bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Furosemide on Biliary Secretion, Pancreatic Blood Flow, and Pancreatic Exocrine Secretion
Authors: WALLACH STANLEY , CHARBON GERARD A. , BEIJER HEIN J. M. , ENDEMAN HERMAN J. , HOEKE J. ODO O. , SCHRIJVER JAAP , STRUYVENBERG ALBERT
Published: March 2013

Abstract: The effects of furosemide on biliary secretion and on pancreatic hemodynamics and exocrine function were studied by quantitative flowmetry and timed collections of biliary and pancreatic exocrine secretion in the anesthetized dog. Biliary flow and the output of its components (Na+, K+, Ca, Mg, 3‐OH bile salts, and bilirubin) increased significantly following a furosemide injection of 0.6 mg/kg and rose progressively to 75–150 per cent above basal levels as the furosemide dose was increased to 9.6 mg/kg. Pretreatment with secretin had no influence on furosemide‐induced biliary secretion. Furosemide doses of 4.8 and 9.6 mg/kg increased blood flow in the superior pancreaticoduodenal arterial bed by 30–60 per cent but did not alter flow in the inferior pancreaticoduodenal arterial bed or the pancreatic branch of the splenic artery. However, small increases were seen in flow in the latter two arterial beds after furosemide when secretin administration preceded furosemide. Basal pancreatic secretion was not affected by furosemide, but pretreatment with a submaximal sustaining infusion of secretin uncovered a furosemide action to increase pancreatic exocrine flow and the outputs of Na+, K+, Ca, Mg, and enzymes by 25–35 per cent. These data extend previous studies of the gastrointestinal vasodilator effects of furosemide to the pancreatic circulation and previous data demonstrating furosemide‐induced ionic transport in nonrenal systems to biliary, pancreatic acinar, and ductular transport in both organs. Whether the augmentation of pancreatic blood flow is secondary to enhanced ion transport in the exocrine pancreas or to an effect on ionic cotransport in vascular smooth muscle is unknown.
Dyphylline Versus Theophylline: A Double‐Blind Comparative Evaluation
Authors: FURUKAWA CLIFTON T. , SHAPIRO GAIL G. , PIERSON WILLIAM E. , BIERMAN C. WARREN
Published: March 2013

Abstract: This study was a randomized double‐blind evaluation of three doses of dyphylline, theophylline, and placebo for blocking exercise‐induced bronchospasm (EIB). Twenty patients aged 12 to 17 years took one of the following on five separate days prior to an exercise challenge: 10,15, or 20 mg/kg dyphylline; 6 mg/kg anhydrous theophylline; or placebo. Linear relationships were found between the log of dyphylline doses and per cent changes from baseline for PEFR, FEV1 and FEF25–75%. The 15 and 20 mg/kg doses differed significantly from placebo in preventing declines in PEFR, FEV1, and FEF26–75%. While significant, these changes were one half to one third those found with 6 mg/kg theophylline. Tremor was twice as common with theophylline. While dyphylline has therapeutic effectiveness compared to placebo for blocking EIB, its benefit is small. Further evaluations are needed to elucidate optimal dosaging for maximal effectiveness.
Medroxalol Combined with Hydrochlorothiazide in the Treatment of Hypertension
Authors: VLACHAKIS NICOLAS D. , ELASQUEZ MANUEL , ALEXANDER NATALIE , MARONDE ROBERT F.
Published: March 2013

Abstract: The antihypertensive effect and safety of hydrochlorothiazide administration as a single drug and together with medroxalol were determined in 20 patients with primary hypertension. Following two biweekly intervals on placebo and hydrochlorothiazide, medroxalol was started at 100 mg three times a day and titrated against blood pressure response up to a maximum of 300 mg three times a day. In nine patients the effect of the single and the combined drug therapy on blood pressure during isometric handgrip exercise, on plasma renin activity, and on plasma catecholamines and their deaminated metabolites was investigated.

The administration of hydrochlorothiazide was associated with a significant decrease in blood pressure, but heart rate did not change. The addition of medroxalol produced a substantial decrease in blood pressure and heart rate in both the recumbent and upright positions (P < 0.001). Due to careful titration of medroxalol, orthostatic hypotension was observed only in one patient. Neither hydrochlorothiazide alone nor the combined drug regimen prevented or diminished the rise in blood pressure with exercise. Although plasma renin activity decreased during the combined drug therapy, there was no correlation between the initial levels or the change in plasma renin activity and the extent of decrease in blood pressure. The concentration of plasma epinephrine increased during the combined drug period, whereas catecholamine metabolites increased significantly during both periods of the study. It is concluded that medroxalol combined with hydrochlorothiazide constituted a potent and safe antihypertensive therapy for the duration of the present study.
Effects of Hemodialysis on Theophylline Kinetics
Authors: ANDERSON JOSEPH R. , POKLIS ALPHONSE , McQUEEN ROBERT C. , PURTELL JAMES N. , SLAVIN RAYMOND G.
Published: March 2013

Abstract: Difficulties encountered in controlling theophylline blood concentrations in an asthmatic patient on hemodialysis prompted us to study the effect of hemodialysis on theophylline kinetics. Plasma theophylline extraction ratios, clearances, and half‐lives were determined during dialysis for 11 adults given an intravenous infusion of 4 mg/kg aminophylline. For comparison, eight of these patients were evaluated for theophylline half‐lives when not dialyzed. Extraction ratios of theophylline during dialysis ranged from 0.22 to 0.51 (0.35 ± 0.08) for these patients, indicating that a mean of 36 per cent plasma theophylline was removed during each pass through the dialyzer. This compares with a mean extraction ratio of urea of 0.63 ± 0.07. Plasma clearance of theophylline during dialysis ranged from 52 to 124 ml/min (83 ± 20 ml/min). Plasma theophylline half‐lives during dialysis ranged from 1.6 to 3.4 hours (2.3 ± 0.5 hours). Theophylline half‐lives when not on dialysis ranged from 3.5 to 8.2 hours (5.0 ± 1.7). Theophylline clearance was significantly faster in every patient during dialysis. Asthmatics requiring hemodialysis should receive additional theophylline during dialysis if therapeutic blood levels are to be maintained. Routine hemodialysis will significantly increase clearance in a toxic patient in whom life‐threatening toxicity is occurring and charcoal hemoperfusion is unavailable.
Effect of Food on Bioavailability of Rifampicin
Authors: POLASA KALPAGAM , KRISHNASWAMY KAMALA
Published: March 2013

Abstract: The area under the plasma concentration‐time curve of rifampicin was determined with and without food administration in six healthy male volunteers. Rifampicin (10 mg/kg) was administered orally in the fasting state on one occasion and following a wheat‐based breakfast on another. Administration of rifampicin with food reduced mean peak plasma concentration and prolonged the time to reach peak concentration (2 versus 4 hours). Total area under the concentration‐time curve from 0 to 8 hours and the rate of absorption were also significantly reduced when rifampicin was administered with food.
Specificity of Renal Tubular Damage Criteria for Aminoglycoside Nephrotoxicity in Critically III Patients
Authors: SCHENTAG JEROME J.
Published: March 2013

Abstract: Two populations of critical care patients were studied using indices of renal tubular damage (β2‐microglobulin, enzymes, casts) and indices of glomerular filtration (creatinine, creatinine clearance). The purpose of these studies had been initially to elucidate the type of renal failure typical of the critically ill patient treated with aminoglycoside gentamicin or tobramycin, then to determine its frequency. The second study population included a control group of patients given the nonnephrotoxic cephalosporin moxalactam, in order to assess the specificity of the renal tubular damage criteria for aminoglycoside nephrotoxicity versus other types of renal injury in critical care patients. Creatinine rise occurred in approximately 30 per cent of each tobramycin‐treated group and in only 12 per cent in the moxalactam control patients (P < 0.05). Thus, the data indicate that aminoglycosides are associated with an approximate doubling of the renal damage in those older, critically ill patients. Renal tubular damage criteria appear specific for the aminoglycoside effect, but a substantial percentage of the renal damage in this population is not associated with detectable alterations in renal tubular status.
Long‐Term Therapy for the Pain of Osteoarthritis: A Comparison of Zomepirac Sodium and Aspirin
Authors: HONIG STEPHEN
Published: March 2013

Abstract: In this long‐term, double‐blind, multicenter study, efficacy and safety of zomepirac sodium were compared with those of aspirin for treatment of the chronic pain associated with osteoarthritis in 607 patients, 405 of whom received zomepirac and 202 of whom received aspirin. Final evaluations during one year of treatment showed zomepirac significantly more effective than aspirin for reducing pain at rest (P = 0.02) and average pain (P = 0.04). Moreover, zomepirac was rated better than aspirin in physician global evaluations of overall response to therapy (P = 0.02) and patient evaluations of pain relief (P = 0.03). At the end of the one‐year study, patients were permitted to extend double‐blind treatment for an additional year. In final evaluations for patients who continued, zomepirac was significantly better than aspirin for relief of pain on motion (P = 0.05) and also in patient global evaluations of therapeutic response (P = 0.02). Side effect profiles during the first year of therapy were generally comparable for zomepirac and aspirin. However, complaints related to the special senses, especially tinnitus and hearing disturbances, were reported more frequently during aspirin therapy, and urogenital side effects were more common during zomepirac therapy. For both drug groups, the overall incidence of side effects was lower in the second year than in the first. This is the first published study to show a nonsteroidal anti‐inflammatory agent to be more effective than aspirin for the long‐term treatment of pain associated with osteoarthritis.
The Prolactin Response to Flutroline Hydrochloride in Schizophrenic Patients
Authors: KURLAND ALBERT A. , NAGARAJU ARRAMARAJU , HANLON THOMAS E. , WILLIAMS T. GLYNE
Published: March 2013

Abstract: Flutroline hydrochloride, a gamma carboline manifesting neuroleptic activity, was administered in a double‐blind fashion in single daily dosages of 1, 5, 10, 20, and 100 mg to 48 hospitalized schizophrenic patients over a period of four weeks. During this period, weekly evaluations were made of response employing standardized psychiatric ratings. Plasma prolactin (PRL) levels were obtained at the termination of previous neuroleptic medication and at two‐week intervals during treatment with the investigational compound. Examination of the initial PRL levels indicated that they could be grouped into those above, within, and below the normal range. Comparisons of these initial levels with those following the administration of flutroline suggested an improved methodology for determining optimal neuroleptic dosage.
Ibuprofen Does Not Impair Antipyrine Clearance
Authors: ABERNETHY DARRELL R. , GREENBLATT DAVID J.
Published: March 2013

Abstract: The influence of therapeutic doses of ibuprofen on the distribution and clearance of antipyrine in humans was evaluated in a series of healthy volunteers. Subjects received a single intravenous dose of antipyrine on two occasions, once in the drug‐free control state and again during coadministration of ibuprofen, 1.6 to 2.4 Gm per day in divided doses. Compliance was verified by measurement of plasma ibuprofen levels, which averaged 22 μg/ml. Kinetic variables for antipyrine were determined from multiple plasma antipyrine concentrations measured during 24 hours after each dose. Between drug‐free control and ibuprofen coadministration trials, there was no significant difference in antipyrine volume of distribution (0.69 vs. 0.69 liter/kg), elimination half‐life (12.2 vs. 12.5 hours), or total metabolic clearance (0.69 vs. 0.70 ml/min/kg). Thus, ibuprofen does not impair the clearance of the marker compound antipyrine, often used as an index of drug oxidizing capacity in humans.
Pharmacokinetics of Stiripentol in Normal Man: Evidence of Nonlinearity
Authors: LEVY RENE H. , LIN HUEY‐SHIN , BLEHAUT HENRI M. , TOR JACQUES A.
Published: March 2013

Abstract: The pharmacokinetics and metabolism of stiripentol, a new antiepileptic drug, were investigated in normal male subjects after single‐dose and multiple‐dose administration. Each of six subjects received single doses of 300,600, and 1200 mg of stiripentol in powder form and another 600 mg in solution. In the multiple‐dose study, each of six subjects received a 300‐mg dose on day 1 and multiple doses (1200 mg/day) from day 2 to day 8. Five of these six subjects participated also in the single‐dose study. Stiripentol and several of its metabolites, namely, stiripentol conjugate, DiOH, P‐OH, and M‐OH, were analyzed in plasma and urine. After single doses, the elimination curve of stiripentol appeared multiphasic. The oral clearance was 1.3 to 1.8 liter/hr/kg. The average mean residence time was 4 hours. There were no statistically significant differences in clearance or mean residence time among the three doses. However, dose dependence was found in all the four pathways when formation clearances were compared. Only trace amounts of the drug were excreted unchanged in urine. The active metabolite, P‐OH, was not detectable in plasma. Stiripentol was very highly bound to plasma proteins in plasma from dosed subjects as well as spiked human plasma (free fraction of 1 per cent). In the multiple‐dose study, there was a decrease (nearly eightfold) in oral clearance of stiripentol between day 1 and day 8. The fractions of dose metabolized through conjugation and methylenedioxy ring opening increased 183 and 49 per cent, respectively, but the formation clearances for all the pathways were decreased. These findings suggest that the steady‐state plasma level/dose ratio of stiripentol will increase with the daily dose.
Food Increases the Bioavailability of Isotretinoin
Authors: COLBURN WAYNE A. , GIBSON D. M. , WIENS R. E. , HANIGAN J. J.
Published: March 2013

Abstract: Twenty healthy male subjects received 80 mg (2 × 40 mg SEG capsules) oral isotretinoin separated by two‐week washout periods in an open randomized crossover design. Isotretinoin was administered during a complete fast, 1 hour after a standard breakfast, with a standard breakfast, or 1 hour before a standard breakfast. Blood samples were obtained at specific times over a 72‐hour period. Isotretinoin blood concentrations were determined by a specific HPLC method. The relative bioavailability (AUC) of isotretinoin was found to be approximately 1.5 to 2 times greater when the dose was administered 1 hour before, concomitantly with, or 1 hour after a meal than when it was given during a complete fast. In addition, because the Cmax, value is lower when the dose is administered with food rather than 1 hour after a meal, coadministration of isotretinoin with food may be the best method of administration.
Inhibitory Effect of Isoniazid on Antipyrine Clearance in Man
Authors: GRECH‐BELANGER ODETTE , BELANGER PIERRE‐M. , LACHANCE JOHANNE
Published: March 2013

Abstract: The effect of both concomitant administration and pretreatment with isoniazid on the activity of the hepatic drug‐metabolizing enzymes of healthy young volunteers, as indicated by the antipyrine clearance test, is reported. Concomitant administration of isoniazid with antipyrine results in a significant decrease in the hepatic clearance of the latter compound. In contrast, pretreatment for 14 days with isoniazid had no effect on antipyrine elimination kinetics. It is concluded that isoniazid depresses hepatic drug metabolism only when present in significant amounts at the hepatic site of drug oxidation.
Captopril Versus Hydralazine in Primary Pulmonary Hypertension
Authors: PODEROSO JUAN J. , BIANCOLINI CÉSAR A. , del BOSCO CARLOS G. , CATALANO HUGO N. , PERALTA JORGE G. , GOLDENBERG DANIEL B. I. , SUÁREZ LUIS D.
Published: March 2013

Abstract: Captopril was tested as the treatment for a patient with primary pulmonary hypertension (PPH) and its effects were compared with those of hydralazine. Captopril induced a rise in pulmonary pressures and in intrapulmonary shunt; hydralazine lowered pulmonary resistances and increased paO2 and blood O2 transport. Prospective studies in PPH treated with captopril are recommended and evaluation of all drugs not only by hemodynamic but also respiratory and O2 transport measurements.
A Multiclinic Double‐Blind Comparison of Timolol and Hydrochlorothiazide Alone and in Combination in the Treatment of Essential Hypertension
Authors: LEON ARTHUR S. , HUNNINGHAKE DONALD B.
Published: March 2013

Abstract: In a multicenter randomized double‐blind trial, we compared the antihypertensive effects of 12 weeks of therapy using timolol maleate, a new beta‐adrenergic blocking agent, alone and in combination with hydrochlorothiazide, and hydrochlorothiazide alone in 70 outpatients with mild to moderate uncomplicated essential hypertension (61 of whom completed the study). All three groups showed significant blood pressure reductions in both supine and standing positions which were most marked in the timolol—hydrochlorothiazide group (154/103 → 129/85 mm Hg). A good or excellent therapeutic response was obtained in 20 of 21 patients in the timolol—hydrochlorothiazide group, in 16 of 20 patients receiving timolol alone, and in 10 of 20 receiving hydrochlorothiazide alone. Adverse reactions were minimal in all treatment groups but highest in the hydrochlorothiazide group. It was concluded that timolol—hydrochlorothiazide combination is more effective than either drug alone for management of hypertension and that timolol alone or with hydrochlorothiazide is well tolerated.
An Electrophysiologic Study of the Digoxin—Quinidine Interaction
Authors: GESSMAN LAWRENCE , DANILO PETER , ROSEN MICHAEL R.
Published: March 2013

Abstract: To study the electrophysiologic mechanisms responsible for the digitalis—quinidine interaction, 27 mongrel dogs were given either quinidine alone, digoxin alone, or digoxin followed by the digoxin—quinidine combination, via the oral route for sufficient time to permit accumulation of steady‐state plasma levels. As anticipated, digoxin levels increased significantly in the presence of quinidine (P < 0.05). Whereas digoxin alone had no significant effect on the ECG, quinidine alone prolonged the Q—T interval (P < 0.05), and the combination prolonged both the QRS complex and the Q—T interval (P < 0.05). Digoxin alone had no significant effect on the Purkinje fiber transmembrane potential, whereas quinidine reduced action potential (AP) amplitude and maximum upstroke velocity (V̇max) significantly. The combination significantly reduced AP amplitude, V̇max, and maximum diastolic potential and prolonged AP duration. The changes induced by the drug combination appeared to be the sum of changes induced by each drug alone.
Effect of Desipramine and Cocaine on Plasma Norepinephrine and Pressor Responses to Adrenergic Stimulation in Pithed Rats
Authors: BAYORH MOHAMED A. , ZUKOWSKA‐GROJEC ZOFIA , KOPIN IRWIN J.
Published: March 2013

Abstract: Sympathetic neuronally released norepinephrine appears to act at intrajunctional α1‐adrenoceptors, whereas administered norepinephrine acts mostly at extra‐junctional α2‐adrenoceptors. We examined the effects of inhibition of neuronal uptake of norepinephrine by desipramine (0.3 mg/kg iv) and cocaine (5 mg/kg iv) on the pressor effects and on plasma norepinephrine levels in pithed rats after the administration of norepinephrine (0.1, 0.3, and 1.0 μg/kg iv) or during stimulation of sympathetic outflow (0.1, 0.3, and 1.0 Hz at 50 V for 1 minute). Desipramine and cocaine potentiated the cardiovascular effects of administered norepinephrine to a greater extent than they potentiated the effects of sympathetic stimulation. Plasma levels of norepinephrine during sympathetic stimulation or after iv administration of norepinephrine were increased significantly after either desipramine or cocaine. The cardiovascular effects of sympathetic stimulation, but not of exogenous norepinephrine, were reduced in adrenomedullectomized rats compared to intact rats. In adrenomedullectomized rats, desipramine potentiates the pressor responses and enhances the increase in plasma norepinephrine levels during sympathetic stimulation to the same extent as in intact pithed rats. The preferential potentiation of administered norepinephrine by uptake inhibition is most likely due to enhancement of accessibility of circulating norepinephrine to otherwise inaccessible intrajunctional α1‐adrenoceptors. The higher concentrations of norepinephrine in the region of the nerve‐ending limit release of the neurotransmitter by feedback inhibition via presynaptic α2‐adrenoceptors, thereby masking potentiation by uptake inhibition of the postsynaptic responses to sympathetic stimulation.
Comparative Hypnotic Activity of Single Doses of Loprazolam, Flurazepam, and Placebo
Authors: ELIE ROBERT , CAILLÉ GILLES , LEVASSEUR FRITZ ANTOINE , GAREAU JACQUES
Published: March 2013

Abstract: Loprazolam is a benzodiazepine derivative which possesses, in animals, a potent hypnotic effect. In a double‐blind single‐dose study, three dose levels of loprazolam (0.5, 1.0, and 2.0 mg) were compared to each other as well as to 15 mg flurazepam and placebo in 60 insomniac outpatients. The 0.5‐ and 1.0‐mg doses demonstrated hypnotic potency comparable to that of flurazepam, and all three treatments were superior to placebo. The hypnotic effect of the 2‐mg dose of loprazolam was significantly greater than that of the other treatments, but at this dose, patients experienced significantly more side effects and morning hangover.
Suppression of Postoperative Pain by Preoperative Administration of Ibuprofen in Comparison to Placebo, Acetaminophen, and Acetaminophen Plus Codeine
Authors: DIONNE RAYMOND A. , CAMPBELL ROBERT A. , COOPER STEPHEN A. , HALL DAVID L. , BUCKINGHAM BARBARA
Published: March 2013

Abstract: The analgesic effect of preoperatively administered ibuprofen was evaluated in 107 dental outpatients undergoing the removal of impacted third molars. Subjects were given 800 mg ibuprofen prior to the procedure and 400 mg ibuprofen 4 and 8 hours later. Comparison was made to groups receiving either placebo at all three doses, 600 mg acetaminophen administered on the same schedule, or preoperatively administered placebo followed by two doses of postoperatively administered 600 mg acetaminophen plus 60 mg codeine. Ibuprofen pretreatment resulted in significantly less pain than placebo or acetaminophen pretreatment as the local anesthetic wore off. Ibuprofen also resulted in less postoperative pain than acetaminophen plus codeine following the second dose. Side effects were similar across drug teatments and placebo with the exception of greater reports of drowsiness following the opiate—analgesic combination. These findings indicate that pretreatment with a nonsteroidal antiinflammatory drug, such as ibuprofen, results in a suppression of postoperative pain when compared to standard therapy without an increase in side effects.
Further Efficacy Evaluation of Doxpicomine for Postoperative Pain
Authors: WANG RICHARD I.H. , ROBINSON N.
Published: March 2013

Abstract: In this single‐dose, double‐blind study, the analgesic activity of 400 and 200 mg doxpicomine was compared with 100 and 50 mg meperidine and placebo when given intramuscularly in 102 subject patients experiencing severe postoperative pain. Results indicate that 400 mg doxicomine is similar to 100 mg meperidine in analgesic activity, onset, and duration of action. Side effects were of the same order as those produced by other centrally acting analgesics.
Plasma Levels and Analgesia Following Deltoid and Gluteal Injections of Methadone and Morphine
Authors: GRABINSKI PATRICIA Y. , KAIKO ROBERT F. , ROGERS ADA G. , HOUDE RAYMOND W.
Published: March 2013

Abstract: The objective was to determine whether deltoid as compared to gluteal injection of morphine and methadone produce differential plasma levels and analgesic effects. Thirty‐two postoperative cancer patients received deltoid and gluteal injections of morphine, 8 and 16 mg, within a double‐blind, twin crossover design. Forty‐four patients received deltoid or gluteal methadone, 10 mg. Deltoid morphine resulted in peak plasma levels 1.8 times (P < 0.05) those observed following gluteal morphine. Deltoid methadone resulted in peak levels 2.5 times (P < 0.005) those following gluteal injection. Deltoid morphine resulted in an area under the drug level—time (0 to 4 hours) curve 1.4 times (N.S.) the area observed following gluteal injection. Deltoid methadone resulted in an area under the drug level—time (0 to 4 hours) curve 2.2 times (P < 0.001) the area observed following gluteal injection. Deltoid methadone, but not morphine, provided greater (1.7‐fold, P < 0.05) pain relief than gluteal injection. If more rapid and enhanced analgesia is indicated, then the deltoid site may be preferable over the gluteal site for standard doses of methadone and other lipid soluble analgesics. In addition, the relative potency of compounds of widely differing lipid solubility may depend upon the site of intramuscular injection.
A Furosemide Test in the Functional Evaluation of the Human Nephron in Vivo
Authors: BARTOLI ETTORE , SATTA ANDREA , FAEDDA ROSSANA , OLMEO NINA A. , SOGGIA GIOVANNI , BRANCA GIANFRANCO
Published: March 2013

Abstract: A new renal function test was developed based upon the pharmacologic effects of furosemide to quantify separately the rates of electrolyte and water reabsorption by different segments of the human nephron in vivo. Since furosemide impairs active NaCl transport to Henle's loop and the attendant hypertonicity of the interstitium, osmotic water reabsorption from collecting ducts decreases and the unreabsorbed volume is lost into the urine, causing a rise in flow rate. This volume is computed from the difference in urine flow rate during furosemide with respect to that previously measured during maximal water diuresis alone. Starting from this value, an appropriate set of equations allows the separate calculation of Na reabsorption by the loop of Henle and by the distal tubule. Studies to validate this hypothesis were performed by clearance techniques during maximal water diuresis in 58 normal controls, in 19 patients with liver cirrhosis and ascites, and in 11 patients with chronic renal failure. Measurements were performed before and after the intravenous administration of 50 mg furosemide. The quantitative measurements of segmental solute reabsorption in normal subjects were consistent with results obtained by different methods in man and experimental animals, fully validating this new method. In addition, the data allowed to establish that distal reabsorption is depressed because of reduced proximal delivery in cirrhosis, as a result of impaired transport along Henle's loop in chronic renal disease, while permeability of collecting ducts to water was normal in both conditions. Though still approximate, this new furosemide test represents a considerable improvement over current methods for measuring segmental transport by the human nephron.
Dextroamphetamine with Morphine: Respiratory Effects
Authors: BOURKE DENIS L. , ALLEN PAUL D. , ROSENBERG MORTON , MENDES ROBERT W. , KARABELAS ARGERIS N.
Published: March 2013

Abstract: The combination of dextroamphetamine and morphine has been shown to be synergistic for analgesia and antagonistic for most other effects. However, the claim that dextroamphetamine antagonizes the respiratory depression caused by morphine has not been well substantiated. In this double‐blind study, we investigated respiratory effects, including resting respiration, isohypercapnic ventilation, CO2 response, dose response, and duration of these effects with dextroamphetamine alone and in combination with morphine. Dextroamphetamine alone (0.215 mg/kg) caused increases in minute ventilation and a leftward shift of the CO2 response curve that lasted for less than 2 hours. Dextroamphetamine combined with low‐dose morphine (0.15 mg/kg) antagonized respiratory depression throughout the 5‐hour observation period. Dextroamphetamine combined with high‐dose morphine (0.30 mg/kg) was unable to completely antagonize depressed ventilation, and some residual effects of morphine persisted at 2 hours.
Pharmacokinetic Principles of Antineoplastic Drug Therapy
Authors: ALLEN LARRY M.
Published: March 2013

Abstract: Determinants of host—drug interaction comprise a complex of potentially variable factors. The complexity of this variability compromises the forecasting of favorable response in individual patients given standard therapy. Substantial success with current forms of chemotherapy may require that biochemical, pharmacologic, and clinical profiles be established for each cancer patient whereby the use of drug and drug combination can be rationally applied. The significance of evaluating clinical pharmacokinetic parameters in patients with cancer is placed in perspective with other factors relevant to individual drug response.
Comparison of Fenoterol, Isoproterenol, and Isoetharine with Phenylephrine Aerosol in Asthma
Authors: SPELLMAN GEORGE G. , GRUEBEL BARBARA J. , EPSTEIN JOEL D. , ROTMAN HAROLD H. , WEG JOHN G.
Published: March 2013

Abstract: The bronchodilator effect of fenoterol hydrobromide (0.5, 1.25, and 2.5 mg) was compared with either isoproternol (2.8 mg) or isoetharine (5 mg) with phenylephrine (1.25 mg) in a double‐blind placebo‐controlled study. When delivered by an intermittent positive‐pressure breathing device to 24 nonsmoking young adult asthmatic subjects, fenoterol produced significant improvement in forced expiratory volume at 1 second (FEV1), in maximum midexpiratory flow (FEF25–75%), and in forced expiratory flow at 25 per cent of vital capacity (FEF25%) for 6 to 8 hours, whereas isoproterenol and isoetharine with phenylephrine produced improvement for 1 and 2 hours, respectively. The lowest dosage of fenoterol was as effective as the highest but had fewer adverse effects.
Mexiletine in the Treatment of Recurrent Ventricular Tachycardia. Prediction of Long‐Term Arrhythmia Suppression from Acute and Short‐Term Response
Authors: WANG REBECCA Y.C. , LEE PUI K. , WONG KEE L. , CHOW MOSES S.S.
Published: March 2013

Abstract: Acute intravenous and short‐term oral mexiletine therapy was effective in suppressing the arrhythmia in six of eight patients with recurrent ventricular tachycardia. Five of the six patients who were placed on maintenance therapy remained asymptomatic during a mean follow‐up of 15 months. The study shows that the acute and short‐term suppression of ventricular tachycardia by mexiletine can be a useful predictor of its long‐term efficacy.
Acute Electrophysiologic Effects of Nadolol
Authors: COHEN IRA S. , WIDRICH WARREN , DUCHIN KENNETH L. , WHARTON THOMAS P. , FLURI‐LUNDEEN JOAN , HARGUS STANLEY M.
Published: March 2013

Abstract: The acute effects of intravenous nadolol (0.01 and 0.02 mg/kg) on cardiac electrophysiologic parameters were assessed with His bundle recording and programmed atrial stimulation. The higher dose of nadolol reduced resting heart rate (71 vs. 65 beats/min, P < 0.02), and the degree of slowing was related to the initial heart rate (r = −0.68, P < 0.05). Atrioventricular conduction time as defined by the paced A—H interval, rose by 12 msec (P < 0.001) after nadolol (0.02 mg/kg) administration. Atrial refractoriness increased (by 10 msec, P < 0.02) only at the higher dose level with nadolol. At both dose levels, atrioventricular nodal effective and functional refractory periods were increased (P < 0.02) by a mean of 45 and 21 msec, respectively, suggesting greater sensitivity of atrioventricular nodal refractoriness to beta‐adrenergic blockade. Nadolol's effects were generally similar to those of previously reported studies with other beta‐adrenergic blockers. These data suggest that nadolol slows conduction through the atrioventricular node and increases atrial and atrioventricular nodal refractoriness.
High‐Dose Benzodiazepine Therapy in Hospitalized Anxious Patients
Authors: FANN WILLIAM E. , GARCIA JOSE , RICHMAN BRUCE W.
Published: March 2013

Abstract: Severely anxious hospitalized patients were treated with rapidly increasing doses of two benzodiazepine compounds to test the feasibility of rapid pharmacotherapy of the condition. Twenty‐one subjects completing the study all obtained substantial relief from symptoms; in only three subjects were symptoms completely eliminated. No serious side effects were encountered.
Chloramphenicol Dosage and Pharmacokinetics in Infants and Children
Authors: BURCKART GILBERT J. , BARRETT FRED F. , VALLE ROBERT DELLA , MEYER MARVIN C.
Published: March 2013

Abstract: Twenty infants and children receiving intravenous chloramphenicol were studied to examine the pharmacokinetics of the parent compound and its precursor, the succinate ester (CAP‐S). Plasma samples were obtained just prior to a 30‐minute infusion of chloramphenicol succinate, immediately after or 30 minutes after infusion, and 90, 210, and 330 minutes after infusion. Complete 6‐hour urine collections were obtained during 11 studies. Plasma and urine were assayed for chloramphenicol and its succinate ester by high‐performance liquid chromatography. Peak plasma concentrations ranged from 11.0 to 51.1 μg/ml on doses of 50 to 100 mg/kg/day and were higher in the youngest age group. The elimination half‐life of chloramphenicol averaged 4.0 hours. Multilinear regression analysis demonstrated an excellent relationship between body surface area, trough plasma chloramphenicol concentration, and total body chloramphenicol clearance. The hydrolysis of succinate ester to free chloramphenicol may delay the peak free concentration, and its renal elimination (average 21 per cent of the dose administered) significantly affects chloramphenicol pharmacokinetics. The clearance of chloramphenicol exhibited enzyme saturation kinetics in one patient studied at two different doses. Dosage adjustments of intravenous chloramphenicol in children must be made in relation to the trough chloramphenicol plasma concentration, renal elimination of CAP‐S, and possible saturation of chloramphenicol metabolism.
Disposition of Intravenous Pirmenol
Authors: SANDERS STEVEN W. , NAPPI JEAN M. , FOLTZ RODGER L. , LUTZ JOAN REGEDANZ , ANDERSON JEFFREY L.
Published: March 2013

Abstract: Twelve patients having frequent premature ventricular complexes (PVCs) averaging more than 60 per hour received a single 150‐mg intravenous dose of pirmenol. Plasma pirmenol concentration declined biexponentially following the infusion and was analyzed according to a two‐compartment open model. Following an erratic distribution phase, the terminal elimination half‐life ranged from 4.2 to 16.9 hours, with a geometric mean of 7.6 hours. Total body clearance averaged 164 ± 58 ml/min, and the mean volume of distribution was 1.45 ± 0.38 liter/kg. Renal clearance averaged 46.6 ± 21.2 ml/min, representing 30 ± 10 per cent of total body clearance. Excretion of unchanged drug in the urine averaged 31.8 ± 8 per cent of the dose. Renal clearance and elimination half‐life were correlated (r = −0.61, P < 0.05). Eight of the 12 patients achieved greater than 95 per cent suppression of PVCs with a duration between 20 minutes and 23 hours. These favorable pharmacokinetics indicate that pirmenol may be a useful addition to the therapy of ventricular arrhythmias.
Plasma Dipyridamole Concentrations After Two Different Dosage Regimens in Patients
Authors: MAHONY CHERYL , COX JAMES L. , BJORNSSON THORIR D.
Published: March 2013

Abstract: Twenty patients received dipyridamole by two different dosage regimens yielding a total daily dose of 150 mg, either as 50 mg three times a day or 75 mg twice a day. The rationale for comparing these two regimens is that dipyridamole is usually given three times a day, but recent studies have revealed a final elimination half‐life of the drug of about half a day. Based on drug cumulation during chronic dosing, the final half‐life of dipyridamole observed in this study also averaged about half a day. The 75 mg b.i.d. regimen did not result in lower trough concentrations than the 50 mg t.i.d. regimen. There was wide interpatient variability in observed plasma dipyridamole concentrations for both regimens, averaging about 10‐fold. These results suggest that dipyridamole could be administered twice a day and that dipyridamole levels should be monitored in clinical studies on the antithrombotic effect of the drug.
Comparison of Bronchial Effects of Nabilone and Terbutaline in Healthy and Asthmatic Subjects
Authors: GONG HENRY , TASHKIN DONALD P. , CALVARESE BARRY
Published: March 2013

Abstract: The acute bronchomotor effect of nabilone, a synthetic cannabinoid compound, was compared to that of terbutaline sulfate and placebo in six healthy and six asthmatic subjects. Bronchodilation following nabilone was intermediate between that of terbutaline and placebo in the healthy subjects but was equivalent to placebo in the asthmatics. We conclude that oral nabilone (2 mg) does not result in significant acute bronchodilation in patients with asthma.
Relationship Between Urine Flow Rate and Renal Clearance of Caffeine in Man
Authors: BLANCHARD JAMES , SAWERS STEWART J. A.
Published: March 2013

Abstract: The renal clearance of caffeine was calculated following both oral and intravenous doses of 5 mg/kg caffeine in eight young and eight elderly, healthy human volunteers. There was a highly statistically significant positive correlation (P < 0.001) between the renal clearance of both unbound (CLRu) and total (CLR) caffeine and the mean urine flow rate over the 24‐hour period after dosing. Attempted correlations of CLRu and CLR with hydrogen ion concentration or creatinine clearance and of creatinine clearance with urine flow rate all proved to be statistically nonsignificant. It is suggested that the control of salt and fluid intake and other factors affecting urine flow rate may be a worthwhile endeavor in pharmacokinetic studies of drugs with properties similar to caffeine.
Effects of Oxaprozin Alone or in Combination with Aspirin on Hemostasis and Plasma Protein Binding
Authors: KAHN S. BENHAM , HUBSHER JEROME A.
Published: March 2013

Abstract: Oxaprozin, a new nonsteroidal antiinflammatory agent, was studied alone and in combination with aspirin for it for its effects on hemostasis and protein binding in 10 healthy adults. When both oxaprozin and aspirin were given separately for seven days and in combination for five days, both drugs prolonged bleeding time and inhibited collagen‐ and epinephrine‐induced platelet aggregation to a similar degree. The effects of the combination of oxaprozin and aspirin were not additive. The data from the protein binding study showed that oxaprozin was more than 99 per cent bound to plasma proteins. Aspirin displaced oxaprozin from its binding sites. As a result, the rate of plasma clearance of oxaprozin significantly increased from 20 to 26 ml/min/kg (P < 0.05), and the plasma half‐life decreased from 45 to 40 hours. Platelet count and the humoral clotting mechanism were not affected by either drug alone or in combination. There was no clinical evidence of bleeding. One subject who received oxaprozin for 12 days and, in addition, aspirin for the last five days developed a rash that subsided after both drugs were discontinued; one subject treated with aspirin experienced tinnitus. These data suggest that oxaprozin, like aspirin and other nonsteroidal antiinflammatory drugs, should be used with caution when administered to patients who have suffered trauma, who undergo surgery, or who have known deftasis.
Antihypertensive and Metabolic Effects of Hydrochlorothiazide, Amiloride—Hydrochlorothiazide, and Timolol
Authors: CHRYSANT STEVEN G. , BROWN JANET L. , HAGSTROM DAVID
Published: March 2013

Abstract: The antihypertensive and metabolic effects of hydrochlorothiazide and amiloride—hydrochlorothiazide combination, alone and in combination with timolol, were studied in 26 patients with mild to moderately severe uncomplicated essential hypertension. All drugs were given in single daily doses as follows: hydrochlorothiazide 50 mg/day, amiloride—hydrochlorothiazide 5/50 mg/day (5 mg amiloride and 50 mg hydrochlorothiazide), timolol 20 mg/day. After six weeks of placebo treatment, the 26 patients were equally randomized into a double—blind HCTZ and HCTZ‐amiloride treatment period (weeks 7–18). Timolol was added to both groups of patients if the supine diastolic pressure at week 10 was higher than 90 mm Hg. Drug washout effects were observed for two weeks (weeks 19–20). Hydrochlorothiazide and amiloride—hydrochlorothiazide significantly lowered systolic and diastolic arterial pressure with the patient in the supine and upright position; the addition of timolol reduced the pressure further, and its effect was smooth and sustained. The heart rate was not affected by hydrochlorothiazide and amiloride—hydrochlorothiazide but was significantly decreased with the addition of timolol. The most common clinical and metabolic side effects observed, although not serious, were bradycardia from timolol and hypokalemia from hydrochlorothiazde. No hyperkalemia was noted with the combination of amiloride—hydrochlorothiazide and timolol. The results of the present study indicate that (1) the combination of timolol with either hydrochlorothiazide or amiloride—hydrochlorothiazide has equivalent antihypertensive actions; (2) the drugs can be effectively given in single daily doses; and (3) the combination of timolol with amiloride—hydrochlorothiazide has the additional advantage of preventing hypokalemia.
A Crossover Trial of Oxdralazine in Hypertension
Authors: SALVADEO ALESSANDRO , VILLA GIUSEPPE , SEGAGNI O , GALLI FRANCO , CRISCUOLO DOMENICO
Published: March 2013

Abstract: Twenty‐nine moderate and severe essential hypertensive patients completed a crossover study aimed at evaluating efficacy and tolerability of a double combination (chlorthalidone plus propranolol) and of a triple combination (chlorthalidone plus oxdralazine plus propranolol). After one month on 25 mg/day chlorthalidone, which caused nonsignificant reduction in blood pressure of 7/4 mm Hg, patients were randomized to receive either the double or triple regimen for a three‐month period. Then, after another month on chlorthalidone alone at the same dose of 25 mg/day, treatments were crossed over and the study continued for another three‐month period. The double regimen caused a drop in pressure of 16/11 mm Hg after one month (daily doses 25 mg chlorthalidone, 103 ± 25 mg propranolol), and this reduction did not change at the third month in spite of dosage increases (daily doses 25 mg chlorthalidone, 222 ± 77 mg propranolol). The triple regimen reduced blood pressure 35/15 mm Hg after one month (daily doses 25 mg chlorthalidone, 20 mg oxdralazine, 40 mg propranolol), and further increase in dosages caused a reduction of 45/24 mm Hg at the third month (daily doses 25 mg chlorthalidone, 56 ± 20 mg oxdralazine, 112 ± 40 mg propranolol). Both treatments were well tolerated; in particular, at the end of the third month of each treatment period, 25 patients on the triple regimen achieved a stable diastolic blood pressure of 90 mm Hg or less, as compared to 10 patients on the double regimen (P < 0.01).
Nifedipine Kinetics and Bioavailability After Single Intravenous and Oral Doses in Normal Subjects
Authors: FOSTER T. S. , HAMANN S. R. , RICHARDS V. R. , BRYANT P. J. , GRAVES D. A. , McALLISTER R. G.
Published: March 2013

Abstract: Nifedipine kinetics have not been described in clinically relevant detail because of difficulties in formulating a stable preparation for intravenous use and lack of a specific and sensitive assay for plasma nifedipine. We recently developed a gas‐chromatographic method and determined conditions in which nifedipine could be protected from photodegradation. Therefore, we evaluated the kinetics and bioavailability of nifedipine in 12 normal subjects after single intravenous (1 mg/5 min) and oral (10 mg) doses. After intravenous dosing, the drug was eliminated with a half‐time of 1.77 ± 0.25 hour, and total clearance was calculated at 0.62 ± 0.09 liter/kg/hr. With oral drug administration, the elimination half‐time was twice as long for the group; but within these subjects, marked variability in the rate of appearance of the drug in plasma was observed, giving profiles consistent with fast and slow absorption. In the latter group, peak plasma drug concentrations were only one third the level seen in those exhibiting a faster absorption profile, although the extent of drug absorption (as derived from areas under the plasma level‐time curves) did not vary. Bioavailability was 0.45 ± 0.08. Untoward effects resulting from the drug's pharmacologic activity was observed in five of the subjects after oral drug (headache) and three subjects after intravenous administration (flushing).
Clinical Experience with Atenolol in Patients with Chronic Liver Disease
Authors: KIRCH W. , SCHÄFER‐KORTING M. , MUTSCHLER E. , OHNHAUS E. E. , BRAUN W.
Published: March 2013

Abstract: The pharmacokinetics of atenolol were investigated following single intravenous (25 mg) and oral administration (100 mg) of atenolol in 13 patients with chronic liver disease and normal renal function and in 12 normal healthy volunteers. Four of the patients with chronic liver disease were not included in the statistical evaluation of kinetic data, since a reduction of creatinine clearance was observed during the course the study after ingestion of atenolol. A tendency to an increased distribution volume of atenolol could be observed in subjects with liver disease compared to normal volunteers. After intravenous and oral administration of atenolol, pharmacokinetic parameters such as elimination half‐life, plasma clearance, and renal clearance did not differ significantly between patients with chronic liver disease and healthy volunteers. Thus, plasma half‐life after intravenous dosing of atenolol was 6.0 ± 0.46 hours in patients with hepatic disease and 5.0 ± 0.4 hours in the controls, indicating absence of atenolol accumulation in hepatic failure. In the first days after starting beta‐blocker therapy such as atenolol administration, parameters of kidney function as plasma creatinine, or possibly creatinine clearance, should be initially monitored at regular intervals, as there may be transient changes of renal function in patients with chronic liver disease, leading to delayed elimination of the drug.
The Toxicity of Metabolites of Sodium Valproate in Cultured Hepatocytes
Authors: KINGSLEY ED , GRAY PHILLIP , TOLMAN KEITH G. , TWEEDALE ROWAN
Published: March 2013

Abstract: Sodium valproate is hepatotoxic in both humans and rat hepatocytes. The toxicity is dose related and frequently associated with simultaneous ingestion of drugs which induce the drug metabolizing system. For these reasons, metabolites of sodium valproate were tested for toxicity using rat hepatocyte cultures. The sodium salts of three metabolites, 2‐propylpent‐4‐enoate, 4‐hydroxyvalproate, and perhaps 5‐hydroxyvalproate, were toxic in this system. In addition, 2‐propylpent‐4‐enoate was toxic in a dose‐related fashion. All are ω and ω‐1 oxidation products in the microsome‐mediated pathway of valproate metabolism.