Genotyping Test and Methods for Diagnosing Statin Induced Myopathy
Abstract
The present invention methods and compositions for genotype guided diagnosis of statin induced myopathy. The invention provides biomarkers and genotyping panels, algorithms and methods for diagnosing statin-induced myopathy and individualized assessment. Compositions and methods based on genetic polymorphisms associated with variations in normal, non-pathological plasma CK levels and with pathological plasma CK levels are provided. The polymorphisms of the invention are further useful as targets for the design of diagnostic and prognostic reagents and the development of therapeutic and preventive agents for use in the prognosis, treatment, and/or prevention of statin induced myopathy and other muscular disorders, as well as for investigating a patient`s response to statins and adverse events associated with their administration and informing clinical decision making including the selection of a alternative therapy to statins.
Derwent title : not currently available
Statut: Technology under development. U.S. provisional application filed.
Priority Date: September 28, 2012
Inventors : Dr. Marie-Pierre Dubé, Dr. Jean-Claude Tardif
Background
Cardiovascular disease is the leading cause of death and hospitalization. Treating CVD costs ~$22.2 billion/year including direct and indirect costs. A significant portion of this spending can be attributed to drugs that on an individual or sub-population bases provide little or no therapeutic benefit due to poor efficacy, non-compliance or early discontinuation. One such example is statin treatment. Compliance is substantial problem in statin treatment. Noncompliance is often due to misdiagnosis of statin induced myopathy which leads to patients unnecessarily discontinuing statin treatment. More accurate statin diagnosis could lead to improved clinical outcomes and more efficient health care spending. Statins are the cornerstone of hyperlipidaemia treatment and primary and secondary prevention of CVD; and are the most prescribed drug by class. However, up to as much as 40% of current spending on statins, $ 18 B worldwide in 2010, provides no clinical benefit due to noncompliance. As much as 50% of patients prescribed statins discontinue treatment within the first 18 months after initiation and as a result do not experience a therapeutic benefit. Noncompliance is thought to be due to aches and pains that are mistakenly identified by patients and physicians as statin-induced myopathy. In fact clinical data indicates that statin-induced myopathy occurs in only 7-10% of patients and has life-threatening
complications in only 0.001%. Thus it is likely that up to 40% of patients who stop taking statin do so for the wrong reason and would have benefited had they continued to take the drug. In addition to this, because statins prevent hard vascular outcomes (such as death, myocardial infarction) in only a minority of patients, even the majority of compliant individuals are at risk. A test that enables reliable and accurate diagnosis of statin induced myopathy could ensure compliance in a larger percentage of the population treated reducing wasteful spending and increase the overall clinical benefit derived.
Genetic Predictors of INR Fluctuation for Improved Warfarin Therapy
Abstract
The invention relates to methods and kits for determining a predisposition to abnormal international normalized ratio (INR) fluctuation in patients administered warfarin. In one embodiment, the method includes testing the subject to check for a presence of a predetermined genetic variation. The predetermined genetic variation is correlated with abnormal INR fluctuation during warfarin therapy. The subject is identified as having a predisposition to abnormal INR fluctuation during warfarin therapy when the testing indicates the presence of the predetermined genetic variation. In one embodiment, a kit includes a test to check the subject for a presence of a predetermined genetic variation. T he predetermined genetic variation is correlated with abnormal INR fluctuation during warfarin therapy. The kit includes an indicator to identify the presence of the
predetermined genetic variation so as to identify the subject as having a predisposition to abnormal INR fluctuation during warfarin therapy.Derwent Title: Identifying a subject having genetic predictors of predisposition to abnormal international normalized ratio fluctuation during warfarin therapy comprises testing the subject to check for a presence of a predetermined genetic variation.
Derwent Title : Identifying a subject having genetic predictors of predisposition to abnormal international normalized ratio fluctuation during warfarin therapy comprises testing the subject to check for a presence of a predetermined genetic variation
Status : Demandes en cours d’examen au Canada (CA 2,706,021) et aux États-Unis (US20100304393).
Priority Date : May 28, 2009
Inventor : Dr Marie-Pierre Dubé
Background
Warfarin is the most widely prescribed oral anticoagulant for the treatment and prevention of thromboembolic diseases. The high inter-individual variability in warfarin dosing is an ongoing problem that is worsening as the population ages and eligible patients increase in numbers. Effectiveness and safety of warfarin therapy are routinely monitored by the international normalized ratio (INR), the ratio of time required for coagulation relative
to a reference. More particularly, the international normalized ratio (INR) is a system for reporting the results of blood coagulation tests. For example, a person taking the anticoagulant warfarin might optimally maintain a prothrombin time of 2 to 3 INR. Despite the large number of anticoagulation clinics and efficient INR monitoring programs, up to 15% of warfarin users suffer from bleeding and 11% from thromboembolic events that can lead to hospitalizations and deaths. INR fluctuations above the targeted therapeutic INR range
in particular are associated with an accrued risk of bleeding. For every unit increase in INR, one study reported an increase in odds of major bleeding by 0.6 in younger patients and by 0.4 in older patients. In a hospital-based study, INR values ≧4 were shown to be associated with a marked increase in bleeding risk (OR 13, 95% CI 1.2-150). Still, patients fluctuate above their target therapeutic INR range in as high as 30% of the time in the first 3 months of treatment, and 14% subsequently. The relative contribution of different polymorphisms to warfarin dosing has been studied in various patient populations and ethnic comparisons
have been made. Most previous studies have focused on the use of genetic polymorphisms to predict stable therapeutic dose, the impact of the algorithm on the percentage of patients who are outside of the therapeutic range or the time to stable INR and warfarin dose. However, many adverse events associated with warfarin therapy, occur after dose stabilization and it is likely that some individuals are more prone to fluctuations
in response than others. A question of immediate clinical relevance is how an individuals genetic information can be used to identify individuals at high risk of fluctuations in response, following dose stabilization. A genetic test that provides this information could be used in clinical decision making in ways that c reduce the occurrence of adverse events in patients administered warfarin .
Related References : Marin-Leblanc M, Perreault S, Bahroun I, et al. Validation of warfarin pharmacogenetic algorithms in clinical practice. Pharmacogenomics. 2011;13(1):21–9.
Available from : http://www.futuremedicine.com/doi/abs/10.2217/pgs.11.120?url_ver=Z39.88-...
Angiopoietin-Like 2 as a Biomarker of Vascular Endothelial Cell Abnormal Function and Senescence
Abstract
A method for assessing a physiological state of a mammal. The method includes: obtaining from the mammal a biological sample; measuring the expression of angiopoietin-like 2 in the biological sample; and assessing the physiological state of the mammal by comparing the measured expression of the angiopoietin-like 2 to a predetermined normal expression level in normal subjects, wherein an increase in angiopoietin-like 2 level
over the predetermined normal expression level indicates an abnormal physiological state.
Derwent Title : Assessing physiological state of a mammal comprises measuring angiopoietin-like 2 expression in the biological sample (Évaluation de l’état physiologique d’un mammifère par mesure de l’expression d’ANGPTL2 dans un échantillon biologique).
Status: U.S. Patent granted (US 7,972,795) and pending in Canada (CA 2,592,372)First Claim US 7,972,795: 1. A method for assessing a physiological state of a mammal, said method comprising: - obtaining from the mammal a biological sample; - measuring the expression of angiopoietin-Iike 2 in the biological sample; and - assessing the physiological state of the mammal by comparing the measured expression of the angiopoietin-like 2 to a predetermined normal expression level in normal subjects, wherein an increase in angiopoietin-Iike 2 level over the predetermined normal expression level indicates an abnormal physiological state.
Priority Date : June 20, 2006
Inventors: Dr. Éric Thorin; Nada Farhat; Nathalie Trescases
Background
Atherosclerotic lesions commonly develop as part of the aging process and can lead to coronary artery disease (CAD), promoting cardiac ischemia and death. Cardiovascular diseases are associated with numerous risk factors such as aging, diabetes, obesity, hypertension, dyslipidemia but also viral and bacterial infection. These risk factors are associated with increased oxidative stress at the vascular endothelium which promotes
atherogenesis. Vascular endothelial cells (ECs) become dysfunctional before clinical signs of vascular diseases. A biomarker that could be used to detect damage of the endothelium and predict the level of damage could support early intervention and prevent the development of CAD and its outcomes.
Related References
Farhat N, Thorin-Trescases N, Mamarbachi M, et al. Angiopoietin-like 2 promotes atherogenesis in mice.
Journal of the American Heart Association. 2012;2(3):e000201. Pubmed: http://www.ncbi.nlm.nih.gov/pubmed/23666461
Farhat N, Thorin-Trescases N, Voghel G, et al. Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers.
Canadian Journal of Physiology and Pharmacology. 2008;86(11):761–9. Pubmed: http://www.ncbi.nlm.nih.gov/pubmed/19011671
Method for Detecting a Biomarker of Oxidative Stress in a Biological Sample
Abstract
The present invention relates to methods for detecting a oxidative stress in a biological sample, methods of determining a cumulative record of oxidative injury, and methods of diagnosing diseases of aging, such as cardiovascular diseases, based on the presence or absence of a biomarker or a component thereof. The present invention also relates to a kit for detecting oxidative stress in a biological sample comprising a stabilizing reactant and an antibody. In some embodiments of the invention, the biomarker of oxidative stress is selected from an aldehyde-protein adduct and an aldehyde metabolite-protein adduct, and the proposed method further comprises measuring separately for the same protein biomarkers of oxydative stress formed with different amino acids of the protein.
Derwent Title: Detecting oxidative stress using biological sample, involves obtaining sample comprising biomarker of oxidative stress, chemically stabilizing biomarker in sample, and extracting and measuring quantity of measurable component
Status : U.S. patents granted (US 7,993,859, US 8,030,010), Canadian application pending (CA 2672322)
Priority Date : 14 Octobre, 2005
First Claim US 7,993,859:A method for detecting oxidative stress using a biological sample, comprising: (a) obtaining the biological sample comprising a biomarker of oxidative stress having a measurable component; (b) chemically stabilizing the biomarker in the sample; (c) isolating the measurable component; (d) extracting the measurable component; and (e) measuring the quantity of the measurable component.
First Claim US 8,030,010: 1.A method for detecting oxidative stress using a biological sample, comprising: (a) obtaining the biological sample comprising a biomarker of oxidative stress having a measurable component, said biological sample being selected from whole blood, blood derivatives, and combinations thereof; (b) chemically stabilizing the biomarker in the sample; (c) isolating the measurable component; (d) extracting the measurable component; and (e) measuring the quantity of the measurable component.
Inventors: Christine Des Rosiers, Jean-François Lesgards, Dr Jean-Claude Tardif (US7, 993,859): Christine Des Rosiers, Caroline Asselin, Bertrand Bouchard, Jean-Claude Tardif, Blandine Comte (US8, 030010)
Background
Related References
Lesgards J-F, Frayne I, Comte B, et al. répartition différentielle des adduits 4-hydroxynonénal de soufre et les résidus d'azote dans les protéines du sang comme l'a révélé l'utilisation du nickel Raney et spectrométrie de masse gaz. [Pubmed]. Gratuit biologie et médecine radicale. 2009; 47 (10) :1375-85 disponible à partir de: http://linkinghub.elsevier.com/retrieve/pii/S0891-5849 (09) 00471-7.
Asselin C, Shi Y, Clément R, J Tardif, C. Des Rosiers supérieur circulant 4 protéines hydroxynonénal-adduits thioéther en corrélation avec de graves dysfonctionnement diastolique plus chez les rats spontanément hypertendus. [Pubmed]. Rapport Redox: communications dans la recherche des radicaux libres. 2006; 12 (1) :68-72 disponible à partir de:.
Véronneau M, Comte B, C. Des Rosiers quantitative gaz dosage par spectrométrie de masse chromatographique de 4 hydroxynonénal lié aux protéines thiols dans les cœurs ischémiques / reperfusé rat. [Internet]. Gratuit biologie et médecine radicale. 2002; 33 (10) :1380-8 Disponible à partir de: http://linkinghub.elsevier.com/retrieve/pii/S089158490201.