bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Triple Drug Therapy on Renal Function in Patients with Essential Hypertension
Authors: Reams Garry P. , Bauer John H.
Published: March 2013

The effects of long‐term triple drug therapy on renal function in patients with moderate to severe essential hypertension have not been evaluated systematically. We prospectively studied fifteen male patients with moderate to severe essential hypertension receiving triple drug therapy (metolazone, atenolol or betaxolol, and minoxidil) for 16 weeks. Supplemental potassium was prescribed in an attempt to maintain serum potassium above 3.5 mEq/liter. Systemic blood pressure was well controlled with this regimen. However, glomerular filtration rate (assessed by inulin clearance), effective renal plasma flaw (assessed by paraaminohippurate clearance), and renal blood flow were reduced. Filtration fraction and renal vascular resistance were not significantly altered. Plasma renin activity remained stimulated throughout the protocol. Weight gain occurred, and serum potassium remained low. These results suggest that triple drug therapy employing a diuretic, beta‐adrenergic antagonist, and a potent vasodilator is effective therapy for controlling moderate to severe systemic hypertension. However this antihypertensive regimen may be associated with a decrement in renal function.
Effects of Methyldopa on Psychometric Performance
Authors: Johnson Brian , Hoch Kathy , Errichetti Ann , Johnson Johanna
Published: March 2013

Double‐blind, crossover comparisons of methyldopa with placebo were performed in 16 patients with mild to moderate hypertension. Methyldopa (250 mg tid) for 14 days significantly reduced blood pressure, impaired card‐sorting time and digital symbol substitution score, and caused trends for impairment of other psychometric tests. Effects of practice were greater than those of treatment on all tests other than card sorting, although no interaction between treatment and practice was seen. Continued dosage impairs psychometric performance, but practice effect is a major confounder. Simple crossover studies are inadequate for detecting moderate drug effects on intellectual performance.
Influence of H2 Receptor Antagonists on the Disposition of Flurbiprofen Enantiomers
Authors: PharmD Ralph E. Small , Cox Steven R. , Adams Wade J.
Published: March 2013

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the R and S enantiomers of the nonsteroidal anti‐inflammatory drug flurbiprofen and its major metabolite, 4′‐hydroxyflurbiprofen, was evaluated. Nine healthy volunteers participated in a randomized crossover design study with the following treatments: (A) flurbiprofen 200 mg; (B) flurbiprofen 200 mg plus ranitidine 150 mg bid for 7 days before and for 2 days after receiving flurbiprofen and (C) flurbiprofen 200 mg plus cimetidine 300 mg qid for 7 days before and for 2 days after receiving flurbiprofen. Blood and urine samples were collected at various intervals during a 48‐hour period. These samples were assayed stereospecifically for flurbiprofen and its metabolite.

Small but statistically significant differences in the terminal elimination rate constant (K), maximum peak serum drug concentration (Cmax), time to reach peak concentration (tmax). oral clearance (Cl/F) and area under the curve (AUC) were noted for flurbiprofen enantiomers. No significant treatment*isomer interactions were observed, indicating that neither cimetidine nor ranitidine interacted stereospecifically with flurbiprofen. Cimetidine, but not ranitidine, resulted in small (≤15%) but statistically significant changes in flurbiprofen pharmacokinetic parameters. The interaction between H2‐antagonists and flurbiprofen is unlikely to be clinically important.
Steady State Pharmacokinetics of Propranolol in Saudi Arabian Patients and Comparison with Data for Different Populations
Authors: El‐Yazigi Adnan , El‐Baage Thar , Al‐Humaidan Abdulkarim , Yusuf Ahmed
Published: March 2013

The steady state pharmacokinetics of propranolol was examined in 48 Saudi Arabian patients chronically treated with oral doses [mean (SEM) = 85.8 (5) mg] of this drug. The mean (SEM) of the steady state concentration (Css) per mg/kg daily dose was 21.8 (3.1) ng · ml−1/mg · kg−1. A 6‐fold variability in Css was observed between patients treated with 40 mg every 8 hours and 14‐fold between patients treated with 40 mg twice daily. The frequency distribution of the apparent oral clearance (TCLor) of propranolol was bimodal with 88% of the patients showing TCLor of 18 to 372 l · hr−1 while the remainder had TCLor of 471 to 749 l · hr−1. The mean (SEM) of the TCLor per kg body weight for all 48 patients was 3.16 (0.38) l · hr−1 · kg−1. Both Css and TCLor obtained for Saudi Arabian patients are not significantly different from those reported for subjects from Western populations. While Css increased proportionally (P < .001) with dosing, a near‐significant (P < .06), inverse, linear relationship was found between age and TCLor. No significant effect of sex, body weight, or disease state (i.e., heart diseases, hypertension, depression, migraine) on Css or TCLor was detected.
European Registration: Today, Tomorrow, and Beyond
Authors: Currie William J. C.
Published: March 2013

Within the European Community (EC) countries the national pharmaceutical regulatory systems work with varying degrees of efficiency and scientific sophistication. At the Community level the objective of mutual recognition has failed to he realized. To achieve for one registration application within the EC, timely and simultaneous marketing approvals throughout the member states will require changes to the present regulatory procedures or the single market concept for pharmaceuticals will not be realized. To have the greatest chances for success we should move cautiously, identifying and correcting deficiencies in the present procedures, which are known from experience, rather than abandoning such hard won knowledge for a new system with all its attendant potential unknowns and uncertainty. The free movement of drugs within the Internal European market will be a reality. The question remaining is at what price will it be achieved? It is vital to the European economy and consumer, as well as to the innovative pharmaceutical industry, that Europe does not exchange its present competitive edge in the time to develop and register new drugs for a costly drug lag. The experiment must equally succeed as a torch showing the way forward not only for an enlarging European Community, but also to the ever increasing interest in global harmonization of drug regulation.
Beta Blockers Induce Different Intrarenal Effects in Humans: Demonstration by Selective Infusion of Tertatolol and Propranolol
Authors: Nitenberg A. , Chemla D. , Blanchet F. , Guery O. , Prost JF. , Dutray‐Dupagne C.
Published: March 2013

The effects of tertatolol and propranolol on renal circulation were studied in patients with normal renal function to test the hypothesis that various beta blockers may have different vasomotor effects within the renal vascular bed. Left renal blood flow was measured by the continuous thermodilution method before (t0), and 5 (t1), 10 (t2), 20 (t3), and 30 (t4) minutes after a selective infusion of tertatolol (0.25 mg, N = 4) or propranolol (2.5 mg, N = 4) into the left renal artery. Heart rate, cardiac output, aortic and right atrial pressures, and systemic vascular resistances did not significantly vary after either drug throughout the study. Plasma renin activity and plasma aldosterone in arterial and renal venous blood started to decrease at t1 after each drug. After propranolol, renal blood flow, renal vascular resistance and the renal arteriovenous oxygen difference were unchanged. Conversely, after tertatolol at t3, renal blood flow was increased (from 426 ± 18 mL/min/1.73 m2 to 509 ± 56 mL/min/1.73 m2, P = .03), renal vascular resistance and renal arteriovenous oxygen difference were decreased (P < .001), and the renal blood flow/cardiac output ratio was increased (P = .03). The filtration fraction did not vary after either drug, as attested by the unchanged polyfructosan extraction coefficient. This clinical study shows that selective infusion of a single low dose of tertatolol into the renal artery results in a delayed intrarenal vasodilator effect, while at the dose tested propranolol does not modify renal hemodynamics.
Globalization of the Pharmaceutical Industry: The Physician's Role in Evaluating Drug Safety
Authors: Beg Mirza M. A.
Published: March 2013

The trend toward uniformity of drug registration procedures due to imminent European Economic Community globalization has encouraged pharmaceutical companies to conduct studies on a worldwide basis. This standardization of methods will facilitate the “poolability” of efficacy and safety data generated by these international studies into a common database. With the internationalization of the pharmaceutical marketplace, physicians in industry may be required to collect and interpret such reports from all over the globe. The globalization of the pharmaceutical industry will thus broaden the opportunities for physician involvement in safety detection.
Pharmacokinetics of Loratadine in Patients with Renal Insufficiency
Authors: Matzke Gary R. , Halstenson Charles E. , Opsahl John A. , Hilbert James , Perentesis George , Radwanski Elaine , Zampaglione Nicola
Published: March 2013

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearances less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2β were observed between the three groups (8.7 ± 5.9, 7.6 ± 6.9, 8.6 ± 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC0∞ however was significantly greater in group II subjects: (212.4 ± 37.8, 469.5 ± 95.4, 325.2 ± 114.6 ng · hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half‐life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.
Betaxolol: A New Long‐Acting Beta1‐Selective Adrenergic Blocker
Authors: Frishman William H. , Tepper David , Lazar Eliot J. , Behrman Douglas
Published: March 2013

Betaxolol (Searle, Skokie, Illinois) is a new beta1‐selective adrenergic blocker with no partial agonist action and minimal membrane stabilizing activity. Its pharmacokinetic profile is characterized by a long serum half‐life and excellent oral bioavailability, with little first‐pass metabolism. The mean 16‐hour half‐life of betaxolol has been shown to provide full 24‐hour control of blood pressure and heart rate. Betaxolol has been proven to be a safe and effective antihypertensive agent, and was recently approved for clinical use in the United States for this indication.
A Comparison of the Anti‐Hypertensive Effectiveness of Two Triameterene/Hydrochlorothiazide Combinations: Maxzide Versus Dyazide
Authors: Casner Paul R. , Dillon Kevin R.
Published: March 2013

The hydrochlorothiazide component of Maxzide (Lederle Laboratories, Pearl River, NY) has been shown to be more bioavailable than the hydrochlorothiazide component of Dyazide (Smith, Kline and French Laboratories, Philadelphia, PA). The authors compared the antihypertensive effectiveness of a half‐tablet of Maxzide (25 mg of hydrochlorothiazide and 37.5 mg of triamterene) to one capsule of Dyazide (25 mg of hydrochlorothiazide and 50 mg of triamterene) to determine if the difference in bioavailability would be reflected in differences in blood pressure control and metabolic changes. Thirty patients were studied in a randomized open‐label crossover design study. There was a significant reduction in systolic blood pressure for both treatments although there was no difference in blood pressures at any time during the study between the two agents. There were no statistically significant differences between Maxzide and Dyazide in terms of metabolic changes for potassium, magnesium, glucose, cholesterol, triglycerides, uric acid, or calcium. Although the hydrochlorothiazide component of Maxzide is more bioavailable than that of Dyazide this did not translate into enhanced hypotensive efficacy.
The Pharmacodynamics of Ethanol: Effects on Performance and Judgment
Authors: Gengo F. M. , Gabos C. , Straley C. , Manning C.
Published: March 2013

The objective and subjective effects produced by increasing and decreasing ethanol concentrations were studied in healthy volunteers on three separate occasions. A randomized, double‐blind, placebo‐controlled, four‐way crossover study was used to determine whether there is any disparity between the time course of blood ethanol concentration and its effects on either objective test performance or self rated impairment. On each study day the subjects received one of four treatments consisting of either placebo or sufficient alcohol to achieve peak estimated blood alcohol concentration (Est.BAC) of 0.07 gm/dL, 0.1 gm/dL or 0.14 gm/dL. Est.BAC determined from breath alcohol concentrations were measured 20 minutes after each “dose” until peak Est.BAC was achieved, then 1, 2, 3.5, and 4.5 hours after peak Est.BAC. Digit symbol substitution (DSS), simulated driving reaction time (SDRT), choice reaction time (CRT) and self assessment of impairment (SRI) were measured simultaneously with Est.BAC.

Changes in objective performance test scores were well correlated with Est.BAC (r2 = 0.60 P < .01). Maximum impairment in test performance occurred at the same time as peak Est.BAC. Threshold Est.BAC needed to produce changes in objective test scores greater than placebo were 0.06 ± 0.01 for DSS, 0.04 ± 0.01 for SDRT, and 0.04 ± 0.02 for CRT. There was no evidence of between dose or within dose tolerance to the effects produced by various Est.BAC on any of these performance tests.

Subjects' self rated degrees of impairment at various Est.BAC were influenced by whether alcohol concentrations were rising or falling. Subjective impairment ratings were greater while alcohol concentrations were increasing compared to the same Est.BAC occurring during falling alcohol concentrations. Disparities between self rated degree of impairment and decrements in test performance were greatest 1.0 hour after peak Est.BAC and maximum decrements in test performance. The delay in subjects' ability to accurately rate their impairment relative to peak Est.BAC may be a contributing factor to motorists choosing to drive while their performance is still impaired.
Drug Delivery Systems 5A. Oral Drug Delivery
Authors: Ranade Vasant V.
Published: March 2013

The two main advantages of controlled drug delivery systems are: maintenance of therapeutically optimum drug concentrations in the plasma through zero‐order release without significant fluctuations; and elimination of the need for frequent single dose administrations. The oral and other therapeutic systems in human use have validated the concept that controlled continuous drug release can minimize the daily dose of a drug required to maintain the required therapeutic effect, while minimizing unwanted pharmacological effects. By minimizing patient intervention, a design feature of therapeutic systems, compliance is automatically enhanced.

Oral drug delivery systems, in particular, have required innovation in materials science to provide materials biocompatible during prolonged contact with body tissues, bioengineering to develop drug delivery modules, and clinical pharmacology for elucidation of drug action under conditions of continuous controlled drug administration.

Recent work in advanced oral delivery has been primarily focused on liposome technology and the concept that substances that are normally destroyed by the stomach can be protected long enough before they could be absorbed downstream. For cost and patient convenience, oral delivery certainly would be an attractive method. The nature of biologic substances, however, with their unique technical problems, will probably limit greatly those that can be delivered orally. Besides, where delivery rate control is critical, oral delivery, even when possible, would probably be insufficiently precise. Oral delivery would also limit the substance to bloodstream delivery to the disease site.

Even so, oral controlled drug delivery systems will likely find primary usefulness in specific carefully controlled therapies and prophylactic situations with due regard for drug interactions. This system represents a potentially very significant therapeutic modality. These delivery systems will find usefulness primarily in certain well‐defined and well‐controllable areas with due regard for individual patient variations. The purpose of the present article is to review oral controlled‐release drug delivery systems, with particular emphasis on the practical aspects of testing and fabricating these systems and the underlying mechanisms by which control over drug release rate is accomplished.
Development of Lower Body Negative Pressure as a Countermeasure for Orthostatic Intolerance
Authors: Fortney Suzanne M.
Published: March 2013

Exposure to prolonged (1–4 hr) lower body negative pressure (LBNP) is a countermeasure against postflight orthostatic intolerance which is used in the Soviet space program and planned for use in the American space program. LBNP in combination with fluid‐loading is believed to act by promoting a transient positive fluid balance resulting in an increase in vascular, as well as extravascular fluid. Inflight LBNP also may provide beneficial orthostatic effects by restoring baroreceptor reflex functions and/or lower body venous compliance. Current research efforts at the Johnson Space Center are directed towards increasing the effectiveness and efficiency of the LBNP and saline countermeasure. A promising avenue may involve combining pharmacologic agents, such as inhaled anti‐diuretic hormone, or mineralocorticoids, with mechanical stimuli such as LBNP.
Effects of Gravity on Gastric Emptying, Intestinal Transit, and Drug Absorption
Authors: Amidon Gordon L. , DeBrincat Gary A. , Najib Naji
Published: March 2013

The effects of microgravity on the physiologic response of the human body, the physical properties of gastrointestinal contents, and the influence these responses have on drug absorption are becoming more and more critical as the duration of humans in the hostile space environment dramatically increases. In this environment, some conventional oral dosage forms may be severely limited as an effective drug regimen. To understand the effects of microgravity, one must first understand the basic forces acting on a particle moving through a walled‐tube such as the small intestine: gravity (FG), buoyancy (FB), and drag (FD). These forces can be combined and rearranged into a dimensionless ratio of gravitational forces to viscous forces. This is the most important dimensionless group influencing the motion of a particle relative to the fluid. Gastric emptying is highly influenced by several factors: volume, calories, exercise, size, density, temperature, viscosity, osmolality as well as those factors associated with physiologic responses: splanchnic blood flow, body position, and electrolyte balance. This array of factors can lead to variability in drug plasma levels. In the absence of gravity, the factors of size and density would appear to be most directly altered due to their dependence on the force of gravity. Intestinal transit rate in a gravity environment is highly dependent on the motility state of the GI tract either fasted or fed partly due to the higher viscosities of chyme in the fed state. In space, the absence of gravity may tend to increase the transit rate along the small intestine by decreasing the dimensionless ratio of gravitational forces to viscous forces. In zero gravity, therefore, these alterations in GI emptying and intestinal transit rate could lead to erratic plasma levels and inefficient absorption.
Digoxin‐Like Immunoreactive Substance in Renal Transplant Patients
Authors: Schrader Bruce J. , Maddux Michael S. , Veremis Susan A. , Mozes Martin F. , Maturen Andrew , Bauman Jerry L.
Published: March 2013

Digoxin‐like immunoreactive substance (DLIS) has been detected in several patient populations that were not receiving digoxin, including those patients with end‐stage renal disease. The structure and physiologic significance of this compound are unknown, and the fate of DLIS after renal transplantation has not been studied. The authors prospectively evaluated 163 patients (not receiving digoxin) before and after transplantation for the presence of DLIS. Three different assays were used: radioimmunoassay (RIA), affinity mediated immunoassay (ACA), and fluorescence polarization immunoassay (TDX I). Depending on the assay method used, 11% (RIA), 6% (ACA), and 9% (TDX) of patients had detectable DLIS pretransplant. Using all 3 assays, a total of 34 patients (21%) were found to have DLIS. The mean serum digoxin concentration was 0.41 ± 0.13 ng/mL (range: 0.2–1.2 ng/mL) and DLIS was detectable by > 1 assay method in seven patients. DLIS persisted longer in patients who had delayed allograft function (13.7 ± 7 days) than in those who did not (3 ± 1.9 days), P <.05. In summary, detection of DLIS in renal transplant recipients appears to be an infrequent occurrence when using a single digoxin assay method. When detected, the concentration of DLIS is often below the usual therapeutic range for digoxin and disappears once allograft function is established. The authors conclude that the presence of DLIS is unlikely to be clinically significant in the renal transplant population.
Drug Dose Prediction With Flexible Test Doses
Authors: Swartz Conrad M.
Published: March 2013

This article presents the first known practical method to apply one‐compartment pharmacokinetic modeling to prediction of doses for drugs from one or more blood—drug concentrations, without requiring approximations or a computer. It should be useful for regulating doses of orally administered CNS drugs whose effects develop over a day or more, e.g., lithium, antidepressants, and anticonvulsants. Pharmacokinetic calculations for sequences of one, two, and three test doses are condensed into graphs that can be rapidly applied for clinical purposes. These graphs account for dose division, blood sampling time, and drug elimination rate; they show that the ratio of the steady‐state day‐mean drug level to the test‐drug blood level is independent of the half‐life if the test level is about a day after the last test dose. The calculations show the same value as experimental measurements for the ratio between steady‐state serum lithium level and serum lithium level measured after a test dose. A rational strategy for drug‐loading doses is discussed.
The Propionic Acids: A Personal Perspective
Authors: Adams Stewart S.
Published: March 2013

In searching during the early 1950s for new drugs for the treatment of rheumatoid arthritis, little information was available to allow a rational approach. The mode of action of the few drugs available was unknown and even the analgesic action of aspirin could not be demonstrated in animals. A speculative concept was developed that aspirin possessed a specific unidentified action in rheumatoid arthritis and that this and its analgesic properties were related to its ability to delay the development of ultraviolet (UV) erythema in the guinea pig. A series of substituted phenoxypropionic acids proved to be active as antierythemic agents, but the most potent was inactive clinically in rheumatoid arthritis. Refinements to the testing systems led to a series of substituted phenylacetic acids, three of which although active in rheumatoid arthritis produced unacceptable adverse reactions (ADRs). Attempts to relate laboratory data to clinical ADRs suggested that the substituted phenylpropionic acids (originally rejected because of concerns about toxicity) might be better tolerated than we had anticipated. Ibuprofen was selected from this large group. It was proven to be effective and well tolerated and became “the first of the propionics” when it was launched in 1969. In the 1970s, ibuprofen proved to be effective as a prescription drug in a range of painful nonrheumatic conditions and on the basis of its good safety record was approved as an OTC analgesic in 1983 in the United Kingdom and in 1984 in the USA. It has proven to be popular and effective and much safer than aspirin or acetaminophen in overdosage.
The Antidotal Action of Sodium Nitrite and Sodium Thiosulfate Against Cyanide Poisoning
Authors: Baskin Steven I. , Horowitz Arthur M. , Nealley Eric W.
Published: March 2013

The combination of sodium thiosulfate and sodium nitrite has been used in the United States since the 1930s as the primary antidote for cyanide intoxication. Although this combination was shown to exhibit much greater efficacy than either ingredient alone, the two compounds could not be used prophylactically because each exhibits a number of side effects. This review discusses the pharmacodynamics, pharmacokinetics, and toxicology of the individual agents, and their combination.
Comparison of the Efficacy and Safety of Ketorolac and Meperidine in the Relief of Dental Pain
Authors: Fricke James R. , Angelocci Diann , Fox Kathleen , McHugh Dennis , Bynum Lincoln , Yee James P.
Published: March 2013

A single‐dose, randomized, double‐blind study of parallel design was conducted to determine the analgesic efficacy and safety of ketorolac tromethamine in patients who experience moderate or severe pain after the surgical removal of three or more third molars, one of which was a bony‐impacted mandibular molar. Meperidine hydrochloride was used as the control analgesic. In this 8‐hour study, assessments were made of pain intensity, pain relief, and overall rating of the medication in 145 patients, each of whom had received an intramuscular injection of 10 mg, 30 mg, or 90 mg of ketorolac, or 50 mg or 100 mg of meperidine. The summed pain intensity and total pain relief scores showed that, at 3 and 8 hours, the effectiveness of 30 mg of ketorolac was similar to that of 90 mg of ketorolac and that both of these doses were significantly more efficacious than 10‐mg ketorolac, 50‐mg meperidine, or 100‐mg meperidine. Patients who received 30 mg or 90 mg of ketorolac gave the study medication significantly higher ratings overall than did patients who received 50 mg or 100 mg of meperidine. Significantly fewer patients treated with ketorolac reported adverse events in comparison with those treated with meperidine (17% and 59%, respectively), which suggests that it possesses a better therapeutic index than meperidine. Thus, ketorolac appears to represent an important advance in analgesic therapy.
Comparative Investigation of the Influence of Nizatidine, Ranitidine, and Cimetidine on the Steady‐State Pharmacokinetics of Theophylline in COPD Patients
Authors: Bachmann Kenneth , Sullivan Timothy J. , Mauro Laurie S. , Martin Mary , Jauregui Luis , Levine Louise
Published: March 2013

The influence of usual regimens of the H2 blocking drugs, cimetidine, ranitidine, and nizatidine on the steady‐state plasma concentrations and pharmacokinetic characteristics of theophylline was studied in seventeen patients with chronic obstructive pulmonary disease (COPD). Patients were dosed to steady‐state with an oral, sustained‐release formulation of theophylline given in therapeutic doses twice daily for 2 weeks. Over the next 4 weeks, each patient received a week‐long regimen of each H2 blocker concomitantly with theophylline, and a week‐long regimen of theophylline alone (control). At the end of each of the latter 4 weeks the steady‐state pharmacokinetics of theophylline were assessed. Neither ranitidine nor nizatidine treatment altered the steady‐state pharmacokinetics of theophylline relative to the control phase (i.e. no H2 blocker treatment). Values for theophylline Cave, Cssmax, AUC0–12, and CLoral were significantly different during cimetidine treatment compared with all other treatments (ranitidine, nizatidine, and control). Cimetidine increased theophylline Cssmax, AUC0–12 and Cave by approximately 32%, and decreased theophylline oral clearance by approximately 23%. The authors conclude that cimetidine alters the steady‐state pharmacokinetics of theophylline in COPD patients, whereas ranitidine and nizatidine are without effect.
Cetirizine Pharmacokinetics and Pharmacodynamics in Primary Biliary Cirrhosis
Authors: Simons F. Estelle R. , Watson Wade T. A. , Minuk Gerald Y. , Simons Keith J.
Published: March 2013

The new H1‐receptor antagonist, cetirizine, is eliminated primarily unchanged by renal excretion and is thus potentially useful for relief of pruritus in patients with hepatic dysfunction, in whom many H1‐receptor antagonists are contraindicated. The authors studied the elimination of cetirizine in six patients with primary biliary cirrhosis. In contrast to data obtained in healthy adults with normal hepatic function reported in the medical literature, they found that the mean serum elimination half‐life value of cetirizine, 13.8 ± 1.8 hours, was longer, and the mean clearance rate, 0.44 ± 0.10 mL/min/kg, was lower (P < .05). The mean peak serum cetirizine concentration, 498 ± 118 ng/mL, was higher, the mean area under the curve, 6438 ± 1621 ng/mL/hr, was larger, and the mean fraction of the dose excreted as unchanged cetirizine in the urine, .32 ± .14, was lower (P < .05). The duration of action of cetirizine was prolonged, as evidenced by significant suppression of the histamine‐induced wheal and flare for 48 and 72 hours, respectively, after a single dose. Cetirizine elimination was impaired in patients with hepatic dysfunction.
Clinical Cardiotoxicity of 5‐Fluorouracil
Authors: Keefe Deborah L. , Roistacher Nancy , Pierri Mary Kathryn
Published: March 2013

5‐Fluorouracil is widely known to be toxic to the hematopoietic and gastrointestinal systems. It also has cardiac toxicity, but this is perceived to be rare. During a 16‐month period from January 1990 through April 1991, approximately 910 patients were treated with 5‐fluorouracil. Five of these developed life‐threatening toxicity consistent with coronary artery spasm for an incidence of .55%. The acute events occurred on the third or fourth day of the 5‐day infusion and after the fourth intravenous bolus in the patient on bolus therapy. Each of the patients had ST elevation and ventricular arrhythmias, four had acute myocardial infarction, and two had cardiac arrests. In these cases and those previously reported, cardiac toxicity is consistent with drug‐ or metabolite‐mediated increases in coronary vasomotor tone and spasm, leading to the full spectrum of signs and symptoms of myocardial ischemia in susceptible individuals.
Use of Lower Body Negative Pressure to Counter Symptoms of Orthostatic Intolerance in Patients, Bed Rest Subjects, and Astronauts
Authors: Lathers Claire M. , Charles John B.
Published: March 2013

This report briefly discusses some aspects of autonomic cardiovascular dysfunction as related to changes in orthostatic function in patients, bed rest subjects, and astronauts. This relationship is described in normal individuals to provide the basis for discussion of parameters that may be altered in patients, bed rest subjects, and astronauts. The relationships between disease states, age, periods of weightlessness during space flight, and autonomic dysfunction, and their contribution to changes in orthostatic tolerance are presented. The physiologic effects of lower body negative pressure are illustrated by presenting data obtained in bed rest subjects and in astronauts. Finally, the usefulness of lower body negative pressure to counter symptoms of orthostatic intolerance in patients, bed rest subjects, and astronauts is discussed.
Codeine Disposition in Sickle Cell Patients Compared With Healthy Volunteers
Authors: Mohammed Sumia S. , Ayass Mohab , Mehta Paulette , Kedar Amos , Gross Samuel , Derendorf Hartmut
Published: March 2013

The pharmacokinetics of codeine were determined after oral administration of codeine sulfate (60 mg) with sickle cell patients (SCPs) and healthy controls (HCs). Plasma concentrations of codeine were measured by reversed‐phase high‐pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated using both compartmental and noncompartmental analysis. No significant differences were observed in time to reach maximum peak plasma concentration (tmax) (1.0 ± 0.4 versus 1.4 ± 1.0 hours), maximum peak plasma concentration (Cmax) (172 ± 25 versus 225 ± 97 ng/mL), area under the curve (AUC∞) (590 ± 96 versus 779 ± 234 ng*h/mL), and Cl/F (104 ± 17 versus 89 ± 27 L/h) between SCPs and HCs. Conversely, significant differences were observed in mean residence time (MRT) (3.7 ± 0.3 versus 4.7 ± 0.3 hours) and half‐life (t1/2) (1.7 ± 0.2 versus 2.8 ± 0.3 hours). In a separate study, significant differences were observed in the in vitro plasma protein binding of codeine in SCPs (66.0 ± 8.6%) and HCs (30.5 ± 2.7%) as well as in vivo binding (68.4 ± 11.1% for SCPs versus 29.2 ± 3.4% for HCs). Codeine is a relatively high‐extraction drug that is primarily eliminated by metabolism in the liver. Generally, the clearance of such drugs is approximately equal to hepatic blood flow and is not affected by changes in protein binding. Therefore, the change in t1/2 observed in SCPs can be attributed to changes in volume of distribution rather than clearance.
An Intelligent and Cost‐Effective Computer Dosing System for Individualizing FK506 Therapy in Transplantation and Autoimmune Disorders
Authors: McMichael John , Lieberman Ronald , Doyle Howard , McCauley Jerry , Fung John , Starzl Thomas E.
Published: March 2013

The accuracy and precision of an intelligent dosing system (IDS) for FK506 in predicting doses to achieve target drug levels has been prospectively evaluated in transplant and autoimmune patients. For dose individualization, the knowledge base is updated with patient‐specific feedback including the current dose, drug level, and the new target level. The study population of 147 patients consisted of 97 transplant patients (liver and kidney) and 50 patients with autoimmune disorders. Patients in the transplant study group were entered sequentially and followed as a cohort. Patients in the autoimmune study group were randomly assigned to one of three predefined FK506 concentration windows (low, 0.1–.3; medium, 0.4–.7; and high, 0.8–1.3 ng/mL) as part of a concentration controlled clinical trial. Predictions of steady‐state plasma drug levels were made throughout the clinical course of autoimmune patients and during the first 6 weeks post‐transplant in liver and kidney recipients. FK506 concentration in plasma was measured by a monoclonal antibody based ELISA assay. Accuracy was computed as the mean prediction error (mpe). Precision was computed as the root mean squared prediction error (rmspe). The accuracy of the IDS in each study group was as follows: 0.016 ng/mL (liver), −0.034 ng/mL (kidney), and −0.022 ng/mL (autoimmune). Because the 95% confidence interval included zero in each case, the IDS showed no bias. The precision of the IDS in each study group was as follows: 0.133 ng mL (liver), 0.1903 ng/mL (kidney), and 0.1188 ng/mL (autoimmune). These results indicate that the FK506 IDS is both accurate and very precise (reproducible) in transplant and autoimmune patients. The performance of the FK506 compares favorably with previously reported pharmacokinetic dosing methods such as population nomograms and adaptive control feedback methods (least‐squares and Bayesian). Based on our findings, this IDS should have a number of important uses relevant to the drug development process, the prescribing physician and the individual patient. It provides an evident method for implementing concentration controlled clinical trials. It should accelerate the physician's learning curve while at the same time help to maximize therapeutic drug efficacy and minimize toxicity with drugs exhibiting nonlinear kinetics and narrow therapeutic indices. Preliminary studies suggest that these assets result in a significant cost‐benefit advantage by reducing the duration of hospitalization. Current studies are in progress to validate this and carefully measure its pharmacoeconomic impact.
Lack of Interaction Between Glipizide and Co‐Trimoxazole
Authors: Kradjan Wayne A. , Witt Daniel M. , Opheim Kent E. , Wood Francis C.
Published: March 2013

To identify the effects of co‐trimoxazole on the elimination and disposition kinetics of glipizide, eight healthy male volunteers were studied in an unblinded, randomized, cross‐over trial with two phases (no treatment or co‐trimoxazole 160/800 mg twice a day). During each phase, subjects were treated at home for 7 days with one of the treatment regimens, followed by a 24‐hour hospitalization for a single‐dose challenge with 10‐mg oral glipizide and detailed blood studies. A 7‐day washout period was interspersed between the phases. Pharmacokinetic and pharmacodynamic parameters were determined and compared using the Student's t‐test for paired observations. Glipizide area under the curve (AUC), clearance, and half life for treatment and control phases were 5758 ± 1874 versus 5176 ± 1505 μg/L/hour (P = .21), 0.41 ± 0.15 versus 0.45 ± 0.14 mL/min/kg (P = .27), and 5.13 ± 2.10 versus 3.95 ± 1.37 hours (P = .04), respectively. Twenty‐four‐hour glucose AUCs for treatment and control phases were 112.24 ± 8.76 versus 114.86 ± 11.98 mmol/L/hour (P = .55), respectively. The only parameter reaching statistical significance was glipizide half life, but the difference is of doubtful clinical significance because of difficulty in identifying a clear elimination phase in several subjects. It is concluded that co‐trimoxazole administration did not significantly alter glipizide disposition and elimination kinetics in this study population.
Pharmacokinetics of Cefodizime in Volunteers with Normal or Impaired Renal Function
Authors: Conte John E.
Published: March 2013

The pharmacokinetics of single, 1‐ or 2‐g intravenous doses of cefodizime were studied in subjects with normal, impaired renal function or requiring chronic hemodialysis. Drug concentrations were measured using high‐performance liquid chromatography. Forty‐five subjects (20 with creatinine clearance of ≥90 mL/min, 15 with creatine clearances between 5 and 89 mL/min, and 10 requiring chronic hemodialysis) were studied. The concentration—time curve of cefodizime was best represented by an open two‐compartment model. The elimination half‐lives in subjects with normal (Group 1) and impaired renal function (Group 2) or requiring chronic hemodialysis (Group 3) were 4.14 ± 1.55, 5.10 ± 2.24, and 10.1 ± 6.01 hours, respectively (Group 3 versus 1 or 2, P < .05; Group 1 versus 2, P > .05). The total body (serum) clearances in the same groups were 3 ± 0.52, 2.22 ± 0.61, and 0.99 ± 0.33 L/hour, respectively (Group 1 versus 2 or 3, P < .05; Group 2 versus 3, P < .05). Although renal function has an effect on the pharmacokinetics of cefodizime, its effect on the elimination half life is marginal in subjects with creatinine clearance of more than 25 mL/min. In individuals with more severe renal impairment or those requiring chronic hemodialysis, dosage adjustment would be required.
Intravenous Torsemide as Adjunctive Therapy in Patients with Acute Pulmonary Edema
Authors: Stringer Kathleen A. , Watson William , Gratton Matthew , Wolfe Rich
Published: March 2013

The safety and efficacy of intravenous (IV) torsemide as adjunctive therapy for acute cardiogenic pulmonary edema was evaluated. Thirteen patients were treated with IV torsemide and six patients, with IV furosemide, as a positive control. Doses of torsemide, 20 mg or 40 mg, and furosemide, 40 mg or 80 mg, were administered initially. The dose was titrated as necessary over the next 24 hours. In patients who received IV torsemide, median fractional sodium excretion significantly increased from 2.88% (0.04–10.1%) at baseline to 6.76% (0.71–11.6%) at peak (P = 0.0342). Hourly urine volume increased from 134 mL (25–400 mL) to 375 mL (145–790 mL) (P = 0.0034). Torsemide administration resulted in a significant improvement in both pulmonary rales and orthopnea. None of the patients experienced serious adverse events or required withdrawal from the study. These results suggest that IV torsemide is an effective and well‐tolerated diuretic in patients with acute cardiogenic pulmonary edema.
Therapeutic Drug Monitoring in Pediatrics: A Need for Improvement
Authors: Tange Susan M. , Grey Vijay L. , Senécal Pierre E.
Published: March 2013

Therapeutic drug monitoring (TDM) is practiced for a number of frequently used drugs in infants and children. It is believed that monitoring drug levels will increase the probability of a therapeutic response and minimize the probability of adverse drug sequelae. Dose adjustments are based on measured drug levels interpreted relative to published therapeutic ranges which may or may not reflect the true relationship with either therapeutic or adverse effects. Potential errors derive from many sources, some amenable to solutions based on current knowledge, others awaiting improved understanding of the causes and consequences of unreliable therapeutic ranges.
Pharmacokinetics of Famciclovir in Subjects with Chronic Hepatic Disease
Authors: Boike Steven C. , Pue Martin , Audet Patricia R. , Freed Martin I. , Fairless Amanda , Ilson Bernard E. , Zariffa Névine , Jorkasky Diane K.
Published: March 2013

The pharmacokinetic profile of penciclovir was determined after a single 500‐mg dose of its oral precursor, famciclovir, in 9 healthy volunteers and in 14 patients with chronic hepatic disease. Plasma and urine samples were analyzed for concentrations of penciclovir and 6‐deoxy‐penciclovir using a reverse‐phase high‐performance liquid chromatography (HPLC) method. Famciclovir was not quantifiable in patients with hepatic disease, and 6‐deoxy‐penciclovir was quantifiable in only a limited number of specimens. The extent of systemic availability of penciclovir, as measured by AUC0‐∞, was similar in patients with hepatic disease and in healthy subjects. In contrast, Cmax was significantly lower (average decrease of 43%) in subjects with hepatic disease relative to healthy normal subjects. Median Tmax for subjects with hepatic disease was significantly increased (by 0.75 hours) compared with subjects with normal liver function. These data suggest a decrease in the rate, but not the extent, of systemic availability of penciclovir in patients with hepatic disease. It should be unnecessary to modify the dose of famciclovir for subjects with compensated hepatic disease and normal renal function.
Manipulation of Norepinephrine Metabolism with Yohimbine in the Treatment of Autonomic Failure
Authors: Biaggioni Italo , Robertson Rose Marie , Robertson David
Published: March 2013

It has been postulated that α2‐adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of α2‐receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as α‐methyldopa. Presynaptic α2‐receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of α2‐adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of α2‐adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.
Comparison of the Nicotine Pharmacokinetics of Nicoderm (Nicotine Transdermal System) and Half‐Hourly Cigarette Smoking
Authors: Gupta Suneel K. , Hwang Stephen S. , Causey Donna , Rolf Clyde N. , Gorsline Jane
Published: March 2013

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half‐hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half‐hourly intervals on days 1 and 5; ad libitum smoking on days 2–4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking.