John Pieper
St Louis College Of Pharmacy, Pharmacy, Faculty Member
Contemporary management of patients with the acute coronary syndromes (ACS), unstable angina and non-Q-wave myocardial infarction, includes nitrates, beta blockers and/or calcium channel blockers, aspirin, anticoagulation (heparin or... more
Contemporary management of patients with the acute coronary syndromes (ACS), unstable angina and non-Q-wave myocardial infarction, includes nitrates, beta blockers and/or calcium channel blockers, aspirin, anticoagulation (heparin or low-molecular-weight heparin), and antiplatelet therapy (glycoprotein IIb-IIIa inhibitor). Low-molecular-weight heparins have several pharmacological advantages over unfractionated heparin, including a more predictable anticoagulant response, subcutaneous administration, greater activity against factor Xa, and no aPTT monitoring requirement. Several large clinical trials have demonstrated that low-molecular-weight heparins, in particular enoxaparin, are superior to unfractionated heparin for the in-hospital management of ACS. In addition, the total patient care costs at 30 days appear to be lower. Existing data do not support the use of low-molecular-weight heparins after hospital discharge. Low-molecular-weight heparin efficacy has not been adequately ...
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INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic has precipitated a myriad of challenges to the United States (US) healthcare system Predictive models have sought to forecast the extend of healthcare resource deficient in order to... more
INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic has precipitated a myriad of challenges to the United States (US) healthcare system Predictive models have sought to forecast the extend of healthcare resource deficient in order to prepare the US healthcare system, based on the assumption that fatalities are linked to intensive care (ICU) and hospital utilization This study aims to construct a predictive model for ICU utilization, based on COVID-19 positivity rates and COVID-19 related fatalities METHODS: Data was obtained from each state's public health department dashboard and validated via the Institute for Health Metrics and Evaluation, the Center for Disease Control and Prevention, and the COVID Tracking Project databases Data from the five states (California (CA), Florida (FL), New Jersey (NJ), New York (NY), and Texas (TX)) with the highest incidence of COVID-19 related fatalities, ICU utilization, and inpatient deaths were collected from April 1, 2020 to July 14, 2020 The rates of positive COVID-19 tests and death were utilized to construct a linear model predicting ICU utilization referenced to July 14, 2020 The actual incidence of COVID-19-related ICU utilization for each state was compared to the model using the root-mean-square-error (RMSE) RESULTS: Linear models were created for all assessed states, except TX For the TX model, the fit of the data was non-significant In all cases, there was a positive linear correlation observed between daily ICU utilization and mortality and COVID-positivity rates (CA R2=0 66, FL R2=0 88, NJ R2=0 68, NY R2=0 32) The RMSE was 1 81 for CA, 0 21 for FL, 0 30 for NJ, and 0 77 for NY As expected, incidence of ICU and hospital utilization was higher than the US average for all states assessed, except for FL The incidence of ICU and hospital utilization in Florida remained significantly lower than the US average (ICU OR 0 64, 95% CI 0 51 - 0 77;hospital OR 0 02, 95% CI 0 017 - 0 021) CONCLUSIONS: Increased ICU utilization was associated with both COVID-19-related mortality and COVID-19 positivity Overall, for CA, FL, NJ, NY the there was a correlation between observed ICU utilization and these values
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OILTIAZEM is a member of the new class of pharmacologic agents known as calcium channel blockers or calcium antagonists, which have recently become available for the treatment of arrhythmias and ischemic heart disease. The available... more
OILTIAZEM is a member of the new class of pharmacologic agents known as calcium channel blockers or calcium antagonists, which have recently become available for the treatment of arrhythmias and ischemic heart disease. The available agents, diltiazem, verapamil, and nifedipine, owe their beneficial cardiac effects to their ability to influence calcium ion entry and movement in both myocardial and smooth muscle cells. Although these agents demonstrate many similar effects, they are structurally a diverse group (Figure 1). The purpose of this article is to review the pertinent literature concerning diltiazem and to place this drug in perspective for the clinician. ~ s, I NO,
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Research Interests: Pharmacokinetics, Drug interactions, Clinical Pharmacology, Enzyme Inhibitors, Adolescent, and 15 moreProspective studies, Humans, Blood Pressure, Female, Male, Adult, Losartan, Drug Interaction, Isozyme, Dizziness, Area Under Curve, Gastrointestinal Diseases, Diastole, Antihypertensive agents, and Pharmacology and pharmaceutical sciences
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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... more
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. A MEDLINE search (1990-May 2003) was conducted using the key terms coronary heart disease, secondary prevention and elderly. Primary and tertiary literature relating to the use of aspirin, beta-blockers, lipid-lowering agents, and ACE inhibitors in the elderly were reviewed. 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 ...
Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the... more
Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady-state AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require bot...
Research Interests: Pharmacokinetics, Drug interactions, Clinical Pharmacology, Enzyme Inhibitors, Adolescent, and 15 moreProspective studies, Humans, Blood Pressure, Female, Male, Adult, Losartan, Drug Interaction, Isozyme, Dizziness, Area Under Curve, Gastrointestinal Diseases, Diastole, Antihypertensive agents, and Pharmacology and pharmaceutical sciences
The effect of high-protein meal on the hepatic clearance (ClH) of intravenous lidocaine, because of its conceptual importance in understanding first-pass metabolic phenomena, was evaluated in nine healthy males. Our randomized crossover... more
The effect of high-protein meal on the hepatic clearance (ClH) of intravenous lidocaine, because of its conceptual importance in understanding first-pass metabolic phenomena, was evaluated in nine healthy males. Our randomized crossover study demonstrated that mean ClH rose from 1245 to 1477 ml/min (P less than 0.03) as a result of the meal (i.e., mean area under the blood concentration-time curve decreased 20%). The magnitude of the change in clearance correlated weakly with fasting ClH (r = 0.54; slope = -0.037% per ml/min; intercept = 67.2%; P less than 0.15). In a separate study, it was observed that the meal did not influence lidocaine serum protein binding; the free fraction of lidocaine in samples drawn from the subjects in the fasting state averaged 0.305 +/- 0.027 while that from subjects who had eaten was 0.321 +/- 0.042. These data suggest that the mean clearance of lidocaine is increased by stimulation of hepatic blood flow rate. Furthermore, the magnitude of this increase is consistent with expectations based on a simple physiologic model. Thus, these data provide experimental support for the hypothesis that transient increases in splanchnic blood flow rate observed after a high-protein meal may explain apparent improvement of the oral bioavailability of model high intrinsic clearance drugs.
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ABSTRACT A high performance liquid chromatographic method was developed for the determination of imipenem concentrations in plasma. This method involves stabilization of plasma with a mixture of 2-(N-morpholine)-ethanesulf onic acid and... more
ABSTRACT A high performance liquid chromatographic method was developed for the determination of imipenem concentrations in plasma. This method involves stabilization of plasma with a mixture of 2-(N-morpholine)-ethanesulf onic acid and ethylene glycol (1:1). Samples are ultrafiltered using a membrane separation system and the ultrafiltrate injected directly onto a octyldecyl column. Chromatography is performed in the reverse-phase mode with a mobile phase of acetonitrile-phosphate buffer-triethylamine (pH 7.0). The lower limit of sensitivity was 1mcg/ml using UV detection at 300nm. Recovery and reproducibility results, and interferences from other therapeutic agents are presented and discussed. The assay procedure is applied to estimate pharmacokinetic parameters of imipenem in a thermally injured patient.
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The negative inotropic and chronotropic effects of beta-blocker therapy have been reported to reduce morbidity and mortality in patients with Marfan syndrome; however, little is known about the pharmacokinetics of atenolol after oral... more
The negative inotropic and chronotropic effects of beta-blocker therapy have been reported to reduce morbidity and mortality in patients with Marfan syndrome; however, little is known about the pharmacokinetics of atenolol after oral administration of multiple doses to patients with the Marfan syndrome. We studied the pharmacokinetics of atenolol in 13 such patients aged 18.7 +/- 2.9 years who were receiving 1.78 +/- 0.58 mg/kg/day (70.1 +/- 20.3 mg/m2/day) of atenolol for 6 weeks or longer. Mean +/- SD percentage change in baseline heart rate after the administration of atenolol was -18.03 +/- 16.59% and mean +/- SD percentage change in exercise heart rate after atenolol was -33.22 +/- 14.75% (P < .01). Six to 8 atenolol serum concentrations were collected in each patient during a 12-hour dosing interval and were determined by high-performance liquid chromatography with ultraviolet detection. Serum atenolol concentrations at 0 (123 +/- 70 micrograms/L) and 12 (116 +/- 66 micrograms/L) hours were within 20% of each other and were thus assumed to be at steady-state. A one-compartment, steady-state pharmacokinetic model with first-order absorption and elimination was fitted to the concentration-time data for each patient using nonlinear regression. Maximal concentration was 343 +/- 120 micrograms/L, and the mean half-life was 4.72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
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The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release... more
The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.
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Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the... more
Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the pharmacokinetics and pharmacologic response of losartan and E3174. Ten healthy volunteers were studied to assess the effects of CYP3A4 inhibition and nonspecific P450 enzyme induction on the pharmacokinetics of losartan and E3174. Subjects completed three 1-week phases separated by 6 days: 50 mg losartan every morning, losartan plus 500 mg erythromycin four times a day, and losartan plus 300 mg rifampin (INN, rifampicin) twice a day. On the eighth day of each phase, serial plasma concentrations of losartan and E3174 were obtained over 32 hours and steady-state pharmacokinetics were determined. Rifampin decreased the area under the concentration-time curve from time zero to 24 hours after the dose (AUC[0-24]) of losartan by 35% (349 +/- 246 versus 225 +/- 130; p = 0.0001) and decreased the AUC(0-24) of E3174 by 40% (1336 +/- 445 versus 792 +/- 302; p < 0.005). Losartan oral clearance was increased by 44% (p = 0.0001). The half-life values of both compounds were decreased by 50% (p < 0.005). In contrast, erythromycin did not significantly affect the AUC(0-24) or half-life of either losartan or E3174. Rifampin is a potent inducer of losartan and E3174 elimination. Given the magnitude of the effect, this interaction is likely to be clinically significant. On the basis of the minimal inhibitory effects observed with erythromycin, CYP3A4 appears to play a minor role in the in vivo metabolism of losartan to E3174. Further studies are needed to define the contribution of other isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.
Research Interests: Drug interactions, Clinical Pharmacology, Humans, Female, Male, and 15 moreEnzyme, Steady state, Anti-Bacterial Agents, Adult, Time Factors, Phase Separation, Erythromycin, Losartan, Imidazoles, Reference Values, Tetrazoles, Clinical Pharmacology and Therapeutics, Antihypertensive agents, Pharmacology and pharmaceutical sciences, and Rifampin
A high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of verapamil, norverapamil, N-dealkylverapamil (D617) and N-dealkylnorverapamil (D620) concentrations in serum is developed. Analysis is performed... more
A high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of verapamil, norverapamil, N-dealkylverapamil (D617) and N-dealkylnorverapamil (D620) concentrations in serum is developed. Analysis is performed on a microparticulate (10 microns) silica column using a counter-ion solvent system (0.6 mM NaBr in methanol). Column effluent is monitored by fluorescence detection at an excitation wavelength of 203 nm. The limit of sensitivity is less than 1 ng for all compounds in serum. No potential sources of interference are identified and a coefficient of variation of less than 10% is observed on replicate verapamil determinations. The method has the advantages of complete resolution of the metabolites of verapamil, low limits of detection, high degree of reproducibility, and short analysis time.
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We have determined the extent and variability in the binding of gallopamil to human serum proteins. Binding was determined by equilibrium dialysis in healthy volunteer serum, human serum albumin (45 g.l-1), and alpha-1 acid glycoprotein... more
We have determined the extent and variability in the binding of gallopamil to human serum proteins. Binding was determined by equilibrium dialysis in healthy volunteer serum, human serum albumin (45 g.l-1), and alpha-1 acid glycoprotein (AAG) (600 mg.l-1) at a pH of 7.4. Nonlinear regression analysis of gallopamil binding over a wide range of concentrations (10(-9) to 10(-4) M) in healthy volunteer serum suggested two classes of binding sites (kass.1 = 4.7 x 10(5)M-1, kass.2 = 4.1 x 10(4)M-1). These values were in close agreement with those obtained from binding to AAG and human serum albumin. Gallopamil free fraction over the concentration range of 10 to 100 ng.ml-1 was independent of concentration. The free fraction in 20 volunteers was 0.075 at a concentration of 10 ng.ml-1. Gallopamil free fractions were also determined in human serum albumin, to which various concentrations of AAG were added. Bound/free ratios correlated with AAG. As we changed the pH of the serum from 7.0 to 8.0, the free fraction changed from 0.1 to 0.05. Verapamil, lignocaine, procainamide, propranolol, 40 H-propranolol, MEGX, and NAPA all caused an increase in the free fraction of gallopamil in serum. However, tocanide, quinidine, diltiazem, GX, norverapamil, D620, D617, and desacetyl diltiazem had no effect on gallopamil binding. Therefore, the data strongly suggest AAG as the high affinity, low capacity binding site and albumin as the low affinity, high capacity binding site for gallopamil, variability in gallopamil binding can be explained by alterations in AAG concentrations, pH, and the presence of other drugs and their metabolites.
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The extent of propranolol protein binding was determined in three different age groups of healthy drug-free caucasian males. Volunteers selected for study were 6-15 years old, 25-36 years old and 68-76 years old. Ten milliliters of blood... more
The extent of propranolol protein binding was determined in three different age groups of healthy drug-free caucasian males. Volunteers selected for study were 6-15 years old, 25-36 years old and 68-76 years old. Ten milliliters of blood were obtained via venipuncture and collected in glass tubes from the subjects after an overnight fast. Binding determinations were performed by equilibrium dialysis using radiolabelled propranolol. Serum albumin and alpha 1-acid glycoprotein concentrations were determined in all subjects by radial immunodiffusion. The results obtained showed wide intersubject variability in the binding ratio of propranolol and serum concentrations of alpha 1-acid glycoprotein. Mean albumin serum concentration was found to be significantly lower in the elderly group as compared to the adult and pediatric groups (p less than 0.02). A positive correlation was found between the binding ratio of propranolol and the serum concentration of alpha 1-acid glycoprotein in all the subjects (r = + 0.66, p less than 0.005). No significant correlation was found between the binding ratio of propranolol and the serum concentration of albumin (r = -0.03, p less than 0.88). These data suggest that the extent of propranolol binding is influenced primarily by serum concentrations of alpha 1-acid glycoprotein and not by differences in age.
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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... more
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.
Research Interests: Kinetics, Pharmaceutical Chemistry, Professional Role Socialization, Humans, United States, and 15 moreLDL-cholesterol, Sustained Drug Release, Managed care, Pharmacists, High Density Lipoprotein, Side Effect, Lipid Profile, Low Density Lipoprotein (LDL), Total Cholesterol, Lipoprotein a, Extended release, Clinical Trials as Topic, Professional Role, Niacin, and Hyperlipidemias
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The effect of increasing doses of oral diltiazem on airway reactivity to methacholine was evaluated in 10 volunteers with mild asthma. Then the highest tolerated dose was compared with placebo in preventing exercise-induced... more
The effect of increasing doses of oral diltiazem on airway reactivity to methacholine was evaluated in 10 volunteers with mild asthma. Then the highest tolerated dose was compared with placebo in preventing exercise-induced bronchoconstriction. Methacholine challenges were performed 1 h before and 100 min after placebo or after 30, 60, 90, 120, or 180 mg of oral diltiazem, given in a single-blind, crossover manner on different days within 2 wk. Diltiazem, at doses above 60 mg prolonged the P-R interval of the electrocardiograph but had no significant effect on FVC, FEV1, or FEF25-75. The mean +/- SEM ratio of the dose of methacholine required to produce a 20% decrease in FEV1 (PD20) after diltiazem to the PD20 before diltiazem, i.e., the fold increase in PD20, was not significantly different from placebo at any dose: 0.93 +/- 0.11 after placebo, 1.2 +/- 0.1 after 30 mg, 1.3 +/- 0.3 after 60 mg, 1.2 +/- 0.2 after 90 mg, 1.1 +/- 0.1 after 120 mg, and 1.0 +/- 0.1 after 180 mg. One hund...
Research Interests: Asthma, Humans, Female, Male, Heart rate, and 4 moreAdult, Random Allocation, Airway resistance, and physical exertion
Amrinone is the first noncatecholamine inotropic agent with substantial vasodilating properties to be approved by the Food and Drug Administration. Its use in acute congestive heart failure (CHF) is associated with significant increases... more
Amrinone is the first noncatecholamine inotropic agent with substantial vasodilating properties to be approved by the Food and Drug Administration. Its use in acute congestive heart failure (CHF) is associated with significant increases in cardiac index, reductions in pulmonary capillary wedge pressure and systemic vascular resistance and little or no change in mean arterial pressure. Pharmacokinetic studies of amrinone report an elimination half-life of 2.6-8.3 hours, with slower elimination more likely in patients with compromised renal or hepatic function. Intravenous bolus doses of 0.75-3.5 mg/kg followed by infusions of 5-20 micrograms/kg/min produce hemodynamic improvements similar to those with dobutamine. Side effects with amrinone therapy are usually mild, but thrombocytopenia occurs in 2.4% of patients. Amrinone appears equally as efficacious as dobutamine in the management of acute CHF, but its role in therapy depends on efficacy and side effect data in greater numbers of...
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Very little is known about the effects of hepatic enzyme induction with phenobarbital on the disposition of high clearance drugs in humans. Our study was undertaken to investigate the effect of phenobarbital on both alpha-1 acid... more
Very little is known about the effects of hepatic enzyme induction with phenobarbital on the disposition of high clearance drugs in humans. Our study was undertaken to investigate the effect of phenobarbital on both alpha-1 acid glycoprotein concentrations and total and free verapamil and its metabolites. Single oral, single i.v., and multiple oral verapamil administrations were evaluated before and after 21 days of phenobarbital treatment in healthy caucasian male volunteers. Significant changes in the pharmacokinetics of total and free verapamil and its metabolites occurred in a predictable manner. Mean total apparent oral clearance after a single dose of verapamil was increased after phenobarbital treatment (75.1 +/- 49.2 vs. 376.2 +/- 221.8 ml/min/kg, P less than .05). Clearance of free drug increased to a similar magnitude. Mean total verapamil systemic clearance was increased (9.95 +/- 1.3 vs. 18.9 +/- 8.7 ml/min/kg, P less than .05); however free drug clearance was not altere...
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We analyzed 99 patients' serum samples for concentrations of a new antiarrhythmic agent, flecainide acetate, by fluorescence polarization immunoassay (FPIA) and "high-performance" liquid chromatography (HPLC). Within-day and... more
We analyzed 99 patients' serum samples for concentrations of a new antiarrhythmic agent, flecainide acetate, by fluorescence polarization immunoassay (FPIA) and "high-performance" liquid chromatography (HPLC). Within-day and between-day coefficients of variation at concentrations in the low and high ends of the therapeutic range were less than 7% for HPLC and less than 9% for FPIA. There was no statistical difference in the mean (+/- SD) concentrations of the clinical serum samples measured by the two methods (607 +/- 334 micrograms/L by HPLC, 602 +/- 344 micrograms/L by FPIA), but results by each differed by a mean of 0.13%. FPIA and HPLC measurements correlated significantly (r = 0.98, P less than 0.05), and were linearly related (slope = 0.970, intercept = 13 micrograms/L) as assessed by orthogonal regression. Both assay methods produced similar concentration measurements and were sufficiently accurate and precise to be used in therapeutic drug monitoring.
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The death rate from coronary heart disease (CHD) declined by 25% in the United States during 1987-1997, but the actual number of deaths fell by only 9%. Modifiable risk factors for CHD include hypertension, elevated low-density... more
The death rate from coronary heart disease (CHD) declined by 25% in the United States during 1987-1997, but the actual number of deaths fell by only 9%. Modifiable risk factors for CHD include hypertension, elevated low-density lipoprotein cholesterol, reduced high-density lipoprotein cholesterol, cigarette smoking, and diabetes. Several randomized clinical trials demonstrated that calcium channel blockers reduce the frequency of strokes in patients with hypertension, with particular benefit observed in patients with both hypertension and diabetes. Results of a meta-analysis suggest that calcium channel blockers are similar to beta-blockers in preventing death or myocardial infarction and in improving exercise tolerance among patients with established CHD. In addition, amlodipine, a long-acting dihydropyridine, was reported to reduce nonfatal vascular events and major vascular procedures in patients with angina. Ongoing clinical trials are comparing amlodipine with an angiotensin-converting enzyme inhibitor for slowing the onset and progression of coronary artery plaque and cardiovascular events.
Research Interests: Treatment, Prevention, Humans, Hypertension, Female, and 14 moreMale, Risk factors, Pharmacotherapy, Middle Aged, Risk Factor, Coronary heart disease, Disease Progression, Risk Factors, Amlodipine, Coronary Artery Disease, Calcium Channel Blockers, Clinical Trials as Topic, Antihypertensive agents, and Pharmacology and pharmaceutical sciences
Research Interests: Life Sciences, Beta decay, Animals, Male, Cardiovascular system, and 13 moreRats, Myocardium, Drinking, Propranolol, Species Specificity, Reaction Kinetics, Genetic Variability, Binding Site, Biochemistry and cell biology, Isoproterenol, Pindolol, Stress Physiological, and Pharmacology and pharmaceutical sciences
The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release... more
The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.
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Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to... more
Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.
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Kimberly A. Dornbrook-Lavender, Pharm.D., Melanie S. Joy, Pharm.D., Cynthia J. Denu-Ciocca, MD, Hyunsook Chin, BS, MPH, Susan L. Hogan, Ph.D., and John A. Pieper, Pharm.D., FCCP ... Study Objectives. To determine the effects of... more
Kimberly A. Dornbrook-Lavender, Pharm.D., Melanie S. Joy, Pharm.D., Cynthia J. Denu-Ciocca, MD, Hyunsook Chin, BS, MPH, Susan L. Hogan, Ph.D., and John A. Pieper, Pharm.D., FCCP ... Study Objectives. To determine the effects of atorvastatin on ...
Research Interests: Dialysis, Humans, Cholesterol, Chronic Disease, Female, and 15 moreMale, Hypercholesterolemia, Risk factors, Phenotype, Triglycerides, Pharmacotherapy, Aged, Middle Aged, C reactive protein, Particle Size, Risk Factors, Pilot Projects, Renal Dialysis, Low density lipoprotein cholesterol, and Pharmacology and pharmaceutical sciences
Serum concentrations of verapamil and its pharmacologically-active metabolite, norverapamil, were measured in six patients with angina at rest after six to fifteen months of therapy. Optimal daily doses were selected during a previous... more
Serum concentrations of verapamil and its pharmacologically-active metabolite, norverapamil, were measured in six patients with angina at rest after six to fifteen months of therapy. Optimal daily doses were selected during a previous in-hospital titration period and ranged from 240 to 640 mg per day. There was no significant relationship between dose, corrected for body weight, and area under the verapamil serum concentration-time curve (AUC). The mean apparent oral clearance of verapamil was highly variable with a mean of 21.9 +/- 9.1 ml/min/kg and a range of 7.7 to 32.0 ml/min/kg. The ratio of verapamil AUC to norverapamil AUC, used to assess accumulation kinetics of parent drug and metabolite, was less than 1.0 in five of six patient (mean 0.93). However, one patient with verapamil concentrations ranging from 300 to 900 ng/ml had a ratio of 1.37 suggesting saturation of the enzymes that convert verapamil to norverapamil. When the relationship between serum concentration at the end of the dosing interval and angina frequency was studied, it was observed that patients in whom angina was completely suppressed had concentrations greater than 160 ng/ml and patients with poor control (greater than 5 anginal episodes per week) had concentrations less than 60 ng/ml. The findings suggest that the oral clearance of verapamil following long-term (greater than 6 mo.) administration may be different than after short-term therapy and that it is difficult to predict verapamil serum concentrations and antianginal effect during long-term oral therapy. Individualizing verapamil therapy to maintain serum concentrations greater than 100 ng/ml may improve therapeutic response and appears to more reliably predict response than daily dose.
Research Interests: Kinetics, Humans, Male, Aged, Middle Aged, and 4 moreTime Factors, Angina pectoris, Biotransformation, and Verapamil
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Research Interests: Multivariate Analysis, Humans, Female, Male, Bilirubin, and 13 moreAged, Middle Aged, Adult, Neoplasms, In Vitro Studies, Bovine Serum Albumin, Protein Binding, Blood Proteins, Serum albumin, Etoposide, Clinical Pharmacology and Therapeutics, plasma proteins, and Pharmacology and pharmaceutical sciences
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... more
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.
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Research Interests: Drug interactions, Adolescent, Humans, Child, Liver, and 13 moreFemale, Male, P-glycoprotein, Lorazepam, Blood Flow, Protein Binding, Acute Lymphocytic Leukemia, Blood Proteins, Antipyrine, Child preschool, Clinical Pharmacology and Therapeutics, Indocyanine green, and Pharmacology and pharmaceutical sciences
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Research Interests: Aging, Adolescent, Humans, Child, Liver, and 8 morePharmaceutical Sciences, Female, Male, Infant, Shell Half-Life, Adult, Protein Binding, and Blood Proteins
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... more
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 sig- nificantly reduce levels of total cholesterol, low- density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a), while having the greatest high- density lipoprotein
Research Interests: Kinetics, Pharmaceutical Chemistry, Professional Role Socialization, Humans, United States, and 12 moreLipoprotein(a), LDL-cholesterol, Sustained Drug Release, Managed care, Pharmacists, High Density Lipoprotein, Side Effect, Lipid Profile, Low Density Lipoprotein (LDL), Total Cholesterol, #Hypolipidemic Agents, and Extended release
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... more
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, wh...
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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... more
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 absorp...
Research Interests: Kinetics, Pharmaceutical Chemistry, Professional Role Socialization, Humans, United States, and 12 moreLipoprotein(a), LDL-cholesterol, Sustained Drug Release, Managed care, Pharmacists, High Density Lipoprotein, Side Effect, Lipid Profile, Low Density Lipoprotein (LDL), Total Cholesterol, #Hypolipidemic Agents, and Extended release
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Calcium channel blockers are theoretically effective in the treatment of chronic systolic heart failure because of their actions as arteriolar dilators, antiischemic agents, and relaxants of diastolic left ventricular function, and... more
Calcium channel blockers are theoretically effective in the treatment of chronic systolic heart failure because of their actions as arteriolar dilators, antiischemic agents, and relaxants of diastolic left ventricular function, and because they may prevent progression of myocardial dysfunction. The first-generation calcium channel blockers nifedipine, verapamil, and diltiazem cause hemodynamic and clinical deterioration and may increase the frequency of cardiac events in postmyocardial infarction patients with heart failure. These drugs depress left ventricular contractility in the short term, and can activate neurohormonal systems due to their hypotensive effects. The second-generation calcium channel blocker felodipine does not activate the sympathetic nervous and renin-angiotensin systems, but has no effect on exercise capacity or mortality. Amlodipine increases exercise time and reduces symptoms and plasma norepinephrine concentration in heart failure. It also reduces morbidity ...
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Research Interests:
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... more
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.
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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... more
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. The purpose of this article was to review the available scientific literature evaluating the use of clopidogrel in the management of ACS. 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. 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. 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.