David F. Lehmann

The Cardiovascular Toxicity of Selective and Nonselective Cyclooxygenase Inhibitors: Comparisons, Contrasts, and Aspirin Confounding

The premature suspension of the Alzheimer Disease Anti‐inflammatory Prevention (ADAPT) and the Adenoma Prevention with Celecoxib (APC) trials prompted intense review of the cardiovascular safety profile of selective and nonselective cyclooxygenase (COX) inhibitors. This article reviews the current state of selective COX‐2 inhibitors, discusses the mechanistic evidence underlying the cardiovascular risk associated with selective COX‐2 inhibition, outlines the pharmacodynamics of aspirin effects on platelets and the interference of propionic acid derivatives (ibuprofen and naproxen) with these effects, and poses that aspirin confounding may have led to the erroneous conclusion of naproxen‐associated adverse cardiovascular outcomes in the ADAPT trial. Finally, recommendations regarding selective COX‐2 inhibitors and appropriate timing of aspirin coadministration with traditional NSAIDs are proposed in relevance to patient safety and future trial design.

Mississippi Mud No More: Cost‐Effectiveness of Pharmacokinetic Dosage Adjustment of Vancomycin to Prevent Nephrotoxicity

Objective. To determine the cost‐effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity. An analysis was performed for subpopulations of patients receiving nephrotoxic agents (aminoglycosides, amphotericin, and acyclovir), those in the intensive care unit, and those on the oncology service.

Polymorphisms and the pocketbook: the cost-effectiveness of cytochrome P450 2C19 genotyping in the eradication of Helicobacter pylori infection associated with duodenal ulcer

The clinical outcome of duodenal ulcer treated with proton pump inhibitor (PPI)–based, anti—Helicobacter pylori (H.p.) regimens varies according to cytochrome P450 2C19 (CYP2C19) genotype. CYP2C19 genotypes differ markedly in peoples of Pacific Rim descent compared with another ethnicity. The authors sought to determine the specific impact that these factors have on the cost‐effectiveness of duodenal ulcer management. Their model consisted of two patient cohorts with Helicobacter pylori and duodenal ulcer, trichotomized into CYP2C19 homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs), altering the anti‐H.p. regimen in the genotyped cohort only. The authors took the perspective of a third‐party payer, and the denominator was ulcer episode prevented. In the reference case, the use of CYP2C19 genotyping prior to initiating anti‐H.p. therapy was dominant (costs were saved with each ulcer episode prevented) in all geographic regions of the United States. The subsequent break‐even analysis showed a range of

Enzymatic shunting : Resolving the acetaminophen-warfarin controversy

89.20 to

Every Error a Treasure: Improving Medication Use with a Nonpunitive Reporting System

118.96—from Hawaii to the Midwest, respectively—required to eliminate the cost‐savings from each genotype test performed. Using probabilities most unfavorable to genotyping, the variation of peoples with Pacific Rim origins from 0% to 100% altered the cost‐effectiveness from

Lack of Attenuation in the Antitumor Effect of Tamoxifen by Chronic CYP Isoform Inhibition

495 to

Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End‐Stage Renal Disease Requiring Chronic Hemodialysis

2125 per ulcer event prevented, respectively. The results suggest that treatment decisions for H.p. infection that are based on a patients CYP2C19 genotype decreases expenses for health plans implementing testing. This analysis provides an economic basis to support recent calls to expand this technology into routine clinical care to prevent toxicity of narrow therapeutic index drugs.

Hospital Pharmacology: An Alternative Model for Practice and Training in Clinical Pharmacology

Observational studies in patients have shown a dose‐dependent enhancement of the anticoagulant effect of warfarin by acetaminophen whereas pharmacodynamic studies in healthy human volunteers have shown no such effect. This controversy is further intensified because any interaction between acetaminophen and racemic warfarin can involve only the weaker R‐warfarin enantiomer. Certain drugs exclusively competing for the metabolism of R‐warfarin enhance the anticoagulant effect of racemic warfarin and others do not. Because R‐warfarin is a weak inhibitor of vitamin K epoxide reductase and is metabolized by cytochrome P450 (CYP) 1A2 and 3A4, it is hypothesized that simultaneous competition with R‐warfarin for CYP1A2 and 3A4 is required for drug interactions to be clinically significant with compounds exclusively affecting the R enantiomer, such as acetaminophen. The discrepant observations in the literature regarding the clinical significance of the acetaminophen‐warfarin interaction may be resolved if the hepatic enzyme activity of CYP1A2 and 3A4 is enhanced relative to CYP2E1 and the nonoxidative pathways of glucuronidation and sulfation responsible for acetaminophen metabolism. Conditions such as aging and tissue hypoxia alter the relative activity of these enzymatic pathways in vitro and in small human studies. These phenomena may be manifested clinically when acetaminophen is administered to older anticoagulated patients and those with conditions that affect cardiac output such as atrial fibrillation and congestive heart failure. Verifying this hypothesis may provide insight into the clinically relevant interplay between common conditions as they affect oxidative and nonoxidative pathways of drug metabolism.

Profound metoprolol-induced bradycardia precipitated by acetaminophen-propoxyphene.

BACKGROUND The fear of reprisal, combined with the additional time required for reporting, are significant disincentives to reporting of medical events. Such considerations provided an incentive for the Upstate Medical University Hospital (Syracuse, New York) to develop monitoring systems to decrease the potential for drug harm. IMPLEMENTING A NONPUNITIVE REPORTING SYSTEM: Previously, a convenient, point-based score card system for punishment and remediation led to underreporting and hindered the identification of safety improvement opportunities in medication use processes. Nursing buy-in was accomplished through careful initial negotiations that emphasized that patients were best served by learning from errors in the medication use process. The revised medication event reporting policy, as established in October 2000 for all staff, severed the link between reporting errors and performance evaluations. RESULTS Data collected 18 months before the policy change was compared with data collected after the policy change was enacted in October 2000. The number of reports received each month increased from an average of 19 to 102 (p < .001). DISCUSSION Substantive quality improvements in medication have been achieved by using a systematic approach to the analysis of the markedly increased number of reported medication events following the introduction of a nonpunitive reporting system.

Observation and experiment on the cusp of collaboration: a parallel examination of clinical pharmacology and pharmacoepidemiology.

Tamoxifen is a selective estrogen receptor modulator used in estrogen receptor‐positive breast cancer. Tamoxifen is metabolized to an extremely potent antiestrogen by cytochrome P450 (CYP) 2D6, 2C9, and 3A isoforms. The selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of these CYPs. Since the prevalence of depression in breast cancer patients is nearly triple that of the general population, it is likely that a subgroup of breast cancer patients will receive long‐term treatment with both an SSRI and tamoxifen. A case control design was used to investigate the possibility that a resultant decrease in production of the 4‐hydroxy metabolite from chronic inhibition results in the attenuation of the antitumor effect of tamoxifen. Twenty‐eight patients without recurrences of breast cancer (controls) were matched to an equal number of cases (recurrences) by cancer stage and year of diagnosis. Data were analyzed on all chronic medication exposure (> 3 months) in both cases and controls classified as to their status as CYP 2D6, 2C9, and 3A inhibitors, substrates, or inducers. No significant difference was found for CYP inhibitor or substrate exposure between cases and controls. Indeed, controls showed a slightly greater exposure to inhibitors of the relevant CYP isoforms compared to cases. These results suggested a trend toward the null hypothesis. It is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4‐hydroxy metabolite, supporting the safety of the continued practice of concomitant SSRI administration to breast cancer patients with depression.