bluuebunny/crossref_metadata_2025 huggingface dataset:
Adverse Effects of Drugs and Chemicals in Breast Milk on the Nursing Infant
Authors: Kacew Sam
Published: March 2013

Breastfeeding is an essential physiologic process that provides nutrition to the infant and protects the child against infection and immunologic disorders. The incidence of various diseases and metabolic disorders is known to be less in a breastfed infant compared with a child given a milk substitute. Psychologically, a breastfed infant forms a maternal bond that enables adaptation more readily to a social environment. It is well‐established that all drugs are excreted into breast milk and are bioavailable to the infant. In general the majority of drugs do not pose a significant problem to the nursing in/ant and breastfeeding should be encouraged. The physician should be aware of which drugs are contraindicated during lactation and which drugs should be used with caution. There are also environmental chemicals that readily enter breast milk and may induce adverse effects. At present, the advantages of breastfeeding for infant development outweigh the potential adverse consequences and this physiologic process should be encouraged. With the use of available data on pharmacokinetics, milk‐to‐plasma ratio, excretion, etc. a supportive approach can be delineated by the pediatrician to reassure the nursing mother that they can safely breastfeed and continue therapy with minimal effects on the infant. It is thus imperative to document the extent to which a drug or chemical appears in breast milk and any apparent effects in the infant.
The Place of Alpha Blockers in the Antihypertensive Armamentarium
Authors: Carruthers S. George
Published: March 2013

Although beta‐blockers and diuretics are presently the only medications shown to reduce morbidity and mortality in hypertensives in large clinical trials, these drugs have not exerted optimal expected benefits in reducing cardiac events. Alpha‐1 selective blockers exhibit a favorable impact on lipids, particularly on HDL‐cholesterol. Unlike beta‐blockers, they do not increase triglycerides and they do not produce the increase in LDL‐cholesterol observed with traditional doses of diuretics. Alpha‐blockers should be considered in the treatment of hypertensives with lipid disorders or diabetes and in those who have contraindications, failure to respond or toxicity associated with diuretics and/or beta‐blockade.
Mechanisms of Action of Adrenergic Receptor Blockers on Lipids During Antihypertensive Drug Treatment
Authors: Rabkin Simon W.
Published: March 2013

The objective of this article is to focus on the antihypertensive agents blocking adrenergic receptors, both alpha and beta blockers, and attempt to construct potential explanations for their effects on lipids in a mechanistic manner. The essential thesis is that adrenergic control of lipid metabolism is responsible for the effect on lipids and lipoproteins of antihypertensive agents that block adrenergic receptors. Agonists and antagonists show the opposite action on lipoprotein lipase, lecithin: cholesterol acyltransferase (LCAT) and LDL‐cholesterol uptake by LDL receptors in a manner that might explain the findings of increases in triglycerides and LDL cholesterol with decreases in HDL cholesterol in patients receiving beta blockers without intrinsic sympathomimetic activity and the reverse in patients on treatment with alpha adrenergic receptor blockers.
Immunopharmacology and Adverse Drug Reactions
Authors: Rieder Michael J.
Published: March 2013

Adverse drug reactions are common and troublesome complications of contemporary pharmacotherapy. Adverse drug reactions are frequently, and often incorrectly, referred to as “allergy.” Although there are multiple mechanisms for adverse drug reactions, adverse drug reactions mediated by the immune system account for a disproportionate number of fatal and serious adverse reactions, and constitute a major clinical problem for patients and physicians. The immune system has evolved in multicellular organisms as a defence against infection, interactions between drugs and the immune system occur as inadvertent consequences of the protective function of the immune system, with drug molecules or drug‐carrier haptens being recognized as “non‐self” by the immune system. The classical mechanisms for drug hypersensitivity described by Gell and Coombs (Types 1 to 4) include IgE‐mediated, cytotoxic, immune complex‐mediated and delayed mechanism. These mechanisms provide elegant models for drug‐immune interactions that can provide mechanistic explanations for events such as urticaria associated with penicillins. However, these mechanisms do not account for many of the immunologically mediated adverse reactions commonly encountered in clinical practice. Over the last two decades, there has been an increasing awareness of the importance of reactive drug metabolites and drug‐protein interactions in the initiation of immunologic events mediating adverse drug reactions. Reactive drug metabolites may produce direct and profound effects on various functions of the immune system. Although some adverse reactions mediated by the immune system occur with equal frequency among adults and children, some of these reactions appear to be markedly more common among children than adults. There are a number of confounding factors that make the evaluation of immunologically mediated adverse reactions among children difficult, including differences in the formulations commonly used among children. There are considerable gaps in our understanding of the role and importance of the immune system in producing adverse reactions to drugs and chemicals. Laboratory assessment has a limited role in the investigation of adverse drug reactions believed to be mediated by the immune system. Clinical examination remains the cornerstone for the evaluation of adverse drug reactions.
Pharmacokinetics of Clentiazem After Intravenous and Oral Administration in Healthy Subjects
Authors: Shah Ajit K. , Bhargava Vijay O. , Weir Scott J. , Giesing Dennis H.
Published: March 2013

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty‐four healthy male subjects (28.5 ± 5.2 years; 77 ± 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four‐way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high‐pressure liquid chromatography method. The values (mean [CV,%])/or systemic clearance, volume of distribution at steady‐state, and half‐life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N‐desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first‐pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration‐time data of CLZ can be described by either a one‐ or two‐compartment pharmacokinetic model.
Effect of Hypothermia and Sampling Site on Blood Esmolol Concentrations
Authors: Jacobs James R. , Croughwell Narda D. , Goodman David K. , White William D. , Reves J. G.
Published: March 2013

Esmolol hydrochloride was administered by constant‐rate continuous infusion to 10 patients undergoing hypothermic cardiopulmonary bypass for coronary artery revascularization surgery. After a suitable loading dose, the esmolol infusion was started approximately 30 minutes before bypass and was stopped 10 minutes after termination of bypass. Esmolol concentrations were measured in arterial and venous blood samples collected before and after bypass and in samples taken from the inflow and outflow ports of the membrane oxygenator during bypass. Blood esmolol concentrations increased during hypothermia in a manner that correlated significantly and inversely with temperature. All patients were separated from the extracorporeal circulation without difficulty, and the average arterial esmolol concentration was slightly below the prebypass concentration within minutes of discontinuing bypass. Esmolol disappeared from the blood rapidly on terminating the infusion. There was no difference between esmolol concentrations measured simultaneously from the inflow and outflow ports of the membrane oxygenator during bypass, but radial arterial esmolol concentrations before and after bypass were on average about sevenfold higher than forearm venous esmolol concentrations during the esmolol infusion! The results of this study lead to two important conclusions: (1) in vivo clearance of esmolol demonstrates acute temperature dependence and (2) esmolol is removed irreversibly as it passes through the microcirculation of the hand, making measurement of peripheral esmolol concentrations markedly dependent on sampling site (arterial versus venous).
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Kidney, Proteins and Drugs Bianchi C, Bocci V, Carone FA, and Rabkin R, Editors.

Pain Versus Man (Advances in Pain Research and Therapy, Vol. 20) Sicuteri F, Vecchiet L, Terenius L, and Maggi CA, Editors; Nicoloci M and Alessandri M, Associate Editors.

The Biology of Nicotine Lippiello PM, Collins AC, Gray JA, and Robinson JH, Editors.

Cardiovascular Drugs and the Management of Heart Disease, 2nd Edition Ewy GA and Bressler R, Editors.

Clinical Immunotoxicology Newcombe DS, Editor‐in‐Chief, Rose NR and Bloom JC, Editors.
Comparison of the Effects of Terazosin and Enalapril on Laboratory Stress Testing Blood Pressure in Patients with Essential Hypertension
Authors: Cardillo Carmine , Degen Claudia , Campia Umberto , de Felice Francesco , Folli Giuseppe
Published: March 2013

It is the current opinion that an ideal antihypertensive drug should reduce blood pressure (BP) not only at rest but also during stressful situations. The current study was aimed to compare the effects of the selective α1‐adrenergic blocker terazosin (5 mg once daily) and of the angiotensin‐converting enzyme inhibitor enalapril (20 mg once daily) on cardiovascular response to a set of standardized laboratory stressors, such as mental arithmetic, handgrip test and cycle ergometry, in a group of 16 essential hypertensive patients. The study was a randomized, double‐blind, cross‐over trial preceded by a placebo run‐in period. Terazosin and enalapril had a comparable effect on resting BP, reducing systolic (SBP) and diastolic (DBP) blood pressure from 159.5 ± 13.9/101.6 ± 8.8 mm Hg during placebo by 7.8%/6.7% and by 11.3%/10.2%, respectively. The “response” rate to the two treatments was approximately the same, being 69% and 75% after terazosin and enalapril, respectively. During mental arithmetic, from an average of 181.6 ± 17.8/118.6 ± 11.5 mm Hg during placebo, BP was reduced by 11.5%/7.9% after terazosin and by 13.6%/8.5% after enalapril; during handgrip test, BP decreased from 207.2 ± 22.2/142.2 ± 13.6 mm Hg by 7.3%/8.4% after terazosin and by 7.7%/7.1% after enalapril; finally, during cycle ergometry, terazosin and enalapril lowered BP by 5.4%/6.7% and 7%/3.1%, respectively, from a placebo value of 215.5 ± 17.3/127.6 ± 11.2. No significant difference in antihypertensive efficacy was observed between the two drugs, either at rest and during stress testing. Neither terazosin nor enalapril induced any significant change in resting and stress testing heart rate. Our data suggest that doses of terazosin and enalapril able to reduce resting BP are also effective in lowering BP during a variety of stressful situations, and thereby are potentially able to ameliorate the impact of recurring stress‐induced increases of BP on the cardiovascular system.
Fenoldopam Mesylate Versus Sodium Nitroprusside in the Acute Management of Severe Systemic Hypertension
Authors: Pilmer Betsy L. , Green Jeffrey A. , Panacek Edward A. , Elliot William J. , Murphy Michael B. , Rutherford William , Nara Andrew R.
Published: March 2013

Thirty‐three patients with severe systemic hypertension defined as a diastolic blood pressure (DBP) ≥ 120 mm Hg were randomized in a single‐blind fashion to be treated with either intravenous fenoldopam mesylate (FNP) or sodium nitroprusside (NTP). Fenoldopam mesylate and NTP infusion rates began at 0.1 μg/kg/minute and 0.5 μg/kg/minute, respectively and were titrated to achieve a goal DBP of between 95 and 110 mm Hg; or a reduction of at least 40 mm Hg if the baseline DBP was > 150 mm Hg. Fenoldopam mesylate (n = 15) reduced blood pressure from 217/145 ± 6/5 to 187/112 ± 6/3 mm Hg (P < .001) at an average infusion rate of 0.5 ± 0.1 μg/kg/minute. The average time to achieve goal DBP with FNP was 1.5 ± 1.4 hours. Nitroprusside (n = 18) reduced blood pressure from 210/136 ± 5/2 to 172/103 ± 6/2 mm Hg (P < .001) at an average infusion rate of 1.2 ± .24 μg/kg/minute. Nitroprusside response time averaged 2 ± 2.5 hours. There was no significant difference between the magnitude of effect seen with either FNP or NTP; nor was there any difference observed in the adverse effect rates of the two agents. Fenoldopam mesylate and NTP demonstrate similar overall efficacy in the treatment of severe systemic hypertension.
Contrasting Effects of Pyrazinoylguanidine and Hydrochlorothiazide in Patients with Renal Insufficiency
Authors: Beyer Karl H. , Ward Thomas D. , Vary Jean E. , Gelarden R. Thomas , Knutson David W. , Vesell Elliot S.
Published: March 2013

A single blind crossover study with washout phases showed that pyrazinoylguanidine (PZG) reduced elevated serum concentrations of urea, triglycerides, and cholesterol in patients with renal insufficiency. Pyrazinoylguanidine was saluretic, without affecting serum potassium or glucose concentrations. The onset of PZG's antihypertensive effect occurred within 4 hours. In contrast, hydrochlorothiazide (HCTZ) increased serum concentrations of urea, triglycerides, and glucose, without affecting cholesterol.
Determination of Gentamicin Pharmacokinetics by Bioelectrical Impedance in Critically Ill Adults
Authors: Zarowitz Barbara J. , Robert Sylvie , Mlynarek Mark , Peterson Edward L. , Horst H. Mathilda
Published: March 2013

This investigation compares the accuracy of calculating gentamicin pharmacokinetic parameters by a noninvasive body composition technique (bioelectrical impedance analysis; BIA) with an empiric method, against the two‐point method as the criterion standard. A prospective concurrent open label design was used. The 32 medical and surgical intensive care unit beds at Henry Ford Hospital, a not‐for‐profit, university‐affiliated teaching hospital, served as the setting. Twenty critically ill adults, Therapeutic Index Scoring System (TISS) = 4, who required gentamicin as part of their normal course of therapy for gram‐negative bacillary infections, were evaluated. Gentamicin Vd and k were calculated by three methods. After measurement of body composition parameters by BIA, previously derived gentamicin dosing equations were used to predict gentamicin volume of distribution (Vd) and elimination rate constant (k) (BIA method). Empiric estimates of these parameters (Vd = 0.3L/kg and k derived from creatinine clearance) were compared with the BIA parameters against a criterion standard Vd and k determined from a two‐point sampling of gentamicin serum concentrations. Measurements of BIA parameters and gentamicin serum concentrations were made in duplicate with coefficients of variation, ≤2% and ≤3%, respectively. The BIA and empiric methods produced resultant pharmacokinetic parameters (Vd and k) not different than those measured by the two‐point method. There were no statistically significant differences in mean error (bias), or mean squared error (precision) for both Vd and k assessed by the empiric or BIA methods. In this sample of critically ill adults there is no apparent advantage of BIA‐derived predictive pharmacokinetic equations over an empiric method of predicting gentamicin Vd and k. Further study with variable frequency BIA technology is needed to assess BIA applications in the critically ill.
Distribution of Myocardial β‐Adrenoceptor Subtypes and Coupling to the Adenylate Cyclase in Children With Congenital Heart Disease and Implications for Treatment
Authors: Kozlik‐Feldmann Rainer , Kramer Hans‐H. , Wicht Holger , Feldmann Regina , Netz Heinrich , Reinhardt Dietrich
Published: March 2013

In congestive heart failure, down‐regulation of myocardial β‐adrenoceptors (β‐AR) due to an elevated sympathetic tone is well known. In infancy and childhood, heart failure is usually related to congenital heart disease (CHD). Therefore, 71 samples of right atrial tissue of infants and children with CHD undergoing cardiac surgery were studied for β‐adrenoceptor density and distribution of the β1‐/β2‐AR subtypes. In 49 cases, the coupling of the β‐AR to the adenylate cyclase (AC) was examined. In a further study of 19 myocardial samples, AC was selectively stimulated with β1‐ or β2‐AR whereas the other subtype was blocked by an antagonist. The following results were obtained: (1) Infants and children with severe acyanotic or cyanotic CHD had severely reduced β‐AR densities. (2) In most of the cases, the β‐AR down regulation is β1‐subtype selective, but in critically ill newborns with congenital aortic valve stenosis or transposition of the great arteries, there is additional significant β2‐AR down‐regulation. In Fallot patients treated with the β‐antagonist propranolol, a significant increased β‐AR number compared with untreated Fallot patients was found. (3) β‐Adrenoceptor reduction in CHD is correlated with elevated noradrenaline plasma levels, thus proving a sympathetic dysregulation. (4) In CHD with moderate hemodynamic load, β2‐AR coupling to AC was markedly more efficient than β1‐AR coupling. The small number of myocardial β2‐AR produced most of the cyclic adenosine monophosphate. (5) In severe acyanotic and cyanotic CHD, a partial decoupling of the β2‐AR to the AC occurred. This may be a first step before β2‐AR are reduced in number in severe cardiac failure. These results explain why catecholamine therapy in in/ants and children with CHD sometime fails. Because the contractile force can be increased by β2‐AR, partial β2‐agonists may improve cardiac performance in acute heart failure. The most appropriate drugs are those that modulate or bypass the neurohumoral pathomechanisms in chronic heart failure like angiotensin‐converting enzyme‐inhibitors, β‐AR antagonists, dopamine2‐agonists, and phosphodiesterase‐inhibitors. Further studies are needed to validate the actions of these therapeutics in infants and children with CHD.
Pharmacokinetics of FK506 in Liver Transplant Recipients After Continuous Intravenous Infusion
Authors: Jain Ashok B. , Abu‐Elmagd Kareem , Abdallah Hisham , Warty Vijay , Fung John , Todo Satoru , Starzl Thomas E. , Venkataramanan Raman
Published: March 2013

The first‐dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of 0.15 mg/kg/day. Multiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured by enzyme‐linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.8 L/minute, and the half‐life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FK506 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1% of the administered dose being excreted in the urine as unchanged FK506. The large variability in FK506 kinetics during the immediate postoperative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half‐life of FK506, it takes more than 45 hours to reach steady‐state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of 0.05 mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment.
Pharmacodynamics and Dose‐Response Relationship of Famotidine: A Double‐Blind Randomized Placebo‐Controlled Trial
Authors: Laskin Oscar L. , Patterson Patricia M. , Shingo Sumiko , Lasseter Kenneth C. , Shamblen E. Cooper
Published: March 2013

The dose‐response relationship of oral famotidine at doses up to 10 mg was evaluated in 10 healthy male subjects to assess the extent and duration of inhibition of meal‐stimulated intragastric acid secretion. Each subject received single oral administrations of famotidine 0.5, 2.5, 5.0, and 10.0 mg and placebo in a double‐blind, randomized, crossover fashion. Intragastric pH was measured every 4 seconds for 24 hours and expressed as the mean pH for each 10‐minute interval. Standard high‐protein meals were provided 1 hour before each dose of study drug and at 3 and 9 hours postdose. The mean intragastric pH was significantly higher after famotidine doses 2.5, 5.0, and 10.0 mg than after placebo at times 2.5 to 3.0,1.8 to 3.2, and 1.7 to 4.2 hours postdose, respectively. There were no significant differences in mean pH seen between famotidine 0.5 mg versus placebo. The range of the pH means between 1.7 and 3.2 hours postdose was placebo (1.0 to 1.3), famotidine 0.5 mg (1.1 to 1.4), 2.5 mg (1.4 to 1.7), 5.0 mg (1.7 to 2.1), and 10.0 mg (2.0 to 2.3). There was a statistically significant linear dose‐response relationship between famotidine dose and intragastric pH between 1.7 and 3.8 hours and from 6.3 to 8.7 hours after ingestion.
The Phenomenon of Abusable Psychotropic Use Among North American Youth
Authors: Pagliaro Louis A. , Pagliaro Ann Marie
Published: March 2013

Abusable psychotropic use can, and does, affect all North American youth, either directly or indirectly, regardless of age, gender, culture, ethnic background, education, race, or socioeconomic status. Over the last decade, the morbidity and mortality associated with abusable psychotropic use among youth have become staggering. A current overview of the phenomenon of abusable psychotropic use among youth in North America, including the use of alcohol, cannabis, cocaine, LSD, nicotine, and polyabusable psychotropic use, is presented with attention to the expanding role of clinical pharmacologists in relation to both prevention and treatment. The Mega Interactive Model of Abusable Psychotropic Use Among Youth is presented as a heuristic device to assist clinical pharmacologists, and other health care providers, in addressing the multifactorial interactive aspects of this complex phenomenon as observed in the pediatric age group. In this regard, attention is given to the interaction of the Abusable Psychotropic Dimension, including the Abusable Psychotropic Variables (e.g., pharmacokinetics, abuse potential) and Pattern of Use Variables (e.g., social use, abuse, compulsive use), with the Young Person, Societal, and Time Dimensions.
Evaluation of the Pharmacokinetic and Pharmacodynamic Interaction Between Quinidine and Nifedipine
Authors: Bowles Susan K. , Reeves Richard A. , Cardozo Lavoisier , Edwards David J.
Published: March 2013

Quinidine and nifedipine appear to be subject to metabolism by the same isozyme of cytochrome P‐450. In addition, both drugs have been reported to alter the pharmacokinetics of other compounds. To investigate a potential interaction, 10 healthy subjects (five male, five female) received quinidine sulfate (200 mg orally), nifedipine (20 mg orally), or the combination of both drugs every 8 hours for 4 doses using a randomized, cross‐over study design with a 2‐week washout period between treatments. Drug concentration, heart rate, and mean arterial pressure were measured at frequent intervals after the final dose. Quinidine concentrations were unchanged by the co‐administration of nifedipine. Nifedipine area under the curve (AUC0–8) increased 36.6% from 333 to 455 μg · hr/L (P <.05) after quinidine administration. Heart rate was significantly higher in the nifedipine‐quinidine treatment at 0.5, 1.0, 1.5, and 2.0 hours when compared with either drug alone. The maximum increase in heart rate (17.9 beats/minute) occurred at 0.5 hours after nifedipine administration and was significantly correlated with serum concentrations at that time (r = .78). These results suggest that quinidine inhibits nifedipine metabolism, and this pharmacokinetic interaction results in enhanced pharmacologic response.
The Effect of Nifedipine on the Pharmacokinetics and Dynamics of Diltiazem: The Preliminary Study in Normal Volunteers
Authors: Tateishi Tomonori , Ohashi Kyoichi , Sudo Toshiaki , Sakamoto Kouichi , Fujimura Akio , Ebihara Akio
Published: March 2013

To evaluate the influence of nifedipine on the pharmacokinetics and the pharmacodynamics of diltiazem, five healthy subjects received 60 mg diltiazem orally on two occasions, diltiazem alone or after nifedipine pretreatment (10 mg three times daily for 3 days). After nifedipine pretreatment, the maximum concentration (Cmax) of diltiazem was increased and the time of Cmax was shortened, and the area under the concentration curve (AUC) tended to be increased. Although heart rate was increased, the corrected PQ interval tended to be prolonged after the nifedipine pretreatment. Both a decreased hepatic clearance and an increased bioavailability of diltiazem probably accounts for the increase in the Cmax and AUC of diltiazem after nifedipine pretreatment, and that might affect the pharmacodynamics of diltiazem.
Combination Drug Therapy with Calcium‐Channel Blockers in the Treatment of Systemic Hypertension
Authors: Frishman William H. , Landau Andre , Cretkovic Alexander
Published: March 2013

Calcium‐channel blockers have been shown to be both safe and effective for treatment of patients with systemic hypertension. These drugs reduce peripheral vascular resistance predominantly by the inhibition of transmembrane calcium ion fluxes in vascular smooth muscle, and by this mechanism can reduce elevated blood pressure. To maximize blood pressure lowering efficacy in patients, calcium‐channel blockers have also been used in combination with other antihypertensive treatments that have included diuretics, β‐adrenergic blockers, and angiotensin‐converting enzyme inhibitors.
Book Reviews
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Patient Recruitment in Clinical Trials Spilker B, Cramer J.

Ophthalmic Toxicology Target Organ Toxicology Series, Chiou G, Editor.

Cardiovascular Toxicology, Second Edition Target Organ Toxicology Series, Acosta D, Editor.

Toxicology of the Kidney, Second Edition Target Organ Toxicology Series, Hook J, Goldstein R, Editors.
Central Nervous System Effects of HMG CoA Reductase Inhibitors: Lovastatin and Pravastatin on Sleep and Cognitive Performance in Patients with Hypercholesterolemia
Authors: Kostis John B. , Rosen Raymond C. , Wilson Alan C.
Published: March 2013

Sleep disturbances and decrements of daytime performance have been attributed to HMG‐CoA reductase inhibitors. As a rule, lipophilic compounds more readily cross the blood‐brain barrier and are more likely to affect central nervous system function. The authors compared the effects of lovastatin (40 mg), a lipophilic compound, to pravastatin (40 mg), a hydrophilic compound, in a 6‐week, double‐blind, randomized, placebo‐controlled, three‐way Latin square design, cross‐over study on 22 men with hypercholesterolemia. Patients had LDL cholesterol of more than 165 mg/dL and triglyceride of less than 350 mg/dL after 6 weeks of a low‐fat (<30%), low‐cholesterol (<300 mg/day) diet. Compared with placebo, there were no significant effects of lovastatin or pravastatin on the following subjective and polysomnographic sleep measures: changes in total sleep time, time in each sleep stage, sleep efficiency, sleep latency, REM density, REM activity, and number of arousals. Similarly, there were no effects of the two drugs on measures of cognitive performance. A significant increase in the duration of nocturnal tumescence (NPT) was observed after 2 weeks of treatment with both study drugs. This effect was not significant after 6 weeks of treatment. Both lovastatin and pravastatin caused significant (P < .05 compared with placebo) decreases in total cholesterol (by 20.9 and 20.6%, respectively), LDL cholesterol (by 27.8 and 29.9%), and triglycerides (by 13.6 and 3.7%). Subjects' HDL increased by 2.3% with lovastatin (NS) and by 3.1% with pravastatin (P < .05). Lipoprotein(a) increased by 20.5% with lovastatin and by 1.1% with pravastatin; these changes were not significantly different from placebo. In patients with hypercholesterolemia, lovastatin and pravastatin have nearly identical effects on lipids and no significant effects on sleep and cognitive performance.
Estimation of Pharmacokinetic Parameters for Simulations of Time Courses of Drug Concentrations After Oral Administration
Authors: Bjornsson Thorir D. , Lui Nelson L. , England Michael J.
Published: March 2013

Simulations of time courses of drug concentrations after oral administration are frequently hampered by the lack of pharmacokinetic parameters after oral dosing. This article presents methods by which to estimate such parameters from pharmacokinetic parameters after intravenous dosing and knowledge of time of peak concentration and bioavailability after oral dosing. The application of these approaches enables the generation of meaningful graphic simulations of time courses of drug concentrations after oral administration that can have educational and illustrative uses.
Hematologic Disposition of Hydroxychloroquine Enantiomers
Authors: Brocks Dion R. , Skeith Kenneth J. , Johnston Carol , Emamibafrani J. , Davis Paul , Russell Anthony S. , Jamali Fakhreddin
Published: March 2013

Hydroxychloroquine (HCQ) is a racemic antiarthritic agent that has a long half‐life (t1/2) in plasma and accumulates in blood cells. To study the relationships between HCQ concentrations in plasma, serum, and whole blood and to determine the optimal blood fraction to use for therapeutic drug monitoring of the drug, we studied the relative distribution of the HCQ enantiomers in various fractions of human blood under in vivo and in vitro conditions. Substantially greater concentrations of both enantiomers were found in serum as compared with plasma because of release via platelet activation. After in vitro incubations of the separated blood cells with HCQ, high concentrations of both enantiomers were found in leukocytes, and low concentrations in erythrocytes and platelets; the R:S ratio in vitro was near unity in all of the cells examined. Unlike the in vitro cellular uptake, the concentrations of HCQ in vivo were significantly lower and stereoselective (R: S ratio = 2). There was almost no drug in the polymorphonuclear cells (PMN) in vivo, despite a substantial uptake in vitro after incubation of separated cells. The enantiomeric (R:S) ratio in the urinary excretion of the enantiomers was significantly correlated with that in plasma. The plasma—protein binding of the enantiomers was stereoselective and complimented the cellular uptake findings; the unbound fraction was dependent on the plasma concentrations of α1‐acid glycoprotein, but not albumin. Although concentrations in whole blood correlated well with those in lymphocytes and monocytes (the proposed site of HCQ action), stronger correlations were found between concentrations in serum and in the mononuclear cells.
Angiotensin‐Converting Enzyme Inhibitors and Cough: A Prospective Evaluation in Hypertension and in Congestive Heart Failure
Authors: Ravid Dorit , Lishner Michael , Lang Ruth , Ravid Mordchai
Published: March 2013

Angiotensin‐converting enzyme inhibitors (ACE‐I) have become the mainstem of antihypertensive therapy and first‐choice agents for vasodilatation in congestive heart failure (CHF). A typical dry cough is the main cause for discontinuation of ACE‐I therapy. Data about the incidence, course, and clinical significance of this side effect are conflicting. This study determined the incidence of cough in ACE‐I treated patients with hypertension and with CHF and to appreciate its clinical significance; 268 ACE‐I treated patients, 164 with hypertension and 104 with CHF were prospectively followed for at least 1 year and specifically questioned about cough and other side effects. In those in whom cough developed, a second and then a third ACE‐I were tried. Cough developed in 50 (18.6%) of the 268 patients; 23 patients with hypertension (14%) had coughs 24.7 ± 17.1 (SD) weeks after initiation of therapy; 27 patients with CHF (26%) had coughs 12.3 ± 12 (SD) weeks after the start of ACE‐I therapy (P = 0.005). All but three patients had coughs also on the second and third ACE‐I. The time from the beginning of therapy to the onset of cough was significantly shorter with the second than the first drug. ACE‐I agents had to be discontinued in 50% of the patients in whom coughs developed, most of them in the CHF group. In the others, cough was well tolerated or disappeared during subsequent months. The incidence of cough, which necessitated discontinuation of ACE‐I treatment, was 4% among patients with hypertension and 18% among patients with CHF (P < 0.001). ACE‐I‐induced cough is common in patients with CHF and usually dictates the interruption of this treatment. In hypertension, ACE‐I therapy may be continued in most patients despite the cough, which will subsequently regress in intensity or disappear. Alternative ACE‐I agents should not be tried because cough will reappear.
Epidemiologic Evaluation of Drug Use in Children
Authors: Bonati Maurizio
Published: March 2013

To define and evaluate the attention devoted to drug use in children rather than just review existing reviews, the present attempt is to seek out the primary sources of information in the hope that this effort would not only yield more reliable data, but would also provide an opportunity for reconsidering methodological problems which are possibly even more important. An English‐language literature search for drug use in children from 1988 was conducted on two databases and a manual search was made of the literature, with a check of references quoted in main original articles, reviews and textbooks. The review was then organized in two main sections: an overall evaluation of the recent literature concerning drug use in children; the epidemiological profile of drug exposure as described cumulatively by the drug‐utilization studies. A substantial lack of systematic attention to this area of drug epidemiology was found: drug use in the children is a ‘hidden’ reality in the literature; the wealth of methodologic developments that have taken place in the general field of drug use monitoring has scantly reached children. Children can be considered still “methodologic orphans” with respect to the transferable knowledge on the benefit/risk profile of therapies they receive. A network has to be developed to monitor clinical problems, including drug use, as part of an “audit” of the overall management of children.
A Placebo‐Controlled Evaluation of Single, Escalating Doses of CL 284,846, a Non‐Benzodiazepine Hypnotic
Authors: Beer Bernard , Ieni John R. , Wu Wen‐Hui , Clody Donald , Amorusi Peter , Rose James , Mant Time , Gaudreault Jacques , Cato Allen , Stern Warren
Published: March 2013

This report describes the first evaluation in humans of CL 284,846, a non‐benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double‐blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9‐1.5 hr, T1/2 = 0.9‐1.1 hr), with a dose‐proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.
Heart Rate Variability to Monitor Autonomic Nervous System Activity During Orthostatic Stress
Authors: Butler Gary C. , Yamamoto Yoshiharu , Hughson Richard L.
Published: March 2013

Exposure to microgravity with space flight, or to earth‐based analogs such as head‐down tilt (HDT) bedrest, results in cardiovascular deconditioning. With reapplication of gravity, deconditioning is most often observed as an elevated heart rate, a narrowed pulse pressure, and possibly even a failure to maintain blood pressure with symptoms of presyncope or syncope. Noninvasive measurements of heart rate variability (HRV) have been used to study cardiovascular control mechanisms during orthostatic stress (head‐up tilt and lower body negative pressure [LBNP]). Recently, the authors developed a new approach to study heart rate and blood pressure control mechanisms. Coarse graining spectral analysis (CGSA) allows simultaneous extraction of not only parasympathetic (PNS) and sympathetic (SNS) indicators from the HRV signal, but also determines the fractal dimension (DF), calculated from the slope (β) of the log spectral power‐log frequency relationship. The fractal dimension is an index of the complexity of the cardiovascular control system. Our investigations have indicated patterns of HRV consistent with reduced PNS and increased SNS activity and reduced DF with the HRV signal during orthostatic stress. These findings also indicate that the cardiovascular system may be less stable when operating at a reduced level of complexity.
A Retrospective Study of Promethazine and Its Failure to Produce the Expected Incidence of Sedation During Space Flight
Authors: Bagian James P. , Ward David F.
Published: March 2013

Since March 1989, intramuscular (IM) promethazine has been successfully used to treat the symptoms of space motion sickness. The incidence of sedation associated with promethazine administration on the ground is large and may result in operational impact. The authors undertook a retrospective study to quantify the incidence of sedation from promethazine use during Space Shuttle flights. Crew medical debriefings from 14 shuttle missions were reviewed for crew members who had been treated with IM promethazine and their corresponding symptoms were identified. Twenty‐one crew members received IM promethazine (25–50 mg), and only one experienced any associated sedation with no operational impact. This sedation incidence of less than 5% is in stark contrast to the 60 to 73% incidence of sedation seen in ground‐based studies. The incidence of sedation during space flight from IM promethazine is substantially less than that seen on the ground and does not present an operational problem during Space Shuttle flights. Future investigations of environmental stressors and pharmacodynamic changes associated with space flight may explain the huge disparity between the space‐flight and ground‐based data.
Space Sickness and Fluid Shifts: A Hypothesis
Authors: Simanonok Karl E. , Charles John B.
Published: March 2013

In a sample of 64 first‐time Space Shuttle crew members, 9 preflight variables related to fluid, electrolyte, and cardiovascular status were previously found to be significantly related to space sickness. The nine variables are serum uric acid, red cell count, environmental temperature at the launch site, serum phosphate, urine osmolality, serum thyroxine, sitting systolic blood pressure, calculated blood volume, and serum chloride. Using discriminant analysis, these preflight variables were used to correctly classify the 64 astronauts according to their space sickness incidence (NOTSICK or SICK) with 80% success, using two methods of pseudo‐crossvalidation. Symptoms of motion sickness may be induced on Earth, either with a sufficiently high level of vestibular stimulation or with less vestibular stimulation after reducing the threshold for motion sickness induction. Some of the nine predictor variables support a fluid shift hypothesis of space sickness etiology by which central volume expansion in weightlessness may lower the threshold required for novel vestibular stimulation to cause space sickness. According to this hypothesis, some astronauts suffer a greater central volume expansion than do others, causing them to have greater physiologic responses to fluid shifts, which, in turn, proportionally reduces their threshold for induction of space sickness. The hypothesis is supported by preflight and postflight echocardiographic comparisons of heart volumes in 19 shuttle astronauts. The postflight left ventricular diastolic volume index was decreased by 34 ± 3% in the astronauts with MODERATE or SEVERE space sickness, but only 9 ± 5% (P < .05) in the NONE or MILD group, indicating that an exaggerated physiologic adaptation to fluid shifts is associated with space sickness.
Factors Affecting Drug Bioavailability in Space
Authors: Tietze Karen J. , Putcha Lakshmi
Published: March 2013

Microgravity‐induced changes in the bioavailability of drugs may influence the efficacy or toxicity of drugs. The bioavailability of orally administered drugs may be altered by changes in dissolution rate, intestinal microflora, intraluminal enzymes, epithelial enzymes, rate of passage across the gastrointestinal epithelium, gastric emptying rate, intestinal transit time, hepatic first pass metabolism, and gastrointestinal and hepatic blood flow. Limited data from antiorthostatic bed rest and inflight studies provide preliminary evidence that the bioavailability of orally administered drugs in space may be decreased or subject to more interindividual variation than expected from ground‐based studies.
Pharmacokinetic/Pharmacodynamic Consequences of Space Flight
Authors: Derendorf Hartmut
Published: March 2013

As astronauts prepare for long‐term space missions, the question arises of whether drug medication in a zero gravity environment will have the same effects as under normal gravity. There are two potential kinds of changes that must be evaluated: alterations of pharmacokinetics and pharmacodynamics. Pharmacokinetic changes will affect the drug concentrations produced by a certain dosage regimen. They can be caused by changes in: (1) intrinsic clearance (e.g., enzyme activity and renal function), (2) drug binding (e.g., protein binding and tissue binding), (3) blood flow (e.g., liver blood flow and renal blood flow), and (4) bioavailability (e.g., rate and extent of absorption). Pharmacodynamic changes will affect the response that is produced by a given drug concentration. They can be caused by changes in drug‐receptor interaction or changes in disease characteristics. Studies of pharmacokinetic and pharmacodynamic changes in microgravity are limited, and predictions of any alterations are mainly extrapolated from known relationships between certain physiologic parameters and their effects on pharmacokinetics in normal gravity. Almost no data is available on changes in pharmacodynamics. Also, no information is available on the relationship between pharmacokinetics and pharmacodynamics. More studies are needed to elucidate the changes in pharmacokinetics and pharmacodynamics in microgravity to ensure the optimum use of drug therapy during space flight.
Pharmacodynamics of Racemic and S(—)‐Atenolol in Humans
Authors: McCoy Randall A. , Clifton G. Dennis , Clementi William A. , Smith Mikel D. , Garvey Thomas Q. , Wermeling Daniel P. , Schwartz Sheldon E.
Published: March 2013

The cardiovascular actions of racemic atenolol (RSATN) have been well characterized in humans, but the actions of S(—)‐atenolol (SATN) when administered alone are unknown. In this study, responses of heart rate (HR) and Doppler‐derived aortic blood flow profiles to upright treadmill exercise were compared after oral administration of 50 mg SATN and 100 mg RSATN in eight healthy, adult, male volunteers. After a single‐blind, placebo run‐in period, subjects were randomly allocated in a double‐blind, crossover fashion to receive SATN and RSATN. Each study period was separated by a 7‐day washout period. Multiple submaximal exercise tests were performed and data were collected over the 24 hours after each treatment. Both SATN and RSATN significantly (P < .05) blunted peak exercise HR by 38 ± 3 and 37 ± 3 beats/mint, respectively. Aortic blood flow acceleration measured during peak exercise decreased after SATN and RSATN, by 13 ± 4 and 13 ± 3 m/sec2, respectively (P < .05). No difference in hemodynamic effect was observed between treatments. Pharmacodynamic parameters derived from plasma S(—)‐atenolol concentration‐effect (HR) curves after SATN, RSATN, and total atenolol plasma concentrations after RSATN did not differ significantly. Predicted maximum reductions in heart rate (Emax) and EC50 for S(—)‐atenolol after SATN were 39.6 ± 5.8 beats/min and 38.4 ± 40.9 ng/ml versus 34.5 ± 8 beats/min and 25.9 ± 29.9 ng/ml for RSATN, respectively. The Emax and EC50 for total atenolol plasma concentrations after RSATN were 35.1 ± 8.4 beats/min and 50.2 ± 68 ng/ml, respectively. These data indicate that, after a single dose: (1) the negative chronotropic and inotropic activities of 100 mg oral RSATN reside in the S(—)‐enantiomer and R(+)‐atenolol exerts no detectable cardiovascular activity, and (2) pharmacodynamic modeling of the total plasma concentration accurately describes the HR effect of the active enantiomer.
New Antithrombotic Strategies for Resistant Thrombotic Processes
Authors: Harker Laurence A.
Published: March 2013

Life‐threatening thrombo‐occlusive events producing heart attacks and strokes develop in patients at sites of atherosclerotic arterial stenoses when plaques rupture, a process resistant to both aspirin and heparin. Resistant thrombotic complications are also troublesome during therapeutic thrombolytic or mechanical interventions for symptomatic atherosclerotic vascular disease, including angioplasty, various types of atherectomies, endarterectomy, endovascular stent deployment, or implanted small caliber vascular grafts. In this review therapeutic strategies for more effective management of these resistant, platelet‐dependent, occlusive thrombi are discussed, including: a) inhibition of platelet recruitment by anti‐GPIIb/IIIa monoclonal antibodies, naturally occurring peptides containing RGD sequences, or synthetic competitive analogs; b) direct inactivation of thrombin bound to thrombus by natural or synthetic antithrombin peptides; c) interruption of thrombin's production by natural or synthetic antagonists of Factor Xa or extrinsic and intrinsic coagulation pathways; and d) elimination of thrombogenicity at sites of vascular injury by immediately restoring confluent endothelium or prior therapy with dietary n‐3 fatty acids. However, antagonists of both GPIIb/IIIa‐ and thrombin‐dependent platelet recruitment produce equivalent inhibition of thrombus formation and platelet hemostatic function. Interestingly, hemostasis is spared by therapies that inhibit thrombin's production. Recommendations for development strategies are related to the relative hemostatic risks and antithrombotic benefits.