bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Ratings and End‐of‐Phase II Conferences: Initiatives to Accelerate the Availability of Important New Drugs Kenneth I. Kaitin, PhD
Authors: Phelan Natalie R. , Raiford Drusilla , Morris Betsy
Published: March 2013

To facilitate the availability of important new therapeutic agents, the Food and Drug Administration (FDA) in the mid‐1970s began assigning therapeutic ratings to investigational new drugs and holding end‐of‐phase II conferences with drug sponsors. To determine whether these initiatives are associated with faster approvals, we examined new drug application (NDA) review times of new chemical entities (NCEs) approved during the 12‐year period 1978 through 1989. Mean NDA review time for 1A drugs (22.5 months) was 22% shorter than that for 1B drugs (28.7 months), which in turn was 25% shorter than that for 1C drugs (38.4 months). For drugs approved during the recent 4‐year period 1986 through 1989, however, the gap between 1A and 1C review times has narrowed considerably from 19 to 9 months. When drugs were grouped by FDA reviewing division, 1A drugs had the shortest mean review time in each division except the Cardio‐Renal Division; in that division, 1B drugs had the shortest mean review time. Mean NDA review time for drugs that had end‐of‐phase II conferences (28.6 months) was 15% shorter than that for drugs without such conferences (33.7 months). These results suggest that NCEs that receive 1A or 1B ratings and are the subject of end‐of‐phase II conferences benefit by having shorter review times.
The Pharmacokinetics of Racemic Verapamil in Patients with Impaired Renal Function
Authors: Zachariah Prince K. , Moyer Thomas P. , Theobald H. Michael , Frantz Robert P. , Kurtz Stephen B. , McCarthy James T. , Smith Robin L.
Published: March 2013

The pharmacokinetics of verapamil were studied in patients with renal failure who were undergoing maintenance hemodialysis and in normal subjects after an IV infusion of 10 mg and a single oral dose of 120 mg. Plasma levels of verapamil and its active metabolite, norverapamil, were analyzed by a sensitive and specific HPLC procedure. Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose. The terminal elimination rate constant, clearance, volume of distribution, and bioavailability of verapamil were not significantly different between the two groups of subjects. In addition, the apparent maximal plasma concentration, terminal elimination rate constant, and area under the curve for norverapamil were similar in patients with renal failure and normal subjects. The study showed that the plasma disposition of verapamil and norverapamil was not affected in patients with impaired renal function. Furthermore, this study does not indicate that any change in dosage is necessary when single doses of verapamil are administered to patients with renal failure.
The Pharmacokinetics and Colonic Tissue Concentrations of Cyclosporine After IV, Oral, and Enema Administration
Authors: Sandborn William J. , Strong Richard M. , Forland Steven C. , Chase Resa E. , Cutler Ralph E.
Published: March 2013

This study compares pharmacokinetic parameters and colonic tissue concentrations of cyclosporine administered by olive‐oil or water‐retention enemas with conventional intravenous (IV) and oral dosing. Five medical students were enrolled in a prospective crossover study. All subjects received a single dose of cyclosporine on four separate occasions, once orally, once as an olive‐oil enema, once as a water enema, and once IV. Cyclosporine concentration was measured in blood and in colonic tissue obtained by flexible sigmoidoscopy. Bioavailability was 18 ± 7% (mean ± SDJ for the oral dose and was unmeasurable for the oil and water enemas. The concentration of cyclosporine in colon tissue was 32,443 ± 17,251 ng/g (mean ± SDJ for the IV dose, 2797 ± 1812 ng/g for the oral dose, 21,727 ± 14,090 ng/g for the oil enema, and 25,318 ± 30,408 ng/g for the water enema. The authors conclude that the bioavailability of cyclosporine, and thus the systemic absorption after administration by a retention enema, is negligible. The colonic tissue concentration of cyclosporine after IV or rectal administration via an enema is tenfold higher than that for oral dosing. These findings suggest that cyclosporine‐retention enemas produce high distal colonic tissue concentrations with negligible systemic absorption after a single dose in healthy subjects and should be evaluated as treatment for patients with left‐sided colitis. Because cyclosporine administered by the IV route provided sharply higher colonic tissue concentrations than those seen with oral therapy, pulse IV cyclosporine should be tried for patients with severe ileitis and colitis.
The Effect of Ciprostene in Patients with Peripheral Vascular Disease (PVD) Characterized by Ischemic Ulcers
Authors: Linet Otto I.
Published: March 2013

This randomized, double‐blind study investigated the effect of ciprostene, a stable epoprostenol (prostacyclin) analog in patients with peripheral vascular disease (PVD) characterized by ischemic ulcers. A total of 211 patients (106 ciprostene, 105 placebo) received IV infusions of ciprostene (120 ng/kg/min in 8‐hour daily infusions for 7 days) or placebo. The two groups were comparable with regard to demographic data. Only 45% of the patients receiving ciprostene and 55% of the placebo patients completed the trial. The groups were similar in frequency of amputations, vascular surgery, and development of new ulcers. Among those who completed the trials an insignificantly higher percentage of patients receiving ciprostene had all ulcers heal completely. The reduction of ulcer size by at least 50% was higher in the ciprostene‐treated group at month 4 (P = .005). Both ciprostene and placebo reduced the severity of a patient's rest pain. There was no difference in the ankle brachial index between the groups. Ciprostene induced a higher incidence of headache, nausea, and flushing during infusion when compared with the placebo group. The results confirmed inherent problems with studies in PVD, namely, scarcity of patients with ischemic ulcers, inclusion of severely ill patients leading to a high dropout rate, and a high placebo effect. Good tolerance and safety of ciprostene was documented in this patient population, and the therapeutic benefit was limited to partial reduction of ulcer size. Selection of patients with less advanced disease and a longer infusion of ciprostene may improve the clinical benefit of this agent.
The Absolute Bioavailability and Dose Proportionality of Intravenous and Oral Dosage Regimens of Recainam
Authors: Troy Steven M. , Cevallos William H. , Conrad Kenneth A. , Chiang Soong T. , Latts Jeffrey R.
Published: March 2013

Recainam is a novel class I antiarrhythmic agent with electrophysiologic characteristics of all three subclasses. The authors evaluated the absolute bioavailability and dose proportionality of three oral doses and two 2‐stage intravenous (IV) infusion doses. Single oral doses of 200, 400, and 800 mg and IV infusions consisting of 0.8 mg/kg/5 min + 1.2 mg/kg/hr (3.75 mg/kg) and 1.6 mg/kg/5 min + 1.2 mg/kg/hr for 4 hours and 55 minutes (7.50 mg/kg) were administered to 15 healthy men. Plasma and urine samples were collected during the 36‐hour period after drug administration and analyzed for recainam concentrations by HPLC. No significant differences were found in any of the pharmacokinetic parameters between the two IV dosage regimens. The absolute bioavailability of orally administered recainam increased from 73% for the 200 mg dose to 81% and 84% for the 400 and 800 mg doses, respectively. Dose proportionality deviated from linearity by 13% for the 200 vs. 400 mg doses, and 10% for the 400 vs. 800 mg doses. The slight deviation from linearity was apparently caused by increased absorption at the higher oral doses. The slight disproportionality in the disposition of recainam is not expected to be clinically significant.
Hydrochlorothiazide Versus Spironolactone: Long‐Term Metabolic Modifications in Patients with Essential Hypertension
Authors: Puig J. García , Miranda Ma E. , Mateos F. , Herrero E. , Lavilla P. , Gil A.
Published: March 2013

The metabolic side effects of thiazide diuretics are believed to be responsible for the failure of thiazide diuretics to reduce cardiovascular morbidity in patients with hypertension. However, the decrease in the incidence of osteoporotic fractures that are associated with thiazide administration may be relevant in elderly patients with arterial hypertension. Spironolactone (SP) appears not to influence the metabolic risk profile of the patient with hypertension, and no studies have examined its effect on calcium metabolism. Therefore, in 22 patients with mild to moderate essential hypertension, the authors performed a parallel, randomized, double‐blind, placebo‐controlled study that compared the effects on serum urate and lipid, potassium, magnesium, and calcium metabolism of hydrochlorothiazide (HC) (mean [±SD] dose, 72 ± 26 mg/d) and SP (144 ± 53 mg/d) during a 52‐week period. As compared with placebo, HC significantly increased serum urate and total cholesterol concentrations, and decreased serum potassium levels. SP did not affect serum urate or cholesterol levels but increased serum potassium concentrations. Neither diuretic significantly modified magnesium metabolism. Little changes were seen in serum calcium levels during HC or SP treatment, whereas urinary calcium excretion was significantly decreased by HC (mean decrease, 45%; P < .01) or SP (40%; P < .01). The authors conclude that SP, in addition to its potassium‐sparing properties, has a calcium‐sparing effect that may be beneficial for patients in whom reduction of urinary calcium excretion has a therapeutic value.
Pharmacokinetic Comparison of Flurbiprofen in End‐Stage Renal Disease Subjects and Subjects with Normal Renal Function
Authors: Cefali Eugenio A. , Poynor Wesley J. , Sica Domenic , Cox Steven
Published: March 2013

This study compared the pharmacokinetics of flurbiprofen (F) and three major metabolites in patients with end‐stage renal disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD) with the pharmacokinetics of F in normal subjects. A single 100‐mg dose of F was administered to each of nine normal subjects and eight ESRD subjects. Blood and urine samples were collected in both groups; serial and end of dwell dialysate samples were obtained from the ESRD subjects. Plasma was analyzed for both the R and S optical isomers of F and its major metabolite, 4′‐hydroxy‐flurbiprofen (HF). Urine and dialysate were analyzed for F and three known metabolites. Plasma concentrations of F in the ESRD subjects were approximately 50% of the values obtained from the normal subjects (P < .05). Flurbiprofen half‐life and Tmax were not different. Elimination of HF was reduced in ESRD subjects. Urinary data suggest that HF was the major metabolite excreted (36% of the dose) in normal subjects whereas 3′, 4′ ‐dihydroxy‐flurbiprofen was the major metabolite (9% of the dose) excreted in the ESRD group. Mean urinary recovery of the dose was 73% in the normal subjects, but only 16% in ESRD subjects. Neither F nor its metabolites were detected in dialysate. Small enantiomer differences were seen. This study suggests that ESRD subjects have lower plasma levels of F than normal subjects when administered equal size doses. Accumulation of metabolites may occur in ESRD subjects upon multiple dosing. Enantiomer differences are not clinically significant.
Blood and Urine Responses to Ingesting Fluids of Various Salt and Glucose Concentrations
Authors: Frey Mary Anne B. , Riddle Jeanne , Charles John B. , Bungo Michael W.
Published: March 2013

Several hours before returning to Earth, Space Shuttle astronauts consume fluid and salt tablets equivalent to a liter of 0.9% saline as a countermeasure to postflight orthostatic intolerance. This countermeasure is not completely successful. Therefore, in search of a countermeasure that would protect against orthostatic intolerance better and for a longer duration, the authors compared the blood and urine responses of five men (21–41 yr) after they drank 1 L of 0.9% saline to their responses after drinking five other solutions: distilled water, 1% glucose, 0.74% saline with 1% glucose, 0.9% saline with 1% glucose, and 1.07% saline. Each subject ingested a different solution on 6 different days and remained seated for the ensuing 4 hours. Heart rate, blood pressures, and urine variables were measured before ingestion of the fluids and every 30 minutes thereafter; blood samples were drawn before, immediately after, and every 60 minutes after ingestion. Change in plasma volume, which was estimated from hemoglobin and hematocrit, was considered the most critical variable. Data for all solutions were compared by analysis of variance. Since plasma volume was increased most after ingestion of 1.07% saline, all variables (at 2 hours, at 3 hours and at 4 hours) were compared between 1.07% saline and 0.9% saline, the current countermeasure. Plasma volume was increased more after 1.07% saline than after 0.9% saline, and this difference was most significant at 4 hours after ingestion (P = .056). Diuresis occurred promptly after ingestion of the two saline‐free solutions, water and 1% glucose. Subjects' heart rates and blood pressures did not differ as a function of the solution consumed or the time after ingestion except that heart rate (for all drinks) was higher immediately after ingestion than at all other times. The solutions containing glucose did not significantly enhance any variables as compared with 0.9% saline. The authors conclude that the addition of 1% glucose will not improve the effectiveness or the duration of plasma volume expansion as compared with the present fluid countermeasure but that increasing salt concentration may.
Human Vestibular Function and Weightlessness
Authors: Parker Donald E.
Published: March 2013

This article presents the concept of a spatial orientation/motion perceptual system, the contributions of the vestibular receptors to this system, and apparatus and training procedures and observations to allow astronauts to preadapt to weightlessness. The author also discusses perceptual reactions to prolonged weightlessness.
Human Autonomic Responses to Actual and Simulated Weightlessness
Authors: Eckberg Dwain L. , Fritsch Janice M.
Published: March 2013

Orthostatic dysfunction occurs after exposure to microgravity, and is not completely understood. The authors developed a device for stimulating carotid baroreceptors to test the hypothesis that exposure to microgravity leads to impairment of arterial baroreflex mechanisms. Data obtained before and after two head‐down bedrest studies and before and after brief Space Shuttle missions indicate that baroreceptor‐cardiac reflex control is impaired by simulated or actual weightlessness. The authors speculate that arterial baroreflex derangements combine with blood volume reductions and increased venous compliance to provoke orthostatic hypotension after microgravity exposure. Altered baroreflex function after missions may result from autonomic neuronal plasticity that develops during missions secondary to changes of cardiopulmonary and arterial dimensions and consequent changes of autonomic sensory input proxies.
Electrophysiologic Mechanisms for Ventricular Arrhythmias in Left Ventricular Dysfunction: Electrolytes, Catecholamines and Drugs
Authors: Levy Matthew N. , Wiseman Martin N.
Published: March 2013

Cardiac arrhythmias are generated as the result of disorders of automaticity or of impulse conduction. Regardless of the mechanism, calcium is likely to he involved, although calcium antagonists are rarely useful antiarrhythmics in ventricular arrhythmias. Myocardial cells that do not ordinarily initiate action potentials may do so when they are partially depolarized, giving rise to an ectopic focus. Early afterdepolarizations (EADs) are also induced in cardiac cells by partial depolarization, whereas delayed afterdepolarizations (DADs) are induced by Ca++ overloading. EADs may be the initiating mechanism of torsade de pointes, a complication of QT prolongation associated with quinidine therapy. Both in the animal model and in humans, treatment with magnesium, isoproterenol, or pacing, all of which suppress EADs, will also suppress torsade de pointes. Ventricular tachycardia is a manifestation of ordered re‐entry, and may be exacerbated by antiarrhythmics, especially class 1c drugs. In the individual patient, prediction of proarrhythmia is not possible. The risk of proarrhythmia is increased in patients with episodes of sustained ventricular tachycardia or with significant left ventricular dysfunction.
Sudden Death in Congestive Heart Failure
Authors: Sami Magdi H.
Published: March 2013

Despite significant advances in recent years in the diagnosis and treatment of congestive heart failure, sudden unexpected cardiac death is still considered a major epidemiologic problem among those patients. This article lists some of the predisposing factors to the development of cardiac arrhythmias and sudden death in patients with congestive heart failure. These include electrolyte or autonomic nervous system inbalance, the use of certain anti‐arrhythmic drugs, or intermittent myocardial ischemia. This paper shows that an advanced degree of left ventricular dysfunction and the preference frequent or complex ventricular arrhythmias appear to be major predictors of total and sudden mortality among patients with congestive heart failure. A screening of 24 hours ambulatory Holter monitor recording appears to be useful in identifying patients at risk of sudden cardiac death.
Long‐Term Treatment of Ventricular Tachycardia with Amiodarone in Presence of Severe Left Ventricular Dysfunction
Authors: Burckhardt Dieter , Robertson Alan , Hoffmann Andreas , Pfisterer Matthias
Published: March 2013

A group of 34 consecutive patients with coronary artery disease (n = 29) or dilated cardiomyopathy (n = 5) (3 women, 31 men, age 38–80 yr) who had severely impaired left ventricular function (left ventricular ejection fraction ≤ 40%) and high‐grade ventricular ectopic activity (sustained or nonsustained ventricular tachycardia or ventricular fibrillation) were treated with amiodarone (mean dose: 206 mg/d) and followed for 1–117 (mean: 49) months. In the total group, there were seven sudden deaths, five deaths due to pump failure, one non‐cardiac death, and two successful heart transplantations during follow‐up. Thus the annual cardiac mortality in these carefully selected and followed patients was 8, 6%, the annual cardiac event rate was 10, 1%. The cumulative cardiac survival‐rate was 62% after 5 years and 41% after 10 years. In jive patients, treatment was interrupted after 10 to 43 months, three of the patients were alive at follow‐up and two suffered cardiac death, resulting in an annual cardiac death rate of 12% in this subgroup off treatment. Based on the results of this retrospective analysis we conclude that in patients with low left ventricular ejection fraction and nonsustained or sustained ventricular tachycardia treated with low dose amiodarone, mortality was unexpectedly low. Thus, it may be the antiarrhythmic treatment to be considered in patients with ventricular tachycardia and severe left ventricular dysfunction.
Pharmacokinetics of Intravenous Immunoglobulin (Gammagard) in Bone Marrow Transplant Patients
Authors: Rand Kenneth H. , Gibbs Katherine , Derendorf Hartmut , Graham‐Pole John
Published: March 2013

The pharmacokinetics of an intravenous immunoglobulin (IVIG), Gammagard (Baxter Healthcare Corp., Glendale, CA), were measured in 31 cytomegalovirus (CMV) antibody negative bone marrow transplant (BMT) patients as part of a multicenter efficacy trial of 2 weekly dose regimens. Since all patients lacked antibody to CMV and received only screened CMV negative blood products, the half‐life of the exogenous CMV antibody could be measured with an ELISA assay. The CMV antibody titer was related to the immunoglobulin concentration using a standard curve. Compared with the 22‐day half‐life in normal subjects, the half‐life in BMT patients was approximately 6 days for either the 250 mg/kg or 500 mg/kg dose regimen. The half‐life did not change over the subsequent 3 weekly doses. Peak concentrations were 3.5 ± 1.4 and 2.6 ± 0.7 mg/mL of IVIG in week 1 as well as 5.5 ± 2.6 and 3.4 ± 1.2 mg/mL in week 3 after the 250 mg/kg and 500 mg/kg, respectively. Total body clearance of IVIG was 0.61 and 0.46 mL/kg/hr for the 500 mg/kg and 250 mg/kg, respectively.
Significance of Classifying Antiarrhythmic Actions Since the Cardiac Arrhythmia Suppression Trial
Authors: Williams E. M. Vaughan
Published: March 2013

The Cardiac Antiarrhythmic Suppression Trial (CAST) showed flecainide and encainide induced excess mortality compared with placebo. Labeling drugs as Class 1C is based on clinical observations, comprising measurements of the electrocardiographic parameters QRS, H‐V and J‐T intervals and of effective refractory period (ERP) as follows: 1—(QRS) wide, 2—(HV) long, 3—(ERP) unchanged, 4—(JT) unchanged. In vitro electrophysiology helped to explain the clinical findings. Flecainide and encainide rendered Na channels as nonconducting, but F and E were only slowly released from the channels after repolarization. At any given drug concentration, a proportion of total channels were eliminated, and the steady‐state proportion increased at rising heart rate. It is not proven that the properties that lead to classification of a drug as 1C were those that caused excess deaths in the CAST. The proarrhythmic tendency of 1C drugs can be reduced by beta‐blockade, and the mechanisms of adrenergic arrhythmogenicity are discussed. Propafenone is both a 1C drug and a beta‐blocker, and its pharmacologic profile is reviewed to illustrate how it resembles and differs from flecainide and encainide. Some features of the CAST are assessed with particular reference to the extent to which conclusions drawn from the results may be justifiably extrapolated to other drugs classified as 1C.
Pharmacokinetics of the Antidepressant Tianeptine at Steady State in the Elderly
Authors: Demotes—Mainard Fabienne , Galley Pierre , Manciet Gérard , Vinson Gérard , Salvadori Catherine
Published: March 2013

The pharmacokinetics of tianeptine, an antidepressant with an original serotoninergic neurochemical action, was investigated in elderly patients. Kinetic profiles were developed in 12 elderly patients (age range: 72–81 yr) after single (12.5 mg) dose and multiple oral dosages (12.5 mg tid for 17 days). Multiple dosing of tianeptine was well tolerated; no accumulation of the unchanged drug was observed. Tianeptine and its MC5 metabolite (C5 acid analogue of tianeptine) reached maximum plasma levels after 1.81 ± .99 and 2.96 ± 1.44 hr, respectively, with values of 353 ± 198 and 81 ± 20 ng/mL, respectively, after a single dose and of 405 ± 202 and 175 ± 85 ng/mL, respectively, after multiple dosing. Minimum plasma concentrations of tianeptine were about half those of its MC5 metabolite (68 ± 41 and 121 ± 64 ng/mL−1 on day 5), and for each compound, they were not statistically different from day 5 to day 18 of the chronic administration. This finding is compatible with the terminal half‐lives that were observed after the single dose that was 2.8 ± .9 hr for tianeptine and 12.3 ± 7 hr for the MC5 metabolite. For both compounds, the area‐under‐the‐plasma levels time curve at steady state was as predicted from the initial single dose that showed no deviation from linearity with time. The kinetics of tianeptine in elderly patients were similar to those reported for young adults. However, MC5 metabolite plasma levels were higher in elderly patients than in younger patients. This observation has led to a recommendation to start the prescription with a reduced daily dose of tianeptine in elderly patients aged 70 years or older and to prescribe 12.5 mg twice daily.
Comparison of Adinazolam Pharmacokinetics and Effects in Healthy and Cirrhotic Subjects
Authors: Kroboth Patricia D. , BS Rae Ann Maxwell , Fleishaker Joseph C. , Van Thiel David H. , Smith Randall B.
Published: March 2013

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex‐matched control subjects. These subjects received a single 30‐mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono‐desmethyl‐adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit‐symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer‐rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 ± 27.9 L/hr) than in normal subjects (73.7 ± 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 ± .084 vs. .278 ± .070; P = .007), whereas the mean t½ in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 ± 95.5 vs. 153 ± 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t½ in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 ± 254 vs. 1162 ± 254 ng · hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation. The large differences in adinazolam kinetics and small differences in NDMAD kinetics, and effects support previous reports that suggest that NDMAD is the major component responsible for responses that were assessed. These kinetic and side‐effect data from this single‐close study in a small population suggest that patients with cirrhosis may not be more sensitive to this benzodiazepine, but that accumulation of drug and metabolite may lead to greater effects in patients with cirrhosis during multiple‐dose therapy.
Dose‐Dependent Response to Phenylpropanolamine: Inhibition of Orthostasis
Authors: Lake C. Raymond , Rosenberg David B. , Gallant Sheryle , Zaloga Gary , Chernow Bart
Published: March 2013

Phenylpropanolamine, a widely consumed over‐the‐counter drug, is known to elevate blood pressure, but the mechanism is unknown; it may be both a direct and indirect sympathomimetic. This study investigated the effects of 75‐mg sustained‐release phenylpropanolamine, 75‐mg phenylpropanolamine plus 400‐mg caffeine, and 150‐mg phenylpropanolamine on blood pressure, plasma norepinephrine, and epinephrine levels in 16 normotensive subjects in a double‐blind, placebo‐controlled crossover design. Mean peak phenylpropanolamine levels of 317 ± 26, 152 ± 17, and 157 ± 17 ng/mL for 150‐mg phenylpropanolamine, 75‐mg phenylpropanolamine, and 75‐mg phenylpropanolamine plus 400‐mg caffeine, respectively, were reached at about 3.6 hours after dosing. The maximal increases in supine diastolic blood pressures after all three phenylpropanolamine‐containing drugs were almost three times that after placebo (P <.05), but peak blood pressures occurred at about 2.3 hours earlier than peak phenylpropanolamine levels. Blood pressure increases correlated with phenylpropanolamine plasma levels (r = .49 for systolic blood pressure and r = .34 for diastolic blood pressure; P <.0001 for both). Norepinephrine levels increased after the administration of 150‐mg phenylpropanolamine and 75‐mg phenylpropanolamine plus 400‐mg caffeine; norepinephrine increases correlated with phenylpropanolamine levels (r = .34, P<.0001). The expected increment in norepinephrine induced by standing was significantly decreased by phenylpropanolamine in a dose‐dependent mode. The study supports the idea that phenylpropanolamine is both a direct (at alpha‐1 and alpha‐2 receptors) and an indirect sympathomimetic agent.
Decreased Systemic Clearance of Lorazepam in Humans With Spinal Cord Injury
Authors: Segal Jack L. , Brunnemann Sherry R. , Eltorai Ibrahim M. , Vulpe Michael
Published: March 2013

Serum concentration‐time course profiles, serum protein binding, and disposition parameters of lorazepam (LRZ), a benzodiazepine with sedative‐hypnotic, anxiolytic, and antiseizure properties, were studied as part of a systematic effort to define population‐specific pharmacokinetic behavior in humans with chronic spinal cord injury (SCI). Twenty‐four healthy subjects (nine tetraplegic, six paraplegic, nine able‐bodied) were given an IV bolus of 2.0 mg of LRZ. Noncompartmental estimation of pharmacokinetic parameters disclosed a 37% decrease in the total systemic clearance (CL) of LRZ in tetraplegic patients. Altered LRZ clearance was observed independently of significant changes in volume of distribution or serum protein binding. The early elimination of LRZ (0–10 hr) was characterized by wide fluctuations in serum concentration suggestive of impaired enterohepatic circulation and could be distinguished from LRZ elimination observed in able‐bodied subjects. We conclude that decreased systemic CL and the altered terminal elimination profile of LRZ are attributable to the pathophysiology of SCI.
Theophylline Pharmacokinetics: Effect of Continuous Versus Intermittent Cimetidine IV Infusion
Authors: Gaska Janice A. , Tietze Karen J. , Rocci Mario L. , Vlasses Peter H.
Published: March 2013

The comparative effects of continuous versus intermittent cimetidine infusion on theophylline pharmacokinetics were evaluated in 12 nonsmoking healthy male volunteers. Each subject received aminophylline 0.9 mg/kg/hr over 6 hours alone (control) and in random order at 1 week intervals, in combination with intermittent cimetidine (300 mg IV over 15 minutes every 6 hours) and continuous cimetidine (50 mg/hr W) infusions. Both cimetidine regimens were administered for a total of 50 hours. Serial plasma samples were obtained and assayed for theophylline by HPLC. No significant differences existed in mean theophylline clearance and mean volume of distribution among control, intermittent or continuous cimetidine regimens; the power was >80% to detect a 30% change in clearance. Only a minor difference in theophylline half‐life between control and continuous cimetidine infusion (7.59 ± 2.52 vs. 9.05 ± 3.17 hr; P <.05) was observed. These findings do not support a clinically significant interaction between IV aminophylline and cimetidine administered IV either as a low dose continuous infusion or as an intermittent infusion.
Hypnotic Efficacy of Estazolam Compared with Flurazepam in Outpatients with Insomnia
Authors: Cohn Jay B. , Wilcox Charles S. , Bremner James , Ettinger Milton
Published: March 2013

Eslazolam is a new benzodiazepine hypnotic agent with an intermediate half‐life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double‐blind, placebo‐controlled, multicenter, 7‐night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.
Prophylactic Antiparkinson Drug Use: I. Initial Prophylaxis and Prevention of Extrapyramidal Side Effects
Authors: Lavin Michael R. , Rifkin Arthur
Published: March 2013

The use of prophylactic antiparkinson medications during neuroleptic treatment is controversial. Although the efficacy of these agents in the treatment of extrapyramidal side effects is well established, the questions of when to initiate therapy and for how long remain unanswered. There are only a few double‐blind, placebo‐controlled studies on the value of concurrent antiparkinson drug use at the beginning of neuroleptic treatment. The authors reviewed all studies on initial prophylaxis, and found most to be methodologically deficient. There is evidence to support the use of these agents to prevent acute dystonic reactions. Further work needs to focus on other types of extrapyramidal symptoms. In light of the inability to predict who will experience these side effects, the authors conclude that initial prophylaxis is beneficial for most patients who are starting neuroleptic medications.
Lack of Effect of a High‐Fat Meal on the Volume of Distribution of Theophylline in Humans
Authors: Parish Roy C. , Wade William E. , Middendorf Wayne F.
Published: March 2013

The pharmacokinetics of intravenously administered theophylline were studied in five healthy nonsmokers. Each subject received 5 mg/kg of theophylline as aminophylline after an overnight fast and again after a standard high‐fat meal. Although there was wide between‐day variation in the elimination rate constant in three of the five subjects, no statistically significant differences were observed in area under the time‐versus‐concentration curve, maximum serum theophylline concentration, elimination rate constant, or apparent volume of distribution between the two treatments. A statistical power analysis indicated that if differences in volume of distribution and maximum serum theophylline concentration occur in the general population, the mean differences are less than 15% and 20%, respectively. This suggests that alterations in intravascular drug distribution resulting from eating a high‐fat meal do not contribute importantly to previously reported effects of food on serum theophylline concentrations after oral dosing.
Evaluation of a Potential Interaction Between Erythromycin and Glyburide in Diabetic Volunteers
Authors: Fleishaker Joseph C. , Phillips J. Paul
Published: March 2013

The effects of erythromycin on the pharmacokinetics and pharmacodynamics of glyburide were evaluated in 12 patients with non—insulin‐dependent diabetes mellitus (fasting blood glucose levels 140–280 mg/dL), who received 4 days of treatment with erythromycin base (333 mg administered orally every 8 hr) and a control treatment in a randomized crossover design; 5 mg glyburide was administered on day 4 of each study period. Serum glyburide concentrations were determined by high‐performance liquid chromatography. Peak serum glyburide concentrations were increased by 18%, and mean time to peak glyburide concentrations (Tmax) decreased from 4.9 to 3.0 hours during erythromycin treatment; only the difference in Tmax was statistically significant. No significant effects on glyburide clearance were observed. No significant differences in glucose clearance after carbohydrate loads were observed between erythromycin + glyburide and glyburide treatments. These data show that oral erythromycin base treatment does not affect glyburide metabolism but does affect the rate of glyburide absorption. This effect may be mediated by the stimulation of gastric motility by erythromycin. The clinical significance of the effects of erythromycin on glyburide kinetics appear to be minimal, based on the determinations of serum glucose concentrations.
Clinical Pharmacokinetics of Albendazole in Patients with Brain Cysticercosis
Authors: Jung Helgi , Hurtado Morcela , Sanchez Monica , Medina Marco T. , Sotelo Julio
Published: March 2013

Albendazole pharmacokinetics were studied in eight patients who were receiving albendazole in doses of 15 mg/kg per day for 8 days as treatment of brain cysticercosis. Albendazole was not detected in plasma, but its main metabolite albendazole sulphoxide could be measured. Maximum plasma levels for albendazole sulphoxide ranged from 0.45 to 2.96 pg/mL. The half‐life of albendazole sulphoxide was between 10 and 15 hours. A double peak was found in three patients. Mean residence time values were from 14 to 20 hours. Plasma levels of albendazole sulphoxide at the steady state showed great intraindividual variability. The results suggest that albendazole can be administered twice daily rather than three times as is currently done.
Antihypertensive and Metabolic Effects of Single and Combined Atenolol Regimens
Authors: Chrysant Steven G. , Chappel Christopher , Farnham D. John , Levin Bruce , Lueg Mark , McCluskey Dennis , Steiner Charles
Published: March 2013

The antihypertensive and metabolic effects of placebo (PL), a fixed combination of hydrochlorothiazide (25 mg) and triamterene (50 mg) (HCTZ/TRI), atenolol (25 mg) (Ate‐25), atenolol (50 mg) (Ate‐50) and their combination with HCTZ/TRI given once daily, were tested on 256 patients with mild‐to‐moderate essential hypertension. After 3 weeks of PL monotherapy, 43 patients were randomized to PL (group 1), 41 patients to HCTZ/TRI (group 2), 44 patients to Ate‐25 (group 3), 42 patients to Ate‐50 (group 4), 43 patients to Ate‐25/HCTZ/TRI (group 5), and 43 patients to Ate‐50/HCTZ/TRI (group 6) in a double‐blind parallel design study and were followed for 4 weeks. At the end of week 7, those patients who were randomized to groups 5 and 6 were allowed to continue for an additional 12 weeks, if their arterial pressure was satisfactorily controlled. Complete blood counts, blood chemistries, urinalyses, and electrocardiograms were done initially and during the study. Monotherapy with HCTZ/TRI, Ate‐25, and Ate‐50 had significant and equal antihypertensive effects compared with placebo. (P <.01). However, the combination of Ate‐25/HCTZ/TRI and Ate‐50/HCTZ/TRI resulted in further reduction of arterial pressure with the effect being greatest with Ate‐50/HCTZ/TRI (P <.001). Patient groups 3 through 6 had also slower heart rates compared with groups 1 and 2 (P <.01). Mild, but statistically significant, increases in BUN, glucose, triglycerides, and uric acid were noted in groups 2, 5, and 6 (P <.05). These results suggest: 1) Ate‐25 was equipotent to Ate‐50, 2) their antihypertensive effectiveness was further enhanced with the addition of HCTZ/TRI, and 3) the greatest effect was noted with the combination of Ate‐50/HCTZ/TRI.
Pharmacodynamic and Pharmacokinetic Evaluation of a New Transdermal Delivery System with a Time‐Dependent Release of Glyceryl Trinitrate
Authors: Wiegand A. , Bonn R. , Trenk D. , Jähnchen E. , Bauer K.‐H.
Published: March 2013

The pharmacokinetics of glyceryl trinitrate (GTN) and its main metabolites as well as the hemodynamic effects of a new transdermal delivery system (TDS) were investigated in ten healthy male volunteers using a single blind, placebo‐controlled study design with an application period of active drug of 4 successive days. The adhesive‐type matrix system contains 20‐mg GTN and released about 75% in a time‐dependent manner. The plasma concentrations of GTN and its metabolites 1–2‐ and 1–3 glyceryl dinitrate reflected the time‐dependent release with higher plasma concentrations during the first 12 hours than during the second 12 hours. Continuous administration of the TDS, which released 15 mg GTN/day, caused an accumulation of GTN in the plasma (about 70% greater AUC at the fourth day in comparison with the first day). The total effect per dose on the a/b‐ratio of the digital pulse (height of the peak of the systolic wave divided by the height of the peak of the dicrotic wave) and the reflex tachycardia were diminished by about 50% and 37%, respectively, at the fourth treatment day. The effect on systolic blood pressure measured under orthostatic conditions was blunted already 8 hours after the first application. The effect of sublingually administered GTN on digital pulse was attenuated during administration and also 1 hour after removal of the last TDS. The effect was restored 8 to 12 hours after removal of the TDS. Thus, the discontinuous release of GTN from the new system does not prevent the decline of hemodynamic efficacy during continuous therapy.
Optimization of Sampling Time for Cyclosporine Monitoring in Transplant Patients
Authors: Regazzi M. B. , Rondanelli R. , Gastaldi L. , Martinelli L. , Vigano' M.
Published: March 2013

Cyclosporine (CsA) dosing is based on CsA plasma or blood concentrations measured 12 to 24 hours after drug administration (trough levels). This study evaluated the relationship between the timing of CsA concentrations and subsequent pharmacokinetic parameters to predict an optimal sampling period. Plasma samples were obtained from 22 patients before their morning dose of CsA and at 2,4,6,8,10, and 12 hours after the dose on the 7th and on the 21st day after heart transplantation. The plasma samples were assayed by both HPLC and FPIA. The Cmax for CsA was achieved over a period ranging from 2 to 6 hours (mean/median = 4.7/4.0) during the day 7 and the day 21 studies. The mean (±SD) half‐life was 3.2 (1.0) hours on day 7 and 2.9 (1.1) hours on day 21, (P > 0.05); the mean apparent oral clearance was 276 (117) L/hr on the day 7 and 269 (209) L/hr on day 21, (P > 0.05). When CsA plasma concentration by either FPIA and HPLC was monitored, the drug concentration best correlated with AUC was found to correspond to the plasma samples taken 4 to 8 hours after drug administration. The authors conclude that trough blood sampling for therapeutic drug monitoring of CsA is not optimal, and that further studies are necessary to correlate concentration monitoring during the dosing interval with pharmacologic and toxicologic parameters.
The Stereoselective Pharmacokinetics of Etodolac in Young and Elderly Subjects, and After Cholecystectomy
Authors: Brocks Dion R. , Jamali Fakhreddin , Russell Anthony S. , Skeith Kenneth J.
Published: March 2013

The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 ± 3.3 years), 6 nonarthritic elderly subjects (ages 73 ± 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R‐etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S‐enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali‐labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers between the young and elderly subjects. The results reflect the importance of considering stereoselectivity in evaluating the pharmacokinetics of etodolac.
Acceptability and Efficacy of Two Associations of Paracetamol with a Central Analgesic (Dextropropoxyphene or Codeine): Comparison in Osteoarthritis
Authors: Boissier Ch. , Perpoint B. , Laporte‐Simitsidis S. , Mismetti P. , Hocquart J. , Gayet J. L. , Rambaud C. , Queneau P. , Decousus H.
Published: March 2013

A double‐blind randomized parallel group trial was undertaken to compare the acceptability and efficacy of 2 forms of analgesic treatment, DI‐Antalvic (Houde Laboratories, Puteaux, France) (30 mg dextropropoxyphene and 400 mg paracetamol per capsule) and Efferalgan‐Codeine (UPSA Laboratories, Rueil Malmaison, France) (30 mg codeine and 500 mg paracetamol per tablet) prescribed for 1 week at doses of 6 capsules/day and 6 tablets/day, respectively, in 141 outpatients with active osteoarthritis of the knee or hip. The principal aim of the trial was concerned with acceptability, with efficacy as its secondary aim. The principal trial criterion was defined as overall assessment of acceptability by the patient at the end of the trial (success or failure) or by treatment dropouts because of an adverse effect (failure). Comparability of the groups was confirmed before any treatment regarding the physical characteristics of the patients, characteristics of osteoarthritis, and the initial level of pain and functional consequences of pain. Results show that the analgesic efficacy of the treatment was similar, but that the acceptability of Efferalgan‐Codeine was significantly worse than that of DI‐Antalvic: 53% failure with Efferalgan‐Codeine versus 29% failure with DI‐Antalvic (P = .005). Other trials of the same type would seem necessary (comparison of lower doses, other types of pain) before being able to generally extrapolate such findings.
Effectiveness and Duration of Intramuscular Antimotion Sickness Medications
Authors: Wood Charles D. , Stewart John J. , Wood Mary J. , Mims Malcolm
Published: March 2013

Motion sickness inhibits gastric motility, making the oral route ineffective for medications. The intramuscular route is an effective alternative. The rotating chair was used to produce the M 111 level of motion sickness on the Graybiel Symptom Scale. The intramuscular medications given 30 minutes before rotation were compared with placebo (saline, 1 mL) for effectiveness and duration in increasing the number of tolerated head movements. Average placebo number of head movements was 294. Promethazine 25 mg increased head movements by 78% (P < .05), with a duration of 12 hours. Scopolamine 0.2 mg increased head movements by 91% (P < .05), with a duration of 4 hours. The effect of caffeine 250 mg and ephedrine 25 mg was not significant. When combined with scopolamine, ephedrine produced an 32% additive effect. Scopolamine 0.08 mg, 0.1 mg, and 0.2 mg and also promethazine 12.5 mg and 25 mg were significant (P < .05). Promethazine appears to be the drug of choice for intramuscular use because of a longer duration and a high level of effectiveness. Scopolamine was of high effectiveness, but had a duration of 4 hours. It was eight times as potent by the intramuscular as by the oral route.
Pharmacokinetics of Nadolol in Children with Supraventricular Tachycardia
Authors: Mehta Ashok V. , Chidambaram Balasubrahmanyam , Rice Peter J.
Published: March 2013

The pharmacokinetics of intravenous and oral nadolol, a long‐acting β‐adrenoceptor blocking agent, were investigated in six children receiving the drug for treatment of supraventricular tachycardia. In the youngest patient (age 3 months), no distribution phase was seen. In children younger than 22 months of age, nadolol is more rapidly eliminated (t1/2 = 4.3 hours or less) than in older children, in whom elimination is more similar to that in adults (t1/2 ∼ 7.3–15.7 hours). After intravenous administration, nadolol displayed two‐compartment pharmacokinetics with a distribution phase (t1/22 = 0.2–1.1 hours) followed by elimination. Large changes in nadolol pharmacokinetics may occur during the first year of life. Nadolol should be used cautiously in infants.