bluuebunny/crossref_metadata_2025 huggingface dataset:
New Pharmacologic Approaches to the Prevention of Space/Motion Sickness
Authors: Kohl Randall Lee , MacDonald Scott
Published: March 2013

Fundamental approaches in selection of new agents for evaluation in prevention of space/motion sickness (SMS) are reviewed. The discussion centers on drugs under investigation at the Johnson Space Center. Methodology that employs the rotating chair for measuring SMS symptomatology and susceptibility is described. The most obvious approach to the development of new agents relies on selection of agents from drug classes that possess pharmacologic properties of established anti‐motion sickness agents. A second approach selects drugs that are used to prevent emesis caused by means other than exposure to motion. The third approach relies on basic research that characterizes individual differences in susceptibility. The hypothesis is: detection of individual differences leads to identification of specific drugs, which target physiologic systems that show individual differences. These physiologic systems are targets for therapy and may play a role in the etiology of SMS. Two drugs that reduce susceptibility to SMS include dexamethasone and d(CH2)5Tyr(Me)AVP, a vasopressin (AVP)V1 antagonist. The latter peptide has demonstrated complete blockade of emesis and other significant symptoms in squirrel monkeys. These studies were predicated on observations that subjects who were more resistant to SMS had higher plasma AVP after severe nausea than subjects with lower resistances. Investigations are underway to test a 0.5‐mg intravenous dose in humans. Kappa opioid agonists inhibit AVP release and offer new therapeutic possibilities and advantages over AVP peptides. This review details the experimental data collected on AVP and adrenocorticotropic. The literature supports interrelated roles for AVP and opioid peptides in SMS. Experimental testing of kappa agonists is warranted because specific opioid agonists act at neuroanatomical sites causing nausea and vomiting. It is argued opioid receptors in the chemoreceptor trigger zone and vomiting center stimulate and inhibit the emetic response, respectively. The evidence suggests kappa and/or mu receptors at VC are involved in inhibition of emesis, whereas delta opioid receptors at CTZ are involved in stimulation of emesis.
Effects of Aprindine on Conduction Velocity and Vmax in Guinea‐Pig Papillary Muscles
Authors: Hirai Shozo , Hasegawa Junichi , Kurata Yasutaka , Nawada Takahiro , Noguchi Noriyasu , Matsuoka Satoshi , Hisatome Ichiro , Kotake Hiroshi , Mashiba Hiroto
Published: March 2013

One of the effects of antiarrhythmic drugs is the reduction of conduction velocity. Cable theory predicts that there is a nonlinear relationship between conduction velocity and upstroke velocity (V̇max) of action potential. By using conventional microelectrode techniques, aprindine‐induced reduction of V̇max of action potential and conduction velocity in guinea‐pig papillary muscles were measured. Aprindine‐produced, use‐dependent, and concentration‐dependent changes in conduction velocity and the decline of square of conduction velocity was well fit by a single exponential. Time constants for square of conduction velocity were comparable to simultaneously measured time constants for effects of V̇max. At a concentration of 1 to 10 μM aprindine, onset changes between V̇max and conduction velocity had a log‐linear relationship in a predicted fashion. Whereas, in the recovery process from aprindine‐induced depression, slow recovery time course of conduction velocity was observed. In conclusion, in the presence of aprindine, only onset block of conduction velocity can be analyzed quantitatively in the relationship to observation on V̇max in vitro. These results suggested that in the presence of aprindine, the recovery of internal conductance may be slower than that of V̇max.
Influence of Mexiletine on the Pharmacokinetics of Theophylline in Healthy Volunteers
Authors: Stoysich Anne M. , Mohiuddin Syed M. , Destache Christopher J. , Nipper Henry C. , Hilleman Daniel E.
Published: March 2013

Preliminary reports suggest an interaction exists between theophylline and mexiletine. We conducted a two‐way crossover study in 15 healthy male subjects to assess the magnitude of the pharmacokinetic interaction between mexiletine and theophylline. Twelve subjects completed 5 days of therapy on sustained‐release theophylline 200 mg every 12 hours alone and 5 days of therapy with theophylline and mexiletine 150 mg every 8 hours. The two treatment periods were separated by a minimum of 7 days. On the morning of day 5 of each treatment period, blood samples for theophylline to be assayed by fluorescence immunoassay were collected over 24 hours. Mexiletine significantly increased the mean AUC, Cmax, t1/2β, and Cl of theophylline. Mexiletine did not affect tmax or Vd. Side effects occurred in 4 subjects during treatment with theophylline alone all of which were judged to be mild in intensity. During concomitant theophylline‐mexiletine therapy, 10 subjects reported side effects of which 4 were judged to be severe, 1 moderate, and 5 mild. The magnitude of the increase in theophylline plasma concentrations induced by mexiletine as measured by AUC (0–24) was 58%, which is similar to other preliminary reports of this interaction. The authors conclude that the magnitude of the pharmacokinetic interaction between theophylline and mexiletine may be clinically significant in patients in light of the increased incidence of side effects in our healthy subjects. Theophylline dosage adjustments will be required in patients who receive concomitant mexiletine therapy.
Influence of Sucralfate on Trilisate Bioavailability
Authors: Schneider Doreen K. , Gannon Richard H. , Sweeney Kevin R. , DeFusco Patricia A.
Published: March 2013

Twelve healthy human volunteers were randomized to receive either choline‐magnesium trisalicylate (CMT) 1.5 g orally every 12 hours or a combination of CMT plus sucralfate 1 g orally every 6 hours for 5 days before the blood sampling day. After a 3‐week washout period, the subjects were crossed over to receive the alternate treatment for 5 days. The mean (± SD) area under the curve was 2668 (729) mg — hr/L and 2748 (716) mg — hr/L for CMT and CMT/sucralfate treatments, respectively. Mean (± SD) maximum concentration was 275 (69) mg/L and 283 (75) mg/L for CMT and CMT/sucralfate administrations, respectively. Mean (± SD) time to maximum concentration for CMT and CMT/sucralfate treatments was 1.8 (0.6) hours and 1.7 (0.7) hours, respectively. There were no significant differences detected for any parameter, therefore sucralfate does not affect rate or extent of CMT absorption.
The Effect of Tobramycin on the Renal Handling of Vancomycin
Authors: Munar Myrna Y. , Elzinga Lawrence , Brummett Robert , Golper Thomas A. , Bennett William M.
Published: March 2013

Studies in experimental animals and humans have suggested that enhanced renal and auditory toxicity occur with concurrent vancomycin and aminoglycoside treatment. In volunteers, systemic vancomycin clearance at steady‐state was measured simultaneously with renal clearances of vancomycin, creatinine, inulin, and para‐aminohippurate. Group 1 (n = 9) received vancomycin 5 mg/kg IV for 1 hour, then 1.1 mg/kg/hr for 3 hours. Group II (n = 7) received vancomycin plus tobramycin (2 mg/kg IV over 30 min). Groups did not differ demographically. Audiograms were obtained before and after vancomycin. Plasma samples were collected serially for vancomycin and tobramycin pharmacokinetic studies. Serum concentration versus time data were fit to a two‐compartment model for vancomycin and a one‐compartment model for tobramycin. For all volunteers, creatinine, inulin and para‐aminohippurate clearance, and audiograms were not altered from baseline and were not statistically different between groups. No significant effect of tobramycin on vancomycin pharmacokinetics was observed. Conversely, vancomycin had no significant effect on tobramycin pharmacokinetics. The nephrotoxic synergism of vancomycin and tobramycin is not explained by short‐term differences in renal handling.
A New Clinical Bioassay for Antipyresis
Authors: McMahon F. Gilbert , Vargas Ramon
Published: March 2013

Three studies that describe an antipyretic bioassay are detailed. Reference Standard Endotoxin (RSE) was used to induce fever in healthy male volunteers under randomized, single‐dose, double‐blind, parallel, and standard drug‐control conditions. Thirty minutes before administering RSE, the subjects were medicated with test drug, and oral temperatures were recorded every 15 minutes for 6 to 8 hours. Two NSAIDs and a centrally acting analgesic were evaluated. Both doses of a propionic derivative, three high doses of tebufelone (a new NSAID), as well as the high dose of flupirtine effectively obtunded the fever response to RSE. Adverse reactions consisting of flu‐like symptoms such as myalgia, headache, and chills were also significantly reduced with the standard as well as test drugs. The authors conclude that the RSE model is a quick, safe, and reliable method to evaluate antipyresis and to predict other pharmacologic effects of these types of drugs, such as analgesia.
Pharmacologic Study of Etoposide and Cisplatin by the Intraperitoneal Route
Authors: O'Dwyer Peter J. , LaCreta Frank , Hogan Michael , Rosenblum Norman , O'Dwyer Joyce L. , Comis Robert L.
Published: March 2013

Based on the previous demonstration of a high peritoneal‐to‐plasma ratio of drug exposure for intraperitoneal (IP) etoposide, the authors performed a clinical/pharmacokinetic trial of etoposide (600 mg/m2) in combination with cisplatin (100 mg/m2). The drugs were administered concurrently IP, and allowed to dwell for 4 hours, after which the peritoneum was drained. Six patients received 13 cycles of treatment. Grade 4 neutropenia occurred in three patients; toxicity was otherwise moderate. Plasma etoposide concentrations reached a peak at 4.2 ± 2.5 hours, and declined exponentially with a terminal half‐life of 9.5 ± 3.6 hours. Peritoneal etoposide concentrations declined monoexponentially with a half‐life of 3.7 ± 2.6 hour. The calculated peritoneal‐to‐plasma ratio of unbound etoposide was 35. The plasma and peritoneal half‐lives of ultrafilterable cisplatin were 21.7 ± 14.1 hours and 1.8 ± 0.7 hours, respectively. The peritoneal/plasma area under curve AUC ratio was 18.3. These pharmacokinetic indices for both drugs are consistent with those obtained with the use of each drug as a single agent. Thus, the concomitant use of one does not alter the pharmacokinetic activity of the other. The high AUC ratios support the further clinical development of these drugs in combination in the intraperitoneal setting.
Marine Bioactive Compounds: Stereospecific Anti‐Inflammatory Activity of Natural and Synthetic Cordiachromene A
Authors: Benslimane Abdel Fattah , Pouchus Yves François , Verbist Jean‐François , Petit Jean‐Yves , Khettab En Nassiri , Welin Lucien , Brion Jean Daniel
Published: March 2013

A new synthesis is proposed for cordiachromene A (CCA), a bioactive component of the ascidian Aplidium antillense Gravier, using a method producing a racemic mixture. The anti‐inflammatory activities of a natural extract and a chemically synthetic form of CCA were assessed in vivo by carrageenan‐induced rat‐paw edema. The activity of synthetic CCA was confirmed by a test on kaolin‐induced granuloma in the rat. Strong activities were measured for both CCA, but comparison of results of the first test suggests that only the natural optically active isomer has an anti‐inflammatory effect. CCA is similar to indomethacin in its effect on carrageenan‐induced rat‐paw edema and ten times as active as phenylbutazone.
Disposition of Cefpodoxime Proxetil in Hemodialysis Patients
Authors: Borin Marie T. , Hughes George S. , Kelloway Judy S. , Shapiro Bruce E. , Halstenson Charles E.
Published: March 2013

The disposition of cefpodoxime after single, oral 200‐mg doses of cefpodoxime proxetil (cefpodoxime equivalents) was investigated in an open‐Jabel study of six patients with end‐stage renal disease currently maintained on hemodialysis. Subjects were randomly assigned to one of two treatment groups, which differed in the sequence of the interdialytic and intradialytic periods. Doses were separated by at least 2 weeks. Blood samples were serially collected for 48 hours after each treatment; if obtainable, urine was also collected over this same period. During the intradialytic period, hemodialysis was scheduled to begin approximately 3 hours after dosing, and dialysate was collected before and until the end of dialysis. Average cefpodoxime elimination half‐life for the interdialytic period was 18.0 ± 6.5 hours; apparent total body clearance was 28.6 ± 13 mL/minute. The half‐life during hemodialysis, 2.66 ± 0.74 hours, was considerably shorter than that after hemodialysis, 19.2 ± 3.5 hours, in the intradialytic period of the study. Hemodialysis clearance of cefpodoxime was 120 ± 31 mL/minute, which was 57.1 ± 13% and 71.7 ± 25% of the hemodialysis clearance for urea nitrogen and creatinine, respectively. The 2.86 ± 0.25 hour hemodialysis session removed 22.4 ± 2.9% of the administered dose, as assessed by cefpodoxime recovery in dialysate. A maximum rebound in cefpodoxime plasma concentration of 0.41 ± 0.33 mcg/mL was observed, at about one‐half hour after the end of hemodialysis. Based on these results, dosage adjustment is not required, but extension of the dosing interval is warranted. The recommended dosing interval for cefpodoxime proxetil in patients with end‐stage renal disease is three times a week, after hemodialysis.
Effect of the Anti‐Inflammatory Agent Tenidap on the Pharmacokinetics and Pharmacodynamics of Prednisolone
Authors: Garg Varun , Blum Robert , Wilner Keith D. , Jusko William J.
Published: March 2013

The effect of tenidap, a new nonsteroidal anti‐inflammatory agent, on the pharmacokinetics and pharmacodynamics of prednisolone was studied in healthy male subjects. In a randomized crossover study, 12 subjects received either tenidap sodium 120 mg daily or placebo orally for 28 days. On day 21, each subject received a single dose of either 0.8 mg/kg oral prednisone or 0.66 mg/kg intravenous prednisolone followed by the other steroid on day 28. Blood and urine samples were collected, and the pharmacokinetic parameters of prednisone and prednisolone were determined in each treatment period. Pretreatment with tenidap did not cause any significant changes in the overall disposition of prednisone or prednisolone. For example, for free prednisolone, the intravenous area under concentration was 1,144 ± 195 ng · h/mL and 1,244 ± 140 ng · h/mL, and the systemic availability after oral prednisone was 53 ± 10% and 51 ± 12% with placebo and tenidap, respectively. The renal clearance of prednisolone was significantly reduced after tenidap pretreatment, however (from 143 to 77 mL/min/1.73 m2). The suppression of plasma cortisol and whole blood histamine levels were analyzed to evaluate the potential pharmacodynamic interactions between tenidap and prednisolone. There were no significant changes in the pharmacodynamic parameters between placebo and tenidap groups. The excretion of less than 20% of the dose of prednisolone in urine makes the overall effects of tenidap on prednisolone kinetics and dynamics of inconsequential clinical importance.
Population Pharmacokinetic Analysis of Didanosine (2′,3′‐Dideoxyinosine) Plasma Concentrations Obtained in Phase I Clinical Trials in Patients with AIDS or AIDS‐Related Complex
Authors: Pai Sudhakar M. , Shukla Umesh A. , Grasela Thaddeus H. , Knupp Catherine A. , Dolin Raphael , Valentine Fred T. , McLaren Colin , Liebman Howard A. , Martin Russell R. , Pittman Kenneth A. , Barbhaiya Rashmi H.
Published: March 2013

Plasma didanosine concentration data from 36 patients receiving once‐a‐day therapy and from 33 patients receiving twice‐a‐day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once‐ or twice‐a‐day regimens of didanosine were administered intravenously (IV) (dose: 0.8–33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6–66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady‐state) IV and oral doses. Population pharmacokinetic parameters for the combined IV and oral steady‐state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady‐state distribution volume, Vdss, 0.84 (6.8) L/kg; first‐order absorption rate constant, Ka, 1.3 (9.5) hr−1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined IV and oral first‐dose data were generally similar to those for the steady‐state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach.
Pharmacokinetic Characterization of the Postdistribution Phase of Prohormone Atrial Natriuretic Peptides Amino Acids 1–98, 31–67, and Atrial Natriuretic Factor During and After Rapid Right Ventricular Pacing in Dogs
Authors: Ackerman Bruce H. , Wyeth Richard P. , Vesely David L. , Ngo William L. , Bissett Joe K. , Winters Chris J. , Sallman Alan L.
Published: March 2013

Release rate constants and disappearance rate constants were determined for three atrial natriuretic peptides consisting of amino acids 1–98 (i.e., proANF 1–98), the midportion of the ANF prohormone consisting of amino acids 31–67 (i.e., proANF 31–67) and amino acids 99–126 (i.e., ANF) after right ventricular pacing at 100, 125, 150, and 180 bpm in six male mongrel dogs. Right atrial and femoral vein blood was obtained at baseline, and at 5, 12, 19, 26, 56, 86, 116, 146, and 206 minutes after right ventricular pacing. Resulting plasma concentration‐time data derived parameters were compared. The disappearance rate constants for atrial and femoral venous proANF 1–98 were 0.0144 ± 0.0087 (X ± SD) and 0.0175 ± 0.0075 min−1, respectively (t = 0.6158) and release rate constants were 0.1569 ± 0.1504 and 0.0670 ± 0.0393 min−1, respectively (t = 1.8269; P > .05). The proANF 31–67 disappearance rate constants were 0.0139 ± 0.0082 and 0.0148 ± 0.0132 min−1, respectively (t = 0.1192) and release rate constants were 0.0957 ± 0.0414 and 0.1984 ± 0.1762 min−1, respectively (t = 1.4812). The ANF elimination phase disappearance rate constants were 0.0663 ± 0.0273 and 0.1116 ± 0.0539 min−1 (t = 2.0923, P > .05), respectively, and the release rate constants were 0.1335 ± 0.0532 and 0.1638 ± 0.0520 min−1 (t = 0.7878, P > .05), respectively. These data indicate that proANF 1–98 and proANF 31–67 circulating β post‐distribution half‐lives are approximately 45 minutes whereas β half‐life of ANF is 10 minutes. Persisting concentrations of proANF 1–98 and proANF 31–67 in plasma may better explain the proported sustained pharmacologic effects that have been attributed to ANF, which has a mean a distribution phase half‐life of 3.5 minutes and a β half‐life of 10 minutes.
Double‐Blind Placebo‐Controlled Trial of Terazosin Effect on Blood Pressure and Urinary Output of Dopamine in Hypertensive Patients
Authors: Romero E. , Angeli M. , Velasco M. , Azar E. , Bueno O. , Lema G. , Morales N. , Nuchi Y. , Rasines C. , Wagner A.
Published: March 2013

In a parallel, double‐blind study, 12 untreated hypertensive patients received terazosin (2–4 mg/day for 4 weeks), and 12 received placebo during the same period. Systolic and diastolic blood pressure decreased significantly in the terazosin group, from 150 ± 5.0 mmHg systolic and 99.6 ± 2.0 diastolic before treatment, to 134.0 ± 7.0 systolic and 85.6 ± 3.0 mmHg diastolic at week 4 of treatment. No significant blood pressure changes occurred in the placebo group. Blood pressure decrease showed a positive correlation (r = .62 and r = .52 for systolic and diastolic blood pressure, respectively) with the patient's age (P < .05). Total plasma cholesterol decreased 18% in the terazosin group (P < .05) and 9% in the placebo group (P > .05). Urinary dopamine excretion decreased significantly from 692.8 ± 180.0 to 330.5 ± 52.0 μg/24 hours in the terazosin group (P < .05) and showed a nonsignificant increase in the placebo group. Compared with 22 age‐ and sex‐matched healthy volunteers, urinary dopamine excretion in the hypertensive group before treatment was not statistically different (779.3 ± 83.1 μg/24 hours). Dopamine excretion was higher in untreated hypertensive men and in male healthy volunteers compared with women. The decrease of urinary dopamine excretion observed under terazosin treatment could be due to a decrease of kidney dopamine synthesis or release induced by blood pressure reduction, or secondarily to the blockade of kidney α1‐receptors, modulating dopamine excretion. No significant changes were observed in urinary excretion of noradrenaline and adrenaline.
Facilitation of Adaptation and Acute Tolerance to Stressful Sensory Input by Doxepin and Scopolamine Plus Amphetamine
Authors: Kohl Randall Lee , Sandoz Gwenn R. , Reschke Millard F. , Calkins D. S. , Richelson Elliott
Published: March 2013

This work characterizes a new methodologic and pharmacologic approach to control terrestrial and space motion sickness (SMS). The experimental design allowed separate evaluation of drug action on susceptibility and adaptability, and used repeated measures to approximate the chronic stressful motion of microgravity. Daily exposure to cross‐coupled angular acceleration for 5 consecutive days demonstrated that the efficacy of doxepin and scopolamine plus amphetamine in the prevention of autonomic system dysfunction was not only apparent on the first test day (P < .01), but was also evident in the substantially enhanced resistance developed over the 5‐day test period (P < .01) as compared with placebo. This indicates that daily use of these medications does not diminish therapeutic efficacy (tolerance). The efficacy of doxepin was anticipated because it possesses pharmacologic properties similar to those of established anti‐motion sickness drugs. Comparable efficacy after doxepin loading for 4 hours, 3 days, or 21 days suggests a mechanism distinct from its antidepressant effects, possibly related to its potent antihistaminergic actions. Use of doxepin has operational significance to the National Aeronautics and Space Administration, in comparison with current preparations of scopolamine plus amphetamine, because of doxepin's minimal impact on cognitive performance, and most importantly, its favorable pharmacokinetic profile, particularly its long half‐life.
Phase I Study of DQ‐2556, a New Parenteral 3‐Quaternary Ammonium Cephalosporin Antibiotic
Authors: Nakashima M. , Uematsu T. , Kanamaru M. , Mizuno A. , Matsubayashi K. , Okazaki O. , Hashimoto S. , Hakusui H. , Osada Y.
Published: March 2013

The safety and pharmacokinetic properties of DQ‐2556, a new parenteral cephalosporin, were evaluated using healthy volunteers after 5‐minute intravenous infusion of doses of 250, 500, 1000, or 2000 mg and a 1‐hour infusion of 2000 mg, and an intramuscular dose of 500 mg. The half‐lives of DQ‐2556 ranged from 1.64 to 2.15 hours. The peak serum concentrations and area under the curve values were linearly correlated to the doses. The mean urinary recoveries were 80.0 to 85.5% of a dose within 24 hours. Salivary concentrations of the drug were low. There was no accumulation of DQ‐2556 after 9 administrations every 12 hours. DQ‐2556 was well tolerated.
The Safety of Ranitidine in Elderly Versus Non‐Elderly Patients
Authors: Sirgo Mark A. , Mills Rose , Euler Arthur R. , Walker Susan
Published: March 2013

The authors conducted a retrospective review of 21 United States trials of ranitidine in acid peptic diseases and compared the adverse events in elderly (≥65 years) and nonelderly (<65 years) patients. Ranitidine dosages ranged from 150 mg/day to 300 mg twice daily for treatment periods of 4 to 52 weeks. Of the 4041 patients included in this review, 402 elderly and 2188 nonelderly patients received ranitidine and 245 elderly and 1206 nonelderly patients received placebo; 29%, 29%, 32%, and 26% of these patients, respectively, reported some type of adverse event. When only drug‐related adverse events (as judged by the investigators under blinded conditions) were evaluated, these percentages dropped to 2%, 2%, and 1% and 2%, respectively. Gastrointestinal adverse events (e.g., nausea and diarrhea) and central nervous system adverse events (e.g., headache and dizziness) were the most common (0.7% and 0.8%, respectively), with comparable incidence rates in the elderly and nonelderly patients. The authors conclude that ranitidine is as safe in elderly patients as it is in nonelderly patients. No difference in the incidence of adverse events was found between older and younger patients who received ranitidine or placebo.
Steady‐State Pharmacokinetics and Dose Relationship of Nicotine Delivered from Nicoderm® (Nicotine Transdermal System)
Authors: Gorsline Jane , Gupta Suneel K. , Dye Dan , Rolf Clyde N.
Published: March 2013

An open‐label, randomized, crossover study determined nicotine pharmacokinetics at steady state of a new Nicotine Transdermal System in 24 healthy adult male smokers. Three doses were each administered for 5 days: 7, 14 and 21 mg nicotine per day. Plasma nicotine concentrations reached steady state by the third day and were sustained throughout the 24‐hour application periods. Mean steady‐state nicotine and cotinine area under the curve (AUC0–24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), average plasma concentration (Cavg), and total urinary cotinine were proportional to the dose of nicotine released in vitro from Nicotine Transdermal System. Time to reach peak concentration (tmax), half‐life (t 1/2), relative degree of fluctuation (DF) in steady‐state plasma nicotine and cotinine concentrations, and renal cotinine clearance were similar for all three dosages, indicating linear pharmacokinetics and no change in nicotine metabolism with increasing dose. Findings from a second study also reflect the linear dose relationship for this Nicotine Transdermal System within the 7 to 21 mg/day dosage range. Bioequivalence based on the confidence interval test was demonstrated for a single application of Nicotine Transdermal System 21 mg/day and the same total dosage achieved by combined administration of Nicotine Transdermal System 7 mg/day plus Nicotine Transdermal System 14 mg/day, although there were small statistical differences. This Nicotine Transdermal System has a well‐defined pharmacokinetic profile, with sustained plasma nicotine concentrations, and nicotine pharmacokinetics that are independent of the dose of this Nicotine Transdermal System.
Pediatric Pharmacology: The Path Clears for a Noble Mission
Authors: Wilson John T.
Published: March 2013

Unlabeled use of drugs in children occurs frequently and contributes to the therapeutic orphan dilemma. This situation can no longer be condoned; few acceptable reasons still exist for not evaluating potentially effective drug therapy in children. An apparent lack of research funds is not one of these reasons; only allocation of these funds to pediatric pharmacology is found wanting. Availability of clinical pharmacology programs, pediatric pharmacology manpower, sensitive analytical techniques, and acceptable ethical approaches to pediatric research reveal that drug evaluation is feasible in children. Studies readily include the required therapeutic indication for drug use in pediatrics. Efforts of academia, government and industry are now converging to show that the path for the noble mission of pediatric pharmacology—rational use of FDA approved drugs for children—is now clear for action.
The Role of the Research‐Based Pharmaceutical Industry in Medical Progress in the United States
Authors: Kaitin Kenneth I. , Bryant Natalie R. , Lasagna Louis
Published: March 2013

The development of innovative new drugs is a time‐consuming, expensive, and risky process. Despite these challenges, the pharmaceutical industry has been remarkably successful in developing a broad range of important new medicines. This report examines several aspects of new drug development in the pharmaceutical industry and provides a quantitative evaluation of the role of the drug industry in medical progress. Results indicate that of the 196 new chemical entities approved by the FDA from 1981 through 1990, the source of 92% was the pharmaceutical industry. Within the industry, there was a sizeable increase in the level of clinical research activity (based on the number of investigational new drug [IND] filings) from the mid‐1970s to the mid‐1980s; moreover, for U.S.‐owned firms IND filings increased 46% between 1976 and 1989. Analysis by therapeutic category indicates that much of this clinical research activity was directed towards the development of drugs for cardiovascular disease and mental illness, and more recently towards the treatment of cancer and acquired immunodeficiency syndrome (AIDS). These represent therapeutic areas in which there is an urgent need for new and more effective medicines. The high level of research activity was also reflected in the relative number of drug approvals in these areas. It is hoped that the present findings will contribute to the current debate on drug policy issues and encourage policy‐makers to consider what impact proposed health care policies might have on pharmaceutical innovation.
A Comparison of Once‐Daily Atenolol and Metoprolol Using Office and Ambulatory Blood Pressure Monitoring
Authors: Rutan Gale H. , Feig Peter U. , May Sherryl , Kriegman Audrey G. , Brady Ellen M.
Published: March 2013

The authors compared the relative safety and efficacy of changing treatment from once‐daily atenolol to metoprolol in patients with essential hypertension. A parallel‐group randomized clinical trial was conducted in two phases: a 4‐week baseline single‐blind phase using atenolol 50 mg, followed by a 4‐week randomized double‐blind treatment phase using either atenolol 50 mg or metoprolol 100 mg administered once daily at noontime. Patients with well‐controlled hypertension already prescribed 50 mg of atenolol (with or without the addition of a diuretic) for control of hypertension were selected for participation from the outpatient hypertension clinic of the Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania. Seated blood pressure (BP) and pulse were obtained during the baseline phase and during the randomized treatment phase. Twenty‐four‐hour ambulatory BP monitoring was performed once during the baseline phase and once during the randomized treatment phase, near the end of each 4‐week period. There were no within‐ and between‐treatment differences in office systolic and diastolic BP. There was a slight increase in pulse (average = 5.2 beats/minute; P = .02) for those participants treated with metoprolol. For within‐treatment groups, the ambulatory BP data showed no significant differences in systolic and diastolic BPs, except for an increase in morning diastolic BP for those randomized to metoprolol (average = 6.2 mm Hg; P = .01). For between‐treatment groups, the metoprolol arm had a higher morning systolic BP (P = .01), a higher morning diastolic BP (P = .03), and a higher nighttime heart rate (P = .01). There were no study withdrawals due to adverse events. Once‐daily administration of both atenolol and metoprolol appear to control BP as measured by office and ambulatory monitoring techniques, but atenolol appears to maintain BP control more effectively than metoprolol during the end of the dosing interval.
Effect of Secobarbital and Morphine on Arterial Blood Gases in Healthy Human Volunteers
Authors: Zsigmond Elemer K. , Flynn Kathleen
Published: March 2013

Secobarbital is still widely used as a hypnotic and morphine as an analgesic perioperatively in surgical patients. Their combination is often used as a preanesthetic medication. Although their ventilatory depressant effect is recognized, the resulting blood gas changes have not been studied as yet adequately in a sufficiently large population of healthy volunteers. Therefore this study was undertaken. Thirty healthy volunteers who gave valid written consent were studied. Secobarbital 2.0 mg/kg intravenously caused a significant (P < .05) decrease in arterial oxygen pressure (PaO2), peaking at 10 minutes (n = 10; mean age, 23.4 years). Morphine, 0.2 mg/kg intravenously also caused a significant decrease in PaO2 at 5 minutes (n = 10; mean age, 26.3 years). The combination of the same doses of morphine and secobarbital caused a significantly (P < .01) greater decrease in PaO2 at 5 and 10 minutes than the sole administration of either drug (n = 10; mean age, 23.5 years). Arterial oxygen pressure remained significantly (P < .05) reduced for 30 minutes. Although the PaO2 increases after secobarbital and morphine did not reach statistical significance, their combination caused a significant (P < .05) increase in Paco2. Both secobarbital and morphine alone caused significant (P < .05) decrease in pHa at 30 minutes. Their combination caused a significant (P < .01) reduction in pHa from 5 minutes until 60 minutes. In conclusion, both secobarbital and morphine alone caused ventilatory depression. The duration of ventilatory depression was greater with the intravenous combination than with either drug alone.
A New Extended‐Release Formulation of Diltiazem HCl for the Treatment of Mild‐to‐Moderate Hypertension
Authors: Frishman William H.
Published: March 2013

Calcium‐channel blockers are a safe and effective treatment modality and have been used extensively in the treatment of angina and hypertension. Dilacor™ XR capsules, a new extended‐release formulation of diltiazem, has been developed for the treatment of hypertension. Dilacor XR (Rhône‐Poulenc Rorer Pharmaceuticals Inc., Collegeville, PA) uses a novel drug delivery system, the Geomatrix™ (JAGO Research AG, Zollikon, Switzerland) controlled‐release system, to deliver diltiazem at a constant rate for 24 hours. The rate of absorption is also slower. As doses of Dilacor XR were increased from 120 mg to 540 mg/day, there were disproportionate increases observed in area under the curve, maximum peak plasma concentration, minimum peak plasma concentration, and average peak plasma concentration. The efficacy data from two clinical trials have confirmed the established efficacy of diltiazem and the 24‐hour efficacy of Dilacor XR in the control of mild‐to‐moderate hypertension. The incidence of adverse effects with Dilacor XR in doses as high as 540 mg/day was generally comparable to that of placebo. This new extended‐release formulation of diltiazem should significantly facilitate blood pressure control because of better patient compliance with a once daily regimen.
Disposition of Olsalazine and Metabolites in Breast Milk
Authors: Miller Lucinda G. , Hopkinson Judy M. , Motil Kathleen J. , Corboy Jane E. , Andersson Stig
Published: March 2013

This study examined the disposition of olsalazine and its metabolites into breast milk after the ingestion of a single dose of 500 mg olsalazine. Blood and serum samples were obtained for 48 hours after the ingestion of 500 mg olsalazine in a 39‐year‐old lactating woman. Blood samples were obtained at .0, .5, 1, 2, 4, 6, 24.5, 26, and 48 hours. Maternal milk samples were obtained at .0, .5, 2, 4, 6, 14, 24, 28, 36, and 48 hours. Olsalazine and olsalazine‐S underwent high‐pressure liquid chromatography analysis, and 5‐ASA and Ac 5‐ASA underwent fluorometric detection. Acetylated‐5‐ASA achieved concentrations of .8, .86, and 1.24 μmol/L in breast milk at 10,14, and 24 hours, respectively. Olsalazine, olsalazine‐S, and 5‐ASA were undetectable in the breast milk for 48 hours after drug administration. Clinically significant drug exposure in the breast‐fed infant is unlikely after a maternal single dose of olsalazine. Idiosyncratic hypersensitivity, however, remains a possibility even if the infant is exposed to only minute quantities.
Issues and Problems Associated with Drug Delivery in Pediatric Patients
Authors: Roberts Robert J.
Published: March 2013

Inherent problems exist in the actual delivery of doses of medications to pediatric patients, particularly with the IV route of drug administration. Standardized policies and procedures for recognized problems with specific routes of drug administration, along with pharmaceutical industry cooperation, are essential for solving drug delivery problems in pediatric therapeutics.
Hyperlithemia Correction and Persistent Delirium
Authors: Swartz Conrad Melton , Jones Patricia
Published: March 2013

Experience with three patients whose courses are described suggested that delirium and persistent neurologic dysfunction follow rapid correction of hyperlithemia, which develops after regular lithium doses. From all retrievable published reports of adult hospitalization for hyperlithemia, all cases that described cognitive dysfunction after lithium administration for at least 10 days with insubstantial neuroleptic exposure were selected. Lithium was universally discontinued before or on admission. Of the 65 such cases, 50 were at least somewhat responsive on admission; of these, substantial deterioration during hospitalization occurred in 56%. Dialysis was associated with greater incidence of persistent neurologic sequelae (62% vs. 22%, P = .012) and deterioration during hospitalization (65% vs. 46%, P = .016), although cognitive dysfunction on hospital admission was less (P < .001) for patients who were then dialyzed. The greater neurotoxicity after dialysis suggests that while hyperlithemia can be toxic, its rapid correction can be more toxic. Parallels with hyponatremia, including a potential mechanism, suggest that gradual rather than abrupt correction of hyperlithemia might decrease the risk of neurotoxicity.
Effects of Long‐Term Treatment with Sustained‐Release Nicardipine on Left Ventricular Hypertrophy and Function in Patients with Essential Hypertension
Authors: Sumimoto Takumi , Hiwada Kunio , Ochi Takaaki , Matsubara Wataru , Joh Tadafumi , Imamura Yoichi
Published: March 2013

The effects of long‐term treatment with sustained‐release nicardipine (nicardipine SR) on left ventricular hypertrophy and junction were studied. Ten uncomplicated essential hypertensive patients with left ventricular hypertrophy, aged 61 ± 7.6 years old, were treated with nicardipine SR alone for an average of 20 months (range: 12–26 months). All patients underwent echocardiography for assessment of left ventricular diameters and function before and after the treatment At the end of the treatment, systolic and diastolic blood pressures significantly decreased from 176.0 ± 13.9 to 140.0 ± 14.3 mm Hg and from 97.0 ± 5.3 to 77.4 ± 7.2 mm Hg, respectively (each P < 0.01), while heart rate did not change (73.6 ± 14.6 vs. 69.9 ± 13.5 beats/min). The left ventricular mass index significantly decreased from 132.1 ± 14.4 to 114.4 ± 15.7 g/m2 (P < 0.01) due to significant reductions in both interventricular septal thickness (P < 0.01) and left ventricular posterior wall thickness (P 0.05). The ejection fraction (EF), fractional shortening (FS), peak shortening rate (PSR), and peak lengthening rate (PLR) were also improved significantly by the treatment (EF and FS, P < 0.05; PSR and PLR, P < 0.01). Significant inverse relationships existed between end‐systolic wall stress and peak shortening or lengthening rate before the treatment (r = 0.80, P < 0.05; r = 0.86, P < 0.05, respectively). These relationships were unchanged after the treatment. Nicardipine SR reduced left ventricular hypertrophy and improved both left ventricular systolic and diastolic functions without causing any consistent augmentation of intrinsic left ventricular function in essential hypertensive patients with left ventricular hypertrophy.
Acute Effects of Sublingual Nitroglycerin on Hepatic Blood Flow in Healthy Volunteers
Authors: Reiss William G. , Bauer Larry A. , Horn John R. , Zierler Brenda K. , Easterling Thomas R. , Strandness D. E.
Published: March 2013

Duplex sonography was used to assess the effects on hepatic blood flow after administering 0.6 mg nitroglycerin (NTG) sublingually to ten healthy volunteers. The study was a randomized, placebo‐controlled, cross‐over study in which subjects were studied on three separate occasions. Each visit involved administering either placebo or NTG followed by estimation of blood flow through a particular branch of the hepatic artery, portal vein, and hepatic vein every minute for 15 minutes after NTG and placebo administration. Two hours later, subjects were crossed over to the other treatment and the same vessel branch was again examined for 15 minutes. Total blood flow increased 7% in the portal vein and 27% in the hepatic vein during NTG treatment, but did not change significantly in the hepatic artery. Vascular resistance was increased in the hepatic artery and decreased in the portal and hepatic veins after NTG. Qualitatively, flow changed dramatically in the hepatic vein after NTG with the disappearance of normal retrograde flow. The results indicate that nitroglycerin effects hepatic blood flow through the portal and hepatic veins with a decrease in vascular resistance in the portal and hepatic veins and an increase in resistance in the hepatic artery.
Blood Volume Responses of Men and Women to Bed Rest
Authors: Fortney S. M. , Turner C. , Steinmann L. , Driscoll T. , Alfrey C.
Published: March 2013

This paper reviews a series of studies that indicate that estrogens play an important role in blood volume regulation. The first study illustrates that the plasma volume (PV) of ambulatory women fluctuates during the menstrual cycle, increasing during periods of elevated estrogens. In the second study, it was shown that exogenous and endogenous elevations in blood estrogens attenuate the decrease in PV during bed rest. In the third study, the hypothesis was tested that women, who naturally have a higher blood estrogen content compared with men, will have a smaller loss of PV during bed rest. Ten men and ten women underwent a 13‐day, 6° head‐down bed rest. Plasma volume and red cell mass (RCM) were measured before and after bed rest using 125I and 51Cr labeling, respectively. Before bed rest, the men and women had similar blood volume (BV) and PV (mL/kg body weight), but the women had a smaller (P < .01) RCM (22.2 ± 0.9 versus 26.2 ± 0.8 mL/kg, mean ± SE). During bed rest, the decrease in RCM (mL/kg) was similar in men and women. However, the decrease in BV was greater in men (8.0 ± 0.8 mL/kg versus 5.8 ± 0.8 mL/kg), because of a greater reduction in PV (6.3 ± 0.6 mL/kg versus 4.1 ± 0.6 mL/kg). Because the decline in BV has been proposed to contribute to the cardiovascular deconditioning after bed rest, it is possible that women may experience less cardiac and circulatory strain on reambulation.
Safety, Tolerance, and Preliminary Pharmacokinetics of Nefazodone After Administration of Single and Multiple Oral Doses to Healthy Adult Male Volunteers: A Double‐Blind, Phase I Study
Authors: Barbhaiya Rashmi H. , Marathe Punit H. , Greene Douglas S. , Mayol Robert F. , Shukla Umesh A. , Gammans Richard R. , Pittman Kenneth A. , Robinson Donald
Published: March 2013

Safety, tolerance, and preliminary pharmacokinetics of nefazodone, a new antidepressant, were assessed in a randomized, double‐blind, parallel group study carried out in two sequential segments: a single and a multiple daily dose segment. Nine subjects in the single daily dose segment were divided into three treatment groups and received nefazodone doses in a leapfrog fashion. Each day of treatment with nefazodone was followed by 2 days of placebo treatment and then administration of the next higher drug dose. Single doses ranged from 5–500 mg. 8 subjects enrolled in the multiple daily dose segment were divided into two treatment groups. In each group, 3 subjects received nefazodone and one received placebo 3 times a day. Each dosage level was administered for 2 days before proceeding to the next higher dose from 5 mg or 10 mg 3 times a day to a maximum of 500 mg 3 times a day. After the dose‐escalation period, the subjects in the multiple daily dose segment underwent a 3‐day washout, after which they received a single dose of nefazodone at the maximum tolerated level. Safety and tolerance assessment involved analyses of adverse events, laboratory tests, vital signs, ophthalmic examinations, and ECGs. Blood and urine samples were obtained only in the multiple daily dose segment and analyzed for nefazodone and its two pharmacologically active metabolites, hydroxynefazodone and mCPP. A single blood sample was collected on 8 different days for assessment of trough levels (Cmin) and serial samples were obtained on days 5, 9, and 22 of dosing for pharmacokinetic profiles. Additional serial samples were also obtained after the last single dose of 500 mg after a 3‐day washout. Nefazodone was found to be safe and well‐tolerated in total daily doses as high as 1350 mg (450 mg 3 times a day). Nefazodone was rapidly absorbed after oral administration and converted to hydroxynefazodone and mCPP. The pharmacokinetics of nefazodone, hydroxynefazodone, and mCPP were found to be dose‐dependent, as evidenced by dose normalized values of Cmin, Cmax, and AUC0–8, that progressively increased with dose. Although exposure of normal subjects to nefazodone and its 2 pharmacologically active metabolites was disproportionately higher than the corresponding increase in dose, the safety and tolerance profiles did not show a parallel increase in adverse events. Nefazodone may be well‐tolerated by patients receiving expected therapeutic doses from 200–600 mg per day when administered in divided doses every 8 to 12 hours.
Pharmacokinetics of Moricizine in Young Patients
Authors: Rice Peter J. , LeClair Irene O. , Stone William L. , Mehta Ashok V.
Published: March 2013

Moricizine is a novel phenothiazine antiarrhythmic agent that depresses the activity of ectopic foci, has a low incidence of adverse effects relative to other agents, and is useful in treating pediatric atrial ectopic tachycardia. A study was conducted to determine the pharmacokinetics of moricizine in children after oral administration. Moricizine was isolated from frozen serum obtained from four male patients (ages 7, 8, 9, and 18 years) receiving the drug for supraventricular tachycardia and analyzed by high‐performance liquid chromatography with ultraviolet detection according to an established protocol. Peak serum levels were between 400 and 2000 ng/mL. Elimination of moricizine did not follow simple single‐compartment pharmacokinetics. In three patients we observed an increase or slower decline in blood level occurring after 4 hours. Because of the paroxysmal nature of the tachycardias, decreases in patient heart rate could not be correlated with moricizine blood level. These results suggest that the pediatric pharmacokinetics of moricizine excretion are complex and may differ from those seen in adults.