bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug Effects on Orthostatic Intolerance Induced by Bedrest
Authors: Vernikos J. , Dallman M. F. , Van Loon G. , Keil L. C.
Published: March 2013

Effective and practical preventive procedures for postflight orthostatic intolerance are highly desirable. The current practice of attempts to expand plasma volume by ingestion of salt and fluids before reentry has proven benefits. This study evaluated alternative options using fludrocortisone (F) to expand plasma volume (PV), dextroamphetamine (Dex) to enhance norepinephrine (NE) release and atropine (A) to reduce the effects of vagal stimulation. Seven subjects with proven post‐bedrest orthostatic intolerance returned for a 7‐day 6° head‐down bedrest study. F (0.2 mg) was given at 8:00 AM and 8:00 PM the day before and 8:00 AM the day the subjects got out of bed (2 hours before standing). PV was measured before and 1 hour after the last dose of F. D (5 mg) and A (0.8 mg) were then taken orally 1 hour before the stand test. F expanded PV by 16% and caused sodium retention. Four of the 7 subjects stood for 1 hour post‐bedrest and HR, plasma NE and PRA responses to standing were greatly enhanced and sustained. Although there was a narrowing of pulse pressure, the ability to overcome orthostatic intolerance with these countermeasures was largely due to vasoconstriction and sustained high heart rate. The existing literature on pharmacologic countermeasures for post‐flight and post‐bedrest orthostatic hypotension is reviewed, and the results are discussed in that context.
Protein Crystal Growth in Microgravity
Authors: Bugg Charles E. , DeLucas Lawrence J.
Published: March 2013

Protein crystallography is a powerful method for determining the three‐dimensional structures of biological macromolecules. Although new methods, such as two‐dimensional NMR, have demonstrated promise for determining the structures of small proteins and nucleic acids, the complete atomic arrangements within large proteins can only be determined at present using crystallographic techniques. Such crystallographic studies have been of major importance for establishing structure/function relationships that are fundamental to understanding how enzymes, nucleic acids, and other macromolecules function in biological systems. More recently, crystallographic studies of proteins have become of considerable practical interest within the pharmaceutical and biotechnology industries, as promising tools in drug design and in protein engineering.
The Effect of Diltiazem on Hepatic Drug Oxidation Assessed by Antipyrine and Trimethadione
Authors: Ohashi Kyoichi , Sakamoto Koichi , Sudo Toshiaki , Tateishi Tomonori , Harada Kazuhiro , Fujimura Akio , Ebihara Akio , Tanaka Einosuke
Published: March 2013

The effect of pretreatment for 3 days with diltiazem 60 mg three times a day on the pharmacokinetics of 500‐mg antipyrine and 250‐mg trimethadione was studied in six healthy male subjects. Diltiazem decreased the total body clearance from 34.0 ± 8.0 to 28.6 ± 6.1 mL/min (P <.01), and prolonged the elimination half‐life from 12.6 ± 3.0 to 14.3 ± 2.5 hours (P <.01) of antipyrine without any changes in volume of distribution. The cumulative renal excretion (% dose) of antipyrine was significantly increased from 2.23 ± 0.73 to 2.78 ± 0.83% (P <.05). Clearances of production for three major antipyrine metabolites, norantipyrine (4.31 ± 1.64 to 3.50 ± 1.28 mL/min, P <.01), 3‐hydroxymethy‐lantipyrine (4.67 ± 1.63 to 3.82 ± 1.34 mL/min, P <.01) and 4‐hydroxyantipyrine (10.47 ± 3.41 to 8.16 ± 2.82 mL/min, P <.01) were reduced significantly by diltiazem. On the other hand, diltiazem did not produce any significant changes in pharmacokinetic parameters of trimethadione and plasma concentration ratio, oxidative major metabolite of trimethadione to trimethadione itself. These results suggest that other drugs metabolizing the same hepatic oxidative pathways as antipyrine, may be influenced by diltiazem.
Pharmacokinetic and Tolerance Studies of Cefpodoxime after Single‐ and Multiple‐Dose Oral Administration of Cefpodoxime Proxetil
Authors: Borin Marie T. , Hughes George S. , Patel Rajendra K. , Royer Max E. , Cathcart K. Sue
Published: March 2013

Cefpodoxime proxetil, a third generation, broad‐spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as Cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of Cefpodoxime proxetil were determined. Results from the single‐dose study indicate that Cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose‐normalized AUC and Cmax, urinary recovery, and half‐life between one or more of the higher‐dose treatment groups and the 100‐mg dosing group. After multiple‐dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC‐ and microbioiogic‐determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single‐dose study and antibiotic‐associated diarrhea in one subject in the multiple‐dose study.
Bactericidal Activity of Clarithromycin and its 14‐Hydroxy Metabolite Against Haemophilus Influenzae and Streptococcal Pathogens
Authors: Gu Jian‐Wei , Scully Brian E. , Neu Harold C.
Published: March 2013

The serum bactericidal activity of clarithromycin in six normal human volunteers was determined after oral doses of 500 mg. The mean plasma levels of clarithromycin plus 14‐hydroxy clarithromycin were 2.11 μg/mL after the second dose and 4.36 μg/mL after the sixth dose. The mean serum bactericidal titer against Haemophilus influenzae after the second dose was 1:8 and after the sixth dose 1:16 when unheated serum was used. Similar values were obtained when serum to which clarithromycin and 14‐hydroxy clarithromycin was added was tested. Mean serum bactericidal titers against H. influenzae determined in Haemophilus test broth or heated serum were 1:2 and 1:4, respectively. Against Streptococcus pneumoniae and Streptococcus pyogenes, there was greater than 1:16 serum bactericidal levels at 12 hours after the sixth dose of clarithromycin.
Differential Side Effect Profile of Triazolam Versus Flurazepam in Elderly Patients Undergoing Rehabilitation Therapy
Authors: Woo Elaine , Proulx Susan M. , Greenblatt David J.
Published: March 2013

Patients (aged 65 years or older) who were hospitalized for rehabilitation therapy after a cerebrovascular accident or other acute debilitating condition participated in a 6‐week controlled clinical trial. After a 2‐week period of receiving nightly single‐blind placebo, patients were randomly allocated to receive either triazolam (0.125 mg) or flurazepam hydrochloride (15 mg) nightly under double‐blind conditions. For the final 2 weeks, patients again received single‐blind placebo. The study groups' were comparable in their performance on four psychomotor tests done in the morning during the initial placebo period. Triazolam‐treated patients showed subsequent improvement on the tests, consistent with practice effects, whereas flurazepam recipients showed performance impairment during treatment. Triazolam—flurazepam differences were significant in the cardsorting and arithmetic tests, and they approached significance for the Purdue pegboard test. Blind ratings by physical therapists indicated significant impairment among flurazepam recipients in their capacity to cooperate with and participate in the rehabilitation tasks; the impairment persisted into the post‐treatment placebo period. Similar flurazepam—triazolam differences, although not significant, were reported by occupational therapy and nursing staff members. The findings suggest that the kinetic differences between flurazepam and triazolam may have clinical implications in elderly patients undergoing rehabilitation therapy.
The Bleeding Time Effects of a Single Dose of Aspirin in Subjects Receiving Omega‐3 Fatty Acid Dietary Supplementation
Authors: Mueller Bruce A. , Talbert Robert L. , Tegeler Charles H. , Prihoda Thomas J.
Published: March 2013

Dietary supplementation with omega‐3 fatty acids reduces platelet aggregation in subjects who usually eat a diet low in these fatty acids. Aspirin also has an antiplatelet effect. The clinical effects of the concomitant administration of these agents were examined in this double‐blind controlled crossover trial. Twelve healthy adults were randomized to supplement their diet for 21 days with 8 g of omega‐3 fatty acids or identical‐looking olive oil capsules. At the end of each treatment period, bleeding times were obtained before and after the administration of one 325‐mg aspirin tablet. Overall, percent change in bleeding time after omega‐3 fatty acid supplementation was significantly prolonged compared with olive oil supplementation before aspirin administration but not after. Bleeding times were influenced significantly by the order of randomization in the two treatment groups. Changes in post‐aspirin bleeding time varied in subjects after they received olive oil. Post‐aspirin bleeding times after omega‐3 fatty acid supplementation were prolonged compared with baseline values but not significantly prolonged when compared with those after olive oil administration. The authors concluded that the concomitant administration of a single dose of aspirin does not prolong bleeding time in subjects who eat a diet enriched by omega‐3 fatty acids versus a diet enriched by olive oil.
Dose‐Ranging Study to Delineate the Additive Antihypertensive Effect of Guanabenz and Captopril
Authors: Baez Mayra A. , Woo‐Ming Rex B. , Garg Dyal C. , Shapse Deborah B. , Deitch Marc W. , Weidler Donald J.
Published: March 2013

This open crossover study in eight hypertensive patients defined a possible additive effect of oral guanabenz and captopril and determined a safe and effective dose range. Each group of four patients received placebo followed by ascending doses (on alternate days) of either guanabenz (2, 4, 8 mg) or captopril (6.25, 12.5, 25 mg) as initial monotherapy and were subsequently crossed over to the alternate monotherapy. Guanabenz and captopril were given concomitantly in increasing doses—the highest dose for both groups being 8 mg guanabenz/25 mg captopril. When guanabenz and captopril were given concomitantly, blood pressure decreased, both from the values during placebo administration and from the lead‐in values recorded before each dose. Mean supine systolic and diastolic blood pressures after combination therapy decreased significantly (P < .05) in a dose‐related manner at most evaluations. The authors conclude that guanabenz and captopril have an additive effect when administered in combination to patients with hypertension.
Antihypertensive Efficacy of Guanfacine and Methyldopa in Patients with Mild to Moderate Essential Hypertension
Authors: Wilson Michael F. , Blackshear Jack , Parsons Oscar A. , Lovallo William R. , Mathur Pershottam
Published: March 2013

Guanfacine, an alpha‐2 adrenoceptor agonist, was compared with methyldopa as step‐2 therapy for patients with mild‐to‐moderate essential hypertension in a 12‐week, double‐blind, randomized, parallel evaluation of efficacy and safety. The study consisted of a 2‐week screening/weaning period (phase I), a 3‐week treatment period with a diuretic (phase II), and a 12‐week treatment period with a diuretic plus methyldopa or guanfacine (phase III). Patients were weaned from prior anti‐hypertensive medication during the screening/weaning period and began receiving chlorthalidone 25 mg every morning. Patients received only 25 mg of chlorthalidone each morning during the phase II period. Those who had an average seated diastolic blood pressure (BP) of 95–114 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 guanfacine, 1 mg every night, or methyldopa, 250 mg tid. Seated and standing systolic and diastolic BP and pulses were measured biweekly for 12 weeks after randomization. Of the 112 patients who were randomly assigned to guanfacine or methyldopa, 87% completed the entire study. The mean seated systolic and diastolic BP were reduced 13/13 mm Hg by guanfacine administration and 15/13 mm Hg by methyldopa administration. No significant changes in seated pulse were seen in either group. Similar changes occurred in the standing position. Very few adverse effects were reported during the study, the most prevalent side effect was xerostomia (13% guanfacine, 9% methyldopa). No significant differences were observed between treatment groups for the incidence of cardiac arrhythmias after methyldopa or guanfacine administration was stopped. No significant effects of these agents were seen on a set of memory function tests. Thus, guanfacine (1 mg each night) and methyldopa (250 mg tid) were equi‐effective in reducing systolic and diastolic BP in combination with diuretic in patients with mild‐to‐moderate essential hypertension.
Lovastatin Therapy in Hypercholesterolemia: Effect on Fibrinogen, Hemorrheologic Parameters, Platelet Activity, and Red Blood Cell Morphology
Authors: Beigel Yitzhak , Fuchs Jacob , Snir Moshe , Green Pnina , Lurie Yoav , Djaldetti Menachem
Published: March 2013

The effect of lovastatin therapy on blood rheology was investigated in 26 hypercholesterolemia patients. Treatment with lovastatin was associated with a significant improvement in whole blood filtration time and a tendency toward normalization in red blood cell morphology. A significant increase was observed in fibrinogen level, in ADP‐induced platelet aggregation, in the percentage of “big” platelets, and in platelet count. The viscosity of whole blood and plasma and the percentage of aggregated platelets did not change significantly. The cause for these hemorrheologic changes and their role in influencing the coronary risk of lovastatin‐treated hypercholesterolemia patients should be further investigated.
Effect of Nifedipine on Oxygen Delivery in Patients with Angina Pectoris: Relation Between Blood Viscosity and Hematocrit
Authors: Kato Tadashi , Yoneda Shunki , Kako Toshio , Koketsu Masaaki , Fujinami Takao
Published: March 2013

The effect of nifedipine on blood viscosity and hematocrit was investigated. Blood was sampled from eight patients with angina pectoris (mean age: 59 ± 8 yr) treated with nifedipine (20–30 mg/day) for 5 months. Using a cone‐plate type viscometer, blood viscosity was determined at the shear rates of 37.5 and 375 sec−1 at 37°C. Hematocrit was also measured at the same time. Since the ratio of hematocrit to blood viscosity at a shear rate of 375 sec−1 can be considered to reflect oxygen delivery, this ratio (oxygen delivery index) was also calculated. Blood viscosity at a shear rate of 37.5 sec−1 was significantly (P <.05) decreased by nifedipine treatment, but hematocrit and the blood viscosity at a shear rate of 375 sec−1 were not changed. The oxygen delivery index, however, was significantly (P <.01) increased after the administration of nifedipine. These results suggest that oxygen delivery increased by the treatment with nifedipine and inhibited erythrocyte aggregation by decreasing blood viscosity at low shear rate.
Digoxin Pharmacokinetics and Spirapril, a New Ace Inhibitor
Authors: Johnson Brian F. , Wilson John , Johnson Johanna , Flemming Janeth
Published: March 2013

As concurrent use of digoxin with the novel ACE inhibitor spirapril should be common, potential for spirapril to affect steady‐state digoxin kinetics was studied. Fifteen healthy white male volunteers aged 22–42 and weighing 135–225 lbs took digoxin tablets 0.25 mg every 12 hours for 5 weeks. In crossover design, each also received spirapril or matching placebo capsules during weeks 1 and 2, or 4 and 5. Dosage of spirapril was increased from 12 mg to 48 mg once daily. Spirapril produced no significant effect on mean (±SD) serum digoxin concentration in the steady state, area under curve for 12 hours, peak digoxin level, time to peak, or urinary digoxin excretion over 12 hours. No change in renal or whole body digoxin clearance was seen. Unlike some other cardiovascular drugs, spirapril does not alter steady‐state digoxin kinetics in healthy adults.
Interactions of Clonidine and Nifedipine in Moderately Severe Hypertensive Patients
Authors: Mitrovic V. , Patyna W. , Bruchhausen V. v. , Hüting J. , Schlepper M.
Published: March 2013

In ten patients (age: 47–59 yr) with moderately severe essential hypertension, the humoral and hemodynamic effects of a 4‐day therapy with 2 × 75 μg clonidine, 2 × 20 mg nifedipine (slow‐release), and their combination were investigated and compared with baseline values. The following measurements were observed under clonidine (C), nifedipine (N), and on combination (C/N), respectively: heart rate fell significantly under C from a mean of 79 to 67/min (P <.05), increased to 73/min after N (P > .05) and fell again to 68/min under combination (P <.05). Systolic blood pressure (Riva‐Rocci method) decreased from a mean of 184 to 171 (C), 168 (N) and 161 mm Hg (C/N), respectively (P <.01). Diastolic blood pressure was also significantly altered (113 vs. 104 (C), 107 (N), and 100 mm Hg (C/N); P <.05). Stroke volume (ECHO) was not altered significantly (77 vs. 71 (C), 79 (N), and 80 mL (C/N), respectively), whereas cardiac output dropped from 5.9 to 4.9 L/min (C; P <.05), increased to 5.7 (N; P > .05), and dropped again to 5.3 L/min (C/N; P > .05). Peripheral vascular resistance increased from a mean of 2091 to 2297 (C), fell to 1933 (N), and increased again to 2138 dyn/sec/cm−5 (C/N). Plasma norepinephrine levels fell from 440 to 281 (C; P <.01), increased to 391 (N; P > .05), and fell again to 404 pg/mL (C/N; P > .05). PRA decreased significantly from a mean of 1.77 to 0.96 (C), increased to 2.11 (N; P <.05), and was unchanged on combination (1.77 vs. 1.76 ng/mL/hr). Aldosterone levels fell after clonidine administration and combination therapy, but were unchanged after nifedipine administration. Epinephrine, vasopressin, and ANF showed no significant changes. This study showed that combined administration of low‐dose nifedipine and clonidine leads to a purely additive reduction in blood pressure and a compensation of the nifedipine‐induced increase in heart rate. The disadvantages of neurohumoral counter‐regulation of nifedipine therapy are neutralized by clonidine, testifying to the usefulness of combined therapy of low‐dose clonidine and nifedipine, which, in addition, is well tolerated.
Albuterol Extended‐Release Products: Effect of Food on the Pharmacokinetics of Single Oral Doses of Volmax® and Proventil® Repetabs® in Healthy Male Volunteers
Authors: Hussey Elizabeth K. , Donn Karl H. , Powell J. Robert , Lahey Avis P. , Pakes Gary E.
Published: March 2013

The absorption of albuterol from a single 4‐mg oral dose of Volmax® and Proventil® Repetabs® was investigated under both fasting and fed conditions in an open‐label, randomized, four‐period, crossover study in 24 healthy male volunteers. Blood was collected for determination of albuterol plasma concentrations by HPLC over 30 hours postdose. Twenty subjects were evaluable for data analysis. The mean Cmax for Volmax;® administered after a meal was 19% lower than that of the drug administered in a fasting state (3.9 ng/mL vs. 4.8 ng/mL; P <.01). An almost equivalent lowering of the mean Cmax (by 21%) was observed for Proventil® Repetabs® after administration with a meal versus fasting (4.2 ng/mL vs. 5.3 ng/mL; P <.01). There were no significant differences between the two formulations in the degree of Cmax reduction due to the presence of food. The tmax occurred significantly later during the fed treatment for Volmax® only (4.9 hours fasted vs. 6.4 hours fed; P <.01). The lag time was significantly greater during the fed treatments for Volmax®. No differences were observed in the area under the plasma concentration—time curve (AUC) for either formulation under fasting versus fed conditions, suggesting that the extent of absortion was not altered by food. Overall, food caused a more sustained release of albuterol from both Volmax® and Proventil® Repetab®.
Serum/Saliva Correlations for Theophylline in Asthmatics
Authors: Blanchard James , Harvey Suzanne , Morgan Wayne J.
Published: March 2013

Theophylline levels in mixed saliva (both stimulated and unstimulated) were compared with total and free (unbound) serum theophylline levels in 28 asthmatic outpatients using theophylline regularly. Stimulated saliva predicted both total and unbound serum theophylline concentrations within ± 1 μg/mL in 62.5% and 92.9%, respectively, of the samples examined. In addition, the total serum levels could be used to predict unbound serum concentrations to within ±1 mg/L in 100% of the cases that were examined. These results indicate that saliva levels predict the unbound serum theophylline levels with greater accuracy and precision than they predict total serum theophylline levels. In addition, total serum levels can be used to reliably predict unbound serum levels. The use of mixed stimulated saliva is recommended as a reliable non‐invasive method for monitoring unbound serum theophylline levels. The therapeutic range for saliva, which corresponds to the accepted total serum concentration range of 10–20 mg/L, is approximately 5.6–11.3 mg/L.
Alprazolam in End‐Stage Renal Disease: I. Pharmacokinetics
Authors: Schmith Virginia D. , Piraino Beth , Smith Randall B. , Kroboth Patricia D.
Published: March 2013

In a double‐Wind, randomized, placebo‐controlled study, the pharmacokinetics of alprazolam and its active metabolite, α‐hydroxyalprazolam, were determined in 12 normal subjects and 12 dialysis patients [7 hemodialysis (HD) patients and 5 continuous ambulatory peritoneal dialysis (CAPD) patients]. Blood samples were collected over 48 hours after alprazolam 0.5 mg and alprazolam 2 mg administration. Alprazolam and α‐hydroxyalprazolam concentrations and alprazolam free fraction were determined. The pharmacokinetics of alprazolam were similar in normal subjects and HD patients with the exception of higher free fraction in HD patients. Differences were detected, however, in the pharmacokinetics of alprazolam in CAPD patients when compared with normal subjects and HD patients. These differences included a higher free fraction and a lower apparent oral clearance and free clearance in CAPD patients than in normal subjects or in HD patients. There was also a tendency for a later Tmax and a longer elimination half‐life in CAPD patients than in normal subjects or HD patients. Alpha‐hydroxyalprazolam concentrations were <15% of corresponding alprazolam concentrations in normal subjects and dialysis patients. Thus, end‐stage renal disease is associated with changes in absorption, distribution, and/or elimination of alprazolam.
Influence of Chlorthalidone on the Pharmacokinetics and Pharmacodynamics of Org 10172 (Lomoparan®), A Low Molecular Weight Heparinoid, in Healthy Volunteers
Authors: De Boer Anthonius , Stiekema Jacobus C. , Danhof Meindert , Breimer Douwe D.
Published: March 2013

The influence of chlorthalidone (100 mg po) on the pharmacokinetics and pharmacodynamics of Org 10172 (IV bolus injection of 3250 anti‐Xa units), a low molecular weight heparinoid, was studied in six healthy male volunteers using an open randomized two‐way crossover design. Chlorthalidone produced a slight decrease in clearance of anti‐Xa activity from 7.1 ± 1.0 to 6.6 ± 0.8 mL/min and a decrease of the volume of distribution from 0.20 ± 0.05 to 0.16 ± 0.04 L/kg, whereas the volume of distribution of antithrombin activity increased from 0.14 ± 0.05 to 0.26 ± 0.10 L/kg (all differences P <.05). During the entire study period no adverse events occurred. In summary, chlorthalidone showed separate effects on different fractions of Org 10172. The clinical implication of the slight change observed in plasma anti‐Xa activity is likely to be limited, whereas the 80% increase in distribution volume of plasma antithromhin activity can not be defined as yet in terms of clinical relevance.
Validity of Self‐Reports of Caffeine Use
Authors: Kennedy John S. , von Moltke Lisa L. , Harmatz Jerold S. , Engelhardt Nina , Greenblatt David J.
Published: March 2013

The relationship between self‐reports of caffeine ingestion on two occasions and measured plasma concentrations of caffeine and its major metabolites was examined. A subject population [25 men and 25 women, age 20–45 years (mean: 28.7 yr)] that was enrolled in a benzodiazepine pharmacokinetic study underwent general medical screening on two occasions, each including detailed caffeine histories. Before beginning their scheduled study, plasma samples were obtained and evaluated by HPLC for caffeine, paraxanthine, theophylline, and theobromine. These values were compared with estimates of caffeine consumption in mg/day generated from both histories. There was no significant difference between plasma levels of caffeine, metabolites, or caffeine plus metabolites for categories corresponding to reports of low, intermediate or high caffeine use. A self‐reported caffeine consumption of greater than 300 mg/day (high) did correlate, however, with a significant smoking history. The authors conclude that self‐reports of caffeine ingestion do not accurately reflect acute exposure, and that if caffeine use is of importance in a given setting, reports should be confirmed by biochemical means.
Pharmacokinetics of Felodipine in Chronic Hemodialysis Patients
Authors: Buur Tom , Larsson Rutger , Regårdh Carl‐Gunnar , Åberg Jan
Published: March 2013

Five chronic hemodialysis patients (1 woman and 4 men, aged, 46–68 yr) were given an oral dose of 10 mg felodipine followed by 0.057 mg [3H] felodipine IV. After 5 hours, a hemodialysis treatment lasting 4 hours was performed. Blood and dialysate flows were 200 mL/min and 500 mL/min, respectively. Capillary dialyzers with 1.3 m2 cellulose acetate membrane were used. The pharmacokinetic characteristics and reduction in diastolic BP were similar to those in hypertensive patients with normal renal function and in uremic patients who were not treated with dialysis. There was no measurable removal of felodipine by hemodialysis. Dialyzer clearance of radioactive metabolites was about 10 mL/min, and only 8.9% of the dose was eliminated by the treatment. The half‐life of radioactive metabolites was 10 days (6–14 days) in three patients dialyzed thrice weekly. Since the metabolites are biologically inactive, no adjustment of dose is required in hemodialysis patients.
Efficacy of Cardioselective Beta‐Adrenergic Blockade with Intravenously Administered Metoprolol in the Treatment of Supraventricular Tachyarrhythmias
Authors: Amsterdam Ezra A. , Kulcyski James , Ridgeway Michael G.
Published: March 2013

The efficacy of intravenously administered metoprolol, a cardioselective beta‐adrenergic blocking agent, was evaluated in the treatment of supraventricular tachyarrhythmias in 16 patients. The arrhythmias that were treated were atrial fibrillation (11 patients), atrial flutter (2 patients), supraventricular tachycardia (2 patients), and multifocal atrial tachycardia (1 patient). Mean dose of metoprolol was 9.5 mg (range: 2–15 mg) administered in one or two separate infusions of up to 7.5 mg each over a cumulative maximum interval of 25 minutes. In the 13 responders (81%), mean ventricular rate decreased from 134 ± 6 to 106 ± 7 beats/min 10 minutes after metoprolol administration and was controlled for 40 to 320 minutes without further therapy. Minimum ventricular rate (98 ± 6 beats/min) was reached 48 minutes after initiation of metoprolol. Metoprolol reduced ventricular rate by >15% (decrease of 26–60 beats/min) in 11 (69%) of 16 patients, including 9 (82%) of 11 patients with atrial fibrillation. In two other patients, one with atrial fibrillation and one with supraventricular tachycardia, ventricular rate was reduced by >12%. Hypotension, occurring in jive patients, was the most frequent side effect but was transient and readily managed. Cardioselective beta‐adrenergic blockade by metoprolol was rapidly effective in controlling ventricular rate in a majority of patients with supraventricular tachyarrhythmias and may be of particular use in selected patients with chronic obstructive pulmonary disease in whom intravenous beta‐adrenergic blockade is indicated. Hypotension is an important potential side effect.
Minimization of Indomethacin‐Induced Reduction in Renal Function by Misoprostol
Authors: Weir Matthew R. , Klassen David K. , Hall Pamela Sue , Schubert Carolyn , Voss Terry E. , Stromatt Scott C. , Brown Jeffry A.
Published: March 2013

A prospective, randomized, open‐label, triple crossover comparison of the effects of indomethacin, misoprostol, or the combination, on renal function was performed to assess the ability of an oral prostaglandin E analogue, misoprostol, to minimize indomethacin‐induced decline in renal function in middle‐aged women. Twelve healthy women (mean age: 60.5 ±1.6 yr) with normal renal function (serum creatinine: 81 ± 9 umol/L) were studied; six women were normotensive, and six women were hypertensive with their blood pressure controlled with 50‐mg hydrochlorothiazide daily. All patients were placed on a 2‐g sodium daily diet for 2 weeks before initiation of the study. The subjects were prospectively randomized to receive each of three 4‐day treatments of indomethacin (25 mg q 6hr), misoprostol (200 mcg q 6hr), or the combination of drugs with a 4‐day washout between each treatment period. Measurements of GFR (urine accumulation of 99mTc‐DTPA) and RPF (serum disappearance 131I‐Hippuran), and urine collections for electrolytes were obtained before the first treatment period and on the fourth day of each treatment period. Three of the six hypertensive patients and three of the six normotensive patients had a decrease (>10%) in GFR associated with indomethacin therapy. When misoprostol was given with the indomethacin, four of these six patients did not experience a decline in GFR (baseline GFR for six patients: 75.4 ± 6.6 mL/min/1.73m2, GFR after indomethacin: 57.8 ± 9.5 mL/min/1.73m2, GFR with combination of indomethacin and misoprostol: 69.7 ± 3.5 mL/min/1.73m2. RPF was not consistently altered by subacute/chronic dosing of indomethacin, misoprostol, or the combination of the drugs. The authors conclude that misoprostol ameliorates indomethacin‐induced renal dysfunction in salt‐restricted and diuretic‐treated middle‐aged women with normal serum creatinine.
Prophylactic Antiparkinson Drug Use: II. Withdrawal After Long‐Term Maintenance Therapy
Authors: Lavin Michael R. , Rifkin Arthur
Published: March 2013

Although the efficacy of long‐term neuroleptic treatment of schizophrenic patients is generally accepted, the use of concurrent antiparkinson drugs is less well defined. The value of prolonged antiparkinson drug use in preventing extrapyramidal side effects is controversial. More than 30 studies of antiparkinson drug withdrawal have attempted to answer this question. The authors reviewed all double‐blind, placebo‐controlled studies, and found most to contain serious methodologic or statistical flaws. There is evidence to support the long‐term use of these agents in preventing extrapyramidal side effects. The authors offer an analysis of the benefits and risks that are involved with prophylactic antiparkinson drug use, and conclude that most patients would benefit from maintenance therapy.
New Indications for Already‐Approved Drugs: An Analysis of Regulatory Review Times
Authors: DiMasi Joseph A. , Kaitin Kenneth I , Fernandez‐Carol Cecilia , Lasagna Louis
Published: March 2013

A survey of the U.S. pharmaceutical industry was conducted to obtain data on the length of the review process for supplemental indications of already‐approved new chemical entities (NCEs). Responses were received from 51 firms and covered supplemental indications of 348 NCEs that were approved during 1963 to 1988. Since extensive toxicity and safety evaluation would generally not be required for supplemental indication reviews, one would expect supplemental indications, on average, to be reviewed more quickly than applications for the associated original indications. The mean ± standard deviation review time for the 172 supplemental indications in the sample is 21.5 ± 18 months; the average review time for the associated 94 original indications is 23.5 ± 18 months. The difference in average review times is not statistically significant. Analysis of review times for indications grouped by Food and Drug Administration (FDA) reviewing division showed a statistically significant difference between supplemental and associated original indication review times only in the cardio‐renal division. In that division, average review times were longer for supplemental indications (25.6 vs. 19.3 mo; P < .05). Analysis of time trends showed a significant increase in average supplemental indication review time for 1985 to 1988 approvals relative to the average associated original indication review time (P < .01) and to average supplemental indication review time for earlier time periods (P < .01). These results suggest the need for a close examination of the supplemental indication review policy of the FDA.
Classification of the Antiarrhythmic Action of Moricizine
Authors: Williams E. M. Vaughan
Published: March 2013

The subdivision of class 1 antiarrhythmic agents into groups a, b, and c was originally based on clinical electrophysiologic findings. Class 1b compounds did not alter QRS or HV interval in sinus rhythm, but the compounds did lengthen ERP in spite of shortening JT. Class 1c agents widened QRS and prolonged HV at low concentrations in sinus rhythm, but had little effect on ERP or JT. Cellular electrophysiologic studies provided an explanation for these clinical effects by frequency‐dependent onset/offset kinetics. Class 1b drugs became rapidly attached to sodium channels after depolarization, which rendered them nonconducting, but the drugs also dissociated rapidly after repolarization so that by the end of a normal diastole nearly all channels were back to their conducting state. In contrast, class 1c drugs became more slowly attached, and more slowly detached, so that a proportion of sodium channels was permanently eliminated as long as the drug was present. This caused slow conduction in the His—Purkinje system and ventricle. Both clinical and cellular electrophysiologic studies show that moricizine HCl is a class 1c agent.
Mexiletine Versus Quinidine as First‐Line Antiarrhythmia Therapy: Results From Consecutive Trials
Authors: Frank Martin J. , Watkins Laurence O. , Prisant L. Michael , Smith Mark S. , Russell Steven L. , Abdulla Abdulla M. , Manwaring Roger L.
Published: March 2013

The efficacy of mexiletine and quinidine in controlling ventricular couplets (VC) and ventricular tachycardia (VT) was compared in 156 trials (78 for each drug) in 114 consecutive patients. Forty‐two patients received both drugs, whereas 36 patients were given mexiletine, and 36 patients received quinidine only. During acute drug testing, mexiletine was more effective than quinidine in controlling VC and VT (54 vs. 32 patients, respectively, P < .001) and resulted in fewer proarrhythmic events (4 vs. 13, respectively, P < .05). Mean duration of follow‐up for mexiletine (27 ± 14 mo) and quinidine (21 ± 14 mo) did not differ. Long‐term success was more frequent with mexiletine administration than quinidine administration (33/47 vs. 10/30 patients, respectively, P < .01). The incidence of sudden death during follow‐up with the two drugs did not differ overall, but more patients with ejection fraction ≥ 40% died suddenly while taking quinidine than while receiving mexiletine (4/17 vs. 0/24, P < .02). Mexiletine is as effective as quinidine for treating VC and VT and appears to be less proarrhythmic. It should be considered as an initial choice in the management of VC and VT.
Dose Proportionality of Moricizine After Escalating Multiple Doses in Healthy Volunteers
Authors: Benedek Irma H. , Garner Dennis M. , Pieniaszek Henry J.
Published: March 2013

This study was designed to determine the dose linearity and proportionality of moricizine after multiple‐dose administrations of 450 to 900 mg/day. The study design was an open‐label, four‐treatment, four‐period sequentials escalating dose. Twelve subjects each received multiple doses of 150, 200, 250, and 300 mg of moricizine every 8 hours during 7 days of treatment. Blood samples for pharmacokinetic determinations were obtained on day 7 of each treatment period during an 8‐hour time interval. Cmin determinations were also made on specific days of each treatment period. The AUCτ (area under the curve from time 0 to 8 hours), Cmax, and Cmin parameters were all normalized to the 250‐mg (750 mg/day) dose. No statistically significant differences were seen in these parameters at the four treatment levels. It was concluded that moricizine follows first‐order or linear pharmacokinetics after multiple dosing and exhibits dose proportional pharmacokinetics in the dosage‐range studies. This range corresponds to the clinically useful dosage range.
Assessment of Electrocardiographic Ischemia in Hypertensive Patients Treated with Isradipine or Placebo
Authors: Prisant L. Michael , Carr Albert A.
Published: March 2013

A total of 203 patients with hypertension (supine diastolic blood pressure of 100–119 mm Hg) from six centers entered into a 3‐week placebo baseline followed by 5 weeks of active treatment (either placebo or isradipine 2.5, 5, 7.5, or 10 mg BID) to determine the effectiveness of isradipine on blood pressure control. Electrocardiographic criteria for left‐ventricular ischemia were coded blindly using the Minnesota Codes 4‐1 to 4‐4 and 5‐1 to 5‐3 at the end of baseline and active treatment periods. One hundred seventy patients with hypertension and matching and complete electrocardiograms completed the study for analysis: 63 (37%) were white and 117 (69%) were men. They were 52.1 ± 10.3 years old mean ± SD; range: 22–77 years). No myocardial infarction occurred during the active phase. Fifty‐eight of 170 (34%) at baseline and 54 of 116 (32%) at week 5 had left atrial enlargement. Romhilt‐Estes left‐ventricular hypertrophy was not significantly different at baseline versus active treatment: 14 of 170 (8.2%) versus 15 of 170 (8.8%). At baseline, the rate of active ischemia was 28.2% (48/170); 27.8% (10/36) were randomized to receive placebo during active treatment and 28.4% (38/134) were given isradipine (P = NS). For those without ischemia at baseline, the rate of change to electrocardiographic ischemia during active treatment was 0% (0/26) for those receiving placebo and 3.1% (3/96) for those taking isradipine (P = NS). For those with ischemia at baseline, the rate of change to no ischemia during active treatment was 20% (2/10) for those receiving placebo and 10.5% (4/38) for those taking isradipine (P = NS). Overall, ischemia at baseline versus active treatment was: placebo (P = NS)‐27.8% (10/36) to 22.2% (8/36); and isradipine (P = NS)‐28.4% (38/134) to 27.6% (37/134). However, 3 of 96 patients without ischemia at baseline changed to ischemia while receiving isradipine. Such individuals should be investigated for epicardial coronary artery disease. In contrast, 4 of 38 patients with ischemia at baseline reverted to no ischemia while taking isradipine. The group that received isradipine and had good diastolic blood pressure control did not have more electrocardiographic ischemia.
Short‐Term Effects of Atenolol and Nifedipine on Atrial Natriuretic Peptide, Plasma Renin Activity, and Plasma Aldosterone in Patients with Essential Hypertension
Authors: Colantonio Domenico , Casale Raffaele , Desiati Piergiorgio , Giandomenico Gildo , Bucci Valter , Pasqualetti Paolo
Published: March 2013

The short‐term effects of atenonol and nifedipine on plasma levels of atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) were studied in two groups of patients with uncomplicated essential hypertension. Urinary catecholamines, and sodium and potassium excretion were also studied. A group of 20 patients with hypertension, after a wash‐out period of at least 10 days, was randomly subdivided into two protocol therapy subgroups. One group (six men and four women) received atenolol (100 mg/d), and the other group (six men and four women) received nifedipine (30 mg/d). Circulating plasma levels of ANP, PRA, and PA were determined by radioimmunoassay, and other variables were determined by routine laboratory techniques before therapy and at day 3 and day 7 after the treatment began. Arterial blood pressure and heart rate were monitored during the study. Both drugs reduced arterial blood pressure (P < .001) significantly. The atenonol therapy decreased heart rate (P < .001), increased plasma ANP levels and urinary catecholamine excretion, and decreased PRA and circulating PA levels. Nifedipine treatment did not modify plasma ANP values, whereas it increased PRA and PA circulating levels and urinary catecholamine excretion. No differences were shown for urinary volume, urinary sodium, and potassium excretions during the two different treatments. These findings suggest that the increased plasma ANP levels could contribute to the antihypertensive effects of the β‐adrenoreceptor blockers, by a reduction in PRA and PA levels and a vasodilatative effect. On the other hand, short‐term treatment with nifedipine increased PRA and PA circulating levels without modifying ANP values, which suggests that its hypotensive effects are not mediated by ANP.
Effects of Chronic Amantadine Hydrochloride Ingestion on Its and Acetaminophen Pharmacokinetics in Young Adults
Authors: Aoki Fred Y. , Sitar Daniel S.
Published: March 2013

The authors studied the effect of chronic amantadine ingestion on its own disposition and that of acetaminophen in five healthy young adults. The half‐life of amantadine after 42 days ingestion was 15.1 ± 2.3 hours and was not different from 14.8 ± 4.4 hours after an acute ingestion (mean ± SD). However, chronic amantadine ingestion was associated with an increased apparent volume of distribution for acetaminophen, 1.1 ± 0.1 L/kg compared with 0.9 ±0.1 L/kg, when the two drugs were concurrently ingested after a 2‐week washout period. This difference in kinetic distribution was not reflected in terminal acetaminophen half‐life, 149 ± 54 versus 151 ± 55 minutes for chronic and acute amantadine ingestion, respectively. Plasma acetaminophen clearance with chronic amantadine ingestion (5.8 ± 2.6 mL/min/kg) was not different from that determined after acute coingestion of both drugs (4.3 ± 1.1 mL/min/kg). Thus, no change in recommended dose is necessary when these two drugs are coingested.
Pharmacokinetics of Tranexamic Acid in Patients with Ulcerative Colitis and in Healthy Volunteers After the Single Instillation of 2 g Rectally
Authors: Almer Sven , Andersson Tommy , Ström Magnus
Published: March 2013

Topically applied antifibrinolytic drugs may be of value in the control of bleeding in active ulcerative colitis. Any impairment of systemic fibrinolysis in this condition, however, is potentially harmful. Since pharmacokinetic data after the rectal administration of tranexamic acid are non‐existent, plasma concentration and recovery in the urine were recorded after a single dose of 2 g tranexamic acid given rectally to five patients with ulcerative colitis and to five healthy volunteers. The median area under the curve was, for the volunteers, 7.64 mg/L × hr (range: 4.43–11.56) and, for the patients, 13.84 mg/L × hr (range: 9.32–50.22) (P <.05). The median 24‐hour recovery in the urine was 0.8% (0.3–1.1) and 2.7% (1.1–4.0), respectively (P <.05). The median peak plasma concentration was, for the volunteers, 0.40 mg/L (range: 0.20–0.69) 6 hours after administration and, for the patients, 1.10 mg/L (range: 0.53–2.90) 5 hours after administration (P <.05). The plasma concentrations and recovery in the urine that were observed in the patients and volunteers were low compaired with those seen after oral intake of the same dose. The plasma concentrations did not reach levels that were considered liable to impair systemic fibrinolysis.
Comparative Effects of Dopaminergic Agonists on Cardiovascular, Renal, and Renin‐Angiotensin Systems in Hypertensive Patients
Authors: Luchsinger Augusta , Velasco Manuel , Urbina Adalberto , Morillo Julio , Romero Eduardo , Alvarez Rolando , Pieretti Otto Hernandez
Published: March 2013

The role of dopaminergic receptors on renal junction has been extensively studied. Recently dopaminergic receptor has been classified in two subtypes D1 and D2, which seem to have different modulatory junction. However, the role of dopaminergic receptors on cardiovascular junction and more specifically the potential role of dopaminergic agonists as antihypertensive agents has not yet been clarified. Nine outpatients with mild and moderate hypertension were studied in the Cardiology Service of Vargas Hospital with a D1 agonist, piribedil, at 50–100 mg/day, orally, for 8 weeks, and with a D2 agonist, bromocriptine, at 2.5–5 mg/day, orally, for an another 8 weeks by using a placebo comparative crossover design. Piribedil reduced blood pressure with a modest increase in heart rate, plasma renin activity, and of plasma aldosterone, and an important increment of renal junction. Bromocriptine reduced blood pressure with a decrease in heart rate and plasma aldosterone without altering renal junction. There was no orthostatic hypotension with either agent. The authors conclude that activation of dopaminergic D1 receptor induces a vasodilatory and antihypertensive effect with a reflex increase in sympathetic tone, whereas activation of dopaminergic D2 receptor induces a decrease in sympathetic tone, probably due to a decrease in norepinephrine release at adrenergic endings. The potential effect of these compounds as antihypertensive agents is of great interest because blood pressure reduction can be induced by a new mechanism, i. e. activation of dopaminergic receptors which results in a decrease of the renin angiotensin system or a vasodilatory action. This study determined the cardiovascular actions of both dopaminergic agonists bromocriptine and piribedil and dejined the potential antihypertensive effect of these compounds; determined the influence of these compounds on the renin angiotensin system and the cardiovascular and renal systems; and defined drug tolerance.
An Evaluation of the Effect of Food on the Oral Bioavailability of Sustained‐Release Morphine Sulfate Tablets (ORAMORPH SR) After Multiple Doses
Authors: Bass Joeby , Shepard Kirk V. , Lee Jean W. , Hulse James
Published: March 2013

The effect of food on the oral bioavailability of sustained‐release morphine sulfate tablets (ORAMORPH SR; Roxane Laboratories, Inc., Columbus, OH; OSR) was examined in an open‐label, randomized, two‐period crossover study. Healthy male volunteers received a 30‐mg OSR tablet orally every 12 hours for seven doses during both the fasted and fed states. Dosing periods were separated by a 14‐day washout Volunteers in the fasted group received all doses either 2 hours before or after meals. Volunteers in the fed group received all doses immediately after meals. All meals were standardized. Serial blood samples were collected for analysis of plasma morphine concentration by radioimmunoassay. Pharmacokinetic parameters were calculated using plasma concentration data collected after the last dose at 72 hours of each dosing period. The two one‐sided t analysis indicated confidence intervals between 80% and 120% for maximum peak plasma concentration (Cmax), AUC72‐84hr, Cavg, and Cmin. The relative bioavailability of OSR administered after meals was 90.2% of that administered in the fasted state. As compared with the fasted condition, morphine bioavailability was essentially unchanged when multiple oral doses of 30‐mg OSR tablets were given after meals.