bluuebunny/crossref_metadata_2025 huggingface dataset:
Digoxin Levels in Prehospital Sudden‐Death Syndrome
Authors: Olson David S. , Stueven Harlan A. , Teresi Joseph L. , Thompson Bruce M. , Yee Albert S.
Published: March 2013

Digitalis toxicity is common and has been associated with ventricular dysrhythmias. Digoxin levels in patients who suffer prehospital sudden death have never been studied. This study measured digoxin levels in a population of sudden‐death patients. During the 15‐week study period, 252 patients in cardiac arrest were seen by an urban paramedic system. During daytime hours, paramedics were requested to obtain a blood sample from sudden‐death patients; the samples were subsequently analyzed for digoxin by means of radioimmunoassay. Thirty‐nine patients had measured digoxin levels drawn; 28 (71.8%) were in the therapeutic range (0.5‐2.1 ng/mL), and four (10.2%) were in the toxic range (> 2.1 ng/mL). The patients with toxic dogoxin levels and those with nontoxic levels had similar resuscitation rates (50.0% vs. 34.3%, P = NS), but none were found in ventricular fibrillation. Emergency medical services personnel should consider digoxin toxicity as a potential etiology of arrest.
Dietary Salt Intake and the Clonidine Suppression Test
Authors: Zimlichman Reuven , Goldstein David S. , Stull Robin , Folio Carol Joan , Keiser Harry R.
Published: March 2013

We studied the effects of one week of dietary salt restriction and one week of salt loading on hemodynamic and plasma catecholamine responses to clonidine. Among 11 outpatients with essential hypertension, urinary sodium excretion averaged 29 mEq/d during salt restriction and 322 mEq/d during salt loading. Among eight inpatient normotensive subjects, urinary sodium excretion averaged 11 mEq/d during salt restriction and 300 mEq/d during salt loading. Three hours after administration of oral clonidine 300 μg, the hypertensive patients had an average (± one standard deviation) decrease in mean arterial pressure of 20 ± 6% while receiving the low salt diet and 19 ± 9% while taking the high salt diet, with decreases in venous plasma norepinephrine (NE) of 61 ± 15% and 61 ± 16%, respectively. The normotensive subjects had a decrease in mean arterial pressure of 16 ± 8% with the low salt diet and 15 ± 9% with the high salt diet, with decreases in venous plasma NE of 64 ± 10% and 66 ± 8%. Thus, in neither group were the percent decreases in plasma NE or in mean arterial pressure after clonidine affected by diet. Short‐term, large‐magnitude changes in dietary intake of sodium do not affect the sympathetic contribution to blood pressure as indicated by percent responses of plasma NE or of mean arterial pressure to clonidine administration.
Evaluation of the Ulcerogenic Effect of Potassium Chloride by Endoscopy and Fecal Blood Loss
Authors: Lech Yvonne , Hey Henrik , Jørgensen Frank , Matzen Peter , Østergaard Ove
Published: March 2013

In a blinded‐observer crossover study, 16 volunteers ingested equimolar doses of three different potassium chloride preparations and placebo for nine days in a random order. The irritating effect on the mucosa was evaluated by means of upper gastrointestinal endoscopy and fecal blood loss, measured by reference to the amount of radioactivity in three 24‐hour samples after previous injection of 51Cr‐tagged autologous red cells. The microencapsulated KCl capsule preparation induced three ulcers, but the total endoscopic group score was not significantly higher than the score with placebo. The total endoscopic group score for the wax‐matrix formulation was significantly higher than the score for placebo (P < .05) and for a new microencapsulated KCl tablet preparation containing a potent disintegrant (P < .10). We did not find any significant differences in mean fecal blood loss during the four different treatments. A correlation between endoscopic score and fecal blood loss was found in the placebo group (r = .54) and the microencapsulated KCl capsule preparation (r = .56) group.
Gentamicin Disposition in Young and Elderly Patients with Various Degrees of Renal Function
Authors: Matzke Gary R. , Jameson John J. , Halstenson Charles E.
Published: March 2013

The effect of aging on the total body clearance, volume of distribution, and half‐life of gentamicin was examined in 99 febrile patients with various degrees of renal function. In the 50 patients who were 18 to 64 years old, clearance of gentamicin was 79.0 ± 27.0 mL/min (mean ± standard deviation), creatinine clearance was 98.6 ± 33.3 mL/min, volume of distribution was 0.242 ± 0.077 L/kg, and half‐life was 2.63 ± 0.90 hours. In the 49 patients who were 65 to 90 years old, these values were 36.9 ± 16.3 mL/min, 51.2 ± 21.2 mL/min, 0.244 ± 0.102 L/kg, and 5.80 ± 4.13 hours. Significant differences were observed between the two groups for all parameters except volume of distribution. Linear regression revealed good correlations between the disposition characteristics (clearance and elimination‐rate constant) of gentamicin and age as well as creatinine clearance. However, there was no apparent relationship between the ratio of gentamicin clearance to creatinine clearance and age (r = .0731). These findings suggest that the disposition of gentamicin is independent of age but dependent on renal function.
Comparison of the Antihypertensive Efficacy and Adverse Reactions to Two Doses of Bendrofluazide and Hydrochlorothiazide and the Effect of Potassium Supplementation on the Hypotensive Action of Bendrofluazide: Substudies of the Medical Research Council's Trials of Treatment of Mild Hypertension: Medical Research Council Working Party
Authors: Greenberg G.
Published: March 2013

As substudies of the Medical Research Council's trials of treatment of mild hypertension and of hypertension in the elderly, two studies were carried out comparing the effects of different doses of two diuretics on blood pressure, concentrations of some biochemical variables, and the incidence of subjective adverse reactions. In one study, in which 484 patients with mild hypertension participated, daily doses of bendrofluazide 5 mg and 10 mg, with and without oral potassium supplements, were compared. In the second, involving 701 elderly patients with hypertension, daily doses of hydrochlorothiazide 25 mg together with amiloride 2.5 mg were compared with hydrochlorothiazide 50 mg together with amiloride 5 mg. The mean (±SD) durations of treatment were 35 ± 17 months in the first study and 10 ± 7 months in the second. Neither study showed any significant difference in blood pressure response to the two doses of diuretic, whereas biochemical changes and the reported incidence of subjective adverse reactions were dose‐related. In the first study, potassium supplementation with potassium chloride 16.8 or 33.6 mmol did not have a significant effect on the fall in serum potassium level, which was only slightly reduced, and did not have any significant effect on the antihypertensive effect of either dose of bendrofluazide.
The Influence of Food on the Oral Absorption of Bevantolol
Authors: Toothaker Roger D. , Randinitis Edward J. , Nelson Cynthia , PhD Arlyn W. Kinkel , Goulet J. Richard
Published: March 2013

The bioavailability of bevantolol was compared in 12 healthy volunteers given single doses of the drug as the HCl salt after an overnight fast, or 15 minutes before or after a standardized breakfast in a nonblind, randomized crossover design. Bevantolol was rapidly absorbed in all three treatment groups, with maximum concentrations (Cmax) observed at 1.0, 0.9, and 1.8 hours for the fasting, before breakfast, and after breakfast groups, respectively. Time to Cmax was significantly longer than fasting only when bevantolol was given after breakfast. Food ingestion did not significantly affect Cmax, total of absorbed drug, or the drug elimination rate. Since food only slightly decreases the drug absorption rate and has no measurable effect on the extent of drug absorption, the relationship of bevantolol administration to meals is not expected to influence therapeutic efficacy.
Hemodynamic Effects During Rest and Exercise of Bucindolol in Hypertensive Men
Authors: Conner Dale P. , Vlasses Peter H. , Clementi Regina A. , Oren Arie , Deitchman David , Ferguson Roger K.
Published: March 2013

Bucindolol is an investigational beta‐adrenergic blocking agent with intrinsic sympathomimetic and vasodilatory activity in animals. In a double‐blind, six‐way, crossover study of six mild‐to‐moderate hypertensive men, the effects of bucindolol 100, 200, and 300 mg/d on resting blood pressure, heart rate, forearm blood flow, and vascular resistance measured by pneumoplethysmography, and blood pressure and heart rate after cycle and handgrip exercise were compared with those of propranolol 160 and 320 mg/d and placebo after q12h administration for five doses. Both bucindolol and propranolol significantly suppressed heart rate after cycle exercise in comparison with placebo (−33 to −48 beats/min), demonstrating beta blockade. Suppression of resting heart rate by propranolol (−20 beats/min) was significantly (P < .05) greater than bucindolol (−7 to −8 beats/min); a similar treatment difference in heart rate was noted after handgrip exercise (−18 to −19 vs −1 to −8 beats/min, respectively). Bucindolol and propranolol decreased resting blood pressure to the same extent (in comparison with placebo; P < .05 at peak activity, 2 hr postdose). Bucindolol tended to increase forearm blood flow and decrease forearm vascular resistance (P < .05 at 4 hr postdose) in comparison with placebo. The effect of propranolol on forearm blood flow and forearm vascular resistance was not significant compared with placebo. These data are consistent with intrinsic sympathomimetic and vasodilatory activity of bucindolol in hypertensive men.
Determination of the in Vivo Km and Vmax of a Drug With Tracer Studies
Authors: Browne Thomas R. , Greenblatt David , Evans James E. , Evans Barbara A. , Szabo George K. , Schumacher Gerald E.
Published: March 2013

A method is described for determining the in vivo Km and Vmax values for a drug, utilizing a variant of the Michaelis‐Menten equation and the elimination‐rate constants of tracer doses of the drug administered at two different serum concentration values. The new method is the most accurate yet devised; unlike older methods, it is dependent on assumptions that generally are true and can be validated empirically. Application of the method is demonstrated by a study of phenytoin in humans.
A Multiple‐Dose Pharmacokinetic Comparison of Naproxen as a Once‐Daily Controlled‐Release Tablet and a Twice‐Daily Conventional Tablet
Authors: Ling Teck L. , Yee James P. , Cohen Albert , Hsiao Charles , Gonzalez Mario A. , Garg Dyal C. , Weidler Donald J.
Published: March 2013

The bioequivalence and absorption kinetics of naproxen in a new controlled‐release tablet (750 mg or 1,000 mg naproxen) administered once daily were determined relative to an equivalent dose of the conventional naproxen tablet (375 mg or 500 mg naproxen) administered q12h. Naproxen was well absorbed from the controlled‐release tablet (about 90%) compared with the conventional tablet. Absorption was dependent on drug release from the tablet matrix. The mean absorption time of naproxen averaged 8.4 hours for the 750‐mg controlled‐release tablet and 9.2 hours for the 1,000‐mg controlled‐release tablet. Once‐daily administration of the controlled‐release tablet resulted in equivalent trough concentrations of naproxen, and steady‐state plasma concentrations were maintained within narrower limits than with twice‐daily naproxen.
Influence of Hepatic Dysfunction on the Pharmacokinetics of Propafenone
Authors: Lee John T. , Yee Yin‐Gail , Dorian Paul , Kates Robert E.
Published: March 2013

Hepatic metabolism is the primary process of elimination of propafenone. It therefore is important to understand the effect of altered liver function on the disposition and elimination kinetics of this drug. Patients with abnormal liver function probably will require treatment with propafenone for cardiac arrhythmias; an understanding of the relationship between liver function and the pharmacokinetics of propafenone will provide a rational basis for optimal dosage adjustments in these individuals. Our results demonstrate that both systemic clearance and bioavailability of propafenone are sensitive to variability in liver function. The bioavailability of propafenone is inversely related to the clearance of indocyanine green (ICG), whereas a direct relationship exists between systemic clearance of propafenone and ICG clearance. Comparisons of clinical parameters with the propafenone data yielded interesting results. An overall clinical grading of severity of liver disease based on the presence or absence of portal hypertension (i.e., varices and/or splenomegaly), prior encephalopathy, and ascites did not correlate well with propafenone results. However, albumin, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT) concentrations and prothrombin time values correlated strongly with the overall results. No definite relationships with subjects' age; weight; and hemoglobin, alkaline phosphatase, lactic acid dehydrogenose, cholesterol, blood urea nitrogen, or creatinine levels were detected. These results demonstrate that moderate to severe liver disease significantly affects the absorption and disposition of propafenone. In patients with cirrhosis, and presumably other forms of hepatic dysfunction, careful adjustments of propafenone doses are needed to optimize therapy.
Comparative Pharmacodynamics and Pharmacokinetics of Conventional and Long‐Acting Propranolol
Authors: Garg Dyal C. , Jallad Nader S. , Mishriki Amal , Chalavarya Gopal , Kraml Michael , Fencik Monica , Weidler Donald J.
Published: March 2013

This investigation was conducted to compare the pharmacokinetic and pharmacodynamic effects of single and multiple doses of conventional propranolol and long‐acting propranolol in healthy human volunteers. Two double‐blind, randomized, double‐crossover, Latin square studies were carried out. One study evaluated long‐acting propranolol 160 mg/d, conventional propranolol 40 mg qid, or placebo for seven days in 24 men. The other study compared long‐acting propranolol 80 mg/d, conventional propranolol 20 mg qid, or placebo for seven days in 27 men. At specific times after the administration, blood samples were obtained, and heart rate and blood pressure were measured; exercise tests were done both on the first day and at steady state (day 7). In both studies, the area under the plasma propranolol concentration‐time curve and the peak concentration were significantly less (P < .0001) after the administration of long‐acting propranolol compared with conventional propranolol on both day 1 and day 7; in addition, the elimination half‐life was longer after administration of the long‐acting preparation (9 hr) compared with that following the conventional dosage form (4 hr). Both conventional and long‐acting propranolol significantly decreased the exercise heart rate at each of the selected time points (P < .05) compared with placebo. Reduction in exercise heart rate was greater with conventional propranolol than with the long‐acting formulation, but the differences were not statistically significant, when exercise was performed only at trough levels of the conventional drug. The decreases in exercise heart rate were correlated with plasma propranolol concentrations.
Influence of Food on the Pharmacokinetics of Quinapril and Its Active Diacid Metabolite, CI‐928
Authors: Ferry J. J. , Horvath A. M. , Sedman A. J. , Latts J. R. , Colburn W. A.
Published: March 2013

A randomized two‐way crossover study was conducted in 12 healthy volunteers to assess the effect of food on the pharmacokinetics of quinapril (CI‐906) and its active metabolite, CI‐928, after quinapril dosing. Forty‐milligram oral quinapril doses were administered in a fasted or a fed state with a one‐week washout period between treatments. No significant treatment differences were observed in quinapril and CI‐928 values for maximum plasma concentration, area under the plasma concentration‐time curve, or percentage of dose excreted in the urine. Small but significant increases of less than 0.5 hour in quinapril and CI‐928 tmax values were observed after consumption of food. The pharmacokinetic profiles of quinapril and CI‐928 were not significantly altered by the administration of food.
Treatment of Severe Left Ventricular Dysfunction With Calcium Chloride in Patients Receiving Verapamil
Authors: Guadagnino Victor , Greengart Alvin , Hollander Gerald , Solar Mladen , Shani Jacob , Lichstein Edgar
Published: March 2013

This report describes two patients who received verapamil because of supraventricular arrhythmias. The patients both developed severe hypotension and signs of left ventricular compromise. The hypotension and left ventricular compromise were promptly reversed by administration of intravenous calcium chloride. The dramatic improvement was documented clinically and in one case by two‐dimensional echocardiography.
Comparison of Nifedipine and captopril as Third‐Line Agents in Hypertensive Patients Uncontrolled With Beta‐Blocker and Diuretic Therapy
Authors: Potter J.F. , Beevers D.G.
Published: March 2013

The effect of adding either nifedipine or captopril as third‐line agents was studied in a single‐blind crossover fashion in 24 patients with essential hypertension uncontrolled by combination beta blocker and diuretic therapy. Nineteen patients completed both phases of the study. The mean initial sitting blood pressure before the addition of nifedipine was 164/109 mm Hg and captopril 165/108 mm Hg. Both nifedipine and captopril produced further significant reductions in both sitting and standing blood pressure, 47% of the captopril‐treated patients achieving target blood pressure of less than 160/95 mm Hg compared with 67% with nifedipine. Further increase in the dosage resulted in 63% of the captopril‐ and 81% of the nifedipine‐treated patients achieving target blood pressure. There were, however, no statistically significant differences in the mean fall in blood pressure or in the number of patients obtaining target pressure at the end of each treatment period. Captopril treatment also resulted in a small reduction of pulse rate, and, although pulse rates rose with nifedipine, these changes were not significant. Both treatments were generally well tolerated, and serious side effects were not reported. Both nifedipine and captopril were effective and well tolerated as third‐line antihypertensive agents.
Predictive Performance of Sawchuk‐Zaske and Bayesian Dosing Methods for Tobramycin
Authors: Rodvold Keith A. , Blum Robert A.
Published: March 2013

We evaluated the reliability of pharmacokinetic parameter estimations determined by the Sawchuk‐Zaske method and by a Bayesian method for predicting steady‐state tobramycin concentrations on day 4 and day 10 of therapy in 30 patients treated for gram‐negative infections. We also assessed the effect of using only trough tobramycin concentrations on the predictive performance of the Bayesian method. The mean estimation of tobramycin volume of distribution was significantly different for the Bayesian methods compared with the Sawchuk‐Zaske method (0.23 and 0.26 vs 0.31 L/kg). Comparing the Bayesian and Sawchuk‐Zaske methods when the same number of serum concentrations was available, the Bayesian method overpredicted peak concentrations on day 4 of therapy. When only trough concentration data were used, the Bayesian method significantly overpredicted peak concentrations compared with the Sawchuk‐Zaske method on days 4 and 10 of therapy. Each method predicted steady‐state trough concentrations without significant differences in bias or accuracy. The Bayesian method may be useful in providing aminoglycoside dosing recommendations.
System Approaches in Pharmacokinetics: I. Basic Concepts
Authors: Veng‐Pedersen Peter
Published: March 2013

System approaches mathematically describe a general property of a pharmacokinetic system without modeling in specific terms the kinetic processes responsible for the general property considered. Definitions, basic concepts, kinetic basis, and rationale for system approaches as well as advantages and disadvantages of system approaches are presented and discussed. It appears that the system approaches may offer certain advantages over more traditional methods for many practical applications.
Multiple‐dose Cimetidine Administration Does Not Influence the Single‐dose Pharmacokinetics of Quinapril and Its Active Metabolite (CI‐928)
Authors: Ferry J. J. , Cetnarowski A. B. , Sedman A. J. , Thomas R. W. , Horvath A. M.
Published: March 2013

The potential effect of cimetidine on the pharmacokinetic profiles of quinapril and its active metabolite CI‐928 was evaluated in eight healthy volunteers. Each subject received a single 40‐mg quinapril dose on days 1 and 12 and cimetidine 300 mg four times daily on days 8 through 13. Serial blood and urine samples were collected for assay of quinapril and CI‐928 concentrations. No statistically significant differences were observed in quinapril or CI‐928 Cmax, tmax, AUC(0‐∞),β, or percent of dose excreted in urine values for quinapril administered alone and in combination with cimetidine. Therefore, multiple‐dose cimetidine administration does not influence the single‐dose pharmacokinetics of quinapril and its active metabolite, CI‐928, in healthy volunteers.
Pharmacokinetics and Pharmacodynamics of Oral Nizatidine
Authors: Vargas Ramon , Ryan Jerome , McMahon F. Gilbert , Regel Gayle , Offen Walter W. , Matsumoto Charles
Published: March 2013

Nizatidine was studied in six high‐acid‐secretor (basal secretion, ≥ 5 mEq/hr) male volunteers in a randomized, double‐blind, nonbalanced, cross‐over, placebo and standard drug‐controlled study. Doses of 75 mg, 150 mg, and 300 mg bid were compared with placebo and cimetidine 300 mg qid. Nocturnal acid output was significantly reduced (P < .01) by all doses of nizatidine (36 ± 22, 36 ± 31, and 26 ± 20 mEq) with 75 mg, 150 mg and 300 mg, respectively, and also by cimetidine (43 ± 39 mEq) as compared with placebo (101 ± 61 mEq). Nizatidine also significantly reduced meal‐stimulated acid secretion at breakfast (14 ± 9, 9 ± 7, and 5 ± 6 mEq/2 hours with 75 mg, 150 mg, and 300 mg, respectively, P < .01), at lunch (50 ± 22, 57 ± 22 and 50 ± 35 mEq/2 hours, P < .05) but did not have any effect at dinner (65 ± 16,78 ± 24, and 71 ± 17 mEq/2 hours) whereas cimetidine, given every 6 hours, significantly (P < .01) reduced meal‐stimulated acid secretion (25 ± 16, 27 ± 20 and 31 ± 15 mEq/2 hours, breakfast, lunch, and dinner, respectively) as compared with placebo (81 ± 30, 76 ± 25, and 66 ± 16 mEq/2 hours, breakfast, lunch, and dinner, respectively). Both drugs have a similar pharmacokinetic profile. Nizatidine seems to be a promising H2 antagonist, more potent than cimetidine (on an mg/mg basis), and efficacy studies on gastric acid disorders should be performed.
Effect of Rioprostil on Aspirin‐induced Gastrointestinal Mucosal Changes in Normal Volunteers
Authors: Tolman Keith G. , Detweiler Mark K. , Harrison Craig A. , Rollins Douglas E. , Simon David A. , Brady Carolyn , McCormack Geraldine H. , Bryant Edward C.
Published: March 2013

Rioprostil, a 15‐deoxy‐16‐methyl prostaglandin E1, was evaluated for its effect on aspirin‐induced gastrointestinal mucosal changes in normal volunteers. Fifty‐six normal male volunteers were evaluated by endoscopy in a double‐blind, placebo‐controlled study. Aspirin was given at a dose of 975 mg four times per day. Rioprostil was given at doses of 60, 120, and 300 μg four times per day. Rioprostil, at both antisecretory and subantisecretory doses, prevented or reduced aspirin‐induced injury. Increased stool frequency was the most common side effect and appeared to be a dose‐related effect of rioprostil occurring at only antisecretory doses.
Pharmacodynamics of Procainamide in Patients With Ventricular Tachyarrhythmias
Authors: Liem L. Bing , Yee Y. Gail , Swerdlow Charles D. , Kates Robert E.
Published: March 2013

The onset and offset of the electropharmacologic effect of procainamide was studied in nine patients with ventricular arrhythmias. Procainamide was given at a constant infusion rate of 0.27 ± 0.05 mg/kg/min for 50 to 60 minutes to an average total dose of 15.5 ± 4.4 mg/kg. The QRS interval (used as an index of electropharmacologic effect) at a paced cycle length of 500 ms, and the plasma procainamide concentration were measured simultaneously every 5 minutes during infusion and at frequent intervals for up to 4 hours during a washout period. The average peak plasma concentration was 15.8 ± 9.6 μg/ml and the average maximum QRS interval prolongation was 23.9 ± 6.8% from baseline. The temporal and static plasma concentration‐effect relationships were evaluated by pharmacodynamic modeling and linear regression. For six patients, there was a minimal (<2 minutes) delay in the plasma concentration‐effect relationship, and the data fit a linear relationship with an average slope of 3.2 ± 1.1 msec/μg/ml. For the other three patients, there was a significant delay (3, 10, and 18 minutes respectively) in the plasma concentration‐ejfect relationship. In most patients, the electropharmacologic effect of procainamide is rapid and proportional to plasma concentration; but in a minority of patients, significant delay occurs and could influence the results and interpretation of electropharmacologic studies.
Amlodipine Pharmacokinetics in Healthy Volunteers
Authors: Williams Dennis M. , Cubeddu Luigi X.
Published: March 2013

In the present study we investigated the pharmacokinetics and comparative bioavailability of three oral doses of amlodipine in 12 healthy male volunteers. A randomized, open‐label, three period crossover study design was employed. Each subject received, on three separate occasions a single oral dose of 2.5, 5 and 10 mg amlodipine. Standing diastolic blood pressure was reduced by 1.1,4.8 and 8 mmHg six hours after 2.5, 5 and 10 mg amlodipine, respectively. There were no significant changes in pulse rate, nor on the EKG. The curves for the mean plasma concentrations versus time for the three doses showed parallel time‐courses. Highly significant positive correlations were observed between dose and AUC (0–72 hrs) and between dose and Cmax. However, dose corrected AUC and Cmax were 10–20% lower with 2.5 mg, than with 5 and 10 mg. Peak levels were achieved 5.6 to 6.4 hours postdose. Half lives were 31.2, 33 and 36.8 hours for 2.5, 5 and 10 mg respectively. Headache was the most common side effect, and was more frequently observed with the highest dose. In summary, linear relationhips were found between the dose and the plasma levels of amlodipine. Decreases in standing diastolic blood pressure were also dose related. Because of its long half‐life and gradual absorption, amlodipine should be effective in lowering blood pressure given once daily and the incidence of side effects due to rapid absorption should be minimized.
Pregnancy‐Specific Changes of Antipyrine Pharmacokinetics Correlate Inversely with Changes of Estradiol/Progesterone Plasma Concentration Ratios
Authors: Loock W. , Nau H. , Schmidt‐Gollwitzer M. , Dvorchik B. H.
Published: March 2013

Antipyrine pharmacokinetics as well as estradiol and progesterone concentrations were measured in plasma of 11 healthy pregnant women during the first two trimesters and again in the same patients 6 to 20 weeks after interruption of pregnancy. During pregnancy, the clearance of antipyrine increased and its half‐life decreased in all but two instances. A significant inverse relationship was found between the degree of pregnancy‐specific changes of plasma clearance of antipyrine and estradiol‐progesterone plasma concentration ratios: high estradiol‐progesterone ratios during pregnancy corresponded to decreased plasma clearance of antipyrine; low ratios of the two hormones during pregnancy corresponded to increased plasma clearance of antipyrine. The current results indicate that the balance between circulating estrogens and progesterone may be an appropriate indicator for pregnancy‐specific changes of a particular hepatic drug metabolism during pregnancy.
Phase I Clinical Studies of 7432‐S: Effect of 7432‐S on Platelet Aggregation and Blood Coagulation
Authors: Nakashima M. , Uematsu T. , Takiguchi Y. , Mizuno A. , Uchida K. , Matsubara T.
Published: March 2013

The effects of 7432‐S, a new oral cephalosporin antibiotic, on platelet functions and vitamin K‐dependent blood coagulation parameters were studied in human volunteers and animals. Although the ADP‐ and collagen‐induced aggregations of human and animal platelets were inhibited in vitro by extremely high concentrations of 7432‐S, the inhibitory effect of 7432‐S was weaker than that of latamoxef or cefotaxime. When administered orally to human volunteers or animals, 7432‐S caused no inhibition of platelet aggregation. Its administration also caused no change in prothrombin time and activated partial thromboplastin time both in human volunteers and in rats. The conclusion reached was that the new oral antibiotic 7432‐S does not affect platelet functions and blood coagulation.
Preserved Renal Perfusion During Beta Blockade by Tertatolol with and without Cyclooxygenase Inhibition in Normal Humans
Authors: Reuse Charles , Leeman Marc , Degaute Jean‐Paul , Abramowicz Michel , Prost Jean‐Francois , Naeije Robert
Published: March 2013

The systemic and renal hemodynamic effects of tertatolol, a new noncardioselective beta blocker without partial agonist activity, given alone or in combination with cyclooxygenase inhibition by acetylsalicylic acid (aspirin), were investigated in eight healthy volunteers. Tertatolol 5 mg, aspirin 1 g, tertatolol 5 mg together with aspirin 1 g and placebo were administered at 1‐week intervals in a random order and in a double‐blind fashion. Cardiac output was measured by Doppler echography and renal blood flow and glomerular filtration rate (GFR) by constant infusion techniques using (123I) iodohippurate and (51Cr) EDTA, respectively. Measurements were performed before and then successively 2 and 4 hours after oral intake of drugs or placebo. Tertatolol decreased cardiac output by 22% (P < .05) and heart rate by 17% (P < .05) without change in blood pressure, renal blood flow, and GFR. The same effects occurred when tertatolol was given together with aspirin. Either placebo or aspirin alone had no effect on systemic and renal hemodynamics. These results suggest that cardiac output is redistributed to the kidneys after tertatolol intake in normal humans. This favorable effect on renal hemodynamics is probably not mediated by a local release of vasodilating prostaglandins.
Verapamil Increases the Toxicity of Local Anesthetics
Authors: Tollman Richard D. , Rosenblatt Richard M. , Weaver Joel M. , Wang Yanlin
Published: March 2013

The calcium channel blocker verapamil has, in addition to its other properties, been shown to be a local anesthetic. Its concurrent use in a patient undergoing regional anesthesia may, therefore, increase the potential risk for local anesthetic toxicity. To evaluate this possibility, the effect of verapamil on the median lethal dose (LD50) of lidocaine and bupivacaine in mice was determined. Immediate pretreatment with verapamil increased the mortality of mice given the LD50 dose of lidocaine to 74%, and in mice given the LD50 doses of bupivacaine, to 82%. In animals pretreated with verapamil and calcium chloride, the mortality associated with the administration of LD50 doses of lidocaine and bupivacaine decreased to 43% and 48%, respectively, thus returning the mortality rate back to the LD50 of the local anesthetics when administered alone, It seems that the combined administration of local anesthetic and verapamil results in a significant drug interaction: the resulting blockade of sodium and calcium channels apparently impairs membrane function to a greater degree than with either drug alone. Additional investigation is warranted, and caution should be exercised in giving verapamil to patients during regional anesthesia. Should an adverse drug interaction ensue, the administration of calcium may be beneficial.
Antihypertensive Efficacy of Cetamolol: A Dose‐Titrated Study
Authors: Klausner Mark A. , Sanghvi Indravadan S. , Mullane John F. , Irwin Christopher
Published: March 2013

This double‐blind, placebo‐controlled, randomized multicenter study evaluated the antihypertensive efficacy and safety of cetamolol hydrochloride in 108 patients diagnosed as having mild to moderate hypertension. After a placebo lead‐in period, patients received either cetamolol 5–10‐15 mg/d (low dose), cetamolol 15–25‐50 mg/d (high dose), or placebo, once daily for four weeks. Patients began at the lowest dose and were titrated to higher doses based on the first two assessments of diastolic blood pressure and heart rate, which were conducted each week after double‐blind treatment was dispensed. After four weeks of treatment 82.4%, 81.3%, and 93.3% of the low‐dose group, high‐dose group, and placebo group, respectively, were titrated to the maximum dose level. After four weeks of treatment and 24 hours since the patient's last dose, both cetamolol groups showed a significantly greater (P ≤ .05) reduction in supine systolic/diastolic blood pressure (−18.1 ± 2.3/−9.2 ± 1.5 mm Hg [low dose] and −17.3 ± 2.3/−8.3 ± 1.6 mm Hg [high dose]) than the placebo group (−9.9 ± 2.5/−3.5 ± 1.7 mm Hg). In general, the changes in standing (stabilized) systolic and diastolic blood pressure were similar to those seen in supine measurements. Significantly more patients receiving cetamolol than those receiving placebo showed a “good response” (a decrease in diastolic blood pressure of 10 mm Hg or more or measuring < 90 mm Hg with a decrease of at least 4 mm Hg). There was no apparent treatment effect on most safety parameters analyzed, including the incidence of orthostatic changes in blood pressure or heart rate. These results indicate that treatment with cetamolol in titrated oral doses of 5‐10‐15 mg or 15‐25‐50 mg once daily was safe and effective in patients with mild to moderate hypertension.
Hemodynamic Effects of Labetalol in Young and Older Adult Hypertensives
Authors: Buell James C. , Eliot Robert S. , Plachetka John R. , Little Mark R.
Published: March 2013

Twenty young (45 years or younger) and 20 older (55 years or older) adult patients with mild hypertension were enrolled in this study to compare the hemodynamic effects of labetalol versus placebo in two age groups. Ten patients in each group were randomly assigned to receive either a single oral dose of labetalol (200 mg) or placebo. Hemodynamic parameters were recorded immediately before and two hours after ingestion. Labetalol was more effective than placebo in significantly lowering systolic blood pressure (−11 versus + 5 mm Hg, −23 versus +4 mm Hg), diastolic blood pressure (−9 versus + 2 mm Hg, −12 versus +5 mm Hg), and total systemic resistance (−259 versus +42 dynes‐sec cm−5, −390 versus + 74 dynes‐sec cm−5) in young and older hypertensive subjects, respectively. There was no signifcant changes in heart rate, stroke volume index, or cardiac index in either age group. These data indicate that labetalol lowers blood pressure in young an older hypertensives primarily by reducing peripheral resistance and that the antihypertensive effect may be somewhat greater in older patients.
Effects of Chronic Antihypertensive Treatment with Ketanserin Versus Metoprolol on Blood Pressure and Large Arteries' Compliance in Humans: A Cross‐Over Double‐Blind Study
Authors: de Luca Nicola , Rosiello Giovanni , Crispino Mariarosaria , Volpe Massimo , Galletti Piergiorgio , Buzzetti Giuliano , Trimarco Bruno
Published: March 2013

The antihypertensive efficacy of a serotonin‐receptor antagonist, ketanserin, was compared with that of a well‐established antihypertensive drug, metoprolol, and their cardiac and forearm hemodynamic effects were investigated using echocardiography and bidimensional pulsed Doppler flowmetry, respectively. Twenty hypertensive subjects completed a double‐blind, cross‐over, randomized study using ketanserin and metoprolol. Two 5‐week courses with ketanserin or metoprolol were preceded by a placebo period; the total duration of the study was 15 weeks. Despite a comparable efficacy in reducing systolic and diastolic blood pressure (about 10% of the basal value), the two drugs showed quite different effects on forearm hemodynamics. Ketanserin increased forearm blood flow and induced a significant decrease in forearm vascular resistance (from 141 ± 16 to 75 ± 11 mm Hg/mL/sec, P < .01). Furthermore, this treatment was able to improve brachial artery compliance (from 1.89 ± .3 to 3.2 ± .3 cm4/dyne 10‐7, P < .01). On the contrary, metoprolol did not modify forearm hemodynamics. Both drugs did not significantly modify cardiac performance, as evaluated by left ventricle circumferential fiber shortening. Cardiac output was increased by ketanserin (from 5.9 ± .3 to 6.6 ± .5 L/min, P < .05) and fell during treatment with metoprolol (from 5.9 ± A to 4.9 ± .3 L/min P < .01). Thus, the two drugs reduce blood pressure through different hemodynamic mechanisms and the effects of ketanserin on systemic and peripheral circulation seem more favorable.
Clinical Use of Intermediate to High Dose of N4‐Behenoyl‐1‐β‐D‐arabinofuranosylcytosine in Children with Acute Leukemia
Authors: Takashima Yoshiki
Published: March 2013

N4‐behenoyl‐l‐β‐D‐arabinofuranosylcytosine (BH‐AC) is one of the ara‐C derivatives resistant to deamination. Administration of BH‐AC in an intermediate (500 mg/m2) or a high dose (1000 mg/m2) resulted in maximum BH‐AC plasma levels that were 10 to 20 times as high as those obtained at the conventional BH‐AC dose and prolonged maintenance of comparatively high levels. High concentrations of ara‐C in the plasma were observed just after BH‐AC administration and at 24 hours were proportionally far higher than the ratio between the BH‐AC doses administered in this study and those usually administered. To prevent the occurrence of shock, which has reportedly occurred in other studies, because of the presence of HCO‐60, hydrocortisone was administered together with BH‐AC in this study. In the two patients studied, no shock was observed and the only side effects were transient nausea and vomiting. The results suggest that administration of intermediate and high doses of BH‐AC, accompanied by HDC, will prove a safe, effective means of enhancing the efficacy of leukemia therapy.
A Double‐Blind, Multiple‐Dose, Placebo‐Controlled, Cross‐Over Study to Compare the Incidence of Gastrointestinal Complaints in Healthy Subjects Given Doryx R and Vibramycin R
Authors: Berger Richard S.
Published: March 2013

Ninety‐eight healthy subjects completed a double‐blind, placebo‐controlled, multiple‐dose cross‐over study to compare the incidence of gastrointestinal side effects of Doryx (Parke‐Davis, Morris Plains, NJ) capsules (enteric‐coated doxycycline hyclate pellets) and Vibramycin (Pfizer, New York, NY) capsules (doxycycline hyclate powder). Doryx produced statistically significantly fewer episodes of nausea, vomiting, stomach of abdominal discomfort, and decreased appetite than did Vibramycin. For every symptom, Vibramycin produced statistically significantly more symptom reports than did placebo. Although Doryx produced significantly more reports of nausea than did placebo, there was no significant difference for the other symptoms. Based on these results, Doryx is superior to Vibramycin when considering the incidence of gastrointestinal side effects.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Brain Peptides and Catecholamines in Cardiovascular Regulation Edited by J. P. Buckley and C. M. Fenario

Prostacyclin and Its Stable Analogue Iloprost Edited by R. J. Gryglewski and G. Stock

Autonomic and Enteric Ganglia—Transmission and Its Pharmacology Edited by A. G. Karczmar, K. Koketsu, and S. Nishi

Polymers in Medicine II Edited by E. Chiellini, P. Giusti

Progress in Cardiology Edited by P. N. Yu and J. F. Goodwin

Drug Interactions in Anesthesia Edited by N. Ty Smith and A. N. Carbascio

Delivery Systems for Peptide Drugs Edited by S. S. Davis, L. Illum and E. Tomlinson

Toxicologic Emergencies Edited by L. R. Goldfrank, N. E. Flomenbaum, N. A. Lewin
The Antithrombotic Activity and Pharmacokinetics of Enoxaparine, A Low Molecular Weight Heparin, In Humans Given Single Subcutaneous Doses of 20 to 80 mg
Authors: Frydman A. M. , Bara L. , Roux Y. He , Woler M. , Chauliac F. , Samama M. M.
Published: March 2013

The pharmacokinetics of enoxaparine, a low molecular weight heparin, was randomly studied in 12 healthy male volunteers. Doses of 20, 40, 60, and 80 mg were injected subcutaneously in randomized cross‐over fashion. Anti‐IIa and anti‐Xa activities (using amidolytic methods), and calcium thrombin time, were measured over 36 hours. The maximum Amax of the anti‐IIa and anti‐Xa activities appeared 3 to 4 hours after administration. The terminal half‐lives ofanti‐IIa and anti‐Xa activities were approximately 2 and 4 hours, respectively, with no significant variation between the different doses. For the anti‐Xa activity, there was a highly significant positive correlation between the dose injected and individual values of Amax (r = +0.915; P < .001) and AUC (r = +0.913; P < .001). Enoxaparine displays a relatively small apparent volume of distribution (about 7.0 L) and its total body clearance is about 1.25 L/hr. The mean residence time ranges from 4.6 to 7.6 hours. Thus, the pharmacokinetic profile of enoxaparine is characterized by a linear relationship between dose and absorption, a relatively low clearance and long elimination half‐life, and a high anti‐Xa/anti'IIa ratio.
Propranolol and Inspiratory Muscle Performance in Normal Subjects
Authors: Mucciardi Nick , Muspratt James , Miller Michael J.
Published: March 2013

We studied the effects of propranolol on respiratory muscle performance during inspiratory threshold‐loaded endurance breathing in eight normal subjects. Propranolol (mean daily dose = 160 + 17 mg, SEM) reduced loaded 15‐second MW (92 versus 81 L/min, P = .01) and maximal sustainable ventilatory capacity (52.3 versus 44.5 L/min, P = .02) but did not affect the fraction of MW, which was sustainable. Maximal static inspiratory pressures were reduced at two of three lung volumes, whereas maximal static expiratory pressures were unaffected by propranolol. The reduction in inspiratory muscle performance in the whole population could be accounted for almost entirely by four subjects who developed symptoms of “tiredness” and easy fatigability while receiving propranolol. There was no significant difference in propranolol dose, in degree of beta‐receptor blockade, or in physical fitness in symptomatic and asymptomatic groups, and in neither group did propranolol alter pulmonary function test results. Propranolol directly depresses inspiratory muscle strength in subjects who develop drug‐induced symptoms of fatigue by a mechanism probably unrelated to beta‐adrenergic‐receptor blockade.
The Effect of Histamine‐2 Receptor Antagonists on Tocainide Pharmacokinetics
Authors: North Donald S. , Mattern Allan L. , Kapil Ram P. , Lalonde Richard L.
Published: March 2013

The effects of cimetidine and ranitidine on tocainide pharmacokinetics were assessed in seven healthy subjects, using a randomized, double‐blind, placebo‐controlled, cross‐over study design. After a 400‐mg oral dose of tocainide, the area under the concentration‐time curve decreased from (mean ± SD) 31.64 ± 14.16 μg ṁ hr/mL during placebo, to 23.10 ± 7.33 μg ṁ hr/mL during cimetidine (P < .05). Similarly, the peak tocainide concentrations were 2.81 ± 0.89 μg/mL and 1.70 ± 0.44 μg/mL with placebo and cimetidine, respectively (P < .05). There was no change in the above parameters between ranitidine and placebo. The terminal half‐life and renal clearance of tocainide were not altered by either H2‐receptor antagonists, compared with placebo. However, the total amount of tocainide excreted unchanged in the urine, decreased from 159.8 ± 14.7 mg with placebo to 136.8 ± 26.8 mg with cimetidine (P < .05), whereas there was no change with ranitidine. These data indicate that cimetidine, but not ranitidine, causes a decrease in the bioavailability of tocainide and that neither agent alters the apparent elimination rate of tocainide.
Pharmacokinetics and Bioavailability of Dilevalol in Normotensive Volunteers
Authors: Kramer William G. , Nagabhushan Nagamani , Affrime Melton B. , Perentesis George P. , Symchowicz Samson , Patrick James E.
Published: March 2013

The bioavailability and pharmacokinetics of dilevalol following oral and intravenous administration were investigated in 12 healthy male volunteers. Dilevalol HCl was administered as a 200‐mg oral tablet and a 50‐mg intravenous infusion using a randomized cross‐over design. Blood and urine samples were collected over 60 hours and analyzed for unchanged and total (unchanged plus Glusulase‐released) dilevalol using an high performance liquid chromatography (HPLC) assay. After intravenous administration, total body clearance and volume of distribution of unchanged dilevalol were determined to be 23.2 mL/min/kg and 24.6 L/kg, respectively. After oral administration, a mean maximum concentration of 62 ng/mL was reached at an average peak time of 1.4 hours. Drug was eliminated with a half‐life of 8.3 hours after oral administration and 12 hours after intravenous administration. Based on plasma levels and urinary excretion of total dilevalol, the drug was completely absorbed; however, due to first‐pass metabolism, the absolute bioavailability of unchanged drug was 11 to 14%.
Acute Effects of the New Angiotensin‐Converting Enzyme Inhibitor Cilazapril: A Pilot Study
Authors: Mulinari Rogerio A. , Gouni Ioanna , Gavras Irene , Gavras Haralambos
Published: March 2013

This study assesses the magnitude and duration of action of three different oral doses of the new orally active angiotensin‐converting enzyme (ACE) inhibitor RO 312848 (cilazapril, Hoffman‐LaRoche, Nutley, NJ) on blood pressure and plasma ACE levels. Twelve hypertensive patients were separated into two groups: Group A (n = 6) received two single daily doses of 5 and 10 mg, each preceded and followed by two placebo days, and Group B (n = 6) received 10 and 20 mg on an identical protocol. The onset and duration of an appreciable blood pressure lowering effect were at 2 hours and at least for 12 hours, respectively, whereas suppression of ACE levels occurred at 1 hour and lasted for more than 72 hours. Response of these two parameters was partial after 5 mg, but was maximal after 10 mg and did not increase further with the 20‐mg dose. A 5–10 mg dose daily may be sufficient to maintain chronic blood pressure control with this agent, but long‐term dose trials are necessary to establish its clinical utility.