bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Pharmacodynamics of a New Transdermal Clonidine, M‐5041T, in Healthy Subjects
Authors: Fujimura Akio , Ebihara Akio , Shiga Tsuyoshi , Kumagai Yuji , Ohashi Kyo‐ichi , Nakashima Hajime , Kotegawa Tsutomu
Published: March 2013

The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M‐5041T (M), and its safety were evaluated after single and repeated applications. In the single‐application study, one patch of M (4 mg → 6 mg → 8 mg) was applied for 3 days in eight healthy subjects. In the repeated‐application study, first (0–72 hours), second (72–144 hours), and third (144–216 hours) patches of M 6 mg were applied in seven healthy subjects. In the single‐application study, plasma clonidine concentration increased in a dose‐dependent manner after application of M. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner, but the difference did not reach significance. Time to maximum concentration, elimination half‐life, and total and renal clearance did not differ significantly among three trials. Blood pressure (BP) decreased gradually after application of each dose of M. The BP‐lowering effect of M 8 mg was greater than that of M 4 mg and 6 mg. Adverse effects such as erythema and drowsiness were reported in some subjects. No subject had to be withdrawn from the study because of the appearance of adverse effects. In the repeated‐application study, plasma concentration of clonidine increased up to 48 hours after application of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ significantly among three trials. Blood pressure during an active period decreased significantly during treatment with M, whereas BP at midnight did not change significantly. Two subjects complained of orthostatic vertigo caused by hypotension and were dropped out of the study. Mild erythema and systemic adverse effects were reported. These results suggest that M is a promising tool for the treatment of hypertension without unacceptable skin reactions. Orthostatic change in BP should be monitored carefully during treatment with M.
Receptor‐Based Pharmacokinetic‐Pharmacodynamic Analysis of Corticosteroids
Authors: Derendorf Hartmut , Hochhaus Günther , Mölimann Helmut , Barth Jürgen , Krieg Michael , Tunn Sabine , Mölimann Carsten
Published: March 2013

The pharmacodynamics of three corticosteroids were investigated after intravenous administration of the phosphate esters of methylprednisolone, dexamethasone, and triamcinolone acetonide to healthy subjects at 20, 50, and 80 mg as well as placebo. Twenty‐two different pharmacodynamic parameters were followed as a function of time for 48 hours. Statistically significant effects of the glucocorticoids were an increase in blood glucose levels, a decrease in the number of lymphocytes, eosinophils, basophils, and monocytes, and an increase in the number of granulocytes and stab cells. For the most significant pharmacodynamic effects (lymphocytes, granulocytes, and glucose) a previously derived integrated pharmacokinetic/pharmacodynamic model using plasma concentrations, protein‐binding data, and in vitro receptor‐binding affinities was used to predict the pharmacodynamic effect‐time profiles. Good agreement of predicted and measured effects was observed, confirming the validity of the model. The clinical significance of the model was demonstrated by comparison of model‐predicted maintenance doses with empirically determined clinical equivalency doses.
Effect of Unbound Clearance on Binding Parameters of Valproic Acid to Serum Proteins
Authors: Kodama Yasuo , Tsutsumi Kimiko , Teraoka Iwao , Fujii Isao , Takeyama Masaharu
Published: March 2013

Nine healthy subjects received 400 mg sodium valproate orally in the fasting state. Binding parameters of valproic acid to serum proteins were determined by Scatchard analysis for individual series of valproic acid data. Total and unbound (intrinsic) clearances (Cht and CLu) were calculated by dividing the dose by the appropriate area under the serum drug concentration‐time curve. Unbound clearance correlated positively with the product of association constant (Ka) and concentration of free protein ((UP)) (P < .05). Conversely, no significant correlation was found between CLt and binding parameters. The average unbound concentration correlated negatively with both CLu and ka(P) values. The result indicates an effect of CLu on Ka(P) value of valproic acid.
Therapeutic Advances in Migraine
Authors: Solomon Glen D.
Published: March 2013

Migraine is a common and debilitating disorder of uncertain pathogenesis. Recent research into the pathophysiology of migraine and serotonin receptors has revolutionized the approach to pharmacotherapy. New medications, such as sumatriptan, and new dosage forms of older medications, including dihydroergotamine, NSAIDs, and phenothiazines are available to treat acute attacks. New prophylactic approaches include the use of calcium‐channel blockers, NSAIDs, fluoxetine, and valproate. The addition of several new agents for the acute and prophylactic therapy of migraine has improved the outlook for this disabling disorder.
Performance of Human Mass Balance/Metabolite Identification Studies Using Stable Isotope (13C, 15N) Labeling and Continuous‐Flow Isotope‐Ratio Mass Spectrometry as an Alternative to Radioactive Labeling Methods
Authors: Browne Thomas R. , Szabo George K. , Ajami Alfred , Wagner David
Published: March 2013

Stable isotope labeling in therapeutic and subtherapeutic quantities of drug (15N213C‐phenobarbital) can be quantitated in biological matrices (urine) and high performance liquid chromatography (HPLC) peaks from urine using continuous‐flow isotope‐ratio mass spectrometry (CF‐IRMS). Standard curves for 15N213C‐phenobarbital were reproducible and linear (R2 > 0.985) over the ranges of 3–100 μg/mL for whole urine (1SN2 or 13C labeling) and 0.1–8.0 μg/mL for HPLC peaks derived from urine (15N2 labeling). The lower limit of quantitation values for urine drug concentration was 0.46–2.62 μg/mL in whole urine and 0.10–0.70 μg/mL in HPLC peaks. Validation samples quantitated with these standard curves yielded close to expected values. These data suggest stable isotope labeling and CF‐IRMS may be used as an alternative to 14C labeling and radioactivity counting methods in mass balance/metabolite identification and other biomedical studies.
Cocaine Abuse in North America: A Milestone in History
Authors: Das Gopal
Published: March 2013

The euphoric effects of coca leaves have been known to mankind for thousands of years. Yet the first epidemic of cocaine use in America occurred during the late 19th century. Initially, there were no laws restricting the consumption or sale of cocaine. In fact, cocaine was freely available in drug stores, saloons, from mail‐order vendors, and even in grocery stores, it is reported that one drug manufacturer, in 1885, was selling cocaine in 15 different forms, including cigarettes, cheroots, inhalants, cordials, crystals, and solutions. Many famous imported wines, such as “Vin Mariani,” contained a mixture of wine and coca. For consumers on budgets, the wonder drug was available as Coca‐Cola and dozens of other soda pops and pick‐me‐up drinks. One of them even had a simple and direct name, Dope. Soon enough, the ill effects of cocaine became apparent, and by the 1920s cocaine was the most feared of all illicit drugs. Most states began enacting laws against cocaine use. President William Taft proclaimed cocaine as Public Enemy No. 1, and in 1914 the Congress passed the Harrison act, which tightly regulated the distribution and sale of cocaine. By the late 1950s, cocaine use in the United States was simply considered a problem in the past. Unfortunately, the people who were aware of the nation's first cocaine epidemic gradually passed away, and America once again was ready for its fling with cocaine in the 1960s. Today, it is estimated that upwards of 50 million Americans, that is one in four, have used cocaine. In addition, another fifty thousand people use this substance for the first time each day. More than 6 million Americans use cocaine on a regular basis. Little wonder, then, that America as well as the other countries have declared a “War on Drugs.” In this review, pharmacology of cocaine, major complications arising from its use, and efforts to curb its abuse are discussed.
Renal Effects of Antihypertensive Medications: An Overview
Authors: Abbott Kevin C. , Bakris George
Published: March 2013

A variety of antihypertensive agents are available for management of elevated arterial pressure. Although these agents all effectively lower arterial pressure, they have somewhat diverse renal hemodynamic proxies. This report reviews the various similarities and differences in renal hemodynamic profiles among the different antihypertensive agents.
Development of PharmTest: A Unique Personal Computer‐Mediated Tool for Assessment of Pharmacology
Authors: Burford H. J. , Balfour D. J. K. , Stevenson I. H.
Published: March 2013

This report concerns the development of an assessment* model (PharmTest)† for further evaluation by academic pharmacologists. The content area chosen for this model is the pharmacology of affective disorders. The components of the PharmTest system are: 1) a cognitive map of the content area used to develop the learning objectives (Figure): 2) both lower‐ and higher‐level objectives developed jointly by basic and clinical faculty; 3) a bank of multiple choice questions (MCQ) judged to be congruent to the objectives by an expert panel; 4) a software program (SP) to manage the testing process; and 5) an annotated self‐study document to aid students in their review after computer self‐testing. PharmTest is designed to assist faculty in producing tests, making possible student self‐testing and study. PharmTest was developed during a 6‐month cooperative project between a faculty member from the University of North Carolina (HJB) and faculty of the University of Dundee. This report presents the learning objectives and cognitive map developed for the model content topic of “Pharmacology of Affective Disorders.” Also it suggests a recipe for development of other content areas of pharmacology based on this project. Also, it presents the development process for PharmTest. Finally a plan for collecting evaluation data from academic pharmacology faculty is presented. Implications of the increased efficiency to faculty in linking learning objectives and testing are discussed, and a suggestion is made for national evaluation of learning in pharmacology.
Evaluation and Counseling of Teratogenic Risk: The Motherisk Approach
Authors: Koren Gideon , Graham Karen , Feigenbaum Annette , Einarson Tom
Published: March 2013

The authors present a new approach for evaluation and counseling of teratogenic risk, The Motherisk program in Toronto presently deals with 60 inquiries per day from the public and health professionals. Most calls are answered through the telephone, and 16–20 women per week are scheduled for our clinic following exposure to known or suspected teratogens, to new drugs with sparse information, to chronic drug therapy, or drugs of abuse. Also seen in clinic are women who want to he counseled or whose physicians want them to meet us due to high levels of anxiety. Since its inception in 1935 the Program has been very effective in preventing unnecessary terminations of otherwise wanted pregnancies. In addition to the clinical service we followup the outcome of these prospectively collected exposures, thus creating a large data base necessary to verify safety/risk of various agents. During the last 2 years Motherisk has completed singly, or in collaboration, large prospective studies on gestational exposure to lithium, antiepileptics, cocaine, and fluexitime. To study the reproductive risks of cocaine we compared first‐trimester exposure to cocaine with two control groups. Infants exposed to cocaine did not have higher rates of any adverse perinatal outcome. Their cognitive function at 16 months of age was identical to the control infants. Meta analysis of all studies assessing gestational risks of cocaine reveals that the results of these studies were dependent on the type of comparison conducted. When babies exposed to cocaine were compared with middle class nonusers, the cocaine groups seemed to he more often different from their controls. Conversely, when cocaine‐exposed infants were compared with babies of women exposed to other drugs of abuse but not cocaine, most of these differences cancelled out, suggesting that clustering of other risk factors may cause some of these adverse effects.
Impaired Elimination of Atenolol in a Nephropathie Patient with Self‐Medication Overdose
Authors: El‐Yazigi Adnan , Bouchama Abderrezak , Al‐Abdely Hail , Yusuf Ahmed , Sieck Jens O.
Published: March 2013

A case of intoxication with atenolol (plasma concentration of 2.71 mg/L) caused by an improper self‐medication combined with impaired renal function is presented. The patient was supported with atropine, isoproterenol dopamine, and dobutamine, and a thorough pharmacokinetic monitoring of atenolol was conducted. As the serum creatinine concentration returned slowly to baseline with good diuresis, the concentration of atenolol decreased (biologic half‐life = 2.95 days) and the blood pressure gradually recovered. The patient improved and was subsequently discharged in good health. Had pharmacokinetic monitoring of atenolol not been performed, hemodialysis would have been indicated.
Pharmacokinetics of Intravenous and Intraperitoneal Ceftazidime in Chronic Ambulatory Peritoneal Dialysis
Authors: Demotes‐Mainard F. , Vinçon G. , Ragnaud J. M. , Morlat P. , Bannwarth B. , Dangoumau J.
Published: March 2013

The pharmacokinetics of ceftazidime have been investigated in eight patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis. Each subject was given ceftazidime 1 g intravenously and 1 g intraperitoneally at an interval of 1 week. Ceftazidime was assayed by high‐pressure liquid chromatography. After intravenous administration, the pharmacokinetic parameters of ceftazidime were: elimination plasma half‐life (t1/2β) = 24.6 ± 4.6 hours; apparent volume of distribution (Varea): 0.37 ± 0.09 1/kg, total plasma clearance (CL): 11.9 ± 3.3 mL/minute, peritoneal clearance (CLp): 1.7 ± 0.3 mL/minute. Over 72 hours, only 15.6 ± 4.7% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftazidime appeared in the plasma rapidly, and the peak plasma concentration of 24.5 ± 5.2 mg/L was achieved at the fourth hour; the elimination half‐life (t1/2ke) was 20.8 ± 1.7 hours. The absorption of ceftazidime from the peritoneal space was 74.1 ± 7.4%. These data suggest that ceftazidime has bidirectional exchange characteristics through the peritoneal membrane. A single 1‐g intraperitoneal dose led to serum and dialysate concentrations of ceftazidime above the minimum concentrations for susceptible pathogen germs for 24 hours.
What is Nitric Oxide and Why Are So Many People Studying It?
Authors: Gibaldi Milo
Published: March 2013

From social outcast to citizen of the year in less than a decade is the stuff of fiction. That is precisely what has happened, however, to a remarkably simple molecule, nitric oxide. Nitric oxide is still an environmental pollutant, suspected carcinogen, and precursor of acid rain, but biologists are looking past its dark side. They now see a molecule that is uniting neuroscience, physiology, and immunology. Its ubiquitous distribution in the body and its multifaceted roles are revising our understanding of how cells communicate and protect themselves. This report examines nitric oxide's role in physiology and pathophysiology and reviews novel therapeutic approaches which involve inhibition or induction of the activity of endogenous nitric oxide.
Sotalol: A Novel Beta‐Blocker with Class III Anti‐Arrhythmic Activity
Authors: Leibowitz David
Published: March 2013

Initially synthesized in 1960, Sotalol is a novel beta‐adrenoreceptor blocking agent that also possesses class III anti‐arrhythmic properties. The drug's ability to lengthen repolarization and prolong effective refractory periods in all cardiac tissues in addition to its beta‐blocking effects make Sotalol an attractive agent for use in a variety of supraventricular and ventricular arrhythmias.
Echocardiograms During Six Hours of Bedrest at Head‐Down and Head‐Up Tilt and During Space Flight
Authors: Lathers Claire M. , Riddle Jeanne M. , Mulvagh Sharon L. , Mukai Chiaki , Diamandis Peter H. , Dussack Larry G. , Bungo Michael W. , Charles John B.
Published: March 2013

Left ventricular end‐diastolic volume increased after 4 1/2 to 6 hours of space flight, but was significantly decreased after 5 to 6 days of space flight. To determine the role of acute gravitational effects in this phenomenon, responses to a 6‐hour bedrest model of 0 gravity (G; 5° head‐down tilt) were compared with those of fractional gravity loads of 1/6G, 1/3G, and 2/3G by using head‐up tilts of 10°, 20°, and 42°, respectively. On 4 different days, six healthy male subjects were tilted at one of the four angles for 6 hours. Cardiac dimensions and volumes were determined from two‐dimensional and M‐mode echocardiograms in the left lateral decubitus position at control (0), 2, 4, and 6 hours. Stroke volume decreased with time (P < .05) for all tilt angles when compared with control. Ejection fraction (EF) at −5° was greater than at +20° and +42° (not significant); EF at +10° was greater than at +42° (not significant). For the tilt angles of −5°, +10°, and +20°, mean heart rate decreased during the first 2 hours, and returned to control or was slightly elevated above control (+20°) by 6 hours (not significant). At the +42° angle of tilt, heart rate was increased above control at hours 2, 4, and 6. There were no significant differences in cardiac output at any time point for any tilt angle. Left ventricular end‐diastolic volume did not change significantly with time or tilt angle, but there was a trend to a decrease by hour 2. Left ventricular end‐systolic volume was increased at hour 2 (not significant) and at hour 4 (not significant) for subjects at −5°. Systolic blood pressure did not change significantly. Left ventricular end‐diastolic volume, left ventricular end‐systolic volume, stroke volume, ejection fraction, heart rate, and cardiac output were at control values by hour 6 for all tilt angles. The lack of a significant immediate change in left ventricular end‐diastolic volume despite decrements in stroke volume (P < .05) and heart rate (not significant) suggests that multiple factors may play a role in the adaptation to simulated hypogravity. The data indicate that no angle of tilt, whether head‐down or head‐up for 4 to 6 hours, mimicked exactly the changes in cardiovascular function recorded after 4 to 6 hours of flight. Thus space and bedrest changes in left ventricular end‐diastolic volume may be similar but possess a different time course. Nevertheless, head‐down tilt at 5° for 6 hours mimics some (stroke volume, systolic and diastolic blood pressure, mean arterial blood pressure, total peripheral vascular resistance), but not all, of the changes occurring in an equivalent time of space flight.
Comparisons of Beta‐Adrenergic Blocking Properties of S‐ and R‐Timolol in Humans
Authors: Rotmensch Heschi H. , Vlasses Peter H. , Feinberg Jerry A. , Abrams William B. , Ferguson Roger K.
Published: March 2013

In animals, the R‐enantiomer of timolol causes a significant reduction in intraocular pressure but had only 1/80 the activity of the S‐enantiomer at extraocular receptors. The beta1‐ and beta2‐adrenoceptor blocking properties of orally administered R‐and S‐timolol were compared in a double‐blind placebo controlled trial in two groups of healthy men. Each subject in group A (n = 6) received placebo, 1 and 3 mg S‐timolol and 25 and 75 mg R‐timolol in random order, group B (n = 5) received placebo, 0.5, and 1 mg S‐timolol and 3 and 10 mg R‐timolol. In both groups, R‐and S‐timolol comparably inhibited isoproterenol‐induced increases in heart rate (P < .05), forearm blood flow (P < .05, except at 3 μg/minute of isoproterenol after the R‐doses in group B), and finger tremor (P < .05) in comparison with placebo. The findings for the R‐enantiomer in this study were unexpected based on the animal studies and previous studies that demonstrated marked differences in beta blocking effects of other beta‐blockers in which the R‐enantiomers were less inhibitory.
The Hepatic First‐Pass Metabolism of Problematic Drugs
Authors: Lalka David , Griffith Robert K. , Cronenberger Carol L.
Published: March 2013

The first‐pass hepatic metabolism of a number of important therapeutic agents is inconsistent with traditional models that assume that the hepatic extraction ratio of a drug is constant in each individual (independent of the concentration of drug in the hepatic sinusoidal blood and also independent of the history of exposure to the drug). In this review, the authors examine the first‐pass metabolism of five “problematic drugs” (propranolol, lidocaine, propafenone, verapamil, and nitroglycerin). Each of these compounds has unique facets to its hepatic clearance and pharmacokinetics as well as striking similarities. Selected aspects of first‐pass metabolism are reviewed, and a theory that may explain some of the unusual behavior of the four lipophilic bases (propranolol, lidocaine, propafenone, and verapamil) is presented. Finally, the unusual and variable clearance of nitroglycerin is discussed.
The Clinical Implications of First‐Pass Metabolism: Treatment Strategies for the 1990s
Authors: Somberg John , Shroff Girish , Khosla Sandeep , Ehrenpreis Seymour
Published: March 2013

The first‐pass effect is real. It may pose obstacles to the treatment of disease, and strategies need to be developed to address the problem that first pass can cause. First we have to look at identifying the problem, and this symposium has helped to further emphasize that the problem exists and awareness is increasing. The first‐pass effect has been a basic tenant of pharmacology but an area not receiving active research interest and one that is often overlooked in the clinical arena. Avoiding drug interactions is a consideration, and that is a major challenge to the field of clinical pharmacology. Clinicians need to be aware of the problem, aware of the danger areas with drugs, and first pass. Another alternative is to turn to chemical modification of a drug that avoids needing to take first pass into consideration.
Renal Effects of A Nonhypotensive IV Dose of Felodipine
Authors: Larochelle P. , Cusson J. R. , du Souich P. , Thibault G. , Edgar B.
Published: March 2013

To evaluate the natriuretic effect of a nonhypotensive dose of felodipine, 11 healthy volunteers (age: 21–28 years) on a high‐sodium diet received the drug or its vehicle in a double‐blind, randomized, crossover study. Administered intravenously at a dose level of 7.5 μg/min for 30 minutes followed by 5 μg/min for 120 minutes, felodipine increased natriuresis (546 ± 69 vs. 454 ± 39 μmol/min, P <0.001) and diuresis (8.9 ± 0.6 vs. 7.5 ± 0.5 mL/min), compared to its vehicle. Renal plasma flow tended to be augmented, but there was a significant reduction of renal vascular resistance (0.085 ± 0.004 vs. 0.101 ± 0.012 mm Hg/mL/min, P <0.03). The glomerular filtration rate was slightly decreased and proximal sodium reabsorption was diminished with no measurable effect on distal function. Felodipine stimulated plasma renin activity, but produced no changes in plasma atrial natriuretic factor, cGMP, aldosterone, and atrial vasopressin levels. In conclusion, felodipine induced natriuresis and diuresis while reducing proximal tubular sodium reabsorption.
Differences of Chronopharmacokinetic Profiles Between Propranolol and Atenolol in Hypertensive Subjects
Authors: Shiga Tsuyoshi , Fujimura Akio , Tateishi Tomonori , Ohashi Kyoichi , Ebihara Akio
Published: March 2013

Previous studies have shown that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the night dosage than after the morning dosage in nocturnal rodents. The present study examines whether such a difference in chronopharmacokinetic proxies between lipophilic and hydrophilic agents also exists in humans. Propranolol (20 mg), a lipophilic β‐blocker, or atenolol (50 mg), a hydrophilic β‐blocker, was given orally to 13 hypertensive patients at 9:00 am (day trial) or 9:00 pm (night trial) by a crossover design. Plasma concentrations of propranolol and its metabolites, 4‐hydroxypropranolol and naphthoxylactic acid, and atenolol were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours after treatment. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) of propranolol in the day trial were significantly greater than those in the night trial Time to maximum plasma concentration (tmax) was significantly shorter in the day trial. No significant difference was observed in the elimination half‐life between the two trials. There were similar administration time‐dependent changes in the Cmaxfor 4‐hydroxypropranolol and naphthoxylactic acid. On the other hand, although the Cmax of atenolol was greater and its tmax was shorter in the day trial, the differences did not reach significance. These results suggest that propranolol, but not atenolol is absorbed more rapidly after the morning dosage than after the night dosage. Based on these findings, the authors speculate that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the morning dosage than after the night dosage in humans.
Interspecies Scaling and Pharmacokinetic Parameters of 3TC in Humans
Authors: Hussey Elizabeth K. , Donn Karl H. , Daniel Mick J. , Hall Susan T. , Harker Andy J. , Evans Gary L.
Published: March 2013

3TC is a dideoxy‐nucleoside analogue that has demonstrated in‐vitro activity against human immunodeficiency virus (HIV). 3TC concentrations in humans were predicted before the initiation of clinical trials by interspecies scaling of pharmacokinetic parameters observed in animal species. Clearance and volume of distribution were estimated for humans using linear regression on a log‐log scale of each parameter versus body weight for rats and dogs. The concentration‐time profile and the average serum concentration at steady state after various dosage regimens were estimated as a basis for initial dose selection for clinical trials. The predicted parameters (clearance of 16.3 L/hr and volume of distribution of 40 L for a 70‐kg man) were compared with that observed (mean clearance of 24 L/hr and mean volume of distribution of 96 L, mean weight of 74 kg) in 20 asymptomatic, HIV positive, volunteers after single intravenous doses of 3TC. Interspecies scaling was applied prospectively as a rationale for dose selection of 3TC in clinical trials.
Drug Chirality: On the Mechanism of R‐Aryl Propionic Acid Class NSAIDs. Epimerization in Humans and the Clinical Implications for the Use of Racemates
Authors: Wechter William J.
Published: March 2013

This review summarizes and comments on the current understanding of both the biochemical and clinical implications of the epimerization of R‐aryl propionic (APA) class (1) nonsteroidal anti‐inflammatory agents (NSAIDs) to S‐enantiomers in humans. This article focuses principally on rac‐ibuprofen and its enantiomers. In the United States, five commercialized NSAIDs are APAs. Only two of them, rac‐ibuprofen and rac‐fenoprofen, are subject to significant epimerization in humans. The remaining three, rac‐flurbiprofen, rac‐ketoprofen, and S‐naproxen, are not of interest in this context.
Pediatric Medication Errors: Predicting and Preventing Tenfold Disasters
Authors: Koren Gideon , Haslam Robert H.
Published: March 2013

Tenfold errors in pediatric doses are not uncommon. Because the needed volume of stock solution is generally small, even a tenfold higher volume may still appear deceivingly normal. Such errors are much less likely to occur in adults, because it would result in unacceptably large volumes of stock solution. Other sources of tenfold errors are communication difficulties with parents and illegible writing of orders by physicians. Testing health professionals may identify subgroups of individuals who are prone to commit such errors. Independent double checking of calculations and a mechanism to resolve disagreement is being practiced in most academic institutions. Transition to patient's unit dose is likely to decrease calculation errors, because pharmacists commit fewer errors. Hazardous drugs that are not required on a stat basis should be removed from the wards.
Concentrated Potassium Chloride Infusions in Critically Ill Patients with Hypokalemia
Authors: Kruse James A. , Clark Vivian L. , Carlson Richard W. , Geheb Michael A.
Published: March 2013

Although concentrated infusions of potassium chloride commonly are used to treat hypokalemia in intensive care unit patients, few studies have examined their effects on plasma potassium levels. Forty patients with hypokalemia were given infusions of 20 mmol of potassium chloride in 100 mL of normal saline over 1 hour; 26 patients received the infusions through the central vein and 14 patients through the peripheral vein. Plasma potassium ([K]p) was measured at 15‐minute intervals during and after the infusion in 31 patients. ΔK was defined as the difference between each potassium determination and baseline plasma potassium concentration. Continuous electrocardiographic recording was carried out during the infusion and during the 1‐hour period immediately preceding the infusion. Mean baseline [K]pwas 2.9 mmol/L and all subsequent plasma concentrations significantly increased from baseline. Mean peak [K]pwas 3.5 mmol/L, [K]p(1 hour postinfusion) was 3.2 mmol/L, and mean postinfusion ΔK was 0.48 mmol/L (range −0.1–1.7 mmol/L). Arrhythmias, changes in cardiac conduction intervals, and other complications did not occur. The frequency of premature ventricular beats decreased significantly during the infusion compared with that of the control period. The high concentration (200 mmol/L) and rate of delivery (20 mmol/hr) of the potassium chloride infusions were well tolerated, decreased the frequency of ventricular arrhythmias, and did not cause transient hyperkalemia.
Habituation and Motion Sickness
Authors: Wood Charles D. , Stewart John J. , Wood Mary J. , Struve Frederick A. , Straumanis John J. , Mims Malcolm E. , Patrick Gloria Y.
Published: March 2013

The vestibular, cerebellar, and reticular systems are central in importance, in motion sickness and habituation, to the effects of motion. Nuclear medicine single photon emission computed tomography (SPECT) studies of cerebral blood flow and power spectral electroencephalographic recordings during motion sickness were used to determine alterations in the central nervous system. The rotating chair with and without visual stimulation was used to study the rate of habituation and the effect of antimotion sickness medications on this rate. An increase of theta waves over the frontal cortex indicated a decreased activation of the higher centers during motion sickness. Motion sickness also produces an increase of blood flow in the central cerebellum that has connections to the reticular system. This increase in cerebellar activity is relayed to the reticular system whereby neural recruitment builds up to trigger the vomiting center, producing motion sickness. Habituation may be a conditioned compensatory activation of the reticular neurons that prevents this disruption of normal activation. The rate of habituation when motion sickness was prevented by scopolamine was slowed, indicating that, if the central nervous system is not challenged by disruption of normal activation, it does not produce the compensatory reactions that result in habituation.
Effects of Motion Sickness and Antimotion Sickness Drugs on Gastric Function
Authors: Stewart John J. , Wood Mary J. , Wood Charles D. , Mims Malcolm E.
Published: March 2013

This study examined the effects of motion sickness and antimotion sickness drugs on gastric emptying (GE). Drugs were tested in normal and motion sick subjects. To induce motion sickness, subjects performed head movements while seated in a rotating chair. Gastric emptying of liquid (300 mL) was determined by nuclear medicine techniques, whereas gastric electrical activity, the electrogastrogram (EGG), was monitored from surface (cutaneous) electrodes positioned over the abdominal area. Gastric emptying was severely inhibited at the peak of motion sickness symptoms, but returned to normal 15 minutes later when symptoms abated. In normal (non—motion sick) subjects intramuscular (IM) scopolamine (0.1 mg) and IM promethazine (25 mg) inhibited GE, whereas erythromycin ethylsuccinate (EES) suspension (200 mg) given orally increased GE. When administered to motion sick subjects, IM scopolamine and IM promethazine added slightly, but not significantly, to the inhibition of GE already present. Oral EES did not significantly alter GE in motion sick subjects. Although EGG frequency remained within normal limits (∼2.5–3.5 cpm) after liquid ingestion in both normal and motion sick subjects, EGG amplitude was differentially affected in the two groups. Electrogastrogram amplitude increased twofold to fourfold after liquid ingestion in normal, but not in motion sick subjects. The results suggest that (1) maximal inhibition of GE is coincident with peak motion sickness symptoms, (2) both IM scopolamine and IM promethazine inhibit GE in normal subjects, but do not add significantly to the inhibition of GE already established during motion sickness, (3) orally administered erythromycin enhances GE in normal, but not in motion sick subjects, and (4) the normal stimulatory effect of liquid ingestion on gastric motility does not occur in motion sick subjects. Both motion sickness and parenterally administered antimotion sickness drugs are potential sources of inhibited GE in space.
Use of Promethazine to Hasten Adaptation to Provocative Motion
Authors: Lackner James R. , Graybiel Ashton
Published: March 2013

In an earlier study, the authors found that severely motion sick individuals could be greatly relieved of their symptoms by intramuscular injections of promethazine (50 mg) or scopolamine (.5 mg). Comparable 50‐mg injections of promethazine also have been found effective in alleviating symptoms of space motion sickness. The concern has risen, however, that such drugs may delay or retard the acquisition of adaptation to stressful environments. In the current study, we controlled arousal using a mental arithmetic task and precisely equated the exposure history (number of head movements during rotation) of a placebo, control group and an experimental group who had received promethazine. No differences in total adaptation or in rates of adaptation were present between the two groups. Another experimental group also received promethazine and was allowed to make as many head movements as they could, before reaching nausea, up to 800. This group showed a greater level of adaptation than the placebo group. These results suggest a strategy for dealing with space motion sickness that is described.
Oral Ondansetron Pharmacokinetics: The Effect of Chemotherapy
Authors: Hsyu Poe‐Hirr , Pritchard J. Frederick , Bozigian Haig P. , Gooding Ann E. , Griffin Rita H. , Mitchell Rodney , Bjurstrom Toni , Panella Timothy L. , Huang Andrew T. , Hansen Lea Ann
Published: March 2013

The effect of a typical 5‐day chemotherapy treatment with cisplatin (20–40 mg/m2 per day) and 5‐fluorouracil (5‐FU, 1 gm/m2 per day) on the pharmacokinetics of ondansetron was investigated. Twenty cancer patients received 8 mg of ondansetron in three periods, including an oral tablet on day 1, an intravenous infusion on day 4, and an oral tablet on day 5. Absolute bioavailability after the oral dosing on day 1 was 87.5 ± 31.3%, and on day 5 was 85.2 ± 22.1% (P > .05). Mean values of AUC, Cmax, Tmax, and half life on days 1 and 5 were 399 ± 275 and 381 ± 222 ng · hour/mL, 53.3 ± 26.8 and 43.6 ± 21.7 ng/mL, 1.9 ± 1.4 and 2± 1.4 hours, and 5.21 ± 1.78 and 6.19 ± 1.99 hours, respectively. These values were not significantly different (P > .05). In summary, this study showed that cisplatin and 5‐FU did not significantly alter the pharmacokinetics of oral ondansetron in cancer patients during the 5 days of chemotherapy. Oral bioavailability of ondansetron appeared to be greater in cancer patients than in healthy subjects.
Pharmacokinetics of Zidovudine in HIV‐Positive Patients with Liver Disease
Authors: Bareggi Silvio R. , Cinque Paola , Mazzei Mauro , D'Arminio Antonella , Ruggieri Alessandro , Pirola Rodolfo , Nicolin Angelo , Lazzarin Adriano
Published: March 2013

The pharmacokinetics of zidovudine (ZDV) have been studied in eight AIDS patients with normal liver function, and in four AIDS patients with liver disease. Patients who were previously untreated with ZDV were given 250 mg ZDV, and plasma levels of ZDV and its glucuronic metabolite, GZDV, were determined at 0.5, 1, 1.5, 2, 3, and 4 hours after the dose. In patients with liver disease, Cmax and AUC of ZDV were higher, the oral clearance was only one‐eighth that of patients without liver disease, and the elimination half‐life was longer. There was a trend for concentrations of the principal metabolite, GZDV, to be lower in patients, and, therefore, the ratio of the AUC for GZDV to that for ZDV was much lower in patients with liver disease. Therefore, HIV‐seropositive patients with liver disease had the same markedly altered disposition of ZDV as seronegative patients with liver disease. Although this therapy was not clearly associated with a higher incidence of toxicity, some patients with liver disease had to discontinue therapy because of intolerance; therefore, plasma levels of these patients should be monitored when such therapy is undertaken.
Dose Proportionality of Bisoprolol Enantiomers in Humans After Oral Administration of the Racemate
Authors: Dutta Atanu , Lanc Robert , Begg Evan , Robson Richard , Sia Luisa , Dukart Gary , Desjardins Robert , Yacobi Avraham
Published: March 2013

Dose proportionality of racemic bisoprolol and the stereoselectivity of its enantiomers were studied after single oral dosing of 5 to 40 mg of bisoprolol hemifumarate in eight healthy male volunteers in an open‐label, randomized, four‐way cross‐over trial. There were dose‐proportional increases in mean peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values for the racemate and the individual enantiomers. No statistically significant differences were detected between the mean half life (t1/2), Cmax, and time to reach Cmax (tmax) of the R‐ and S‐isomers at each of the four dose levels studied. These findings support dose proportionality and absence of stereoselective pharmacokinetics for bisoprolol in the dose range studied.
Comparison of the Pharmacokinetics of Naproxen Tablets and Suspension in Children
Authors: Wells Thomas G. , Mortensen Mary Ellen , Dietrich Ann , Walson Philip D. , Blasier R. Dale , Kearns Gregory L.
Published: March 2013

Twenty‐three children, aged 8 to 14 years, with postoperative pain, were randomly assigned to receive a fixed 250‐mg dose (4.66–7.58 mg/kg) of naproxen as either a liquid suspension or tablet. After an overnight fast, the serum concentrations were measured before and at 0.5,1,2,3,4, 8,12,18, and 24 hours after administration of naproxen. The concentration versus time data were best fit to a one‐compartment open model. The area under the concentration versus time curve, apparent volume of distribution (VDss/F), and elimination parameters (CL/F, Ke, elimination half‐life) were similar in children who received suspension or tablets. Although the apparent maximum peak plasma concentration (Cmax) was greater in children who received tablets compared with those who received the suspension, Cmax/area under the curve (AUC), apparent time to maximum peak concentration (tmax), Ka, and estimated time to 10%, 50%, and 90% absorption (T10, T50, T90) were not different. The dose range was relatively narrow; hence, direct relationships between dose and elimination parameters, VDss/F, apparent tmax, Ka, T10, T50 or T90 were not observed. Neither VDss/F or CL/F were age related over the relatively narrow range of ages that were studied. Elimination of naproxen in our patients was more rapid than has previously been reported in children or adults, however. From a practical standpoint, naproxen tablets and suspension seem to be bioequivalent in fasting children ages 8 to 14 years.
Adverse Drug Reactions in Neonates
Authors: Knight Matthew
Published: March 2013

Adverse drug reactions (ADR) are uncommon causes of admission of neonates to the neonatal intensive care unit. The neonate, however, is potentially at significant risk for adverse drug reactions because of underdeveloped mechanisms and systems for handling drugs (the Gray Baby Syndrome with chloramphenicol as a classic example), the fact that infants in neonatal intensive care units are often critically ill with multiple organ system dysfunction, that they may be on multiple drugs, and that they may present with an adverse drug reaction as a result of exposure while still a fetus. There is also a history of misadventures in the neonatal intensive care unit and newborn nurseries due to exposure to antibacterial agents that produced systemic effects from percutaneous absorption. In this review, an overview of the mechanisms of adverse drug reactions will be presented, followed by a general review of the experience of adverse drug reactions in neonates and some specific examples of current adverse drug reactions and a suggested approach for the prevention and evaluation of adverse drug reactions in neonates.
Comparison of Fixed‐Dose Transdermal Nicotine, Tapered‐Dose Transdermal Nicotine, and Buspirone in Smoking Cessation
Authors: Hilleman Daniel E. , Mohiuddin Syed M. , Delcore Michael G.
Published: March 2013

The authors compared the outcome of 208 smokers treated with fixed‐dose transdermal nicotine (n = 69), tapered‐dose transdermal nicotine (n = 71), or Buspirone (n = 68). At baseline, there were no significant differences among the three treatment groups with regard to age, gender, educational level, duration of smoking, number of cigarettes smoked per day, concomitant disease states or drug use, or Fagerstrom score. All smokers participated in a behavior modification program. Fixed‐dose transdermal nicotine was given at a dose of 21 or 22 mg/day for 6 weeks. Tapered‐dose transdermal nicotine was given at a dose of 21 or 22 mg/day for 4 weeks, 14 mg/day for 4 weeks and 7 mg/day for 4 weeks. Both transdermal nicotine regimens were initiated on the evening before the attempted quit date. Buspirone was started 21 days before the quit attempt and continued for 7 days after the quit attempt. Buspirone was initiated at 5 mg TID for 7 days and then 10 mg TID for 21 days. Smoking cessation was assessed by patient diaries and random plasma thiocyanate determinations. Dropouts for any reason were considered treatment failures. Quit rates were as shown in the Table I. Discontinuation of treatment for perceived side effects and dropouts for all reasons were not significantly different among the treatment groups. The authors conclude that fixed‐dose transdermal nicotine, tapered‐dose transdermal nicotine, and buspirone are associated with similar efficacy and safety when combined with behavior modification in smoking cessation.
Interaction in Crossover Studies: A Modified Analysis with More Sensitivity
Authors: Cleophas Ton J.M.
Published: March 2013

The crossover trial has an intuitive appeal to clinicians because each patient is used as his own control Thus, between‐subject variability of symptoms is eliminated. However, this study design suffers from the bias of treatment‐by‐period interaction. If, for example, the effect of the first treatment period carries on into the next one, then it influences the response to the latter period (carryover effect). A second problem is, that the standard approach (Hills‐Armitage analysis) for interaction has a low sensitivity. An alternative method that looks at the performance of the separate treatment groups and not, as the standard approach, at the means of the groups is presented. This alternative approach does have more sensitivity than the standard in the common clinical situation where there is interaction in just one of the treatment groups. This study shows that this is so. However, the standard approach is more sensitive in the case of two‐group interaction. One approach supplements the other.
Renin Inhibition: A New Approach to Cardiovascular Therapy
Authors: Frishman William H. , Fozailoff Alan , Lin Cherry , Dike Chidiadi
Published: March 2013

The renin‐angiotensin system (RAS) functions as a primary regulator in the short‐term and long‐term control of blood pressure. Pharmacologic inhibition of the RAS with angiotensin‐converting enzyme (ACE) inhibition is effective for treating systemic hypertension and congestive heart failure. As a more specific therapy, the development of renin inhibitors has evolved through various approaches: specific renin antibodies, peptides developed from prosegments of renin precursor, oligopeptides related to pepstatin a universal inhibitor of aspartyl proteinase enzyme, and analogs of angiotensinogen (the renin substrate). Angiotensinogen analogs are promising as therapeutic agents because of high potency, metabolic stability, and good oral bioavailability. Ongoing research is directed towards the application of renin inhibition, the treatment of various cardiovascular disorders, and as a biological probe for understanding the role of the RAS in control of blood pressure and blood volume.
Lack of Hepatotoxicity with Naltrexone Treatment
Authors: Sax Daniel S. , Kornetsky Conan , Kim Anthony
Published: March 2013

Naltrexone, a specific opiate receptor antagonist, is used clinically in the treatment of heroin addiction and more recently, for the treatment of dyskinesia associated with Huntington's disease (HD). Naltrexone may act as a potential hepatotoxin, as reflected in the elevation of transaminase levels. However, one study concluded that, for a brief treatment period of 12 weeks, there is no contraindication to naltrexone treatment based solely on increased hepatic enzyme values. This study monitored liver transaminase levels, in ten HD patients receiving daily doses, between 50 mg/day and 300 mg/day, of naltrexone for periods of 10 to 36 months. Serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were obtained before treatment and at intervals of 1 to 4 months during treatment. Only one of the ten patients treated with naltrexone had increased levels of both SGOT and SGPT, whereas one other patient showed elevated levels of SGPT. These elevations, which initially appeared dose related decreased to normal limits with continued treatment. Because many of the patients were receiving other medications, a combination of drugs with naltrexone may contribute to the increased transaminase levels seen in two of the patients. In summary, chronic administration of naltrexone in doses up to 300 mg/day for periods up to 36 months does not significantly change hepatic function, as measured by SGOT and SGPT levels.