bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug Delivery Systems—2. Site‐Specific Drug Delivery Utilizing Monoclonal Antibodies
Authors: Ranade Vasant V.
Published: March 2013

Monoclonal antibodies (MAbs) are purified antibodies produced by a single clone of cells. They are engineered to recognize and bind to a single specific antigen. Accordingly, when administered, MAbs home in on a particular circulating protein or on cells that bear the correct antigenic signature on their surfaces. It is the specificity of MAbs that has made them valuable tools for health professions.

Following the discovery of Kohler and Milstein regarding the method of somatic cell hybridization, a number of investigators have successfully adopted this technique to obtain T‐lymphocyte hybrid cell lines by fusion of activated T (thymus derived) lymphocytes with a T lymphoma cell line leading to an immortalization of a specific differentiated function. The hybrids thus obtained were subsequently shown to produce homogeneous effector molecules with a wide variety of immune functions such as enhancement or suppression of antibody responses, generation of helper T cells, suppressor T cells and cytotoxic T cells.

Study of these regulatory molecules has been further shown to provide a greater insight into the genetic, biochemical and molecular mechanisms responsible for cellular development, and the interaction and triggering of various cell types.

The successfull application of hybridoma technology has now resulted into several advances in the understanding the mechanism and treatment of diseases, especially cancer and development of vaccines, promotion of organ transplantation and therapy against parasites as well. Since monoclonal antibodies could be made in unlimited supply, they have been used in genetic studies such as mRNA and gene isolation, chromosomal isolation of specific genes, immunoglobulin structure, detection of new or rare immunoglobulin gene products, structural studies of enzymes and other proteins and structural and population studies of protein polymorphisms. In some instances, the monoclonal antibodies have been found to replace conventional antisera for studies of chromosome structure and function, gene mapping, embryogenesis, characterization and biosynthesis of developmental and differentiation antigens. These antigens are those that are specific for various cell types and tissues, species specific antigen, antigens involved in chemotaxis, immunogenetics and clinical genetics including genetically inherited disorders, chromosome aberrations and transplantation antigens.

Besides these monoclonal antibodies, their complexes have recently been investigated as exquisitely sensitive probes to be guided to target cells or organs. They have been used to deliver cytotoxic drugs to malignant cells or enzymes to specific cell types. Current research efforts indicate that antibodies against different subsets of T lymphocytes, particularly suppressor lymphocytes will continue to be of great value in the diagnosis and treatment of patients with multiple sclerosis, various heart diseases, different types of leukemias and malaria.
Effect of Salt Balance on the Renal and Hemodynamic Actions of Benazepril in Normal Men
Authors: Noormohamed Faruq H. , Fuller Geraint N. , Lant Ariel F.
Published: March 2013

Renal and hemodynamic effects of diet alone and of single oral doses of the nonsulphydryl angiotensin converting enzyme (ACE) inhibitor, benazepril (10 mg), were investigated in eight healthy volunteers under stable conditions of high salt intake (300 mmol NaCl/day) and low salt intake (10 mmol NaCl/day), in a double blind, placebo controlled study. There were no changes in blood pressure between the two dietary extremes either during the run‐in period or once sodium balance had been achieved. Mean renal plasma flow was higher, by approximately 10% and renal vascular resistance lower by 15%, on high salt diet compared to low salt diet. Glomerular filtration rates were found to be similar irrespective of the state of salt balance. Both plasma urate concentration and plasma renin activity were significantly elevated in the low salt compared to high salt state. Benazepril caused a greater fall in blood pressure in the sodium depleted state. Significant increases in the mean renal plasma flow, in the order of 15–20%, were seen over 6 h postbenazepril when compared with placebo response, regardless of the level of salt intake. Glomerular filtration rate over the same period remained unaltered. Benazepril doubled the urinary excretion of sodium over the first 4 hours after dosing whilst on the low salt diet; the equivalent increase during salt loading was approximately 20%. These results suggest that benazepril may exert direct effects on renal tubular function additional to those achieved through ACE blockade.
Clinical Pharmacology of Dilevalol (III). A Pharmacokinetic Study of Dilevalol in Elderly Subjects with Essential Hypertension
Authors: Fujimura Akio , Sugimoto Kouichi , Kumagai Yuji , Nakashima Hajime , Ebihara Akio
Published: March 2013

Dilevalol (100 mg) was given once daily for 8 days in eight elderly subjects with essential hypertension. Blood samples for plasma dilevalol concentrations were taken during an 8‐hour post‐drug period following the first and eighth dosages, and the time to maximum concentration (tmax), maximum plasma concentration (Cmax), distribution half‐life (t1/2α), elimination half‐life (t1/2β) and area under the plasma concentration‐time curve (AUC) were determined.

A wide intra‐subject variability was observed in tmax during the repeated administration. A high inter‐subject variability was also demonstrated in tmax, Cmax, t1/2β and AUC during both observation periods. No significant difference was observed, however, in these pharmacokinetic parameters between the first and eighth dosages.

These data indicate that the pharmacokinetic profiles of dilevalol are not altered during 8 days of therapy in elderly subjects with essential hypertension. Since elderly subjects are potentially heterogenous in capacities for handling the drug, the observed variability in pharmacokinetic parameters may reflect the heterogeneity in the sample chosen for examination in the current study.
A Double‐Blind Study with Placebo Control of Intramuscular Ketorolac Tromethamine in the Treatment of Cancer Pain
Authors: Staquet Maurice J.
Published: March 2013

The analgesic efficacy of ketorolac tromethamine was compared to placebo in 126 patients suffering moderate or severe chronic pain due to cancer in a double‐blind parallel randomized study. Ketorolac was administered intramuscularly in doses of 10, 30 or 90 mg. Pain intensity and pain relief were assessed for 6 hours by scoring standard verbal scales and an overall assessment of the medication was given by the patients and the observer on completion of the study. Each dose of ketorolac was statistically superior to placebo for the sum of pain intensity difference (SPID) but no difference was seen between the three ketorolac regimens. When the ketorolac groups are combined, there was a significantly better pain relief as compared to placebo. The global evaluation scores were also statistically superior in the ketorolac groups combined than in the placebo group. A total of 15 patients reported minor adverse events, 10 being after ketorolac doses. This study shows that single intramuscular doses of ketorolac of 10 mg and above are effective in the relief of cancer pain, and are associated with a low incidence of side‐effects.
Determination of Saliva: Total Plasma Chloroquine Levels Relationship by High Performance Liquid Chromatography
Authors: Brown‐Awala E. A. , Thomas W. O. A. , Essien E. E. , Ette E. I.
Published: March 2013

The use of saliva chloroquine concentrations measurement as a noninvasive technique in the evaluation of the pharmacokinetics of the drug was investigated. Chloroquine concentrations in saliva and plasma were measured in eight healthy volunteers after a single oral dose of two tablets of chloroquine sulfate. The saliva:total plasma concentrations (S/P) ratio was found to be approximately constant in the absorption (0.4 ± 0.07), distribution (0.47 ± 0.08), and elimination (0.46 ± 0.05) phases. Thus, saliva sampling for chloroquine concentrations was found to be a useful noninvasive technique for the estimation of all the pharmacokinetic parameters of the drug and hence, for chloroquine pharmacokinetic studies.
Antiarrhythmic Efficacy of Desipramine
Authors: Fenster Paul E. , Bressler Rubin , Kipps Julie
Published: March 2013

The effect of desipramine on chronic ventricular ectopic depolarizations (VEDs) was studied in 10 patients with at least 30 VEDs per hour. A single‐blind, placebo‐controlled, dose‐ranging protocol was followed. Efficacy was defined as a decrease in VED frequency of at least 75%, based on three 24 hour ambulatory ECGs obtained on each dose. Among seven patients with analyzable data, one responded to 75 mg daily, and three others responded to 150 mg daily. Six of the seven patients demonstrated decreases in VED frequency with increases in desipramine serum concentration. Among five patients with episodes of nonsustained ventricular tachycardia, desipramine completely abolished the episodes in two, and reduced the frequency of episodes by at least 90% in two others. Adverse reactions were common, and necessitated drug discontinuation or dose reduction in five patients. Desipramine has an antiarrhythmic effect in patients with chronic ventricular ectopy, but its clinical utility is limited by adverse effects.
Comparison of Once‐Daily Captopril or Enalapril in Mild Essential Hypertension
Authors: Pixley John S. , Marshall Maureen K. , Stanley Harriet , Starich Gale H. , Ferguson Roger K.
Published: March 2013

The purpose of this study was to assess the effect of a daily low dose of the angiotensin‐converting enzyme (ACE) inhibitors, captopril or enalapril, in mild essential hypertension. Nine men with seated diastolic blood pressure between 95 and 104 mm Hg on placebo participated in the study. After one month of placebo, captopril 25 mg was administered; blood pressure, heart rate, ACE activity and plasma renin activity were measured hourly for 4 hours. Each patient then received captopril 50 mg once daily for 8 weeks and similar measurements were made 24 hours post‐dose every 2 weeks. After another month of placebo, the identical protocol was repeated after enalapril 5 mg. Although blood pressure and ACE activity decreased significantly (P < 0.05) within 2–4 hours of the acute doses of each inhibitor, neither captopril or enalapril produced significant reductions 24 hours after the small daily dose. Thus, neither ACE inhibitor alone was adequate to control blood pressure in mild hypertension when given once daily during 8 weeks of treatment.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Gastric Protection Rodolfo Cheli

Chloride Channels and Their Modulation by Neurotransmitters and Drugs (Advances in Biochemical Psychopharmacology, Vol. 45) [Biggio, Giovanni, and Costa, Erminio, Editors.

Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs. Edited by: Enno Christophers, Erwin Shopf, Albert M. Kligman, and Richard B. Stoughton.

Glial Cell Receptors Edited by Harold K. Kimelberg

Advances in Second Messenger and Phosphoprotein Research, Volume 21 (Sixth International Conference on Cyclic Nucleotides, Calcium and Protein Phosphorylation, Bethesda, Maryland, September 2–7, 1988) Edited by Robert S. Adelstein, Claude B. Klee, and Martin Rodbell.

Advances in Second Messenger and Phosphoprotein Research, Volume 21A, Abstract Volume (Sixth International Conference on Cyclic Nucleotides, Calcium and Protein Phosphorylation, Bethesda, Maryland, September 2–7, 1988) Edited by Robert S. Adelstein, Claude B. Klee, and Martin Rodbell.
Treatment of Diet‐Resistant Polygenic Hypercholesterolaemic Patients with a New Nicotinate Derivative; In Vivo and In Vitro Low Density Lipoprotein Metabolic Studies
Authors: Masana L. , Escobar A. , Joven J. , Sola R. , Vilella E. , Bargallo T. , Turner P. R.
Published: March 2013

Six patients (four women and two men) with mild to moderate hypercholesterolemia, but with no clinical evidence of the disease being monogenic familial hypercholesterolaemia and who, over the previous 3 months on a rigidly controlled hypolipidaemic diet therapy, showed no reduction in plasma cholesterol levels, were recruited into a study to assess the metabolic effects of Pirozadil, a new nicotinic acid derivative. After a 3 month treatment period, a significant reduction in plasma cholesterol from 299.8 ± 31.2 mg/dl (mean ± SD) to 256.8 ± 18.1 mg/dl (P < 0.02) and Low Density Lipoprotein (LDL) cholesterol from 211.7 ± 44.9 mg/dl to 168.8 ± 19.0 mg/dl (P < 0.05) was observed. Although there was a trend toward decreased plasma and Very Low Density Lipoprotein (VLDL) triglyceride, the differences did not reach statistical significance. High Density Lipoprotein (HDL) cholesterol was unchanged. The drug was well tolerated with no side effects noted. To assess the mode of action, autologous125I‐labelled LDL was injected and apoprotein B (apo B) kinetic parameters were measured; production rate (PR) and fractional catabolic rate (FCR). An in vitro measurement of the in vivo catabolism (LDL‐apo B receptor activity in freshly isolated lymphocytes) was also measured pre‐ and post‐treatment. The pharmacological intervention resulted in a significant decrease of 19.9% in PR from 10.5 ± 1.81 mg/kg/d to 8.41 ± 1.13 mg/kg/d (P < 0.05) while the FCR remained relatively unchanged (0.260 ± 0.042 vs 0.248 ± 0.040 pools/d) as did the LDL receptor activity (78.2 ± 20.9 vs 69.3 ± 21.4 ng LDL/mg cell protein/hr). Our data suggest that in polygenic hypercholesterolaemia, a condition in which the LDL receptor and hence catabolism is normal, the alternative therapy to facilitating enhanced catabolism is one that decreases the synthesis of the lipoprotein and, as such, nicotinic acid and its derivatives may be effective hypolipidaemic agents.
Single Dose Safety, Tolerance, and Pharmacokinetics of HP 029 in Healthy Young Men: A Potential Alzheimer Agent
Authors: Puri Surendra K. , Hsu Robert S. , Ho Irwin , Lassman Howard B.
Published: March 2013

1,2,3,4‐tetrahydro‐9‐aminoacridin‐1‐ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double‐blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half‐life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug‐related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within‐subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaingful or drug related after any of the doses of HP 029. After the 75 mg dose one subject reported mild dizziness, diarrhea and vomiting, and a moderate headache. These side effects were considered to be possibly/probably drug related and none required treatment. Two subjects in the 200 mg dose group experienced a moderate to severe headache that was not considered drug‐related. Based upon the results of this single dose safety study in young men, testing of the safety, tolerance and pharmacokinetics of multiple oral doses of HP 029 is indicated.
Influence of Indomethacin on a Reduction in Forearm Blood Flow Induced by Propranolol in Healthy Subjects
Authors: Sugimoto Kouichi , Fujimura Akio , Kumagai Yuji , Kotegawa Tsutomu , Ebihara Akio
Published: March 2013

The influence of indomethacin on a reduction in forearm blood flow (FBF) induced by propranolol was investigated in eight healthy subjects. Indomethacin was orally administered (75 mg daily for 3 days) in a randomized cross‐over design. Blood pressure (BP) was slightly decreased after a single oral administration of propranolol (40 mg) alone. However BP was slightly increased after the drug with indomethacin pretreatment. FBF was significantly decreased after propranolol with or without indomethacin. No significant difference was observed in FBF before or after propranolol between both groups. Plasma renin activity (PRA) was reduced by indomethacin pretreatment. These results suggest that the reduction in FBF induced by propranolol is not augmented with indomethacin.
Bioavailability of Citrate from Two Different Preparations of Potassium Citrate
Authors: Harvey Jean A. , Zobitz Margaret M. , Pak Charles Y. C.
Published: March 2013

The bioavailability of citrate from two different preparations of potassium citrate was examined in eighteen normal volunteers during three phases of study. After stabilization on a constant metabolic diet, subjects took a single dose of placebo, “slow‐release” potassium citrate tablets (60 meq) or rapid‐release liquid potassium citrate preparation (60 meq). Timed urine specimens were collected for 24 hours and analyzed for citrate, potassium, and pH. Similar biochemical findings were observed following administration of the two different preparations with the onset and decline of changes being slightly more rapid for the liquid potassium citrate than the tablet preparation. These equivalent bioavailability data indicate that the liquid preparation is a comparable therapeutic alternative to the tablet form.
Acetazolamide Blood Concentrations are Excessive in the Elderly: Propensity for Acidosis and Relationship to Renal Function
Authors: Chapron Dennis J. , Gomolin Irving H. , Sweeney Kevin R.
Published: March 2013

Elderly glaucoma patients are often treated with acetazolamide, a carbonic anhydrase inhibitor with clearance dependent on renal function. A high incidence of metabolic acidosis and other adverse effects have been noted among these patients but the reasons for this have not been explained. We hypothesized that commonly used doses of acetazolamide among the elderly result in excessive blood concentrations and that these concentrations are related to acid‐base disturbances. We measured steady‐state acetazolamide levels in plasma, plasma ultrafiltrate (unbound), and erythrocytes among 12 elderly subjects (79.2 ± 7.6 years old). Mean plasma (18.9 ± 10.9 ug/mL) and ultrafiltrate concentrations (1.0 ± 0.7 ug/mL) exceeded the therapeutic range (plasma 5–10 ug/mL; ultrafiltrate 0.25–0.50 ug/mL) for glaucoma control by two fold and were elevated in 75% of subjects. Plasma and ultrafiltrate acetazolamide levels significantly correlated with the dose adjusted for creatinine clearance (r = 0.91, P < 0.001; r = 0.89, P < 0.001, respectively). Acidotic subjects (serum total carbon dioxide ≤ 22 mEq/L) tended to have higher plasma, ultrafiltrate, and erythrocyte acetazolamide levels compared with nonacidotic subjects. Serum total carbon dioxide levels were significantly correlated with erythrocyte acetazolamide concentrations (r = −0.75, P = 0.03). The ratio of erythrocyte acetazolamide concentration to creatinine clearance separated acidotic from nonacidotic subjects (P < 0.01). These findings suggest that some of the adverse effects of acetazolamide can be avoided by reducing the dose to compensate for age‐related reductions in renal drug clearance.
An Evaluation of the Effect of Repeated Doses of Oral Activated Charcoal on Salicylate Elimination
Authors: Ho Julie L. , Tierney Michael G. , Dickinson Garth E.
Published: March 2013

The authors investigated the effect of repeated doses of oral activated charcoal on salicylate elimination in six healthy volunteers. On two occasions (phase 1 and phase II; separated by one week) each subject received 1300 mg of aspirin as an aqueous solution. On the second occasion (phase II) each subject also received a total dose of 55 g of aqueous activated charcoal initiated 4 hours after salicylate administration (25 g initial dose, followed by three 10 g doses at two hour intervals). Serum salicylate levels were measured from one to twelve hours post aspirin ingestion. The pharmacokinetic analysis showed no significant change between phase I and phase II for either the salicylate elimination half‐life or the area under the concentration versus time curve from 4–12 hours post aspirin ingestion. Reasons for the lack of effect of repeated doses of charcoal on salicylate elimination are discussed and, these results cannot necessarily be extrapolated to the overdose situation. Further investigation is warranted to assess the effect of repeated doses of activated charcoal in the salicylate‐overdosed patient.
Cardiovascular Effects of H2‐receptor Antagonists
Authors: Hughes David G. , Dowling Elizabeth Anne , DeMeersman Ronald E. , Garnett William R. , Karnes H. Thomas
Published: March 2013

The type II histamine receptor antagonists, cimetidine and ranitidine, widely used in treatment of peptic ulcer disease have been reported to cause bradycardia. To evaluate the cardiovascular effects of H2 antagonists nineteen healthy volunteers were entered into a double‐blind crossover comparison of cimetidine 300 mg qid, ranitidine 150 mg bid, and placebo. Subjects ingested study medicine for 7 days prior to being tested by the Bruce Exercise Test Heart rate, blood pressure, oxygen consumption, expiratory volume, and fractional expiration of CO2 and O2 were measured at rest, exercise and recovery. A plasma sample for determination of cimetidine and ranitidine levels were obtained prior to the exercise period. Multivariate analysis and paired t test revealed no significant differences for the cardiovascular or pulmonary variables. However, in 5 subjects, the heart rate at 25% maximum VO2 was depressed 8% (P ≤ 0.03). This effect in a small percentage of the population suggests that further studies are needed to determine if subpopulations are affected.
Sustained‐Release Diltiazem: Duration of Antihypertensive Effect
Authors: Pool Peter E. , Herron Jerry M. , Rosenblatt Sidney , Reeves Robert L. , Nappi Jean M. , Staker Larry V. , Dipette Donald J. , Evans Robert R.
Published: March 2013

The antihypertensive activity of a sustained‐release preparation of diltiazem (given each 12 hours) was assessed in 96 patients with supine diastolic blood pressure (BP) between 95 and 110 mm Hg in a multicenter, randomized, double‐blind, placebo run‐in, parallel‐group trial comparing optimally titrated doses of diltiazem and placebo. The aim was to assess the onset of action as well as the extent and variability of BP control of this formulation during the 12‐hour interval. Diltiazem was titrated from 120 mg bid to 180 mg bid as necessary to lower BP. At baseline, on the first day of titration, and at the end of 8 weeks, BP was evaluated at 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The onset of action was within 2 hours, and the effect was maintained throughout the 12‐hour period. Mean BP for the diltiazem group at baseline was 154/101 mm Hg. At week 8, BP was 148/93 mm Hg at hour “0” (P < .02 and P = .0001 for systolic and diastolic BP vs. placebo), 139/84 mm Hg at the nadir at hour 5 (P = .0001), and 149/91 mm Hg at the end of the 12‐hour period (P < .02 and P = .0001 for systolic and diastolic BP). Diltiazem was significantly more effective than placebo (P = .0001) with 50% of patients controlled to a diastolic pressure of <90 mm Hg at 7 of the 10 evaluation points, including the evaluation point of 12 hours post‐dose. There was no exaggeration of the magnitude of daily BP fluctuation nor any increase in orthostatic effect noted.
Phase I Study of Y‐20811, a New Long‐Acting Thromboxane Synthetase Inhibitor by Oral Administration
Authors: Nakashima Mitsuyoshi , Uematsu Toshihiko , Takiguchi Yoshiharu , Mizuno Atsuhiro , Kanamaru Mitsutaka
Published: March 2013

The safety, pharmacological action and pharmacokinetics of the thromboxane (TX) synthetase inhibitor Y‐20811, a prospective medication for ischemic vascular disorder, were investigated in Phase I clinical trials in which single and repeated doses were administered orally to 32 healthy adult male volunteers. In the single‐dose study, subjects were given single doses of 2.5, 5, 10, 25, 50, and 100 mg; in the repeated‐dose study, a single dose of 50 mg was administered daily for 5 days.

In the repeated‐dose study, slight elevation of liver function test parameters in 1 subject was observed, but throughout the trials, no abnormality attributable to the test drug was found in other routine laboratory tests, subjective and objective findings, vital signs (blood pressure, pulse rate, body temperature, respiration rate), ECG, or bleeding time; nor did any finding indicate a problem concerning the safety of Y‐20811.

In both single‐ and repeated‐dose studies, inhibition of the serum TXB2 production and an increase in the 6‐keto‐prostaglandin F1α production during whole‐blood coagulation, and inhibition of arachidonic acid‐induced platelet aggregation were observed from 1 hour after administration of Y‐20811. The duration of these actions was long, the former two lasting 168 hours (1 week) and the latter 48–72 hours or more. Slight inhibition of adenosine diphosphate‐induced secondary platelet aggregation was also observed.

The maximum plasma concentration time (tmax) of Y‐20811 was 0.5–1.1 hours. The initial‐phase half‐life (t1/2α) was 0.8–1.1 hours and the final‐phase half‐life (t1/2β) was 4.7–9.2 hours. Maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) increased dose‐dependently. When Y‐20811 was administered after a meal, tmax was delayed and Cmax was decreased, but there was almost no change in AUC. In the repeated‐dose study, plasma concentrations after each administration showed a good conformity with the simulation curve worked out using the pharmacokinetic parameters obtained at the time of the initial dose, indicating that repeated administration did not result in accumulation of the drug.

In all dose groups, 47–62% of the dose was excreted in unchanged form and 8–14% was excreted in conjugated form in the urine within 48 hours after administration. No daily change was observed in the 24‐hour urinary excretion with repeated administration.

The duration of pharmacological action did not parallel the change in plasma concentration.

Oral administration of Y‐20811 was concluded to be safe and well‐tolerated with long‐acting inhibition of the serum TXB2 production and platelet aggregation.
Acute Hemodynamic Responses to Weightlessness in Humans
Authors: Lathers C. M. , Charles J. B. , Elton K. F. , Holt T. A. , Mukai C. , Bennett B. S. , Bungo M. W.
Published: March 2013

As NASA designs space flights requiring prolonged periods of weightlessness for a broader segment of the population, it will be important to know the acute and sustained effects of weightlessness on the cardiovascular system since this information will contribute to understanding of the clinical pharmacology of drugs administered in space. Due to operational constraints on space flights, earliest effects of weightlessness have not been documented. We examined hemodynamic responses of humans to transitions from acceleration to weightlessness during parabolic flight on NASA's KC‐135 aircraft. Impedance cardiography data were collected over four sets of 8–10 parabolas, with a brief rest period between sets. Each parabola included a period of 1.8 Gz, then approximately 20 seconds of weightlessness, and finally a period of 1.6 Gz; the cycle repeated almost immediately for the remainder of the set. Subjects were semi‐supine (Shuttle launch posture) for the first set, then randomly supine, sitting and standing for each subsequent set. Transition to weightlessness while standing produced decreased heart rate, increased thoracic fluid content, and increased stroke index. Surprisingly, the onset of weightlessness in the semi‐supine posture produced little evidence of a headword fluid shift. Heart rate, stroke index, and cardiac index are virtually unchanged after 20 seconds of weightlessness, and thoracic fluid content is slightly decreased. Semi‐supine responses run counter to Shuttle crewmember reports of noticeable fluid shift after minutes to hours in orbit. Apparently, the headword fluid shift commences in the semi‐supine posture before launch,1 is augmented by launch acceleration, but briefly interrupted immediately in orbit, then resumes and is completed over the next hours.
The Influence of Intravenous Cimetidine Dosage Regimens on the Disposition of Theophylline
Authors: Gutfeld Marcia B. , Welage Lynda S. , Walawander Cynthia A. , Wilton John H. , Harrison Nedra J.
Published: March 2013

The influence of the method of cimetidine administration on theophylline disposition was studied in nine healthy, cigarette smoking male volunteers. The treatment phases consisted of: A) theophylline alone, B) theophylline plus intermittent cimetidine therapy (300 mg IV every 6 hr), and C) theophylline in combination with continuous infusion cimetidine (50 mg/hr). Theophylline (4.8 mg/kg) was administered intravenously as aminophylline over 30 minutes during each treatment phase. During study phases B and C subjects received 48 hours of cimetidine therapy beginning 24 hours prior to theophylline dosing. Blood samples for determination of theophylline concentrations were collected serially over 24 hours. Serum theophylline concentrations were determined in duplicate using fluorescence polarization immunoassay (Abbott Diagnostic TDx®).

The average age of the subjects was 27.4 ± 4.7 years, and the individual smoking histories ranged from 0.5 to 1.5 packs per day (average 0.89 ± 0.33). The mean (±SD) body weight was 79.1 ± 8.2 kg and all subjects were within 20% of their ideal body weight. Theophylline pharmacokinetic parameters were determined using noncompartmental analysis. ANOVA for repeated measures and Tukey's multiple comparison test were used for statistical analysis. The mean (±SD) theophylline clearance for each of the treatment groups was: 1.4 ± 0.4, 1.2 ± 0.3, and 1.2 ± 0.2 ml/min/kg for phases A, B and C, respectively.

Cimetidine decreased the clearance of theophylline, however, theophylline clearance was not statistically different between regimens B and C. Thus, the method of cimetidine administration (intermittent versus continuous infusion) did not influence the magnitude of the drug‐drug interaction.
Pharmacokinetics of a New Macrolide, Roxithromycin, in Infants and Children
Authors: Demotes‐Mainard F. M. , Vinçon G. A. , Albin H. C.
Published: March 2013

The pharmacokinetics of roxithromycin was investigated after oral administration of 2.5 mg/kg doses given 12 hours apart during 6 days in infants and children. These 18 subjects suffering from a respiratory tract infection were divided into three age groups: group I < 18 months, group II < 5 years, group III < 13 years. At day 6, the elimination plasma half‐life had an average value (mean ± SD) of 19.8 ± 9.7 h (group I), 21.0 ± 9.4 h (group II) and 20.8 ± 6.9 h (group III), respectively. The maximum concentration of roxithromycin (Cmax) was attained between 1 and 2 hours after dosing with mean values of 10.1 ± 3.0 mg/l (group I), 8.7 ± 4.9 mg/l (group II), 8.8 ± 7.0 mg/l (group III). All the calculated pharmacokinetic parameters did not significantly differ from one group to another. The kinetics of roxithromycin in infants and children seemed to be age independent and showed no accumulation after repeated doses. During 12 hours, the plasma concentrations were above MIC of microorganisms generally present in respiratory tract infections. Two daily doses of 2.5 mg/kg of roxithromycin 12 hours apart may be proposed in infants and children.
Analgesic Efficacy of Acetaminophen Sustained Release
Authors: Ström Christer , Forsberg Olle , Quiding Hans , Engevall Sigfrid , Larsson Ola
Published: March 2013

The analgesic efficacy of acetaminophen sustained release (SR) and acetaminophen immediate plus sustained release (IR + SR) was evaluated in 200 outpatients with pain after oral surgery. Under double‐blind conditions SR high dose (2000 mg) or low dose (1000 mg), IR + SR high dose (500 + 1500 mg) or low dose (250 + 750 mg), or acetaminophen standard tablet high dose (1000 mg) or low dose (500 mg) were randomly administered after removal of a lower third molar. The hourly pain intensity was rated on a visual analog scale during 12 hours. The efficacy was based on peak effect (maximum pain intensity difference in percent), pain reduction (mean percentage pain intensity difference), duration of effect (time to remedication) and pain reduction index (pain reduction multiplied by duration of effect). Pain reduction was 37% with the 500‐mg tablet and 54% with SR 2000 mg. The peak effect increased from 53% after 1.9 hours for the 500‐mg tablet to 67% after 2.6 hours for SR 2000 mg. The SR formulation significantly increased the duration of effect without reduction in peak effect.
Pharmacokinetics of Single‐Dose Oral and Intramuscular Ketorolac Tromethamine in the Young and Elderly
Authors: Jallad Nader S. , Garg Dyal C. , Martinez Juan J. , Mroszczak Edward J. , Weidler Donald J.
Published: March 2013

The elderly are likely candidates to receive analgesics for pain from a variety of etiologies. Ketorolac tromethamine is a nonsteroidal, analgesic, anti‐inflammatory, antipyretic investigational drug with anti‐prostaglandin synthetase activity. Sixteen healthy, young men (mean age 30 years and mean weight 75 kg) and 13 healthy, elderly subjects (11 men and two women; mean age 72 years and mean weight 75 kg) participated in an open‐label, parallel single‐dose study. On each day of ketorolac tromethamine administration the subjects fasted overnight and for 2 hours post‐dose. A single intramuscular (IM) dose of 30 mg of ketorolac tromethamine was administered followed by an oral dose (PO) of 10 mg after a 1 week washout period for the elderly subjects. Plasma samples were taken from 0 through 48 hours post‐dose and analyzed for ketorolac by HPLC. The elimination of ketorolac was decreased slightly in the elderly following both doses, as evidenced by a prolongation in half‐life (4.7 to 6.1 hours for PO and 4.5 to 7.0 hours for IM) and a reduced total plasma clearance compared to the young adult subjects. These differences were statistically significant (P < .001). Considerable overlap frequently was observed when comparing the range of values obtained for the young and elderly for plasma half‐life, clearance, AUC, Tmax and Cmax. The absorption of ketorolac tromethamine was not altered substantially in the elderly following either dose route. Ketorolac plasma protein binding was not altered substantially in the elderly. The present results show that the elderly may need slightly less frequent dosing of ketorolac than young adults to maintain similar plasma levels. In these studies there has been no evidence of drug accumulation in the elderly after long‐term ketorolac tromethamine administration when given in a tid or qid regimen.
A Double‐Blind Study of the Efficacy of Topical Ketorolac Tromethamine Gel in the Treatment of Ankle Sprain, in Comparison to Placebo and Etofenamate
Authors: Diebschlag Wilfred , Nocker Wolfgang , Bullingham Roy
Published: March 2013

In a double‐blind, placebo‐controlled study the efficacy and safety of topical ketorolac tromethamine were assessed in the reduction of inflammation and pain due to ankle sprain. Ketorolac 2% gel was compared with etofenamate and placebo (ketorolac vehicle) in a 15‐day study. Patients attended for visits on days 1 (admission), 2, 3, 4, 8, and 15 of the study. Measurements of efficacy were ankle voiume, pain measured on visual analogue scales (VAS) and verbal rating of pain. Safety was assessed by volunteered adverse events and vital signs. A total of 37 patients was admitted to the study of whom 13 received ketorolac, 12 placebo, and 12 etofenamate. One patient receiving ketorolac was lost to follow‐up on day 15 owing to an unrelated accident. The remaining 36 patients completed the study. Ketorolac was significantly better than placebo in reducing the volume of the injured ankle based on the maximum, the area under the curve, and the day 15 percentage changes in ankle volume. Results for etofenamate were similar to those for ketorolac for all three variables and there were no significant differences between the active treatments. Reductions in VAS pain at rest were more marked in the ketorolac group than either of the other groups at all visits. On day 4 the differences between ketorolac and each of the other groups were statistically significant. Reductions in VAS pain on movement were also greatest for the ketorolac group at all visits. The differences between ketorolac and each of the other groups achieved statistical significance on days 4 and 8, but were marginal in terms of significance on day 2. The incidence of VAS pain at night was lower for ketorolac than for either of the other groups, but only the difference from placebo achieved statistical significance. There were greater improvements in verbal ratings of pain severity for ketorolac than for placebo. This difference was statistically significant on day 4. Results for the two active treatments were slightly in favor of ketorolac, but differences were not statistically significant. Mean plasma concentrations of ketorolac were 0.183 μg/ml on day 4, and 0.170 μg/ml on day 15. Only two minor adverse events were reported, one each for ketorolac and etofenamate, and no important changes occurred in any of the vital sign measurements. The results of this small scale study of the topical application of ketorolac gel are encouraging. A good effect in the early relief of pain and reduction in ankle swelling, with few side‐effects, occurs at plasma ketorolac concentrations not inconsistent with one local effect.
Bile Acid Sequestrants
Authors: Ast Martin , Frishman William H.
Published: March 2013

The bile acid sequestrants, cholestyramine and colestipol, are the drugs of choice for the treatment of patients with hypercholesterolemia caused by increases in LDL‐cholesterol levels without concurrent hypertriglyceridemia (type IIA and type IIB hyperlipoproteinemia). Longitudinal clinical studies with these drugs have shown their ability to slow the progression of atherosclerosis and to limit the consequences of the disease. Bile acid sequestrants can be used with other lipid‐lowering drugs such as nicotinic acid or HMG CoA reductase inhibitors, to maximize the cholesterol‐lowering effects. The side effect profile of the bile acid sequestrants is tolerable, with most complaints related to effects on the gastrointestinal tract and the bulkiness of the resins.
Biochemical, Endocrine, and Mineral Effects of Indapamide in Black Women
Authors: Prisant L. Michael , Beall Sharon P. , Nichoalds George E. , Feldman Elaine B. , Carr Albert A. , Feldman Daniel S. , Hames Curtis G.
Published: March 2013

Black women with established essential hypertension, without renal insufficiency or diabetes mellitus, were withdrawn from their usual antihypertensive therapy for 2–3 weeks prior to entry into a study to evaluate pertinent biochemical and mineral effects of indapamide treatment. Twenty patients with a sitting diastolic blood pressure greater than 90 mm Hg had baseline measurements of plasma total cholesterol, HDL cholesterol, triglycerides, glucose, uric acid, potassium, magnesium, calcium, selenium, renin, norepinephrine, whole blood ionized calcium, and glycosylated hemoglobin. Low‐density lipoprotein (LDL) cholesterol was calculated by the Friedewald equation. The patients were placed on a fixed daily dose of 2.5 mg indapamide. Blood pressure and blood tests were repeated at 4, 8, and 12 weeks of treatment. The systolic and diastolic blood pressure were both lowered significantly at week 12. Plasma renin activity was significantly increased. There was no significant change in norepinephrine, glucose, glycosylated hemoglobin, uric acid, ionized calcium, calcium, triglycerides, potassium, magnesium, or selenium. Total cholesterol increased with an increase in both high‐density lipoprotein (HDL) and LDL cholesterol; however, these increases did not alter significantly either the total/HDL cholesterol or LDL/HDL cholesterol ratios. It is concluded that 2.5 mg of indapamide per day effectively lowers blood pressure with no significant adverse metabolic effects.
Hemofiltrability of H2‐Receptor Antagonist, Famotidine, in Renal Failure Patients
Authors: Saima Shigeki , Echizen Hirotoshi , Yoshimoto Keiko , Ishizaki Takashi
Published: March 2013

To determine if a new H2‐receptor antagonist, famotidine, would be significantly removed by arteriovenous hemofiltration, we measured plasma concentrations and amounts of the drug recovered in ultrafiltrate during 18 sessions of an intermittent hemofiltration performed in five patients with renal failure receiving the repeated intravenous dosings of the drug (5–20 mg/day). Plasma and ultrafiltrate drug concentrations were determined by using a high performance liquid chromatography with fluorescent detection. The mean (±SD) amount of the drug removed by the procedure, which was performed at the mean ultrafiltration rate of 19.0 ± 6.0 ml/min over the mean duration of 212 ± 168 min, corresponded to 4.1 ± 2.2% of the daily maintenance doses. There was a significant (r = 0.90, P < .01) linear relationship between the hemofiltration clearance and the ultrafiltration rate, indicating that the sieving coefficient, an index of filtration efficiency, for the drug was largely constant (i.e., 0.73 ± 0.10) over the ranging filtration rates (i.e., 3.9–29.5 mL/min) employed in the present study. When the mean filtration efficiency of 0.73 obtained from the study is extrapolated into a 24‐hour continuous arteriovenous hemofiltration performed at commonly used filtration rates (i.e., 6–12 ml/min), the 24‐hour hemofiltration clearances are estimated to range from 4 to 9 ml/min. These clearance values are found to correspond to only 10 to 25% of the mean total body clearance (about 35 ml/min) reported from anuric patients. Based upon the present findings coupled with the above‐assumed extrapolation, we recommend that no supplemental doses of famotidine be required for patients with renal failure during or after the intermittent or continuous (at least 24‐hour) arteriovenous hemofiltration.
An Evaluation of the Therapeutic Effects and Dosage Equivalence of Glyburide and Glipizide
Authors: Jaber Linda A. , Wenzloff Nancy J. , Komanicky Pavel , Antal Edward J.
Published: March 2013

Nineteen noninsulin‐dependent diabetic patients [ten women, nine men, aged 36–80 years (mean ± SE 56.8 ± 2.7 years)] were randomized to receive either glyburide or glipizide for 16 weeks, in a double‐blind crossover fashion. A 2‐week washout period preceded each treatment period. The patients measured blood glucose concentrations 16 times weekly using Chemstrip‐bG® medication dosages were titrated to achieve fasting blood glucose concentrations of ≤6.2 mM and preprandial and postprandial concentrations of ≤9.0 mM, or to a total daily dose of 20 mg for glyburide and 40 mg for glipizide. Glyburide therapy resulted in a significant decline in fasting, preprandial, postprandial and bedtime blood glucose levels, while glipizide treatment led to a significant lowering of postprandial and bedtime blood glucose. Furthermore, fasting, preprandial and postprandial blood glucose concentrations were significantly lower during glyburide as compared to glipizide treatment phase. Glycosylated hemoglobin levels were decreased only with glyburide. Serum C‐peptide and insulin concentrations were not altered over the entire study. The mean final daily dose of glyburide (15.4 ± 1.6 mg) was markedly lower than that of glipizide (29.7 ± 3.1 mg). Thus, in this patient population, glyburide was twice as potent on a weight basis than glipizide.
Lack of Effect of Enoximone on the Pharmacokinetics of Digoxin in Patients with Congestive Heart Failure
Authors: Trenk D. , Hertrich F. , Winkelmann B. , Glauner T. , Dieterich H. A. , Jähnchen E.
Published: March 2013

The aim of this study was to investigate if the concomitant administration of the positive inotropic drug enoximone (100 mg tid) has any effect on the morning trough levels of the cardiac glycoside digoxin in 17 patients with congestive heart failure (NYHA II‐IV). Plasma concentrations of digoxin were 1.05 ± 0.37 ng/mL before enoximone, 0.95 ± 0.31 ng/mL at the end of the enoximone treatment period of 1 week and 0.95 ± 0.36 ng/mL 1 week after cessation of enoximone treatment. Thus, concomitant administration of enoximone had no effect on plasma concentrations of digoxin while on the other hand the hemodynamics as assessed by NYHA‐classification and determination of the heart volume improved significantly.
Estazolam and Flurazepam: A Multicenter, Placebo‐Controlled Comparative Study in Outpatients with Insomnia
Authors: Scharf Martin B. , Roth Paul B. , Dominguez Roberto A. , Ware J. Catesby
Published: March 2013

A multicenter, double‐blind placebo‐controlled clinical trial was designed to compare the safety and efficacy of estazolam compared with flurazepam as hypnotics. Outpatients complaining of insomnia were randomized to receive either estazolam 2 mg, flurazepam 30 mg or placebo for 7 consecutive nights. The analysis of efficacy was based on the patients' daily assessments of sleep and the investigators' global evaluations. Adverse events which were considered by the investigator to be attributable to, or of unknown relationship to the test medication were analyzed. The patient subjective questionnaire indicated that estazolam and flurazepam signiflcantly improved all parameters (P < .05) as compared to placebo. A marked or moderate improvement in sleep was reported by 81% (58/72), 78% (63/81) and 36% (27/76) of estazolam, flurazepam, and placebo recipients, respectively. There were no significant differences in hypnotic effect between estazolam and flurazepam. All efficacy parameters of the investigators' global evaluation improved signiflcantly more (P < .05) for patients receiving estazolam or flurazepam (except quality of sleep) than for those receiving placebo. The percentage of patients reporting any adverse experience was greatest for flurazepam (72%), followed by estazolam (59%), and placebo (43%). Somnolence and hypokinesia were the most commonly reported adverse events. An analysis of the global evaluation of side effects showed that flurazepam had a significantly worse side effect profile than estazolam (P < .05) or placebo (P = .001). Estazolam and flurazepam effectively, and comparably, relieved insomnia when administered for 7 nights in adult patients complaining of insomnia. Estazolam demonstrated a more favorable side effect profile than flurazepam.