bluuebunny/crossref_metadata_2025 huggingface dataset:
Excretion of Quazepam Into Human Breast Milk
Authors: HILBERT JAMES M. , GURAL R. P. , SYMCHOWICZ S. , ZAMPAGLIONE N.
Published: March 2013

Abstract: Previous metabolic studies have established that two major metabolites, 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam, are present in plasma after dosing with quazepam, a new benzodiazepine hypnotic. The excretion of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam into human breast milk was studied in four lactating nonpregnant volunteers. Each volunteer received one 15‐mg quazepam tablet following an overnight fast. Nursing of offspring was discontinued after drug administration. Milk and blood samples were collected prior to and at specified times (up to 48 hours) after dosing. Plasma and milk levels of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam were determined by specific GLC methods. The concentrations of the three compounds found in milk appeared to depend on their relative lipophilicities, which were determined by log P values. The mean milk/plasma AUC ratios of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam were 4.19, 2.02, and 0.091, respectively. Levels of quazepam and 2‐oxoquazepam declined at about the same rate in plasma and in milk. The total amount of the administered quazepam dose found in the milk as quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam through 48 hours was only 0.11 per cent.
The Efficacy of Cibenzoline in Preventing PES Induction of Ventricular Tachycardia in the Dog
Authors: KEREN GAD , TEPPER DAVID , BUTLER BRENDA , MIURA DENNIS , AOGAICHI KEIKO , SOMBERG JOHN
Published: March 2013

Abstract: The electrophysiologic effects of cibenzoline were studied using programmed electrical stimulation (PES) techniques and were compared to those of quinidine. Cibenzoline, like the conventional class 1 agent quinidine, was effective in preventing arrhythmia induction. Twelve dogs were given 0.02 mg/kg digoxin intravenously for seven days to achieve a steady‐state digoxin level. On the eighth day, cibenzoline was administered in incremental doses (0.5 to 10.5 mg/kg) and PES was performed at 30‐minute intervals. A mean dose of 2.6 ± 0.8 mg/kg cibenzoline prevented ventricular tachycardia induction. At this dose, cibenzoline had no significant effect on mean arterial blood pressure, but PR interval increased by 17 ± 9 per cent, QRS duration by 27 ± 14 per cent, and the ventricular refractory period (ERP) for the first extra stimulus increased by 35 ± 9 per cent. A gradual decrease in heart rate and an increase in PR interval and QRS duration was caused by incremental doses of cibenzoline. In six additional animals, quinidine was administered in incremental doses (1 to 30 mg/kg) and PES performed at 30‐minute intervals. A mean of 15 ± 5 mg/kg prevented induction of ventricular tachycardia in five animals. No significant change in heart rate, PR, QRS, and ERP was found at the effective dose.
Protection Against Sodium Valproate Injury in Isolated Hepatocytes by α‐Tocopherol and N,N'‐Diphenyl‐p‐phenylenediamine
Authors: BUCHI KENNETH N. , GRAY PHILLIP D. , ROLLINS DOUGLAS E. , TOLMAN KEITH G.
Published: March 2013

Abstract: The possibility that lipid peroxidation is involved in valproic acid (VPA) hepatotoxicity was explored by testing the ability of the free‐radical scavengers α‐tocopherol (vitamin E) and N,N'‐diphenyl‐p‐phenylenediamine (DPPD) to protect against VPA toxicity. Rat hepatocyte cultures were treated with toxic doses of VPA, in conjunction with varying doses of vitamin E and DPPD. Lactate dehydrogenase (LDH) release into the culture media was used to calculate an LDH index as a measure of toxicity. Vitamin E afforded increasing protection against VPA toxicity at concentrations of 1.0 to 4.0 μM but then leveled off and did not give complete protection at concentrations up to 8.0 μM. No protection was seen at less than 1.0 μM. DPPD showed increasing protection from 0.05 to 0.50 μM, with complete protection at the highest concentration. These data indicate that VPA toxicity can be prevented by simultaneous administration of free‐radical scavengers and support the concept that VPA hepatotoxicity is due to lipid peroxidation.
Double‐Blind Multiple‐Dose Crossover Study of the Antiemetic Effect of Intramuscular Levonantradol Compared to Prochlorperazine
Authors: SHEIDLER VIVIAN R. , ETTINGER DAVID S. , DIASIO ROBERT B. , ENTERLINE JOHN P. , BROWN MICHAEL D.
Published: March 2013

Abstract: Twenty cancer patients who received chemotherapy were entered into a double‐blind crossover design antiemetic study comparing 1 mg levonantradol, an investigational synthetic cannabinoid, to 10 mg prochlorperazine. Sixteen patients completed the crossover. For each antiemetic course, four doses of each study medication were given intramuscularly 2 hours before chemotherapy and then 2,6, and 10 hours after chemotherapy administration. There were no statistical differences in patients' responses to levonantradol and prochlorperazine. The frequency of side effects was greater with levonantradol than with prochlorperazine. The most common side effect of levonantradol were somnolence, dry mouth, dizziness, tachycardia, postural hypotension, and blurred vision, while those for prochlorperazine were somnolence, dry mouth, and tachycardia.
Methemoglobin Levels Produced by Organic Nitrates in Patients with Coronary Artery Disease
Authors: ARSURA EDWARD , LICHSTEIN EDGAR , GUADAGNINO VICTOR , NICCHI VINCENT , SANDERS MICHAEL , HOLLANDER GERALD , GREENGART ALVIN
Published: March 2013

Abstract: To determine if ordinary doses of nitrates produce a significant increase in methemoglobin, methemoglobin levels were measured in 59 randomly selected patients with coronary artery disease and unstable angina pectoris who were receiving organic nitrate therapy. Patients were taking isosorbide dinitrate, 2% nitroglycerin ointment, or a combination of the two. Patients were subdivided according to whether they were using one (group A) or more than one (group B) organic nitrate preparations. These results were compared with 17 control patients. Mean methemoglobin levels in group B were 1.78 ± 1.29%, and this differed significantly (P < 0.05) from both group A mean methemoglobin, 1.13 ± 0.92%, and controls, 0.99 ± 0.55%. The proportion of patients with elevated methemoglobin concentration increased from the control to group A to group B. It is concluded that commonly used dosages of nitrates are capable of causing elevations of methemoglobin which are probably not of routine clinical significance. However, these elevations may be of import in certain patient populations such as those with coronary insufficiency or anemia.
Pharmacokinetics and Hemodynamic Effects of Tiapamil: Exercise Performance, Thallium Stress Scintigraphy, and Radionuclide Ventriculography
Authors: ECKERT MARCEL , POZENEL HANS , PILLAT BURKHARD
Published: March 2013

Abstract: The pharmacokinetic behavior and hemodynamic effects of tiapamil, a calcium antagonist, were studied in 16 cardiac patients during an eight‐day treatment course, giving oral doses of 600 mg daily. The hemodynamic effects were investigated using exercise performance tests, thallium stress scintigraphy, and radionuclide ventriculography. The areas under the plasma concentration‐time curve after the final dose were greater than after the first dose for both tiapamil (+53 per cent) and its metabolite (+24 per cent). One possible explanation is that tiapamil undergoes saturable intestinal wall metabolism. Alternatively, like verapamil, it may undergo a saturable hepatic elimination process. The hemodynamic test series showed that, despite increasing the exercise tolerance, tiapamil significantly reduced the rate‐pressure product, an index of myocardial oxygen requirement. Regional myocardial perfusion clearly improved. Ventriculography showed a significant increase in ejection fraction (+18 per cent), cardiac index (+12 per cent), and stroke volume index (+19 per cent). At the same time, the measured mean arterial pressure decreased significantly by about 10 per cent and the calculated peripheral vascular resistance, by about 19 per cent.
Pharmacokinetic Interaction of Aztreonam with Other Antibiotics
Authors: CREASEY WILLIAM A. , ADAMOVICS JOHN , DHRUV ROHINI , PLATT THOMAS B. , SUGERMAN ARTHUR
Published: March 2013

Abstract: The pharmacokinetic interaction of the monobactam antibiotic aztreonam with cephradine, clindamycin, gentamicin, metronidazole, and nafcillin was investigated in five separate studies in 48 healthy male volunteers. All drugs were administered by 30‐minute intravenous infusions in single‐dose, three‐way balanced crossover studies. Drug levels were measured in serum, protein‐free filtrate of serum, and urine. Small changes of no clinical significance were seen when aztreonam was given simultaneously with another antibiotic as compared with each drug alone. Maximum serum concentrations of aztreonam were reduced by 12.6 and 9.8 per cent when it was given with gentamicin and metronidazole, respectively. The percentage of serum aztreonam bound to protein fell by a maximum of 5.0 per cent when the monobactam was given in conjunction with nafcillin and rose by 5.1 per cent when accompanied by cephradine. Twenty‐four‐hour cumulative urinary excretion of aztreonam and clindamycin rose by 5.2 and 10.9 per cent, respectively, when they were administered simultaneously.
Comparative Bioavailability of Intravenous and Oral Chloramphenicol in Adults
Authors: KRAMER WILLIAM G. , RENSIMER EDWARD R. , ERICSSON CHARLES D. , PICKERING LARRY K.
Published: March 2013

Abstract: The comparative bioavailability of chloramphenicol from intravenous succinate, oral palmitate, and oral base preparations was studied in a crossover manner in 12 adult patients. Chloramphenicol was administered at a dose of 1 Gm every 6 hours, and blood samples were collected at steady state. For the succinate study, total urine output was also collected. The bioavailability of active chloramphenicol from the succinate preparation averaged 85.8 ± 42.3 and 78.8 ± 50.1 per cent of the free base and palmitate forms, respectively. This lower availability appeared to be due to variable excretion of unchanged succinate in the urine, averaging 27 ± 11 per cent of the dose. Regardless of dosage form or route of administration, plasma chloramphenicol concentrations remained in the therapeutic range (5 to 25 mg/liter) for the entire dosage interval, implying that no change needs to be made when changing dosage form or route of administration. The interpatient variability, however, supports the need for monitoring of plasma chloramphenicol concentrations, especially in newborn infants, persons with liver disease, or those receiving other medications that alter chloramphenicol metabolism.
Interaction of Cimetidine with Oxazepam, Lorazepam, and Flurazepam
Authors: GREENBLATT DAVID J. , ABERNETHY DARRELL R. , KOEPKE HANS H. , SHADER RICHARD I.
Published: March 2013

Abstract: The influence of Cimetidine coadministration, 300 mg every 6 hours, on the kinetics of single oral doses of oxazepam (30 mg), lorazepam (2 mg), and flurazepam (30 mg) was evaluated in healthy volunteers. Cimetidine had no significant effect on the peak plasma concentration or the time of peak concentration for either oxazepam, lorazepam, or desalkylflurazepam (formed from flurazepam). Cimetidine likewise did not alter the elimination half‐life of oxazepam (9.4 hours) or lorazepam (11.6 hours), and did not change total AUC for lorazepam. Oxazepam AUC was increased an average of 10 per cent by Cimetidine (P < 0.02). In contrast, Cimetidine prolonged desalkylflurazepam elimination half‐life (141 vs. 94 hours, P < 0.1) and increased AUC an average of 65 per cent (P < 0.05). Thus, Cimetidine has little or no influence on the absorption or disposition of oxazepam and lorazepam, two benzodiazepines biotransformed by glucuronide conjugation. However, Cimetidine slows the elimination of flurazepam's metabolite, desalkylflurazepam, which is biotransformed by oxidation.
Influence of Food on the Bioavailability of Trimoprostil: An Overview
Authors: WILLS ROBERT J.
Published: March 2013

Abstract: The influence of food on the bioavailability of trimoprostil, a new antiulcer prostaglandin E2 derivative, was investigated in healthy male volunteers in four separate studies. Doses of 0.75, 1.5, and 3.0 mg were administered orally in both the presence and absence of food followed by serial blood sampling through 24 hours. Plasma trimoprostil concentrations were determined by a gas chromatographnegative chemical ionization‐mass spectrometric method for pharmacokinetic evaluation. Food decreased the absorption rate of trimoprostil as indicated by a later tmax (P < 0.01) and corresponding lower Cmax at each dose. However, the food effect on tmax diminished as the dose increased. Although Cmax was reduced, food did not alter the extent of absorption, indicated by similar AUC (P > 0.05) between fed and fasted states. Both Cmax and AUC increased proportionately with an increase in dose. The harmonic mean half‐lives of elimination were similar (P > 0.05) across all doses and ranged from 27 to 55 minutes.
Comparison of Haloperidol and Chlorpromazine in the Treatment of Phencyclidine Psychosis
Authors: GIANNINI A. JAMES , EIGHAN MICHAEL S. , LOISELLE ROBERT H. , GIANNINI MATTHEW C.
Published: March 2013

Two neuroleptics, haloperidol and chlorpromazine, have been reported to be effective in the treatment of phencyclidine (PCP) psychosis. Both neuroleptics are thought to exert their antipsychotic PCP effects by blockade of central dopamine receptors. They have been studied extensively in animal populations and less extensively in human populations. There has, however, been no comparison of their relative effects in human populations. We describe such a study below.
Effect of Hydroxyethyl Starch and Dextran on Plasma Volume and Blood Hemostasis and Coagulation
Authors: KORTTILA K. , GRÖHN P. , GORDIN A. , SUNDBERG S. , SALO H. , NISSINEN E. , MATTILA M. A. K.
Published: March 2013

Abstract: Six healthy male subjects were given in a crossover fashion medium molecular weight (HES 125) and low molecular weight (HES 40) hydroxyethyl starch, dextran, and balanced salt solution by intravenous infusion. The plasma volumes were determined using labeled albumin and plasma protein measurements. Three properties of factor VIII protein complex and indices of blood coagulation and hemostasis were measured before and after the infusions. Both the salt solution and HES 40 increased plasma volume, but their effect wore off within 3 hours. Dextran and HES 125 increased plasma volume significantly (P < 0.001) more than the salt solution did, and the expansion was maintained for 24 hours. Plasma volume increases (dextran and HES 125) were associated with high nonglucose carbohydrate levels in plasma and low levels in urine. No or slight increases in plasma volumes (HES 40), on the other hand, were associated with low and high carbohydrate levels in plasma and urine, respectively. Serum α‐amylase activity increased significantly after both HES preparations as compared to salt solution. Dextran and HES 125 decreased all the three values of factor VIII, these decreases being maximal 3 to 6 hours after administration and highest (about 25 per cent) for F VIII R:Ag and F VIII R:cof. It is concluded that HES 125 and dextran are equally effective plasma expanders.
Single‐Dose Pharmacokinetics and Dose Proportionality of Oral Cibenzoline
Authors: KHOO K.‐C. , SZUNA A. J. , COLBURN W. A. , AOGAICHI K. , MORGANROTH J. , BRAZZELL R. K.
Published: March 2013

Abstract: The pharmacokinetics of cibenzoline were evaluated in four young healthy volunteers who received ascending oral doses of 65, 97.5, 130, 162.5, 195, 227.5, and 260 mg separated by one week. Cibenzoline plasma concentrations exhibited an apparent biexponential decline following oral absorption. Maximum plasma concentrations and area under the plasma concentration‐time curve increased in proportion to the dose. The mean elimination half‐life among subjects was independent of dose and ranged from 7.3 to 8.7 hours. Oral clearance ranged from 380 to 575 ml/min and was also independent of dose. A single pharmacokinetic equation was used to adequately describe the plasma concentration data over the entire range of doses for each subject, indicating dose‐proportional and linear pharmacokinetics.
Effect of the Surface Area of Activated Charcoal on Theophylline Clearance
Authors: PARK GLEN D. , SPECTOR REYNOLD , GOLDBERG MARK J. , JOHNSON GEORGE F. , FELDMAN ROSS , QUEE CONNIE K.
Published: March 2013

Abstract: The effect of the surface area of activated charcoal on theophylline clearance was studied. Eight fasting, healthy men received intravenous infusions of either aminophylline (6 mg/kg, N = 3) or theophylline (5 mg/kg, N = 5) over 1 hour followed by either 5 Gm standard activated charcoal every 2 hours, 20 Gm every 2 hours, or 5 Gm PX‐21 activated charcoal (with 3.6 times the surface area) every 2 hours. Theophylline t1/2 and AUC with each regimen were respectively 6.3 ± 0.5 (S.E.) hours and 88.9 ± 8.4 mg/liter · hr with 5 Gm standard activated charcoal, 5.3 ± 0.3 hours and 75.4 ± 4.9 mg/liter · hr with 5 Gm PX‐21, and 4.9 ± 0.2 hours and 67.7 ± 3.6 mg/liter · hr with 20 Gm standard activated charcoal. There was a relationship between the activated charcoal surface area and the reduction in theophylline t1/2 and AUC. We conclude that the clearance of theophylline is related to the surface area of activated charcoal administered and that PX‐21 may be a more potent activated charcoal product for enhancing theophylline removal.
Antiarrhythmic Therapy: Clinical Pharmacology Update
Authors: WOOSLEY RAYMOND L. , CERSKUS IRENE , RODEN DAN M.
Published: March 2013

Abstract: Currently available antiarrhythmic agents are limited by side effects and the potential for increasing arrhythmias. In addition, drug interactions, altered disposition of drug as a result of changes in protein binding or concomitant disease processes, active metabolites, and poorly defined therapeutic ranges with great interpatient variability are some of the factors which complicate therapy. An awareness of the possible contribution of these factors in the use of antiarrhythmics is invaluable in both the choice of agent and the establishment of an optimum benefit‐to‐risk ratio for the patient.
The Effect of Antiarrhythmic Agents on Myocardial Contractility and Arrhythmia Frequency
Authors: KEEFE DEBORAH L. , WILLIAMS SHARON
Published: March 2013

Abstract: Most patients requiring antiarrhythmic therapy for ventricular arrhythmias have underlying organic heart disease which causes left ventricular dysfunction. Treatment of these patients' arrhythmias requires knowledge of the hemodynamic as well as antiarrhythmic effects of the available agents. These effects may differ during acute and chronic oral therapy. Several of the newer agents and quinidine are very effective in suppressing ventricular ectopic activity, allowing demonstration of drug effect during ambulatory monitoring. The clinical significance of this for prevention of sudden death has yet to be shown. However, prevention of ventricular tachycardia or fibrillation in the electrophysiology laboratory and suppression of ambient ectopy may generally be separate phenomena, as has been demonstrated for amiodarone.
Can Antiarrhythmic Drugs Cause Arrhythmia?
Authors: PODRID PHILIP J.
Published: March 2013

Abstract: The recognition that certain types of ventricular premature beats, specifically repetitive forms, may be forerunners of more serious tachyarrhythmias has led to the practice of prophylactic therapy with antiarrhythmic drugs to suppress these forms in patients who have underlying cardiac disease. Several antiarrhythmic drugs are available for oral therapy, and many others are undergoing investigation. The usefulness of these agents is often limited by frequent side effects, which include idiosyncratic and unpredictable reactions that are not related to drug level. One such effect is the aggravation of the arrhythmia being treated. Noninvasive drug testing in 245 patients for a total of 1024 single drug tests showed 113 studies (11 per cent) to have been aggravated by the antiarrhythmic drug. At least one drug was proarrhythmic in 78 patients (32 per cent). Aggravation of arrhythmia is a potentially serious drug complication that occurs with all antiarrhythmic agents.
New Approaches to Drug Selection and Serial Drug Testing
Authors: SOMBERG JOHN CHARIN
Published: March 2013

Abstract: Sudden cardiac death is a major problem in the United States. Our goal is to identify high‐risk patients and to be able to target antiarrhythmic therapy to this population. Ambulatory electrocardiography, exercise tolerance testing, and programmed electrical stimulation studies may aid in the identification of patients at risk for sudden cardiac death and the selection of antiarrhythmic therapy. Each technique has its advantages, disadvantages, and limitations. These considerations must be taken into account if the procedure is to be optimally employed. We are in a period of rapid development of new antiarrhythmic agents. It is essential to fully understand the techniques employed to evaluate antiarrhythmic therapy.
The Assessment of Antidysrhythmic Drugs
Authors: LEVITT BARRIE
Published: March 2013

Abstract: Assessments of efficacy of antidysrhythmic drugs at different clinical arrhythmia centers frequently produce discordant data, probably because of differences in patient population, technology to assess efficacy, study design, and concomitant drugs such as digitalis, diuretics, beta‐adrenergic blocking agents, and calcium channel blockers. Furthermore, different doses employed may greatly influence the toxicity and efficacy of both conventional and experimental antiarrhythmic drugs. These variables make the design of studies in the field of antiarrhythmic therapy both difficult and of critical importance. The serious and complex nature of the disease entity against which these drugs are directed constitutes a considerable public health problem which requires that the problems be addressed in a definite and timely way.
New Directions in the Development of Antiarrhythmic Drugs
Authors: MIURA DENNIS S. , ROSEN MICHAEL R.
Published: March 2013

Abstract: To identify new antiarrhythmic drugs and their mechanisms of actions, it has been necessary to use appropriate models to describe arrhythmias. Recently introduced concepts in cellular electrophysiology of arrhythmias provide the newest models in which drug development have been attempted. Arrhythmias have been attributed to abnormalities of conduction, abnormalities of impulse formation, or a combination of both. Recent descriptions of abnormally triggered rhythms have been ascribed to a phenomenon called afterdepolarizations. An ionic basis for the formation of these arrhythmias has been recently described. Further, specificity of the drug effects at a cellular level to modify these arrhythmias are being observed by a variety of new techniques. Microelectrode methods have provided direct access to the intracellular milieu to determine the biophysical changes brought about by antiarrhythmic agents. These observations have led to a greater understanding of the underlying abnormalities at the cellular level. Testing of antiarrhythmic drugs in the intact heart has led to the development of clinical use of invasive electrophysiologic techniques. Intracardiac catheters are being used to describe abnormalities of impulse initiation as well as conduction. Efficacy of antiarrhythmic drugs in the intact heart may be determined with greater accuracy using these techniques. Abnormal rhythms can be initiated and terminated using intracardiac catheter methods with antiarrhythmic agents as therapeutic adjuncts.
Evaluation of the Hypothalamic—Pituitary Effects of Digoxin
Authors: BELLMANN OTTO , OCHS HERMANN R. , KNÜCHEL MARTIN , GREENBLATT DAVID J.
Published: March 2013

Abstract: Normally menstruating young female volunteers with no evidence of cardiovascular disease participated in a controlled study of digoxin effects on serum thyroid stimulating hormone (TSH) and prolactin levels in the basal state and after stimulation with thyrotropin releasing hormone (TRH). In the first study, subjects received oral digoxin, 0.5 mg daily, or matching placebo, on days 10 through 22 of a menstrual cycle, then crossed over to placebo or digoxin for days 10 through 22 of the next cycle. Basal serum TSH and prolactin on days 7 through 9 and 20 through 22 did not differ significantly between placebo and digoxin cycles. Levels of both hormones rose after a 200‐μg intravenous dose of TRH given on days 8 and 21, but the response to TRH did not differ between placebo and digoxin cycles. In the second study, subjects received 0.5 mg intravenous digoxin daily for days 7 through 21 of a menstrual cycle. Basal serum TRH and prolactin did not change significantly in response to digoxin. The findings suggest that hormonal changes associated with digoxin therapy, if they exist, are more likely to reflect direct effects on the target organ rather than indirect effects on the hypothalamic‐pituitary axis.
Dose Ranging Evaluation of the Antiemetic Efficacy and Toxicity of Intramuscular Levonantradol in Cancer Subjects with Chemotherapy‐Induced Emesis
Authors: STAMBAUGH JOHN E. , McADAMS JANET , VREELAND FRANZANNE
Published: March 2013

Abstract: A phase II double‐blind placebo‐controlled, randomized dose‐ranging trial was undertaken to determine the antiemetic efficacy and toxicity of the synthetic cannabinoid levonantradol at doses of 0.5, 1.0, 1.5, and 2.0 mg. Intramuscular levonantradol was prophylactically administered in random dosing to 20 subjects with a documented history of refractory emesis due to chemotherapy in advanced cancer. The selected dose was administered prior to the chemotherapy and was serially repeated over 12 hours, and efficacy and toxicity data were evaluated for 24 hours. Significant (P < 0.01) antiemetic activity over placebo was observed with all doses of levonantradol administered, and a dose‐effect response was not observed. Doses up to 2.0 mg were well tolerated, and observed toxicity increased with increased doses and with repeated dosing. Psychomimetic effects were mild and tolerable, and the limiting side effects were somnolence and hypotension.
Double‐Blind Parallel Comparison of Single Oral Doses of Ketoprofen, Codeine, and Placebo in Patients with Moderate to Severe Dental Pain
Authors: MEHLISCH D. , FRAKES L. , CAVALIERE M. B. , GELMAN M.
Published: March 2013

Abstract: Ketoprofen, 25, 50, and 100 mg, was compared with 90 mg codeine and placebo for relief of pain due to removal of impacted third molar teeth. Treatment was self‐administered as a single oral dose under double‐blind conditions in five parallel groups established by a random code in healthy young adults. Based on 129 patient evaluations of pain experience and pain relief, ketoprofen was shown to have a more rapid onset and longer duration of action than codeine. In the derived variables of SPID (Sum of Pain Intensity Differences) and TOPAR (Total Pain Relief), all three doses of ketoprofen, with no dose‐related differences among them, were found to provide statistically superior analgesia to codeine and placebo. All five treatments were associated with some adverse reactions.
Do Beta Blockers Differ in Their Effects on Hepatic Microsomal Enzymes and Liver Blood Flow?
Authors: PARKER GLYNIS , ENE M. D. , DANESHMEND T. K. , ROBERTS C. J. C.
Published: March 2013

Abstract: The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise‐induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P < 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P < 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.
The Influence of H2‐Receptor Antagonists on Steady‐State Concentrations of Propranolol and 4‐Hydroxypropranolol
Authors: DONN KARL H. , POWELL J. ROBERT , ROGERS JOHN F. , ESHELMAN FRED N.
Published: March 2013

Abstract: Twelve healthy male volunteers were treated with 1200 mg/day cimetidine, 300 mg/day ranitidine, or no H2‐receptor antagonist (control) tor seven days in a sequence determined by Latin‐square design. Each treatment period was separated by a seven‐day washout. On the third day of each treatment period, 80 mg propranolol every 12 hours for nine doses was initiated. Whole blood concentrations of propranolol and 4‐hydroxypropranolol were measured at 12 time points during the 12‐hour period following administration of the last propranolol dose. Heart rate was measured before each blood sample was withdrawn. Cimetidine treatment was associated with a 47 per cent increase in the area under the propranolol concentration‐time curve and a 17 per cent increase in elimination half‐life of propranolol. Ranitidine had no significant effect on the concentration‐time profile of propranolol. There were no significant differences in the 4‐hydroxypropranolol pharmacokinetic parameters during any of the treatments. There was, however, a significant decrease in the average 4‐hydroxypropranolol‐to‐propranolol steady‐state concentration ratio during the cimetidine treatment. There was no significant difference in heart rate between any of the treatments. The elevation of propranolol concentrations during cimetidine treatment is likely due to metabolic inhibition by cimetidine.
Time‐Dependent Absorption of Theophylline in Man
Authors: WATANABE HIROKAZU , NAKANO SHIGEYUKI , NAGAI KEISUKE , OGAWA NOBUYA
Published: March 2013

Abstract: Sixteen healthy volunteers were given either oral or intravenous doses of aminophylline (125 mg) at 9:00 a.m. and 9:00 p.m. under controlled food conditions. Measured at regular time intervals by homogeneous enzyme immunoassay, the plasma theophylline concentrations 1.5 and 2 hours after oral aminophylline were significantly higher in the morning than in the evening (P < 0.05). Also, the mean peak plasma concentration was significantly higher (P < 0.05) and the time to peak concentration was faster (P = 0.02) after the morning dose. Neither the morning mean elimination half‐life nor the morning mean area under the plasma concentration‐time curve differed significantly from those after the evening dose. After intravenous aminophylline, no significant differences were found in the plasma theophylline concentrations and in the elimination half‐life between morning and evening. Therefore, the small but statistically significant time‐dependent differences in theophylline kinetics must be due to changes in absorption from the gastrointestinal tract and not to changes in distribution or elimination of the drug.
Oxaprozin Dose Proportionality
Authors: CHIANG SOONG T. , LASSETER KENNETH C. , FLUCK EUGENE R. , JANSSEN FRANK W. , LEELAVATHI DODDA , HUBSHER JEROME A.
Published: March 2013

Abstract: Twelve normal subjects each received single 300‐, 600‐, and 1200‐mg oral doses of oxaprozin according to a three‐period crossover design. Total drug plasma concentrations did not increase in proportion to the dose administered. Total clearance (Clo) and volume of distribution (Vd) increased with dose, though elimination t1 2 remained unchanged. The fraction of unbound oxaprozin in plasma (fup) varied linearly with total plasma concentration: it increased from 0.068 per cent at 10 μg/ml to 0.180 per cent at 170 μg/ml. A parameter f̂up was therefore introduced to express the average degree of unbound drug plasma for a given dose, and to allow the calculation of unbound volume of distribution (Vdu) and intrinsic clearance (Cli) as if binding were constant. Even though f̂up increased with dose, the overall binding in the body (f̂ub ∼0.52 per cent) was relatively stable. Neither Vdu nor Cli changed with dose; hence, unbound oxaprozin kinetics can be considered to be linear. Protein binding had no effect on unbound oxaprozin plasma levels within the given dose range, and there was a one‐to‐one proportionality between the dose administered and the unbound drug concentration in plasma.
Influence of Bariatric Surgery on Erythromycin Absorption
Authors: PRINCE RANDALL A. , PINCHEIRA JEANNETTE C. , MASON EDWARD E. , PRINTEN KENNETH J.
Published: March 2013

Abstract: Seven adult, morbidly obese patients scheduled for bariatric surgery were studied in an identical manner preoperatively and postoperatively. Six patients underwent gastroplasties, and one patient underwent a gastric bypass procedure. A single 250‐mg dose of erythromycin as a Filmtab was administered orally after an overnight fast. Multiple venous blood samples were collected over a 12‐hour period. After surgery, each patient had a decrease in peak concentration and an increase in the time to reach peak concentration compared to presurgery values. Mean peak concentration was reduced from 1.04 μg/ml preoperatively to 0.55 μg/ml postoperatively, and the mean time to peak increased from 3:9 hours to 6.7 hours. Mean weight‐corrected AUC was reduced 41 per cent, with two patients having no detectable serum levels postoperatively. The results suggest that the erythromycin product evaluated is of questionable value for use in bariatric surgery patients.
The Clearance of Cyclosporine by Hemodialysis
Authors: VENKATARAMANAN RAMAN , PTACHCINSKI RICHARD J. , BURCKART GILBERT J. , YANG SHIN L. , STARZL THOMAS E. , VAN THEIL DAVID H.
Published: March 2013

Abstract: The pharmacokinetics of cyclosporine were studied in five liver transplant patients when they were on and off hemodialysis. There was no significant difference in the blood clearance of cyclosporine between these two periods. Less than 1 per cent of the dose of cyclosporine was recovered in the dialysate. The mean dialysis clearance was less than 1 ml/min. This represents less than 1 per cent of the total blood clearance of cyclosporine. Dosage alterations of cyclosporine during or after hemodialysis do not appear to be necessary.
Absorption of Labeled Triethanolamine Salicylate in Human and Canine Knee Joints. II
Authors: RABINOWITZ JOSEPH L. , BAKER DANIEL
Published: March 2013

Abstract: The transdermal absorption by tissues of salicylate from triethanolamine salicylate (TEA/S) ointment applied to canine and human skin was shown to be consistent, significant, and reproducible. Salicylate levels were measured using thin‐layer chromatography, nuclear magnetic resonance, and radiochemistry. Absorption was directly proportional to the concentrations of the active ingredient in the ointment, up to the 10 per cent preparation. Tissue salicylate levels were not influenced by the sex of the canine subjects. In humans, the activity of the patients affected both tissue levels and urinary excretion. Autoradiographic and doubly labeled studies suggest that during transdermal absorption of TEA/S, the salt may disassociate; this could permit the salicylate to have a longer transit time in the area of application.
A Comparative 25‐Night Sleep Laboratory Study on the Effects of Quazepam and Triazolam on Chronic Insomniacs
Authors: MAMELAK M. , CSIMA A. , PRICE V.
Published: March 2013

Abstract: The short‐ and intermediate‐term actions, as well as the carryover and withdrawal effects, of quazepam, a new benzodiazepine hypnotic with a half‐life of 60 to 100 hours, were compared with those of triazolam, a triazolodiazepine hypnotic with a half‐life of 2 to 3 hours. Both the subjective effects of these drugs as well as their objective actions on the sleep EEG were sought. The study was conducted on two groups of six subjects with chronic insomnia who ranged in age from 32 to 56 years. Each subject was studied for 25 consecutive nights. Placebo was administered at bedtime on the first four nights, followed by 30 mg quazepam or 0.5 mg triazolam on the next 14 nights and by placebo again on the ensuing seven withdrawal nights. Both drugs increased the total sleep time during their administration and improved the subjective quality of sleep. Major differences, however, were observed on withdrawal. A significant and marked decrease in the total sleep time occurred with triazolam on the first withdrawal night. With quazepam, rebound insomnia was not observed at any time during the seven‐day withdrawal period.
The Effects of a New Thromboxane Synthetase Inhibitor, CGS‐13080, in Man
Authors: MACNAB MALCOLM W. , FOLTZ E. L. , GRAVES BETTY S. , RINEHART ROY K. , TRIPP SPENCER L. , FELICIANO NANCY R. , SEN SUPRADIP
Published: March 2013

Abstract: CGS‐13080 is a new potent selective inhibitor of thromboxane synthetase. This study reports the results of a safety and efficacy study of single oral doses in normal healthy volunteers. The compound was well tolerated by all subjects without evidence of any adverse reactions. Serum thromboxane B2 levels (the stable metabolic product of thromboxane A2) were significantly reduced after administration of the compound, with the maximal effect of a 99 per cent reduction occurring at 0.5 and 1 hour after administration. There was a concomitant increase in PGE2 and 6‐keto‐PGF1α (the stable metabolic product of PGI2), suggesting a shunting of cyclic endoperoxide metabolism. The apparent half‐life of the compound is about 1 hour, but return to 50 percent of the original thromboxane B2 levels was achieved between 4 and 6 hours. Platelet aggregation to collagen and bleeding times failed to demonstrate significant changes after drug administration. Bleeding times showed a slight increase 2 hours after administration of the compound.
A New Scintigraphic Technique for Cholecystokinin Gallbladder Dose‐Response Study: Validation in Rabbits
Authors: TURNER FREDRICK E. , KRISHNAMURTHY G. T. , BOBBA V. R. , LANGRELL KELLI
Published: March 2013

Abstract: An investigation was undertaken to test whether the dose‐response curve of a cholecystokinin‐like agent (ceruletide) could be established by administering it in graded doses sequentially on the same day. The results were compared to individual doses given on separate days. The gallbladder ejection fraction (EF) was calculated for each dose using the Tc‐99m‐IDA counts to represent the gallbladder bile volume. The mean ejection fraction following 1,2.5,5, and 10 ng/kg given sequentially on the same day was 10 ± 8,22 ± 12,53 ± 13, and 85 ± 3 per cent, respectively. The ejection fraction for 2.5,5, and 10 ng/kg given on separate days was 29.7, 57.14, and 93.3 per cent, respectively, and was similar to the values obtained when the identical dose was given sequentially on the same day (P < 0.05). It is concluded that the sequential method is as accurate as the single‐dose regimen and carries the advantages of simplicity in the establishment of dose‐response curve for any future CCK‐like agent.
A Controlled Endoscopic Study Comparing the Toxic Effects of Sulindac, Naproxen, Aspirin, and Placebo on the Gastric Mucosa of Healthy Volunteers
Authors: LANZA FRANK L. , NELSON ROBERT S. , RACK MARY FRANCES
Published: March 2013

Abstract: Sixty volunteers were endoscopically evaluated to compare gastric mucosal injury following oral administration of sulindac, naproxen, aspirin, or placebo for two consecutive seven‐day periods. A single‐blind technique was utilized wherein the endoscopist was unaware which drug each volunteer had received. The following dosages were employed for the two study periods: sulindac, 150 and 200 mg, b.i.d., naproxen, 250 and 375 mg, b.i.d., and aspirin, 650 and 975 mg, q.i.d. The only subject who developed a frank ulcer with mucosal bleeding was in the sulindac group, however volunteers taking sulindac demonstrated statistically less significant mucosal injury on endoscopic examination than those receiving naproxen or aspirin.
An Appraisal of Codeine as an Analgesic: Single‐Dose Analysis
Authors: HONIG STEPHEN , MURRAY KATHLEEN A.
Published: March 2013

Abstract: Codeine, a relatively weak oral narcotic agent, is the most frequently prescribed oral opiate drug. It is also frequently utilized as a control drug in comparative analgesic efficacy studies. These studies are often single dose analysis of pain relief following surgery or childbirth. We conducted a single dose, post‐operative analysis of 116 patients who were randomly assigned to receive codeine 60 mg, acetaminophen 600 mg, the combination of codeine and acetaminophen at these doses, or a placebo. Only the combination agent was uniformly superior to placebo. Codeine 60 mg was not consistently superior to placebo in this post‐operative single dose analysis. A review of the literature confirms the difficulty in unequivocally establishing the value of codeine as an analgesic, in acceptable oral doses, in the single dose setting. Previous reports, however, suggest that the multiple doses of codeine may afford adequate analgesia. Interpretation of single dose studies with extrapolation to repeated dosing in the practice setting is difficult.
The Combined Alpha‐ and Beta‐Adrenergic Blocker Labetalol and Propranolol in the Treatment of High Blood Pressure: Similarities and Differences
Authors: WEBER MICHAEL A. , DRAYER JAN I. M. , KAUFMAN CAROL A.
Published: March 2013

Abstract: Labetalol, an agent with both alpha‐ and beta‐adrenoreceptor blocking properties, and the beta blocker propranolol were each given for one month to groups of 15 patients with essential hypertension. With either treatment, 11 of the 15 patients experienced decreased supine diastolic blood pressure to less than 90 mm Hg without evidence of fluid retention. Propranolol significantly increased plasma concentrations of uric acid and potassium, whereas labetalol significantly increased plasma concentrations of high‐density lipoproteins (HDL) and decreased the total cholesterol:HDL ratio; neither drug significantly changed renal function. During three additional months of labetalol treatment, there was a slight tendency to orthostatic decreases in systolic blood pressure as compared with the values after the initial month. Labetalol had variable effects on plasma renin activity and aldosterone excretion, but within individual patients the values were constant; there were close correlations between changes measured after one month and after four months for both renin (r = 0.86) and aldosterone (r = 0.94). The manifestations of labetalol's alpha‐blocking component appeared to be a small postural effect on systolic blood pressure and an increase in plasma HDL.
Alprazolam Pharmacokinetics in Alcoholic Liver Disease
Authors: JUHL RANDY P. , VAN THIEL DAVID H. , DITTERT LEWIS W. , SMITH RANDALL B.
Published: March 2013

Abstract: Alprazolam, a triazolobenzodiazepine, was administered to 17 patients with alcoholic liver disease. The pharmacokinetic parameters derived from plasma alprazolam concentrations were compared with data obtained from 17 normal subjects who were matched for age and sex. The rate of absorption of alprazolam was slower in patients with alcoholic liver disease. The time of maximum serum concentration was 3.3 hours, compared with 1.5 hour in normals (P < 0.02). The maximum concentrations, however, did not differ (18.4 vs. 17.2 μg/ml). The elimination half‐life of drug was longer in the patients (19.7 hours) than in the normal subjects (11.4 hours), while the clearance of the drug was slower in the patients with alcoholic liver disease (0.6 vs. 1.2 ml/min/kg). The volumes of distribution (area) did not differ between the two groups (1.1 vs. 1.2 liter/kg). The changes in elimination half‐life and clearance indicate that the metabolism of the drug is slowed in patients with alcoholic liver disease.
The Excretion of Caffeine in the Semen of Men: Pharmacokinetics and Comparison of the Concentrations in Blood and Semen
Authors: BEACH CYNTHIA A. , BIANCHINE JOSEPH R. , GERBER NICHOLAS
Published: March 2013

Abstract: The concentration of caffeine in the blood and semen of men was measured after an oral dose of 200 or 400 mg caffeine. Caffeine was rapidly absorbed (mean tmax = 0.76 ± 0.12 hour), with an average maximum concentration in the blood of 7.4 μg/ml for the 400‐mg dose and 3.4 μg/ml for the 200‐mg dose. The mean clearance of caffeine was 161 and 156 ml/min, while the mean volume of distribution was 50 and 47 liters for the 400‐ and 200‐mg doses, respectively. Distribution of caffeine into the semen was rapid, with a concentration of caffeine in the semen almost identical to that observed concurrently in the blood (blood/semen concentration ratio = 0.97). The mean half‐life of caffeine in the blood and semen was 3.7 and 3.6 hours, respectively, indicating that the decline of caffeine in the blood is very similar to that in semen. Thus, caffeine partitions rapidly into and out of the prostatic and seminal vesicular secretions, which contribute to the formation of the ejaculate.
False‐Positive Urine Protein Reaction with Cibenzoline, a New Antiarrhythmic Agent
Authors: KOVACS JOHN L. , TUZEL ILHAN , AOGAICHI KEIKO , HEGER JAMES J. , RICHMOND LINDA , SOMBERG JOHN C. , BUTLER BRENDA
Published: March 2013

Abstract: Following treatment with cibenzoline, a new antiarrhythmic agent, 23 of 53 patients showed positive proteinuria reactions. In all cases, these results were obtained with bromphenol reagent strips. Subsequent exposure of serial dilutions of cibenzoline to these reagent strips showed positive protein reactions at concentrations as low as 1 mg/ml. Treatment of these same solutions with acetic acid‐sodium acetate heat coagulation technique produced negative findings. Specimens from 14 of the above patients were then retested employing both techniques, and in all cases the reagent strips produced positive results while the heat coagulation technique (or sulfosalicylic acid) produced negative results. Therefore, it appears that cibenzoline produces false‐positive proteinuria results when bromphenol reagent strips are employed for analysis.
Blood Lipid Effects of Antihypertensive Therapy: A Double‐Blind Comparison of the Effects of Methyldopa and Propranolol
Authors: LEON ARTHUR S. , AGRE JAMES , McNALLY CARL , BELL CATHY , NEIBLING MARGARET , GRIMM RICHARD , HUNNINGHAKE DONALD B.
Published: March 2013

Abstract: Thirty‐two middle‐aged men with essential hypertension completed a double‐blind randomly allocated comparison of the effects of methyldopa versus propranolol on blood lipid levels. After a four‐week period on a placebo for each drug, subjects were titrated for the next six weeks with either methyldopa from 500 to 2000 mg/day or propranolol from 80 to 320 mg/day plus a placebo for the other drug until supine diastolic blood pressure was below 90 mm Hg or the ceiling dose was reached. Subjects were then maintained on the achieved drug dose for an additional six weeks and finally switched back to a placebo for each drug for four more weeks. Blood lipid levels were measured twice during each study period and the values averaged and compared. Neither drug significantly affected levels of total plasma cholesterol. However, both drugs reduced high‐density lipoprotein (HDL) cholesterol levels about 10 per cent and increased the total cholesterol to HDL cholesterol ratio. In addition, propranolol significantly increased plasma triglyceride levels (28.3 per cent). The changes in lipid levels were not dose related. Whether or not these blood lipid changes persist and their possible clinical implications during prolonged therapy remain to be elucidated.