bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Pharmacodynamics of Intravenous Cibenzoline in Normal Volunteers
Authors: Brazzell Romulus K. , Khoo Ko‐Chin , Szuna Alice J. , Sandor Deborah , Aogaichi Keiko , Wills Robert J.
Published: March 2013

The pharmacokinetics of intravenous (IV) cibenzoline were studied in six healthy male volunteers ranging in age from 51 to 78 years. The subjects received intravenous (IV) cibenzoline 100 mg over 20 minutes, and plasma and urine specimens were collected for 48 hours. Cibenzoline plasma concentrations at the end of the infusion ranged from 730 to 1,420 ng/mL and exhibited triexponential decline thereafter. The following mean model independent pharmacokinetic parameters were calculated from the plasma and urine concentration data: terminal half‐life, 9.8 hours (range, 8.5–11.9); plasma clearance, 523 mL/min (range, 387–687); volume of distribution, 445 L (range, 328–506); and renal clearance, 289 mL/min (range, 202–334). Approximately 31% to 59% of the dose was recovered unchanged in the urine in 48 hours. A triexponential pharmacokinetic equation with zero order input was used to curve fit the plasma and urine data, and the model‐dependent parameters agreed well with the model‐independent estimates. A hysteresis loop was observed in the relationship between cibenzoline plasma concentration and QRS prolongation, indicating an initial lag between plasma concentration and effect after IV administration. Based on these results, the following preliminary dosing regimen was proposed to rapidly achieve and maintain therapeutic plasma concentrations equal to or slightly greater than 200–400 ng/mL: 0.25 mg/kg/min IV bolus over one minute followed by 1‐1.5 mg/kg/hr for one hour and 0.2‐0.4 mg/kg/hr for long‐term infusion.
Effect of Food on the Bioavailability of Pentopril, an Angiotensin‐Converting‐Enzyme Inhibitor, in Healthy Subjects
Authors: Rakhit Ashok , Hurley Margaret E. , Redalieu Elliot , Kochak Gregory , Tipnis Vijay , Coleman Jean , Rommel Alan
Published: March 2013

Pentopril (CGS 13945) was administered in 125‐mg capsules to eight healthy men on two occasions according to a randomized schedule; on one occasion in the fasting state and on the other occasion immediately following the ingestion of a standardized meal. Unlike captopril, a prototype angiotensin‐converting‐enzyme inhibitor, there was no significant difference in the peak plasma concentration for either the drug or its active metabolite (CGS 13934) between the fasting and the fed states. There was also no appreciable change in the area under the plasma curve for the drug and its metabolite after administration of drug in the presence of food compared with a fasting state. There was, however, a lag time in drug absorption after ingestion of food, which resulted in a significant increase in peak time for the active metabolite in plasma. Food delays the body's absorption of the drug and hence the appearance of its active metabolite in plasma without any significant effect on the relative bioavailability. Because relative bioavailability is not affected in the presence of food, such a delay may not have any therapeutic importance on chronic administration.
Nifedipine in the Treatment of Essential Hypertension
Authors: Gavras Irene , Gavras Haralambos
Published: March 2013

The antihypertensive efficacy of nifedipine as a second‐step drug in 24 patients, uncontrolled by a diuretic alone, was studied according to a double‐blind placebo‐controlled protocol. A significant blood pressure lowering was observed in nine out of 12 patients receiving the active drug and four out of 12 receiving placebo. Average mean blood pressure decreased by 13 ± 1 mm Hg in the active drug group versus 5 ± 3 mm Hg in the placebo group (P < .02). There were no consistent changes or significant differences in heart rate or in the levels of plasma renin activity and plasma catecholamines between the two groups. In conclusion, nifedipine appears to be a safe and effective antihypertensive agent when used in conjunction with a diuretic for the treatment of moderately severe hypertension.
Concomitant Therapy With Labetalol and Hydrochlorothiazide in Moderate to Moderately Severe Essential Hypertension
Authors: Kochar Mahendr S. , Tyson JoAnn , Kalbfleisch John H.
Published: March 2013

Labetalol is a competitive, nonselective antagonist of both beta1 and beta2 adrenoceptors. It has been suggested that labetalol reduces blood pressure (BP) predominately by decreasing peripheral vascular resistance while maintaining cardiac output. We conducted a double‐blind, randomized study to assess the antihypertensive effect of labetalol in patients with a standing diastolic blood pressure (SDBP) between 105 and 119 mm Hg. The study consisted of three separate phases in succession. Phase I was a single‐blind, placebo washout phase, two to four weeks in length. Those patients with a SDBP 105 mm Hg at the end of phase I entered phase II, in which they were administered labetalol in a forced titration of 100 mg bid to 400 mg bid. Those with a SDBP 90 mm Hg on the 400 mg bid regimen for two weeks were maintained on labetalol alone (N = 8). Those patients whose BP was not controlled (SDBP 90 mm Hg, N = 15) were randomized in a double‐blind fashion to receive either hydrochlorothiazide (HCTZ) or placebo in addition to labetalol for the next five weeks. Eight of the 15 patients received HCTZ and seven received placebo. The BPs at baseline and at the end of phase II were similar in the two groups. With the addition of HCTZ, the standing BP decreased (P < .01) from 146/102 ± (7/4) mm Hg to 125/89 ± (3/3) mm Hg and supine BP decreased (P < .01) from 151/101 ± (5/5) mm Hg to 136/90 ± (3/3) mm Hg (X̄ ± SEM). Placebo had no significant effect on BP. The SDBP was normalized (< 90 mm Hg) in four of the eight patients who received HCTZ as compared with one of seven who received placebo. Heart rate decreased significantly (P < .05) with labetalol and the addition of HCTZ had no effect on heart rate. We conclude that labetalol alone can normalize BP in approximately one third of hypertensive patients and that the addition of a diuretic can normalize it in another one third without significant side effects.
Pharmacokinetics of Ranitidine Following Oral Administration With Ascending Doses and With Multiple‐Fixed Doses
Authors: Garg Dyal C. , Eshelman Fred N. , Weidler Donald J.
Published: March 2013

The aim of these studies was to further delineate pharmacokinetic characteristics of ranitidine, a new histamine H2‐receptor antagonist In one study, ranitidine was administered orally to six normal men in increasing doses of 100 mg, 150 mg, 250 mg, and 400 mg weekly over a four‐week period. The peak serum concentrations increased with the corresponding increases in dose but the time needed to reach peak serum concentration did not vary significantly with increased doses. The pharmacokinetic parameters were calculated for each subject at each of the four dose levels. The total area under the curve (AUC) at the four different doses was linearly related to the dose for each individual subject; and a plot of AUC versus dose had a correlation coefficient of .886 (P < .001). The apparent plasma clearance did not vary with the increase in dose; and the average corrected clearance values ranged between 6.7 and 10 mL/(min × kg). Elimination half‐life was between 2.6 and 3.0 hours; and the volume of distribution (Vd area) was between 1.6 and 2.4 L/kg. About 35% of the ranitidine dose was excreted in the urine in the unchanged form over a 12‐hour excretion interval. In the second study, ranitidine was administered orally to 12 normal subjects in doses of 150 mg and 200 mg twice daily for 28 days. The pharmacokinetic parameters for ranitidine with multiple‐dose treatment were similar to those obtained with single‐dose administration. Predose ranitidine concentrations (trough levels) did not increase with multiple dose administration. These studies indicate that the pharmacokinetics of ranitidine are linear in the dose range of 100 mg to 400 mg, and were similar with both single‐ and multiple‐dose administrations.
The Pharmacokinetics of Doxylamine: Use of Automated Gas Chromatography With Nitrogen‐Phosphorus Detection
Authors: Friedman H. , Greenblatt D. J.
Published: March 2013

Sixteen healthy male volunteers received a single oral dose of 25 mg doxylamine succinate. Doxylamine concentrations in plasma were measured by a newly developed gas chromatographic methodology, utilizing direct alkaline extraction into hexane:isoamyl alcohol followed by concentration and autoinjection. Doxylamine kinetics were determined from multiple plasma doxylamine concentrations measured during the 24 hours postdose. Mean kinetic variables were: peak plasma level, 99 ng/mL; time of peak, 2.4 hours postdose; elimination half‐life, 10.1 hours; and apparent oral clearance, 217 mL/min. Analogous analytic methodology can be used to study the pharmacokinetics of other drugs of this class.
BOOK REVIEW
Authors: Cavaliere Beth
Published: March 2013

Book reviewed in this article:

Unstable Angina: A Clinical Approach by G. Plotnick

Second SCI‐RSC Medicinal Chemistry Symposium edited by J. C. Emmett

Chemistry of the Prostaglandins and Leukotrienes (Advances in Prostaglandin, Thromboxane, and Leukotriene Research, vol 14), edited by John E. Pike and Douglas R. Morton, Jr

Thymic Factor Therapy (Serono Symposia Publications from Raven Press, vol 16), edited by N. A. Byrom and J. R. Hobbs

Platelets, Prostaglandins, and the Cardiovascular System (Advances in Prostaglandin, Thromboxane, and Leukotriene Research, vol 13), edited by Gian G. Neri Serneri, John C. McGiff, Rodolfo Paoletti, and Gustav V. R. Born

Dual Regulation of Adenylate Cyclase (Advances in Cyclic Nucleotide and Protein Phosphorylation Research, vol 19), edited by Dermot M. F. Cooper and Kenneth B. Seamon

Serotonin and the Cardiovascular System edited by Paul M. Vanhoutte
Effect of Meals on the Kinetics of Etretinate
Authors: Colburn W. A. , Gibson D. M. , Rodriguez L. C. , Buggé C. J. L. , Blumenthal H. P.
Published: March 2013

Eight healthy men received 100 mg oral doses of etretinate separated by two‐week washout periods in an open, randomized, crossover study. Etretinate was administered during a complete fast, with a standard high fat breakfast, a standard high carbohydrate breakfast, and 16 ounces of whole milk. Plasma samples were obtained at specific times over a 48‐hour period. Plasma concentrations of etretinate as well as two of its major metabolites were determined by a specific, reverse‐phase, high‐performance liquid chromatography method. Plasma concentrations of etretinate were greater when administered with a high fat meal and whole milk compared to ingestion with a high carbohydrate meal or during a complete fast. In contrast, there was no increase in the plasma concentrations of the active metabolites following any of the meals. These data indicate that chronic dosing of etretinate with milk or a high fat meal compared with fasting conditions will result in higher concentrations of etretinate, which may ultimately lead to higher metabolite concentrations.
A Study of the Analgesic Potency of Indoprofen and Pentazocine in Postoperative Pain
Authors: Sartani Abraham , Papatheodossiou Nicolas , Parrinello Loredana , Mandelli Virginio
Published: March 2013

The relative potency of intravenous indoprofen and intramuscular pentazocine in postoperative pain was evaluated. Indoprofen was administered in 200‐ and 400‐mg single doses and pentazocine was given in 15‐ and 30‐mg doses. Pain was assessed at different time intervals, and additional medication consumption was recorded, as well as side effects and overall evaluations. An analysis of peak pain intensity difference (PID) has shown a significant dose‐effect relationship for both drugs and a potency ratio of 1:7 between indoprofen and pentazocine (mg to mg). Based on the frequency of patients requiring remedication and those reporting total pain relief in at least one instance, the potency ratio of indoprofen:pentazocine was 1:13 and 1:10, respectively. The mean peak PID of the pooled data for both doses of each drug was significantly greater for indoprofen. Intravenous indoprofen 400 mg was ranked the most effective overall.
Antihypertensive Effect of Carteolol in Thiazide‐Treated Hypertensive Subjects
Authors: Velasquez Manuel T. , Byrne Deborah , Hoffmann Raymond G.
Published: March 2013

The antihypertensive effect of carteolol, a new potent nonselective beta‐adrenergic antagonist, was investigated in a double‐blind, parallel study of 35 patients with mild‐to‐moderate, essential hypertension whose blood pressures were not adequately controlled with a diuretic. Patients were randomly assigned to receive placebo, carteolol 5 mg, or carteolol 20 mg once a day in addition to hydrochlorothiazide 50 mg for six weeks. Thirty‐four patients completed the study: 11 patients received placebo (group 1), 12 patients received carteolol 5 mg (group 2), and 11 patients received carteolol 20 mg (group 3). After six weeks of treatment, the two groups that received carteolol had significant reductions in systolic (SBP) and diastolic (DBP) blood pressure from baseline in both the supine and standing positions. In group 2, mean SBP decreases for supine and standing positions were 11 ± 2.1 and 11 ± 1.9 mm Hg, respectively (P < .01) and 8 ± 1.2 and 9 ± 1.3 mm Hg, respectively, for DBP (P < .01); whereas in group 3, values were 8 ± 2.8 and 12 ± 3.0 mm Hg for SBP, in 5 ± 1.9 and 9 ± 3.1 mm Hg, respectively, for DBP (P < .01). The hypotensive effect was associated with slight but significant decreases in heart rate (P < .01 in group 2 and P < .05 in group 3). Reductions in SBP and DBP with the 20‐mg dose were not significantly different from those with the 5‐mg dose. With both carteolol regimens, the fall in mean blood pressure did not correlate with the initial level; but in the group taking the 5‐mg dose, it did correlate significantly with the decrease in heart rate (r = .72, P < .01). Side effects attributable to carteolol were infrequent and did not persist during continued therapy. It is concluded that carteolol, when combined with hydrochlorothiazide, is effective in reducing blood pressure in patients with mild to moderate hypertension.
Tissue Distribution of Diazepam and Its Metabolite Desmethyldiazepam: A Human Autopsy Study
Authors: Friedman H. , Ochs Hermann R. , Greenblatt David J. , Shader Richard I.
Published: March 2013

Concentrations of diazepam (DZ) and desmethyldiazepam (DMDZ) were determined quantitatively in the brain, skeletal muscle, heart, liver, lung, fat, adrenal gland, and kidney in 14 autopsied patients who had been treated with DZ or clorazepate (a DMDZ prodrug) during their hospital course. To facilitate interpatient comparisons, all tissue concentrations from the same patient were normalized as ratios to the concentration of DZ or DMDZ found in that patient's skeletal muscle. Tissue uptake ratios were not influenced by gender or chronicity of dosage. Distribution equilibrium was reached in at least two hours. Tissue uptake ratios differed considerably among tissues for DZ and DMDZ. Mean (± SE) DZ uptake ratio was highest for adrenal gland (12.1 ± 5.9), liver (5.9 ± 1.9), heart (4.3 ± 1.0), and kidney (4.0 ± 1.0), with lower values for lung (2.1 ± 0.5), fat (2.2 ± 0.4), and brain (1.9 ± 0.4). Similar patterns were observed for DMDZ, except for significantly lower fat uptake. Extrapolating to an average body composition for a 70 kg man with 16% body fat, the largest fractions of total body stores of DZ would be found in muscle (42%), fat (35%), and liver (12%), with smaller stores in brain (4.3%), lung (3.3%), heart (1.7%), kidney (2.0%), and adrenal gland (0.24%).
Book Reviews
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Epilepsy and GABA Receptor Agonists: Basic and Therapeutic Research, (L.E.R.S. Monograph Series, Vol 3) edited by G. Bartholini, L. Bossi, K. G. Lloyd

Optimization of Drug Delivery: Alfred Benzon Symposium 17 edited by H. Bundgaard, A. B. Hansen, and H. Kofod
Clinical Pharmacokinetics of Suramin in Patients With HTLV‐III/LAV Infection
Authors: PhD Jerry M. Collins , Klecker Raymond W. , Yarchoan Robert , Lane H. Clifford , Fauci Anthony S. , Redfield Robert R. , Broder Samuel , Myers Charles E.
Published: March 2013

Suramin has been reported to inhibit the reverse transcriptase activity of a number of retroviruses and to reduce the in vitro infectivity and cytopathic effect of HTLV‐III/LAV, the etiologic agent of acquired immune deficiency syndrome (AIDS). The clinical pharmacokinetics of suramin were investigated as part of a pilot study to evaluate the safety and efficacy of this drug for the treatment of patients with diseases caused by HTLV‐III/LAV. A dose of suramin 6.2 g was given intravenously over a five‐week period to four patients. After the last dose, the plasma half‐life of suramin was 44 to 54 days. This is among the longest half‐lives reported for any therapeutic substance given to humans. Total plasma levels of suramin were greater than 100 μg/mL for several weeks. In vitro activity of suramin was found at concentrations as low as 50 μg/mL. Metabolites were not found in plasma, and urinary excretion accounts for elimination of most of the drug. Suramin is approximately 99.7% bound to plasma proteins. The results from these initial clinical pharmacokinetic studies might assist the design of further therapeutic trials of suramin, especially the selection of frequency of dosing and adjustments for renal impairment.
The Effect of Flecainide Acetate, a New Antiarrhythmic, on Plasma Digoxin Levels
Authors: Weeks Charles E. , Conard Gordon J. , Kvam Donald C. , Fox Jeanne M. , Chang Shaw F. , Paone Robert P. , Lewis George P.
Published: March 2013

The possible effect of oral flecainide acetate on steady‐state digoxin levels was assessed in 15 healthy men. Each volunteer received digoxin 0.25 mg daily (8 am) for 22 consecutive days and flecainide 200 mg bid (8 am and 8 pm) on days 11 through 15. Plasma digoxin and flecainide levels were measured by radioimmunoassay and gas‐liquid chromatography methods, respectively. Flecainide levels were within the range associated with suppression of premature ventricular contractions in patients. Mean plasma digoxin levels just before the 8 am dose were 0.46 ng/mL on days 9 and 10 (baseline), 0.57 ng/mL (P < .05) on day 13, and 0.49 ng/mL (not significant [NS]) on day 15. Compared with a mean six‐hour postdose baseline digoxin level of 0.58 ng/mL, postdose levels were 0.62 ng/mL (NS) and 0.65 ng/mL (P < .05) on days 13 and 15, respectively. On an average for each subject, predose and six‐hour postdose digoxin levels increased by 24 ± 35% and 13 ± 19%, respectively, during coadministration. The changes in electrocardiographic intervals and vital signs that occurred during concomitant drug administration were not clinically significant although a slight prolongation of the PR interval was noted in some subjects. Unless plasma digoxin levels are in the upper end of the therapeutic range, changes in magnitude as observed in this study should be clinically inconsequential for most patients.
Effect of Celiprolol, a New Beta1‐Alpha2 Blocker, on the Cardiovascular Response to Exercise
Authors: Caruso Frank S. , Berger Bruce M. , Darragh Austin , Weng Teng , Vukovich Robert
Published: March 2013

The pharmacodynamics of beta blockade with single oral doses of celiprolol 200 and 400 mg, compared with placebo, atenolol 50 and 100 mg, propranolol 80 and 160 mg, metoprolol 100 and 200 mg, and pindolol 5 and 10 mg, were evaluated in an open, incomplete‐block study design employing 11 healthy male volunteers. Each subject received five of the 11 possible treatments at weekly intervals. The maximal rate‐pressure product (RPP) induced by standardized treadmill exercise was measured 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after each treatment. During the course of the exercise test, heart rate and systolic blood pressure were recorded at one‐minute intervals for five minutes. The maximal RPP, heart rate, and the maximum change from baseline were calculated for each exercise period. The data were analyzed using absolute reduction and percentage reduction of these parameters. All of the beta blockers tested produced significant decreases (P < .05) in the exercise RPP, ranging from 16% reduction for celiprolol 200 mg to 47% reduction for propranolol 160 mg at peak response. Celiprolol 400 mg reduced the RPP by 31% at peak effect and did not differ significantly from the other treatments. Celiprolol 400 mg and atenolol 100 mg were the only agents that significantly reduced the RPP 24 hours posttreatment (20.7% and 21.7%, respectively) compared with placebo. Celiprolol 400 mg was the only agent to significantly reduce exercise heart rate 24 hours posttreatment (26.6 beats, P < .05). Pharmacodynamic half‐lives, calculated by means of linear regression analysis using absolute reduction of RPP, ranged from 13.2 hours for propranolol 80 mg to 24.1 hours for celiprolol 400 mg. Thus, celiprolol appears to have pharmacologic duration of effect in excess of its plasma elimination half‐life, and should be suitable for once‐daily administration in patients.
Enalaprilat in Hypertensive Emergencies
Authors: Strauss Ruth , Gavras Irene , Vlahakos Demetrios , Gavras Haralambos
Published: March 2013

Enalaprilat (MK‐422), an intravenously administered angiotensin‐converting enzyme inhibitor, which is the parent compound of the oral angiotensin‐converting enzyme inhibitor enalapril (MK‐421), was studied in 11 patients with asymptomatic accelerated hypertension. Each patient received an initial intravenous dose of 1 mg, followed at one‐hour intervals by enalaprilat 10 mg, furosemide 40 mg, and enalaprilat 40 mg. Six of 11 patients responded with a drop in mean arterial pressure > 15 mm Hg to diastolic levels below 110 mm Hg; there were four partial responders and one nonresponder. Pretreatment renins were not predictive of blood pressure response. No patient had any adverse reaction to the drug; there were no significant changes in posttreatment laboratory values. We conclude that enalaprilat is an effective, well‐tolerated agent for the treatment of uncomplicated accelerated hypertension and its use does not imperil nonresponding uncomplicated patients.
Metabolism and Urinary Excretion of Esmolol in Humans
Authors: Achari R. , Drissel D. , Matier W.L. , Hulse J.D.
Published: March 2013

The urinary excretion patterns of esmolol, a short‐acting beta blocker, and its major metabolite were investigated in eight healthy men after intravenous infusion of 50, 100, 200, and 300 μg/kg/min of esmolol for six hours and 150 μg/kg/min for 24 hours. Esmolol and the metabolite concentrations in urine were determined by high‐performance liquid chromatography. The mean urinary recoveries of the unchanged drug were 0.64%, 0.67%, 0.69%, 0.77, and 0.98% after the 50, 100, 150, 200, and 300 μg/kg/min dose, respectively. Recovery of the metabolite was independent of dose, and the overall mean recovery accounted for 73% of administered dose. The results of this study indicate that esmolol is extensively metabolized, and the extent of the metabolism is not dose related in the dosage range used. The renal route plays a very minor role in the elimination of the drug but is important for the elimination of the metabolite.
Trimoprostil Plasma Concentration‐Gastric Acid Inhibition Relationships in Duodenal Ulcer Patients
Authors: Wills Robert J. , O'Leary Ann , Givens Samuel V. , Scheinbaum Monte L.
Published: March 2013

The effect of single 0.25 mg, 0.75 mg, 1.5 mg, and 3.0‐mg oral doses of trimoprostil and placebo on the inhibition of meal‐stimulated gastric acid secretion was investigated in duodenal ulcer patients. Drug and placebo were administered in a double‐blind, randomized, crossover study under fasting conditions. A bactopeptone meal was administered 30 minutes after dosing. Gastric acid output was measured by intragastric titation (pH 5.5) and trimoprostil plasma concentrations were measured by a specific gas chromatography‐negative chemical ionization‐mass spectrometric method. Meal‐stimulated gastric acid secretion was significantly reduced when compared to placebo for one hour after 0.25 mg, 1.5 hours after 0.75 mg, and for 2.5‐3.0 hours after both 1.5 mg and 3.0 mg doses. The maximal inhibition of gastric acid ranged from 65% reduction after 0.75 mg to 74% after 1.5 mg to 82% after 3.0‐mg doses. Trimoprostil was rapidly absorbed and eliminated; terminal elimination half‐life ranged from 21 to 45 minutes. Both maximum concentration and area under the plasma concentration‐time curve increased proportionately with an increase in the dose. The concentration‐effect data at a given dose were simultaneously fit to a pharmacokinetic/pharmacologic effect model. An IC50 (plasma concentration needed to elicit a 50% inhibition effect) value of 0.2 ng/mL was observed at doses of 0.75 mg to 3.0 mg. Overall, trimoprostil was effective in inhibiting acid output in a dose‐related manner in duodenal ulcer patients.
Influence of Food on Midazolam Absorption
Authors: Bornemann Larisa D. , Crews Theodore , Chen Susan S. , Twardak Stefan , Patel Indravadan H.
Published: March 2013

The influence of food on the absorption of midazolam, a new benzodiazepine derivative, was investigated in 18 healthy volunteers in a four‐way, randomized, crossover study with a one‐week washout period between treatments. Single 15‐mg oral doses of midazolam were administered one hour before, with, and one hour after a standard meal as well as under fasting conditions (control). Following serial blood sampling over the next 24‐hour period, midazolam plasma concentrations were determined by gas chromatography and mass spectrometry for pharmacokinetic evaluation. The maximum plasma concentration (Cmax), time of maximum concentration (tmax), lag time prior to absorption (tlag), area under the plasma concentration‐time curve (AUC), and elimination rate constant of midazolam and 1‐hydroxymethylmidazolam were determined. Significant changes in these parameters were not found when midazolam was taken one hour before or with a meal as compared with the control condition. Significant changes in the Cmax, tmax, and AUC parameters for both midazolam and its metabolite were seen when midazolam was ingested one hour after a meal: There was a delayed and reduced rate of absorption as well as a small reduction in the extent of absorption. Thus, ingestion of midazolam within one hour after a meal may result in a delay in the onset of the pharmacologic effect These changes may be of some clinical significance in that they may potentially delay the onset of sleep.
The Pharmacokinetics of Alfentanil in Gynecologic Surgical Patients
Authors: Reitz Jeffrey A. , Howie Michael B. , Hoffer Lee , Kryc Joseph , MacKichan Janis J.
Published: March 2013

The pharmacokinetics and serum protein binding of alfentanil during continuous intravenous infusion were determined in 11 women who were either healthy (American Society of Anesthesiologists [ASA] physical status 1) or had mild systemic disease (ASA physical status 2). Anesthesia was induced with intravenous thiopental 2 mg/kg and alfentanil 50 μg/kg and maintained with constant intravenous alfentanil infusions of 1–3 μg/kg/min until approximately ten minutes before the end of surgery. Venous blood samples were obtained after the bolus of alfentanil was administered and at various times during and after the alfentanil infusion. Serum alfentanil concentrations were measured by gas‐liquid chromatography. There was considerable interpatient variability in alfentanil pharmacokinetics and serum protein binding. The mean ± SD alfentanil serum clearance, volume of distribution at steady state (Vss), and elimination half‐life were 5.2 ± 2.0 mL/min/kg, 0.47 ± 0.1 L/kg, and 97 ± 52 minutes, respectively. The mean fraction of alfentanil unbound in serum (fu) was 0.18 ± 0.08. There was a time‐dependent decrease in alfentanil serum clearance that correlated with increasing duration of surgery. This decrease in clearance resulted in a prolonged alfentanil half‐life. These results indicate there is considerable interpatient variability in the pharmacokinetic parameters and serum protein binding of alfentanil in these patients and suggest that the infusion rate of alfentanil during maintenance anesthesia should be adjusted for individual patient response. Infusion rates may need to be tapered during prolonged operations.
Ibuprofen Kinetics In Plasma and Synovial Fluid of Arthritic Patients
Authors: Gallo J.M. , Gall Eric P. , Gillespie W.R. , Albert K.S. , Perrier Donald
Published: March 2013

After administration of a single dose and at steady state, ibuprofen concentrations were measured simultaneously in plasma and synovial fluid obtained from eight patients with rheumatoid arthritis. By seven hours after a dose at steady state, the mean synovial fluid: plasma ibuprofen concentration ratios were constant, and the synovial fluid levels were, on average, greater than those in plasma. The extent to which ibuprofen was bound to protein was somewhat greater in plasma than in synovial fluid. As a result, the mean synovial fluid:plasma free concentration ratio for seven‐hour and later specimens was greater than that based on total concentrations. The degree of accumulation of ibuprofen in each fluid was minimal, consistent with its short half‐life.
Verapamil Pharmacodynamics After Intravenous and Oral Dosing: Theoretic Consideration
Authors: Colburn Wayne A. , Brazzell Romulus K. , Holazo Alice A.
Published: March 2013

Differences in the potency of intravenous (IV) and oral verapamil have recently been reported with the concentration‐response curve for PR‐interval prolongation being shifted further to the right following oral administration relative to IV administration. Using well‐established pharmacokinetic models, a theoretic basis for these observations is presented. Simultaneous curve fitting of the IV and oral verapamil plasma concentration and PR‐interval data to a single pharmacokinetic‐pharmacodynamic model allowed prediction of differences in the pharmacodynamic potency of verapamil as a function of the rate of drug administration. These data indicate that the rate of input of drug into the systemic circulation can influence the rate and extent of entry of drug into an effect compartment, which in turn can result in different plasma concentration‐response relationships.
Factors Associated With Nephrotoxicity and Clinical Outcome in Patients Receiving Amikacin
Authors: Williams Paul J. , Hull J. Heyward , Sarubbi Felix A. , Rogers John F. , Wargin William A.
Published: March 2013

Data from 60 patients treated with amikacin were analyzed for factors associated with nephrotoxicity. In 42 of these patients, data were examined for factors associated with clinical outcome. Variables evaluated included patient weight, age, sex, serum creatinine level, creatinine clearance, duration of therapy, total dose, mean daily dose, organism minimum inhibitory concentration (MIC), mean peak levels, mean trough levels, mean area under the serum concentration‐time curve (AUC), total AUC, mean AUC > MIC, total AUC > MIC, mean Schumacher's intensity factor (IF), total IF, and ln (mean maximum concentration [Cmax]/MIC). Model‐dependent pharmacokinetic parameters were calculated by computer based on a one‐compartment model. When the parameters were examined individually, duration of therapy and total AUC correlated significantly (P <.05) with nephrotoxicity. In contrast, a stepwise discriminant function analysis identified only duration of therapy (P < .001) as an important factor. Based on this model and on Bayes' theorem, the predictive accuracy of identifying “nephrotoxic” patients increased from 0.17 to 0.39. When examined individually, mean IF, MIC, total dose, mean daily dose, and ln (mean Cmax/MIC) correlated significantly (P < .05) with cure. In contrast, a simultaneous multivariable analysis identified IF, MIC, and total dose according to one model and ln (mean Cmax/MIC) according to a second statistical model of parameters selected to have the greatest prospective value. Based on Bayes' theorem and the first model, the predictive accuracy of identifying patients not cured increased from 0.19 to 0.83. For the second model, the predictive accuracy increased from 0.19 to 0.50. These findings may assist clinicians in improving cure rates while minimizing the occurrence of nephrotoxicity.
Protein Binding and Pharmacokinetics of Lincomycin Following Intravenous Administration of High Doses
Authors: Gwilt P. R. , Smith R. B.
Published: March 2013

High‐dose infusions of lincomycin 600, 1,200, and 2,400 mg were administered to 14 healthy, adult men. Using model‐independent pharmacokinetics, it was found that the half‐life, mean residence time, and steady‐state volume of distribution of total drug increased with dose, whereas the same parameters remained unchanged for the unbound lincomycin. Although the mean clearance value for total drug increased, this change fell short of being significant at the 5% level and was associated with a decrease in unbound clearance following administration of the 2,400 mg dose. Protein binding studies using ultrafiltration gave direct evidence of saturable serum protein binding and indicated that binding involved at least two distinct classes of binding sites.
Attenuation of Protection With Repeated Cromolyn Dosing Before Exercise Challenge in Subjects With Asthma
Authors: Brooks Carter D. , Nelson Amy L. , Metzler Carl
Published: March 2013

Though cromolyn sodium exhibits tachyphylaxis in laboratory models of allergy, this pattern has not been identified in clinical use or in human asthma provocation models. We looked for it using a treadmill exercise challenge scheme that had previously confirmed cromolyn's protective effect. Twelve exercise‐sensitive asthmatic volunteers received in random order, 12 20‐mg cromolyn inhalations, 12 placebo inhalations, and 11 placebo inhalations with a final 20‐mg dose of cromolyn. Each regimen was given over a three‐day period, with the final dose administered 30 minutes before exercise. Subjects' respiratory functions were measured before and repeatedly after exercise with body plethysmography and peak flow rates. Beginning six minutes after the end of exercise, parameters measured after single‐dose cromolyn and placebo administration differed in all endpoints at most of the measurement intervals. Results with 12‐dose cromolyn pretreatment were significantly different from those seen with placebo only at 40 minutes after exercise, whereas single‐ and multiple‐dose cromolyn results differed at 20 and 30 minutes. Cromolyn accelerated recovery from exercise‐induced falls in lung function; this effect was attenuated with multiple dosing. These results are consistent with development of tachyphylaxis.
Effects of Ranitidine and Cimetidine on Plasma Lipoproteins in Healthy Subjects
Authors: Howden C. W. , Fletcher C. D. , Farish E. , Reid J. L.
Published: March 2013

Serum lipoproteins were monitored in 24 healthy subjects receiving either ranitidine or cometidine for four weeks. Ranitidine produced a significant (P < .05) reduction in high‐density lipoprotein (HDL)‐cholesterol in both men and women. Cimetidine caused a nonsignificant increase in HDL‐cholesterol and a reduction in LDL‐cholesterol that was significant (P < .05) only in women. As these drugs had opposite effects on HDL‐cholesterol levels, the mechanism of action is unlikely to be medicated by H2‐receptor blockade.
Effects of Low‐Dose Aspirin on Responses to Furosemide
Authors: Wilson Thomas W. , McCauley Frances A. , Wells Holly D.
Published: March 2013

We assessed the effects of low‐dose aspirin (0.5 and 15 mg/kg/d) on renal prostaglandin synthesis and action in healthy volunteers using intravenous furosemide as a stimulus. Inhibition of platelet cyclo‐oxygenase was assessed by changes in serum thromboxane B2 (TXB2) level. After one week of treatment, ten healthy subjects did not show any change in weight, blood pressure, or diuretic and natriuretic responses to furosemide with either dose of aspirin. Serum TXB2 level was reduced to 3% of control by aspirin 0.5 mg/kg/d and to 0.1% by the higher dose. In contrast, urine excretion of TXB2 was only reduced to 68% and 51% of the placebo value, whereas 6‐keto‐prostaglandin F1α (6kPGF1α) excretion was not decreased by either dose. Furosemide produced a transient increase in excretion rates of TXB2 and 6kPGF1α that was of lesser duration than the diuretic response. These transient increases were slightly reduced by aspirin. Baseline plasma renin activity was not affected by either dose of aspirin. The brisk increment in plasma renin activity seen ten minutes after furosemide, as well as later values (30 and 240 min) were not changed by aspirin. We conclude that chronic low‐dose aspirin can profoundly affect platelet PG production without affecting stimulated renal PGI2 production or plasma renin activity. There is a modest reduction in urine TXB2 excretion that is consistent with a primarily renal source of this metabolite.
Comparative Efficacy Study of Chewable Aspirin and Acetaminophen in the Antipyresis of Children
Authors: Walker Paul C. , Helms Richard A. , Wall Hershel P. , Jabbour J.T.
Published: March 2013

Aspirin and acetaminophen are the most widely used antipyretics in pediatrics. Most clinicians believe the drugs to be equally effective, though clinical opinion often suggests that aspirin is more effective at higher temperatures. Fifty‐nine outpatients (age range, 2–8 years), presenting with rectal temperatures of 38.8 to 40.5°C, were enrolled in this double‐blind trial. The children were stratified by weight and initial temperature. One dose of chewable aspirin or acetaminophen (10–15 mg/kg based on current recommendations for weight) was administered, and rectal temperatures were monitored for three hours. Of the 59 patients enrolled, 46 successfully completed the protocol. Both drugs significantly reduced temperatures in the groups studied. Age did not influence the response of the children to the antipyretic effects of either drug. Aspirin and acetaminophen appeared equally effective when initial temperatures were between 38.8 and 39.9°C. However, when the initial temperature was between 40.0 and 40.5°C, the duration of effect of acetaminophen was shorter than that for aspirin. This suggests that therapeutic differences in the antipyretic activities of aspirin and acetaminophen may exist at higher temperatures.
Oral Ciramadol: A New Analgesic for Postoperative Pain
Authors: Reines H. David , Hunt Peggy , Rambo William , Loadholt C. Boyd
Published: March 2013

Ciramadol a new synthetic narcotic agonist‐antagonist analgesic, was compared in 30 and 60 mg doses with pentazocine 50 mg, aspirin 650 mg, and placebo in the treatment of 153 patients with postoperative pain. All drugs were administered between six and 72 hours after surgery. Analgesic efficacy was assessed for six hours after study drug administration using verbal pain intensity, analog pain intensity, and verbal pain relief scales. Significantly (P < .05) higher analgesic efficacy scores were seen with ciramadol 30 mg than with pentazocine 50 mg and placebo at most of the evaluation points. Doses of ciramadol 30 mg were significantly (P < .05) more effective than aspirin 650 mg at several time periods, and ciramadol 60 mg was better than pentazocine and placebo at several evaluation times. The 30‐mg dose of ciramadol was generally more effective than the 60‐mg dose. The mean six‐hour cumulative sum of pain intensity difference scores, total pain relief scores, and sum of pain analog intensity difference scores showed that the best analgesic response occurred in the ciramadol 30 mg group, followed by the ciramadol 60 mg, aspirin 650 mg, pentazocine 50 mg, and placebo groups. Side effects were rare and mild. There were no medically important changes in vital signs in any treatment group.
Enhancement of the Antiemetic Action of Metoclopramide Against Cisplatin‐Induced Emesis by Transdermal Electrical Nerve Stimulation
Authors: Saller Reinhard , Hellenbrecht Dieter , Bühring Malte , Hess Helmut
Published: March 2013

In a double‐blind sequential trial, the influence of transdermal electrical nerve stimulation (TENS) was studied in patients who were treated with total infusions of metoclopramide 3.5 mg/kg to counter the emetic action of cisplatin 60–90 mg/m2. Transdermal electrical nerve stimulation further reduced the emetic episodes in ten of 11 treatment pairs (2α = .10). This effect was blocked by naloxone. More surprisingly, TENS reduced the incidence of extrapyramidal effects of metoclopramide (i.e., akathisia and dystonia). These effects may be explained by the involvement of central nervous and peripheral TENS‐induced production of opioid neuromodulators. An alternate hypothesis is the stimulation of serotonergic mechanisms via neuromodulation by opioid peptides, or by involvement of both systems.
Temporal Variation in Triazolam Pharmacokinetics and Pharmacodynamics After Oral Administration
Authors: Smith Randall B. , Kroboth Patricia D. , Phillips J. Paul
Published: March 2013

The effect of time of day of drug administration on triazolam pharmacokinetics was studied in ten healthy men. In a randomized, two‐way, crossover investigation, each subject received one 0.5 mg triazolam tablet either in the morning (7am) or evening (10 pm). Blood samples were obtained immediately before dosing and at selected times up to 12 hours after dosing. Triazolam plasma concentrations were determined by gas chromatography with electron capture detection. Psychomotor performance tests, including digit symbol substitution, card sorting by suits, and card sorting by fours, were administered, and the subjects' sedation was rated before drug and at two, ten, and 12 hours after drug administration. In addition, anterograde amnesia was assessed by showing objects to subjects two hours after dosing and testing aided and unaided recall at ten hours following administration. Triazolam's apparent elimination half‐life after evening administration was significantly longer than after daytime ingestion (3.77 hr vs. 2.94 hr, P < .05). There was no difference between times of dosing in total oral clearance or apparent volume of distribution. The absorption of triazolam was slower after evening administration, with an absorption half‐life of 21.9 vs 13.3 minutes after daytime dosing. Performance decrements were significantly greater two hours after dosing in evening than in the daytime, but anterograde amnesia was more pronounced after daytime dosing. There was no effect on psychomotor performance at ten or 12 hours after administration in daytime or evening. These results indicate temporal variation in triazolam absorption and elimination. However, the previously documented efficacy triazolam in reducing sleep latency and the lack of performance defects at ten hours after dosing indicate that these effects are not clinically significant.
Pharmacokinetics of Cibenzoline After Single and Repetitive Dosing in Healthy Volunteers
Authors: Massarella Joseph W. , Khoo Ko‐Chin , Szuna Alice J. , Sandor Deborah A. , Morganroth Joel , Aogaichi Keiko
Published: March 2013

Twenty‐five healthy, adult male volunteers entered two open‐label parallel studies, each designed to define the pharmacokinetics of single and multiple oral doses of cibenzoline. Each volunteer received a single 160‐mg oral dose of cibenzoline followed two or three days later by 160 mg of cibenzoline q12h for seven days. Plasma concentration‐time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for unchanged drug. The apparent half‐life following administration of the last dose (9.7 hours) was slightly longer than that observed after the first dose (8.4 hours). Total body clearance and nonrenal clearance were decreased after the last dose compared with the first dose, whereas renal clearance was not significantly altered. After both the first and last dose, the renal clearance greatly exceeded the glomerular filtration rate, suggesting that tubular secretion participates in the renal excretion of cibenzoline. Plasma concentrations from samples collected during the multiple‐dose regimen suggest that a slight but statistically significant diurnal variation in the absorption and/or clearance of drug occurred during the course of the study. Overall, the pharmacokinetics of cibenzoline are characterized by a slightly longer half‐life during multiple dosing than that observed following a single dose, due to a decrease in the nonrenal clearance. The multiple‐dose pharmacokinetics reported herein are consistent with bid dosing for the maintenance of therapeutic plasma concentrations in patients taking chronic therapy.
Tolerance and Pharmacology of Ciprostene, a Stable Epoprostenol (Prostacyclin) Analogue in Humans
Authors: Linet Otto I. , Nishizawa Edward E. , Schaub Robert G. , VanderLugt James T. , Greenwald Cynthia A.
Published: March 2013

Safety, tolerance, and pharmacology of 9‐beta‐methylcarbacyclin calcium (ciprostene calcium) was investigated in healthy male volunteers. This stable prostacyclin analogue was infused intravenously into groups of 12, 11, and three volunteers for three, six, and eight hours, respectively, in doses up to 480 ng/kg/min. Based on the tolerance data obtained, a single‐blind, placebo‐controlled study was conducted. Seven subjects were infused for 8 hr/d for three days with ciprostene at a maximum dose of 160 ng/kg/min and seven subjects received placebo. One subject from each group did not complete the infusion schedule, and they were not included in the final analysis. During infusion of ciprostene, consistent changes in blood pressure and heart rate did not occur. Most frequent adverse drug reactions consisted of headache, restlessness, nausea, perspiration, flushing, and jaw pain. As compared with placebo, ADP‐induced platelet aggregation was inhibited during the infusion period (P = .048). Significant (P = .04) elevations of platelet cyclic AMP were observed in subjects during infusion of ciprostene. Pre‐ versus postinfusion routine laboratory evaluations, fibrinogen concentration, antiplasmin activity, and plasminogen and template bleeding times remained unchanged. Placebo‐ and drug‐treated subjects had a daily postinfusion shortening of euglobulin clot lysis time (ECLT). The preinfusion minus postinfusion ECLT for ciprostene subjects on days 2 and 3 (133 and 118 min, respectively) compared with placebo (239 and 217 min) suggest a trend to increased fibrinolytic activity. Based on the outcome of this trial, it is estimated that ciprostene is about 15 times less potent than prostacyclin. A safe and well‐tolerated dose of ciprostene in healthy subjects is 120 ng/kg/min given for 8 hr/d. Further investigation of ciprostene in patients with thrombotic disorders is warranted.