bluuebunny/crossref_metadata_2025 huggingface dataset:
Tiapamil and Hydrochlorothiazide: A Double‐Blind Comparison of Two Antihypertensive Agents
Authors: Storm T. L. , Badskjaer J. , Hammer R. , Kögler P.
Published: June 2007

Tiapamil is an investigational calcium‐channel antagonist that is chemically related to verapamil. The antihypertensive efficacies of tiapamil and hydrochlorothiazide (HCTZ) were compared in a randomized double‐blind trial. Thirty patients, age 44 to 80 years, with mild to moderate hypertension (World Health Organization stage I‐II) entered and completed the study. Previous therapy, if any, was stopped for at least one week prior to study initiation, and patients received placebo tablets for two weeks. The participants were then given active medication, which was titrated for the next three weeks; HCTZ 25 to 50 mg bid or tiapamil 300 to 600 mg bid was given until supine diastolic blood pressure (BP) was no higher than 90 mm Hg or the ceiling dose was reached. Both drugs caused a significant reduction in systolic as well as in diastolic blood pressure (P <.01). The reduction was seen in both the supine and erect position. The median decrease in supine systolic blood pressure from baseline to the end of treatment was 20 mm Hg in the tiapamil group and 27 mm Hg in the hydrochlorothiazide group, whereas the median decrease in supine diastolic blood pressure was 14 mm Hg and 18 mm Hg, respectively. The median difference in supine diastolic BP reduction after HCTZ and tiapamil administration was 3.8 mm Hg (not significant). There were no significant changes in heart rate. Dizziness occurred in one patient taking tiapamil and in three receiving HCTZ. One patient receiving HCTZ developed acute arthritis urica. In conclusion, tiapamil is an effective antihypertensive agent and could be used as an alternative to diuretics as a first‐line drug in the treatment of mild to moderate hypertension.
The Effects of Bendroflumethiazide Added to Nifedipine in Patients With Hypertension
Authors: Zezulka A. V. , Gill J. S. , Beevers D. G.
Published: June 2007

It has been suggested that a diuretic added to a calcium antagonist may not reduce blood pressure further in patients with hypertension. Bendroflumethiazide 5 mg was given to 17 patients with essential hypertension who had persistent mild to moderate hypertension despite treatment with nifedipine slow‐release tablets 20 mg bid. One group received bendroflumethiazide before (N = 8) and the other after placebo (N = 9) in a double‐blind, randomized cross‐over trial. Supine blood pressure following active bendroflumethiazide administration was significantly reduced in both groups compared with trial entry (166/105 to 150/96 mm Hg, P < .01; 170/108 to 156/98 mm Hg, P < .01). A reduction in serum potassium level and a rise in serum uric acid concentration were seen with combined treatment. We cannot substantiate theoretic arguments for the ineffectiveness of a bendroflumethiazide‐nifedipine combination on blood pressure.
Comparison of Moxonidine and Clonidine HCl in Treating Patients With Hypertension
Authors: Plänitz Vera
Published: June 2007

In a six‐week multicenter, double‐blind comparison study, moxonidine and clonidine HCl were tested in 122 and 30 outpatients, respectively, with mild to moderate hypertension (World Health Organization stage I and II; highest measured diastolic blood pressure, 90 to 115 mm Hg). Each agent reduced systolic and diastolic blood pressure to a similar significant extent: moxonidine, 25.4 and 12.4 mm Hg, respectively; clonidine, 25.3 and 10.0 mm Hg, respectively (P < .001 vs baseline). The mean individually titrated dose of moxonidine and clonidine HCl was found to be 0.36 mg/d. Clonidine slightly reduced heart rate in patients assuming an upright position by 3 beats/min at the end of dose titration (P = .018), while moxonidine did not. Two patients receiving moxonidine and three patients taking clonidine HCl discontinued therapy because of side effects. However, patients administered clonidine experienced significantly more side effects (53%) compared with a 30% incidence of adverse effects associated with moxonidine (P = .031). The most frequent adverse effect of both agents was dryness of mouth, which was mentioned significantly more often with clonidine (47%) than with moxonidine (20%) (P = .005). Edemas were found in 0.8% and 17% of patients during six‐week treatment with moxonidine and clonidine, respectively (P = .001). Accordingly, moxonidine was tolerated significantly better than clonidine (P < .001) in this parallel comparison study. Moxonidine is as effective as clonidine in monotherapy of mild to moderate essential hypertension and, additionally, neither drug produces clinically important changes in biochemical parameters.
Pharmacokinetics and Pharmacodynamics of Flestolol, a New Short‐Acting, Beta‐Adrenergic Receptor Antagonist
Authors: Achari Ramanuj , Drissel Debra , Hulse James D. , Bell Valerie , Turlapaty Prasad , Laddu Atul , Matier William L.
Published: June 2007

The pharmacokinetics and pharmacodynamics of flestolol, a new short‐acting, beta‐adrenergic receptor antagonist, were examined in nine healthy subjects after a constant intravenous infusion of 5 μg/kg/min for 72 hours. Flestolol blood levels were determined by high‐performance liquid chromatography. In all subjects, flestolol blood concentration attained steady state 30 minutes after initiation of infusion. The mean ± standard deviation steady‐state concentration of flestolol was 31.1 ± 12.0 ng/mL. The elimination half‐life averaged 7.2 minutes. The mean ± standard deviation total body clearance was 181 ± 66 mL/min/kg. The apparent volume of distribution and the area under the curve averaged 1.89 L/kg and 2.23 μg‐hr/mL, respectively. Flestolol did not cause any significant change (P > .05) in the heart rate or systolic or diastolic blood pressure from the baseline. Flestolol significantly (P < .05) attenuated the isoproterenol‐induced increase in heart rate and systolic blood pressure and decrease in diastolic blood pressure in comparison with baseline. The average maximum reduction in isoproterenol tachycardia was in the range of 63% to 79% during flestolol infusion. There was a rapid recovery from beta blockade after termination of flestolol infusion; the recovery averaged 96% 20 minutes after the infusion was stopped. We conclude that flestolol exhibits a very short half‐life and is cleared mainly by extrahepatic routes. It is an effective beta blocker and possesses a short duration of action.

CONCLUSION

The results of this study show that there is little intersubject variability in the disposition of flestolol. The drug is rapidly eliminated from blood, and it is cleared mainly by extrahepatic routes. Flestolol is an effective beta‐adrenergic blocking agent and exhibits both a rapid onset and short duration of action. None of the subjects experienced clinically significant adverse effects, and there were no clinically significant alterations in the blood chemistry, hematology, or creatinine clearance in any participant during the flestolol‐infusion period. Although infusion site induration was observed in three subjects, it did not necessitate discontinuation of infusion. Furthermore, in another investigation, subjects tolerated flestolol at the same dosage level for seven days.
Alterations in Intrauterine Pressure, Menstrual Fluid Prostaglandin F Levels, and Pain in Dysmenorrheic Women Treated With Nimesulide
Authors: Pulkkinen M. O.
Published: June 2007

A double‐blind crossover study was carried out to evaluate the therapeutic efficacy of nimesulide and its effects on uterine activity, menstrual fluid prostaglandin F, and pain in women suffering from primary dysmenorrhea. Twenty‐three women entered the clinical pharmacologic study. Intrauterine pressure was monitored with a microballoon‐tipped catheter on the first day of menstruation. During the maximal pain period (based on monitoring in six patients), nimesulide significantly decreased intrauterine pressure; the measure of pain relief was consistent with decrease of uterine activity. In another six patients, the registration of intrauterine pressure during the submaximal pain period demonstrated that both in the nimesulide‐ and placebo‐treated cycles, the uterine activity was at a lower mean level than that registered during maximal pain. Furthermore, when two 100‐mg oral doses of nimesulide were administered to 11 dysmenorrheic women, in double‐blind, crossover conditions with placebo as a blank reference, it brought about a reduction of menstrual fluid prostaglandin F2 levels from 382 to 94 ng/mL, (P < .001). Fourteen women entered a four‐cycle, double‐blind, crossover therapeutic trial. Each patient was randomly assigned to one of two treatment sequences with nimesulide 200 mg/d PO or placebo. The therapy was judged very effective or good in 22 of 28 cycles treated with nimesulide compared with nine of 27 cycles treated with placebo (P < .01). The amount of bleeding during the treated cycles did not change, and there were no complaints of untoward signs or symptoms related to the therapies.
Metabolism of Desciclovir, a Prodrug of Acyclovir, in Humans After Multiple Oral Dosing
Authors: Krasny Harvey C. , Petty Brent G.
Published: June 2007

Desciclovir (DCV), a prodrug of the antiherpetic agent acyclovir (ACV), is converted in humans to ACV, presumably by xanthine oxidase. Further metabolism of these two compounds was investigated in six human volunteers given 250 mg DCV orally every eight hours for ten days plus one dose on day 11. The mean percent dose recovered in urine (24 hr) on days 2, 5, and 10 as carboxy‐DCV (2%) and as carboxy‐ACV (14%) along with recoveries of DCV (6%) and ACV (62%) gave a mean total of 84% cleared over a 24‐hour period at steady state. Carboxyl metabolites were not found in the plasma of these same subjects at peak DCV concentration on dose day 11. The ratios of DCV and ACV to their corresponding carboxyl metabolites in urine were 4:1 and 3:1, respectively, suggesting that there is little or no difference in the efficiency of these two substrates for oxidation to their carboxylic acid metabolites.
Pharmacokinetics of Antituberculosis Drugs in Patients
Authors: Israili Zafar H. , Rogers C. Milford , El‐Attar Hanan
Published: June 2007

The pharmacokinetics of rifampin, isoniazid, and ethambutol were determined in 26 ambulatory male patients (aged 49.5 ± 9.9 yr) with tuberculosis. Rifampin and isoniazid were given individually or together, with or without ethambutol; studies were done after a single dose and after chronic administration. Under the study conditions, with large variability in the extent of disease and physical status and history of alcohol and tobacco abuse and narrow age range, the pharmacokinetics of these three antituberculosis drugs were not modified significantly by patient age. Furthermore, appreciable drug‐drug interactions did not occur when the three drugs were administered concurrently. Self‐induction of rifampin clearance by chronic dosing with the drug may lead to subtherapeutic levels of rifampin. Administration of isoniazid and ethambutol in two divided doses resulted in peak plasma concentrations below the accepted therapeutic levels of the two drugs. Our findings indicate that at least in the middle‐aged patients with tuberculosis, the current single daily dose, multiple‐drug regimen is therapeutically sound pharmacokinetically, and clinicians do not have to make adjustments in dosages of these drugs for age and the extent of disease.
The Case Conference Approach to Teaching Clinical Pharmacology
Authors: Ingenito Alphonse J. , Noble Baxter G. , Wooles Wallace R.
Published: June 2007

This article analyzes the development of the small group case conference format, historically, elsewhere, and at the authors' institution, as a way of introducing second‐year medical students enrolled in a basic pharmacology course to the practicalities, nuances, and challenges of contemporary drug therapy. A number of goals and purposes for these conferences have been identified and incorporated into the development and execution of a plan carried out over the past 14 years. Two examples of the conferences were presented, including an analysis of their teaching features. A listing of the general topics of 40 individual conferences used by the authors was provided. The authors reviewed evidence based on several methods of evaluation that the conferences are enthusiastically accepted by second‐year medical students as an adjunctive approach to teaching both basic and applied clinical pharmacology. In addition, the authors find that the conferences subserve a number of other teaching functions such as problem‐solving, information retrieval and presentation, and peer co‐instruction. The conferences provide a mechanism for faculty‐student interaction and an additional way to evaluate student knowledge and performance beyond the more conventional examination approaches.
Terazosin: A New Alpha Adrenoceptor Blocking Drug
Authors: Achari Ramanuj , Laddu Atul
Published: June 2007

Terazosin (Hytrin®; Abbott Laboratories, North Chicago, IL) is a new, selective alpha‐adrenoceptor blocking agent used on once‐a‐day basis for therapy of mild‐to‐moderate hypertension. Its pharmacologic properties are similar to those of prazosin. Terazosin however, differs from prazosin in that its water solubility is 25 times greater than that of prazosin and its elimination half‐life is about three times that of prazosin. Greater water solubility facilitates intravenous formulation, and longer half‐life allows once‐daily administration of terazosin. Terazosin is effective in lowering blood pressure and has a beneficial effect on plasma lipid profile. The major advantage of terazosin compared with prazosin, however, is its long duration of action. Terazosin is safe and effective when used in combination with diuretics and other antihypertensive agents, and in the long‐term treatment of patients with mild to moderate essential hypertension.
The Role of Ambulatory Monitoring of the Blood Pressure for Assessment of Antihypertensive Agents
Authors: White William B.
Published: June 2007

For many decades, the casual blood pressure (BP) has been the standard for assessing BP response to antihypertensive agents in clinical trials. Noninvasive ambulatory BP technology has improved vastly in the last 15 years and has been increasingly used in dose‐response studies as well as efficacy trials. Through these studies we have learned that casual BP may not be representative of the average daily blood pressure, that it may be quite susceptible to observer bias, and that it may result in inaccurate calculation of the trough‐to‐peak ratio of an antihypertensive drug. Perhaps more importantly is that a large body of data now supports the superiority of average daily BP over that of the casual or clinic BP in predicting several indexes of hypertensive target organ damage. Thus, use of the ambulatory BP technique in antihypertensive trials yields BP data that are far less susceptible to improper diagnosis and are representative of the hypertensive burden that causes vascular disease.
Cholestyramine‐Induced Hyperchloremic Metabolic Acidosis
Authors: Scheel Paul J. , Whelton Andrew , Rossiter Kevin , Watson Alan
Published: June 2007

Cholestyramine is a nonabsorbable anion exchange resin that is used predominantly for the treatment of hypercholesterolemia in adults and the management of acute diarrhea in children. The authors report two cases of severe hyperchloremic nonanion gap metabolic acidosis associated with the use of cholestyramine therapy. The authors recommend that patients taking cholestyramine who have concomitant renal insufficiency or who are volume depleted or who are taking spironolactone be monitored carefully for the emergence of a hyperchloremic metabolic acidosis.
Lovastatin Alters Blood Rheology in Primary Hyperlipoproteinemia: Dependence on Lipoprotein(a)?
Authors: Koenig Wolfgang , Hehr Reinhard , Ditschuneit Herwig H. , Kuhn Klaus , Ernst Edzard , Rosenthal Julian , Hombach Vinzenz
Published: June 2007

As part of a randomized, single‐blind, comparative study evaluating the efficacy of lovastatin and bezafibrate retard in the treatment of primary hypercholesterolemia, hemor‐heologic parameters (whole blood viscosity, hematocrit, plasma viscosity, red blood cell aggregation and de for mobility, and fibrinogen) were studied in 35 patients. Whole blood viscosity and plasma viscosity improved significantly after 3 months of treatment with lovastatin, whereas other hemorheologic variables remained unchanged. Stratifying 24 patients by their lipoprotein Lp(a) levels showed that in those with low Lp(a) (≤ 25 mg/dL) high‐density lipoprotein cholesterol increased and red blood cell aggregation as well as deformability decreased considerably, whereas in the group with high Lp (a) levels (>25 mg/dL), the opposite behavior was observed. Treatment of primary hypercholesterolemia with lovastatin may not only reduce the risk for atherosclerotic complications by its pronounced decrease of low‐density lipoprotein cholesterol, but also may favorably alter blood rheology, and may decrease insudation of plasmatic components into the arterial wall and improve tissue perfusion, in particular on the microcirculatory level. The possible relevance of Lp(a) levels for the hemorheologic effects of lovastatin remains to be elucidated.
A Comparison of Tablets with Oral Suspension Formulation of Dipyridamole in Thallium Myocardial Imaging
Authors: Lavie Eli , Gergans Gregory , Somberg John C.
Published: June 2007

Dipyridamole stress thallium imaging has been widely employed to diagnose and assess the extent of coronary heart disease in patients who cannot exercise. When oral dipyridamole administration was used, a wide range of results for sensitivity, specificity, hemodynamic response and side effect profile has been reported. The authors hypothesized that the formulation used for oral administration of dipyridamole plays a major factor in this variability, and that the pulverized form of dipyridamole will achieve faster and more consistent response than the standard tablet form. The authors studied 13 consecutive patients who underwent thallium scintigraphy. Eight patients received dipyridamole pulverized and dissolved in a glycol/aqueous base diluent (group A), and jive patients received the standard form of dipyridamole (group B). In group A, mean peak systolic blood pressure decreased from 142 ± 31 (mean ± standard deviation) to 109 ± 30 (P = .05), and mean diastolic blood pressure decreased from 76 ± 14 to 51 ± 5. The mean heart rate changed from 78 ± 26 to 80 ± 10. In group B, baseline systolic blood pressure was 165 ± 12 and decreased to 156 ± 7 at 45 minutes and to 155 ± 14 at 90 minutes. Heart rate increased from baseline of 69 ±9 to 75 ±8 at 45 minutes and to 76 ± 11 at 90 minutes. At 45 minutes, the systolic blood pressure of the 8 group A patients dropped by 33 ± 19 mm Hg, whereas group B's changed by 9 ± 6 mm Hg (P < .005). The total dipyridamole dose used was significantly lower for group A as compared with group B (425 ± 66 mg and 800 mg, respectively; P < .0001). The time from start until thallium injection was shorter for group A (33 ± 7 minutes) as compared with 90 minutes for group B (P < .001). Sixty‐three percent of the patients who received the pulverized dipyridamole had a reversible perfusion defect on thallium imaging, but no patient had a positive study in group B. Side effects were observed in one patient receiving pulverized dipyridamole (13%), whereas 2 of 5 patients (40%) receiving tablets had side effects at 90 minutes and 4 of 5 patients (80%) had side effects between 90 and 180 minutes. The authors conclude that yield at thallium imaging with dipyridamole tablets is low, and late side effects appear high. Pulverized dipyridamole appears to be a sensitive provocative agent for thallium imaging with mild side effects over a shorter period.
Evaluation of Bioavailability and Pharmacokinetics of Two Isosorbide‐5‐Mononitrate Preparations in Healthy Volunteers
Authors: Hutt V. , Theodor R. , Pabst G. , Bonn R. , Fritschi E. , Jaeger H.
Published: June 2007

The objective of this study was to determine both the pharmacokinetic parameters and the bioavailability of two commercial 20‐mg isosorbide‐5‐mononitrate (IS‐5‐MN) preparations (test and reference preparation) after single oral administration. For this purpose, the test and the reference preparation were examined in 24 healthy male volunteers according to a randomized 2‐way cross‐over design, blood samples were withdrawn up to 24 hours postadministration, and plasma concentrations of IS‐5‐MN were quantified by a gas chromatography (GC) method. Both preparations led to peak plasma levels of approximately 360 ng/mL IS‐5‐MN in the mean 0.76 hour (test) and 0.94 hour (reference preparation) after application; the plasma half‐lives were about 5.2 hours, and for the areas under the curve (AUC(0‐∞)), mean values of 2741 (test preparation) and 2742 hour · ng/mL (reference preparation) were found. The statistical comparison (analysis of variance, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both IS‐5‐MN preparations. The undesired side effects/concomitant symptoms observed are known to occur after IS‐5‐MN administration.
Multiple Dose Pharmacokinetics of Four Different Doses of Nisoldipine in Hypertensive Patients
Authors: Chandler Mary H. H. , Clifton G. Dennis , Lettieri John T. , Mazzu Arthur L. , Allington Douglas R. , Thieneman Andrew C. , Foster Thomas S. , Harrison Michael R.
Published: June 2007

This randomized double‐blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoidipine (core‐coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoidipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose‐normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P < .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 ± 3.47 (5 mg), 11.84 ± 13.85 (10 mg), 11.48 ± 7.49 (20 mg), and 10.36 ± 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoidipine core‐coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoidipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.
Comparison of Plasma Nicotine Concentrations After Application of Nicoderm (Nicotine Transdermal System) to Different Skin Sites
Authors: Gorsline Jane , Okerholm Richard A. , Rolf Clyde N. , Moos C. Diane , Hwang Stephen S.
Published: June 2007

Drug absorption through the skin can vary according to the application site. The nicotine transdermal system, Nicoderm (Alza Corp., Palo Alto, CA) contains a rate‐controlling membrane designed to regulate delivery of nicotine to the skin and thus limit variability in nicotine plasma levels. Plasma nicotine concentrations were compared after application of NTS 14 mg/day to three different skin sites (upper back, upper outer arm, upper chest) in a randomized, crossover study involving 12 healthy male smokers. Plasma nicotine proxies from ail three sites were similar: nicotine concentrations increased rapidly within 2 to 4 hours, reached broad peaks of approximately 11 to 14 ng/mL, and then remained relatively constant between 8 and 24 hours after application. The mean nicotine maximum peak plasma concentration values for nicotine transdermal system application to the arm, back, and chest were equivalent (13.8, 14.6, and 13.2 ng/mL, respectively). The mean time to reach peak concentration (tmax) (3 to 6 hours), and area under the curve (168, 186, and 183 ng · h/mL) values for the arm, back, and chest, respectively, were not significantly different. Thus, bioequivalent plasma nicotine concentrations were achieved irrespective of the application site on the upper body.
A Cardiologist's Perspective on Evolving Concepts in the Management of Congestive Heart Failure
Authors: Forker Alan D.
Published: June 2007

The conceptual framework for treatment of congestive heart failure has changed dramatically in the past 30 years. The 1950s and 1960s were characterized by manipulation of the left ventricular function curve by digitalis and diuretics. The 1970s focused on relief of symptoms by afterload reduction with vasodilators. Then stimulation of cardiac output with inotropes was shown to relieve symptoms, but patients died sooner. Now the focus is on the neurohumeral milieu and methods to counteract excess renin‐angiotensin and sympathetic nervous system stimulation. Angiotensin‐converting enzyme inhibitors are the drugs of choice because they also improve survival, but β‐blockers are becoming popular. The effect of molecular cardiology on practice guidelines for congestive heart failure is yet to be seen.
No Effect of High‐Protein Food on the Stereoselective Bioavailability and Pharmacokinetics of Verapamil
Authors: Hashiguchi Masayuki , Ogata Hiroyasu , Maeda Akira , Hirashima Ms. Yuka , Ishii Ms. Shizuka , Mori Ms. Yuko , Amamoto Toshiaki , Handa Toshiya , Otsuka Norio , Irie Shin , Urae Akinori , Urae Ryuji , Kimura Ryoji
Published: June 2007

The effects of high‐protein food on the bioavailability of both the racemate and individual enantiomers of verapamil were investigated in 12 healthy volunteers using a randomized crossover design. Food had no effect on any parameter of bioavailability for both the racemate and the individual enantiomers of verapamil except time to maximum concentration (tmax), which was significantly prolonged after food intake. The pharmacokinetics of the enantiomers of norverapamil were not significantly changed by food intake. These results suggest that high‐protein food does not alter the pharmacokinetics and bioavailability of either the racemate or the individual enantiomers of verapamil. Therefore, the clinical efficacy of verapamil is not related to food intake, except for a slight prolongation in the time to onset of the pharmacologic effects. The present data can be applied to the high‐protein content meal intake.
Comparison of Methods for the Assessment of Central Nervous System Stimulant Response after Dextroamphetamine Administration to Healthy Male Volunteers
Authors: Slattum Patricia W. , Venitz Jürgen , Barr William H.
Published: June 2007

The objective of this investigation was to evaluate a series of potential pharmacodynamic measures of central nervous system stimulation, including quantitative electroencephalography (EEG) and neuroendocrine, mood, and psychomotor performance measures. The reproducibility and sensitivity of the measures were compared. The study was conducted in two parts. The first part investigated the interindividual and intraindividual variability associated with a series of potential pharmacologic response measures under baseline (i.e., drug‐free) conditions. It was an open‐label, three‐period pilot study in which healthy male volunteers underwent a series of tests (EEG, a visual continuous performance task, a finger tapping task, and self‐rated mood scales) repeatedly during each study period. The second part evaluated the sensitivity of a series of potential response measures to detect the effects of dextroamphetamine, and was a double‐blind, placebo‐controlled, four‐period crossover study in nine healthy male volunteers. Subjects received 5 mg, 10 mg, or 20 mg of dextroamphetamine or placebo orally and underwent the same series of tests as in Part I in addition to blood collection for determination of serum prolactin and dextroamphetamine levels. Peripheral response to dextroamphetamine was assessed by heart rate and blood pressure measurement. The greatest variability among days, within days, and among participants was associated with the quantitative electroencephalographic parameters studied. First‐session effects were apparent for several of the tests, including EEG. Consistent response on EEG (increased alpha power) to dextroamphetamine was observed only in the three subjects who had a baseline alpha activity greater than 35%. Serum prolactin levels were inversely associated with the amount of dextroamphetamine administered, with the largest decrease in serum prolactin levels observed after the 5‐mg dose, and this finding was statistically significant. Mood scales showed that three of nine participants experienced dysphoria after at least one dose level of dextroamphetamine. The effect on mood was generally greater as the dose increased. Doses could not be distinguished based on the results of the performance tests. Serum prolactin concentration was the most sensitive measure of central nervous system stimulation on EEG produced by dextroamphetamine under these study conditions. Cardiovascular measures were more sensitive measures of dextroamphetamine effects than the central nervous system measures.
Bioavailability of Sublingual Buprenorphine
Authors: Mendelson John , Upton Robert A. , Everhart E. Thomas , III Peyton Jacob , Jones Reese T.
Published: June 2007

Buprenorphine administered sublingually is a promising treatment for opiate dependence. Utilizing a new, sensitive, and specific gas chromatographic electron‐capture detector assay, the absolute bioavailability of sublingual buprenorphine was determined in six healthy volunteers by comparing plasma concentrations after 3‐ and 5‐minute exposures to 2 mg sublingual and 1 mg intravenous buprenorphine. The amount of unabsorbed buprenorphine in saliva was measured after 2‐, 4‐, and 10‐minute exposures to 2 mg sublingual buprenorphine in 12 participants. Pharmacokinetic parameters were analyzed by analysis of variance; bioequivalence was evaluated by the Schuirmann two‐sided test. The 3‐ and 5‐ minute sublingual exposures each allowed 29 ± 10% bioavailability (area under the plasma concentration—time curve unextrapolated) and were bioequivalent. Buprenorphine recovered from saliva after 2‐, 4‐, and 10‐minute exposures was, on average, 52% to 55% of dose. Increased saliva pH was correlated with decreased recovery from saliva. Study results indicate that bioavailability of sublingual buprenorphine is approximately 30%. Sublingual exposure times between 3 and 5 minutes produce equivalent results. Buprenorphine remaining in saliva causes an almost twofold overestimation of bioavailability.
A Dose‐Ranging Study of Azathioprine Pharmacokinetics After Single‐Dose Administration of a Delayed‐Release Oral Formulation
Authors: Zins Bradley J. , Sandborn William J. , McKinney Jeffrey A. , Mays Dennis C. , VAN Os Erik C. , Tremaine William J. , Mahoney Douglas W. , Zinsmeister Alan R. , Lipsky James J.
Published: June 2007

6‐Mercaptopurine and its prodrug azathioprine are an effective treatment for inflammatory bowel disease, but widespread use has been limited by concern about toxicity. Ileocolonic delivery of azathioprine as a 50‐mg delayed‐release oral capsule has been shown to decrease bioavailability, thus potentially decreasing toxicity. This study aimed to determine the bioavailability and pharmacokinetic parameters of delayed‐release oral azathioprine capsules at doses of 200 mg, 400 mg, and 600 mg relative to 100 mg of standard oral azathioprine tablets. Thirty healthy human volunteers each received delayed‐release oral azathioprine at one of the three doses (n = 10 for each group). All participants also received a 100‐mg tablet of standard oral azathioprine. Plasma concentrations of 6‐mercaptopurine were determined by high‐pressure liquid chromatography. The relative bioavailabilities of 6‐mercaptopurine after ileocolonic azathioprine administration via delayed‐release oral capsules at doses of 200 mg, 400 mg, and 600 mg (means of 15%, 15%, and 12%, respectively) were all significantly less than 100% compared with standard oral azathioprine at a 100‐mg dose. Ileocolonic delivery of azathioprine by a delayed‐release oral capsule formulation at doses up to 600 mg considerably reduces 6‐mercaptopurine bioavailability, relative to standard oral azathioprine tablets. The therapeutic potential of this ileocolonic delivery formulation, which can limit toxicity by local delivery of azathioprine, should be investigated in patients with inflammatory bowel disease.
Noninvasive Method for Measuring Thrombus Formation in Patients After Peripheral Angioplasty Using Three‐Dimensional B‐Mode and Color‐Coded Doppler Ultrasonography
Authors: Eisert W. G. , VAN Ryn J. , Kallmeyer M. , Birk G. , Hoffmann B. , Schlachetzki F. , Kubale R. , Schneider E. , Hoffmann U.
Published: June 2007

Clinical investigations studying the effect of newer medications on such complex pathophysiology as the formation of an arterial or venous mural thrombus have been limited to clinical symptomatic endpoints. Biochemical markers so far have not been convincing in quantifying ongoing thrombus formation. Consequently, clinical development of new antithrombotic compounds has had to rely on clinical symptoms that occur either comparably late in the course of the disease and may therefore be influenced by many other factors, or on those symptoms that occur at a relatively low incidence rate. Both circumstances make studies for dose‐finding and determination of optimal drug regimens more difficult and time consuming. Using conventional clinical noninvasive ultrasonography, the volume and geometry of a peripheral arterial segment can be measured with high sensitivity and reproducibility in healthy volunteers (% coefficient of variation = 8.01%). In patients, thrombus volume was monitored after peripheral transluminal angioplasty of the femoral artery. All patients received a standard anticoagulant treatment with heparin for 24 hours after the procedure. Volume measurements were performed at 20, 29, 44, 53, and 68 hours after angioplasty. When compared with the obstruction volume at 20 hours, a slight increase could be detected at 29, 44, and 53 hours. At 68 hours there was a significant increase in obstruction volume. This indicates that volume measurements may detect changes in the course of thrombus formation, related to the antithrombotic treatment regimen, at a level at which clinical symptoms may not be present.
Pharmacokinetics and Pharmacodynamics of Bumetanide in Critically Ill Pediatric Patients
Authors: Marshall James D. , Wells Thomas G. , Letzig Lynda , Kearns Gregory L.
Published: June 2007

This prospective, open‐label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl−, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean ± standard deviation values for total clearance and apparent volume of distribution of 3.9 ± 2.4 mL/min/kg and 0.74 ± 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect‐compartment pharmacodynamics.
Population Pharmacokinetics and Pharmacodynamics of Cisplatin in Patients with Cancer: Analysis with the NONMEM Program
Authors: Nagai Naomi , Ogata Hiroyasu , Wada Yuji , Tsujino Daijiro , Someya Kazuhiko , Ohno Tetsuro , Masuhara Keisou , Tanaka Yoshio , Takahashi Haruki , Nagai Haruki , Kato Katsuhiko , Koshiba Yoichi , Igarashi Tamotsu , Yokoyama Akira , Kinameri Koichi , Kato Toshiyuki , Kurita Yuzou
Published: June 2007

The population pharmacokinetics and pharmacodynamics of cisplatin (CDDP) were evaluated based on a mixed‐effect model using the NONMEM program. Unchanged CDDP in plasma was measured as a biologically active platinum species during CDDP chemotherapy, using high‐performance liquid chromatography. Plasma concentration measurements (157) of unchanged CDDP from 26 patients with cancer receiving 80 mg/m2 CDDP by infusion over 2 hours, 3.5 hours, or 4 hours were analyzed according to a one‐compartment model. The influences of individual characteristics such as body weight, dose schedule, course, and clinical laboratory values (renal function markers, albumin) on total body clearance (Cl) and volume of distribution (Vd) were examined. In the final pharmacokinetic model, body surface area and dose schedule affected Cl of unchanged CDDP. The Cl of CDDP was increased by 27.3% after the 2‐hour infusion schedule compared with Cl after the longer infusions. The Vd was estimated as 13.4 L/m2. The interindividual variability for Cl and Vd and residual variability were 22.9%, 30.9%, and 35.5%, respectively. The relationships between maximum concentration (Cmax) of unchanged CDDP and maximum blood urea nitrogen (BUNmax), or minimum creatinine clearance (ClCr,min) over a 1‐month period after CDDP administration were evaluated according to linear, exponential, or maximum response (Emax) models. The linear or Emax model described pharmacodynamics most successfully, with relatively large interindividual variability for both slope and EC50 (more than 25%). Residual variability was 15.3% and 17.1% in BUNmax and ClCrmin, respectively. The population means and interindividual and residual variability of pharmacokinetics and pharmacodynamics of CDDP were evaluated using the NONMEM program. The results of this study show that the population pharmacokinetic and pharmacodynamic approach could be useful to manage CDDP nephrotoxicity using sparse data in a clinical setting.
Lack of Pharmacokinetic Interaction between Tiagabine and Erythromycin
Authors: Thomsen Mikael Søndergård , Groes Lisbet , Agersø Henrik , Kruse Trine
Published: June 2007

This study was conducted to investigate the effects on the pharmacokinetics of tiagabine at steady state when coadministered with therapeutic doses of erythromycin. Tiagabine doses of 4 mg twice daily and erythromycin doses of 500 mg twice daily were administered for 4 days in an open‐label, crossover, two‐period interaction trial in 13 healthy volunteers. No statistically significant differences in maximum plasma concentration (Cmax), area under the concentration—time curve (AUCτ), or half‐life (t1/2) of tiagabine were observed when tiagabine was administered alone or in combination with erythromycin. A statistically significant treatment effect was observed for time to maximum concentration (tmax; 0.72 after tiagabine alone versus 0.56 hours after administration with erythromycin). No statistically significant differences were seen between men and women except in tmaxand t1/2; these differences were thought to be of no clinical significance. The decrease in tmaxseen in women in this study is interpreted as a differential effect of erythromycin on gastric emptying of females and not as an interaction between tiagabine and erythromycin. No changes in laboratory parameters or vital signs were attributable to trial medication. The most common treatment‐emergent adverse events that were possibly related to trial medication were central nervous system effects (e.g., headache, dizziness); all adverse events were transient, the majority were rated mild in severity, and did not require additional action. Coadministration of erythromycin in healthy subjects does not significantly affect the pharmacokinetics of tiagabine at the doses tested.
Effect of High‐Dose Oral Ganciclovir on Didanosine Disposition in Human Immunodeficiency Virus (HIV)‐Positive Patients
Authors: Jung Donald , Griffy Kay , Dorr Albert , Raschke Robert , Tarnowski Thomas L. , Hulse James , Kates Robert E.
Published: June 2007

This study was designed to investigate the interaction between high‐dose oral ganciclovir (6,000 mg/day) and didanosine at steady state in patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection. The study was conducted as an open‐label, randomized, three‐period crossover study. Patients received (in random order) multiple oral doses of didanosine 200 mg every 12 hours alone, ganciclovir 2,000 mg every 8 hours alone, and ganciclovir 2,000 mg every 8 hours in combination with didanosine 200 mg every 12 hours. Blood and urine samples for determinations of drug concentrations were obtained on day 3 of each dose regimen. When ganciclovir was administered either before or 2 hours after didanosine, the mean increases in maximum concentration (Cmax), area under the concentration—time curve (AUC0–12), and percent excreted in urine of didanosine were 58.6% and 87.3%, 87.3% and 124%, and 100% and 153%, respectively. There were no statistically significant effects of didanosine on the steady‐state pharmacokinetics of ganciclovir in the presence of didanosine, irrespective of sequence of administration. There were no significant changes in renal clearance of didanosine, suggesting that the mechanism for the interaction does not involve competition for active renal tubular secretion. The mechanism responsible for increased didanosine concentrations and percent excreted in urine during concurrent ganciclovir therapy may be a result of increased bioavailability of didanosine. However, the mechanism appears to be saturated at oral ganciclovir doses of 3 g/day.
Pharmacodynamic Interactions of Ciprofloxacin, Piperacillin, and Piperacillin/Tazobactam in Healthy Volunteers
Authors: Strenkoski‐Nix Laura C. , Forrest Alan , Schentag Jerome J. , Nix David E.
Published: June 2007

Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four‐period crossover design. Serum drug concentrations were analyzed by means of high‐performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill‐type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.
Pharmacokinetic Interaction between Finasteride and Terazosin, but not Finasteride and Doxazosin
Authors: Vashi Vijay , Chung Menger , Hilbert James , Lawrence Victor , Phillips Kern
Published: June 2007

The α1‐adrenoceptor antagonists doxazosin and terazosin and the 5α‐reductase inhibitor finasteride are used in the treatment of benign prostatic hyperplasia. The aim of this study was to assess the potential pharmacokinetic interaction of doxazosin or terazosin when coadministered with finasteride. This was a randomized, placebo‐controlled, multi‐center study. Ninety healthy men were assigned to one of six treatment groups: doxazosin; doxazosin plus finasteride; terazosin; terazosin plus finasteride; placebo; and placebo plus finasteride. Plasma concentrations, maximum plasma concentration (Cmax), time to maximum concentration (tmax), and area under the plasma concentration—time curve from 0 to 24 hours (AUC0–24) of doxazosin, terazosin, and finasteride were determined. Ratios of Cmax and AUC for doxazosin and terazosin were not significantly altered by coadministration with finasteride. The Cmax and AUC0–24 of finasteride were not significantly altered by coadministration with doxazosin. However, Cmax and AUC0–24 of finasteride were significantly higher after coadministration with terazosin. There is no statistically significant pharmacokinetic interaction between finasteride and doxazosin; however, there is a statistically significant interaction between finasteride and terazosin, which affects the pharmacokinetics of finasteride but not those of terazosin. The clinical significance of this interaction remains to be determined.
Multiple Realities: Characteristics of Loan Defaulters at a Two-Year Public Institution
Authors: Christman Dana E.
Published: June 2007

Data from the National Student Loan Data System and a college's student data base for cohort years 1993, 1994, and 1995 yielded descriptive statistics on 260 borrowers who defaulted on student loans at one public two-year college. After describing characteristics associated with defaulters, the author provides supporting information from a qualitative survey that elicited perceptions about loan defaulters from 12 respondents representing students, faculty, and staff at the college. Findings indicate that student background characteristics play as great a role in loan default behavior as institutional influences, and the author provides suggestions for future research and policy efforts.
ERIC Review: Community College Teaching-Toward Collegiality and Community
Authors: Outcalt Charles L.
Published: June 2007

This review of the literature focuses on community college faculty and their teaching practices. After summarizing faculty demographic changes since the 1970s, the author describes both obstacles to effective teaching and the innovations that faculty use to overcome them. Although isolation, growing reliance on part-timers, pressure to produce research, underprepared students, and inadequate resources for development continue to challenge community college faculty, they have responded by using innovative methods such as learning communities, collaborative learning, and self-directed learning. The review concludes with descriptions of institution-wide efforts that have transformed teaching and produced innovative curricula.
ERIC Review: The Role of Community Colleges in Training Tomorrow's School Teachers
Authors: Gerdeman R. Dean
Published: June 2007

This review of the literature focuses on the need for teachers and how community colleges are presenting themselves as a source for teacher recruitment. After describing the need for teachers in different contexts, the author explores why students enter teaching careers, how community colleges are a recruitment source, and how community colleges educate prospective teachers. The author then illustrates the community college's role in teacher training with three examples of training programs. The review concludes with goals for the future such as expanding articulation agreements and partnerships with four-year colleges, offering counseling and student support services, and involving students in local schools.