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Objective:To review the pharmacology, efficacy, and safety of vorapaxar, a protease activator receptor-1 (PAR-1) antagonist, in the management of atherosclerotic diseases. Data Sources:Peer-reviewed clinical trials and review articles were identified from MEDLINE and Current Content database (both 1966 to December 31, 2014) using the search terms vorapaxarand protease activator receptor antagonist. Study Selection and Data Extraction:A total of 30 clinical studies were identified (16 clinical trials, including subanalyses, 14 related to pharmacology, pharmacokinetics, and pharmacodynamics and drug interactions). Data Synthesis:Two phase III clinical trials with vorapaxar have been published. In patients with non–ST segment elevation myocardial infarction (MI), vorapaxar failed to significantly reduce the primary efficacy end point (composite of cardiovascular death, MI, stroke, recurrent ischemia with hospitalization, and urgent coronary revascularization). Conversely, in a study of secondary prevention for patients with cardiovascular disease, the composite end point of cardiovascular death, MI, or stroke was significantly reduced. In both trials, the safety end points of major/minor bleeding were increased compared with placebo. In the secondary prevention trial, an increased incidence of intracranial hemorrhage led to the exclusion of patients with a prior history of stroke. Conclusion:Vorapaxar is approved for use with aspirin and/or clopidogrel in the secondary prevention of cardiovascular events in stable patients with peripheral arterial disease or a history of MI. However, the addition of vorapaxar to other antiplatelets can significantly increase the risk of bleeding. It is, therefore, essential to balance the need for further reduction of risk of thrombotic event with patient’s individual bleeding risk.

Background: In 2003, the World Health Organization reported that 50% of patients are adherent to long-term therapies. Frequently, the reason for a patient's nonadherence is the cost of medications. Even with prescription insurance coverage, patients may not be able to afford their medications.Objective: To assess prescriber knowledge of the cost of commonly prescribed medications including atorvastatin, gabapentin, levofloxacin, losartan, pantoprazole, pioglitazone, and quetiapine. Secondary objectives were to evaluate how often prescribers consult a discounted drug list and a patient's prescription insurance coverage.Methodology: One hundred prescribers from the Medical University of South Carolina were surveyed from November 2010 to January 2011. Prescribers consisted of medical residents, attending physicians, fellows, nurse practitioners, and physician assistants. Wholesale prices of medications were determined using the Red Book, and prescription insurance prices were calculated from an average of the top 3 prescription insurance companies’ copayments.Results: Medical residents made up 72% of those surveyed, fellows 3%, attending physicians 12%, physician assistants 3%, and nurse practitioners 10%. The prescriber groups were unable to correctly determine the cost of medications of more than 50% of total possible responses. The majority of prescribers rarely asked about a patient's prescription insurance coverage or consulted a discounted drug list before writing a prescription.Conclusions: Prescribers are more likely to know the cost of medications for patients who have prescription insurance coverage versus those who do not.

Background: Nonadherence to clopidogrel after drug-eluting stent (DES) placement is associated with in-stent thrombosis and adverse cardiac events.Objective: To identify the incidence of and barriers associated with nonadherence to clopidogrel in patients receiving DES.Methods: Patients who received a DES between March 1, 2004, and August 31, 2005, from a single academic medical center were eligible. Telephone interviews were conducted 6 or more months following discharge. Nonadherence was defined as premature discontinuation of or less than 80% adherence to clopidogrel. Patients were asked to identify barriers to adherence. Differences between adherent and nonadherent patients were analyzed using χ2and t-test analysis.Results: Of the 674 patients identified, 257 (38%) participated. The nonadherence rate was 20%. The majority (58%) of nonadherent patients discontinued therapy prematurely. Patients identified the main reason for discontinuation as medical barriers (18.56%), including perceived adverse effects (9.28%). The Incidence of rash was higher in patients who were nonadherent (12% vs 4%; p = 0.049). Overall, 49% of patients recalled receiving discharge counseling regarding adverse effects. A financial barrier was identified by 22 (42%) patients in the nonadherent and 73 (36%) in the adherent group, of whom 64% and 52%, respectively, reported having insurance coverage for medications. Adherent patients reported higher copays ($29.69 vs $18.14; p = 0.01).Conclusions: Prospective studies should be conducted to aid in identifying patients at risk for nonadherence and possible in-stent thrombosis in order to identify interventions to improve adherence.

BACKGROUND: Nonadherence to clopidogrel after drug-eluting stent (DES) placement is associated with in-stent thrombosis and adverse cardiac events. OBJECTIVE: To identify the incidence of and barriers associated with nonadherence to clopidogrel in patients receiving DES. METHODS: Patients who received a DES between March 1, 2004, and August 31, 2005, from a single academic medical center were eligible. Telephone interviews were conducted 6 or more months following discharge. Nonadherence was defined as premature discontinuation of or less than 80% adherence to clopidogrel. Patients were asked to identify barriers to adherence. Differences between adherent and nonadherent patients were analyzed using chi(2) and t-test analysis. RESULTS: Of the 674 patients identified, 257 (38%) participated. The nonadherence rate was 20%. The majority (58%) of nonadherent patients discontinued therapy prematurely. Patients identified the main reason for discontinuation as medical barriers (18.56%), including perceived adverse effects (9.28%). The incidence of rash was higher in patients who were nonadherent (12% vs 4%; p = 0.049). Overall, 49% of patients recalled receiving discharge counseling regarding adverse effects. A financial barrier was identified by 22 (42%) patients in the nonadherent and 73 (36%) in the adherent group, of whom 64% and 52%, respectively, reported having insurance coverage for medications. Adherent patients reported higher copays ($29.69 vs $18.14; p = 0.01). CONCLUSIONS: Prospective studies should be conducted to aid in identifying patients at risk for nonadherence and possible in-stent thrombosis in order to identify interventions to improve adherence.

Background: The importance of achieving a low-density lipoprotein cholesterol (LDL-C) level less than 100 mg/dL in patients with coronary artery disease (CAD) or cerebrovascular disease (CVD) is well established. Emerging evidence supports the recognition and management of secondary lipid goals, high-density lipoprotein cholesterol (HDL-C) level greater than 40 mg/dL, and triglyceride level less than 150 mg/dL.Objective: To evaluate whether inpatient services within an academic setting were achieving/addressing primary and secondary lipid goals in patients with established CAD or CVD.Methods: Patients with a discharge diagnosis of acute myocardial infarction, myocardial revascularization procedures, and/or ischemic stroke were identified. A retrospective chart review was done to assess adherence to the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for lipid management.Results: On average, 63% of patients with CAD or CVD had a lipid panel assessed during their hospitalization. Of the patients who had a fasting lipid panel checked, only 40% (72/178) had an LDL-C level less than 100 mg/dL. Of those patients, only 31% (22) also had an HDL-C level greater than 40 mg/dL. Even fewer patients (24%; 17) met both primary and secondary goals. Of the 287 patients included in the study, 69% (199) were prescribed a statin, 3% (9) a fibrate, and 3% (8) niacin on discharge.Conclusions: Few patients with CAD or CVD met the AHA/ACC goals for lipid management, yet a significant number were not prescribed appropriate lipid-lowering therapy at discharge. This finding strongly suggests that more awareness in this area is needed.

OBJECTIVE: To describe the pharmacology, pharmacokinetics, efficacy, and safety of bosentan in the treatment of pulmonary arterial hypertension (PAH).DATA SOURCES: A MEDLINE and Current Contentssearch (1966–June 2002) of the English-language literature was conducted to identify published dose-ranging, pharmacokinetic, pivotal efficacy trials and review articles of bosentan and endothelin antagonists. Additional references were identified from the bibliographies of the retrieved articles.DATA SYNTHESIS: Bosentan is the first orally active, nonpeptide endothelin receptor antagonist approved by the Food and Drug Administration for use in patients with World Health Organization (WHO) functional class III and IV PAH. Titrated to a dose of 125 mg twice daily, bosentan produces pulmonary vasodilation, improving cardiopulmonary hemodynamics leading to better outcomes for patients. It is metabolized primarily by the hepatic system via the cytochrome P450 enzyme pathway and eliminated by biliary excretion. Bosentan is an inducer of the isoenzymes CYP3A4 and 2C9. It possesses a unique pharmacokinetic profile with a terminal elimination half-life of approximately 5 hours, yet steady-state plasma concentrations are not achieved for 3–5 days as a result of enhanced drug clearance and autoinduction following multiple daily dosing. The major adverse effects of bosentan are the potential for birth defects and hepatotoxicity.CONCLUSIONS: The use of bosentan in patients with WHO functional class III and IV PAH is associated with improved exercise tolerance, cardiopulmonary hemodynamics, and increased time to clinical worsening when compared with placebo. It offers significant advantage in ease of administration and quality of life compared with epoprostenol therapy, with similar efficacy.

OBJECTIVE: To review the contemporary role of the glycoprotein (GYP) IIb/IIIa receptor inhibitors abciximab, eptifibatide, and tirofiban in patients undergoing percutaneous coronary intervention (PCI) and those with an acute coronary syndrome (ACS), and to provide an algorithm based on currently available evidence for specific agents.DATA SOURCES: Primary articles were identified by a MEDLINE search (1966–January 2003); references cited in these articles provided additional resources.STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from data sources were considered for relevant information; this article primarily addresses large, controlled or comparative studies, and meta-analyses.DATA SYNTHESIS: The role of GYP IIb/IIIa inhibitors in patients undergoing PCI and those with ACS has progressed markedly. To date, abciximab has the most robust data in patients undergoing PCI, particularly high-risk individuals. In PCI patients with lower risk (e.g., elective stenting), eptifibatide is a reasonable first-line option. Data do not support tirofiban for routine use in patients undergoing PCI. For individuals with signs and symptoms of ACS, specifically unstable angina or non–ST-segment elevation myocardial infarction (MI), eptifibatide or tirofiban is recommended in high-risk patients when a conservative approach is used (PCI is not planned). Abciximab is not recommended in this situation. In patients with ST-segment elevation MI (STEMI), abciximab is the only GYP IIb/IIIa inhibitor evaluated in large, well-designed investigations. For medical management in combination with a fibrinolytic agent, the role of abciximab remains unclear. For patients undergoing primary PCI for the management of STEMI, the available evidence supports the use of abciximab, albeit further investigation is warranted.CONCLUSIONS: The role of GYP IIb/IIIa inhibitors in clinical cardiology continues to evolve. Choice of the agent depends on situation of use, patient-specific characteristics and risk stratification, and, in the case of ACS, chosen management strategy (medical management or intervention).

To present two case reports of patients who received suboptimal oral antiplatelet therapy and to review recent changes in national guidelines for management of acute coronary syndromes.

Objectives.To present two case reports of patients who received suboptimal oral antiplatelet therapy and to review recent changes in national guidelines for management of acute coronary syndromes.

OBJECTIVE: To report a case of rhabdomyolysis and acute hepatitis associated with the coadministration of atorvastatin and diltiazem.CASE SUMMARY: A 60-year-old African American man with a significant past medical history presented to the emergency department with acute renal failure secondary to rhabdomyolysis. In addition, liver enzymes were elevated to greater than 3 × normal. The only change in medication was the initiation of diltiazem 3 weeks earlier for atrial fibrillation to a complicated medication regimen that included atorvastatin.DISCUSSION: Rhabdomyolysis has been reported in patients receiving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors when coadministered with agents that may inhibit their metabolism. Atorvastatin is the most potent of this class of agents currently available and is commonly used in the treatment of hyperlipidemia. Rhabdomyolysis resulting from the drug interaction between diltiazem and other HMG-CoA reductase inhibitors has been described in the literature. However, no report has specifically associated this adverse event with atorvastatin and diltiazem. We describe a patient with a complex medication regimen who was admitted for rhabdomyolysis and accompanying acute renal failure, along with acute hepatitis, thought to be secondary to a drug interaction between atorvastatin and diltiazem.CONCLUSIONS: While optimizing the patient's lipid profile should be the primary factor in choosing one statin over another, the potential for drug interactions requires close attention. All patients beginning HMG-CoA reductase inhibitor therapy should be counseled regarding the signs and symptoms of muscle injury; particular attention should be paid to those patients who are taking medications that may interact.

OBJECTIVE: To review the literature assessing the differences in response to angiotensin-converting enzyme (ACE) inhibitors and β-blockers in black patients compared with the response in non-black patients in the management of systolic heart failure.DATA SOURCES: A MEDLINE search (January 1966–May 2001) was performed using heart failure, blacks, Negroid race, adrenergic β-antagonists, and angiotensin-converting enzyme inhibitors as key words. English-language articles were identified. Additional pertinent articles were identified from review of the references of these articles.STUDY SELECTION AND DATA EXTRACTION: All identified references were reviewed. All articles deemed relevant to the subject of this article were included.DATA SYNTHESIS: It has been suggested that the antihypertensive effect of ACE inhibitors and β-blockers may be less in black patients than in other racial groups. Retrospective reanalyses of major heart failure trials have suggested that black patients may not realize a significant benefit in morbidity or mortality when heart failure is managed with ACE inhibitors or β-blockers. It has also been suggested that black patients may respond more favorably than non-black patients to the combination of hydralazine and isosorbide dinitrate.CONCLUSIONS: Published reanalyses of ACE inhibitor and β-blocker trials in heart failure provide weak data to support a lack of benefit in black patients. The published literature on this topic is limited by its retrospective nature. Firm conclusions regarding the influence of race on effectiveness of ACE inhibitors and β-blockers cannot be made until prospective trials, with planned analysis of the effect of race, have been performed.

Prevention and management of acute coronary syndromes (ACS) are focal points of interest among health care providers. Acute coronary syndromes is an all‐encompassing term that refers to unstable angina, non‐Q wave myocardial infarction, and Q wave myocardial infarction. These syndromes are usually the result of atherosclerotic plaque rupture leading to thrombus formation in a coronary artery. Heparin and aspirin are traditional antithrombotic treatments. They typically are administered with antiischemic therapies and often with fibrinolytic agents for patients with ST segment elevation associated with acute myocardial infarction. Although aspirin and heparin are important, they have significant limitations that have prompted development of newer antithrombotic approaches. Adenosine diphosphate inhibitors have been evaluated as either alternatives or adjunctive treatment to aspirin. Glycoprotein IIb‐IIIa receptor inhibitors, low‐molecular‐weight heparins, and direct thrombin inhibitors have been studied as concurrent therapy with, or as alternatives to, heparin.

OBJECTIVE: To describe the pharmacology, pharmacokinetics, efficacy, and safety of tenecteplase in reducing mortality associated with acute myocardial infarction (AMI).DATA SOURCES: Published articles were identified from MEDLINE (from 1966 to December 2000) and Current Contents(all sections) searches.STUDY SELECTION AND DATA EXTRACTION: Dose-ranging and pivotal studies were included for analysis in the clinical trials section.DATA SYNTHESIS: Tenecteplase is a third-generation thrombolytic indicated for the reduction of mortality associated with AMI. Tenecteplase has a longer half-life that allows for single-dose, intravenous bolus administration. Data from clinical trials support that tenecteplase is similar to alteplase in reducing 30-day mortality rates in patients who have had an AMI. In the ASSENT-2 (Assessment of the Safety and Efficacy of a New Thrombolytic) trial, patients treated with tenecteplase required fewer blood transfusions and experienced fewer episodes of noncerebral bleeding compared with those treated with alteplase.CONCLUSIONS: Tenecteplase is an effective thrombolytic agent for the treatment of AMI. It can be given as a single weight-based dose; however, it appears to offer no significant advantage over other agents in terms of its efficacy or rate of intracranial hemorrhage.

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.

Attention is focusing on the relationship between homocysteine and cardiovascular disease and the role of vitamins in the management of this prevalent ailment. Epidemiologic studies have shown that a relationship between elevated homocysteine concentrations and cardiovascular disease may exist; however, a cause‐and‐effect relationship has not been proven. The B vitamins are key components of homocysteine metabolism, and the trend is toward their being increasingly prescribed for cardiovascular disease. Prescribing of antioxidant vitamins, vitamin E in particular, has increased as well. Vitamin E may decrease the risk of nonfatal myocardial infarction in patients with coronary artery disease, but its benefit in preventing fatal myocardial infarction has not been shown. Vitamin supplements are not warranted in all patients with cardiovascular disease but may have a place in therapy for selected patients.

OBJECTIVE: To discuss the controversy surrounding concomitant therapy with amiodarone and the implantable cardioverter-defibrillator (ICD).DATA SOURCES: A MEDLINE search identified English-language literature sources, including nonhuman studies.STUDY SELECTION: Studies included those that specifically addressed the use of amiodarone plus the ICD as well as reviews of the ICD.DATA EXTRACTION: Studies were evaluated for design, type of defibrillation electrode or defibrillator, method of defibrillation, amiodarone loading and maintenance dosages, duration of amiodarone therapy, and study endpoints.DATA SYNTHESIS: Because the ICD functions by delivering energy to depolarize a mass of myocardium, concomitant use of antiarrhythmic agents that elevate the defibrillation threshold (DFT) beyond an ICD's energy capability may adversely effect patient outcome. Amiodarone has been shown to both increase and decrease the DFT. Trials examining the use of amiodarone plus the ICD have not provided strong evidence that amiodarone will decrease the number of ICD discharges or favorably affect the mortality rate. Amiodarone is also expensive and toxic. Although the cost of the ICD is relatively high, continuing improvements in battery life will decrease long-term costs.CONCLUSIONS: Controlled trials are required to substantiate the improved survival rate with the ICD and to determine the role of antiarrhythmic agents in conjunction with the device. At present, there are no data to support the combination of amiodarone and an ICD in terms of improved quality or duration of life.

Calcium is an integral component in numerous physiological processes and functions. As such, drugs that interfere with the movement of calcium into or out of cells, or the activity of intracellular calcium are useful in treating a variety of disease states. This article will review the calcium channel blockers currently available, along with their approved indications, as well as select dihydropyridine investigational agents and nonapproved indications for their use.

Abstract: Twelve patients having frequent premature ventricular complexes (PVCs) averaging more than 60 per hour received a single 150‐mg intravenous dose of pirmenol. Plasma pirmenol concentration declined biexponentially following the infusion and was analyzed according to a two‐compartment open model. Following an erratic distribution phase, the terminal elimination half‐life ranged from 4.2 to 16.9 hours, with a geometric mean of 7.6 hours. Total body clearance averaged 164 ± 58 ml/min, and the mean volume of distribution was 1.45 ± 0.38 liter/kg. Renal clearance averaged 46.6 ± 21.2 ml/min, representing 30 ± 10 per cent of total body clearance. Excretion of unchanged drug in the urine averaged 31.8 ± 8 per cent of the dose. Renal clearance and elimination half‐life were correlated (r= −0.61, P< 0.05). Eight of the 12 patients achieved greater than 95 per cent suppression of PVCs with a duration between 20 minutes and 23 hours. These favorable pharmacokinetics indicate that pirmenol may be a useful addition to the therapy of ventricular arrhythmias.

Summary The tablet formulation of diltiazem has been available for the treatment of angina pectoris but has not been comprehensively evaluated in hypertension. This study's aim was to evaluate the efficacy, dose-response characteristics, and duration of action of tablet (prompt-release) diltiazem in mild to moderate hypertension. Three placebocontrolled trials were designed. The first (trial #1) evaluated the dose response of 120, 240, and 360 mg/day (q12h regimen) of diltiazem in parallel fixed-dose fashion using hourly blood pressures. The second (trial #2) evaluated a q12h titration from 240 to 360 mg/day, which could be switched to q8h. The third (trial #3) evaluated a q8h titration from 180 to 270 to 360 mg/day, followed by conversion to a q12h regimen. The goal was a supine diastolic blood pressure of <90 mmHg and 10 mmHg less than baseline. With doses of diltiazem increasing from 120 to 240 to 360 mg/day, there was a progressive decrease in the average mean arterial pressure, describing a dose response with 120 mg/day as the ineffective dose. The peak effect for each dose regimen was found at 6 hours, with significant reductions lasting over 10 hours in the 240 mg/day and 360 mg/day groups. Peak plasma concentrations occurred at 3 hours. The residual effect at the trough of the 240 mg/day and 360 mg/day doses was 48% and 53% of the peak effect, respectively. When titration was carried out on a q8h regimen, both systolic and diastolic blood pressures were significantly decreased. When the regimen was switched from q8h to q12h, the effect was not maintained. Thus, the prompt-release preparation is not as effective as the sustained-release preparation in a q12h regimen, since it shows some loss of effect near the end of the 12-hour dosing period. However, the prompt-release preparation clearly produces adequate control of blood pressure in most patients in a q8h regimen.

The antihypertensive activity of a sustained‐release preparation of diltiazem (given each 12 hours) was assessed in 96 patients with supine diastolic blood pressure (BP) between 95 and 110 mm Hg in a multicenter, randomized, double‐blind, placebo run‐in, parallel‐group trial comparing optimally titrated doses of diltiazem and placebo. The aim was to assess the onset of action as well as the extent and variability of BP control of this formulation during the 12‐hour interval. Diltiazem was titrated from 120 mg bid to 180 mg bid as necessary to lower BP. At baseline, on the first day of titration, and at the end of 8 weeks, BP was evaluated at 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The onset of action was within 2 hours, and the effect was maintained throughout the 12‐hour period. Mean BP for the diltiazem group at baseline was 154/101 mm Hg. At week 8, BP was 148/93 mm Hg at hour “0” (P < .02 andP = .0001 for systolic and diastolic BP vs. placebo), 139/84 mm Hg at the nadir at hour 5 (P = .0001), and 149/91 mm Hg at the end of the 12‐hour period (P < .02 andP = .0001 for systolic and diastolic BP). Diltiazem was significantly more effective than placebo (P = .0001) with 50% of patients controlled to a diastolic pressure of <90 mm Hg at 7 of the 10 evaluation points, including the evaluation point of 12 hours post‐dose. There was no exaggeration of the magnitude of daily BP fluctuation nor any increase in orthostatic effect noted.

Twelve patients with chronic ventricular arrhythmias (PVCs) of frequency greater than 60/h received intravenous pirmenol (150 mg/30 min) according to a single-blind, placebo-controlled protocol. Participating patients had previously been inadequately treated with an average of 3.0 (range, 2–6) antiarrhythmics. Eight of these 12 patients (67) responded to pirmenol at a level of over 95 PVC suppression (mean suppression in responders, 99.7). In eight consecutive patients, response to pirmenol was compared with that to lidocaine (250 mg/30 min) in a single-blind random-sequence fashion. Only two of eight patients responded to lidocaine. Mean PVC frequency decreased by 40.4 after lidocaine (p = NS). Five patients (63) had adverse neurologic reactions, which required early discontinuation of lidocaine in two (25). In contrast, seven of these eight patients (88) responded to pirmenol (p < 0.02 versus lidocaine). PVC frequency for this subgroup decreased by 79.8 after pirmenol (p < 0.05). A minor adverse reaction occurred in only one patient (12.5) (p < 0.05, lidocaine versus pirmenol). Pirmenol was well tolerated hemodynamically, with small increases in diastolic blood pressure and heart rate which remained within the normal range. Electrocardiographic intervals (PR, QRS, QT) were modestly increased at the end of infusion. Mean echocardiographic ejection fractions were unchanged after placebo, pirmenol, and lidocaine infusions. Lidocaine plasma concentrations after infusion averaged 4.4 μg/ml (range, 2.6–7.7). Average pirmenol concentrations of 3.1 μg/ml (range, 2.2–8.2) were achieved: geometric mean elimination half-life was 7.6 h (range, 4.2–16.9). Recurrence of PVCs to 10 of control frequency correlated with a fall in pirmenol concentrations to a mean of 1.3 μg/ml in responders. Pirmenol appears to be a safe and effective antiarrhythmic when administered intravenously. Pirmenol appeared superior to lidocaine in our small group of patients with chronic stable ventricular arrhythmias.

Recainam hydrochloride is a newly synthesized propylurea compound demonstrating potent antidysrhythmic effects. Recainam was administered as a loading dose of 3 mg/kg/40 minutes followed by a continuous infusion of 0.9 mg/kg/hr for 23 hours and 20 minutes to ten patients with cardiac disease and frequent PVCs (more than 30/hr). A total of 15 plasma samples were drawn over 36 hours during and after the infusion. Plasma recainam concentration was determined by high performance liquid chromatography (HPLC). The mean (± SD) postload and 24‐hour plasma concentrations were 5.19 ± 0.51 and 3.41 ± 0.71 μg/mL, respectively. The data were best described by a two‐compartment model yielding the following mean (± SD) pharmacokinetic parameters: λ1= 2.62 ± 0.68 hr−1, λ2= 0.144 ± 0.014 hr−1, t1/2λ2= 4.84 ± 0.46 hr, CLT= 0.268 ± 0.057 L/hr/kg, CLR= 0.143 ± 0.052 L/kg/hr, CLNR= 0.125 ± 0.041 L/hr/kg, Vdss=1.3 ± 0.19 L/kg, and Vdλ2= 1.9 ± 0.43 L/kg. There were no adverse reactions. Based on these data, recainam can be safely administered as a loading dose followed by a continuous infusion in patients with stable cardiac disease without significant ventricular dysfunction.

OBJECTIVE: To review the pharmacology, pharmacokinetic, dosing, adverse effects, and therapeutic uses of sotalol.DATA IDENTIFICATION: Articles were identified with an English-language literature computer search via Knowledge Finder, using the term sotalol, and with an extensive search of bibliographies of identified articles.STUDY SELECTION: Relevant or representative animal studies, human trials, and case reports were selected for evaluation.DATA EXTRACTION: The literature was assessed for quality, methodology, and outcome information.DATA SYNTHESIS: Sotalol is a racemic compound with Class II (beta-blocking properties) and Class III (prolonged action potential) antiarrhythmic activity. It has been suggested that the plasma concentration associated with QTc prolongation (a measure of the Class III action) is much greater than that associated with beta-blockade. Therefore, sotalol is categorized as a Class III antiarrhythmic agent. The l-isomer is responsible for the beta-blocking activity, whereas both isomers have Class III properties. After oral dosing in fasting patients with normal renal function, sotalol is >90 percent absorbed, achieves peak serum concentrations in 2–4 h, is excreted unchanged 80–90 percent in the urine, has a volume of distribution of 1–2L/kg, and has an elimination half-life of about 12 h. Sotalol is effective in patients with life-threatening ventricular arrhythmias that have been refractory to other conventional antiarrhythmic drugs. In general, sotalol appears to be well tolerated, with many of its adverse effects caused by beta-blocking activity. As with other antiarrhythmic agents, the possibility of proarrhythmia (frequently torsade de pointes) exists.CONCLUSIONS: Racemic sotalol is an effective Class III antiarrhythmic agent approved by the Food and Drug Administration for the treatment of documented life-threatening ventricular arrhythmias. Investigations continue with racemic sotalol in the management of supraventricular arrhythmias. Trials with the d-isomer are also ongoing.

OBJECTIVE: To discuss a potential pharmacokinetic interaction between quinidine, ciprofloxacin, and metronidazole.CASE SUMMARY: A 51-year-old black woman was admitted for shortness of breath, abdominal pain, and atrial fibrillation. Procainamide and diltiazem were begun for the atrial fibrillation and ciprofloxacin and metronidazole for suspected diverticulitis. The therapy was switched to quinidine on day 5 because of adverse events associated with procainamide. A trough serum quinidine concentration (SQC) on day 7 was 6.3 μg/mL (normal 2–5) with normal QT and QTc intervals. On day 8, the patient was discharged in normal sinus rhythm. She took her last doses of antibiotics on day 15 and a follow-up SQC on day 18 was 2.3 μg/mL.DISCUSSION: The possible explanations for the changes in SQCs include: (1) laboratory error, (2) compliance with medication regimen, and (3) altered hepatic metabolism. The first two are not likely in this case. The laboratory verified the elevated SQC and the patient had her prescriptions refilled within appropriate time limits. The third explanation seems more plausible. Quinidine is metabolized by the hepatic mixed-function oxidase system, specifically cytochrome P450 (CYP) 3A4. We found that metronidazole has been shown to inhibit CYP3A activity and ciprofloxacin has been shown to inhibit certain isozymes in the cytochrome P450 system as well.CONCLUSIONS: When metronidazole and ciprofloxacin are administered concomitantly with quinidine, clinicians should be aware of this potential interaction. Quinidine concentrations should be monitored and patients should be assessed for signs and symptoms of quinidine toxicity.

Choosing the most appropriate statistical test may be routine for statisticians, but not for clinicians. The t-test, a parametric statistical test, may be used inappropriately. This commentary describes the assumptions of and alternatives to the t-test.T-tests are used to compare two groups of data that are from a continuous scale and normally distributed. Determining if data are normally distributed can be difficult but selected methods can be useful. Two nonparametric tests, the Mann-Whitney U test and the Wilcoxon rank sum test, may be more appropriate in analyzing data that are neither continuous nor normally distributed. Statistical results may vary with the test chosen. Investigators are responsible for using the appropriate statistical tests. Statisticians and texts can be consulted. Pharmacy educational and training programs may need further emphasis in the area of statistics.

Objective.To assess the evolution and effectiveness of the Academician Preparation Program to provide knowledge and skills in teaching and evaluating to pharmacy residents, as well as generate interest in academic careers.

To examine trends in the numbers of women and underrepresented minority (URM) pharmacy faculty members over the last 20 years, and determine factors influencing women faculty members’ pursuit and retention of an academic pharmacy career.