bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cannabinoids as Potential Antiepileptics
Authors: KARLER RALPH , TURKANIS STUART A.
Published: March 2013

Abstract: Comparative studies of the anticonvulsant properties of the cannabinoids and prototype antiepileptic drugs in numerous animal seizure models demonstrate that (1) as an anticonvulsant, cannabidiol (CBD), in contrast to Δ9‐tetrahydrocannabinol (THC), is relatively selective in terms of both central nervous system (CNS) depressant and excitatory properties; (2) the potency of cannabidiol, unlike that of phenytoin and phenobarbital, varies greatly with the species; (3) the large potency difference between the cannabinoids and the antiepileptics in the mouse appears to be due to dispositional differences, because brain concentrations of all the drugs are very similar; (4) tolerance to the anticonvulsant properties of cannabidiol is not a prominent feature; in three seizure models, tolerance developed in one, but “reverse tolerance” developed in the other two; and (5) the results of a study of the electrophysiologic mechanisms of action indicate that cannabidiol produces some unique effects and that its spectrum of antiepileptic activity may be different from that of the prototype drugs. The anticonvulsant nature of cannabidiol suggests that it has a therapeutic potential in at least three of the four major types of epilepsy: grand mal, cortical focal, and complex partial seizures.
Electrophysiologic Properties of the Cannabinoids
Authors: TURKANIS STUART A. , KARLER RALPH
Published: March 2013

Abstract: The effects of the psychoactive cannabinoid Δ9‐tetrahydrocannabinol (THC) and the nonpsychoactive cannabinoid cannabidiol (CBD) were investigated comparatively on electrically caused transcallosal cortical evoked responses, electrically induced limbic afterdischarges, photically evoked cortical afterdischarges, spontaneous cortical focal epileptic potentials, and spinal monosynaptic reflexes. In each system, THC produced central excitation; for example, the drug's responses ranged from enhancement of synaptic transmission to precipitation of frank convulsions. In addition to central nervous system stimulation, THC usually elicited depression; the qualitative character of the effect of the drug was dependent upon the dosage and the test system. In contrast to THC, cannabidiol generated no CNS excitation: it was either depressant or inert in these test systems. The results clearly demonstrate the complexity of the CNS properties of THC and the selectivity of the depressant properties of cannabidiol; moreover, the data illustrate the wide range of neuropharmacologic responses that potentially any cannabinoid can effect.
Topical Δ9‐Tetrahydrocannabinol and Aqueous Dynamics in Glaucoma
Authors: MERRITT JOHN C. , PERRY DWIGHT D. , RUSSELL DAVID N. , JONES BRENDA F.
Published: March 2013

Abstract: Systemic Δ9‐tetrahydrocannabinol (THC), administered either by smoking marihuana or as synthetic THC in soft gelatin capsules, lowers ocular tension in various glaucomas, but at the expense of significant decreases in systolic blood pressure. Topical THC in light mineral oil vehicles, though effective in laboratory animals, was not shown effective in 0.05 and 0.1% topical solutions when administered to six subjects with primary open‐angle glaucoma in a randomized, balanced, double‐masked protocol. Light mineral oil, which has an affinity for corneal epithelium, is an optimum vehicle for administering drugs whose mechanisms of action are systemic rather than local within the eye. Further glaucoma research should therefore proceed with marihuanas containing insignificant levels of THC (less than 0.4%) and with various local delivery systems of the ocular‐active cannabinoid found in Cannabis sativa.
Cannabinoids in Glaucoma: A Primary Screening Procedure
Authors: ELSOHLY M. A. , HARLAND E. , MURPHY J. C. , WIRTH P. , WALLER C. W.
Published: March 2013

Abstract: A procedure was developed for screening of cannabinoids for their ability to reduce intraocular pressure (IOP) using normal rabbits. Eight animals per group were used for statistical significance of data. A negative control group was used for every screen as well as a positive control with 1.5 mg/kg Δ9‐THC given intravenously (I.V.). All compounds were tested by I.V. injection and IOP measurements were taken periodically for 5 hours. Data were analyzed by a computer program which takes into account the change in IOP of the control group. Following this procedure we found that Δ8‐THC, Δ9‐THC, cannabinol, and nabilone were active while cannabidiol was inactive.
Isolation of Ocular Hypotensive Agents From Cannabis sativa
Authors: DEUTSCH HOWARD M. , GREEN KEITH , ZALKOW LEON H.
Published: March 2013

Abstract:Recent work in our laboratories has shown that a hydrophilic fraction fromCannabis sativa(marihuana) has extremely potent intraocular pressure (IOP)‐lowering activity as measured in albino rabbits when delivered by intravenous injection. A crude extract reduced IOP by 50–60 per cent (to the episcleral venous pressure) at dosage levels of about 500 μg/animal. Fractionation of this material by solvent extraction, high‐performance liquid chromatography, and gel filtration chromatography has produced samples with high activity at 50 μg/animal. The active material has been shown to be noncannabinoid and of high molecular weight.
Differential Effects of Diuresis and Beta‐Adrenoreceptor Blockade During Angiotensin‐Converting Enzyme Inhibition in Patients with Severe Hypertension
Authors: DRAYER JAN I. M. , WEBER MICHAEL A. , LIPSON JODI L. , MEGAFFIN BERNARD B.
Published: March 2013

Abstract:The orally administered blocker of angiotensin‐converting enzyme, captopril, was given to 16 patients with moderate to severe hypertension in whom blood pressure could not adequately be controlled by combination treatment with a vasodilator (hydralazine 200 mg daily), a beta‐blocker (propranolol 320 mg daily), and a diuretic (hydrochlorothiazide 100 mg daily). Captopril (450 mg daily) alone maintained blood pressure at the same levels as during previous administration of the combination, although in the absence of the diuretic and the beta‐blocker there were increases in body weight of 1.8 ± 0.5 (S.E.) kg (P<0.01) and in supine heart rate of 10 ± 4 beats/min (P< 0.01). After hydrochlorothiazide (100 mg daily) was added to the captopril, the supine mean blood pressure of 122 ± 5 mm Hg was significantly lower than during captopril alone (134 ± 4 mm Hg,P<0.01). Heart rate increased from 79 ± 3 to 90 ± 5 beats/min (P<0.05). In 13 of the 16 patients, in whom supine diastolic blood pressure still remained higher than 90 mm Hg, the addition of propranolol (120–360 mg daily) to the captopril‐hydrochlorothiazide combination decreased heart rate from 88 ± 5 to 65 ± 3 beats/min (P< 0.01), but failed to produce a further blood pressure decrement. However, the supine mean blood pressure during the captopril‐hydrochlorothiazide‐propranolol combination of 120 ± 5 mm Hg was significantly lower (P< 0.05) than that (132 ± 6 mm Hg) during the hydralazine‐hydrochlorothiazide‐propranolol combination. Despite similar diuretic doses in the two regimens, serum potassium concentration was significantly higher during treatment with the captopril combination (4.3 ± 0.2 vs. 3.6 ± 0.2 mEq/l.,P<0.01). It seems likely that converting enzyme inhibition by captopril increases the sensitivity of the blood pressure response to diuretic therapy, in part by blocking the countervailing effects of the reactive rise in renin release that is stimulated by sodium depletion. In these renin‐blocked patients, however, addition of propranolol does not appear to produce any further antihypertensive effect.
Effects of Single Large Doses of Phenytoin on Glucose Homeostasis—a Preliminary Report
Authors: BANNER WILLIAM , JOHNSON DAVID G. , WALSON PHILIP D. , JUNG DONALD
Published: March 2013

Abstract: The effects of a loading dose of 15 mg/kg phenytoin by iv infusion on the serum levels of insulin, glucagon, and glucose were investigated in five fasting healthy male volunteers between the ages of 23 and 35 years. Serum glucose concentrations rose immediately after the infusion of phenytoin followed by a significant increase in serum insulin values (P < 0.05). A slight elevation in mean glucagon concentrations after the infusion was not statistically significant. Further studies are indicated to determine whether phenytoin as used in the treatment of status epilepticus may aggravate the hyperglycemia associated with seizures.
Analgesic Effect of Isoxepac on Postmeniscectomy Pain: A Controlled Trial
Authors: HONIG W. J. , PELGROM R. , CHADHA DEV R.
Published: March 2013

Abstract: The analgesic efficacy of 100 and 200 mg isoxepac was compared with that of 50 mg indomethacin in a double‐blind, single‐dose, between‐patient (parallel) study with placebo control. Oral doses were administered to 120 patients whose postoperative plan justified administration of analgesics on the morning of the day following knee surgery for meniscectomy. No appreciable differences emerged between 100 mg isoxepac and placebo, though 50 mg indomethacin and 200 mg isoxepac gave better analgesia than either 100 mg isoxepac or placebo. Peak and duration of pain relief was of the same order with 50 mg indomethacin, and 200 mg isoxepac would appear to be the minimal effective dose in the clinical setting of postoperative pain following knee meniscectomy. The incidence of side effects on all three active treatments was remarkedly low.
A 12‐Hour Evaluation of the Analgesic Efficacy of Diflunisal, Aspirin, and Placebo in Postoperative Dental Pain
Authors: FORBES JAMES A. , CALDERAZZO JOSEPH P. , BOWSER MICHAEL W. , FOOR VIRGINIA M. , SHACKLEFORD ROBERT W. , BEAVER WILLIAM T.
Published: March 2013

Abstract: Two‐hundred and one outpatients with postoperative pain following oral surgery were randomly assigned, on a double‐blind basis, a single oral dose of diflunisal (250, 500, or 1000 mg), aspirin (650 mg), or placebo. Using a self‐rating record, the subjects rated their pain and its relief hourly for 12 hours after medication. Measures of peak and total analgesia were derived from the patients' subjective reports. Diflunisal 250 and 1000 mg were significantly superior to aspirin for every measure of total and peak analgesia; the 500‐mg diflunisal dose was significantly superior to aspirin for measures of total analgesia only. All doses of diflunisal were significantly superior to aspirin and placebo at each hour from hour 3 through hour 12. Approximately 60 per cent of the patients treated with diflunisal completed the 12‐hour observation period without the need for additional analgesic therapy. Adverse effects were mild and transitory and occurred in less than 10 per cent of the patients.
Factors Moderating the Effect of Oral Sulfonylureas on Free Water Clearance
Authors: DAVIS FAITH B. , BOH DAWN M. , DAVIS PAUL J. , VAN SON ALLENE R. , MYLOTTE KATHLEEN M. , EDWARDS LEILA , ZIELEZNY MARIA , SCZUPAK CHRISTINE
Published: March 2013

Abstract: The effects of the antidiuretic agent chlorpropamide and the diuretic agent tolazamide on solute‐free water clearance (CH2O) were compared in noninsulin‐dependent diabetic patients undergoing water diuresis. Hyperglycmia (fasting serum glucose above 200 mg/dl) obscured the effects of these two sulfonylureas on CH2O. Thiazide or ethacrynic acid enhancement of chlorpropamide antidiuresis was also blunted by hyperglycemia and attendant osmotic diuresis. Thus, the low incidence of symptomatic hyponatremia during chlorpropamide treatment of diabetic patients may be explained by persistent hyperglycemia in such patients.
Heparin Requirements in Pulmonary Embolism and Venous Thrombosis: A Prospective Study
Authors: ELLIOTT CHARLES G. , MICHOCKI ROBERT J. , BROWN ROBERTA , OTTESEN OLE E.
Published: March 2013

Abstract: To investigate the relationship between the clinical diagnosis of thromboembolic disease and heparin requirements for anticoagulation, we prospectively studied 31 patients suspected to have either deep vein thrombosis or pulmonary embolism. Six had the diagnosis of pulmonary embolism confirmed by a combination of ventilation and perfusion scans with pulmonary angiography, eight had venograms showing deep vein thrombosis, seven had diseases which mimicked pulmonary embolism, and ten had normal venograms. These four diagnostic groups were not significantly different with respect to heparin requirements during the first 24 hours of therapy (x̄ ± S.D. = 426 ± 105, 507 ± 105, 434 ± 79, and 457 ± 46 units/kg per 24 hours, respectively). Patients with pulmonary embolism and deep vein thrombosis did not differ significantly with respect to heparin requirements (UNITS/kg per 24 hours) on the second (386 ± 108 vs. 439 ± 127), third (415 ± 136 vs. 464 ± 130), and fourth (374 ± 104 vs. 418 ± 127) days of therapy. Our data suggest that the clinical diagnosis does not affect the dose of heparin necessary to anticoagulate patients with pulmonary embolism and deep vein thrombosis.
The Effects of Propranolol on Thyroxine Metabolism and Triiodothyronines Production in Man
Authors: CHAMBERS JOSEPH B. , PITTMAN CONSTANCE S. , SUDA ABHAY K.
Published: March 2013

Abstract:The effects of propranolol on the turnover of thyroxine (T4), 3,5,3′‐triiodothyronine (T3), and 3,3′,5′‐triiodothyronine (rT3) were determined by a non‐compartmental analysis in seven normal men. Fourteen normal subjects were treated with 0.2 mg T4daily, and half of this group (seven) received in addition 80 mg propranolol daily. Fifteen days of propranolol treatment did not alter serum T4concentration or T4turnover. However, it lowered serum T3concentration from 173 to 102 ng/dl (P= 0.001); T3clearance was unchanged. Propranolol treatment elevated serum rT3concentration from 54 to 69 ng/dl (P= 0.05); rT3metabolic clearance rate fell from 105 to 90 liters/day but the difference did not reach statistical significance. The rT3disposal rate was unchanged by propranolol. The fractional T4disposal which was degraded via the deiodinative pathways was reduced from 82.0 per cent in the control subjects to 65.5 per cent in the propranolol treated subjects. Therefore, propranolol appears to be a potent inhibitor of 5′‐deiodination. The interpretation of serum T3measurements in patients treated with propranolol requires caution.
Bioavailability of Organic Nitrates: A Comparison of Methods for Evaluating Plethysmographic Responses
Authors: HAFFTY BRUCE G. , NAKAMURA YASUYUKI , LONG ROBERT A. , HULL J. HEYWARD , SPODICK DAVID H.
Published: March 2013

Abstract: Erythrityl tetranitrate, a long‐acting organic nitrate, was compared with isosorbide dinitrate in a double‐blind, placebo‐controlled complete crossover study in 15 healthy male volunteers. A digital plethysmogram and ear densitogram were used to assess the physiologic response to these two sublingual nitrates, with the intensity and duration of drug effect calculated by differences in diastolic amplitude intensity before and after drug administration. Both 5 mg sublingual erythrityl tetranitrate and 5 mg isosorbide dinitrate produced significant increases in diastolic amplitude intensity for up to 3 hours. The erythrityl tetranitrate peak effect was less than that of the isosorbide dinitrate, but the incidence of headaches was also less. The ear densitogram was found to be an effective means of assessing the diastolic amplitude intensity changes.
The Effects of Erythromycin on Theophylline Elimination in Normal Males
Authors: MAY DAVID C. , JARBOE CHARLES H. , ELLENBURG DONALD T. , ROE ELSA J. , KARIBO JOHN
Published: March 2013

Abstract: The effects of three erythromycin preparations on theophylline elimination kinetics were examined in 23 male subjects. Subjects received 6 mg/kg of theophylline elixir orally and elimination kinetics were determined. The population was then randomized to receive either a lactose placebo, erythromycin base, erythromycin stearate, or erythromycin ethylsuccinate. Each 250‐mg preparation was given four times a day for six days. On day seven, a repeat kinetic study was performed. The mean theophylline half‐life of controls was 7.8 ± 2.6 hours. The half‐life increased significantly in all erythromycin treatment groups. The increase for the base, stearate, and ethylsuccinate groups was 51.7, 21.3, and 60.3 per cent, respectively. The total body theophylline clearance decreased significantly in all treatment groups. This was not associated with biochemical evidence of hepatitis. Three of four smokers who received erythromycin manifested no increase in theophylline half‐life, in contrast to one of 13 nonsmokers. There was no difference in the percentage theophylline bound to serum protein for any of the erythromycin treatment groups or controls as determined by ultracentrifugation.
Serious Bioavailability Problems with a Generic Prolonged‐Release Quinidine Gluconate Product
Authors: MEYER MARVIN C. , STRAUGHN ARTHUR B. , LIEBERMAN PHILLIP , JACOB JAMES
Published: March 2013

Abstract: A recently marketed prolonged‐release quinidine gluconate tablet was compared with the innovator's tablet in a single‐dose bioavailability study with 12 healthy male subjects. The extent of absorption of quinidine from the new marketed product was only 50 per cent that of the innovator's product. This finding, as well as projections of steady‐state plasma concentrations to be expected during multiple‐dose administration, indicated a bioequivalence problem with medically significant implications. The data obtained in this study resulted in a Class I recall of the less completely absorbed product by the U.S. Food and Drug Administration.
Effect of Food on the Bioavailability of Captopril in Healthy Subjects
Authors: SINGHVI SAMPAT M. , McKINSTRY DORIS N. , SHAW JAMES M. , WILLARD DAVID A. , MIGDALOF BRUCE H.
Published: March 2013

Abstract: 14C‐Captopril was administered as 100‐mg tablets to 12 subjects in a two‐way crossover study in which subjects were either fasted or were given a standard meal immediately prior to dosing. Based on blood level and urinary excretion data, both the absorption of total radioactivity and the bioavailability of captopril were decreased approximately 35 to 40 per cent after a meal. Whether this moderate decrease in the absorption and the bioavailability of captopril caused by food is of clinical significance has not yet been determined.
Phenobarbital Pharmacokinetics and Bioavailability in Adults
Authors: NELSON ERIC , POWELL J. ROBERT , CONRAD KENNETH , LIKES KEITH , BYERS JAMES , BAKER SANDRA , PERRIER DONALD
Published: March 2013

Abstract: The pharmacokinetics and bioavailability of phenobarbital were examined in six healthy adult subjects after a 2.6 mg/kg intravenous and a 2.9 mg/kg oral dose. Serum concentrations of phenobarbital were followed by means of a high pressure liquid chromatographic assay for 21 days after drug administration. After the intravenous dose, the mean distribution half‐life was 0.18 hour and the mean elimination half‐life was 5.8 days. Mean total body clearance and mean renal clearance were 3.0 ml/hr/kg and 0.8 ml/hr/kg, respectively. The apparent volume of distribution was 0.60 liter/kg. After administration of phenobarbital tablets, the maximum phenobarbital serum concentration was 5.5 mg/liter at 2.3 hours after the dose. Adjusted absolute availability of phenobarbital from the tablets studied was 94.9 per cent (range 81–111.9 per cent). The elimination half‐life averaged 5.1 days for the oral dose. There was no evidence of autoinduction of phenobarbital elimination over the study period.
Effects of Terbutaline on Cardiac Automaticity and Contractility
Authors: DANILO PETER , ROSEN TOVE S.
Published: March 2013

Abstract:The effects of terbutaline, a sympathomimetic amine with predominantly β2‐agonist properties, on cardiac automaticity and contractility were studied. For isolated rabbit right atria, terbutaline, 1 × 10−9to 1 × 10−5M, was significantly less potent than isoproterenol. The maximum increase in heart rate induced by terbutaline was 45 ± 17 beats/min, that by isoproterenol, 120 ± 9 beats/min. For canine Purkinje fibers, terbutaline had less effect on spontaneous rate than isoproterenol; maximum increases above control were 9.5 ± 2.5 and 18.6 ± 7.0 beats/min, respectively. For isolated feline ventricular muscle, terbutaline, 1 × 10−9to 1 × 10−6M, was significantly less potent than isoproterenol in increasing peak developed tension and the rate of tension development. Superfusion with Tyrode's solution containing terbutaline, 1 × 10−7M, plus graded concentrations of isoproterenol, 1 × 10−9to 1 × 10−6M, resulted in responses which were less than those observed when isoproterenol alone was super‐fused. Maximal effects of isoproterenol plus terbutaline were equivalent to those of isoproterenol alone. These results suggest that terbutaline is less potent then isoproterenol in its effect on cardiac contractility and automaticity and explain the clinical observation that terbutaline is less toxic than isoproterenol in its effects on cardiac rhythm and contraction when administered for the treatment of bronchial asthma.
Metaproterenol Solution in the Treatment of Asthmatic Patients by Intermittent Positive Pressure Breathing
Authors: BRANSCOMB BEN V.
Published: March 2013

Abstract: The effects of five different doses of a 5% inhalant solution of metaproterenol on pulmonary function were compared in a placebo‐controlled double‐blind crossover study in 40 asthmatic patients who received the drug via intermittent positive pressure breathing (IPPB). The response to metaproterenol in terms of FVC, FEV1, RA, and FEF25–75% was significantly superior to the placebo response. The effect of metaproterenol set in within 5 minutes of administration, and clinically significant improvement in pulmonary function was sustained for 6 hours even at the lowest dose level. Global response evaluations reflected a progressive increase in effectiveness with each successive dose increment. Typical sympathomimetic side effects such as nervousness and shakiness slightly increased in frequency with higher doses. At none of the metaproterenol doses were any clinically significant changes observed in the mean blood pressure and pulse rate values.
Study of Penfluridol and Chlorpromazine in the Treatment of Chronic Schizophrenia
Authors: WANG RICHARD I. H. , LARSON CRAIG , TREUL SHARON J.
Published: March 2013

Abstract: This study presents data on the use of penfluridol, a once‐a‐week orally administered, antipsychotic agent, in the treatment of chronic schizophrenic patients. Fifty‐nine patients participated in the initial dose titration segment during which doses of penfluridol were adjusted weekly until the patients' condition became stabilized. The starting dose did not exceed 60 mg per week, and the maximum weekly dose did not exceed 140 mg. Forty‐one of these patients continued on to participate in a double‐blind comparison of penfluridol with chlorpromazine. Maximum doses did not exceed 140 mg per dose per week for penfluridol and 7350 mg per week for chlorpromazine in the double‐blind segment. Patients were abruptly switched from their previous neuroleptic medication to penfluridol without loss of control. Side effects, mainly extrapyramidal in nature, were readily alleviated with benztropine mesylate. Penfluridol, administered orally once a week, appeared to be well tolerated; it was comparable to daily chlorpromazine in treating and maintaining schizophrenic patients.
Tolerance of Healthy Adult Males to Intravenous Infusion of Cetiedil, a Vasoerythroactive Drug
Authors: LEWIS GEORGE P. , CHO YOUNG W.
Published: March 2013

Abstract: The intravenous infusion of cetiedil to a group of ten male volunteers elicited atropine‐like side effects on salivation, bronchomotor tone and visual accommodation. With repeated infusions of cetiedil, the incidence as well as the duration of the side effects were reduced significantly, indicating the development of tolerance. Since normal subjects can tolerate repeated intravenous infusions of cetiedil, the clinical investigation of this drug in sickle cell disease can proceed, including those patients suffering from vasoocclusive crises.
Efficacy and Duration of Action of Procaterol, a New Bronchodilator
Authors: ZANETTI CLAUDE L. , ROTMAN HAROLD H. , DRESNER A. J.
Published: March 2013

Abstract: Procaterol, a new beta‐adrenergic agonist, was tested in two different doses in patients with reversible airway obstruction. Single oral doses of 0.05 or 0.1 mg produce an increase in measured expiratory flow rates, and the peak and duration of action are both dose related. Side effects reported during this one‐day study were similar to those described with other compounds of this class; they were considered to be mild by the patients and the investigator. From these results, further investigation of this agent in bronchoconstrictive disease appears warranted.
Effect of Furosemide on the Pharmacokinetics of Gentamicin in Patients
Authors: LAWSON D. H. , TILSTONE W. J. , GRAY J. M. B. , SRIVASTAVA P. K.
Published: March 2013

Abstract: The clearances of inulin and gentamicin were studied before and after intravenous furosemide in seven patients. There was a significant fall in glomerular filtration rate after furosemide and a similar though less marked fall in gentamicin clearance in six of the seven subjects. Small but consistent increases in plasma gentamicin concentrations were observed after furosemide. The reduction in clearance may explain the enhanced risk of nephrotoxicity in patients receiving both aminoglycosides and diuretics.
Importance of Protein Binding for the Interpretation of Serum or Plasma Drug Concentrations
Authors: GREENBLATT DAVID J. , SELLERS EDWARD M. , KOCH‐WESER JAN
Published: March 2013

Abstract: The extent of drug binding to plasma protein does not influence the concentration of unbound drug in plasma at steady state but does influence the interpretation of total drug concentrations. An increase in free fraction (reduction in the extent of binding) decreases the therapeutic and toxic ranges for total drug concentrations. Conversely, a reduction in free fraction (increase in the extent of binding) increases these ranges. Laboratories generally measure total rather than unbound drug concentrations, and clinicians must use caution in interpreting these total drug concentrations in clinical situations where the extent of binding of extensively bound drugs may be altered. Free drug serum or plasma concentrations are inherently more reliable indices of the intensity of drug action than are total concentrations. Methodology for routine measurement of free concentration is becoming available and should ultimately be utilized for therapeutic monitoring of drugs that are highly bound to protein.
Assessment of Quinidine Gluconate for Nonlinear Kinetics Following Chronic Dosing
Authors: RUSSO JOHN , RUSSO MARY E. , SMITH RUTH ANN , PERSHING LYNN K.
Published: March 2013

Abstract: Two different chronic dosing regimens of quinidine gluconate were administered to each of four healthy volunteers in a pilot study to evaluate quinidine for nonlinear pharmacokinetics. Analysis of plasma quinidine levels following the last dose indicates that disproportionate increases in steady‐state plasma concentrations can occur in some subjects as the daily dose increases. Measurement of 2′‐oxoquinidinone (2′‐OXO) and 3‐hydroxyquinidine (3‐OH) metabolites revealed that the formation of 2′‐OXO is proportional to the availability of quinidine base. Hydroxylation was a more variable process. Rate‐limited hydroxylation was documented in one subject, and an apparent increase in hepatic microsomal enzyme‐mediated hydroxylation was shown in a second subject who ingested large amounts of caffeine daily. By using a highly selective high‐performance liquid chromatography assay technique, the total body clearance of quinidine was found to be greater than previously published data. Our results suggest that some individuals may exhibit dose‐dependent elimination of quinidine and that the variability in quinidine's pharmacokinetics is related in part to its hydroxylation. Future studies must use highly specific quinidine assays and control for variables that may influence this route of metabolism.
Potential Influence of Body Weight on the Clearance of Polymorphically Acetylated Drugs
Authors: CHAPRON DENNIS J. , KRAMER PAUL A. , MERCIK SUSAN A.
Published: March 2013

Abstract: The acetylation clearance of sulfamethazine was found to be significantly dependent upon body weight in both intermediate and rapid acetylators. The correlation beween acetylation clearance and body weight was stronger in the rapid acetylator. It is recommended that weight‐corrected acetylation clearance values be used when constructing distribution histograms for phenotyping purposes. Within a phenotypic mode, body weight may be useful in providing initial estimates of dosing needs.
The Pharmacokinetics of Thiabendazole and its Metabolites in an Anephric Patient Undergoing Hemodialysis and Hemoperfusion
Authors: BAUER LARRY A. , RAISYS VIDMANTAS A. , WATTS MARK T. , BALLINGER JOHN
Published: March 2013

Abstract: The pharmacokinetics of thiabendazole and its metabolites were determined after the first dose and during hemodialysis and hemoperfusion in an anephric female patient treated for a strongyloides infection. The half‐life, volume of distribution, and clearance for thiabendazole were 1.17 hour, 2.76 liters/kg, and 27.2 ml/min · kg, respectively. While thiabendazole and the 5‐OH metabolite did not accumulate during multiple dosing, the glucuronide and sulfate esters accumulated extensively despite hemodialysis and hemoperfusion. Hemodialysis clearances for all compounds were poor. Hemoperfusion removal was much better but declined rapidly after the first hour. If rapid removal of thiabendazole and its metabolites is required, the hemoperfusion column should be changed hourly.
Ventricular Antiarrhythmic Effects of Beta‐Adrenergic Blocking Drugs: A Review of Mechanism and Clinical Studies
Authors: PRATT CRAIG , LICHSTEIN EDGAR
Published: March 2013

Abstract: Beta‐adrenergic blocking drugs are now commonly used in patients with ventricular arrhythmias. This review examines the possible mechanisms of their ventricular antiarrhythmic effect. Actions on the myocardial cell, as well as actions on the central and autonomic nervous system, are reviewed. Many clinical studies have attempted to show the efficacy of beta blockers in controlling ventricular arrhythmia and decreasing the incidence of sudden death after acute myocardial infarction. Although some of these clinical trials tended to show an impact on sudden death, the size of these trials or their design problems do not allow firm conclusions to be made. The Beta Blocker Heart Attack Trial (BHAT) is a placebo‐controlled, double‐blind, randomized trial of propranolol currently under way in the United States. Important additions to the previous trials include the addition of drug levels to ensure beta‐blocking dosage, long‐term electrocardiographic monitoring, and a study population of 4200 patients followed for an average of three years. These important design features will be of value in addressing some of the unanswered questions presented in this review.
Furosemide Vasodilates the Canine Gastrointestinal Tract
Authors: WALLACH STANLEY , CHARBON GERARD A. , BEIJER HEIN J. M. , STRUYVENBERG ALBERT
Published: March 2013

Abstract: The ability of furosemide to induce vasodilation in the canine gastrointestinal system was studied by quantitative flowmetry. Blood flow and conductance increased maximally by 60 per cent in the stomach and duodenum and by 80 per cent in the small and large intestine. Vasodilation was evident at 2.4 mg/kg furosemide and higher. The onset of vasodilation occurred at 24 to 30 seconds and was maximal at 36 seconds in the stomach, at 66 seconds in the duodenum, at 78 to 84 seconds in the small intestine, and at 90 seconds in the large intestine. Hepatic arterial, splenic, and renal blood flows were unchanged. Simultaneous arteriovenous sampling from the small intestine indicated that the increased blood flow was not associated with increased O2 consumption. However, CO2 addition to the venous effluent decreased by 70 per cent. These data indicate that furosemide has a vasodilatory action on the gastrointestinal tract due either to a delayed effect on the vascular smooth muscle cell or on anaerobic bowel wall metabolism. The CO2 data are compatible with, but do not prove, stimulation of secretion of HCO3– by the intestinal mucosa.
A Phase I Clinical Trial of Aclacinomycin A Administered on a Five‐Consecutive‐Day Schedule
Authors: WOOLLEY PAUL V. , AYOOB MARILYN J. , LEVENSON STANLEY M. , SMITH FREDERICK P.
Published: March 2013

Abstract: In this Phase I study, the new anthracycline aclacinomycin A was given to 22 advanced cancer patients on a schedule of daily intravenous administration for five days repeated every four weeks. The limiting toxicity was myelosuppression, which was severe at a dose of 30 mg/m2 per day for five days. Platelet nadirs were more marked than those of white cells and occurred at about day 11 after the first drug dose, while maximum leukopenia occurred at day 21. Some patients had moderate nausea and vomiting. No hepatic or renal toxicity was observed, and alopecia was minimal. Cardiac function was monitored prospectively, using radionuclide left ventricular ejection fractions and serial ECGs. One patient developed transient atrial fibrillation; and one other, who had previously received 380 mg/m2 doxorubicin, developed congestive heart failure. Otherwise there was no evidence of cardiac toxicity. No tumor regressions were seen. We conclude that 150 mg/m2 given in five daily 30 mg/m2 fractions is a maximum tolerated dose of aclacinomycin A. This is higher than the reported MTD of 120 mg/m2 for single bolus injection. We recommend a Phase II starting dose of 25 mg/m2 per day for good‐risk patients and 20 mg/m2 per day for poor‐risk patients when the drug is given on this schedule.
Loxapine Succinate as Initial Treatment of Hostile and Aggressive Schizophrenic Criminal Offenders
Authors: FELDMAN HAROLD S.
Published: March 2013

Abstract: The efficacy and safety of loxapine were evaluated in 18 acutely ill schizophrenic criminal offenders in the Essex County Jail. The offender patients were treated for three days with intramuscular loxapine (25 mg three or four times a day), followed by seven days of oral concentrate (up to 150 mg/day in three or four divided doses). Psychiatric status was determined with the Brief Psychiatric Rating and the Clinical Global Impression scales at the time of admission, after 8, 24, 48, and 72 hours, and on days 7 and 10 of medication. Three patients did not complete treatment: one was released on bail after 24 hours of therapy, and the other two had adverse reactions (tongue swelling and muscle spasms, each in one patient) which required cessation of treatment. Statistically significant improvement in both rating scale results was evident as early as 8 hours after treatment began. By day 10, all Brief Psychiatric Rating Scale items and factors and the Clinical Global Impression results were statistically improved over baseline measurements. At the end of the study, 87 per cent (13/15) of the patients were well enough to cooperate with their attorneys and understand the procedures of the court. Adverse effects (generally extrapyramidal) appeared in four of 18 patients during parenteral administration and in two of 15 patients during oral therapy.
Efficacy of Acebutolol in Chronic Stable Angina Using Single‐Blind and Randomized Double‐Blind Protocol
Authors: LEE GARRETT , DeMARIA ANTHONY N. , FAVROT LAWRENCE , HERMANOVICH JOHN , KOZINA JOSEPH , KRIEG PAUL , KIMCHI ASHER , LADDU ATUL , MASON DEAN T.
Published: March 2013

Abstract: The clinical effects of a cardioselective beta‐adrenergic blocking drug, acebutolol, were studied in 25 patients with chronic stable angina, using a seven‐week single‐blind placebo→acebutolol (mean dose 913 mg/day) phase followed by 12‐week randomized double‐blind placebo→acebutolol (mean dose 968 mg/day) crossover protocol. Objective parameters from exercise treadmill tests showed consistent reduction in resting and maximal exercise heart rate and rate‐pressure product during both single‐ and double‐blind phases. Duration of exercise and maximal ST segment depression were not significantly altered. Subjective improvement following acebutolol was observed with reduced frequency of anginal attacks and nitroglycerin consumption during the single‐blind phase. However, no differences were seen during the double‐blind phase due to significant subjective improvment during the latter placebo period. Adverse effects observed were mild in nature and were similar to those seen with other beta blockers. These data establish acebutolol as a potent beta‐blocking agent and emphasize the importance of utilizing objective parameters over subjective variables in demonstrating the clinical antianginal efficacy of a beta blocker.
Short‐ and Long‐Term Therapeutic Efficacy of Quinidine Sulfate for the Treatment of Chronic Ventricular Arrhythmias
Authors: PANIDIS IOANNIS , MORGANROTH JOEL
Published: March 2013

Abstract: To determine the efficacy and tolerance of oral quinidine sulfate in the treatment of chronic ventricular arrhythmias using contemporary definitions of drug efficacy, 20 ambulatory patients underwent a short‐term, placebo‐controlled, double‐blind trial consisting of four days of quinidine therapy at 400 mg every 6 hours. A long‐term trial was conducted in 12 additional patients where ventricular ectopic frequency during two weeks of placebo therapy was compared with that during eight weeks on quinidine sulfate at 300 mg every 6 hours. Quinidine efficacy was determined by 48 hours of Holter monitoring. Blood levels were within the therapeutic range in both trials. Side effects consisted of diarrhea, which occurred in 15 per cent of patients on the short‐term trial and 25 per cent of patients on the long‐term trial. Drug effect defined as a statistically significant (P < 0.05) reduction in chronic premature ventricular complexes occurred in 70 per cent of patients on the short‐term trial and in 67 per cent of patients on the long‐term trial. In both trials, all patients with ventricular tachycardia had statistically significant suppression. Statistically significant reduction in ventricular couplets occurred in all patients on the short‐term trial but in only 73 per cent of the patients on the long‐term trial. These data can be used as reference standards for quinidine sulfate in new antiarrhythmic drug comparison trials.
Antihypertensive Effects and Plasma Levels of Guanfacine in Man
Authors: SAFAR MICHAEL E. , LORIA YOLANDE , WEISS YVES A. , BOUTIER JEAN R.
Published: March 2013

Abstract: The antihypertensive effect and the plasma levels of guanfacine were studied for two months in 25 patients with sustained essential hypertension. In three patients, blood pressure was unchanged. In ten patients, blood pressure returned to the normal range within 15 days, at a daily dose of 2 mg. In 12 patients, increasing doses were necessary to normalize the blood pressure within two months. In these cases, the decrease in systolic pressure was negatively correlated with the daily dose of guanfacine (r = −0.40) and the steady‐state plasma level (r = −0.62; P < 0.01); analysis of the curves showed that the normalization of blood pressure coincided with a plasma drug level of 8 ng/ml, i.e., a 4‐mg daily dose. This study demonstrated the efficacy of guanfacine monotherapy in hypertension and suggests that the normalization rate of blood pressure levels does not further increase with daily doses higher than 4 mg.
Racial Background and Lidocaine Pharmacokinetics
Authors: GOLDBERG MARK J. , SPECTOR REYNOLD , JOHNSON GEORGE F.
Published: March 2013

Abstract: The pharmacokinetics of lidocaine were investigated in 17 healthy young adult volunteers seven Caucasians, five Orientals, and five Blacks). With the assumption of a one‐compartment open model and linear pharmacokinetics, analysis of the data determined that there were no significant differences in the volume of distribution, clearance, elimination half‐life, and serum protein binding of lidocaine among these racial groups. Our finding that lidocaine clearance and protein binding are not significantly different in young adult Caucasians and Orientals is consistent with our previous hypothesis that drugs metabolized in the body by N‐dealkylation (lidocaine and diphenhydramine) are cleared at similar rates in young adult Caucasians and Orientals when protein binding is taken into account.
Pharmacokinetics of Isotretinoin Following a Single Oral Dose
Authors: KHOO K.‐C. , REIK D. , COLBURN WAYNE A.
Published: March 2013

Abstract: A pharmacokinetic profile was developed following oral administration of a single 100‐mg oral dose of isotretinoin to 12 normal male volunteers. Concentrations of isotretinoin and its isomer, tretinoin, were measured in blood samples from 12 subjects and in urine and fecal samples from three of the 12 subjects. Blood concentration‐time data during a 72‐hour sampling interval were variable and, in five of the 12 cases, showed pronounced secondary and tertiary concentration maxima which were consistent with the theory of enterohepatic circulation (EHC) of isotretinoin in man. In five of the 12 subjects, adequate fits of the data could not be obtained using classical bi‐ or triexponential equations but were successfully fitted using a recently developed recycling model. Maximum blood concentrations of isotretinoin ranged from 74 to 511 ng/ml and occurred between 1 and 4 hours after dosing. Secondary maxima generally occurred between 6 and 24 hours after dosing. The harmonic mean elimination half‐life was approximately 20 hours. These findings suggest that steady‐state blood concentrations should be observed within one week. Negligible amounts of unchanged isotretinoin were excreted in urine, whereas 53 to 74 per cent of the dose was recovered as intact isotretinoin in the feces. The amount of intact drug in the feces could reflect biliary excretion of the conjugate of isotretinoin that is deconjugated beyond the site where absorption may occur, as well as unabsorbed drug.
Pharmacokinetics of Amikacin and Cephalothin in Bedridden Elderly Patients
Authors: YASUHARA HAJIME , KOBAYASHI SHINICHI , SAKAMOTO KOJI , KAMIJO KAZUYA
Published: March 2013

Abstract: The pharmacokinetics of amikacin (5.5 mg/kg intramuscularly) and cephalothin (1000 mg/body intravenously) in bedridden elderly patients were studied in comparison with those in healthy volunteers. The eliminations of amikacin and cephalothin from the plasma followed the course of a one‐compartment open model. For amikacin, five healthy volunteers, elimination rate constant Kel was 0.396 hr−1 biologic half‐life t½ was 1.80 hour, volume of distribution Vd was 0.201 l./kg; in five bedridden elderly patients, Kel was 0.208 hr−1, t½ was 3.55 hours, Vd was 0.376 l./kg. Cumulative renal excretion of amikacin in 8 hours was 44 per cent of the total dose in bedridden elderly patients and 69 per cent in healthy volunteers. For cephalothin, in seven healthy volunteers, Kel was 0.0353 min−1, t½ was 19.7 min, Vd was 0.176 l./kg; in four bedridden elderly patients, Kel was 0.0127 min−1, t½ was 56.4 min, Vd was 0.283 l./kg. Cumulative renal excretion of cephalothin reached a plateau by 4 hours of 40.8 per cent of the total dose in bedridden elderly patients and of 56.7 per cent in healthy volunteers. These results suggest that in bedridden elderly patients decreased renal excretion of amikacin and cephalothin is related to decreased renal function and an increased Vd.
Effect of Micronization on the Bioavailability and Pharmacologic Activity of Spironolactone
Authors: McINNES GORDON T. , ASBURY MICHAEL J. , RAMSAY LAWRENCE E. , SHELTON JOHN R. , HARRISON IAN R.
Published: March 2013

Abstract: The bioavailability and pharmacologic activity of tablets containing micronized spironolactone chemical (median particle size 2.21 μm) were compared to those of tablets made from standard spironolactone chemical (median particle size 78.8 μm) in healthy men. Apart from particle size, all features of these tablets were identical. After 200‐mg single doses, the bioavailability of micronized tablets was significantly higher than that of standard tablets. Furthermore, as assessed by 24‐hour urine log10 10 Na/K ratio, the pharmacologic activity of micronized spironolactone was significantly greater than that of the standard formulation. The significant influence on renal antimineralocorticoid activity of raised plasma and urinary levels of canrenone, quantitatively the major active metabolite of spironolactone in man, emphasizes the clinical importance of the bioavailability of spironolactone preparations. Since this study, the process used in the manufacture of spironolactone (Aldactone) tablets has been under review.
Feprazone: Absence of Hemolytic Effects in Glucose‐6‐Phosphate Dehydrogenase‐Deficient Subjects
Authors: MELONI TULLIO , FORTELEONI GAVINO , SERRA MARIUCCIA , DANIOTTI SERGIO , NEGRI LUIGI , GIUNTINI PATRIZIA , CANEPA LETIZIA , GAETANI GIAN FRANCO
Published: March 2013

Abstract: Some drugs, including nonsteroidal antiinflammatory compounds, can be hemolytic in glucose‐6‐phosphate dehydrogenase‐deficient patients. We have studied the potential hemolytic activity of feprazone, a nonsteroidal antiinflammatory compound in vitro and in vivo. Agents that may be hemolytic for glucose‐6‐phosphate dehydrogenase‐deficient erythrocytes will stimulate the hexose monophosphate shunt in normal erythrocytes. Eleven normal subjects were treated with feprazone and their erythrocytes were incubated in their own sera (containing active feprazone metabolites) and [1‐14C]‐glucose. Because no statistically significant increase in 14CO2 evolution was observed, 15 pediatric male patients with glucose‐6‐phosphate dehydrogenase deficiency who required antiinflammatory treatment were treated with feprazone. No hemolytic crises and no statistically significant changes of hematologic tests were observed.
Book Reviews
Authors: PROCITA LEONARD
Published: March 2013

Book reviewed in this article:

Cutting's Handbook of Pharmacology, 6th Edition. C. Z. Csaky.

Introductory Medicinal Chemistry. J.B. Taylor and P.D. Kennewell.

Microsomes, Drug Oxidations, and Chemical Carcinogenesis. M. J. Coon, A. H. Conney, R. W. Estabrook, H. V. Gelboin, J. R. Cillette, and P. J. O'Brien, editors.

GLC and HPLC Determination of Therapeutic Agents, Part 2. Chromatographic Science Series, Vol. 9. K. Tsuji, editor.

GLC and HPLC Determination of Therapeutic Agents, Part 3. Chromatographic Science Series, Vol. 9. K. Tsuji, editor.

Neuropsychiatric Side Effects of Drugs in the Elderly. A. J. Levenson, editor.