Larry M. Lopez

Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements

The primary objective of this study was to determine whether variability in warfarin dose requirements is determined by common polymorphisms in genes whose products are involved in the pharmacodynamics and pharmacokinetics of warfarin, namely, the coagulation factors, vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 (CYP) 2C9.

Effects of titrated beta blockade (metoprolol) on silent myocardial ischemia in ambulatory patients with coronary artery disease

This study investigates effects of beta-adrenergic blockade on total silent ischemic time assessed by ambulatory electrocardiographic monitoring and its relation to heart rate and time of day in ambulatory men with coronary artery disease. Metoprolol, when titrated to optimal dose in a controlled trial in 9 patients, reduced both total silent ischemic time (from 156 +/- 65 to 20 +/- 15 minutes, p = 0.04) and frequency of silent ischemic episodes (from 8 +/- 2 to 2 +/- 2 episodes, p = 0.03) compared with placebo. Mean daily heart rate was reduced, from 82 +/- 2 beats/min during placebo to 58 +/- 1 beats/min, as was heart rate at onset of 1 mm of ST-segment depression (106 +/- 2 to 74 +/- 4 beats/min, both p less than 0.001). Heart rate increased 10 +/- 1 beats/min during silent ischemia with placebo therapy, but increased only 4 +/- 1 beats/min during metoprolol treatment (p less than 0.03). During placebo administration the largest proportion of silent ischemic time occurred between 0600 and 1200 hours. Metoprolol attenuated this circadian variation in silent ischemia while reducing (p less than 0.05) total silent ischemic time in all periods. Thus, beta-adrenergic blockade reduces the frequency of silent myocardial ischemic episodes and total silent ischemic time, while mean daily heart rate and heart rate at onset of ischemia and maximal ischemia decrease. Metoprolol treatment also attenuates circadian variation of silent ischemia. These data may be interpreted to suggest that beta-adrenergic activation operates in the pathogenesis of silent myocardial ischemia and its circadian variation.

Dietary supplementation with omega-3 polyunsaturated fatty acids in patients with stable coronary heart disease: Effects on indices of platelet and neutrophil function and exercise performance

It has been suggested that omega-3 polyunsaturated fatty acids (PUFAs) may alter the course of coronary artery disease by influencing platelet and neutrophil function, arachidonic acid metabolism, and circulating lipid concentrations. To examine this hypothesis, placebo or omega-3 PUFAs as Max-EPA (equivalent to 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid daily) was administered to eight patients with stable coronary artery disease and positive exercise stress test results in a randomized, double-blind, crossover fashion over a 12-week period. With Max-EPA administration, platelet aggregation threshold to epinephrine was increased in only two patients, but neutrophil aggregation and chemotaxic functions decreased consistently (both p less than or equal to 0.01 compared with preceding placebo phase) in all eight. Serum and platelet-rich plasma thromboxane B2 concentrations decreased 40 percent and 28 percent, respectively (both p less than or equal to 0.05). Neutrophil leukotriene B4 formation decreased 23 percent (p less than or equal to 0.01) and synthesis of leukotriene B5 became apparent in all subjects. Serum triglyceride concentrations fell 52 percent (p less than or equal to 0.05) without significant change in total cholesterol, high-density lipoprotein-cholesterol, or low-density lipoprotein-cholesterol concentrations. Systolic blood pressure and the double product (heart rate X systolic blood pressure) were lower (p less than or equal to 0.05) at the end of the Max-EPA phase than in the preceding placebo phase. Heart rate, systolic blood pressure, and the double product were also lower (p less than or equal to 0.05) at three as well as at six minutes of an exercise stress test, indicating a significant reduction in myocardial oxygen demand. Despite these alterations in platelet and neutrophil function, arachidonic acid metabolism, serum triglyceride concentrations, and myocardial oxygen demand, there were no significant changes in subjective parameters of coronary artery disease during the Max-EPA phase (angina frequency 3.7 versus 2.8 episodes per week, nitroglycerin consumption 3.0 versus 1.9 tablets per week, both p = NS). Similarly, exercise times to ST-segment depression (6.5 versus 4.1 minutes) and to onset of angina (5.4 versus 5.0 minutes) were not altered by administration of Max-EPA. Thus, short-term dietary supplementation with omega-3 PUFAs to patients with stable coronary artery disease does not appear to alter subjective or objective parameters of myocardial ischemia.

Alterations in nitric oxide synthase activity, superoxide anion generation, and platelet aggregation in systemic hypertension, and effects of celiprolol.

A decrease in endothelium-derived relaxing factor or nitric oxide has been proposed as a potential mechanism of increased vascular resistance in hypertension. An increase in the generation of superoxide anions, which degrade nitric oxide and induce platelet aggregation, may also compromise regional blood flow in hypertension. Recent studies show that human neutrophils generate nitric oxide, which has a similar biologic profile to the endothelium-derived relaxing factor. This study measured nitric oxide synthase activity and superoxide generation in human neutrophils and platelet aggregation in patients with essential hypertension. Nitric oxide synthase activity, measured as conversion of 3H-L-arginine to 3H-L-citrulline, in peripheral blood neutrophils was decreased in hypertensive subjects (percent conversion of 3H-L-arginine: 4.2 +/- 0.5 vs 9.0 +/- 3.0 in control subjects; p < 0.01). Neutrophil superoxide anion generation, measured as conversion of ferricytochrome C to ferrocytochrome C, in response to phorbol-12-myristate 13-acetate (100 ng/ml) was higher in hypertensive subjects (17.5 +/- 8.1 vs 13.2 +/- 3.0 nmoles/10(6) cells/10 minutes in control subjects; p < 0.05). Patients were treated with a selective beta blocker, celiprolol, for 8 weeks. Supine blood pressure decreased from 177/103 mm Hg (mean +/- SD 18/7) to 160/92 mm Hg (mean +/- 10/5; p < 0.02), while heart rate was unchanged (73 +/- 11 vs 69 +/- 10 beats/min). Epinphrine and adenosine diphosphate-induced platelet aggregation was also increased in hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Eicosapentaenoic acid: its relevance in atherosclerosis and coronary artery disease.

E pidemiologic studies have shown a much lower prevalence of atherosclerosis and coronary artery disease {CAD} in Greenland Eskimos and Arctic populations than in populations of Western Europe. 1,2 It has been suggested that the composition of food consumed by different populations may account for these differences in prevalence of atherosclerosis. 3 The major food consumed by the Arctic population is fish and its components such as meat, blubber and intestines. Red meat and dairy products account for only a small portion of the total diet of these people. In contrast, major dietary constituents in Western populations are red meat and dairy products. Generally, the Arctic populations consume more protein, equivalent amounts of fat and less carbohydrate than the Western populations, but the composition of fatty acid in the diet is different. The most significant differences in the fatty acid content of diets of Eskimos and Danes are: higher content of highly polyunsaturated acids and eicosapentaenoic {EPA} and docosahexaenoic {DHA} acids in the Arctic diet and higher linolenic acid content in the Danish diet. It has been hypothesized that a higher content of EPA derived from fish may relate to the lower prevalence of atherosclerosis and CAD in Arctic populations. 1-3 EPA and DHA belong to the omega-3 family, which means that I double bond is only 3 carbon atoms away from the methyl end of the 20-carbon chain. In con-

Impact of a Pharmaceutical Care Intervention on Blood Pressure Control in a Chain Pharmacy Practice

BACKGROUND Hypertension affects over 50 million Americans, with only 50% of patients being adequately controlled. Several pharmacist counseling and pharmacist-physician comanagement studies have documented that community pharmacist interventions improve blood pressure (BP) management. OBJECTIVE To determine whether community pharmacists can improve clinical endpoints including hypertension control, drug therapy dosing, adherence to prescribed regimens, adverse drug reaction incidence, patient understanding, response to therapy, and quality-of-life. METHODS The program included the education and training of a group of 18 chain community pharmacists in hypertension therapies, monitoring, and management. Protocols and documentation tools were based on nationally accepted clinical practice guidelines for hypertension in place at the time of the study. Pharmaceutical care (PC) was then compared with usual care (UC) over a 12-month period. RESULTS The study initially enrolled 180 PC and 196 UC patients, with 44% (PC) and 32% (UC) of the patients reporting a final BP measurement. A larger proportion (50%) of PC patients who had poorly controlled hypertension at baseline (>140/90 mm Hg) were controlled compared with UC patients (22%). The average reduction in systolic BP was 9.9 mm Hg in PC patients compared with 2.8 mm Hg in UC patients (p < 0.05). Changes in diastolic BP were similar in the PC and UC groups. Based on patient self-report, PC patients were more likely to say that they take their medicines as prescribed compared with UC patients (p < 0.05). The 1- to 6-month antihypertensive adherence rate was higher in PC patients (0.91 ± 0.15) compared to UC patients (0.78 ± 0.30) (p = 0.02); there was no significant difference in adherence rate during the 7- to 12-month period. CONCLUSIONS Community pharmacists can positively affect patient medication adherence during the 6-month period following counseling by a pharmacist along with an improvement in patient BP. However, there is much room for improvement in PC programs and in the number of patients who properly adhere to their medications.

New Recommendations from the 1999 American College of Cardiology/American Heart Association Acute Myocardial Infarction Guidelines

OBJECTIVE: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines. STUDY SELECTION: The articles selected influence AMI treatment recommendations. DATA SYNTHESIS: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described. CONCLUSIONS: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST—segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. β -Adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy for vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.

Cholesterol: Point-of-Care Testing

OBJECTIVE: To review the literature regarding point-of-care (POC) cholesterol monitors and describe their role in pharmacy practice. DATA SOURCES: Primary articles were identified by a MEDLINE search (1966–May 2003); references cited in these articles provided additional resources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from this search were reviewed, and all information deemed relevant was included. DATA SYNTHESIS: Hyperlipidemia is a well-established risk factor for coronary artery disease, which is the leading cause of death in the US. The use of POC cholesterol monitors may help to improve the identification and management of this disease. Pharmacists may use many of these devices in their practice and are also in an ideal position to provide patient education on selection and use of these monitors and interpretation of the results. CONCLUSIONS: The availability of POC cholesterol monitors has increased in recent years. Based on currently available data, these monitors are best suited for screening purposes and to assist in the management of hyperlipidemia. There is not enough evidence to support the notion that POC cholesterol monitors can replace laboratory or office monitoring. Their application in the diagnosis of hyperlipidemia is also currently limited.

Improvement in exercise performance with nisoldipine, a new second-generation calcium blocker, in stable angina patients☆

Safety and efficacy of a new dihydropyridine calcium antagonist, nisoldipine, were studied in 15 patients with proved coronary artery disease and positive exercise treadmill tests. After withdrawal of current therapy and a 2-week placebo phase, patients were given nisoldipine 10, 20, and 40 mg daily (divided into two daily doses), each dose for a 2-week period. Exercise treadmill testing was performed twice during the placebo and once at the end of each nisoldipine phase. Maximal duration of exercise increased with all doses of nisoldipine. Time to 1 mm ST segment depression also increased with all doses of nisoldipine. Peak time to angina was similarly prolonged. Peak exercise double product (heart rate X systolic blood pressure) was unaffected by all doses of nisoldipine. Angina frequency and nitroglycerin consumption decreased during nisoldipine therapy in all patients. Side effects from therapy were only minor. Twice daily therapy compared to three to four times daily therapy with other calcium blockers is an advantage of nisoldipine.

Effects of Intermittent Transdermal Nitroglycerin on Occurrence of Ischemia After Patch Removal: Results of the Second Transdermal Intermittent Dosing Evaluation Study (TIDES-II)

OBJECTIVES We sought to evaluate the effects of intermittent transdermal nitroglycerin (TD-NTG) on the occurrence of ischemia during patch-off hours in patients with stable angina pectoris receiving a beta-adrenergic blocking agent or calcium antagonist, or both. BACKGROUND The current recommendations for the use of intermittent TD-NTG may be associated with the occurrence of rebound ischemia. METHODS This was a multicenter, randomized, double-blind, placebo-controlled, crossover trial with three study periods. Tolerability to TD-NTG was assessed in Period I. Seventy-two patients were assigned to receive either double-blind transdermal placebo or maximally tolerated TD-NTG for 2 weeks (Period II) and were then crossed over to the alternative treatment for another 2 weeks (Period III). The patients were instructed to apply medication daily at 8 AM, to remove it at 10 PM and to note symptoms and sublingual nitroglycerin (SL-NTG) use in a diary. The occurrence of ischemia was assessed from patient-perceived angina, symptom-limited exercise treadmill test (ETT) and 48-h ambulatory electrocardiographic (AECG) monitoring. RESULTS Transdermal NTG (0.2 to 0.4 mg/h) significantly reduced the magnitude of ST segment depression at angina onset during ETT compared with placebo. Total angina frequency was not significantly different between TD-NTG (mean [+/-SD] 3.2 +/- 4.2) and placebo (3.3 +/- 5.2). During patch-off hours, angina frequency increased with TD-NTG (1.1 +/- 2.1) compared with placebo (0.7 +/- 1.6) (p = 0.03). Similar trends for an increase in ischemia after TD-NTG were also observed from AECG analyses. Specifically, ischemia frequency tended to be lower during patch-off hours for placebo than with TD-NTG (0.05 +/- 0.09 vs. 0.08 +/- 0.20 episodes/h, respectively, p = 0.08), even though frequency of ischemia tended to be higher during patch-on hours for placebo than with TD-NTG (0.12 +/- 0.19 vs. 0.07 +/- 0.15 episodes/h, respectively, p = 0.11). During placebo, ischemia frequency decreased 58% (patch-on to patch-off, p = 0.01) compared with a 14% increase with TD-NTG. These changes attenuate the usual circadian variation in ischemia. CONCLUSIONS An increase in ischemia frequency during patch-off hours after use of intermittent TD-NTG was perceived by patients, and this subjective finding was supported by a corresponding trend for AECG ischemia to increase during these same hours.