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Russell A Wilke

Publications and source records attributed to Russell A Wilke.

9 recordsLinked to original sources
PubMed2005

Combinatorial pharmacogenetics.

Combinatorial pharmacogenetics seeks to characterize genetic variations that affect reactions to potentially toxic agents within the complex metabolic networks of the human body. Polymorphic drug-metabolizing enzymes are likely to represent some of the most common inheritable risk factors associated with common 'disease' phenotypes, such as adverse drug reactions. The relatively high concordance between polymorphisms in drug-metabolizing enzymes and clinical phenotypes indicates that research into this class of polymorphisms could benefit patients in the near future. Characterization of other genes affecting drug disposition (absorption, distribution, metabolism and elimination) will further enhance this process. As with most questions concerning biological systems, the complexity arises out of the combinatorial magnitude of all the possible interactions and pathways. The high-dimensionality of the resulting analysis problem will often overwhelm traditional analysis methods. Novel analysis techniques, such as multifactor dimensionality reduction, offer viable options for evaluating such data.

Animals↗
PubMed2005

Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage.

Atorvastatin is metabolized through enzymes encoded by members of the cytochrome P-450 (CYP) 3A gene family. Some patients who take atorvastatin along with concomitant medications known to inhibit CYP3A enzyme activity (e.g. itraconazole) develop rhabdomyolysis secondary to a severe drug-induced myopathy. The present study aimed to characterize the relationship between CYP3A gene polymorphisms and atorvastatin-induced muscle damage in the context of concomitant medication. The study employed a retrospective case--control (n=137) design. Study subjects were recruited from the general patient population served by Marshfield Clinic, a large horizontally integrated multispecialty group practice located in central Wisconsin, and case assignment was based upon both subjective (myalgia) and objective inclusion criteria [elevated serum creatine kinase (CK) levels]. The primary outcome was the relationship between serum CK level and CYP3A genotype. CYP3A genotype was not associated with an increased risk for the development of atorvastatin-induced muscle damage. CYP3A4*1B and CYP3A5*3 allele frequencies were similar in cases (n=68) and controls (n=69). Conversely, CYP3A genotype was associated with an increased severity of atorvastatin-induced muscle damage. An association was identified between the non-functional CYP3A5*3 allele and the magnitude of serum CK elevation in case patients experiencing myalgia. Patients who were homozygous for CYP3A5*3 demonstrated greater serum CK levels than patients who were heterozygous for CYP3A5*3, when concomitant lipid-lowering agents were sequentially removed from the analysis (P=0.025 without gemfibrozil, P=0.010 without gemfibrozil and niacin). The study demonstrates that patients who develop myalgia while taking atorvastatin are more likely to experience a greater degree of muscle damage if they express two copies of CYP3A5*3.

Adult↗
PubMed2005

A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data.

BACKGROUND: Rapid genetic screening for cytochrome P450 (CYP) 2C9 variants may play a role in improving the efficacy and safety of warfarin in individuals with CYP2C9 variants. The feasibility of prospective CYP2C9 model-based warfarin dosing has not yet been assessed. OBJECTIVES: To evaluate the feasibility of applying a CYP2C9 gene-based warfarin dosing model in clinical practice. DESIGN: Prospective, randomized, single-blinded clinical pilot trial. SETTING: Large multispecialty group practice. PATIENTS: Candidates were recruited from a list of clinic patients eligible for warfarin initiation. This included patients with newly diagnosed thromboembolic disease or atrial arrhythmia, as well as patients anticipating elective valvuloplasty or arthroplasty. Patients who previously received warfarin were excluded. INTERVENTIONS: Subjects were randomized to receive either 1) a standard initiation dose of 5 mg warfarin/day, or 2) rapid CYP2C9 genotyping and an initiation dose determined using parameters estimated from a previously published multivariate model [including age, body size, co-morbidity (e.g., diabetes), clinical indication (e.g., valvuloplasty) and CYP2C9 genotype]. MEASUREMENTS: Primary outcome measurements were patient willingness to participate, physician willingness to refer, sample processing time, ability to administer calculated dosage and adequacy of follow-up. LIMITATIONS: This pilot trial was designed to assess the feasibility of model-based warfarin dosing. Power was insufficient for statistical comparison of adverse event rates. RESULTS: Forty-three of 117 patients had no prior warfarin treatment and were eligible. Five declined to participate. Twenty patients were randomized to a standard initiation dose of 5 mg daily. Eighteen patients were randomized to model-based dosing. All but one participant received the assigned initiation dose. Blood draw to dosage calculation time (including genotyping) required approximately 4 hours. Six adverse events occurred within the standard dosing group, and two adverse events occurred within the model-based dosing group. CONCLUSIONS: Prospective application of a multivariate CYP2C9 gene-based warfarin dosing model is feasible.

Aged↗
PubMed2005

Impact of age, CYP2C9 genotype and concomitant medication on the rate of rise for prothrombin time during the first 30 days of warfarin therapy.

OBJECTIVES: To characterize the impact of several important clinical variables on the rate of anticoagulation during warfarin initiation (i.e., the first 30 days). DESIGN: Retrospective study. SETTING: An anticoagulation service of a large horizontally integrated, multispecialty group practice in central and northern Wisconsin. PARTICIPANTS: Patients with sufficient laboratory data obtained during the initiation phase of warfarin treatment. METHODS: Patients were consented and genotyped for cytochrome P450 (CYP) 2C9 polymorphisms. Anticoagulation laboratory data were then electronically abstracted and fitted to a logistic growth model. Rate of anticoagulation was compared between groups. RESULTS: During warfarin initiation, the mean slope for rise in International Normalized Ratio (INR) of prothrombin time was significantly associated with age (p = 0.03, n = 166). Because a relationship between diabetes and warfarin dosing has been suggested previously, we assessed the impact of this comorbidity in our model as well. Diabetes showed relatively little impact, but concomitant treatment with an anti-diabetic sulfonylurea medication was associated with an increase in slope (3-fold, p < 0.05). Since this drug interaction may occur at the level of CYP2C9, we also assessed the impact of CYP2C9 genotype in our model. The impact of CYP2C9 genotype was marginally significant (p = 0.119, non-pooled dataset; p = 0.053, data pooled for CYP2C9 *2/*2, *2/*3 and *3/*3). CONCLUSIONS: Age and concomitant sulfonylurea therapy alter the rate of anticoagulation during the first 30 days of warfarin therapy.

Age Factors↗
PubMed2005

Gene-based drug prescribing: clinical implications of the cytochrome P450 genes.

The Institute of Medicine recently mandated an increased effort to improve patient safety and reduce medical error. With the description of genetic polymorphisms in the drug metabolizing enzymes, the field of pharmacogenetics may improve medical care through a reduction in both therapeutic failure and adverse drug reaction. Investigators at the Marshfield Clinic in central Wisconsin are piloting the process of gene-based drug prescribing in a variety of contexts. This paper reviews the field of cytochrome P450 (CYP) genetics and explores factors that impact the utility of this information in clinical practice.

Cytochrome P-450 Enzyme System↗
PubMed2004

Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype.

Patients on warfarin anticoagulant therapy demonstrate wide variation in maintenance dose. Patients possessing variants (*2 and *3) of the cytochrome P450 2C9 gene require reduced maintenance doses compared to those having wild-type alleles (*1). Many other clinical factors have been shown to affect warfarin dose as well. To determine the relative impact of CYP2C9 genotype, age, gender, body surface area, concomitant medication, treatment indication and comorbidity, we conducted a retrospective cohort study in 453 patients managed by the anticoagulation service of a large, horizontally integrated, multispecialty group practice. In this largely Caucasian patient population, the CYP2C9 gene frequencies for *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 65.1%, 19.0%, 12.1%, 1.6%, 1.8% and 0.4%, respectively, approximating Hardy-Weinberg equilibrium. Mean maintenance doses for these genotypes were 36.5, 29.1, 23.5, 28.0, 18.1 and 5.5 mg/week, respectively. In univariate analyses, genotype alone accounted for 19.8% of the variability in maintenance dose. Age, body surface area and male gender accounted for 14.6%, 7.5% and 4.7%, respectively, while cardiac valve replacement as the indication for warfarin accounted for 5.4% of the variability. Collectively, these factors accounted for 33.7% of all dosing variability according to multiple regression. These results will help strengthen the mathematical models that are currently being developed for prospective gene-based warfarin dosing.

Anticoagulants↗
PubMed2003

Methylmercury induces apoptosis in cultured rat dorsal root ganglion neurons.

Methylmercury is known to have devastating effects on the mammalian nervous system. In order to characterize the dose dependence of methylmercury-induced neurotoxicity, we first studied neurite outgrowth from rat dorsal root ganglia explants. In this model, methylmercury inhibited neurite outgrowth with a TD(50) of approximately 0.5 microM. We then used this relationship to optimize dosing for subsequent transcriptional profiling analyses in two independent neuronal model systems: dissociated sensory neurons and PC12 cells. As seen in previous studies, the expression of a number of genes associated with oxidative stress was altered following a 6h challenge with 1 microM methylmercury. When PC12 cells were subjected to a longer exposure (24h), a relative increase was noted in the representation of genes associated with cell cycling and apoptosis. To confirm the presence of apoptosis in cultured neurons, we then applied TUNEL staining and bis-benzimide staining techniques to primary cultures of dissociated sensory neurons. After 24h, 1 microM methylmercury increased both DNA end-labeling (P<0.01) and nuclear fragmentation (P<0.02). The latter effect appeared to be dose-dependent.

Animals↗