ABSTRACT
Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.
Subject(s)
Anticoagulants/administration & dosage , Aryl Hydrocarbon Hydroxylases/genetics , Mixed Function Oxygenases/genetics , Pharmacogenetics , Warfarin/administration & dosage , Aged , Algorithms , Anticoagulants/adverse effects , Anticoagulants/metabolism , Cohort Studies , Cytochrome P-450 CYP2C9 , Dose-Response Relationship, Drug , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Polymorphism, Genetic , Predictive Value of Tests , Vitamin K Epoxide Reductases , Warfarin/adverse effects , Warfarin/metabolismABSTRACT
Dementia affects 5% of persons over age 65 years and 20% of those over 80 years of age and is expected to increase further in the primary care setting as the population ages. The constellation of neuropsychiatric disorders includes dementia, organic personality disorder, and organic psychotic disorder. Dementia is the most prevalent disorder, accounting for approximately 70% of the neuropsychiatric disease of institutionalized patients.
Subject(s)
Antipsychotic Agents/therapeutic use , Dementia/complications , Mental Disorders/psychology , Mental Disorders/therapy , Adrenergic beta-Antagonists/therapeutic use , Anti-Anxiety Agents/therapeutic use , Antipsychotic Agents/adverse effects , Carbamazepine/therapeutic use , Clinical Trials as Topic , Humans , Mental Disorders/drug therapySubject(s)
Dyspnea/etiology , Dyspnea/diagnosis , Female , Humans , Male , Middle Aged , Physical Examination , Practice Patterns, Physicians'/standardsABSTRACT
This study prospectively evaluated the potential interaction between the oral anticoagulant warfarin and the quinolone antimicrobial agent ciprofloxacin. After a 10-day placebo lead-in phase, 16 patients stabilized with long-term warfarin therapy were randomized to receive ciprofloxacin 500 mg or a matching placebo twice/day for 10 days. International normalized ratios (INRs) measured by both standard laboratory analysis and by Coumatrak (finger-stick) methods were evaluated at 3- to 5-day intervals. No patient experienced a significant increase in INR. No patient experienced a bleeding event. These data support the fact that a warfarin-ciprofloxacin interaction does not routinely occur at this dosage and duration of ciprofloxacin therapy.
