Management of the behavioral manifestations of dementia.

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.

Potential warfarin-ciprofloxacin interaction in patients receiving long-term anticoagulation.

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.

A statistical and clinical evaluation of fingerstick and routine laboratory prothrombin time measurements.

STUDY OBJECTIVE: To compare prothrombin time measurements by fingerstick and routine laboratory methods. DESIGN: Prospective cohort study. SETTING: University-affiliated anticoagulation clinic. PATIENTS: Thirty-three patients receiving warfarin with stable anticoagulation for 3 months preceding the two studies. INTERVENTIONS: Groups 1 (17 patients) and 2 (16 patients) provided 150 and 125 paired samples, respectively, for fingerstick and routine laboratory analysis. The fact that no patient required a dosage change allowed for a clinical assessment. MEASUREMENTS AND MAIN RESULTS: Correlation and agreement between methods were good in group 1 but poor in group 2. Fingerstick results were less variable (smaller standard deviation and smaller coefficient of repeatability) in both groups. By analysis of discrepant pairs (25 in group 1, 63 in group 2), the routine laboratory results indicated dosage changes erroneously more often than did the fingerstick method. CONCLUSIONS: In these two trials, the fingerstick system was superior to the routine laboratory method in that it was more reliable (less variability and more repeatable) and less likely to indicate dosage changes erroneously.

Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.

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.

Principles and clinical applications of positron emission tomography.

The basics of positron emission tomography (PET) are presented, including the physics, instrumentation, and radiopharmaceuticals involved; the clinical and research applications; and the cost. In PET, organic molecules labeled with positron-emitting radionuclides are injected or inhaled, and the high-energy photons produced by annihilation events are detected by paired, integrated crystal detectors. A computer uses the lines of origin of these photons to reconstruct a three-dimensional map of a functioning organ system. The positron-emitting radionuclides most often used are carbon 11, oxygen 15, nitrogen 13, fluorine 18, and rubidium 82. PET imaging centers usually consist of a cyclotron facility, a radiochemistry facility, a PET scanner, and computers for image reconstruction. Radiopharmaceuticals used in PET may be divided into blood flow-imaging agents, metabolic imaging agents, and drug receptor-imaging agents. Although PET is still primarily a research tool, it has shown diagnostic potential in neurology, cardiology, and oncology. It has also shown promise as a tool for pharmacologic assessment, as in studies of the effects of the fluorinated quinolones on cerebral blood flow and glucose metabolism. PET may become important in drug development because it yields specific information relatively noninvasively. A single study carries an average break-even price tag of $1500-$2000; rigorous cost-benefit analyses should be conducted before society is asked to subsidize such costs. Positron emission tomography is a frontier technology for which valuable clinical applications are being discovered. Pharmacists can contribute enormously to PET applications and at the same time establish a unique subspecialty for the profession.

The J-curve phenomenon and the treatment of hypertension. Is there a point beyond which pressure reduction is dangerous?

We critically appraised the medical literature to evaluate whether there is a point beyond which blood pressure reduction in hypertensive subjects is no longer beneficial and possibly even deleterious. Thirteen studies that stratified cardiovascular outcomes by level of achieved blood pressure in treated hypertensive subjects who had been followed up for at least 1 year were critiqued by four independent reviewers. Data addressing population, protocol, and methodological characteristics were evaluated. Studies did not show a consistent J-shaped relationship between treated blood pressure and stroke, but they did demonstrate a consistent J-shaped relationship for cardiac events and diastolic blood pressure. The beneficial therapeutic threshold point was 85 mm Hg. We conclude that low treated diastolic blood pressure levels, ie, below 85 mm Hg, are associated with increased risk of cardiac events.

Hypertension in the elderly. Implications and generalizability of randomized trials.

OBJECTIVE: To estimate morbidity and mortality benefits of drug therapy for hypertensive elderly subjects, compare these benefits with effects in younger subjects, and provide a framework for generalizing results derived from trials to actual patients. DATA SOURCES: A literature search using MEDLINE from 1966 to 1993, references from reviews and trial articles, and experts. STUDY SELECTION: Randomized trials lasting at least 1 year that evaluated effects of drug treatment on morbidity and mortality outcomes in hypertensive persons. DATA EXTRACTION: Four independent reviewers appraised protocol characteristics and quality of selected trials. DATA SYNTHESIS: There were 13 trials involving 16,564 elderly persons (age 60 years and older). The prevalence of cardiovascular risk factors, cardiovascular disease, and competing comorbid diseases was lower among trial participants than the general population of hypertensive elderly persons. When the six large high-quality trials were combined, trial results showed 43 subjects (95% confidence interval [CI], 31 to 69) and 61 subjects (95% CI, 39 to 141) needed to be treated for 5 years to prevent one cerebrovascular event and one coronary heart disease event, respectively. Including the other seven trials did not change the results significantly. Only 18 subjects (95% CI, 14 to 25) needed to be treated to prevent one cardiovascular event (cerebrovascular or cardiac). Twelve trials in primarily younger and middle-aged adults involved approximately 33,000 persons. For all outcomes except cardiac mortality, two to four times as many of the younger subjects as the older subjects needed to be treated for 5 years to prevent morbid and mortal events. No significant effect on cardiac mortality was seen among younger subjects, while 78 older subjects (95% CI, 50 to 180) needed to be treated to prevent a fatal cardiac event. CONCLUSIONS: Randomized trials demonstrate that treating healthy older persons with hypertension is highly efficacious. Five-year morbidity and mortality benefits derived from trials are greater for older than younger subjects. Extrapolating benefits from trials to individual patients is difficult, but should take into account multiple issues including the patient's risk factors, preexisting cardiovascular disease, and competing comorbid illnesses.