bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of the Hypotensive Effects of Captopril and Atenolol in the Treatment of Hypertension in Diabetic Patients
Authors: Elving L. D. , de Nobel E. , VAN Lier H. J. J. , Thien Th.
Published: March 2013

In a double‐blind, randomized, cross‐over study in 23 diabetic patients, insulin treated (N = 11) or noninsulin treated (N = 12), with mild to moderate hypertension, the hypotensive effects of captopril and atenolol were compared. Five patients had overt diabetic nephropathy. All patients received 50 mg twice daily of either drug. Treatment periods lasted 6 weeks and were preceded and separated by a placebo period. Two patients dropped out, one because of intermittent claudication during atenolol, one with cardiac arrhythmia during placebo. Blood pressure was reduced from 165 ± 5/96 ± 1 to 154 ± 5/89 ± 2 mmHg (mean ± SEM: P < 0.01) during captopril and from 171 ± 5/98 ± 1 to 159 ± 6/89 ± 2 mmHg (P < 0.01) during atenolol. These antihypertensive effects are not significantly different. There was a wide inter‐ and intraindividual variation in hypotensive response to both drugs, which may have important consequences for treatment strategies. No consistent differences between insulin and noninsulin treated patients were seen. Parameters of glycemic control did not change during any therapy, neither in insulin treated nor in non‐insulin treated patients. Albuminuria and renal function did not change. During captopril treatment one patient complained of a non‐productive cough. Two patients experienced a severe hypoglycemic reaction during atenolol. No other major side‐effects were seen. In conclusion, this study showed equal hypotensive effectivity of 100 mg captopril and 100 mg atenolol daily in hypertensive diabetics, without evident effect on glycemic control.
Pharmacokinetics and Antihypertensive Effects of Low Dose Clonidine During Chronic Therapy
Authors: Anavekar Sadanand N. , Howes Laurence G. , Jarrott Bevyn , Syrjanen Marie , Conway Elizabeth L. , Louis William J.
Published: March 2013

Using a sensitive and specific radioimmunoassay the pharmacokinetic disposition of clonidine was determined in hypertensive patients after a single dose and then after 5, 28 and 56 days of chronic dosing with 75 μg bd. Following a single dose of clonidine maximal plasma concentrations of 0.34 ± 0.06 ng/ml were achieved after 3.6 ± 1.2 hours. After 5 days of repetitive dosing the maximal concentration was significantly higher, 0.66 ± 0.06 ng/ml and remained so throughout chronic therapy (P = 0.018). The AUC, Tmax and T1/2 did not differ significantly between the acute dose and the chronic dosing pharmacokinetic studies. Clonidine also produced a significant fall in blood pressure. Supine diastolic blood pressure fell from 106 ± 5 mmHg predose to 99 ± 6 mmHg 2 hours after the first dose (P < 0.05). The corresponding values after cyclopenthiazide alone were 108 ± 8 and 105 ± 8 mmHg (P = 0.13). Similar falls in blood pressure were produced during chronic therapy.
An Investigation of the Pathological and Physiological Effects of Intraosseous Sodium Bicarbonate in Pigs
Authors: Lathers Claire M. , Jim Kam F. , High Wanda B. , Spivey William H. , Matthews William D. , Ho Teh
Published: March 2013

Recent interest in the intraosseous (IO) route as an alternative venous access for drug and fluid administration has increased. This study examined the physiological and skeletal pathological effects of IO NaHCO3 in pigs. In the pathological studies, swine (8–10 kg) received NaHCO3 (1 mEq/kg) in one tibia and saline (1 ml/kg) in the other tibia via an 18‐gauge spinal needle inserted into the anteromedial surface of the bone. The animals were then observed for one month, sacrificed, and the tibias were isolated, sectioned, and stained for pathological examinations. The physiological effects of IO NaHCO3 infusion were studied and compared with that of intravenous (IV) administration using a cardiac arrest model as previously described.1 The results demonstrated that NaHCO3 had no effect on the mean arterial blood pressure and plasma catecholamine levels, but increased arterial pH values within two minutes of administration. Similar effects were found with IV NaHCO3. Pathological data indicated signs of minimal local increase in skeletal turnover associated with IO NaHCO3 infusion. It is concluded that the IO route is a safe alternative venous access for NaHCO3 administration in swine.
Basic and Clinical Pharmacology of Amiodarone: Relationship of Antiarrhythmic Effects, Dose and Drug Concentrations to Intracellular Inclusion Bodies
Authors: Somani Pitambar
Published: March 2013

Amiodarone is a unique class III antiarrhythmic drug with several unusual pharmacokinetic, pharmacodynamic, and toxicological actions which are quite distinct from those of the standard antiarrhythmic drugs. Extensive animal and clinical studies have demonstrated that amiodarone and its major metabolite, desethylamiodarone, both produce a marked increase in the duration of transmembrane action potential which may be related to their antiarrhythmic as well as clinical electrophysiological activity. Unlike most other cardiovascular drugs, it has been recognized for more than 20 years that optimal antiarrhythmic effects may take several days to weeks after onset of oral therapy. Amiodarone is highly lipid soluble and exhibits at least three separate compartments of drug distribution, with a long elimination half‐life of 14–120 days after chronic therapy. The pharmacokinetic profile of desethylamiodarone is qualitatively similar to that of amiodarone, but its elimination half‐life is even longer and its tissue distribution may be slightly different. Although there may not be any correlation between serum drug levels and clinical toxicity of amiodarone during long‐term therapy, recent animal as well as clinical data suggest that multilamellar intracellular inclusions can be dissociated from cell death or clinical toxicity. Thus, it is possible that amiodarone toxicity can be minimized with low doses or low serum drug concentrations. The metabolite(s) of amiodarone may play a major role in its pharmacological and toxicological actions.
Pharmacokinetics of Acrivastine After Oral and Colonic Administration
Authors: Balasubramanian Ramadas , Klein Kenneth B. , Pittman A. Wayne , Liao Sam H. T. , Findlay John W. A. , Frosolono M. F.
Published: March 2013

Six healthy male volunteers participated in this randomized, crossover open‐label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1‐receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean ± SD pharmacokinetic parameters were obtained: Cmax 179 ± 11 and 13.8 ± 5.2 ng/ml; tmax, 0.85 ± 0.13 and 3.60 ± 0.56 hr; AUC0–12 hr, 576 ± 57 and 104 ± 46 hr · ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P < 0.001). The mean ± SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 ± 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.
Monoexponential Analysis of Plasma Disappearance of 99mTc‐DTPA and 131I‐Iodohippurate: A Reliable Method for Measuring Changes of Renal Function
Authors: Clifton G. Gil , Anderson Catherine , McMahon Gilbert , Vargas Ramon , Wallin J. David
Published: March 2013

Glomerular filtration rate and effective renal plasma flow were measured in 170 subjects using monoexponential analysis of plasma disappearance curves for 99mTc‐DTPA and 131I‐iodohippurate after single injection. In the current study population, glomerular filtration rate and effective renal plasma flow decreased with increasing age, were less in females than in males, and were less in hypertensives than in normotensives. Differences in glomerular filtration rate according to age and sex in the current study were similar to those reported using traditional creatinine clearance methodology. Monoexponential treatment of plasma isotope disappearance gave reproducible values for both glomerular filtration rate and effective renal plasma flow when measured either during the day or on a daily basis. Intraindividual coefficient of variation was less than 10% for both 99mTc‐DTPA and 131I‐iodohippurate clearances derived from monoexponential analysis. These results demonstrate that monoexponential analysis of plasma disappearance curves for 99mTc‐DTPA and 131I‐iodohippurate after a single injection is a useful method for evaluating changes in renal hemodynamics either during chronic drug therapy or acutely after single dose administration.
The Influence of Fever on the Pharmacokinetics of Pranoprofen in Elderly Subjects
Authors: Fujimura Akio , Kajiyama Hiroyuki , Ebihara Akio
Published: March 2013

Pranoprofen (75 mg) was given orally during febrile (mean body temperature 38.3°C) and afebrile (mean body temperature 36.3°C) periods in nine elderly subjects. Blood samples for plasma drug concentrations were taken for a 10 hour post‐drug period.

The mean elimination half‐life (t1/2β) was significantly prolonged and the mean area under the time‐concentration curve from 0 to 10 hrs (AUC0–10) was greater, although not significantly, during fever. No significant difference was observed in the time to maximum concentration (tmax), maximum plasma concentration (Cmax) or apparent volume of distribution (Vd/F) between the both dosages. There was a positive correlation (r = 0.448, 0.05 < P < 0.10) between the body temperature and t1/2β of pranoprofen.

These data indicate that the clearance of pranoprofen is reduced during fever in elderly subjects.
Oral Pharmacokinetics of Felodipine in Patients with Congestive Heart Failure: Variable Prediction Using Intravenous Data
Authors: Dunselman P. H. J. M. , Scaf A. H. J. , Wesseling H.
Published: March 2013

Peak and trough concentrations after 8 weeks oral therapy with felodipine, a vasodilating calciumantagonist of the dihydropyridine group, were predicted from intravenous pharmakocinetic data before therapy in 11 patients, randomly allocated to felodipine treatment 10 mg b.i.d., during a placebo controlled study in patients with congestive heart failure. Peak concentrations were well predictable, but trough levels varied between a good agreement in some patients to a large underestimation in others. Predictability was significantly correlated with half life, plasma clearance and distribution volume of the intravenous pharmacokinetic study. After 8 weeks chronic oral therapy no significant differences could be detected between the oral pharmacokinetics of predictable (n = 6) and unpredictable (n = 5) patients. This demonstrates that felodipine kinetics change during felodipine treatment. Differences in the distribution of blood flow before therapy combined with an interindividual variability in blood flow response during therapy is probably responsible for the observed impossibility to calculate trough levels, and thus oral dosage schedules, from intravenous pharmacokinetic data in patients with congestive heart failure.
Lack of Interaction Between Sulindac or Naproxen and Propranolol in Hypertensive Patients
Authors: Schuna Arthur A. , Vejraska Beth D. , Hiatt Janet G. , Kochar Mahendr , Day Richard , Goodfriend Theodore L.
Published: March 2013

Seventeen patients with hypertension and osteoarthritis participated in a single‐blind crossover study comparing the effects of sulindac 200 mg twice daily, naproxen 500 mg twice daily, and placebo on blood pressure. All patients were treated for hypertension with propranolol monotherapy. Blood pressures were back‐titrated to achieve a baseline diastolic blood pressure of 90 to 100 mm Hg while taking naproxen. There were no significant differences in mean sitting or standing blood pressures among the patients receiving naproxen, sulindac, or placebo treatments. There was no change in pulse, weight, or any of the laboratory measurements at the end of each treatment phase. These results suggest that neither sulindac nor naproxen interferes with propranolol therapy for uncomplicated hypertension.
The Monoamine Oxidase Inhibitor—Tyramine Interaction
Authors: Brown Candace , Taniguchi George , Yip Kelly
Published: March 2013

Reports of hypertensive reactions from monoamine oxidase inhibitors (MAOI) began to proliferate in the early 1960s. Asatoor did extensive research and found that the combination of an MAOI and a food containing tyramine resulted in the hypertensive interaction (“the cheese reaction”). Because of the risk of intracerebral hemorrhage and death, clinicians were hesitant to use the MAOIs. Although progress on the metabolic effects of MAOIs has been slow, use of clinical information in addition to analysis of bioactive amine content of foods has allowed the formulation of dietary recommendations, which are thought to be useful clinically in the administration of MAOIs. This has resulted in the gradual return to use of these psychotropic compounds.
Relationship of Plasma Clonidine to Growth Hormone Concentrations in Children and Adolescents
Authors: Hoffman William H. , DiPiro Joseph T. , Tackett Randall L. , Arrendale Richard F. , Hahn Dorothy A.
Published: March 2013

The relationships of plasma clonidine to increases in growth hormone, blood pressure response and degree of sedation were studied in nine children with short stature after a 0.15 mg/m2 oral clonidine tolerance test. A direct correlation was found between the peak plasma clonidine concentration and the increase in plasma growth hormone (P = 0.055). The patients experienced varying degrees of blood pressure reduction and sedation that were unrelated to age. No correlation was found between the plasma clonidine concentration and degree of blood pressure reduction or degree of sedation. The half‐life of oral clonidine ranged from 1.75 to 2.38 hours, which is significantly less than that for adults.
Ibuprofen and Acetaminophen in the Relief of Postpartum Episiotomy Pain
Authors: Schachtel Bernard P. , Thoden William R. , Baybutt Robert I.
Published: March 2013

A single‐dose, double‐blind, randomized clinical trial was conducted to examine the relative analgesic efficacy of ibuprofen 400 mg (n = 36), acetaminophen 1000 mg (n = 37), and placebo (n = 38) in postpartum patients who had moderate to severe pain after episiotomy. At regular intervals over 4 hours, patients evaluated pain severity and relief on categorical scales and completed a categorical overall evaluation at the end of the trial. Both active agents were effective compared with placebo (P < .05). Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for the sum of pain intensity difference, total pain relief, and reduction of pain by more than 50% (P < .05), suggesting a more rapid onset of action and a more prolonged effect by ibuprofen 400 mg. No adverse effects were reported. Based on the results of this conventional postpartum episiotomy pain model, both agents are considered efficacious and ibuprofen 400 mg is a more effective analgesic for the relief of acute pain than acetaminophen 1000 mg.
The Effects of Flurbiprofen, Aspirin, Cimetidine, and Antacids on the Gastric and Duodenal Mucosa of Normal Volunteers. An Endoscopic and Photographic Study
Authors: Friedman H. , Seckman C. E. , Schwartz J. H. , Lanza F. L. , Royer G. L. , Stubbs C. M.
Published: March 2013

This 7‐day, single blind, randomized endoscopic tolerance study compared daily doses of 100, 150 and 200 mg flurbiprofen with 2600 mg aspirin. After seven days the flurbiprofen 100 and 150 mg groups had significantly less gastric irritation than the flurbiprofen 200 mg and aspirin groups. Flurbiprofen showed a linear dose‐response relationship with respect to gastric injury and serum drug levels. Four subjects each on aspirin and flurbiprofen with the most severe injuries continued on their medications plus cimetidine and antacids for four more weeks. Both drug groups showed clinical improvement in the gastroduodenal area. In conclusion, flurbiprofen and aspirin therapy can be tolerated in the presence of gastroduodenal irritation by concomitantly administering cimetidine and antacids.
The Renal Function and Blood Pressure Effects of Dilevalol in the Normotensive and Hypertensive Elderly
Authors: Clifton G. Gil , Cook M. Eileen , Poland Marcia , Wallin J. David
Published: March 2013

Dilevalol, the R‐R optical isomer of labetalol, is a nonselective beta adrenergic blocking drug with selective beta‐2 agonist properties. In a double‐blind, crossover study the renal function effects of dilevalol were compared to placebo in 12 normotensive elderly volunteers before and after single dose administration. In addition, chronic treatment (>4 weeks) effects of dilevalol were determined in eight elderly patients with mild to moderate essential hypertension. Renal function was determined by plasma disappearance curves from single injections of 99mTc‐DTPA and 131I‐orthohippurate. In both study populations renal function tests commenced two hours after dosing at expected peak plasma levels of dilevalol. Normotensive volunteers had an acute decrease in glomerular filtration rate of 10.3 ml/min, which was significant (P < 0.05), while hypertensive patients had no change in glomerular filtration rate. There were no significant changes in other parameters of renal function measured. In the hypertensive elderly dilevalol treatment resulted in significant reductions, 18 and 19 mmHg respectively, of systolic (P < 0.01) and diastolic (P < 0.001) blood pressure. Heart rate was reduced by 5 beats per minute, and the change was not statistically significant. Dilevalol appears to be an excellent agent for treatment of hypertension in the elderly hypertensive patient, and does not change renal function when administered chronically to the hypertensive patient. Small but significant decrements in glomerular filtration rate occur with acute administration to normotensive volunteers.
Effect of Quinolone Antimicrobials on Theophylline Pharmacokinetics
Authors: Prince Randall A. , Casabar Ed , Adair Colin G. , Wexler David B. , Lettieri John , Kasik John E.
Published: March 2013

The purpose of the research was to ascertain the comparative differences of quinolone antibiotics on theophylline pharmacokinetics. Eight healthy male volunteers were randomly assigned to four treatments. Each was administered norfloxacin (NOR) 800 mg/d, ciprofloxacin (C) 1 g/d, nalidixic acid (NAL) 2 g/d and placebo (P) for 7 days. On the seventh day of each treatment, theophylline (5 mg/kg) iv was administered. The elimination half‐life (T1/2), total body clearance (CL) and volume of distribution at steady state (Vss) of theophylline were calculated using model‐independent methods. ANOVA for repeated measures was used for data comparisons. The mean (SD) theophylline results were: CL 1/kg/h—NOR .038 (.006) C .033 (.006) NAL .045 (.008), P .044 (.007); T1/2 h—NOR 9.2 (1.8), C 10.6 (1.8), NAL 8.3 (1.8), P 7.5 (1.4). Theophylline Vss differences by treatment were not significant. NOR and C significantly decreased theophylline's clearance and the clearance change can be of clinical significance.
Profile of Clinical Pharmacologists in the United States
Authors: Wilson John T. , Brown R. Don , Kimura K. K. , Whelton Andrew
Published: March 2013

The need for clinical pharmacology in research and education, drug development, and health care delivery is well known. However, a current profile of those working in the field is not available. The ACCP authorized a survey of clinical pharmacologists to provide such a profile. Members of the ACCP or ASCPT were solicited by mail with a self‐assessment questionnaire. A response rate of 37% was obtained. Demographic findings agree well with a previous study2 limited to those with the M.D. Our results reveal that most clinical pharmacologists are between 30–59 years of age, have an MD, PhD or PharmD degree; most of those with MDs list their primary specialty as internal medicine, pediatrics, psychiatry, or anesthesiology. They affiliate with the respective departments (including pharmacology) in academia or hold positions in industry or government, but few are in clinical therapeutics per se. About 20% of those with only a MD or PharmD degree cite employment in health care delivery. However, a higher percentage of these respondents work in research and education rather than in drug development or health care delivery. For those with only a PhD, more work in drug development and research and education than in health care delivery. The highest proportion of respondents with any doctoral degree work in the Northeast. The average income is a function of rank, doctoral degree, specialty, department appointment, and type and location of employer. The profile of a typical clinical pharmacologist is presented. An analysis of clinical pharmacology manpower from several perspectives reveals a marked deficit, but the field itself is professionally and economically attractive. Lack of a well defined career track in academia and a poorly defined clinical role for MD clinical pharmacologists are proposed as reasons limiting entry of trainees. These and other results of the survey support an increased emphasis on training programs. Clinical pharmacologist involvement in health care delivery and drug development must be increased if the safe and effective use of new drugs is to be realized. Nine assessments and initiatives are formulated to accomplish this goal within the next decade.
Variability in the Pharmacokinetics of Nisoldipine as Caused by Differences in Liver Blood Flow Response
Authors: VAN Harten Jaap , VAN Brummelen Peter , Ooms Piet , Danhof Meindert , Blauw Gerard‐Jan , Breimer Douwe D.
Published: March 2013

We investigated whether the effect of nisoldipine on liver blood flow depends on its route of administration. Ten healthy subjects took nisoldipine I.V. (infusion) and orally (without and with sotalol pretreatment). Pharmacokinetics of nisoldipine was assessed and liver blood flow (ICG clearance) was measured before dosing and at the end of the infusion or during absorption. During I.V. infusion the ICG plasma clearance increased by only 14%, whereas the increase was 60% during absorption of nisoldipine. Nisoldipine increases liver blood flow considerably only during the absorption phase. A positive correlation was found between the increase in liver blood flow during absorption and the systemic availability of nisoldipine, suggesting that the differences in liver blood flow response to nisoldipine substantially contribute to the variability in pharmacokinetics of the drug.
The Impact of Antianginal Drug Therapy on Asymptomatic Myocardial Ischemia
Authors: Koehn Donna K. , Glasser Stephen P.
Published: March 2013

This study addresses the effect of the three major classes of antianginal agents on asymptomatic myocardial ischemia in patients with chronic stable angina pectoris. The authors found that each class (given as monotherapy) resulted in a 50% reduction in asymptomatic ischemia (both in the number of episodes and the ST product). Dual therapy resulted in an overall four fold reduction compared to placebo. Therapy also resulted in a beneficial alteration in the frequency distribution of asymptomatic ischemia. Stratification into three age groups demonstrated an equal prevalence of asymptomatic ischemia in each. All ages had nearly equivalent reductions in asymptomatic ischemia by monotherapy and dual therapy, but the youngest age group seemingly responded better to monotherapy than did the oldest age group.
The Effect of Verapamil on the Pharmacokinetic Disposition of Theophylline in Cigarette Smokers
Authors: Gin Alfred S. , Stringer Kathleen A. , Welage Lynda S. , Wilton John H. , Matthews George E.
Published: March 2013

In a randomized cross‐over study the effect of verapamil on the pharmacokinetics of theophylline was evaluated in eight cigarette smoking male volunteers. Theophylline was administered as an intravenous infusion of aminophylline, 6 mg/kg based on ideal body weight, over 30 minutes in the control phase. In the treatment phase, aminophylline was administered after a four day regimen of oral verapamil 80 mg every 8 hours. Serial blood samples were collected over a 24 hour period following aminophylline administration. Theophylline serum concentrations were determined by a fluorescence polarization immunoassay, the Abbott TDxR. Theophylline clearance decreased by 11.5%, from a mean (±SD) of 1.39 ± 0.38 mL/min/kg in the control phase to 1.23 ± 0.21 mL/min/kg with the co‐administration of verapamil (P = 0.104). Theophylline elimination rate constant decreased by approximately 9.4% from 0.171 ± 0.032 to 0.155 + 0.023 hr−1 during the treatment phase (P = 0.085). The area under the curve (AUC0‐∞) and volume of distribution at steady‐state (Vss) for theophylline were also not statistically different between the two study phases. These results are inconsistent with those of other investigators and the relevance of a potential theophylline‐verapamil drug interaction remains unclear.
1992. Is There the Will for There to be a Way?
Authors: Currie William J. C.
Published: March 2013

The European Community must become a fully integrated market by 1992. The differing national requirements for pharmaceutical product registration constituted a barrier, unresolved by the creation of a nonmandatory process of mutual recognition of pharmaceutical licences.

Interested parties have been asked to recommend measures to abolish the remaining barriers. The principle sought is that a single authorisation shall afford simultaneous approvals in all member states. Considerable debate has taken place but there is no clear concensus. Recommendations include mandatory mutual recognition, a central FDAlike European Agency and a combination of both.

A tripartite solution is recommended. This is a sharing of responsibility between the National Agencies and a central European body. A small European Secretariat would coordinate activities and, using expert consultants, hear and resolve appeals. The National Agencies would share the licence application assessments and the CPMP would be responsible for, among other things, the education standards of Agency personnel.
Effects of Pentoxifylline on Ca2+‐Dependent Transglutaminase in Rat Erythrocytes
Authors: Swislocki Norbert I. , Tierney Joan M.
Published: March 2013

We have examined the effects of pentoxifylline, a drug used to improve peripheral blood flow in patients with chronic vascular disorders, on shear‐induced Ca2+ entry and Ca2+‐dependent protein crosslinking in the erythrocyte. Cells were washed in isosmotic bicarbonate buffer, pH 7.5, and brought to a 20% suspension. 5 ml samples were sheared by swirling them for seconds; 45Ca2+ uptake, activation of Ca2+‐dependent transglutaminase, and products of the crosslinking reaction were measured. A 5 second shear promoted 45Ca2+ entry, activation of Ca2+‐dependent transglutaminase and crosslinking of proteins in the membrane‐cytoskeletal fraction. Pentoxifylline, a drug that promotes erythrocyte deformability, diminished Ca2+ entry and inhibited activation of Ca2+‐dependent transglutaminase, and had a prophylactic role on the effects of Ca2+ entry due to shear. Incubation of cells with 2.5 mM pentoxifylline before swirling minimized the effects of shear on 45Ca2+ entry, Ca2+‐dependent transglutaminase and crosslinking of proteins. This study indicates that pentoxifylline promotes erythrocyte flexibility by minimizing shear‐induced Ca2+ entry and Ca2+‐dependent crosslinking.
Regression of Left Ventricular Hypertrophy in Treated Hypertensive Patients with Dilevalol and Metoprolol—A Double Blind Randomized Study
Authors: Glasser Stephen P. , Koehn Donna K. , Powell Rodney
Published: March 2013

This study was designed to evaluate the effects of a new beta‐adrenergic blocking agent with beta2 agonist activity (dilevalol, an R‐R' isomer of labetalol) on left ventricular hypertrophy regression as seen by M‐mode echocardiography. The study design was a 2:1 double blind randomization of dilevalol versus metoprolol. There was an equal blood pressure reduction in the two groups (supine diastolic blood pressure fell from 101 ± 4.5 mm Hg to 87 ± 13.7 mm Hg, P < .001 in the dilevalol group, and 101 ± 4.3 mm Hg to 87 ± 8.6 mm Hg, P < .01, in the metoprolol group). At the end of 2 months, there was an overall 7.5% decrease in left ventricular mass index in the 16 dilevalol treated patients (this was due to a 4.4% decrease in posterior wall thickness, end diastolic dimension increased by only 1%). Of the seven patients with an increased left ventricular mass index, all demonstrated hypertrophy regression (mean 17.14%). In contrast, no significant change in left ventricular mass was seen in the metoprolol treated group. Echocardiography left ventricular mass index and electrocardiographic evidence of left ventricular hypertrophy (using the Sokolow‐Lyons criteria and Romhilt‐Estes point score) had poor correlation (r = .30 and r = .38, respectively). Resting ejection fraction increased by 5% and velocity of circumferential fiber shortening by 14% in the dilevalol treatment group (not significant), in conclusion, 1) echocardiographic left ventricular hypertrophy regression occurred with dilevalol treatment 2) this left ventricular regression was a result of a decrease in intraventricular septal thickness and posterior wall thickness 3) the poor correlation between echocardiographic increased left ventricular mass and electrocardiographic left ventricular hypertrophy was supported 4) dilevalol and metoprolol had equal antihypertensive effects.
Antihypertensive Efficacy of Guanfacine and Prazosin in Patients with Mild to Moderate Essential Hypertension
Authors: Lewin Andrew , Alderman Michael H. , Mathur Pershottam
Published: March 2013

Guanfacine, an alpha2 adrenoceptor agonist, was compared with prazosin hydrochloride for the treatment of patients with mild to moderate essential hypertension in an 8‐week, double‐blind, randomized, parallel evaluation to determine efficacy and safety. The study consisted of a 2‐week screening/weaning period (phase I), a 3‐week treatment period with chlorthalidone 25 mg every morning (phase II), and an 8‐week double‐blind treatment period with diuretic plus prazosin or guanfacine (phase III). Those who had an average seated diastolic blood pressure (BP) of 95 to 114 mm Hg at the end of the phase II period were eligible to enter the phase III period and were randomly assigned to chlorthalidone plus either guanfacine, 1 mg every night, or prazosin, 1 mg three times a day. Of the 102 patients who were randomly assigned to guanfacine or prazosin, 80% completed the entire study.

Guanfacine and prazosin appeared to be equally effective and reduced seated as well as standing diastolic and systolic BP. The mean seated systolic and diastolic BP were reduced 11/9 mm Hg by guanfacine and 11/10 mm Hg by prazosin. The mean reduction in seated pulse was 3 beats/minute for guanfacine and no change with prazosin. Similar changes occurred in the standing position. Very few adverse effects were reported during the study. Adverse effects with an incidence of 5% or greater for either drug group were dizziness (6% guanfacine, 8% prazosin), xerostomia (6% guanfacine, 2% prazosin), and somnolence (0% guanfacine, 6% prazosin). Three patients (6%) in the prazosin group experienced symptoms of orthostasis requiring premature discontinuation of the drug and termination from the study.
Comparative Pharmacokinetics and Pharmacodynamics of Pravastatin and Lovastatin
Authors: Pan Henry Y. , DeVault Arthur R. , Wang‐Iverson David , Ivashkiv Eugene , Swanson Brian N. , Sugerman A. Arthur
Published: March 2013

The oral bioavailability of two HMG‐CoA reductase inhibitors, pravastatin and lovastatin, was investigated in this randomized, two‐way crossover study. Twenty healthy men were randomly assigned to treatment with a 40‐mg dose of pravastatin or lovastatin once daily for 1 week; steady state kinetics were assessed after the last dose. After 1 week of washout, each subject received the alternate treatment. Serum specimens were assayed by gas chromatography/mass spectrometry (GC/MS) for intact pravastatin or lovastatin acid and by bioassay for active inhibitor concentration and, after hydrolysis of lactones, for total inhibitor concentration. The systemic bioavailabilities of total (active plus potentially active) inhibitors for the two drugs were different, with the mean AUC value for lovastatin being 50% higher than that of pravastatin (mean ± SEM AUC0−24 values of 285 ± 25 and 189 ± 13 ng‐equiv × hr/mL, respectively, P < .0001). Pravastatin, which is administered as the monosodium salt, is present in the systemic circulation as the open acid; lovastatin, which is administered as the lactone, is present as both open‐acid active metabolites (62%) and closed‐ring lactone metabolites (38%), which are potentially active. Based on mean AUC values, pravastatin accounted for 75% of the active inhibitors from a pravastatin dose. Lovastatin acid accounted for just 25% of the active inhibitors from a lovastatin dose, with the remainder due to other active metabolites. Significant decreases from baseline in total and low‐density lipoprotein (LDL) cholesterol were observed during the first treatment leg for both pravastatin and lovastatin. Pravastatin treatment resulted in 21% and 26% decreases in total and LDL‐cholesterol, respectively (P < .001); lovastatin reduced these parameters by 18% and 22%, respectively (P < .003). These results indicate that, although pravastatin and lovastatin have very similar chemical structures and effects on serum lipids, they differ sharply in pharmacokinetic properties.
Pharmacokinetics of Quinapril and its Active Metabolite Quinaprilat During Continuous Ambulatory Peritoneal Dialysis
Authors: Swartz R. D. , Starmann B. , Horvath A. M. , Olson S. C. , Posvar E. L.
Published: March 2013

The pharmacokinetics of quinapril, a novel angiotensin converting enzyme (ACE) inhibitor, and its active metabolite, quinaprilat, were determined following a single 20‐mg oral dose of quinapril in six patients with chronic renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD). Overall, quinapril was well tolerated by these CAPD patients, with mild and transient side effects, not unexpected in this clinical setting, which included pruritus, headache, nausea, and cough. Blood pressure reduction was observed in four of six patients, with onset reliably two to four hours after dosing and duration up to 48 hours, associated with quinaprilat concentrations in plasma above 90 ng/mL for at least 33 hours postdose. Two patients experienced significant hypotension, systolic blood pressure below 90 mm Hg, which responded promptly to oral fluid administration and/or reduction in dialysate tonicity. The pharmacokinetic profile of quinapril in these CAPD patients was not significantly different from that previously observed in healthy subjects with normal renal function and in patients with moderate to severe renal dysfunction not yet requiring dialysis (RDND). The apparent elimination half‐life of quinapril was approximately one hour, with negligible dialysate excretion. The pharmacokinetic profile of quinaprilat in these CAPD patients was similar to that previously observed in patients with RDND. The elimination half‐life of quinaprilat was markedly prolonged when compared to that in healthy subjects and averaged 20 hours, with only a small amount of quinaprilat excreted in dialysate (mean = 2.6% of total dose). In summary, renal failure prolongs both the half‐life as well as the antihypertensive effect of quinaprilat, and CAPD has little or no effect on the disposition of quinaprilat.
The Effects of Amiodarone on Thyroid Hormone Function: A Review of the Physiology and Clinical Manifestations
Authors: Figge Helen L. , Figge James
Published: March 2013

Amiodarone, an iodinated benzofuran derivative, is used for treatment of refractory cardiac arrhythmias. Certain features of the drug's structure resemble those of the biologically active thyroid hormone, triiodothyronine (T3). In addition, the drug has a variety of complex effects on thyroid hormone physiology, including a number of possible antagonistic effects on thyroid hormone function at the cellular level. The drug occasionally causes clinically overt hyperthyroidism and hypothyroidism. We review these effects and discuss their clinical implications.
Co‐Enzyme Q10: A New Drug for Cardiovascular Disease
Authors: Greenberg Steven , Frishman William H.
Published: March 2013

Co‐enzyme Q10 (ubiquinone) is a naturally occurring substance which has properties potentially beneficial for preventing cellular damage during myocardial ischemia and reperfusion. It plays a role in oxidative phosphorylation and has membrane stabilizing activity. The substance has been used in oral form to treat various cardiovascular disorders including angina pectoris, hypertension, and congestive heart failure. Its clinical importance is now being established in clinical trials worldwide.
Intravenous Captopril in Congestive Heart Failure
Authors: Ahmad Safeer , Giles Thomas D. , Roffidal Louise E. , Haney Yolanta , Given Michael B. , Sander Gary E.
Published: March 2013

Hemodynamic and neurohumoral effects of intravenous captopril were studied in ten patients with severe chronic congestive heart failure (NYHA Functional Class III and IV). Incremental bolus doses of captopril, titrated to a maximum cumulative dose of 15 mg, were given at 10‐minute intervals. Systemic arterial pressure, mean pulmonary capillary wedge pressure, systemic vascular resistance, mean pulmonary artery pressure, and heart rate decreased (P < .05). Cardiac index and stroke volume index increased (P < .05). Maximum hemodynamic effects occurred after cumulative doses of 7 mg and were seen within 30 minutes after initiation of therapy; responses persisted for 30–90 minutes after the last dose. Plasma renin activity increased, and plasma atrial natriuretic factor concentration decreased. No adverse effects were observed with the use of intravenous captopril. Thus, intravenous captopril produces rapid and favorable hemodynamic improvement in advanced heart failure patients.
Intestinal Absorption of Amiodarone in Man
Authors: Pfeiffer Albrecht , Vidon Nicole , Bovet Martine , Rongier Monique , Bernier Jean‐Jacques
Published: March 2013

The jejunal absorption rate of amiodarone and the influence of lipids on it were studied in human volunteers using the intestinal perfusion technique. A nutrient solution (Realmentyl®, Sopharga Laboratories, France) with 300 mg of the drug was infused for 120 minutes at the ligament of Treitz. The segment tested was 25 cm long. Two caloric loads of the nutrient solution, 3.3 Kcal/min (solution A) and 1.3 Kcal/min (solution B), A containing total lipid and caloric load 2.5 times higher than B, were administered. Minor interindividual differences in amiodarone absorption rate were observed (20.2 to 31.7%) with solution A. Amiodarone absorption correlated with lipid absorption significantly. Since the maximal plasma concentrations of the drug and the area under the curve (AUC/24 hours) did not correlate with the amount of amiodarone absorbed, the wide fluctuations of amiodarone pharmacokinetics must mainly be due to amiodarone tissue distribution and metabolic pathway.
Lack of Effect of Hypertonic Sodium Bicarbonate on QRS Duration in Patients Taking Therapeutic Doses of Class IC Antiarrhythmic Drugs
Authors: Pentel Paul R. , Fifield Jeanne , Salerno David M.
Published: March 2013

Hypertonic sodium bicarbonate (HSB) has been reported to reduce the toxicity of Class IC antiarrhythmic agents in rats and, anecdotally, in patients. A pilot study was conducted of the safety and efficacy of HSB for reversing the electrocardiographic effects of therapeutic doses of encainide or flecainide in ten patients taking these drugs for chronic ventricular arrhythmias. Patients had a mean drug‐induced QRS prolongation before treatment of 27.6 ± 8.8%. Each patient received a single dose of HSB 100 mEq or normal saline IV over 5 minutes on two separate occasions. The administration of treatments was blinded and balanced. There were no important side effects of HSB. Venous blood pH, CO2 content and sodium concentration were all significantly increased by HSB in comparison to saline. No differences were found during the 2‐hour observation period in the primary endpoint, QRS duration, the PR or QT intervals, or the frequency of premature ventricular beats.

It was concluded that HSB 100 mEq does not reduce QRS duration in patients taking therapeutic doses of flecainide or encainide. Because HSB was well tolerated, investigation of its use in higher doses or in patients with overt toxicity due to Class IC drugs is feasible.
Efficacy of Nicardipine in Angina Pectoris
Authors: Thomas Madaelil G. , Sander Gary E. , Given Michael B. , Quiroz Antonio C. , Roffidal Louise E. , Giles Thomas D.
Published: March 2013

The dose‐related efficacy and safety of nicardipine, a new calcium antagonist of the dihydropyridine class, was assessed by exercise tolerance testing in a randomized, double‐blinded, placebo‐controlled study in 19 patients with chronic, stable effort angina pectoris. Four patients were assigned to each of four treatment sequences receiving nicardipine three times daily in an extended Latin‐Square study design. An increase in total exercise capacity, time to onset of angina and time to 1 mm ST segment depression was observed with nicardipine 90 mg/day compared to placebo (P < .05). Gradual upward dose titration in 30 mg/day increments starting from 30 mg/day appeared to produce maximal increase in exercise capacity. Two patients developed adverse side effects attributable to the drug when administered nicardipine 90 mg/day directly from placebo.
Apparent Reduced Absorption of Gemfibrozil When Given with Colestipol
Authors: Forland S. C. , Feng Y. , Cutler R. E.
Published: March 2013

Colestipol and gemfibrozil may be used in combination to lower serum cholesterol and triglycerides. Since colestipol is known to bind certain anionic drugs, we studied the effect of colestipol on the pharmacokinetics of gemfibrozil in 10 patients with elevated serum cholesterol and triglycerides. Each patient received 600 mg of gemfibrozil by mouth during four different studies. Gemfibrozil was given randomly either alone, with, 2 hours before, or 2 hours after 5 grams of colestipol. The serum gemfibrozil concentration time curves were similar when gemfibrozil was given alone or two hours before or after colestipol. There was also no statistical difference in peak gemfibrozil concentration (Cmax), time to Cmax (tmax), area under the curve (AUC), or serum elimination half‐life (t1/2) between any of these three treatments. However, when colestipol was given with gemfibrozil, there was a decrease in AUC (43.6 ± 21.9 mg*hr/L) compared with gemfibrozil given alone (62.6 ± 10.3 mg*hr/L) which was statistically different by both ANOVA and paired t‐test. This finding suggests a decrease in gemfibrozil bioavailability. Cmax when colestipol was given with gemfibrozil (14.7 ± 6.6 mg/L) was not statistically different from gemfibrozil alone (20.1 ± 4.9 mg/L). However, the mean serum concentrations when gemfibrozil was given with colestipol were significantly lower at the 0.5, 1.0 and 1.5 hour sampling times when compared to the other regimens. Gemfibrozil serum elimination half‐life was not significantly altered by combination with colestipol. The data suggest a reduction of gemfibrozil bioavailability when colestipol is administered concomitantly. Separating the administration of these two drugs by at least two hours will avoid this drug interaction.
Effect of Concurrent Sucralfate Administration on the Absorption of Erythromycin
Authors: Miller Lucinda G. , Prichard John G. , White Catherine A. , Vytla Bhaskara , Feldman Stuart , Bowman Robert C.
Published: March 2013

To determine the influence of sucralfate on the absorption of erythromycin, prior to evaluating its efficacy in decreasing erythromycin‐associated gastrointestinal (GI) intolerance, we assessed pharmacokinetic parameters in six healthy adult volunteers. Erythromycin ethylsuccinate administered alone or with sucralfate as a single dose was compared. Sucralfate did not significantly alter the elimination rate constant, half‐life, or area under the curve for erythromycin ethylsuccinate. It is therefore unlikely that efficacy of erythromycin ethylsuccinate will be altered when sucralfate is coadministered.
The Inhibitory Effect of Probenecid on Renal Excretion of Famotidine in Young, Healthy Volunteers
Authors: Inotsume N. , Nishimura M. , Nakano M. , Fujiyama S. , Sato T.
Published: March 2013

Effects of coadministration of probenecid on pharmacokinetic behaviors of famotidine, an H2‐receptor antagonist, after oral administration, were studied in eight young, healthy volunteers. They received an oral 20 mg dose of famotidine with and without coadministration of oral 1500 mg doses of probenecid. The mean area under the serum famotidine concentration‐time curve up to 10 hours was increased by coadministration of probenecid from 424 ±19 (SEM) to 76B ± 39 ng·hr/ml. The mean urinary excretion rate of unchanged famotidine, the mean amount of unchanged famotidine excreted in urine up to 24 hours and mean renal clearance were decreased by coadministration of probenecid. The mean tubular secretion clearance of famotidine was decreased from 196.2 ± 21.4 to 22.0 ± 4.2 ml/min. These data suggest that probenecid, which is a classical inhibitor of renal tubular secretion of organic anions, inhibits the renal tubular secretion of famotidine, which exists partly in a cationic form under physiological pH conditions.
Multiple‐Dose Safety Study of Ibuprofen/Codeine and Aspirin/Codeine Combinations
Authors: Friedman H. , Seckman C. , Stubbs C. , Oster H. , Royer G.
Published: March 2013

This multiple‐dose, double‐blind, placebo‐controlled, randomized, normal volunteer study compared formulations of ibuprofen/codeine and aspirin/codeine for systemic safety. Vital signs, hematologic, biochemical and urinary parameters, side effects, mood and mental alertness, were monitored. The placebo group had less gastrointestinal side effects and more frequent stools than the active treatment groups. There was statistical evidence for greater adverse effects of aspirin/codeine on mood and mental alertness in comparison to ibuprofen/codeine and placebo. Ibuprofen/codeine had a more favorable adverse effect profile than aspirin/codeine. A mild respiratory and cardiac depressant effect attributable to codeine was evident in all active treatment groups after 7 days of frequent therapy. More work needs to be done to elucidate the factors regulating the development of tolerance to the respiratory and cardiovascular depressant effects of opiates in general, and for codeine in particular.