs targeting, predicting individual susceptibility to diseases affected by the expression and function of the protein and predicting individual responsiveness to drugs targeting the gene product.
  • the invention provides a method for identifying an association between a gene expression pattern and a trait.
  • the trait is susceptibility to a disease, severity of a disease, the staging of a disease or response to a drug.
  • Such methods have applicability in developing diagnostic tests and therapeutic treatments for all pharmacogenetic applications where there is the potential for an association between a genotype and a treatment outcome including efficacy measurements, PK measurements and side effect measurements.
  • the invention also provides a computer system for storing and displaying polymorphism data determined for the gene.
  • the computer system comprises a computer processing unit; a display; and a database containing the gene expression pattern data.
  • the gene expression pattern data may include the gene expression pattern in a reference population.
  • the computer system is capable of producing a display showing gene expression pattern organized according to their evolutionary relationships.
  • the patient could then be classified or assigned to a particular genotype group based on how similar the measured levels were compared to the control levels for a given group.
  • the standard deviations of the control group levels would be used to make a probabilistic determination and the methods of this invention would be applicable over a wide range of probability based genotype group determinations.
  • the measured level of the gene expression product falls within 2.5 standard deviations of the mean of any of the control groups, then that individual may be assigned to that genotype group.
  • the measured level of the gene expression product falls within 2.0 standard deviations of the mean of any of the control groups then that individual may be assigned to that genotype group.
  • the measured level of the gene expression product falls within 1.5 standard deviations of the mean of any of the control groups then that individual may be assigned to that genotype group. In yet another embodiment, if the measured level of the gene expression product is 1.0 or less standard deviations of the mean of any of the control groups levels then that individual may be assigned to that genotype group.
  • the therapeutic treatment of interest is administered to each individual in the population and each individual's response to the treatment is measured using one or more predetermined criteria. It is contemplated that in many cases, the population will exhibit a range of responses and that the investigator will choose the number of responder groups, e.g., low, medium and high, made up by the various responses. In addition, the gene for each individual in the population is genotyped and/or haplotyped, which may be done before or after administering the treatment.
  • Methods for preventing or treating thrombosis in a mammal embraced by the invention include administering a therapeutically effective amount of a reversible, direct acting P2Yi 2 receptor inhibitor alone or as part of a pharmaceutical composition of the invention as described above to a mammal, in particular, a human.
  • a reversible, direct acting P2Yi 2 receptor inhibitor and pharmaceutical compositions of the invention containing a reversible, direct acting P2Yi 2 receptor inhibitor of the invention are suitable for use alone or as part of a multi-component treatment regimen for the prevention or treatment of cardiovascular diseases, particularly those related to thrombosis.
  • a compound or pharmaceutical composition of the invention may be used as a drug or therapeutic agent for any thrombosis, particularly a platelet-dependent thrombotic indication, including, but not limited to, coronary heart disease (CHD), acute coronary syndromes (ACS), acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic complications following invasive procedures, e.g., angioplasty, carotid
  • CHD coronary heart disease
  • ACS acute coronary syndromes
  • acute myocardial infarction unstable angina
  • chronic stable angina chronic stable angina
  • transient ischemic attacks strokes
  • peripheral vascular disease preeclampsia/eclampsia
  • the indication is selected from the group consisting of coronary heart disease (CHD), acute coronary syndromes (ACS), percutaneous coronary intervention (PCI) including angioplasty and/or stent , acute myocardial infarction (AMI), unstable angina (USA), coronary artery disease (CAD), transient ischemic attacks (TIA), stroke, peripheral vascular disease (PVD), Surgeries-coronary bypass, carotid endarectomy
  • CHD coronary heart disease
  • ACS acute coronary syndromes
  • PCI percutaneous coronary intervention
  • AMI acute myocardial infarction
  • CAD unstable angina
  • CAD coronary artery disease
  • TIA transient ischemic attacks
  • stroke peripheral vascular disease
  • PVD peripheral vascular disease
  • Reversible, direct acting P2Y] 2 receptor inhibitors and pharmaceutical compositions of the invention may also be used as part of a multi-component treatment regimen in combination with other therapeutic or diagnostic agents in the prevention or treatment of thrombosis in a mammal.
  • compounds or pharmaceutical compositions of the invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin or antiinflammatories (non-steriodal antiinflammatories, cyclooxygenase II inhibitors).
  • Coadministration may also allow for application of reduced doses of both the anti-platelet and the thrombolytic agents and therefore minimize potential hemorrhagic side-effects.
  • Compounds and pharmaceutical compositions of the invention may also act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion.
  • the reversible, direct acting P2Y 12 receptor inhibitors of the present invention are selected from the class of compounds in the
  • dihydroquinazolinylphenyl thiophenyl sulfonylurea family dihydroquinazolinylphenyl thiophenyl sulfonylurea family.
  • suitable dihydroquinazolinylphenyl thiophenyl sulfonylurea compounds for use in the present invention have the formula (I):
  • R 1 is selected from the group consisting of H, halogen, -OH, -Ci_io-alkyl and Ci_ 6 -aikylaniino;
  • X is selected from the group consisting of: F and I.
  • the agent is elinogrel or [4-(6-fluoro-7-methylamino-2,4-dioxo- l,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, in all suitable forms.
  • the invention provides a solid composition, wherein the active agent is [4-(6-fluoro-7-methylamino-2,4-dioxo-l,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro- thiophen-2-yl-sulfonylurea potassium or sodium salt.
  • the active agent is [4-(6-fluoro-7-methylamino-2,4-dioxo-l,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro- thiophen-2-yl-sulfonylurea potassium or sodium salt.
  • the agent is ticagrelor or [(lS,2S,3R,5S)-3-[7-[(lR,2S)-2- (3,4-Difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3- yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol, in all suitable forms.
  • Methods for the preparation of compounds of formula (I) are described in US-2007-0123547-A1 and US- 2009-0042916-Al.
  • the compounds and pharmaceutical compositions of the invention may be utilized in vivo, ordinarily in mammals such as primates, (e.g., humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • mammals such as primates, (e.g., humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the biological properties, as defined above, of a compound or a pharmaceutical composition of the invention can be readily characterized by methods that are well known in the art such as, for example, by in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters.
  • Compounds and pharmaceutical compositions of the invention may be in the form of solutions or suspensions.
  • the compounds or pharmaceutical compositions of the invention may also be in such forms as, for example, tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles.
  • Subjects typically mammalian in need of treatment using the compounds or pharmaceutical compositions of the invention may be administered dosages that will provide optimal efficacy.
  • the dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compound employed, the specific use for which the compound or pharmaceutical composition is employed, and other factors which those skilled in the medical arts will recognize.
  • Dosage formulations of a reversible, direct acting P2Yi 2 receptor inhibitor, or pharmaceutical compositions contain a reversible, direct acting P2Y 12 receptor inhibitor of the invention, to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in a solid form, preferably in a lyophilized form. While the preferred route of administration is orally, the dosage formulations of a reversible, direct acting P2Yi 2 receptor inhibitor or pharmaceutical compositions of the invention may also be administered by injection, intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally,
  • dosage forms may be employed as well including, but not limited to, suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • the reversible, direct acting P2Y ]2 receptor inhibitor and pharmaceutical compositions of the invention may also be incorporated into shapes and articles such as implants which may employ inert materials such biodegradable polymers or synthetic silicones as, for example, SILASTIC, silicone rubber or other polymers commercially available.
  • the compounds and pharmaceutical compositions of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound or pharmaceutical composition of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will be influenced by the route of
  • the dosage is delivered into the body's fluids.
  • the absorption efficiency must be individually determined for each compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • the determination of effective dosage levels that is, the dosage levels necessary to achieve the desired result, will be readily determined by one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
  • effective dosage levels that is, the dosage levels necessary to achieve the desired result, i.e., platelet ADP receptor inhibition
  • applications of a compound or pharmaceutical composition of the invention are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
  • the compounds and compositions of the invention may be administered orally in an effective amount within the dosage range of about 0.01 to 1000 mg/kg in a regimen of single or several divided daily doses.
  • a pharmaceutically acceptable carrier typically, about 5 to 500 mg of a reversible, direct acting P2Y 12 receptor inhibitor is compounded with a pharmaceutically acceptable carrier as called for by accepted pharmaceutical practice including, but not limited to, a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc.
  • a pharmaceutically acceptable carrier as called for by accepted pharmaceutical practice including, but not limited to, a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc.
  • the amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained. 10.
  • the P2Y12 receptor inhibitor is administered at a time interval selected from the group consisting of once per day and twice per day.
  • the therapeutic amount of the reversible, direct-acting P2Y12 receptor inhibitor is from at least about 300 to about 450 mg. In another group of embodiments, the therapeutic amount of the reversible, direct-acting P2Y12 receptor inhibitor is from at least about 50 to about 150 mg. In another group of embodiments, the therapeutic amount of the reversible, direct-acting P2Y12 receptor inhibitor is from at least about 75 to about 100 mg. In another group of embodiments, wherein the therapeutic amount of the reversible, direct- acting P2Y12 receptor inhibitor is at least about 20 to about 100 mg. In another group of embodiments, wherein the therapeutic amount of the reversible, direct-acting P2Y12 receptor inhibitor is at least about 45 to about 90 mg. In another group of embodiments, wherein the therapeutic amount of the reversible, direct-acting P2Y12 receptor inhibitor is at least about 50 to about 60 mg.
  • the invention provides an oral dose of the reversible, direct-acting P2Y12 receptor inhibitor of about 45 mg to about 50 mg to about 60 mg to about 75 mg to about 90 mg to about 100 mg to about 150 mg to about 300 to about 450 mg ⁇ see, U.S. Pat. Application No. 61/334068, filed May 12, 2010). In one group of embodiments, these dosage amounts are provided in a single dose.
  • the invention provides an intravenous/injectable dose of the reversible, direct-acting P2Y12 receptor inhibitor of between about 0.1 mg to about 1 mg to about 5 mg to about 10 mg to about 15 mg to about 17 mg to about 20 mg to about 23 mg to about 25 mg to about 40 mg to about 50 mg to about 75 mg to about 80mg to about 100 mg to about 120 mg to about, 125 mg to about 150 mg to about 175 mg to about 200 mg and to about 250 mg ⁇ see, U.S. Pat. Application No. 61/329725, filed April 30, 2010). In one group of embodiments, these dosage amounts are provided in a single dose.
  • Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
  • Typical adjuvants which may be incorporated into tablets, capsules, lozenges and the like are binders such as acacia, corn starch or gelatin, and excipients such as
  • microcrystalline cellulose disintegrating agents like corn starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents.
  • a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline, or a fatty oil.
  • liquid carriers such as water, saline, or a fatty oil.
  • Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • kits generally may further comprise the use of a kit according to the invention.
  • the diagnostic methods of the invention may be performed ex-vivo, and such ex-vivo methods are specifically contemplated by the present invention.
  • a method of the invention may include steps that may be practiced on the human or animal body, methods that only comprise those steps which are not practiced on the human or animal body are specifically contemplated by the present invention.
  • such kit may comprise a DNA sample collecting means.
  • kits for detecting the presence of a polypeptide or nucleic acid corresponding to a marker of the invention in a biological sample e.g., any body fluid including, but not limited to, serum, plasma, lymph, cystic fluid, urine, stool, csf, acitic fluid or blood and including biopsy samples of body tissue.
  • the kit can comprise a labelled compound or agent capable of detecting a polypeptide or an mRNA encoding a polypeptide corresponding to a marker of the invention in a biological sample and means for determining the amount of the polypeptide or mRNA in the sample, e.g., an antibody which binds the polypeptide or an oligonucleotide probe which binds to DNA or mRNA encoding the polypeptide.
  • Kits can also include instructions for interpreting the results obtained using the kit.
  • the kit can comprise, e.g., 1) an oligonucleotide, e.g., a detectably-labelled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a polypeptide corresponding to a marker of the invention; or 2) a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker of the invention.
  • an oligonucleotide e.g., a detectably-labelled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a polypeptide corresponding to a marker of the invention
  • a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker of the invention.
  • the kit can also comprise, e.g., a buffering agent, a preservative or a protein- stabilizing agent.
  • the kit can further comprise components necessary for detecting the detectable-label, e.g., an enzyme or a substrate.
  • the kit can also contain a control sample or a series of control samples, which can be assayed and compared to the test sample.
  • Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.
  • kits of the invention may contain a written product on or in the kit container.
  • the written product describes how to use the reagents contained in the kit to determine whether a patient will experience hepatotoxicity during drug treatment.
  • the use of the reagents can be according to the methods of the invention.
  • the reagents are primer pairs for performing PCR analysis of 2Cl 9*2 genetic polymorphisms.
  • Example 1 Oral Dosing of Elinogrel Overcomes High Platelet Reactivity in Patients Non- responsive to Clopidogrel Therapy and Independent of CYP 2C19*2 Genotype Patients and Study Design
  • Inclusion criteria were clinically stable patients older than 18 years of age who had undergone previous coronary artery stenting and were treated with chronic daily 75 mg clopidogrel and 81 mg aspirin therapy. Fifty patients were screened for HPR (5 patients with HPR had been previously identified). Patients were instructed to take clopidogrel at least 12 hours but no more than 16 hours prior to the initial screening visit (Figure 1).
  • Exclusion criteria were any history of a bleeding diathesis or gastrointestinal bleeding; stroke or transient ischemic attack of any etiology within 30 days of screening, illicit drug or alcohol abuse, consumption of grapefruit or grapefruit juice 48 hours prior to dosing, coagulopathy, major surgery within 6 weeks prior to screening, planned surgical procedure within 30 days of anticipated dosing, enrollment in an investigational drug study within 30 days of screening, a medical or surgical condition which may impair drug absorption or metabolism, platelet count ⁇ 100,000/mm3, hematocrit ⁇ 30%, creatinine >2mg/dL, or current use of nonsteroidal anti-inflammatory drugs, anticoagulants, dietary supplements, herbal products or antiplatelet drugs other than aspirin or clopidogrel within 2 weeks of screening.
  • Elinogrel was supplied by Portola Pharmaceuticals, Inc. as a powder stored at room temperature and was reconstituted with sterile water by an in-hospital pharmacist as a solution containing 2.28 mg/mL. The solution was stored at room temperature to be used within 24 hours of preparation; 30 mL (60 mg) were administered orally to patients together with 100 mL of water.
  • Blood and Urine Collection [0129] Blood was collected from the antecubital vein with an 18 gauge needle at screening and at predosing 12-16 hours after the previous day's clopidogrel dose and then at 4 hours, 6 hours, 24 hours, and 7-10 days after dosing with elinogrel.
  • Three Vacutainer® tubes (Becton- Dickinson, Franklin Lakes, NJ) containing 3.2% trisodium citrate were used for LTA (5 ⁇ M and 20 ⁇ M ADP and 2mM arachidonic acid), thrombelastography (TEG) and vasodilator- stimulated phosphoprotein (VASP) phosphorylation measurements; two tubes containing a proprietary anticoagulant CT921-78 (factor Xa inhibitor; Portola Pharmaceuticals, San Francisco, CA) were used for LTA (lO ⁇ M ADP and 4 ⁇ g/mL collagen) and for the perfusion chamber assay (PCA) to ensure physiologic calcium concentrations; one tube containing lithium heparin (Becton- Dickinson, Franklin Lakes, NJ) was used for TEG
  • Vacuette® North America, Inc., Monroe, NC was used for VerifyNowTM assay.
  • One tube containing ethylene diamine tetraacetate (1.8mg/ml) was used for elinogrel plasma concentration measurements (Becton-Dickinson, Franklin Lakes, NJ).
  • Urine samples were collected at screening and on the day of dosing prior to administration of elinogrel to test for pregnancy in women of childbearing potential and to assess for amphetamine,
  • Platelet aggregation was assessed as previously described using a Chronolog Lumi- Aggregometer (Model 490-4D) with the Aggrolink software package (Chronolog,
  • the VerifyNowTM is a turbidimetric based optical detection assay designed to measure platelet aggregation that is based upon the ability of activated platelets to bind to fibrinogen. Light transmittance increases as activated platelets bind and aggregate fibrinogen- coated beads. The change in optical signal is reported as P2Yi 2 Reaction Units (PRU).
  • PRU P2Yi 2 Reaction Units
  • VASP phosphorylation was determined in whole blood using a flow cytometric assay [Platelet VASP; Diagnostica Stago (Biocytex), Asnieres, France] as previously described (Gurbel et al. JAm Coll Cardiol. 2005;46: 1827-32).
  • Rectangular capillaries with 0.2 mm x 2 mm sections were coated with human type III fibrillar collagen (Chronolog Corp, Havertown, PA) as previously described (Andre et al. Arterioscler Thromb Vase Biol 1996;16:56-63). Evaluation of thrombotic deposits was performed at 8 mm from the proximal end of the capillary.
  • the RTTP-2 consists of an epifluorescence microscope to monitor thrombus formation and a syringe pump (Harvard Apparatus, Holliston, MA) to establish the desired flow and wall shear rate in the capillary perfusion chamber. Platelets were labeled by incubating rhodamine 6G (final concentration 1.25 ⁇ g/ml, EMD, Gibbstown, NJ) in the whole blood at 37 0 C for 15 min. A high-power light emitting diode with a spectral maximum at 530 nm and a spectral half width of 35 nm (Luxeon V, Lumileds Lighting, San Jose, CA) excited the dye.
  • Excitation and emission light were filtered with a set of fluorescence filters (31002, Chroma Technologies, Rockingham, VT).
  • a microscope objective images an area of 360 x 270 ⁇ m on the internal wall of the capillary onto a Sony XCD X-710 digital camera (resulting magnification ca. 13 x). Images were recorded at a frequency of 1 Hz.
  • a personal computer with custom software was used to control the camera, the syringe pump, to display experimental conditions, and record images.
  • Thrombus size was represented as the measurement of the fluorescence intensity divided by total area. Segmentation, partitioning of an image into non-overlapping regions, was accomplished based on a method proposed by Otsu (Otsu et al. IEEE Trans. Syst. Man
  • Total object volume was computed as sum of intensity values of pixels inside the foreground objects.
  • Total area was computed as number of pixels inside the foreground objects. Data were expressed as fluorescence intensity (pixels)/total area ( ⁇ m?).
  • TaqMan® SNP genotyping assays (Applied Biosystems, Foster City, CA).
  • Adverse events were defined as any untoward medical occurrence in a subject that may or may not have been due to treatment with elinogrel, including any unfavorable or unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not it was considered study-drug related. This included any newly occurring event or previous condition that had increased in severity or frequency since the administration of study drug.
  • SAE Serious adverse events
  • the primary objective was to evaluate the change in 5 ⁇ M ADP-induced aggregation from pre- to 4 to 6 hours post- elinogrel treatment in patients with HPR currently on clopidogrel therapy.
  • an absolute change mean of upper tertile minus lower tertile cutpoint
  • 5 ⁇ M ADP-induced platelet aggregation with a standard deviation of 10 a sample size of approximately 10 subjects is required to give a 95% power with an alpha of 0.05 (Bliden et al. JAm Coll Cardiol 2007;49:657-66).
  • the figure indicates that: (1) the primary endpoint of the study, was achieved at 4 hrs (mean aggregation fell from the top to the bottom tertile) and was also significantly reduced at 6 hrs, (2) The majority of patients showed a significant decrease in platelet aggregation at 4 or 6 hrs, relative to their baseline value, and (3) most of the patients had a stable HPR phenotype that persisted from the screening visit to the predose visit, and was reproduced at the follow-up visit, despite ongoing dual antiplatelet therapy. The antiplatelet effect of elinogrel was rapid.
  • Thrombelastography TAG Platelet Mapping Assay
  • PRU also decreased at 4 and 6 hours post-dosing and the effect was reversible at 24 hours postdosing (Figure 8).
  • VASP Vasodilator Stimulated Phosphoprotein
  • VASP PRI significantly decreased from baseline at 4 and 6 hours post-treatment and again the effect was reversible at 24-hours post-dosing (Figure 9)
  • CYP 2C19*3, and *5 and CYP 3A5*3 alleles were not present in any patient. Platelet reactivity was higher in CYP2C19*2 carriers during clopidogrel and aspirin therapy alone (Table 3). Platelet reactivity fell in CYP2C19*2 carriers and non-carriers after elinogrel administration ( Figure 12).
  • Elinogrel is a direct-acting, non-prodrug, competitive inhibitor of the P2Yi2 receptor available in both oral and parenteral formulations. It has a terminal half-life of approximately 12 hours, is cleared by both renal and hepatic routes and undergoes limited metabolism. When given as an intravenous bolus, immediate and full platelet inhibition of ADP-induced platelet aggregation was observed (Lieu et al. / Thromb Haemost 2007; 5 Supplement 2: P-T- 292). Moreover, intravenous bolus doses up to 60 mg administered concurrently with standard therapy were well tolerated in patients undergoing primary angioplasty for ST 16 elevated myocardial infarction.
  • thienopyridine has attempted to address the limitations of delayed and variable inhibition by clopidogrel.
  • irreversible platelet inhibition often precludes prepercutaneous intervention administration of thienopyridines until the coronary anatomy is known.
  • a greater frequency of bleeding was observed with prasugrel versus clopidogrel, with a 4-fold increase seen in patients undergoing coronary bypass graft surgery as well as increased bleeding during chronic prasugrel administration (Wiviott et al. N Engl J Med 2007; 357:2001-15).
  • reversible agents such as elinogrel demonstrate that these agents can achieve immediate high level blockade following parenteral bolus administration, and may have a broader therapeutic index than the irreversible thienopyridine inhibitors, in that they have less effect on hemostasis at equivalent levels of antithrombotic activity in preclinical studies (Andre et al. J Thromb Haemost 2007; 5 Supplement 2: O-W-031).
  • a rapid-acting, reversible agent such as elinogrel can reduce bleeding risk in both the chronic and acute settings, and allow for easier management of surgical procedures for patients with drug eluting stents who require dual antiplatelet therapy.
  • Percutaneous Coronary Intervention (INNOV ATE-PCI) trial is an immediate release tablet.
  • the 60 mg dose in the present study achieved plasma concentrations that are at the low end of the range being studied in INNOV ATE-PCI trial (50, 100, 150 mg twice daily).
  • intravenous and oral elinogrel will allow for a seamless transition from the acute to the chronic setting, and avoids the issues of transitioning from an intravenous reversible inhibitor such as cangrelor, to a thienopyridine prodrug, where the presence of the competitive reversible inhibitor has been shown to block the ability of the active metabolite of clopidogrel or prasugrel to inhibit platelets by irreversibly binding the P2Yi 2 receptor (Dovlatova et al. J Thromb Haemost 2008;6: 1153-9; Steinhubl et al. Thromb Res
  • Table 1 The demographics of clinical pharmacogenetic analysis participants is shown in Table 1 : Table. 1 Patients Demographics
  • ADP adenosine diphosphate
  • VASP vasodilator stimulated
  • TEG thrombelastography
  • Example 2 Differences between pharmalogical inhibition and gene targeting of the ADP receptor with PlYn inhibitors.
  • Clopidogrel was from Sequoia Research Products Ltd. (United Kingdom). Prasugrel was from Albany Molecular Research (USA).
  • C57/BL6J mice (Charles River) were used for determination of antithrombotic activities of clopidogrel and prasugrel, determination of their effects on primary hemostasis and ex vivo platelet aggregation studies.
  • P2Yi2- ⁇ mice (on a pure C57/BL6J background (>10 times backcrossed)) were used for thrombosis and hemostasis studies. All experiments were performed by investigators blinded to the different treatments. All procedures conformed to institutional guidelines and to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, Md).
  • Thrombosis on mouse mesenteric arteries (1000-1300 s-i) was performed and recorded as previously described with minor modifications 20. Platelets were labeled in situ using rhodamine 6G (0.2 mg/niL) administered through the tail vein 10 minutes before visualization of the arteries. Vessel-wall injury was induced by a lxl-mm filter paper saturated with a 10% FeCb solution. After 5 minutes, the filter paper was removed and mesenteric arteries rinsed with warmed saline (37 0 C). Platelet vessel-wall interactions were recorded for 40 additional minutes or until full occlusion occurred and lasted for more than 40 seconds.
  • C57B16J mice were orally gavaged 48, 24 and 2 hours prior to injury with vehicle control (0.5% methylcellulose), clopidogrel (0.25, 1.5, 15 and 50 mg/kg) or prasugrel (0.1, 0.3, 1, 3, 10 mg/kg), or 2 hours prior to injury with elinogrel (0.83, 2.5, 7.5, 20 and 60 mg/kg).
  • vehicle control (0.5% methylcellulose
  • clopidogrel 0.25, 1.5, 15 and 50 mg/kg
  • prasugrel 0.1, 0.3, 1, 3, 10 mg/kg
  • elinogrel 0.3, 2.5, 7.5, 20 and 60 mg/kg.
  • Thrombosis was analyzed in real time using Simple PCI software 11. The fluorescence intensity was recorded at a rate of 2 Hz for 40 minutes and plotted over time. Time to occlusion and time for appearance of first thrombus were analyzed. Tail bleeding time measurement
  • mice Male mice (6-8 weeks old) were anesthetized (by subcutaneous injection) with ketamine cocktail (ketamine [40 mg/kg], xylazine [2.5 mg/kg], and acepromazine [0.75 mg/kg], Henry Schein, Melville, NY, USA) 6 minutes prior to tail transection. Mice were then placed in lateral recumbence on a firm dissecting board (Richard-Allan Scientific, Kalamazoo, MI, USA) with the tail straight out.
  • ketamine cocktail ketamine [40 mg/kg], xylazine [2.5 mg/kg], and acepromazine [0.75 mg/kg], Henry Schein, Melville, NY, USA
  • Mice were then placed in lateral recumbence on a firm dissecting board (Richard-Allan Scientific, Kalamazoo, MI, USA) with the tail straight out.
  • Tails were transected 2 mm from the tip with a number 10 scalpel blade (Bard-Parker; Becton Dickinson, Franklin Lakes, New Jersey, USA) and immediately immersed into a 20-ml scintillation vial (Wheaton Science Products, Millville, NJ, USA) filled with 10 mL normal saline held at 37°C by an unstirred digitally- controlled water bath (VWR International, Buffalo Grove, IL, USA).
  • a stopwatch was started immediately upon trans-section to determine time to cessation of bleeding, frequency, and duration of re-bleed for a 15 minute period.
  • C57B16J mice were orally gavaged with vehicle control, clopidogrel (1.5, 15 and 50 mg/kg) or prasugrel (1, 3, 10 mg/kg) 48, 24 and 2 hours prior to tail trans-section or 2 hours prior to trans-section with elinogrel (7.5, 20 and 60 mg/kg).
  • P2Yi2-/- mice were also orally gavaged (using the same regimen) with maximal doses of clopidogrel, prasugrel, elinogrel and vehicle control.
  • the in vivo primary hemostasis model was performed via micropuncture (using a 27 G needle) of mesenteric veins according to the model developed by van Gestel and colleagues(van Gestel et al. Microcirculation. Apr-May 2007;14(3):193-205).
  • mice previously orally gavaged (48, 24 and 2 hours prior to injury) with either 0.5% methycellulose, clopidogrel (50 mg/kg), prasugrel (10 mg/kg) or elinogrel (60 mg/kg 2 hours prior to micropuncture) were injected with R6G (0.2 mg/ml) to fluorescently label platelets in situ. Bleeding time and platelet recruitment at site of micropuncture was recorded and quantified in real time using intravital microscopy. Ex vivo platelet aggregation
  • C57B16J mice were orally gavaged 48, 24 and 3 hours prior to blood collection with 0.5% methylcellulose, clopidogrel (1.5, 15 and 50 mg/kg) or prasugrel (1, 3, 10 mg/kg) or 3 hours prior to blood collection (elinogrel, 7.5, 20 and 60 mg/kg). Measurements were performed using a 4-channel Chronolog lumiaggregometer using Aggrolink software. Blood samples (0.6 ml per anesthetized mouse) were obtained via intracardiac puncture (on 3.2% trisodium citrate lvol TSC : 9 vol of blood), centrifuged at 200xg for 10 minutes and platelet rich plasma collected.
  • PRP of three animals was pooled for aggregation measurements. Experiments for each dose were repeated on a minimum of 3 sets of three animals. Aliquots (250 ⁇ l) of PRP were placed in cuvettes containing magnetic stirrer bars, warmed at 37°C, and stirred for 1 minute to obtain a stable baseline. Aggregation in PRP was induced using ADP (Chronolog) at 1 and 10 ⁇ M final concentration and change in light transmittance was recorded for an additional 4 minutes.
  • ADP Cholog
  • Blood loss measurement revealed differences between the three P2Yi2 antagonists and P2Yi2 /-mice.
  • the volume of blood loss was significantly lower with elinogrel (20 and 60 mg/kg) than that of its corresponding clopidogrel counterpart doses (*, p ⁇ 0.005; Figure 17A), and significantly lower when compared with its three equivalent prasugrel doses (+., p ⁇ 0.005; Figure 17A).
  • the micropunture model is characterized by a rapid obliteration of the vascular wound by fluorescent platelets in the ⁇ 20 seconds that followed injury in all animals, independently of the treatment or genotype (See Figure 19A), followed by a reopening of the wound.
  • the maximal dose of elinogrel had less effect on the frequency of bleeding than its corresponding thienopyridines treatment doses or than the loss of P2Yi2 via gene targeting (Figure 19B).
  • Measurement of the lumen of the vascular wound revealed differences between thienopyridine-treated and P2 Y 12-/- mice, and between elinogrel-treated and P2Yi2-/-mice ( Figure 19C).
  • mice In vivo vasoconstriction studies in mesenteric veins [0176] Mesenteric veins (100-190 ⁇ m diameter) from 3 to 4 week-old anesthetized P2Yi 2 ⁇ / ⁇ or WT mice were observed using bright- field inverted microscopy. In a first set of experiments, mice were orally gavaged with 0.5% methylcellulose, clopidogrel (50 mg/kg), prasugrel (10 mg/kg) or elinogrel (60 mg/kg) for 3 consecutive days.
  • Veins were stimulated by a superfusion of ⁇ , ⁇ metATP (Sigma-Aldrich; 10 ⁇ l of a 1 ⁇ M solution; a non- hydrolyzable P2X1 agonist not degraded by CD39) 2 hours after last oral gavage. Challenge and evaluation of the vascular tone were performed by an investigator blinded to the treatment regimen.
  • P2Yi 2 7" mice were orally gavaged with prasugrel (10 mg/kg) for three consecutive days. Sixteen hours prior to superfusion of ⁇ , ⁇ metATP, P2Yi 2 "A animals were injected with antiGPIb ⁇ antibodies (2 mg/kg; Emfret laboratories) for platelet depletion.
  • WT mice were orally gavaged with prasugrel (10 mg/kg) for 3 consecutive days and their mesenteric veins challenged 1, 2, 5, 10, 24 and 48 hrs after the last oral gavage. The diameter of the mesenteric veins was monitored for 5 minutes post challenge.
  • FIGS. 21A-D illustrate how thienopyridines block vasoconstriction of mesenteric veins.
  • the present invention directly assessed P2Yi2 contribution to primary hemostasis via comparison of the effects of genetic targeting to those attributed to irreversible
  • clopidogrel prasugrel
  • elinogrel reversible pharmacological inhibitors.
  • the present invention revealed novel and unexpected findings: first, thienopyridine agents in the mouse increase bleeding beyond the levels attributed to P2Yi2 inhibition; second, the competitive, reversible nature of elinogrel allows for a subtle dissociation between effects on arterial thrombosis and primary hemostasis. [0179] Previous studies performed in rats and rabbits have also reported that clopidogrel produced an unexpectedly large amount of bleeding compared to the inhibition of platelet aggregation or thrombosis (Wong et al. Thromb Haemost.
  • mice show that doses of
  • thienopyridine doses showing only intermediate effects on arterial thrombosis induced levels of blood loss similar (clopidogrel) to or greater (prasugrel) than that of the P2Yi2-null mouse.
  • the results of this invention indicate that clopidogrel and prasugrel (whose active metabolites share high structural similarities), can both act on molecular targets other than P2Yi2.
  • a similar observation was made in the micropuncture model applied to mesenteric veins.

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Abstract

Selon l'invention, les polymorphismes génétiques du gène 2C19*2 sont utiles en tant que biomarqueurs pour le diagnostic d'un risque accru de réactivité plaquettaire élevée ou de saignements importants chez un sujet souffrant d'un trouble cardiovasculaire. L'invention concerne en particulier des méthodes de traitement et de prévention d'une coronaropathie à l'aide d'inhibiteurs des récepteurs P2Y-12. En outre, la présente invention concerne des trousses destinées à être utilisées pour l'identification de patients atteints de coronaropathies présentant un risque accru de réactivité plaquettaire élevée ou de saignements importants.
PCT/US2010/041749 2009-07-10 2010-07-12 Méthodes de diagnostic et de traitement de troubles thrombotiques médiés par cyp2c19*2 WO2011006169A1 (fr)

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CN102731510A (zh) * 2011-04-07 2012-10-17 博瑞生物医药技术(苏州)有限公司 替卡格雷的衍生物、制备方法及其药物用途
RU2542434C1 (ru) * 2013-12-30 2015-02-20 государственное бюджетное образовательное учреждение высшего профессионального образования "Сибирский государственный медицинский университет" Министерства здравоохранения Российской Федерации (ГБОУ ВПО СибГМУ Минздрава России) Способ прогнозирования степени риска развития гемолитических осложнений после операции коронарного шунтирования в условиях искусственного кровообращения
RU2746234C1 (ru) * 2020-05-29 2021-04-09 Федеральное государственное бюджетное образовательное учреждение высшего образования "Ярославский государственный медицинский университет" Министерства здравоохранения Российской Федерации Способ прогнозирования риска возникновения тромботических осложнений у пациентов с сердечно-сосудистой патологией

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