Contemporary management of patients with the acute coronary syndromes (ACS), unstable angina and ... 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 ...
INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic has precipitated a myriad of challenges 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
OILTIAZEM is a member of the new class of pharmacologic agents known as calcium channel blockers ... 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,
To review relevant literature supporting the use of aspirin, beta-blockers, lipid-lowering agents... 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 m... 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...
The effect of high-protein meal on the hepatic clearance (ClH) of intravenous lidocaine, because ... 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.
Http Dx Doi Org 10 1080 01483918808082269, Jan 3, 2007
ABSTRACT A high performance liquid chromatographic method was developed for the determination of ... 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.
The negative inotropic and chronotropic effects of beta-blocker therapy have been reported to red... 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)
European Journal of Clinical Pharmacology, Feb 1, 1987
The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacoki... 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.
Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater an... 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.
A high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of vera... 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.
European Journal of Clinical Pharmacology, Feb 1, 1987
We have determined the extent and variability in the binding of gallopamil to human serum protein... 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.
The extent of propranolol protein binding was determined in three different age groups of healthy... 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.
Contemporary management of patients with the acute coronary syndromes (ACS), unstable angina and ... 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 ...
INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic has precipitated a myriad of challenges 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
OILTIAZEM is a member of the new class of pharmacologic agents known as calcium channel blockers ... 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,
To review relevant literature supporting the use of aspirin, beta-blockers, lipid-lowering agents... 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 m... 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...
The effect of high-protein meal on the hepatic clearance (ClH) of intravenous lidocaine, because ... 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.
Http Dx Doi Org 10 1080 01483918808082269, Jan 3, 2007
ABSTRACT A high performance liquid chromatographic method was developed for the determination of ... 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.
The negative inotropic and chronotropic effects of beta-blocker therapy have been reported to red... 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)
European Journal of Clinical Pharmacology, Feb 1, 1987
The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacoki... 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.
Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater an... 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.
A high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of vera... 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.
European Journal of Clinical Pharmacology, Feb 1, 1987
We have determined the extent and variability in the binding of gallopamil to human serum protein... 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.
The extent of propranolol protein binding was determined in three different age groups of healthy... 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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