عنوان

פולימורפיזים גנטי בגן CYP2C9 ובפינוי המטבולי של וורפרין ופניטואין, מחקר באוכלוסייה בריאה ובחולים

شماره

TL58226

زبان متن نوشتاري يا گفتاري و مانند آن

انگلیسی

عنوان اصلي

פולימורפיזים גנטי בגן CYP2C9 ובפינוי המטבולי של וורפרין ופניטואין, מחקר באוכלוסייה בריאה ובחולים

نام عام مواد

[Thesis]

نام نخستين پديدآور

Shaul, Chanan

نام ساير پديدآوران

Caraco, Yoseph

نام ناشر، پخش کننده و غيره

The Hebrew University of Jerusalem (Israel)

تاریخ نشرو بخش و غیره

2019

متن يادداشت

73 p.

جزئيات پايان نامه و نوع درجه آن

Ph.D.

کسي که مدرک را اعطا کرده

The Hebrew University of Jerusalem (Israel)

امتياز متن

2019

متن يادداشت

Targeting of the narrow therapeutic index (NTI) drug warfarin is very challenging for patients and physicians alike. That's because subtherapeutic warfarin level can cause recurrence of the thromboembolic events while supratherapeutic level may significantly raise the bleeding risk. The initiation phase of warfarin's treatment is a critical period, characterized by fluctuations of patients' INR levels. It is well established that genetic factors, as well as environmental and other host factors, affect the individual response to warfarin through changes in the drug's pharmacokinetics (PK) and pharmacodynamics (PD). Genetic polymorphisms in CYP2C9, that mediates the metabolic clearance of (S)-warfarin (the more potent enantiomer of warfarin) accounts for the variability in the response to warfarin due to the drug's altered PK. Furthermore, variability in warfarin PD is partially attributed to genetic polymorphism in the target molecule (i.e. VKORC1) or in any of the coagulation factors including, for example, the coagulation factor VII. However, most of the information concerning inter-patient variability in response to warfarin was derived from cohorts of patients on chronic warfarin therapy (i.e. steady-state anticoagulation phase). In contrast, much less effort has been invested in the exploration of genetic and phenotypic markers that could predict the response to warfarin during the critical initiation period. Consequently, the objectives of my PhD thesis were as follows: 1) To provide an accurate quantitative estimate, among healthy subjects carrying different CYP2C9 genotypes, of (S)-warfarin oral clearance (CL/F) and (S)-warfarin formation clearance (CLf) to its CYP2C9-mediated metabolites, 6-hydroxy- and 7-hydroxy-(S)-warfarin. 2) To explore the influence of factor VII-genetic polymorphism-R353Q on the variability in the initial response to warfarin among healthy subjects. 3) To investigate if phenytoin, via its Phenytoin Metabolic Ratio (PMR), can serve as a phenotypic probe for (S)-warfarin clearance.  The current study provides a quantitative estimate concerning the effect of CYP2C9 genetic polymorphism on (S)-warfarin PK as well as the effect of the impact of R353Q genetic polymorphism on factor VII activity and INR values during the initial period of warfarin treatment. PMR is a reliable marker of CYP2C9 activity in-vivo accounting for more than 30% of the variability in (S)-warfarin CL/F as well as (S)-warfarin CLf to its CYP2C9-mediated metabolites.

اصطلاح موضوعی

Anticoagulants

اصطلاح موضوعی

Drug dosages

اصطلاح موضوعی

Drug interactions

اصطلاح موضوعی

Genetics

اصطلاح موضوعی

Genotype & phenotype

اصطلاح موضوعی

Heart failure

اصطلاح موضوعی

Metabolism

اصطلاح موضوعی

Metabolites

اصطلاح موضوعی

Patients

اصطلاح موضوعی

Pharmaceutical sciences

اصطلاح موضوعی

Pharmacodynamics

اصطلاح موضوعی

Pharmacokinetics

اصطلاح موضوعی

Pharmacology

اصطلاح موضوعی

Physicians

اصطلاح موضوعی

Physiology

اصطلاح موضوعی

Plasma

اصطلاح موضوعی

Polymorphism

اصطلاح موضوعی

Precision medicine

اصطلاح موضوعی

Urine

مستند نام اشخاص تاييد نشده

Shaul, Chanan

مستند نام اشخاص تاييد نشده

Caraco, Yoseph

مستند نام تنالگان تاييد نشده

The Hebrew University of Jerusalem (Israel)

نام الکترونيکي

فرمت انتشار

p

نوع ماده

[Thesis]

کد کاربرگه

276903

سطح دسترسي

a

تكميل شده

Y