bluuebunny/crossref_metadata_2025 huggingface dataset:
Buprenorphine and Morphine Efficacy in Postoperative Pain: A Double‐Blind Multiple‐Dose Study
Authors: OUELLETTE ROBERT D.
Published: March 2013

Abstract: The analgesic activity of buprenorphine was monitored versus that of morphine in a double‐blind, randomized, multiple‐dose, parallel‐design study involving 97 postsurgical patients. Patients could receive intramuscular injections of either buprenorphine (0.3, 0.45, or 0.6 mg) or morphine (10, 15, or 20 mg) every 3 or more hours. Pain intensity, degree of sedation, vital signs, pain relief, and side effects were assessed prior to and at regular intervals after each drug injection. No statistically significant differences were found between the two drugs in total pain relief, sum of pain intensity difference by patient and over time, time to peak pain intensity difference, duration of pain, and side effects. It has been suggested that the addictive potential of buprenorphine may be less than that of morphine. Since both drugs seem to be effective analgesics, buprenorphine appears to offer an effective and safe alternative to morphine for patients with acute pain.
Pharmacokinetics of Hydroxyethyl Starch in Normal Subjects
Authors: YACOBI AVRAHAM , STOLL ROGER G. , SUM CHECK Y. , LAI CHII‐MING , GUPTA SURINDER D. , HULSE JAMES D.
Published: March 2013

Abstract: To determine the elimination of high‐molecular‐weight hydroxyethyl starch (HES, Mw 450,000) in normal subjects, ten volunteers were given 500 ml 6% HES solution by intravenous infusion, and serial blood and urine samples were collected for nonglucose total carbohydrate determination. On the average, 46 and 64 per cent of the dose was excreted in the urine within two and eight days, respectively. The plasma concentration declined rapidly during the first week after infusion. The average terminal half‐life was 17 days during the first 42 days, which accounted for elimination of about 90 per cent of the dose. The remainder was eliminated with a terminal half‐life of 48 days determined between days 42 and 83 of the study. As expected, the infusion of HES resulted in plasma volume expansion over a 48‐hour period during which time levels of nonglucose carbohydrates were above 3.5 mg/ml. HES is metabolized by α‐amylase in the body. During the first 48 hours after infusion of HES, plasma α‐amylase activity was significantly increased over control. Concomitantly, α‐amylase activity in urine was also elevated but not significantly so.
Comparison of Three Doses of Oral Ciramadol and Placebo for the Treatment of Moderate to Severe Postoperative Pain
Authors: FRAGEN ROBERT J. , CALDWELL NANCY J.
Published: March 2013

Abstract: Ciramadol, 20, 40, or 60 mg, or a placebo was administered orally, double blind, to patients complaining of moderate (N = 89) or severe (N = 80) postoperative pain to determine the lowest effective dose. The highest dose used for moderate pain, 40 mg, was statistically more effective than placebo as measured by pain intensity differences and pain relief scores. The highest dose used to treat severe pain, 60 mg, was also more effective statistically than placebo and the lower doses of ciramadol at certain points during the 6‐hour observation period. Drowsiness was minimal, and side effects were infrequent and mild in intensity. We conclude that 40 mg ciramadol for moderate postoperative pain and 60 mg ciramadol for severe postoperative pain would be the minimal oral doses to compare with standard analgesics in future studies.
Disposition of Zomepirac Sodium in Man
Authors: O'NEILL PATRICK J. , YORGEY KARL A. , RENZI NED L. , WILLIAMS ROGER L. , BENET LESLIE Z.
Published: March 2013

Abstract: Five healthy male human subjects were administered 200 mg oral solution doses of zomepirac‐14C sodium. Plasma and urine samples were analyzed for zomepirac, hydroxyzomepirac, and zomepirac glucuronide. Zomepirac was the major circulating compound, with zomepirac glucuronide and hydroxyzomepirac accounting for the remainder of the radioactivity. Elimination half‐lives for zomepirac, zomepirac glucuronide, and hydroxyzomepirac were 7.6, 8.2, and 7.8 hours, respectively. The dose was completely recovered in the urine (95 per cent in 72 hours). Zomepirac glucuronide constituted up to 90 per cent of the urinary radioactivity, with zomepirac and hydroxyzomepirac about 5 per cent each. The urinary zomepirac was probably present as a result of hydrolysis of zomepirac glucuronide. The plasma clearance of zomepirac was 189 ± 23 ml/min. The metabolites were cleared by the kidney at rates of 343 ± 88 ml/min (zomepirac glucuronide) and 339 ± 88 ml/min (hydroxyzomepirac). Thus, metabolic clearance appears to be the sole mode of zomepirac elimination. The metabolites are then rapidly cleared by the kidneys.
Selecting Drug Combinations for Treatment of Drug‐Resistant Mycobacterial Diseases
Authors: NASH DONALD R. , STEINGRUBE VINCENT A.
Published: March 2013

Abstract: Mixtures of antituberculosis drugs were evaluated for their in vitro effects on drug‐resistant isolates of Mycobacterium tuberculosis and M. avium‐intracellulare. The response of individual isolates to representative drug combinations was not always predictable from the results of single‐drug sensitivity assays. For the case of M. tuberculosis, combinations of drugs were often bactericidal even under conditions where two or more drugs were without effect when tested singly. The more widely drug‐resistant M. avium‐intracellulare demonstrated increased growth inhibition when subcultured in the presence of single drugs, particularly rifampin and streptomycin. However, these conditions favored the selection of highly resistant strains. Alternatively, multiple drugs were often bacteriostatic; and under conditions where isolates demonstrated growth inhibition, the selection of highly drug‐resistant strains was delayed. These results suggest a role for multiple‐drug sensitivity assays in selecting drug combinations to be used in the treatment of drug‐resistant mycobacterioses.
Cibenzoline for High‐Frequency Ventricular Arrhythmias: A Short‐Term Comparison With Quinidine and a Long‐Term Follow‐up
Authors: Palakurthy Prasad R. , Maldonado Claudio , Sohi Gurbachan , Flowers Nancy C.
Published: March 2013

Cibenzoline, a new class I antiarrhythmic drug, was compared with quinidine in an open crossover study of 20 patients with frequent (> 30/hr) premature ventricular depolarizations (PVDs). Eight patients treated with cibenzoline experienced more than 75% reduction in PVD frequency. Cibenzoline completely suppressed ventricular couplets in eight of 17 patients and inhibited ventricular tachycardia (VT) in four of 13 patients. Only four patients (20%) responded to quinidine with a similar reduction in PVDs. Quinidine completely suppressed ventricular couplets in eight of 17 patients and episodes of VT in six of 13 patients. Cibenzoline prolonged PR, QRS, and QTc intervals. Eight patients who had shown more than a 75% reduction of PVDs were treated with cibenzoline for an extended period. At the end of three months, only five of eight patients continued to have 75% or greater reduction of PVDs. At the end of six and 12 months, four of five patients continued to have 75% or greater reduction of PVDs. Cibenzoline was similarly effective in suppressing complex arrhythmias. Thus, cibenzoline was only slightly superior to quinidine in suppressing ventricular arrhythmias. With long‐term use of cibenzoline, significant PVD suppression was noted at the end of three months but not afterward.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Chemotherapy of Parasitic Diseases Edited by W. C. Campbell and R. S. Rew

Calcium and Cell Physiology Edited by Dierer Marme'

Advances in Inflammation Research (Volume 10) Edited by Russo‐Marie, Mencia‐Huerta and Chignard

Opioid Analgesics in the Management of Clinical Pain (Advances in Pain Research and Therapy, Volume 8) Edited by Kathleen M. Foley and Charles E. Inturrisi

The Interferon System Edited by F. Dianzani and G. B. Rossi

Thioredoxin and Glutaredoxin Systems: Structure and Function Edited by Arne Holmgren, Carl‐Ivar Branden, Hans Jornvall, and Britt‐Marie Sjoberg
Intravenous Dilazep Reduces Blood Pressure and Peripheral Vascular Resistance in Humans
Authors: Poggesi Loredana , Masotti Giulio , Serneri Gian Gastone Neri
Published: March 2013

Dilazep, a coronary vasodilating drug with adenosine‐mediated activity, was tested (acute double‐blind study versus placebo) for its antihypertensive activity in 12 patients who had mild to moderate hypertension. Dilazep (0.2 mg/kg body weight by IV infusion for ten minutes) significantly reduced systolic and diastolic blood pressure (random‐zero sphygmomanometer) on average by 13.3 and 10.6 mm Hg respectively. The antihypertensive effect started rapidly, reached its maximum 20 minutes after administration, and lasted for 90 minutes. Heart rate significantly increased between 10 and 30 minutes. The antihypertensive effect of dilazep was associated with a relevant vasodilating effect as demonstrated by the changes in upper limb blood flow (strain‐gauge plethysmography, +32%; P < .001) and vascular resistance (‐29%, P < .001). The maximal reduction of vascular resistance was directly correlated to its baseline value. For these characteristics of action, at least in acute administration, dilazep would be useful agent for the treatment of high blood pressure in mild to moderately hypertensive patients.
Antihypertensive Response to Ketanserin: Influence of Race and Weight
Authors: Kosoglou Teddy , Cressman Michael D. , Vlasses Peter H. , Rocci Mario L. , Gabos Christine , Ferguson Roger K.
Published: March 2013

The antihypertensive effects of the 5‐HT2 receptor antagonist ketanserin were evaluated in 16 patients with uncomplicated essential hypertension. Following a three week single‐blind placebo treatment period, patients were randomized to receive in a double‐blind manner oral ketanserin 20 mg or 40 mg twice a day for 10 weeks. In the racially mixed patient population, mean (±SD) seated blood pressure 12 hours after the last dose of placebo was 161 ± 11/99 ± 9 mm Hg and 155 ± 19/98 ± 10 mm Hg after ketanserin (P > .05). Ketanserin 20 mg twice a day did not lower blood pressure significantly. In contrast, 40 mg twice a day significantly decreased systolic blood pressure (P < .02), and lowered diastolic blood pressure (P = .06). White patients (N = 7) showed a significant decrease in blood pressure (BP) with ketanserin treatment (158 ± 5/98 ± 8 vs. 147 ± 13/92 ± 6 mm Hg, P < .05) while black patients (N = 9) did not (165 ± 13/100 ± 9 vs. 161 ± 21/102 ± 10 mm Hg, P > .05). For black patients only, significant correlations were observed between body weight and the change in diastolic BP (r = −.86, P < .005). The racial difference in response to ketanserin could not be attributed to differences between the two groups in age, sex, body weight, pretreatment blood pressure or ketanserin dose. The nature of the racial difference in the chronic antihypertensive response to ketanserin warrants further evaluation.
Sleep Apnea Following Withdrawal of Amitriptyline
Authors: Musa Mahmoud N.
Published: March 2013

A 41‐year‐old man developed sleep apnea following abrupt cessation of amitriptyline. Cessation of antidepressants may result in excessive release of acctylcholine, which increases REM sleep. This in turn increases disordered breathing time and decreases nocturnal oxygenation. Sleep apnea did not recur when amitriptyline was reinstated and later gradually discontinued.
Food Increases the Bioavailability of Acitretin
Authors: McNamara Patrick J. , Jewell Roxanne C. , Jensen Bradford K. , Brindley Charles J.
Published: March 2013

Eighteen healthy male volunteers received 50 mg oral doses of acitretin on two occasions, according to a random crossover design. Acitretin was administered during a complete fast or following a moderate breakfast. Plasma samples were obtained at various times and the concentration of acitretin and its 13‐cis isomeric metabolite (Ro 13–7652) were quantified by a specific HPLC assay. The AUC0–15 for acitretin was increased when administered with food for all subjects (except one) with a mean increase of 90% (from 1175 to 2249 ng/ml ṁ hr). The maximum plasma concentration of acitretin (Cmax) was increased by 70% when administered with food (from 245 to 416 ng/ml), while the time to reach Cmax was unaffected. The ratio of AUC of Ro 13–7652 to acitretin was the same for both the fasted and fed conditions; therefore, the formation of metabolite was not influenced by concomitant ingestion of food. The presence of food increases the apparent bioavailability of acitretin. A likely mechanism behind this observation is an increase in acitretin solubility in addition to an increase in the lymphatic absorption and a prolonged residence time of the drug in the gastrointestinal tract.
Clinical Pharmacokinetics of Controlled‐Release Disopyramide in Patients with Cardiac Arrhythmias
Authors: Capparelli Edmund V. , DiPersio David M. , Zhao Hong , Kluger Jeffrey , Chow Moses S. S.
Published: March 2013

The pharmacokinetics of the controlled‐release preparation of disopyramide phosphate (Norpace CR, Searle Laboratories, Chicago, IL) were studied in ten patients with cardiac arrhythmias. Multiple‐serum disopyramide concentrations were obtained after a 300‐mg oral dose. Each patient then received chronic oral therapy with the controlled‐release preparation (400 to 1000 mg/day) on an every‐12‐hour schedule. At steady state, disopyramide trough concentrations were obtained. Serum disopyramide concentrations were determined by high performance liquid chromatography. The regimen was well tolerated by all patients. The mean (± SD) time to maximum concentration, maximum concentration, and concentrations 11 and 24 hours after the initial dose were 5.5 ±1.3 hours and 2.8 ± 0.8, 2.0 ± 0.9, and 1.2 ± 0.5 μg/mL, respectively. A low cmax to trough concentration ratio of 1.35 ± 0.26 was observed after the initial dose. Linear regression analysis of the serum disopyramide concentrations 11 hours after initial dose (trough) versus trough concentrations at steady state (dose adjusted) showed a strong correlation (r = 0.87, intercept = 0.03, and slope = 1.9). Regression analysis also showed a strong relationship between the area under the curve (AUC) from time 0 to 11 hours after the initial dose and the trough at steady state (r = 0.86). Conclusions: The controlled‐release preparation of disopyramide, when administered every 12 hours in patients with cardiac arrhythmias, should produce low peaks to trough fluctuations. Because disopyramide concentrations after the initial dose correlate well with trough concentrations at steady state, these concentrations may provide a simple and convenient method for prospective monitoring of disopyramide therapy in patients, receiving the controlled‐release preparation.
Multiple‐Dose Pharmacokinetics of Nilvadipine in Healthy Volunteers
Authors: Terakawa Masetto , Tokuma Yoji , Kuwahara Noriyasu , Shishido Akira , Noguchi Hideyo
Published: March 2013

Nilvadipine, a new antihypertensive and antianginal drug, was studied in six healthy male volunteers to evaluate its steady‐state pharmacokinetics after oral dosing. The subjects were given a single dose of 4 mg, followed by 4 mg every 12 hours for six days after a washout period of more than 3 days. The pharmacokinetics of nilvadipine were well described by a linear model of triexponential equation with zero‐order absorption. The steady state was reached by the fourth day of multiple dosing, with a twofold accumulation of trough plasma concentration and no accumulation of peak concentration. The mean plasma concentration at steady state was 1.0 ng/mL. The optical enantiomers of nilvadipine were also determined in the plasma. The plasma concentration of (+)‐nilvadipine was about two and a half times higher than that of (‐)‐nilvadipine, and this ratio was unaffected by multiple dosing.
Serum and Quantitative Electroencephalographic Pharmacokinetics of Loprazolam in the Elderly
Authors: Mamelak Mortimer , Bunting Peter , Galin Howard , Price Victoria , Csima Adele , Young Trevor , Klein Dwora , Pelchat Jocelyn R.
Published: March 2013

This study was undertaken to determine the serum pharmacokinetic parameters of loprazolam, a new benzodiazepine hypnotic, in elderly subjects and to compare these with the kinetics of the drug as determined by quantitative EEG analysis. In addition, a 14‐day study was undertaken to determine the steady‐state serum levels achieved in this population with repeated drug administration. The study was conducted on 16 male and female subjects between the ages of 62 and 72 years, randomly assigned to two groups treated with 0.5 or 1.0 mg of loprazolam. The serum half‐life of loprazolam was found to be 5 hours, and the peak serum concentration was reached after 2 hours. Quantitative EEG changes were observed after 30 minutes suggesting rapid access of the drug into the nervous system. Quantitative EEG changes were evident for 9.5 hours, suggesting the persistent effects of an active metabolite. The 14‐day study indicated that loprazolam did not accumulate with continued use.
Improved Exercise Tolerance by IV Fructose‐l,6‐Diphosphate in Chronic, Stable Angina Pectoris
Authors: Marchionni Niccolo' , Moschi Guya , DI Bari Mauro , Ferrucci Luigi , Paoletti Marco , Salani Bernardo , Fattirolli Francesco
Published: March 2013

The effect of IV fructose‐1,6‐diphosphate (FDP) on transient, reproducible myocardial ischemia was evaluated in ten patients, aged 50 to 66 years, with chronic, stable exertional angina. FDP or placebo (glucose) were administered between basal and posttreatment ergometric stress testing; an identical procedure was repeated in each patient with the second treatment on the following day according to a single‐blind, cross‐over design. FDP improved exercise tolerance and total work capacity, significantly delaying the onset of ST‐segment depression and angina. Nevertheless, the critical level of the rate × pressure (R × P) product, causing appearance of myocardial ischemia, was not remarkably changed. However, the R × P product at same workload was significantly lower after FDP. These results suggest that improved exercise tolerance might have resulted from peripheral (increased oxygen delivery to skeletal muscle) rather than from central (cardiac) effects of FDP.
Effect of a High‐Fat Meal on the Bioavailability of a Polymer‐Coated Erythromycin Particle Tablet Formulation
Authors: Randinitis Edward J. , Sedman Allen J. , Welling Peter G. , Kinkel Arlyn W.
Published: March 2013

The effect of food on the relative bioavailability of an erythromycin particles‐in‐tablet formulation was studied in 27 healthy volunteers, using a four‐way, crossover study design with the following treatments: one or two erythromycin capsules USP (Eryc®, Parke‐Davis), or one polymer‐coated erythromycin particles‐in‐tablet (PCE®, Abbott) administered fasting or with a high‐fat meal. Under fasting conditions the erythromycin particles‐in‐tablet and erythromycin capsule formulations are bioequivalent based on similar tmax and dose‐normalized Cmax and AUC values. The rate and extent of absorption from the particles‐in‐tablet formulation, however, are dramatically reduced following administration with a meal. Mean Cmax and AUC values decreased by 73% and 72%, respectively, and seven subjects had no detectable erythromycin plasma concentrations for 16 hours following administration of the particles‐in‐tablet formulation with the high‐fat meal. Greater than 40% of the subjects had nonfasting Cmax and AUC values that were less than 10% of those values following administration of the dose fasting. Cmax and AUC values in nonfasting subjects were within 75% to 125% of fasting values in only two and one of 27 subjects, respectively. The erythromycin particles‐in‐tablet formulation therefore should not be administered with meals.
Effect of Hydroxyzine and Meperidine on Arterial Blood Gases in Healthy Human Volunteers
Authors: Zsigmond Elemer K. , Flynn Kathleen , Shively John G.
Published: March 2013

Because hydroxyzine hydrochloride is frequently used to tranquilize patients, who are receiving narcotic analgesics for pain relief, its effect alone and in combination with meperidine on arterial blood gases and ventilation in patients at rest was evaluated in 65 healthy volunteers, who gave informed consent. Hydroxyzine hydrochloride, 1.5 mg/kg IV given over 30 seconds, caused no decrease but rather a significant (P < .001) increase in Pao2 and no increase in Paco2 and/or pH at 5, 10, 20, 30, and 60 minutes (N = 29; mean age = 47.0 years). Meperidine, 1.5 mg/kg IV given over 30 seconds, caused a significant (P < .01) reduction in Pao2 at 5 minutes indicating ventilatory depression but no increase in Paco2 and/or pH (N = 19; mean age = 32.4 years). The combination of the same doses of hydroxyzine with meperidine IV caused a significantly greater decrease in Pao2 only at 10 minutes but a greater increase in Paco2 and pH at all times for 60 minutes than did meperidine alone (N = 17; mean age = 39.5 years), which indicates greater ventilatory depression with the combination than with hydroxyzine alone. However, Pao2, Paco2 and pH remained within the awake normal ranges for Pao2, Paco2, and pH for the age group of volunteers even at 10 minutes after IV injection of the drug combination when most of the volunteers were asleep. In conclusion, hydroxyzine even when given IV in excess of the maximum IM therapeutic doses caused no changes in Pao2, Paco2 or pH, which would indicate clinically important ventilatory depression. Furthermore, blood gases remained in the normal awake range even after the combined IV administration of hydroxyzine and meperidine in excess of the maximum IM therapeutic doses.
Dilevalol: A Selective Beta‐2 Adrenergic Agonist Vasodilator with Beta Adrenergic Blocking Activity
Authors: Wallin J. David , Frishman William H.
Published: March 2013

Dilevalol is the R‐R' optical isomer of labetalol and differs pharmacologically from the racemic mixture in the following ways: it is seven‐fold more potent as a selective beta‐2 agonist; it is four times more potent as a nonselective beta antagonist; it has no clinically significant alpha antagonist property. Dilevalol is a vasodilator and reduces blood pressure by reducing systemic vascular resistance. It has a half‐life of 15–18 hours, and is demonstrated to he effective as an antihypertensive agent for 24–30 hours. Hemodynamic studies in humans show that following administration of dilevalol either orally or intravenously, blood pressure falls as a consequence of a decrease in systemic vascular resistance. Cardiac index is unchanged and heart rate decreases slightly. Dilevalol is shown to cause regression of left ventricular hypertrophy in younger individuals, to improve left ventricular performance and to have no effect on parameters of renal function. Prospective double‐blinded clinical trials in comparison with placebo, propranolol, metoprolol and atenolol were conducted and demonstrate dilevalol to be an effective antihypertensive agent with a favorable side effect profile with a particularly low incidence of central nervous system side effects.
Clinical Pharmacokinetics of Levorotatory and Racemic Disopyramide, at Steady State, Following Oral Administration in Patients with Ventricular Arrhythmias
Authors: Le Corre Pascal , Gibassier Denis , Descaves Christian , Sado Pierre , Daubert Jean Claude , Le Verge Roger
Published: March 2013

Electrophysiological effects, antiarrhythmic activity and kinetics of levorotatory disopyramide (R(–) DP) and racemic disopyramide (equimolar mixture of R(–) DP and S(+) DP) were compared in patients with ventricular arrhythmias. This double blind crossover randomized trial was achieved, at steady‐state, following oral administration of 200 mg three times a day. In comparison with baseline values, electrophysiological data indicated that R(–) DP and racemic DP prolonged, significantly and similarly, PR interval (+11.7% and +10%, respectively, P < .01), and QTc interval (+9.2% and +7%, respectively, P < .001), while QRS interval was not significantly affected. The antiarrhythmic activity, assessed by percent reduction in ventricular extrasystoles frequency, showed a similar efficiency of levorotatory and racemic DP: 80% and 74%, respectively (P = .24). Ventricular tachycardias disappeared with both treatments in the three patients concerned. During the racemic period, the mean total plasma clearance, expressed as CL/F, of S(+) DP (114.6 ml/min), was significantly lower than that of R(–) DP (157 ml/min), (P < .001). The mean total plasma clearance of R(–) DP, during the levorotatory period (163 ml/min), did not differ from the respective value determined during the racemic period (P = .32). During the racemic period, the stereoselective difference in total plasma clearances, which is not observed when DP enantiomers are administered separately, may result from an increase in unbound fraction of R(–) DP, due to the presence of S(+) DP, which is known to be a potent displacer of R(–) DP.
The Pharmacokinetics of 2.5‐ to 10‐mg Oral Doses of Minoxidil in Healthy Volunteers
Authors: Fleishaker J. C. , Andreadis N. A. , Welshman I. R. , Wright C. E.
Published: March 2013

The dose proportionality of minoxidil was investigated by studying its pharmacokinetics after administration of single, oral doses of 2.5, 5.0, and 10.0 mg. The study, which was a Latin square cross‐over design, was performed in 30 young, nonobese, normal subjects. Treatments were separated by a 4‐day washout period. Serum and urine levels of minoxidil were determined by high‐performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Supine blood pressure and pulse were monitored during each study phase. Minoxidil concentrations determined by RIA were highly correlated with concentrations determined by HPLC; only the HPLC data was used in the pharmacokinetic analyses. No significant effects were observed for dose normalized Cmax, tmax, volume of distribution, minoxidil renal clearance, or the percentage of the dose excreted as either minoxidil or minoxidil glucuronide. Significant differences in apparent oral clearance, dose normalized AUC, and terminal elimination rate constant (β) were observed between the 2.5‐mg dose and the higher doses, but no differences in these parameters between the 5.0‐ and 10.0‐mg doses were apparent. Thus, the available data support dose‐independent pharmacokinetics for minoxidil over this range of doses. Repeated measures analysis of variance detected significant time and treatment effects on supine blood pressure and pulse rate, but the effects were generally small and of little clinical significance. The results support the hypothesis that minoxidil has little effect on blood pressure in normotensive subjects.
The Influence of Antineoplastic Chemotherapy on Antipyrine Metabolism in Man
Authors: Wissel P. S. , Sordillo P. , Magill G. B.
Published: March 2013

When either Doxorubicin or Mitomycin‐C was administered to patients, antipyrine clearance was respectively unaltered or increased. Antipyrine was administered to patients two days prior to and one day after their first course of the chemotherapeutic drug. Antipyrine clearance increased an average of 11.2% in the 5 patients that received Doxorubicin (not significant) and 15.2% in the six patients that received Mitomycin‐C (P = 0.033, students t‐test). The altered clearance is likely due to a rapid induction of the mixed function oxidase system by the chemotherapy as other parameters that could influence clearance were stable throughout the study (volume of distribution, weight, creatinine clearance and liver function tests). It is unlikely that the prechemotherapy antipyrine dose accounted for this change. The administration of these two antitumor antibiotics in humans may modestly increase the mixed function oxidase activity that is responsible for the metabolism of antipyrine. These findings are in direct contrast to markedly decreased mixed‐function oxidase activity observed in the rodent pretreated with the same chemotherapy.
Pimobendan Increases Calcium Sensitivity of Skinned Human Papillary Muscle Fibers
Authors: Scheld H. H. , Fritsche R. , Schlepper M. , VAN Meel J. C. A.
Published: March 2013

The calcium sensitizing effects of the cardiotonic agent pimobendan on force production were investigated on chemically skinned human papillary muscle fibres. The papillary muscles were obtained from patients undergoing mitral valve replacement operations. Tension was produced by different free calcium concentrations and 100 μmol/l of pimobendan shifted the pCa‐tension relationship significantly to the left. The effects of pimobendan were concentration dependent (10–300 μmol/l) but additionally also correlated with the state of left ventricular performance of the patients. Skinned papillary muscle fibres obtained from patients with reduced ventricular performance were more sensitive to calcium as well as pimobendan compared with fibres from patients with normal left ventricular performance. No differences in response to pimobendan were observed between fibres from NYHA II and NYHA III heart failure patients.
Clinical Pharmacology of Centrally Acting Antihypertensive Agents
Authors: Weber Michael A.
Published: March 2013

The centrally acting agents are one of several differing classes of drugs now available for antihypertensive therapy. The availability of newer pharmacologic classes, including the beta‐blockers, alpha‐blockers, ACE inhibitors and calcium channel blockers, has resulted in a relative decline in the use of the centrally acting drugs. A major reason for this change in emphasis has been the perception by clinicians that the centrally acting agents, although effective, tend to produce symptomatic side effects that are difficult or unacceptable for patients. Some recent innovations in administering the centrally acting drugs appear to have addressed this problem. The pharmacokinetic characteristics of agents such as the transdermally administered clonidine or oral guanfacine appear to provide them with sustained efficacy without concomitant adverse effects. A further attribute of these drugs is their ability to decrease blood pressure without producing sodium retention. A growing awareness of the importance of treatment‐induced metabolic effects has further served to reawaken interest in these agents. Specifically, they do not appear to produce alterations in glucose metabolism, and possibly may even have some slight beneficial effects on the blood lipid profile. Their ability to cause regression of left ventricular muscle hypertrophy, and possibly to enhance diastolic function, may add a further dimension of cardiovascular protection beyond their antihypertensive efficacy.
Clinical Pharmacology of Dilevalol (II). The Pharmacokinetic, Pharmacodynamic, and Tolerance Studies of Dilevalol During Repeated Administration in Healthy Subjects
Authors: Fujimura Akio , Ohashi Kyoichi , Tsuru Masanobu , Ebihara Akio , Kondo Kazuoki
Published: March 2013

Dilevalol (50 mg) was given orally twice daily for eight days in six healthy subjects. All parameters were obtained following 1st (on day 1) and 15th (on day 8) dosages. Blood samples for plasma drug concentrations were taken for a 12‐hour (after 1st dosage) or a 24‐hour (after 15th dosage) post‐drug period. Blood pressure (BP) as well as heart rate (HR) at supine position, during 50° tilting and during a submaximal exercise were measured after each dosage.

The mean time to maximum concentration (tmax) was faster, and the mean area under the plasma concentration‐time curve (AUC) was greater after 15th dosage than following 1st dosage. No significant differences were observed in the maximum plasma concentration (Cmax), the distribution half‐life (t1/2α) or the elimination half‐life (t1/2β) between the two dosages. BP at supine position as well as during 50° tilting decreased significantly after each dosage, and did not differ between 1st and 15th dosages. Postural changes in BP or HR during 50° tilting were not induced following 1st or 15th dosage. The suppressing effects (%R) on an increase in HR during a submaximal exercise were significantly larger after 15th dosage than after 1st dosage. A significant correlation was observed between plasma dilevalol concentration and %R in HR.

These data indicate that the hypotensive effect of dilevalol is not altered during the repeated administration of the drug for 8 days. However, the β‐blocking activity of dilevalol might be enhanced during the repeated dosages, which is, in part, attributed to dosage‐dependent elevation in plasma drug concentrations.
A Dose‐Response Evaluation of Pipecuronium Bromide in Elderly Patients Under Balanced Anesthesia
Authors: Azad Said S. , Larijani Ghassem E. , Goldberg Michael E. , Beach Cynthia A. , Marr Alexander T. , Seltzer Joseph L.
Published: March 2013

Pipecuronium bromide is a new steroidal non‐depolarizing muscle relaxant currently under investigation. It is similar to pancuronium with respect to the duration of action, but lacking its cardiovascular side effects. We examined the dose‐response relation of pipecuronium in 27 patients, ages 66–79 years, utilizing the incremental dose method under balanced anesthesia. The ED50, ED90 and ED95 were 22.42 (5.2) mcg/kg, 31.81 (6.9) mcg/kg and 35.12 (7.8) mcg/kg, respectively (log probit method). Our recovery data also demonstrate that residual neuromuscular blockade due to pipecuronium can easily be antagonized with neostigmine as long as spontaneous recovery of T1 at the time of reversal administration is >13%. The authors conclude that under balanced anesthesia the cummulative dose‐response of pipecuronium in the elderly patients is consistent with those previously described for younger population. Therefore, no dose adjustment appears necessary for the elderly. However, as with all medications, careful administration is appropriate.
The Influence of Gastric Emptying on Droxicam Pharmacokinetics
Authors: Sánchez J. , Martínez L. , García‐Barbal J. , Roser R. , Bartlett A. , Sagarra R.
Published: March 2013

Droxicam is a new nonsteroidal anti‐inflammatory drug that is a pro‐drug of piroxicam. The influence of gastric emptying rate on droxicam pharmacokinetics has been investigated in eight healthy male volunteers. A single, 20 mg dose was administered p.o. together with 1500 mg of paracetamol. Gastric transit was experimentally modified by administration of propantheline (45 mg, p.o.) or metoclopramide (10 mg, i.v.) simultaneously with the droxicam and the paracetamol. Plasma levels of paracetamol were used as markers of gastric transit. The plasma concentrations of piroxicam, the active substance from droxicam, were determined by a high‐performance liquid chromatographic method. The pharmacokinetic parameters of droxicam were: Cmax = 1.03 ± 0.16 μg/mL (mean ± SD), Tmax= 11.1 ± 5.7 hr, AUC = 115.7 ± 29.6 μg hr/mL, T1/2 a = 2.64 ± 0.72 hr, T1/2 el = 73.6 ± 16.7 hr, CL/F = 3.06 ± 0.80 mL/min and MRT = 111.1 ± 23.5 hr. Following modification of gastric emptying, only Tmax (droxicam + metoclopramide = 25.0 ± 10.8 hr and droxicam + propantheline = 20.8 ± 8.8 hr) underwent significant change (P < 0.05). These results indicate that absorption rate of droxicam has been modified but bioavailability does not suffer modification in conditions of altered gastric emptying.
Long‐Term Therapy with Benazepril in Patients with Congestive Heart Failure: Effects on Clinical Status and Exercise Tolerance
Authors: Ribner Hillel S. , Sagar Kiran B. , Glasser Stephen P. , Hsieh Ann‐Ming , Dills Cynthia V. , Larkin Sean , DeSilva Jacqueline , Whalen John J.
Published: March 2013

Benazepril hydrochloride (CGS 14824A) is an orally active, nonsulfhydryl compound that is transformed in vivo to a long‐acting inhibitor of angiotensin‐converting enzyme (ACE). Previous studies have shown benazepril to lower blood pressure in hypertensive patients and to confer acute hemodynamic benefits in patients with congestive heart failure (CHF). In the current multicenter investigation, 16 patients with chronic CHF due to left ventricular systolic dysfunction (ejection fraction < 0.40 at rest) whose symptoms corresponded to New York Heart Association classes II to IV were given open‐label benazepril once daily in ascending doses of 2 to 20 mg and followed biweekly for 12 weeks. Evaluation of the 15 subjects who completed the trial showed a progressive increase in treadmill exercise duration (from 7.65 ± 3.64 [SD] minutes at baseline to 9.74 ± 3.66 minutes at 12 weeks, P < .001); augmentation of the mean left ventricular ejection fraction (from 0.266 ± 0.133 at baseline to 0.292 ± 0.136 at 12 weeks, P < .025); relief of exertional dyspnea in 7 of the 15 patients (P < .02); and improvement in global symptomatic status in 10 of the patients (P < .01). These responses were accompanied by a reduction in serum ACE activity of 75% (from 27.2 ± 10.5 IU/L at baseline to 6.7 ± 1.9 IU/L at 12 weeks, P < .001), which was independent of dose and duration of treatment. The magnitude of ACE inhibition did not correlate with changes in the efficacy variables. Aside from two instances of symptomatic hypotension (one of which was complicated by volume depletion), the drug was well tolerated. Long‐term therapy with benazepril for patients with CHF shows promise. A large‐scale, double‐blind trial of benazepril in this population is currently in progress.
Increased Potency of Nondepolarizing Relaxants After Poliomyelitis
Authors: Gyermek Laszlo
Published: March 2013

The pathophysiology of poliomyelitis and the recognition of the “post‐polio syndrome” suggest that susceptibility to muscle relaxants of patients previously affected by this disease, may be altered. We compared the effects of d‐tubocurarine (dTc), pancuronium (P), and gallamine (G) on two pediatric surgical patient groups: one with a previous history of polio disease, occurring 6 to 12 years prior admission (N = 30, average age: 13 yrs, weight: 43 kg) and another without history of this disease (N = 51, average age: 11 yrs, weight: 39 kg). Following uniform premedication, thiopental, N2O/O2 + narcotic (fentanyl) anesthesia was given for reconstructive surgeries. For orotracheal intubation the patients were briefly paralyzed with 0.7 mg/kg suxamethonium. The thumb adductor responses to supramaximal 1/5 Hz impulses (continuous mode) and to 50 Hz tetanic stimuli (periodically) were recorded. After full recovery from the effect of suxamethonium (100% return of the neurally evoked muscle response) cumulative ED50 values and the recovery index (minutes elapsed from 90% to 50% block of the twitch response) of the three nondepolarizing muscle relaxants were determined. The ED50 of dTc and P were significantly lower with both neuromuscular responses in the post‐polio groups (dTc, N = 12 and P, N = 10) as compared to the controls (N = 24 and 18). A tendency toward lower ED50 values in the polio group was also observed with G (N = 6). The differences, however, as compared to the control group (N = 9) were not significant (P < .2). Recovery times were identical in the polio versus non‐polio groups. These results indicate an approximately twofold increase of potency with nondepolarizing muscle relaxants (e.g., dTc and P) in pediatric patients on a clinically unaffected upper extremity which showed no vasting or motor weakness several years following an acute phase of polio disease. We suggest that a changed receptor sensitivity or density rather than a pharmacokinetic difference could explain these findings.
Influence of Metoprolol CR/ZOK on Plasminogen Activator Inhibitor (PAI‐1) in Man: A Pilot Study
Authors: Teger‐Nilsson Anne Catherine , Dahlöf Carl , Haglund Elisabeth , Hedman Christer , Olsson Gunnar , Åblad Bengt
Published: March 2013

Recent primary and secondary preventive trials have shown that long‐term metoprolol therapy reduces the risk of acute cardiovascular complications. To test whether part of this beneficial long‐term effect may he due to effects on the fibrinolytic system, three pilot studies were performed; two in healthy individuals, and one in patients with mild hypertension or uncomplicated atrial fibrillation. The effect of metoprolol CR/ZOK (controlled release) 100–200 mg daily, on plasminogen activator inhibitor activity (PAI‐1) in plasma was measured. In addition serum triglycerides and orosomucoid were analyzed.

All the individuals were included in double‐blind placebo controlled cross‐over trials with treatment periods ranging from 4 days to 3 weeks. During metoprolol therapy PAI‐1 values were reduced, while orosomucoid and triglyceride levels were unchanged. A linear inverse correlation was found between fibrinolysis and PAI‐1 activity in plasma, indicating that PAI‐1 activity serves as an indicator of fibrinolysis. PAI‐1 activity and triglycerides were significantly correlated during placebo and metoprolol therapy.

In conclusion, our results in these pilot studies suggest that metoprolol enhances fibrinolytic activity as seen by reduced PAI‐1 activity. These results should be further confirmed and put into relation of clinical effects of the therapy.
Clinical Safety of Flurbiprofen
Authors: Brooks Carter D. , Linet Otto I. , Schellenberg Diana , Turner Lana F. , Defesche Charles L. , Teoh Kok‐Wah , Johnson Jian H. , Assenzo Joseph R.
Published: March 2013

Data from 58 premarketing studies of the nonsteroidal antiinflammatory drug flurbiprofen were pooled for analyses of adverse drug reactions (ADRs). These studies included 5602 patients treated with flurbiprofen (N = 4123), aspirin (N = 1033), or placebo (N = 446) for varying durations. Diagnoses included rheumatoid arthritis, osteoarthritis, and other painful musculoskeletal conditions. In these studies serious upper gastrointestinal ADRs occurred in flurbiprofen‐treated patients at less than one half the rate seen in aspirin‐treated patients. The incidence of serious urinary tract ADRs was lower with flurbiprofen than with aspirin. The flurbiprofen group had no serious clinical ADRs related to the hemic/lymphatic system. The most common laboratory abnormality was a decrease in hematocrit, which occurred less often than in the aspirin group. We also evaluated serious flurbiprofen‐related ADRs in 4370 patients in a variety of other studies and reviewed published reports of flurbiprofen clinical trials and case reports. These reviews showed no additional, unanticipated patterns of intolerance. These clinical safety data indicate that in the doses studied, flurbiprofen is a well tolerated agent for patients requiring nonsteroidal antiinflammatory drug therapy.
Clinical Pharmacology and Therapeutics in Primary Care: An Elective for Fourth‐Year Medical Students
Authors: Ellison Mark J. , Cummings Doyle M. , Worthington Ralph C. , Bremer C. Christopher
Published: March 2013

A 1‐month elective course in clinical pharmacology in primary care has been developed and is offered six times a year for fourth‐year medical students. The major course objective is to teach the student to apply the principles of rational therapeutics in the routine practice of primary care.

The faculty includes clinical pharmacists and primary care physicians from the Department of Family Medicine. Two students each month rotate through a combined didactic and experiential curriculum oriented toward the rational selection and monitoring of drugs in inpatient and outpatient settings. Students interact daily with faculty members and have ample opportunity to evaluate drug therapy regimens and assist in designing new therapeutic strategies. Students are evaluated on their performance in conferences, written consultations, and oral case challenges.

Evaluations by students indicate that this elective is a valuable educational experience.
Penbutolol in the Treatment of Mild to Moderate Essential Hypertension in Black South Africans
Authors: Venter C. P. , Joubert P. H. , Venter H. L. , Muntingh G. L. , du Plooy W. J.
Published: March 2013

The antihypertensive effects of penbutolol, a nonselective beta‐adrenoceptor antagonist with intrinsic sympathomimetic activity, was assessed in nonobese black South Africans aged 25 to 65 years with uncomplicated mild to moderate essential hypertension. After a 4‐week placebo run‐in period 50 patients entered a randomized placebo‐controlled study with a crossover design. For 8 weeks they received a once daily dose of 40 mg penbutolol (or placebo) which was increased to 80 mg per day for the next 4 weeks in poor responders. This was followed by a 4‐week placebo washout period after which a crossover of treatment was achieved and a second 12‐week period of treatment initiated. Thirty‐five patients completed the whole study and in 15 patients diastolic blood pressure was reduced below 95 mm Hg. The mean systolic pressures of these patients decreased by 21 mm Hg and their mean diastolic pressure decreased by 11 mm Hg during treatment with penbutolol. These results suggest that penbutolol monotherapy is an alternative therapeutic approach to hypertension in black South Africans.
New Pharmacokinetic Methods III. Two Simple Tests for “Deep Pool Effect”
Authors: Browne Thomas R. , Greenblatt David J. , Schumacher Gerald E. , Szabo George K. , Evans James E. , Evans Barbara A.
Published: March 2013

If a portion of administered drug is distributed into a “deep” peripheral compartment, the drug's actual elimination half‐life during the terminal exponential phase of elimination may be longer than determined by a single dose study or a tracer dose study (“deep pool effect”). Two simple methods of testing for “deep pool effect” applicable to drugs with either linear or nonlinear pharmacokinetic properties are described. The methods are illustrated with stable isotope labeled (13C15N2) tracer dose studies of phenytoin. No significant (P < .05) “deep pool” effect was detected.
Pharmacokinetics, Safety, and Pharmacologic Effects of Fosinopril Sodium, an Angiotensin‐Converting Enzyme Inhibitor in Healthy Subjects
Authors: Duchin Kenneth L. , Waclawski Anothy P. , Tu Jan I. , Manning James , Frantz May , Willard David A.
Published: March 2013

The pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin‐converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril. In a dose‐tolerance study (study II), 80 and 160 mg of the drug were administered in doses of 40 mg bid and 80 mg bid for 2 weeks. Pharmacokinetics were determined on days 1 and 14, and blood pressure and ACE activity were measured daily. One hour after all doses of fosinopril, serum ACE activity was undetectable. Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed. ACE activity remained undetectable for more than 24 hours after the treatment was stopped in study II. Serum aldosterone levels were decreased by 50% of baseline values in both studies. In study I, maximal reductions in mean blood pressure occurred approximately 6 hours postdose; once‐daily doses of 20 mg or greater achieved reductions of 11.3 to 21.6% (P < .05, compared with placebo reductions). Fosinopril was well tolerated. Subjects reported only mild gastrointestinal complications at doses of 80 mg/day or higher. These data show that fosinopril is a safe and effective inhibitor of ACE with a long duration of action on serum ACE activity.