Aileen Luzier

Gender‐related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers

To determine whether there are gender‐specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers.

Impact of angiotensin-converting enzyme inhibitor underdosing on rehospitalization rates in congestive heart failure

In a retrospective, cohort design, clinical usage of digoxin, diuretic, and angiotensin-converting enzyme (ACE) inhibitor was assessed in all patients readmitted over a 36-month period for congestive heart failure (CHF) diagnostic-related group (DRG) 127. ACE inhibitor dose-response analysis used the discharge dose of ACE inhibitor, converted to enalapril-equivalent doses and adjusted for renal function. Principal end points were time-to-readmission and 90-day readmission rate. Of 314 total patients, digoxin was used in 72%, diuretic in 86%, and 67% received an ACE inhibitor. Only 22% of those on an ACE inhibitor received currently recommended doses of enalapril > or = 20 mg/day or equivalent, whereas 41% received enalapril < or = 5 mg/day. Time-to-readmission was increased by an ACE inhibitor (p = 0.002) but not digoxin or diuretic. An ACE inhibitor was the principal covariate of 90-day readmission rate (p <0.05). The readmission rate was not reduced with daily ACE inhibitor doses of < or = 5 mg enalapril, whereas daily doses of > or = 10 mg enalapril reduced 90-day readmission rates by 28% compared to those receiving diuretic or digoxin therapy (p <0.05). Using a dynamic model, the dose required to achieve 90% to 95% of the theoretical maximum ACE inhibitor effect exceeded 100 mg enalapril daily. Thus, CHF readmission rates are lower when daily ACE inhibitor doses exceed 5 mg enalapril or the equivalent daily, but are unaffected by digoxin or diuretic. Modeled maximum ACE inhibitor benefits require doses 8- to 10-fold higher than current usage patterns.

Homocysteine as a Risk Factor for Atherosclerosis

OBJECTIVE: To review the role of homocysteine as a risk factor in the pathogenesis of atherosclerosis and to provide recommendations for the treatment of hyperhomocysteinemia. DATA SOURCES: A MEDLINE search using key terms such as homocysteine, atherosclerosis, folic acid, vitamin B6, and vitamin B12 was conducted for the time period 1966 through January 1999. STUDY SELECTION: An article was selected for inclusion in this review if it assessed the relationship and proposed mechanisms of hyperhomocysteinemia on the vasculature, physiologic changes due to hyperhomocysteinemia, and outcomes due to hyperhomocysteinemia, such as morbidity and mortality. In addition, studies that assessed the treatment outcomes of hyperhomocysteinemia were evaluated. DATA SYNTHESIS: Studies of patients with cerebral vascular disease reveal elevated homocysteine concentrations in 30–40% of patients compared with controls. Many studies demonstrate a correlation between elevated homocysteine concentrations, risk of myocardial infarction, and mortality. In addition, hyperhomocysteinemia and decreased folic acid concentrations have been identified in end-stage renal disease (ESRD) and type 2 diabetic patients, while both concentrations remained normal in healthy controls. Studies using folic acid 650 μg/d reduced homocysteine concentrations to within normal therapeutic range after two weeks of treatment. Studies with vitamins B6 and B12 have demonstrated that the use of either alone is ineffective, but when combined or administered with folic acid, homocysteine concentrations return to normal. All therapies must be given for the lifetime of the patient. In addition, patients must use discretion in their diet, as common beverages, such as coffee, have a strong correlation with hyperhomocysteinemia, while foods high in folic acid, vitamin B6 and vitamin B12 may reduce homocysteine concentrations. Additional prospective studies are needed to determine effects of treatment of hyperhomocysteinemia and various diets on atherosclerotic morbidity and mortality. CONCLUSIONS: Studies demonstrate a positive correlation between hyperhomocysteinemia and atherosclerosis. The treatment of choice for hyperhomocysteinemia is folic acid. Although the optimal dose is not known, 650 μg/d is the minimum effective dose. To date, no studies have assessed the effects on morbidity and mortality when treating high homocysteine concentrations in atherosclerotic patients.

Containment of heart failure hospitalizations and cost by angiotensin-converting enzyme inhibitor dosage optimization

Using our model relating angiotensin-converting enzyme (ACE) inhibitor dosing and outcomes in heart failure (HF), we designed a prospective intervention trial for patients with systolic dysfunction. A clinical pharmacist initiated or titrated ACE inhibitor therapy or adjusted other medications within an HF management program based on Agency for Healthcare Policy and Research guidelines. Entry into the protocol required the approval of the attending physician. All patients received dietary, nursing, rehabilitation, social service, and clinical pharmacy consultations. Treatment conformed to Agency for Healthcare Policy and Research guidelines in 25% of patients (group A). Suboptimal therapy (75% of patients) was usually due to failure to administer an ACE inhibitor (48%) or inadequate dosing of an ACE inhibitor (46%). In 62% of suboptimal cases, the attending physician agreed to follow the clinical pharmacists recommendations (group B). Patients of physicians who declined pharmacist intervention served as a negative control (group C). On admission, mean enalapril-equivalent daily doses in groups A, B, and C were 30, 4, and 6 mg, respectively, and at discharge, 36, 18, and 6 mg, respectively. At 180 days, rehospitalization frequency and total charges were lower in groups A (31% and

The Effects of Gender on Adrenergic Receptor Responsiveness

5,600) and B (35% and

Reteplase: A New Thrombolytic for the Treatment of Acute Myocardial Infarction

3,800) than in group C (63% [p <0.004] and

Intravascular distribution of zidovudine: role of plasma proteins and whole blood components.

9,800 [p <0.04]). Thus, optimization of ACE inhibitor doses by a clinical pharmacist can greatly improve rehospitalization rates and significantly lower cost of care in an HF management program.

Mathematical Examination of Dual Individualization Principles (III): Development of a Scoring System for Pneumonia Staging and Quantitation of Response to Antibiotics: Results in Cefmenoxime-Treated Patients

This study was conducted to determine whether gender differences exist in adrenergic receptor sensitivity and baroreflex response. Adrenergic receptor sensitivity was assessed by administering sequentially increasing intravenous doses of phenylephrine and isoproterenol. Baroreflex sensitivity was determined from the slope of pulse intervals plotted against phenylephrine‐induced rise in systolic blood pressure (SBP). Drug‐induced changes in heart rate, blood pressure, and brachial artery diameter were measured and statistically compared. Women required a lower infusion rate of phenylephrine to increase SBP by 20 mmHg from baseline. There were no statistically significant gender‐related differences in baroreflex sensitivity. The dose of isoproterenol needed to increase heart rate by 25 beats per minute from baseline also did not differ significantly between groups. Percent changes from baseline in brachial artery diameters in response to phenylephrine also were similar between groups. These data suggest that women may have greater α1‐adrenergic receptor sensitivity than men, whereas β‐adrenergic receptor sensitivity is similar between genders. A trend toward a greater baroreflex sensitivity in men than in women was also observed. This study also provides evidence for a possible relationship between adrenergic receptor sensitivity and baroreflex sensitivity.

Acid‐Suppressive Therapy Use Associated with Antihypertensive Agents

OBJECTIVE: To summarize the published data on reteplase, the most recent thrombolytic agent approved by the Food and Drug Administration for use in the management of acute myocardial infarction in adults. DATA SOURCES: Published data on reteplase identified by MEDLINE searches (January 1985–June 1997), as well as other pertinent literature. DATA SYNTHESIS: Reteplase is a new thrombolytic agent derived from human tissue plasminogen activator. Its mechanism of action is similar to that of alteplase, but it differs in pharmacokinetic and pharmacodynamic properties. Certain structural changes contribute to differences in pharmacokinetic properties such as a prolonged half-life (15 min), which allows it to be administered as two 10-MU bolus injections. Reteplase has been shown to have fibrin specificity similar to that of alteplase, but with a lower binding affinity for fibrin. This enables reteplase to bind to the thrombus repeatedly and increases its fibrinolytic potential. In clinical trials, reteplase demonstrated more rapid and complete coronary patency compared with alteplase, without a significant increase in clinical adverse events. However, the improvement in coronary artery patency with reteplase versus alteplase did not result in a reduction in mortality in the GUSTO III trial. CONCLUSIONS: Despite evidence that use of reteplase results in an improved coronary artery patency rate versus accelerated infusion alteplase, an improvement in mortality rate with reteplase was not shown. Reteplase may have an advantage over alteplase due to a more rapid and simpler dosing regimen, but the significance of this difference is yet to be determined.

Patterns of prescribing ACE inhibitors after myocardial infarction

Knowledge of drug protein-binding and blood cell partitioning may be important for evaluating the pharmacokinetic parameters of zidovudine, particularly because of its intracellular site of action and potential to induce side effects. Equilibrium dialysis studies of zidovudine were performed over 2 h to identify the extent and site of binding. Zidovudine was added to anticoagulated whole blood to study blood cell distribution over a 24 h period at 37 degrees C and at 21 degrees C. Concurrent plasma and whole blood samples were determined at various time-points and blood partitioning was determined by application of a mass balance equation. All samples were analyzed using radioimmunoassay. The free fraction of zidovudine at a concentration of 500 ng/ml (1.7 microM) was 0.77 +/- 0.05 in plasma, 0.78 +/- 0.03 in serum, 0.88 +/- 0.03 in 4 g/dl albumin solution, and 1.0 in 100 mg/dl alpha 1-acid glycoprotein solution. A free fraction of 0.72 +/- 0.10 was observed in plasma from HIV-infected patients with zidovudine concentrations ranging from 16 to 91 ng/ml. Zidovudine equilibration between plasma and blood cells occurred rapidly, being complete within 10 min. After equilibrium was complete, the mean whole blood:plasma ratio was 0.86 +/- 0.02 and 0.80 +/- 0.04 (P = 0.20) and mean blood cell Partitioning ratio, [cell]/[plasma-free], was 0.85 +/- 0.06 and 0.66 +/- 0.14 (P = 0.25) for studies at 37 degrees C and 21 degrees C, respectively. The partitioning ratio was relatively consistent over the study period, suggesting no accumulation in blood cells. These results suggest that zidovudine binds to a small extent primarily to albumin. The free concentration equilibrates readily between blood cells and plasma independent of concentration and without signs of accumulation.