Pharm. D. pathways to biomedical research: the National Institutes of Health special conference on pharmacy research.

To address the shortage of research-trained pharmaceutical scientists (or doctor of pharmacy [Pharm.D.] scientists), a 2-day pharmacy research conference titled "Pharm.D. Pathways to Biomedical Research" was convened on December 13-14, 2006, at the National Institutes of Health (NIH) campus (Bethesda, MD). The workshop included invited speakers and participants from academia, industry, and government. Forty-two pharmacy schools were represented, including deans and clinical pharmaceutical scientists with current NIH funding. In addition, several pharmacy professional organizations were represented--American Association of Colleges of Pharmacy, American College of Clinical Pharmacy, American Society of Health-System Pharmacists, and the Accreditation Council on Pharmaceutical Education. The workshop was divided into three sessions followed by breakout discussion groups: the first session focused on presentations by leading pharmaceutical scientists who described their path to success; the second session examined the NIH grant system, particularly as it relates to training opportunities in biomedical research and funding mechanisms; and the third session addressed biomedical research education and training from the perspective of scientific societies and academia. We summarize the discussions and findings from the workshop and highlight some important considerations for the future of research in the pharmacy community. This report also puts forth recommendations for educating future pharmaceutical scientists.

Professional practice plans: recommendations from the 2005 Council of Faculties-Council of Deans Task Force.

OBJECTIVES: Determine the degree to which AACP member schools have established professional practice plans, characterize the nature of existing practice plans, and provide recommendations on the implementation of practice plans at AACP member schools. DESIGN: Survey of CEO Deans of AACP member institutions administered via online survey instrument. RESULTS: Sixty-five schools responded, with 29 (45%) indicating that they had an active practice plan in place. Fifty-two percent of those who do no have practice plans in place anticipate having plans established within three years. A variety of revenue sources are addressed by existing practice plans including sponsored research, patient care, educational activities and consulting. CONCLUSIONS: Academic pharmacy lacks sophistication in regards to developing comprehensive professional practice plans. Colleges of pharmacy should consider differentiating plans that address monies collected from sponsored research vs. professional services. AACP should continue to monitor this topic as increasing participation by member schools is expected.

Effects of atorvastatin on low-density lipoprotein cholesterol phenotype and C-reactive protein levels in patients undergoing long-term dialysis.

STUDY OBJECTIVES: To determine the effects of atorvastatin on low-density lipoprotein cholesterol (LDL) particle size and C-reactive protein (CRP) concentrations in patients undergoing long-term hemodialysis. Another objective was to compare the effects of atorvastatin on lipoprotein profiles as determined by direct versus indirect assessment of lipoprotein composition. DESIGN: Randomized, parallel-group substudy. SETTING: Two university-affiliated outpatient hemodialysis centers. PATIENTS: Nineteen patients with LDL levels above 100 mg/dl and with at least two cardiovascular risk factors. INTERVENTION: Patients were randomized in a 1:1 ratio to atorvastatin 10 mg/day or no treatment (control) for 20 weeks. MEASUREMENTS AND MAIN RESULTS: We compared the differences between LDL particle size and CRP levels at baseline and 20 weeks in the atorvastatin versus control groups. Baseline demographic characteristics were similar between the two groups. Atorvastatin therapy was associated with no change in mean LDL particle size (p=0.23) and with a 90% decrease in mean CRP level (p=0.52). When evaluated by standard chemical analysis, atorvastatin therapy reduced total cholesterol levels by 29% (p=0.025) and resulted in nonsignificant reductions in LDL, high-density lipoprotein cholesterol, and triglyceride levels. Treatment with atorvastatin was not associated with significant changes in lipoprotein profile as determined by nuclear magnetic resonance (NMR) spectroscopy. CONCLUSION: Treatment with atorvastatin did not affect LDL particle size but was associated with a sizable, yet nonsignificant, reduction in CRP concentrations. The drug had variable effects on lipoprotein concentrations as determined by chemical and NMR analytical methods. A larger study is necessary to provide definitive information on the effects of atorvastatin on LDL phenotype and CRP in patients with kidney disease.

Secondary prevention of coronary heart disease in the elderly.

OBJECTIVE: To review relevant literature supporting the use of aspirin, beta-blockers, lipid-lowering agents, and angiotensin-converting enzyme (ACE) inhibitors for the secondary prevention of coronary heart disease (CHD) in an elderly patient population aged >/=65 years. DATA SOURCES: A MEDLINE search (1990-May 2003) was conducted using the key terms coronary heart disease, secondary prevention and elderly. STUDY SELECTION AND DATA EXTRACTION: Primary and tertiary literature relating to the use of aspirin, beta-blockers, lipid-lowering agents, and ACE inhibitors in the elderly were reviewed. DATA SYNTHESIS: CHD is the leading cause of morbidity and mortality in persons >/=65 years of age, and the use of pharmacologic agents has created a considerable opportunity for reducing recurrent events in those with established disease. This, combined with the aging of the US population, is creating an increase in the number of older adults eligible for secondary prevention. In 2002, the American Heart Association issued a scientific statement on the benefits of specific secondary prevention risk factor interventions in older adults. This article reviews pertinent findings from this statement, along with additional data supporting the use of pharmacologic agents for the secondary prevention of CHD in the elderly. CONCLUSIONS: Data suggest that use of aspirin, beta-blockers, lipid-lowering agents, and ACE inhibitors are effective in secondary prevention of CHD in individuals aged >/=65 years. This benefit is similar to, and often greater than, that observed in younger patients. We believe that these agents should be prescribed for all elderly patients without contraindications. Ongoing studies and future clinical trials will more clearly elucidate the benefits of secondary prevention of CHD, particularly in persons >/=75 years of age, to determine the magnitude of benefits that can be achieved in this population.

Primary prevention of coronary heart disease in the elderly.

OBJECTIVE: To review relevant literature supporting the use of antihypertensive agents, lipid-lowering agents (i.e., statins), and aspirin therapy for the primary prevention of coronary heart disease (CHD) in an elderly patient population (age >or=65 y). DATA SOURCES: A MEDLINE search (1988-January 2003) was conducted. STUDY SELECTION AND DATA EXTRACTION: Primary and tertiary literature involving the uses of antihypertensives, statins, and aspirin therapy in the elderly were reviewed. DATA SYNTHESIS: Mortality due to CHD in the US population has decreased 40-50% over the last 30 years; however, CHD remains the leading cause of morbidity and mortality in elderly persons. As the population continues to age, the number of older adults eligible for primary prevention will rise. The American Heart Association clinical practice guidelines for the primary prevention of CHD were updated in 2002; however, they are based on findings from clinical trials that enrolled predominantly middle-aged white men. The recommendations for elderly individuals are predominantly extrapolated from subgroup analyses of randomized clinical trials or cohort studies. This literature suggests that elderly persons are candidates for primary prevention measures and experience reductions in coronary events when treated with appropriate therapies. CONCLUSIONS: Data suggest that use of antihypertensives, statins, and aspirin therapy in the elderly appears effective to an extent similar to, and often greater than, that observed in younger patients. We believe these agents should be prescribed to all appropriate high-risk elderly patients. Ongoing and future studies will more clearly elucidate the benefits of primary prevention therapy, particularly in persons >or=75 years of age.

The role of clopidogrel in the management of acute coronary syndromes.

BACKGROUND: Despite significant advances in the management of coronary heart disease, myocardial infarction (MI) is still associated with a mortality rate of 45%. Acetylsalicylic acid (ASA) has been the oral antiplatelet drug of choice until recently. Thienopyridines such as clopidogrel have been shown to provide significant benefits in the management of acute coronary syndromes (ACS), either as an alternative to or in combination with ASA therapy. OBJECTIVE: The purpose of this article was to review the available scientific literature evaluating the use of clopidogrel in the management of ACS. METHODS: Relevant published data were identified through searches of the English-language literature indexed on MEDLINE and International Pharmaceutical Abstracts through April 2003. Search terms included thienopyridines, platelet aggregation inhibitors, clopidogrel, ticlopidine, acute coronary syndrome, myocardial infarction, and percutaneous coronary intervention. Pertinent conference abstracts were also included. RESULTS: The results of 3 large clinical trials-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Effect of Pretreatment with Clopidogrel and Aspirin Followed by Long-Term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE), and Clopidogrel for the Reduction of Events During Observation (CREDO)-support prolonged use of clopidogrel (up to 12 months) in combination with ASA in patients with non-ST-segment elevation MI and patients undergoing a percutaneous coronary intervention (PCI). A significant increase in bleeding events was observed in the group that received clopidogrel plus ASA compared with ASA alone in the CURE (major bleeding, P = 0.001; minor bleeding, P < 0.001) and PCI-CURE (minor bleeding, P = 0.03) trials. Use of the combination of clopidogrel and ASA with other antiplatelet and/or anticoagulant agents has not been studied extensively. CONCLUSIONS: Use of the combination of clopidogrel and ASA for up to 9 months is recommended for the medical management of non-ST-segment elevation MI and after a PCI. The increased risk of bleeding must be taken into account, and use of this combination with other agents that affect bleeding risk should be considered carefully.

Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety.

The pharmacokinetics, efficacy, and safety of niacin and its various formulations are discussed. Niacin has been used for decades for the treatment of dyslipidemia because of its favorable effects on all lipoprotein parameters. Niacin significantly increases high-density lipoprotein cholesterol (HDL-C) more than any other available agent and reduces total cholesterol, low-density lipoprotein cholesterol (LDL-C), lipoprotein (a), and triglycerides. Niacin is currently available in immediate-release (IR), sustained-release (SR), and extended-release (ER) formulations that differ in their dissolution, pharmacokinetic, efficacy, and safety profiles. Important drawbacks to niacin therapy such as cutaneous flushing, associated with IR niacin, and hepatotoxicity, associated with SR niacin, have historically limited its use. The adverse effect profiles of the different niacin formulations can be explained by differences in their dissolution and absorption rates and metabolic disposition, which result in production of metabolites associated with the respective adverse effects. The ER niacin formulation, with an intermediate dissolution rate between the dissolution rates of IR and SR niacin, demonstrates reduced rates of cutaneous flushing compared with IR niacin and hepatotoxic effects compared with SR niacin. Pharmacists need to be familiar with the pharmacokinetics, efficacy, and safety of available niacin formulations so that they can optimally educate both patients and health care providers on the differences among niacin formulations, counsel on the proper selection of a niacin product, and provide strategies for improving tolerance and adherence to therapy.

Genetic polymorphisms in emerging cardiovascular risk factors and response to statin therapy.

Current strategies for both the primary and secondary prevention of coronary heart disease (CHD) focus on the traditional risk factors, such as hypertension, smoking cessation, and cholesterol, as the primary determinants of the cardiac risk profile, with particular emphasis on the reduction of low-density lipoprotein cholesterol (LDL-C) to targeted goal levels as endorsed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII). Large primary and secondary prevention trials with the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated varying reductions in cardiovascular events associated with similar changes in LDL-C levels, suggesting statins may possess additional beneficial effects on other risk factors. Retrospective analyses of many statin trials have evaluated the association between several polymorphic candidate genes (apolipoprotein E, stromelysin-1, beta-fibrinogen, cholesteryl ester transfer protein, lipoprotein lipase, hepatic lipase, and platelet glycoprotein III) which have been identified as predictors of disease severity and both metabolic and clinical response to statin therapy. These results suggest that statin therapy improves plasma lipid profiles in all patients, but preferentially benefits individuals who carry a high risk, variant genotype for these risk factors as compared to individuals with the wild-type genotype. These observations suggest that determining individual patient genotype may be useful in optimizing the benefits of statin therapy. These hypothesis-generating data need to be prospectively evaluated in genotyped patients.

Losartan and E3174 pharmacokinetics in cytochrome P450 2C9*1/*1, *1/*2, and *1/*3 individuals.

STUDY OBJECTIVE: To determine if differences in the pharmacokinetics of losartan and its pharmacologically active E3174 metabolite exist among individuals expressing the cytochrome P450 (CYP) 2C9*1/*1, *1/*2, and *1/*3 genotypes. DESIGN: Single-dose pharmacokinetic study. SETTING: University general clinical research center. SUBJECTS: Fifteen healthy volunteers, five from each genotype: CYP2C9*1/*1, *1/*2, and *1/*3. INTERVENTION: A single oral dose of losartan 50 mg. MEASUREMENTS AND MAIN RESULTS: Plasma and urine samples were collected for 24 hours, and losartan and E3174 pharmacokinetic data were compared across the three genotypes. Orthostatic blood pressure was measured over 12 hours after dosing. No significant differences were observed among the three groups in losartan or E3174 area under the plasma concentration-time curve, losartan or E3174 elimination half-life, or losartan oral clearance. A significant association between CYP2C9 genotype and losartan to E3174 formation clearance was observed, such that 50% of the variability was accounted for by the genotype. No significant relationship between that genotype and blood pressure was observed at any time. CONCLUSION: Differences in the pharmacokinetics of losartan and its active E3174 metabolite were not observed in healthy subjects with the genotype of CYP2C9*1/*2 and *1/*3 compared with those expressing *1/*1. Alterations in losartan dosing in CYP2C9*1/*2 and *1/*3 individuals does not appear necessary.

Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes.

OBJECTIVE: This study was conducted to examine differences in flurbiprofen metabolism among individuals with the CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. METHODS: Fifteen individuals with the CYP2C9*1/*1 ( n=5), *1/*2 ( n=5), and *1/*3 ( n=5) genotypes received a single 50-mg oral dose of flurbiprofen. Plasma and urine samples were collected over 24 h, and flurbiprofen and 4'-hydroxyflurbiprofen pharmacokinetic data were compared across genotypes. RESULTS: CYP2C9 genotype was a significant predictor of flurbiprofen metabolism and accounted for 59% of the variability in flurbiprofen AUC(0- infinity ), and approximately 50% of the variability in flurbiprofen oral clearance, formation clearance to 4'-hydroxyflurbiprofen, and the 0 to 24-h urinary metabolic ratio of flurbiprofen to 4'-hydroxyflurbiprofen. Flurbiprofen AUC(0- infinity )was significantly higher and all measures of flurbiprofen clearance were significantly lower in the CYP2C9*1/*3 individuals than in those with *1/*1. Significant differences in these parameters were not detected between *1/*2 subjects and *1/*1 subjects. CONCLUSIONS: CYP2C9 genotype is a significant predictor of flurbiprofen disposition in humans by altering CYP2C9-mediated metabolism and reducing systemic clearance. The effects are most pronounced in individuals carrying the *3 allele.

Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans.

The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxytolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism.

Low-molecular-weight heparin in transesophageal echocardiography-guided cardioversion of atrial fibrillation.

Atrial fibrillation is the most common sustained cardiac arrhythmia and is associated with thromboembolic events and hemodynamic impairment that results in considerable morbidity, mortality, and cost. Cardioversion to sinus rhythm is a common approach to the treatment of these patients. However, cardioversion is associated with the risk of thromboembolism. Current guidelines recommend that patients receive anticoagulants for 3-4 weeks before and 4 weeks after cardioversion. With the development of transesophageal echocardiography (TEE), the risk of thromboembolism and alternative anticoagulation strategies have been evaluated in patients with atrial fibrillation. Administration of low-molecular-weight heparin (LMWH) in conjunction with TEE offers several advantages over unfractionated heparin. Limited data suggest that LMWH in this setting is as effective, is safer, and may be more cost-effective than unfractionated heparin. Ongoing research will identify definitively the optimal strategy for pericardioversion anticoagulation.

Evaluation of cytochrome P4502C9 metabolic activity with tolbutamide in CYP2C91 heterozygotes.

OBJECTIVES: Multiple single-nucleotide polymorphisms in the gene encoding cytochrome P450 (CYP) 2C9 have been identified, but the functional significance of the various putative defective genotypes in humans merits further study. METHODS: Using tolbutamide as a probe of CYP2C9 activity, we evaluated CYP2C9 phenotype in 15 healthy individuals expressing the CYP2C9(*)1/(*)1, (*)1/(*)2, and (*)1/(*)3 genotypes (n = 5 per group). CYP2C9 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism methods. Subjects received 500 mg of tolbutamide, with plasma and urine collected over a 24-hour period. Plasma tolbutamide and urinary tolbutamide, 4'-hydroxytolbutamide, and carboxytolbutamide concentrations were determined by an HPLC method. RESULTS: Tolbutamide area under the plasma concentration-time curve from time zero to infinity [AUC(0- infinity )] significantly increased by 1.5-fold and 1.9-fold, respectively, in subjects expressing the CYP2C9(*)1/(*)2 and (*)1/(*)3 genotypes compared with (*)1/(*)1 subjects. Statistically significant reductions in tolbutamide oral clearance (29% and 48%) and formation clearance (38% and 56%) were detected in the (*)1/(*)2 and (*)1/(*)3 individuals, respectively, compared with (*)1/(*)1 subjects. The increases in AUC(0- infinity) and decreases in oral clearance observed in the (*)1/(*)3 individuals were also significantly greater than those expressing the (*)1/(*)2 genotype (P <.05). The amount of urinary 4'-hydroxytolbutamide and carboxytolbutamide excreted in the 0- to 12-hour and 6- to 12-hour collection intervals was significantly less in (*)1/(*)2 and (*)1/(*)3 individuals compared with (*)1/(*)1 subjects. With tolbutamide used as a CYP2C9 probe, CYP2C9 genotype was the major determinant of CYP2C9 phenotype (r(2) = 0.77). CONCLUSIONS: CYP2C9 activity was significantly reduced in (*)1 heterozygotes compared with (*)1 homozygotes, and metabolism was more severely impaired in (*)1/(*)3 individuals compared with those expressing (*)1/(*)2.

Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers.

BACKGROUND: Phenytoin, a cytochrome P450 (CYP) 2C9 substrate, has a narrow therapeutic index and nonlinear pharmacokinetics. Therefore there is the potential for significant concentration-related adverse effects when phenytoin is coadministered with other CYP2C9 substrates. Losartan, an antihypertensive agent, is also a substrate for CYP2C9. OBJECTIVE: Our objective was to assess the effects of losartan on the pharmacokinetics of phenytoin and the effects of phenytoin on the pharmacokinetics of losartan in a healthy population of volunteers. METHODS: A prospective, randomized, 3-period crossover study was conducted in 16 healthy volunteers with phenytoin alone, phenytoin in combination with losartan, and losartan alone. Each treatment was given for 10 days with a 3-week washout period between treatments. On day 10, plasma concentrations of phenytoin and plasma and urine concentrations of losartan and its active carboxylic-acid metabolite E3174 were measured to determine steady-state pharmacokinetic parameters. RESULTS: Coadministration of losartan had no effect on the pharmacokinetics of phenytoin. Coadministration of phenytoin increased the mean area under the concentration-time curve from time zero to 24 hours [AUC(0-24)] of losartan by 17% (355 +/- 220 ng x h/mL versus 427 +/- 177 ng x h/mL; P =.1), but this difference was not statistically significant. In the 14 CYP2C9*1/*1 subjects, the mean AUC(0-24) of losartan was increased by 29% (284 +/- 84 ng x h/mL versus 402 +/- 128 ng x h/mL; P =.008). Coadministration of phenytoin significantly reduced the AUC(0-24) of E3174 by 63% (1254 +/- 256 ng x h/mL versus 466 +/- 174 ng x h/mL; P =.0001) and the formation clearance of losartan to E3174 (1.91 +/- 0.8 mL/h per kilogram versus 0.62 +/- 0.4 mL/h per kilogram; P =.0001). CONCLUSIONS: Losartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9-mediated conversion of losartan to E3174.

Understanding niacin formulations.

Niacin is an important therapeutic option for the treatment of dyslipidemias and is the only agent currently available that favorably affects all components of the lipid profile to a significant degree. Niacin has consistently been shown to significantly reduce levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a), while having the greatest high-density lipoprotein (HDL) cholesterol-raising effects of all available agents. Niacin has also been shown to significantly reduce coronary events and total mortality. Niacin is available in 3 formulations: immediate-release (IR), sustained-release (SR), and a newer formulation, niacin extended-release (ER), all of which differ in their pharmacokinetic, efficacy, and safety profiles. Conventional niacin therapy has notable limitations that include flushing, most often seen with IR formulations, and hepatotoxicity, associated with SR formulations. These side effects are related to the absorption rate and subsequent metabolism of niacin as delivered from the different products. Niacin ER has a delivery system allowing absorption rates intermediate to that of niacin IR and SR. As a result, niacin ER achieves the efficacy of niacin IR with a reduced incidence of flushing and without the hepatic effects seen with niacin SR. The pharmacist should be familiar with the differences among and the advantages and disadvantages of each formulation to educate patients and help them achieve the optimal therapeutic benefit of niacin while minimizing adverse effects.

Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data.

The discovery of six distinct polymorphisms in the genetic sequence encoding for the cytochrome P450 2C9 (CYP2C9) protein has stimulated numerous investigations in an attempt to characterize their population distribution and metabolic activity. Since the CYP2C9*1, *2 and *3 alleles were discovered first, they have undergone more thorough investigation than the recently identified *4, *5 and *6 alleles. Population distribution data suggest that the variant *2 and *3 alleles are present in approximately 35% of Caucasian individuals; however, these alleles are significantly less prevalent in African-American and Asian populations. In-vitro data have consistently demonstrated that the CYP2C9*2 and *3 alleles are associated with significant reductions in intrinsic clearance of a variety of 2C9 substrates compared with CYP2C9*1; however, the degree of these reductions appear to be highly substrate-dependent. In addition, multiple in-vivo investigations and clinical case reports have associated genotypes expressing the CYP2C9*2 and *3 alleles with significant reductions in both the metabolism and daily dose requirements of selected CYP2C9 substrates. Individuals expressing these variant genotypes also appear to be significantly more susceptible to adverse events with the narrow therapeutic index agents warfarin and phenytoin, particularly during the initiation of therapy. These findings have subsequently raised numerous questions regarding the potential clinical utility of genotyping for CYP2C9 prior to initiation of therapy with these agents. However, further clinical investigations evaluating the metabolic consequences in individuals expressing the CYP2C9*2, *3, *4, *5, or *6 alleles are required before large-scale clinical genotyping can be recommended.