bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐Term Captopril in Young and Old Patients with Mild Hypertension
Authors: Penner S. Brian , Mitenko Paul A. , Aoki Fred Y. , Sitar Daniel S. , Smyth Donald D. , McKenzie John K.
Published: March 2013

The decrease in renal blood flow (RBF) observed in patients with hypertension can be increased with converting enzyme inhibition (CEI). It is unknown whether the decrease in RBF observed with age can also be increased with CEI. This study compared the short‐ and long‐term effects of captopril monotherapy in young (<50 years) and old (>65 years) hypertensive patients. Captopril effectively decreased blood pressure in both groups (diastolic blood pressure < 90 mm Hg), with the young patients requiring a lower dose (.7 mg/kg) than the elderly patients (1.2 mg/kg). Creatinine and para‐aminohippurate clearances were maintained in both groups, with a decrease in renal vascular resistance being observed in the younger patients. Serum aldosterone levels fell significantly after each dose of captopril at all phases of the study, with no change observed in plasma renin levels. Atrial natriuretic peptide (ANP) level was increased in the elderly patients receiving placebo (48.8 ± 8 pg/mL) when compared with the young subjects (24 ± 3.8 pg/mL). Captopril did not alter ANP levels in either group.
Innovative Approaches to Teaching Clinical Pharmacology: Problems of an Emerging Curriculum
Authors: Burford Hugh J.
Published: March 2013

The Journal of Clinical Pharmacology is publishing an educational series dealing with Innovative Teaching programs in Clinical Pharmacology. Claire M. Lathers, PhD, FCP, and Alphonse J. Ingenito, PhD, FCP, are coediting this series of articles. Two articles have been published to date. The first is coauthored by AJ Ingenito, CM Lathers, and HJ Burford, and is entitled “Instruction in Clinical Pharmacology: Changes in the Wind” (J Clin Pharmacol 1989;29:7–17) and the second was written by CM Lathers and CM Smith and is entitled “Teaching Clinical Pharmacology: Coordination with Medical Pharmacology Courses” (J Clin Pharmacol 1989;29:581–597). The third article, “Incorporation of Clinical Pharmacology into the Fourth Year of the Medical Curriculum: Teaching Clinical Pharmacology Without a Clinical Pharmacologist,” (J Clin Pharmacol 1990;30:1065–1073) was written by Patricia Williams, PhD at Eastern Virginia Medical School. The fourth article (in press) written by Duncan E. Hutcheon, MD, FCP of UMDNJ in Newark, and Hoda Wadie El‐Gawly, MD, PhD, from the University of Suez, describes a computer‐based problem‐solving system in clinical pharmacology.

A system that isn't innovating is a system that is dying. In the long run, the innovators are the ones who rescue all human ventures from death by decay. So value them. You don't have to be one yourself, but you should be a friend of the innovators around you. And if you don't have any around you, you had better import some.
Effect of Disopyramide on Systolic and Early Diastolic Time Intervals in Patients with Hypertrophic Cardiomyopathy
Authors: Sumimoto Takumi , Hamada Mareomi , Ohtani Takashi , Shigematsu Yuji , Fujiwara Yasushi , Sekiya Michihito , Hiwada Kunio
Published: March 2013

The present study clarified the effect of disopyramide on left‐ventricular function in patients with hypertrophic cardiomyopathy (5 obstructive type: HOCM, 21 non‐obstructive type: HNCM). The systolic and early diastolic time intervals were assessed 3 hours after a single oral administration of 100‐mg disopyramide. The following parameters were evaluated at rest and after administration of disopyramide: 1) left‐ventricular ejection time index (LVETI), 2) pre‐ejection period index (PEPI), 3) the interval from aortic component of the second heart sound to mitral valve opening (IIA‐MVO), and 4) the interval from MVO to O point of apexcardiogram (MVO‐O). LVETI in HNCM did not change after disopyramide but that in HOCM was significantly shortened (P < .05). PEPI in both HOCM and HNCM was significantly prolonged after administration of disopyramide. IIA‐MVO time in both HOCM and HNCM was not influenced by disopyramide. MVO‐O time in both HOCM and HNCM was significantly shortened after disopyramide. These results suggest that 1) shortening of LVETI in HOCM after disopyramide seemed to be due to the decrease in pressure gradient, 2) PEPI prolongation after disopyramide reflected the decrease in myocardial contractility, and 3) shortening of MVO‐O time after disopyramide indicated the improvement of left‐ventricular filling. The authors conclude that disopyramide may be an important new therapeutic agent in the treatment of patients with hypertrophic cardiomyopathy.
Influence of Diuretic Therapy on the Clonidine Suppression Test
Authors: Gretler Daniel D. , Gramelspacher Gregory P. , Fumo Maryann T. , Elliott William J. , Murphy Michael B.
Published: March 2013

Moduretic has been reported to inhibit the suppression of plasma norepinephrine (NE) levels by the alpha2 adrenoceptor agonist, clonidine. To determine whether plasma volume reduction by hydrochlorothiazide (HCTZ) or antagonism of Na+/H+ exchange by amiloride (the constituents of Moduretic) is responsible, the authors performed a modified clonidine suppression test (CST) in nine normal volunteers (aged 25 ± 2 years), pretreated for 1 week with HCTZ 50 mg daily, amiloride 10 mg daily, or placebo, in a randomized, double‐blind, crossover study. Baseline characteristics were identical on all study days, except serum [K+] and weight, which were lowest on HCTZ (3.6 ± 0.2 mEq/L and 78.7 ± 2.5 kg), compared with amiloride (4.2 ± 0.1 mEq/L and 79.9 ± 2.4 kg) and placebo (4.0 ± 0.1 mEq/L and 80.2 ± 2.7 kg, P < .05). Oral clonidine (0.3 mg) produced a reduction in mean blood pressure by about 20%. Plasma norepinephrine levels were similar in patients receiving placebo, HCTZ, and amiloride (205 ± 18, 272 ± 40 and 277 ± 44 pg/mL, P > .20), and decreased significantly during CST. The maximal reduction for each subject averaged 72.7 ± 12.4%, 87.9 ± 3.8%, and 82.9 ± 5.7% for placebo, HCTZ, and amiloride. Clonidine also produced a four to seven‐fold increase in plasma growth hormone levels, reduced salivary flow by about 75%, and increased the level of sedation. There were no differences among the three pretreatment regimens in the effects of clonidine, indicating that diuretic therapy does not need to be systematically discontinued in patients undergoing CST.
The Effect of Nifedipine GITS on Renal Function in Hypertensive Patients with Renal Insufficiency
Authors: Reams Garry , Lau Alisa , Knaus Vicki , Bauer John H.
Published: March 2013

Twelve hypertensive patients with moderately severe renal dysfunction were entered into a protocol to assess the blood pressure and renal effects of the sustained release calcium antagonist, nifedipine GITS (30 — 180 mg/d given once a day) administered for 5 weeks. Nifedipine GITS monotherapy effectively lowered blood pressure in 50% of the patients. Glomerular filtration rate and effective renal plasma flow were increased 18% and 20%, respectively. The filtration fraction and urinary protein excretion remained unchanged. Changes that were observed in renal junction were independent of the blood pressure responses of the patients; there was no correlation between the systemic and renal effect of nifedipine GITS monotherapy. Patients who had a poor systemic blood pressure response exhibited an increase in glomerular filtration rate (+11%) but had a decrease in effective renal plasma flow (‐6%); patients who achieved a goal blood pressure response showed increases in both glomerular filtration rate (+35%) and effective renal plasma flow (+40%). These results show that nifedipine GITS monotherapy has the potential to improve renal function abnormalities that are encountered in hypertensive patients with renal disease; the improvement in renal function may be independent of their effect on systemic blood pressure.
The Effect of Cardiac Catheterization on Fasting Lipids
Authors: Payne Larry J. , Prisant L. Michael , Kuske Terrence T. , Carr Albert A. , Crandall Brian S.
Published: March 2013

Fasting lipid profiles were measured in 20 selected patients the day of and after cardiac catheterization in EDTA tubes. Samples were randomly labelled A or B, centrifuged, and stored at 3° Centigrade. Lipid profiles were analyzed by a laboratory, which was participating in the Center for Disease Control Lipid Standardization Program, by using standard methods. The coefficients of variation for repeated measurements were: cholesterol = 1.9%, triglycerides = 3.6%, HDL cholesterol = 4.3%, and VLDL and LDL cholesterol = 2.6%. Data were evaluated by a two‐tailed paired t‐test and correlation coefficient. The total cholesterol was significantly lower (P < .001) the day after cardiac catheterization as was the LDL cholesterol (P < .002). Both VLDL and HDL cholesterol and triglycerides were lower, but these were not statistically significant. The mean dose of heparin was 3500 ± 1469 units, and the mean dose of contrast was 181 ± 30 cc. The total dose of heparin or contrast did not correlate with any change in lipid profiles. These results have implications on the number and timing of venous blood sampling for lipid measurements in regard to diagnosis and treatment of hyperlipidemia. Lipid proxies should not be drawn after cardiac catheterization but rather before and/or in the free‐living state.
Cerebral Blood Flow Velocities by Transcranial Doppler During Parabolic Flight
Authors: Bondar Roberta L. , Stein Flo , Kassam Mike S. , Dunphy Paul T. , Bennett Barbara S. , Johnston K. Wayne
Published: March 2013

Microgravity is produced for 20 to 30 seconds in NASA's KC‐135 aircraft at the end of a 2 G pullup for each of 40 parabolas per flight. Continuous transcranial Doppler ultrasound, arterial blood pressure, and acceleration levels were recorded for 12 male and 8 female healthy subjects without known cardiovascular or cerebrovascular disease. Recordings were made throughout 10 parabolas per subject in each of the supine, sitting, and standing postures. The data were digitized for off‐line analysis using Fast Fourier Transform and other signal processing methods. A phase lag in changes to transcranial Doppler waveforms from the onset of acceleration was more pronounced in the standing position than in the sitting position. There was less of a phase lag in the supine position. These ultrasound changes preceded the more delayed variations in arterial blood pressure. The KC‐135 provides a unique short‐term environment that allows measurement of the human response to variations in acceleration but limits physiological monitoring of responses to a steady state of microgravity.
Optimal Sampling Theory and Population Modelling: Application to Determination of the Influence of the Microgravity Environment on Drug Distribution and Elimination
Authors: Drusano George L.
Published: March 2013

Newer mathematical techniques such as optimal sampling theory and NON‐linear Mixed Effects Modelling (NONMEM) allow the determination of pharmacokinetics and pharmacodynamics in populations of individuals previously believed to be “too ill” or “too difficult to study.” Optimal sampling determines the most information‐rich times to sample the system, allowing robust parameter estimates to be determined from the minimal number of samples. NONMEM, by taking the population as the unit of analysis, allows even fragmentary patient data sets to contribute to population parameter estimates. Obviously, the microgravity environment presents extreme logistical difficulties to the performance of traditional pharmacokinetic and pharmacodynamic studies. Examples of the validation of these techniques are presented, which indicates their likely utility in the important task of determining the influence of the microgravity environment on drug distribution and elimination, even accounting for the limitations of support which will be faced in this circumstance.
Clinical Pharmacology and Toxicity of Low Daily Administration of Oral Etoposide in Advanced Lung Cancer Patients
Authors: Katoh Osamu , Yamada Hozumi , Hiura Kenya , Aoki Yousuke , Kuroki Shigetaka
Published: March 2013

In this study, pharmacokinetics, clinical effects, and toxicity of daily oral etoposide were studied in 12 patients with advanced lung cancers. Administration schedule was 25 mg/body everyday of a 4‐week cycle or 50 mg (25 mg twice)/body for 14 consecutive days of a 4‐week cycle. The pharmacokinetic parameters of both groups in serum were as follows: 1) mean peak plasma concentration of 0.91 ± 0.18 μg/mL (25 mg) and 1.24 ± 0.12 μg/mL (25 mg twice); 2) elimination half‐lives of 6.46 ± 1.09 hours (25 mg) and 3.64 ± 0.27 hours (25 mg twice); and 3) the area under the plasma concentration curve of 7.09 ± 1.26 μg · hr/mL (25 mg) and 8.67 ± 0.77 μg·hr/mL (25 mg twice). There was a significant difference between those two schedules in terms of the plasma concentration and the duration at a low concentration (> 1 μg/mL) of etoposide. Low daily administration of oral etoposide is shown to be well tolerated and easy on the patient. More studies are needed to study whether prolonged schedules of lower doses of etoposide could result in improved prognosis.
The Effect of Ace Inhibition on Peripheral Hemodynamics in Normotensive and Hypertensive Patients with Type II Diabetes
Authors: Strocchi Enrico , Malini Pier Luigi , Ciavarella Adolfo , Ricci Cristina , Valtancoli Giampaolo , Mustacchio Anna , Vannini Pietro , Ambrosioni Ettore
Published: March 2013

The effect of treatment with enalapril (10 days at 10 mg/d followed by 4 weeks at 20 mg/d) on forearm hemodynamics was assessed in eight normotensive patients and eight patients with hypertension affected by Type II diabetes as well as in eight patients with essential hypertension and normal glucose tolerance. The ACE inhibitor decreased regional vascular resistances and increased the maximum arteriolar‐vasodilating capacity and venous distensibility in the three groups of patients. Thus, this study shows that ACE inhibition by enalapril improves regional hemodynamics in patients with Type II diabetes.
Once‐Daily Verapamil in the Treatment of Mild‐to‐Moderate Hypertension: A Double‐Blind Placebo‐Controlled Dose‐Ranging Study
Authors: Carr Albert A. , Bottini Peter B. , Prisant L. Michael , Fisher Lloyd D. , Devane John G. , O'Brien D. Eugene , Rhoades Robert B.
Published: March 2013

Supine office blood pressures (SOBP) and 24‐hour automated ambulatory blood pressure monitorings (AABPM) showed blood pressure reductions from a stable baseline to active treatment with 120‐, 240‐, and 480‐mg doses of a new verapamil QD capsule (solid—spheroidal—oral once‐daily drug‐absorption system; (SODAS) in patients with mild‐to‐moderately severe (diastolic blood pressures 95–119 mm Hg) essential hypertension. Reductions were documented at 24 hours, hourly, and by the 24 hour average, using SOBP and AABPM, after the once‐daily verapamil administration. Both SOBP and the 24‐hour average by AABPM were significantly reduced from baseline by active verapamil treatment of 120‐, 240‐, and 480‐mg doses. In comparison to verapamil QD (0 mg), blood pressure reductions from baseline to active treatment were significant at the 240‐ and 480‐mg doses but not at the 120‐mg dose. There was a significant linear dose response. This verapamil formulation (SODAS) was effective throughout the 24‐hour period after once‐daily dosing.
An Assessment of Cerebral Blood Flow and Metabolism After Fleroxacin Therapy
Authors: Gardner Stephanie F. , Green Jeffrey A. , Bednarczyk Edward M. , Nelson A. Dennis , Leisure Greg , Miraldi Floro
Published: March 2013

Cerebral blood flow (CBF), glucose (FDG), and oxygen metabolism (OM) were evaluated by positron emission tomography (PET) in 18 healthy volunteers who were randomized to a 72‐hour course of either 600 mg/d of fleroxacin or placebo. Such studies attempted to assess potentially serious, yet unexplained, central nervous system adverse effects of the fluorinated quinolone class. Baseline and postplacebo values for CBF (mL/min/100 g) and FDG (mg/min/100 g) were: 53 ± 6 and 5.7 ± 1.8; and 49.6 ± 4.4 and 5.2 ± 1.2, respectively. Identical values for fleroxacin were: 53.9 ± 4.8 and 6.3 ± 1.1; and 54.4 ± 2.2 and 6.8 ± 1.5, respectively. The differences between fleroxacin and placebo were not significant. There was also no effect seen in OM between placebo and the active drug. The authors conclude that short‐term administration of fleroxacin does not alter CBF, FDG, or OM in healthy volunteers.
A Comparison of the Efficacy of Captopril and Enalapril Given Once Daily for the Treatment of Hypertension: A Study Using 24‐Hour Ambulatory Blood Pressure Monitoring
Authors: Frewin Derek B. , Ryan Gregory J. , Rennie George C.
Published: March 2013

Sixteen patients who had essential hypertension were stabilized on either captopril or enalapril monotherapy and had 24‐hour blood pressure profiles monitored by using one of two automatic, non‐invasive ambulatory systems: Spacelabs 5300 (Squibb, Princeton, NJ) or PAR Physioport II (Kardiotec, Mannheim). In four subjects (group 1), ambulatory pressures were repeated 4 to 6 weeks later using the same equipment and the same drug. In four subjects (group 2), the drug was changed (dose ratio: captopril:enalapril, 5:1) after the first measurement, but the monitoring equipment was not changed. In four subjects (group 3), the drug was constant, but the equipment was changed for the second measurement of ambulatory pressure. In four subjects (group 4), both drug and equipment were reversed after the first measurement. The results showed that both drugs (given once daily) controlled blood pressure during the 24‐hour period, with no clinically significant difference between them.
Acute Hemodynamic Effects of Pinacidil in Hypertensive Patients with and without Propranolol Pretreatment
Authors: Stone Charles K. , Wellington Karen L. , Willick Andrea , Sullebarger J. Thompson , Liang Chang‐seng
Published: March 2013

To study the systemic and regional hemodynamic effects of the new antihypertensive agent pinacidil, the authors administered intravenously two doses of pinacidil (0.1 mg/kg) to patients with hypertension after 3 days of randomized, double‐blind pretreatment with either propranolol or placebo. Pinacidil administration decreased systemic arterial pressure and total peripheral vascular resistance in both groups of patients. It also decreased pulmonary artery wedge pressure, and increased cardiac output, heart rate, and plasma norepinephrine levels; the changes in cardiac output and heart rate were attenuated by propranolol pretreatment. In addition, propranolol‐pretreated patients responded to pinacidil with a decrease in forearm blood flow. In contrast, pinacidil administration exerted no significant effects on right atrial pressure, stroke volume, or mean pulmonary arterial pressure alone or in combination with propranolol. The results show that pinacidil is a potent arterial dilator but has little effect on the venomotor tone in patients with hypertension.
Pharmacokinetics of Cefprozil in Healthy Subjects and Patients with Renal Impairment
Authors: Shyu W.C. , Pittman K.A. , Wilber R.B. , Matzke G.R. , Barbhaiya Rashmi H.
Published: March 2013

Cefprozil, a new broad‐spectrum oral cephalosporin, is composed of cis and trans isomers in an approximate 90:10 ratio. The pharmacokinetics of a single oral 1000‐mg dose of cefprozil were evaluated in 6 healthy subjects and 24 patients with various degrees of renal impairment. Six of these subjects were studied both while receiving hemodialysis and during an interdialytic period. Plasma, urine, and hemodialysate that were collected at predetermined times were analyzed for concentrations of the cis and trans isomers of cefprozil using reverse‐phase HPLC assay with UV detection. The maximum plasma concentration of the cis isomer ranged from 12.3 μg/mL in subjects with normal renal function to 36.7 μg/mL in hemodialysis patients. Similarly the area under the plasma concentration—time curve and the elimination half‐life increased from 46 μg · h/mL to 373 μg · h/mL and from 1.72 hours to 5.94 hours, respectively. Renal clearance of the cis isomer decreased from 198 mL/min in normal subjects to 19 mL/min in volunteers with creatinine clearances of ≤30 mL/min; there was a strong correlation (r2 ≥ .93) between the renal clearance of the cis isomer and creatinine clearance. Urinary recovery of the cis isomer decreased from 57% in those with normal renal function to 24% in the group with a creatinine clearance of ≤30 mL/min. Hemodialysis decreased the half‐life of the cis isomer to 2 hours and removed approximately 55% of it from the body during a 3‐hour dialysis period (hemodialysis clearance equaled approximately 87 mL/min). The pharmacokinetics of the trans isomer were similar to those observed for the cis isomer and were affected similarly by declining renal function. A reduction in dosage is recommended in patients with a creatinine clearance of 30 mL/min or less. It may be necessary to administer a dose after hemodialysis to maintain therapeutic plasma concentrations.
The Influence of Age on Salicylate Pharmacokinetics in Humans
Authors: Abdallah Hisham Y. , Mayersohn Michael , Conrad Kenneth A.
Published: March 2013

The pharmacokinetics of salicylate after a single oral solution dose of 600 mg of sodium salicylate were investigated in 22 male subjects. Subjects were healthy nonsmokers and were not taking any regular medication. The plasma concentration and urinary excretion of salicylic acid and its metabolite, salicyluric acid, as well as the urinary excretion of salicyl glucuronides were determined. Urinary recovery essentially accounted for the administered dose and was not influenced by age, nor was the apparent oral clearance of salicylic acid. Assuming no presystemic elimination, it could be concluded that systemic availability is unaffected by age. An increase in the apparent volume of distribution, Varea, and a decrease in the maximum plasma salicylic acid concentration with age were observed. Renal clearance of salicyluric acid decreased significantly with age and was found to correlate significantly with creatinine clearance. The authors conclude that age does not have a major influence on salicylate disposition in healthy adult men.
Chronic Benzodiazepine Administration: From the Patient to the Gene
Authors: Miller Lawrence G.
Published: March 2013

Chronic benzodiazepine administration is associated with the development of tolerance and dependence. To evaluate the cellular mechanisms for these phenomena the authors developed a mouse model of chronic benzodiazepine exposure. The benzodiazepine agonists lorazepam, alprazolam, and clonazepam produced tolerance in this system, which was associated in each case with benzodiazepine and GABAA receptor downregulation. After discontinuation, a syndrome that included increased motor activity and receptor upregulation occurred with each of these compounds. A benzodiazepine antagonist, flumazenil, and an inverse agonist, FG 7142, were associated with receptor upregulation and increased activity during chronic administration. In contrast, a partial agonist (Ro16–6028) did not produce tolerance or receptor changes. Similar results were obtained in a culture system for clonazepam, flumazenil, and FG 7142. The increase in receptor binding after lorazepam discontinuation may be due to enhanced receptor synthesis. Changes in gene expression for GABAA receptor subunits also occur with chronic lorazepam administration, and they follow alterations in binding.
Prevention by Pentoxifylline of Transient Ca2+ Accumulation and Transglutaminase Activation in Rat Erythrocytes
Authors: Swislocki Norbert I. , Tierney Joan M.
Published: March 2013

The authors have examined the effects of pentoxifylline, a drug used to improve peripheral blood flow in patients with vascular disorders, on shear‐induced periodic Ca2+ entry and its consequences in the rat erythrocyte. To study the effects of periodic Ca2+ entry on Ca2+ dependent processes, erythrocytes, with and without pentoxifylline, were subjected to rotational shear produced by swirling‐cell suspensions in an isosmotic medium for 5‐second intervals. Pulses of increasing duration from 5–30 seconds promoted increased accumulation of 45Ca2+; intermittent 5 sec pulses, at 10‐minute intervals, produced a stepwise accumulation of 45Ca2+. Ca2+ accumulation was accompanied by elevated Ca2+ dependent transglutaminase. Shear induced Ca2+ entry and the increase in transglutaminase activity was reduced in cells treated with pentoxifylline. These findings suggest that pentoxifylline can reduce shear induced periodic Ca2+ entry that leads to transient activation of Ca2+ dependent transglutaminase, accumulation of crosslinked proteins, and loss of erythrocyte deformability.
Lecithin: Cholesterol Acyltransferase Activity in Familial Hypercholesterolemia Treated with Simvastatin and Simvastatin Plus Low‐Dose Colestipol
Authors: Desager J. P. , Horsmans Y. , Harvengt C.
Published: March 2013

In 19 patients with heterozygous familial hypercholesterolemia (FH), the effects of simvastatin (S) 20 mg/d, 40 mg/d, and 40 mg/d plus low‐dose colestipol (10 g/d) on plasma lipids, plasma lipoproteins, and plasma lecithin: cholesterol acyltransferase (LCAT) activity were investigated after an original dose‐range escalation/descalation design. The drug regimen was changed every 8 weeks. A significant reduction in total cholesterol and LDL‐cholesterol was observed, reaching 39% and 54% for the drug combination (week 28), and total apoprotein B and LDL‐apoprotein B were reduced by 39% and 50%, respectively. Triglycerides were significantly lowered by S alone (up to 29% with 40 mg/d). HDL‐cholesterol increased during therapy but the cholesterol content in HDL2‐HDL3 fractions (isolated by ultracentrifugation) did not change significantly during the different steps. The ratio LDL‐C/HDL‐C fell by 57% at week 28. Plasma LCAT activity expressed as FER was significantly enhanced by S alone (+33%), and a further increase on drug combination regimen (+58%) was observed. This effect could be considered as a consequence of the increased fractional clearance of LDL‐C. It tended to be sustained during the descalation part of the study. Biochemical adverse effects were scarce and transient in conclusion, the combination therapy increased the plasma LCAT/FER activity without a preferential enhancement in HDL2‐C concentration. This original design allowed to define the most appropriate individual cholesterol‐lowering drug dosage in FH patients.
Evaluation of Labetalol in Elderly Patients with Essential Hypertension
Authors: Giles Thomas D. , Weber Michael , Bartels David W. , Gregory Martin C. , Burris James F. , Due Deborah , Sirgo Mark A.
Published: March 2013

Labetalol was evaluated in a multicenter, placebo‐controlled study of elderly patients (≥ 60 years) with mild to moderate essential hypertension. After a placebo‐washout period, doses were titrated from 100 mg BID to a maximum of 400 mg BID over a 6‐week period. Once blood pressure control (standing diastolic blood pressure [SDBP] <90 mm Hg and ≥10 mm Hg reduction from baseline) was achieved or the maximum allowable dosage had been given, the dosage remained the same until the end of the study. The titration phase was followed by a 4‐week maintenance period. Blood pressure control was achieved in 37/54 (69%) of the patients who were treated with labetalol compared with 21/58 (36%) of the patients who received placebo (P <.001). Twenty‐nine (78%) of those controlled on labetalol responded to doses of 200 mg or less BID, and there was no significant difference between groups with respect to orthostatic blood pressure changes. Adverse experiences were generally mild and occurred with similar frequency in the labetalol and placebo groups; six patients who received labetalol and five who received placebo withdrew from the study due to adverse experiences, but in only one case (labetalol) was the adverse experience considered drug‐related. In summary, labetalol effectively and safely lowered diastolic blood pressure in the elderly without producing significant orthostatic changes.
The Effect of Pirmenol Administration on the Anti‐coagulant Activity of Warfarin
Authors: Stringer Kathleen A. , Switzer Donald F. , Abadier Ralph , Lebsack M. E. , Sedman Allen , Chrymko Margaret
Published: March 2013

The effect of administration of pirmenol, an extensively metabolized and plasma protein‐bound antiarrhythmic agent, was evaluated in ten patients on chronic warfarin therapy. After a 3‐week baseline period and 7 days of placebo administration, patients received 150 mg of oral pirmenol every 12 hours for 14 days. Prothrombin time was determined during the baseline and placebo periods, during pirmenol administration, and 14 days after the last pirmenol dose (washout). There was no significant difference between mean baseline, placebo, pirmenol, and washout prothrombin times. Coadministration of pirmenol does not appear to affect the anticoagulant activity of warfarin.
Comparison of the Effect of Isosorbide‐5‐Mononitrate and Isosorbide Dinitrate in a Slow‐Release Form on Exercise‐Induced Myocardial Ischemia
Authors: Hennig Lars , Andresen Dietrich , Hennig Ameneh , Levenson Benny , Brüggemann Thomas , Schroder Rolf
Published: March 2013

A randomized, double blind, placebo‐controlled crossover study on 20 patients with exercise‐induced angina pectoris and reproducible ST‐segment depression during exercise‐stress test was performed to compare the effect of a single dose of 120 mg of isosorbide dinitrate in a slow‐release form with that of a twice‐daily application of 20 mg of isosorbide‐5‐mononitrate. Symptom‐limited exercise tests were done, and nitrate plasma levels were measured in the subjects 6, 10, and 24 hours after the first administration of the drug. Both drugs produced a highly significant reduction in the size of exercise‐induced ST‐depressions (P <.001) 6 and 10 hours after the first administration of isosorbide dinitrate as well as 6 hours after the first and 4 hours after the second dose of isosorbide‐5‐mononitrate. The effect was still significant (P <.05) 24 hours after the administration of isosorbide dinitrate in a slow‐release form and 18 hours after the second dose of isosorbide‐5‐mononitrate. In the case of the drug isosorbide dinitrate, nitrate plasma levels for its metabolite, isosorbide‐5‐mononitrate, were highest 10 hours after first application. In the case of the drug isosorbide‐5‐mononitrate, nitrate plasma levels were highest 4 hours after the second dose. Two 20 mg doses of isosorbide‐5‐mononitrate and a single dose of 120 mg isosorbide dinitrate in a slow release form have a comparable effect on the reduction of exercise‐induced ST‐segment depressions.
Nicotinic Acid for the Treatment of Hyperlipoproteinemia
Authors: Drood Jeffrey M. , Zimetbaum Peter J. , Frishman William H.
Published: March 2013

Nicotinic acid is a water‐soluble B‐complex vitamin that has been shown, in high doses, to lower total plasma cholesterol (C), LDL‐C, and VLDL‐triglycerides (Tg), while raising HDL‐C in patients with type II, III, IV, and V hyperlipoproteinemia. Its exact mechanism of action is not known, but it appears to lower the production of VLDL in the liver while activating lipoprotein lipase. The drug may also influence the metabolism of HDL‐C. The drug is a second or third choice for isolated hypercholesterolemia because of a high incidence of side effects. However, it has a therapeutic advantage as a monotherapy when reduction of both LDL‐C and triglycerides are needed in patients with severe combined hyperlipidemia. The drug can be used in combination with other cholesterol‐lowering agents to maximize lipid‐lowering activity. Nicotinic acid has been associated with a reduced risk of cardiovascular morbidity in clinical trials.
Pharmacokinetics of Ritanserin in Patients Undergoing Hemodialysis
Authors: Zazgornik Jan , Kuska Jadwiga , Kokot Franciszek , Koch Sonja , Van Peer Achiel , Huang M. L. , Heykants Jos
Published: March 2013

The pharmacokinetics of ritanserin were studied in five patients with chronic renal insufficiency and who were undergoing periodic hemodialysis. Immediately after breakfast, a single 10‐mg ritanserin tablet was administered to each patient on a day that they did not undergo dialysis. Plasma ritanserin levels were measured by a specific high‐performance liquid chromatographic assay sensitive to 2 ng/mL plasma. After the oral 10‐mg dose, the average time to reach the peak plasma concentration, Tmax, was 4.4 ± 2.2 hours in these uremic patients, with a range of 2 to 8 hours. The average peak plasma concentration was 73.6 ± 26.9 ng/mL (range: 54.6–120.0 ng/mL). Compared with a previous study in healthy volunteers, the uremic patients had a slower absorption profile, with a 39% reduction in peak plasma concentration and a mean delay of 2.5 hours in Tmax. The mean area under the plasma concentration—time curve for ritanserin (2031 ± 636 ng·hr/mL) was 47% lower compared with that in healthy volunteers (3667 ± 1413 ng·hr/mL). The observed delayed and lower ritanserin absorption in these uremic patients may be caused by the chronic use of antacids such as aluminum hydroxide and calcium carbonate in all patients and/or by concurrent pathologic changes in the gastrointestinal mucosa of these patients. The regular hemodialysis sessions every 2–3 days did not affect the elimination rate of ritanserin, as the terminal half‐life in these patients (39 ± 23 hr) is similar to that in healthy volunteers (41 ± 14 hr).
Disposition Kinetics of Orally Administered Enoximone in Patients with Moderate to Severe Heart Failure
Authors: Ruder Michael A. , Lebsack Cynthia , Winkle Roger A. , Mead R. Hardwin , Smith Nellis , Kates Robert E.
Published: March 2013

Enoximone is a phosphodiesterase inhibitor, which has been studied extensively for use in the management of patients with moderate‐to‐severe heart failure. The authors have studied the absorption and disposition kinetics of enoximone and its primary metabolite, enoximone sulfoxide, after both single oral doses of enoximone and at steady‐state after short‐term chronic oral therapy. A total of ten patients (two female, eight male) with moderate‐to‐severe heart failure (NYHA class II—IV) were enrolled into the study after giving written informed consent. The plasma levels of enoximone sulfoxide were greater than those of enoximone at all sampling times. The peak enoximone sulfoxide plasma concentrations ranged from 3.5 to 17.3 times the peak enoximone plasma levels for individual patients. The average steady‐state plasma concentrations for enoximone were 115 ± 40 ng/mL and 190 ± 78 ng/mL for 50 mg every 8 hours and 100 mg every 8 hours dosage regimens, respectively. The absorption and disposition kinetics of enoximone were found to be significantly variable between patients. The authors also evaluated the relationship between dose administered and steady‐state plasma levels as well as the relationship between the observed and predicted steady‐state plasma levels. The authors found a linear relationship between the dose that was administered and the accrued plasma levels, as well as a good correlation between the predicted and observed steady‐state levels. Although these data confirm previous reports that the sulfide metabolite of enoximone accumulates extensively in the plasma during oral therapy, reaching levels much higher than those of enoximone, these data do not support previous suggestions that the disposition of enoximone is nonlinear.
Stereoselective Disposition of Etodolac Enantiomers in Synovial Fluid
Authors: Brocks Dion R. , Jamali Fakhreddin , Russell Anthony S.
Published: March 2013

The synovial fluid (SF) uptake of the chiral nonsteroidal anti‐inflammatory drug, etodolac, was studied in six arthritic patients, 2 hours (n = 1) or 12 hours (n = 5) after a single 200 mg dose of racemate. Marked stereoselectivity was seen in both SF and plasma; concentrations of pharmacologically inactive R‐etodolac were up to 10‐fold greater than active S‐etodolac. Concentrations of S‐etodolac were greater in SF than in plasma (SF:plasma ratio = 1.98 ± 0.8): No such difference was seen for R‐etodolac (SF:plasma = 0.91 ± 0.3). Considerable concentrations of conjugated enantiomers were present in SF. In vitro equilibrium dialysis studies in drug‐spiked samples showed that the unbound fraction of both enantiomers in SF was greater than in plasma; both fluids bound R more extensively than S etodolac. Therapeutically active S‐etodolac has greater concentrations in synovial fluid than plasma during the post‐distributive phase, which may be of possible clinical relevance.
Neutral Endopeptidase Inhibitors and Atrial Natriuretic Peptide
Authors: Achilihu Godfrey , Frishman William H. , Landau Andre
Published: March 2013

A limited number of ectoenzymes appear to be involved in the inactivation of circulating‐regulatory peptides. Neutral endopeptidase 24.11, a metallopeptidase, is known to inactivate atrial natriuretic peptide (ANP), a substance with diuretic, natriuretic, and vasodilatory effects. Synthetic inhibitors of endopeptidase 24.11, which can prolong the activity of ANP, are currently available. These agents are being evaluated as possible innovative therapies for patients with hypertension and congestive heart failure.
Inhaled Epinephrine and Oral Theophylline—Ephedrine in the Treatment of Asthma
Authors: Pinnas Jacob L. , Schachtel Bernard P. , Chen Tien Min , Roseberry H. Randall , Thoden William R.
Published: March 2013

Inhaled and oral over‐the‐counter bronchodilators are used for self‐therapy by asthmatic patients. To evaluate their safety and efficacy, we compared epinephrine and theophylline combined with ephedrine with inhaled metaproterenol and the placebo. Twelve asthmatic patients were studied in a randomized, double‐blind, placebo‐controlled, crossover trial comparing forced expiratory volume in 1 second (FEV1) after two inhalations of epinephrine (0.2 mg/inh), 1 minute apart, followed in 15 minutes by theophylline (130 mg) with ephedrine (24 mg) versus two inhalations of metaproterenol (0.65 mg/inh), 1 minute apart, versus placebo inhaler and tablets. Onset of FEV1 > 15% above baseline values occurred within 15 seconds after inhalations for 100% of epinephrine‐treated patients, 92% of metaproterenol‐treated patients, and 33% of placebo‐treated patients. FEV1 responses were significantly greater (P < .05) for epinephrine at 0.66 to 1.66 minutes compared with the responses of metaproterenol, and epinephrine and theophylline that was combined with ephedrine compared with metaproterenol beginning at 2 hours. Mean duration of activity was 5.7 hours for the epinephrine‐ and theophylline with ephedrine‐treated patients, 4.9 hours for metaproterenol‐treated patients, and 2 hours for the placebo group. There were statistically significant differences for patients receiving epinephrine and theophylline with ephedrine versus the placebo group (P < .001), metaproterenol patients versus the placebo group (P = .02), and patients receiving epinephrine and theophylline with ephedrine versus metaproterenol‐treated patients (P < .05). Compared with inhaled metaproterenol, inhaled epinephrine followed in 15 minutes by a theophylline—ephedrine tablet had a significantly earlier onset, longer duration of action, numerically greater peak effect, and patient preference. This combination of oral and inhaled bronchodilator medication is as safe and effective as inhaled metaproterenol.
The Pharmacokinetics of Flurbiprofen in Younger and Elderly Patients with Rheumatoid Arthritis
Authors: Kean Walter F. , Antal Edward J. , Grace Eileen M. , Cauvier Henriette , Rischke Janice , Buchanan Watson W.
Published: March 2013

The pharmacokinetics of flurbiprofen (Ansaid Tablets, Upjohn Company of Canada, Don Mills, Ontario) were evaluated in both younger (40 to 60 years) and elderly (65 to 83 years) rheumatoid arthritic patients after both a 100‐mg single‐dose administration and at steady state during a 100‐mg twice‐a‐day dosage regimen. Both flurbiprofen plasma concentration‐time profiles and the urinary excretion of flurbiprofen and its major metabolites were evaluated. The results indicate that the pharmacokinetics of flurbiprofen are linear in both age groups based on only minor changes between single‐dose and steady‐state parameter determinations and the agreement between calculated and predicted accumulation values in plasma concentrations. Only minor differences in the pharmacokinetic parameters were observed between the younger and elderly patients. Only free flurbiprofen clearance was found to have a significant but variable correlation to patient age. The effect of flurbiprofen on the urinary excretion of two prostaglandins were also evaluated throughout this study. In both age groups, the maximum decrease in urinary excretion was observed after the first dose, and this effect was maintained throughout the remainder of the study. Percent decreases from baseline in urinary excretion during drug administration were similar for both age groups. Similar side‐effect profiles were observed between age groups.
Transcranial Doppler to Evaluate the Effects of Antihypertensive Medication on Cerebral Blood Flow Velocity
Authors: Fagan Susan C. , Bindlish Vinita , Robert Sylvie , Steigerwalt Susan P. , Ramadan Nabih M.
Published: March 2013

The effect of oral nifedipine on cerebral blood flow velocity was studied in six elderly hypertensive patients using transcranial Doppler. Serial measurements of blood pressure (BP), middle cerebral artery (MCA) flow velocity and nifedipine serum concentrations were obtained over an 8‐hour period. The authors found a significant inverse relationship between MCA velocities and nifedipine concentrations, independent of BP changes. These results are consistent with a direct vasodilatory effect of nifedipine on cerebral vessels and support the use of TCD in pharmacodynamic investigations of the cerebral vasculature.
Epanolol as a Model for Assessing Patient Preference in Anti‐Anginal Drug Therapy
Authors: Blake Paul , Lewis John A.
Published: March 2013

Since drug therapy of angina is likely to produce a similar degree of efficacy for most drugs in common use, treatment choice should additionally focus on other factors, notably adverse events, quality of life, and convenience. Improvements in these factors can also lead to better compliance and can aid the doctor by cutting down the number of patient visits required to optimize therapy. The authors have evaluated the patient's overall assessment of symptomatic relief and adverse experiences in a comparative manner by means of the two‐period crossover design using the patient's declared treatment preference as the primary measurement. This encapsulates several factors in a single assessment that can be understood by both physician and patient The authors carried out two such studies of epanolol (Visacor), a novel anti‐anginal agent with both beta‐1 selective antagonist activity and also beta‐1 selective partial agonist activity. In one study (n = 608) the comparator was metoprolol, and in the other (n = 571) it was nifedipine. This article describes and evaluates the methodology of these studies. To assess preference optimally, each patient had to receive both treatments in short but clinically relevant treatment periods, with no washout Re‐entry into the second period, after withdrawal from the first was permitted. Both studies showed advantages for epanolol, more marked in the case of nifedipine, arising from equivalent efficacy but fewer adverse events. Critical evaluation of the clinical trial design and the results does not cast doubt on these conclusions, so that the methodology has been shown to be of practical value in assisting treatment choice.
Effect of Cimetidine Administration on the Pharmacokinetics of Pirmenol
Authors: Stringer Kathleen A. , Lebsack M. E. , Cetnarowski‐Cropp Anne B. , Goidfarb Alien L. , Raduiovic Louis L. , Bockbrader Howard N. , Chang Tsun , Sedman Allen J.
Published: March 2013

The potential for a drug—drug interaction between pirmenol, an extensively metabolized antiarrhythmic agent, and cimetidine, an inhibitor of hepatic drug‐metabolizing enzymes, was evaluated in eight healthy adults. A single 150‐mg oral dose of pirmenol was administered on study days 1 and 8 and oral cimetidine, 300‐mg qid, was administered on study days 4 through 11. Plasma and urine samples were collected after each pirmenol dose for determination of pirmenol concentration. Mean pirmenol concentration—time curves and pharmacokinetic parameters, including elimination rate constant, were not significantly altered by concomitant administration of cimetidine.
Classifying Antiarrhythmic Actions: By Facts or Speculation
Authors: Williams E. M. Vaughan
Published: March 2013

Classification of antiarrhythmic actions is reviewed in the context of the results of the Cardiac Arrhythmia Suppression Trials, CAST 1 and 2. Six criticisms of the classification recently published (The Sicilian Gambit) are discussed in detail. The alternative classification, when stripped of speculative elements, is shown to be similar to the original classification. Claims that the classification failed to predict the efficacy of antiarrhythmic drugs for the selection of appropriate therapy have been tested by an example. The antiarrhythmic actions of cibenzoline were classified in 1980. A detailed review of confirmatory experiments and clinical trials during the past decade shows that predictions made at the time agree with subsequent results. Classification of the effects drugs actually have on functioning cardiac tissues provides a rational basis for finding the preferred treatment for a particular arrhythmia in accordance with the diagnosis.
Central Nervous System Effects of Meclizine and Dimenhydrinate: Evidence of Acute Tolerance to Antihistamines
Authors: Manning C. , Scandale L. , Manning E. J. , Gengo F. M.
Published: March 2013

Relative daytime drowsiness and performance impairment produced by meclizine and dimenhydrinate was assessed in 24 healthy male volunteers. Subjects received either dimenhydrinate, 100 mg, at 8:00 am, 12:00 pm, and 4:00 pm; meclizine, 50 mg, at 8:00 am, with placebo at 12:00 pm and 4:00 pm; or placebo at all three times in this randomized, double‐blind, three‐way crossover study. Impairment of mental performance was assessed by choice reaction time testing and digit symbol substitution scores. Drowsiness was self‐assessed on the Stanford Sleepiness Scale and on a visual analog scale. Both antihistamines produced changes in digit symbol substitution, recognition time, and subjective assessments of sleepiness different from placebo. Expressed as change from baseline, the greatest reductions in digit symbol substitution scores after dimenhydrinate occurred 3 hours after the first dose (6.6 ± 7) and were not different from the greatest measured change after meclizine (5.8 ± 8), which occurred 9 hours after the dose was administered. Similar results were obtained with the other psychometric test scores. Self‐rated sleepiness after dimenhydrinate was greatest 1 hour after the first dose, and was significantly greater than the largest degree of sleepiness after meclizine, which occurred at 7 hours after the dose. The effects of the first dose of dimenhydrinate on psychometric test scores were compared with the magnitude of the effects produced by subsequent doses. The magnitude of effect of the first dose of dimenhydrinate was significantly greater than the magnitude of effect produced by subsequent doses. The data suggest the possibility that acute tolerance to central nervous system impairment develops with multiple doses of dimenhydrinate.
Salivatory Responses to Classical and Nontraditional Parasympatholytic Agents in Human Subjects: Critical Comments
Authors: Levin S. L.
Published: March 2013

Both classical (atropine, scopolamine) and nontraditional (pirenzepine, telenzepine) cholinolytic agents themselves cause no salivation in human subjects. Ordinarily, they block salivation caused by pilocarpine. Conversely, they all stimulate intense salivatory response in the chronically denervated human parotid gland. The author presents critical comments on the concept that cholinolytic agents cause salivation by suppression of the mechanism of presynaptic autoinhibition. An alternative explanation of the initial cholinomimetic effect of cholinolytic agents is suggested.