bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of a New Angiotensin Converting Enzyme Inhibitor, Enalapril, in Acute and Chronic Left Ventricular Failure in Dogs
Authors: LEDDY CHERYL L. , WILEN MARY , FRANCIOSA JOSEPH A.
Published: March 2013

Abstract: Enalapril (MK‐421) is a new angiotensin converting enzyme inhibitor which effectively lowers elevated blood pressure and might also be useful in heart failure. Enalapril was infused into six awake dogs 2 hours after left circumflex coronary artery embolization (acute failure group) and into six other awake dogs two to six months after coronary embolization (chronic failure group). In the acute failure group 2 hours after embolization, increased left ventricular end‐diastolic pressure and reduced cardiac output remained unchanged during enalapril infusion. In the chronic failure group, increased left ventricular end‐diastolic pressure also remained unchanged during enalapril infusion, but cardiac output, which had fallen to 131.8 ± 11.9 (S.D.) from 165.8 ± 17.9 ml/min/kg (P < 0.01) by two to six months in this group rose during enalapril infusion to 154.5 ± 27.7 ml/min/kg (P < 0.05). Heart rate and blood pressure were not changed during enalapril in either group, but stroke volume rose (26.0 ± 5.9 to 29.2 ± 6.9 ml, P < 0.01) and systemic vascular resistance fell (58.5 ± 10.3 to 39.3 ± 4.3 units, P < 0.01) during enalapril only in the chronic failure group. Plasma renin activity after embolization was slightly but not significantly higher in the acute failure group. Thus, enalapril appears to be an arterial vasodilator in dogs with chronic but not acute left ventricular failure.
Flurazepam and the Sleep of Herniorrhaphy Patients
Authors: KAVEY NEIL B. , ALTSHULER KENNETH Z.
Published: March 2013

Abstract: The effects of flurazepam on the nocturnal sleep patterns of 20 pre‐ and postoperative herniorrhaphy patients were studied polygraphically, in double‐blind fashion, in the clinical setting. Compared to patients who received no hypnotic, patients treated with flurazepam had, preoperatively, significantly more Stage 2 and less REM and, postoperatively, significantly greater total sleep time, fewer awakenings, and less total awake time. The flurazepam group also initially had more delta sleep, but then showed a steady decrease of delta sleep over the hospitalization.
Opposite Effects on Human Distal Colon Motility of Two Postulated Alpha2‐Antagonists (Mianserin and Chlorprothixene) and One Alpha2‐Agonist (Clonidine)
Authors: LECHIN FUAD , DIJS BERTHA van der
Published: March 2013

Abstract: The effects of two postulated alpha2‐antagonists (mianserin and chlorprothixene) and an accepted alpha2‐agonist (clonidine) on the distal colon motility in five healthy subjects were investigated. Opposite effects were induced by these two kinds of drugs. Distinct and characteristic motility responses were obtained from subjects with low distal colon tone and subjects with high distal colon tone. In addition, different and typical behavior responses paralleled motility changes in the two types of subjects. These results suggest that, at the doses employed in this study, both mianserin and chlorprothixene behave as alpha2‐antagonists when tested on human distal colon motility against a known alpha2‐agonist such as clonidine.
Intramuscularly Administered Ciramadol for Management of Postoperative Pain: A Comparative Study
Authors: FRAGEN ROBERT J. , KOUZMANOFF CONNIE , CALDWELL NANCY J.
Published: March 2013

Abstract: Efficacy and safety of the analgesic ciramadol in the management of postoperative pain was evaluated in 139 healthy patients given single, double‐blind, intramuscular injections of either 30 mg ciramadol, 60 mg ciramadol, 10 mg morphine or 0.9% saline on the first or second postoperative day. Differences in pain intensity and relief of pain, changes from baseline on a pain analog scale, percentage of patients with moderate or greater pain relief, and cumulative treatment failures were measured for 6 hours after injection. Morphine proved to be superior to all other treatments. Neither dose of ciramadol could be statistically differentiated from placebo. During the first hour after administration, some measurements showed that 30 mg ciramadol was superior to 60 mg ciramadol. Patients experienced little or no drowsiness in any of the four groups, and other side effects were transient and required no specific therapy. Some patients experienced an acute increase in pain intensity after administration of 60 mg ciramadol; this possibly represents antagonism of the residual effect of the previous narcotic. This study must be interpreted with the knowledge that ciramadol, an agonist—antagonist analgesic, was administered to patients who had been receiving narcotic analgesics before entering the study. Future studies of ciramadol given as the sole analgesic may more clearly define its efficacy in the management of postoperative pain.
Comparative Antihypertensive Effects of Enalapril Maleate and Hydrochlorothiazide, Alone and in Combination
Authors: VLASSES PETER H. , ROTMENSCH HESCHI H. , SWANSON BRIAN N. , IRVIN JOHN D. , LEE ROBYN B. , KOPLIN JANICE R. , FERGUSON ROGER K.
Published: March 2013

Abstract: Enalapril maleate is an investigational oral prodrug whose hydrolyzed diacid metabolite is a potent angiotensin‐converting enzyme inhibitor. Fourteen patients with mild to moderate hypertension were evaluated after receiving placebo, and two weeks of treatment with each of the following: enalapril maleate (20 mg b.i.d.), hydrochlorothiazide (25 mg b.i.d.), and the two in combination. In comparison to placebo, the magnitudes of the blood pressure reduction after enalapril and hydrochlorothiazide alone were comparable. The reduction in blood pressure following enalapril was evident throughout the 12‐hour dosing interval. The combination of enalapril and hydrochlorothiazide resulted in a marked further reduction in blood pressure that was greater than that predicted from the responses to the individual drugs (P < 0.05). Biochemical parameters confirmed inhibition of angiotensin‐converting enzyme during enalapril treatment; serum angiotensin‐converting enzyme activity proved an excellent monitor of compliance. Enalapril was generally well tolerated. Adverse effects included symptomatic hypotension in three patients when enalapril was first added to hydrochlorothiazide and hyperesthesia of the oral mucosa without a loss of taste in one patient on enalapril. Enalapril maleate alone and especially in combination with hydrochlorothiazide appears to be an effective, well‐tolerated converting enzyme inhibitor with at least a 12‐hour duration of action.
Diphenhydramine in Insomniac Family Practice Patients: A Double‐Blind Study
Authors: RICKELS KARL , MORRIS RICHARD J. , NEWMAN HARRIS , ROSENFELD HOWARD , SCHILLER HERBERT , WEINSTOCK ROBERT
Published: March 2013

Abstract: One hundred eleven mildly to moderately insomniac patients participated in a double‐blind, placebo‐controlled study to establish the efficacy of diphenhydramine as an over‐the‐counter (OTC) sleep aid. A two‐week crossover design was employed in which all patients received both diphenhydramine and placebo for one week each. The daily diphenhydramine dose was 50 mg at bedtime. Results obtained indicate that diphenhydramine improved various sleep parameters, including sleep latency, to a significantly higher degree than did placebo. In addition, patients on diphenhydramine reported feeling more restful the following morning and patients preferred the diphenhydramine drug to placebo despite experiencing more side effects. This study thus supports the use of 50 mg diphenhydramine as an OTC sleep aid in the treatment of temporary mild to moderate insomnia.
Relationship Between Gallamine Plasma Concentration and Neuromuscular Paralysis in Surgical Patients
Authors: RAMZAN IQBAL M. , SHANKS COLIN A. , TRIGGS EDWARD J.
Published: March 2013

Abstract: The pharmacodynamics of the neuromuscular blocking drug gallamine were investigated in 10 surgical patients using a constant‐rate infusion regimen, and results are compared to those for d‐tubocurarine (dTc). Gallamine effect (paralysis)–time data gathered during and following the infusion were fitted to a pharmacodynamic effect model, while paralysis—plasma concentration data gathered during (onset) and following (offset) the infusion were fitted separately to a nonlinear form of the Hill equation. The effect model was most appropriate in characterizing the combined (on and off infusion) effect data. While there was also an excellent characterization of onset and offset data with the Hill equation, the two effect—concentration curves were not superimposable. The mean (± S.D.) plasma concentration of gallamine at 50 per cent paralysis during onset of action (Cp50(onset) 8.0 ± 1.8 μg/ml) was significantly higher (P < 0.001) than that noted during offset of action (Cp50(offset) 5.4 ± 1.1 μg/ml) or that predicted to exist at steady state using the effect model (Cp50(ss) 5.4 ± 1.4 μg/ml). Cp50(offset) and Cp50(ss) did not differ significantly, and there was no significant difference in the power factor (γ) estimates for the various model fits. Comparison of the pharmacodynamic parameters for gallamine and dTc using the effect model revealed no significant differences in keo, t½(keo), and γ estimates. However, Cp50(ss) for gallamine (5.4 ± 1.4 μg/ml) was nine times higher than that for dTc (0.61 ± 0.15 μg/ml) in absolute terms and seven times higher when compared on a molar basis.
Cimetidine Disposition in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis
Authors: KOGAN FREDERICK J. , SAMPLINER RICHARD E. , MAYERSOHN MICHAEL , KAZAMA RODNEY M. , PERRIER DONALD , JONES WILLIAM , MICHAEL ULRICH F.
Published: March 2013

Abstract: Cimetidine disposition was determined in six patients undergoing continuous ambulatory peritoneal dialysis to ascertain the need for modification of conventional dosing regimens. Blood, dialysis fluid, and urine were collected for 48 hours after administration of a single intravenous dose of cimetidine. The following values were obtained: elimination half‐life, 4.3 hours; systemic or total body clearance, 191 ± 55 ml/min; and dialysis clearance, 4.2 ± 3.1 ml/min. Approximately 2% of a cimetidine dose is removed by dialysis, indicating that there is no need to adjust the conventional renal failure dosing regimen in patients undergoing continuous ambulatory peritoneal dialysis.
Effects of Amrinone on Atrioventricular Conduction in the Intact Canine Heart
Authors: NUSRAT ALI , TEPPER DAVID , HERTZBERG JEFFREY , SONNENBLICK EDMUND H. , ARONSON RONALD S.
Published: March 2013

Abstract: The effects of amrinone on conduction in the intact canine heart were studied. Intracardiac His‐electrode catheter recordings were used to measure the functional refractory period (FRP) of the AV node and conduction time through the AV node (A2H2 interval) and in the His‐Purkinje system (H2V2 interval). Amrinone (2.5 to 10 mg/kg) shortened the FRP and A2H2 in a dose‐dependent manner but had no significant effect on H2V2. In hearts where AV conduction was depressed by treatment with verapamil, propranolol, or ouabain, amrinone partially reversed this depression. Amrinone also shortened the recovery time of spontaneous sinoatrial (SA) node activity following a train of rapid atrial stimulation. This effect was also observed after depression of SA nodal recovery with verapamil, propranolol, or ouabain. These results indicate that amrinone enhances AV conduction and SA nodal activity in the normal heart and may favorably influence depressed AV conduction and SA nodal activity induced by a variety of cardioactive agents.
Radioreceptor and High‐Performance Liquid Chromatographic Assays for the Calcium Channel Antagonist Nitrendipine in Serum
Authors: JANIS RONALD A. , KROL GEORGE J. , NOE ANSON J. , PAN MARY
Published: March 2013

Abstract: Radioreceptor and high‐performance liquid chromatographic (HPLC) assays for nitrendipine were developed and applied to the analysis of serum samples. The HPLC assay required both extraction and concentration of the serum samples, whereas the radioreceptor assay involved only direct dilution of the serum. The HPLC assay, in contrast to the radioreceptor assay, can be used for detection and quantitative analysis of biologically inactive metabolites. The radioreceptor assay is based on the competition between nitrendipine in serum and [3H]nitrendipine for high‐affinity binding sites on cardiac membranes. Forty‐two serum samples were obtained from five volunteers, and the HPLC and radioreceptor assay results were compared. A correlation coefficient of 0.98 was found between the results of the two assays within the nitrendipine serum concentration range of 1 to 20 ng/ml. No significant levels of active metabolites or any other interferences were found. The radioreceptor assay provides a specific and sensitive alternative to HPLC; it is rapid and inexpensive and with minor modifications may be applicable to most presently available Ca2+ channel antagonists.
Comparative Pharmacokinetics of Theophylline in Peritoneal Dialysis and Hemodialysis
Authors: LEE CHING‐SAN C. , PETERSON JOHN C. , MARBURY THOMAS C.
Published: March 2013

Abstract: Dialysis clearance and drug recovery of theophylline were investigated in three peritoneal dialysis patients and the results were compared with those obtained from five hemodialysis patients. Peritoneal clearance averaged 9.5 ml/min, in contrast with the hemodialysis clearance of 84.8 ml/min, indicating a relative inefficiency of peritoneal dialysis with regard to theophylline removal. Theophylline half‐life was reduced substantially during hemodialysis, 2.0 to 3.2 hours, in comparison with the normal half‐life range of 4.7 to 6.8 hours during peritoneal dialysis. The fraction of theophylline recovered by peritoneal dialysis approximated 3.2 per cent of dose, while hemodialysis recovered up to 40 per cent of the administered dose. The overall observations of half‐life, dialysis clearance, and drug recovery suggest a clear advantage of hemodialysis over peritoneal dialysis for theophylline detoxification. However, peritoneal dialysis may be preferred to hemodialysis for uremic patients requiring theophylline therapy. Since the removal of theophylline by peritoneal dialysis is minimal, an undesirable alteration of the theophylline dosage regimen in association with dialysis therapy can thus be avoided.
Long‐Term Therapy with Tolmetin in Rheumatoid Arthritis
Authors: EHRLICH GEORGE E.
Published: March 2013

Abstract: Data from over 1000 patients with rheumatoid arthritis who received tolmetin sodium in double‐blind and open studies have been pooled to assess long‐term efficacy and safety. Duration of the studies was 12 weeks to 48 months. Mean age of patients was 54 years; ratio of males to females was 1:3. The results showed that tolmetin provided rapid onset of action and continuous progressive decrease in symptoms in all measurements of inflammation. Mean number of painful joints was reduced from 22 at baseline to 16 at one month, to 9 at one year, and to 6 at two years. Duration of morning stiffness was 155 minutes at baseline, 123 minutes at one month, 74 minutes at one year, and 78 minutes at two years. The final global evaluation by the investigators showed that 61 per cent of patients had a marked or moderate response. Mean erythrocyte sedimentation rates did not increase during therapy with tolmetin. Initial dose of tolmetin in the patients pooled for this analysis was generally 600 to 800 mg/day, and the mean dose throughout the study was 1256 mg/day. The drug was well tolerated overall. As anticipated, gastrointestinal symptoms were the most frequently reported; nausea was experienced by 13 per cent of the patients at some time during therapy, and gastrointestinal distress, dyspepsia, or abdominal pain was reported by approximately 8.6 per cent each. Only 12.7 per cent of patients discontinued tolmetin because of untoward reactions; 15.9 per cent of patients discontinued because of insufficient therapeutic response. The results of these long‐term studies of patients with rheumatoid arthritis demonstrated that tolmetin is an effective antiinflammatory agent with an acceptable record of safety.
Clinical Use of Tolmetin Sodium in Patients with Ankylosing Spondylitis: A Review
Authors: CALIN ANDREI
Published: March 2013

Abstract: The efficacy and safety of tolmetin sodium in the management of ankylosing spondylitis are presented in a review of published and unpublished data. In both open and controlled clinical studies, tolmetin was superior to placebo and equal to indomethacin in its capacity to relieve pain, inflammation, and other symptoms of ankylosing spondylitis (AS). Objective and subjective assessments showed that both tolmetin sodium and indomethacin provided significant therapeutic benefits to patients with AS. In AS, the two drugs showed similar adverse reaction profiles. Adverse reactions with both drugs were minimal and predominantly affected the gastrointestinal tract, in most cases these symptoms cleared spontaneously without discontinuing the drugs.
Long‐Term Efficacy and Safety of Tolmetin Sodium in Treatment of Geriatric Patients with Rheumatoid Arthritis and Osteoarthritis: A Retrospective Study
Authors: O'BRIEN WILLIAM M.
Published: March 2013

Abstract: In order to evaluate the effectiveness and safety of tolmetin sodium in the treatment of both rheumatoid arthritis (RA) and osteoarthritis in geriatric patients, a retrospective study was made of patients 65 years and older who participated in long‐term, controlled, double‐blind and open trials during both the investigational period and since marketing of the drug. Standard entrance criteria, methods of evaluating disease activity, and statistical methods were used in the study of both arthritic diseases. A total of 847 geriatric patients were studied for periods of up to one year; 171 had RA, while 676 had osteoarthritis of large or small joints. Average daily dose of tolmetin sodium was 1141 mg for patients with RA and 953 mg for patients with osteoarthritis. The results of this retrospective study of both RA and osteoarthritis patients show that tolmetin was as effective in geriatric patients as in nongeriatric patients. Symptoms responded rapidly to treatment with tolmetin, and both the inflammatory symptoms of RA and the joint pain and functional parameters of osteoarthritis showed improvement that was both statistically and clinically significant throughout the major course of therapy. Tolmetin was also found to be safe and well tolerated by the elderly patient population. The major complaints were gastrointestinal, but serious or limiting side effects occurred in few patients. The dropout rates due to adverse effects during the entire year of therapy were 15.8 per cent in the RA population and 15.4 per cent in osteoarthritis patients. This retrospective evaluation of tolmetin therapy shows significant relief of the symptoms of both RA and osteoarthritis in a geriatric population and fails to reveal any unusual or serious conditions which would contraindicate its use in the elderly patient. Tolmetin, which is an antiinflammatory agent with a short half‐life, can provide adequate, safe therapy in the geriatric population.
Enhancement of Deficient T‐Cell Function in Rheumatoid Arthritis by Tolmetin Sodium
Authors: LEVY JOSHUA
Published: March 2013

Abstract: The in vitro effect of tolmetin on deficient T‐lymphocytes from patients with autoimmune diseases was tested using a mitogen‐stimulation assay. For comparison, levamisole was also tested on T‐cells in the same assay system in this group of patients. Tolmetin and levamisole both showed enhancement of T‐cell function and normalization of mitogenesis in vitro. To evaluate the relevance of these in vitro findings to treatment of disease, four patients who had active rheumatoid arthritis and who had displayed repeated deficiency in vitro of T‐cell mitogenesis were studied. After baseline studies, the patients were started on tolmetin at an oral dose of 800 mg/day in divided doses. If no significant enhancement of T‐cell function was observed by four weeks, the dose of tolmetin was increased to 1600 mg/day. The results of the clinical study confirmed that tolmetin enhanced T‐cell function in vivo as well as in vitro in a manner similar to that which has been reported for levamisole. This normalization of T‐cell function by tolmetin was associated with clinical improvement.
Clinical Pharmacology of Tolmetin: Comparisons in Rheumatoid Arthritis Patients and Normal Volunteers
Authors: FURST DANIEL E. , DROMGOOLE SYDNEY H. , DESIRAJU RAVI K. , PAULUS HAROLD E.
Published: March 2013

Abstract: The pharmacokinetics of tolmetin sodium were studied in five patients with rheumatoid arthritis (RA) and five normal volunteers to determine whether data derived from normals could be applied to RA patients. In addition, prostaglandin E (PGE) levels in synovial fluid were compared with tolmetin levels in serum and synovial fluid. Both groups received 400 mg tolmetin every 6 hours for seven days. During a 24‐hour washout period after the dose of tolmetin (400 mg) on day 8, blood and urine samples were obtained from all study participants, and synovial fluid samples from the RA patients only. The patients continued into a second 24‐hour drug‐free period, after which they received a single 400‐mg dose of tolmetin. Blood and urine samples were again collected. No clinically or statistically significant differences in tolmetin kinetics between normal volunteers and RA patients were found. A comparison of multiple‐dose and single‐dose results in the patient group showed an 11 per cent increase in the tolmetin serum concentration after multiple dosing. Total PGE levels in synovial fluid remained significantly depressed in the patient group for 24 hours after the 400‐mg test dose of tolmetin on day 8. These findings suggest that tolmetin serum kinetics may not be an appropriate indicator of the duration of biologic activity of tolmetin.
Suppression of Atrial Ectopy with Intravenous Metoprolol in Chronic Obstructive Pulmonary Disease Patients
Authors: QUAN STUART F. , FENSTER PAUL E. , HANSON CHRISTINE D. , COAKER LLOYD A. , BASISTA MICHAEL P.
Published: March 2013

Abstract: To determine the efficacy of a cardioselective beta blocker in the treatment of atrial ectopy in patients with chronic obstructive pulmonary disease (COPD), we administered intravenous metoprolol (0.2 mg/kg) to six patients with atrial ectopic depolarizations (AEDs) and chronic partially reversible airflow limitation (FEV1 = 1.24 ± 0.21 liter, mean ± S.E.). Metoprolol reduced the mean frequency of AEDs from 713 ± 237 per hour to 218 ± 127 per hour. Furthermore, three of six patients experienced an 85 per cent or greater decrease in AEDs. No changes were observed in FEV1, FVC, or FEF25–75 over the course of the study. These data suggest that intravenous metoprolol is effective in reducing the frequency of AEDs and that it can be administered to patients with COPD without causing an increase in airflow limitation.
Effects of Prazosin and Clonidine on Sympathetic and Baroreflex Function in Patients with Essential Hypertension
Authors: GUTHRIE GORDON P. , KOTCHEN THEODORE A.
Published: March 2013

Abstract: Prazosin, a peripherally active alpha‐adrenoceptor antagonist, and clonidine, a centrally active alpha‐adrenoceptor agonist, both reduce blood pressure but with different alterations in sympathetic nervous system activity. We studied the effects of monotherapy with either prazosin or clonidine in 10 and 30 patients, respectively, with essential hypertension. Prazosin reduced blood pressure without affecting heart rate or circulating plasma catecholamines. Sensitivity to injected phenylephrine was markedly reduced by prazosin, and sensitivity to isoproterenol was increased, whereas baroreflex sensitivity was not significantly altered. Blood pressure response to prazosin was correlated with basal plasma norepinephrine concentration (r = 0.64, P < 0.04). In contrast, clonidine reduced heart rates and plasma concentrations of both norepinephrine and epinephrine, increased the sensitivity to phenylephrine, and increased baroreflex sensitivity. Blood pressure response to clonidine was correlated with reduction in plasma norepinephrine concentration (r = 0.51, P < 0.004). Thus, blood pressure reduction resulting from monotherapy with either prazosin or clonidine occurs through different antisympathetic effects, suggesting that combined therapy might be useful in those unresponsive to either drug alone.
Terbutaline Infusion in Cardiogenic Shock: Acute Hemodynamic Effects and Clinical Response
Authors: WANG R. Y. C. , LEE P. K. , YU D. Y. C. , TSE T. F. , CHOW MOSES S. S.
Published: March 2013

Abstract:The effect of terbutaline infusion was studied in six patients with cardiogenic shock due to acute myocardial infarction. Terbutaline was initiated at 3 μg/kg/min, and the subsequent infusion rate was adjusted according to heart rate and blood pressure. At 3 hours after infusion, arterial pressure increased from 62 ± 13 mm Hg (mean ± S.D.) to 89 ± 13 mm Hg (P< 0.001), cardiac index increased from 1.38 ± 0.29 liter/min/m2to 2.68 ± 0.47 liter/min/m2(P< 0.001), and heart rate increased from 92 ± 32 beats/min to 112 ± 29 beats/min (P< 0.005). Pulmonary artery wedge pressure fell from 24 ± 7 mm Hg to 17 ± 3 mm Hg (P< 0.01), right atrial pressure fell from 12 ± 4 mm Hg to 6 ± 3 mm Hg (P< 0.005), and systemic vascular resistance fell from 1880 ± 641 dyn‐sec/cm5to 1515 ± 418 dyn‐sec/cm5(P< 0.05). In addition, urine flow increased from 4 ± 6 ml/hr to 314 ± 237 ml/hr (P< 0.05), and subjective improvement was noted in all subjects. Undesirable effects observed were hypokalemia (all subjects), supraventricular tachycardia (one subject), and ventricular ectopic beats (three subjects), which responded to potassium replacement and other treatments. All patients required prolonged maintenance infusion to maintain adequate hemodynamic and clinical response. Four patients were weaned off from maintenance therapy after a mean duration of 4.8 days and eventually were discharged from the hospital. Two patients died, one from cardiogenic shock and one from aspiration pneumonia. This preliminary study indicates that terbutaline infusion produced beneficial hemodynamic and clinical response and may be potentially useful for the management of cardiogenic shock if careful monitoring and potassium replacement are implemented.
Myocardial Metabolic Effects of Intravenous Terbutaline in Patients with Severe Heart Failure Due to Coronary Artery Disease
Authors: WANG REBECCA Y. C. , LEE PUI K. , YU DONALD Y. C. , TSE TAK F. , CHOW MOSES S. S.
Published: March 2013

Abstract:Intravenous terbutaline, 0.3 mg/kg/min for 30 minutes followed by 0.15 mg/min for 60 minutes, was studied in nine patients with severe heart failure due to documented coronary artery disease. Hemodynamic and myocardial metabolic effects were measured during terbutaline infusion. Cardiac index and stroke index increased, whereas mean pulmonary artery wedge pressure and pulmonary vascular resistance decreased significantly. No significant alterations in aortic oxygen content, coronary sinus oxygen content, myocardial oxygen extraction, and myocardial lactate extraction were observed during terbutaline infusion. No patient developed angina or electrocardiographic changes suggestive of ischemia. These results indicate that intravenous terbutaline infusion, at the dosage employed, produces beneficial hemodynamic effects without a deterioration of myocardial metabolism in patients with heart failure due to coronary artery disease.
Prolonged Accumulation of Diazepam in Obesity
Authors: ABERNETHY DARRELL R. , GREENBLATT DAVID J. , DIVOLL MARCIA , SHADER RICHARD I.
Published: March 2013

Abstract: Six obese (mean weight 92 kg) and five normal (60 kg) subjects received 2 mg diazepam nightly for 30 nights. Determination of diazepam and desmethyldiazepam plasma concentrations during the dosing period and for a withdrawal period indicated that accumulation half‐life for both diazepam (7.8 days in obese vs. 3.1 days in normal subjects, P < 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P < 0.05) was markedly prolonged in obese subjects. However, mean steady‐state plasma concentrations of diazepam (68 vs. 67 ng/ml) and desmethyldiazepam (156 vs. 91 ng/ml) did not significantly differ between groups. To determine the basis for this delay in accumulation in obese subjects, single‐dose pharmacokinetics of diazepam and desmethyldiazepam were determined. Diazepam elimination half‐life was greatly prolonged in the obese subjects (82 vs. 32 hours, P < 0.005), with no change in total metabolic clearance (32 vs. 26 ml/min). Instead, a large increase in volume of distribution (228 vs. 70 liters, P < 0.01) was the reason for prolongation of the elimination half‐life. Similarly for desmethyldiazepam, elimination half‐life was prolonged in obese subjects (130 vs. 56 hours, P < 0.01), without a change in total metabolic clearance (13.7 vs. 19.2 ml/min), due to increased volume of distribution (151 vs. 73 liters, P < 0.01). During chronic dosing with diazepam, obese patients may experience a much slower onset of maximal drug effect compared to normal‐weight patients because of the greatly delayed accumulation of diazepam and desmethyldiazepam. After stopping diazepam administration, residual drug effect may likewise persist for a prolonged period in obese patients.
The Disposition of 14C‐indapamide in Man
Authors: KLUNK LEWIS J. , RINGEL SAMUEL , NEISS EDWARD S.
Published: March 2013

Abstract: The metabolism of 14C‐indapamide labeled in the indoline ring was determined after a single oral administration of a solution (4.99 mg, 90.47 μCi) to four fasted adult male volunteers. 14C‐indapamide was rapidly absorbed, and peak blood concentrations of radioactivity occurred by 0.5 hour in three subjects and at 2 hours in one subject. The mean elimination half‐lives of total radioactivity were 27.0 hours in blood and 24.5 hours in plasma. The concentration of total radioactivity in blood was 5.7 times greater than in plasma, indicating extensive binding to red blood cells. Unchanged drug, as analyzed in one subject, reached a peak concentration by 0.5 hour, and had a blood half‐life of 15.8 hours. Radioactivity was primarily excreted in the urine, and more than 50 per cent of the administered radioactivity was eliminated by this route in 48 hours. By eight days, 92.8 per cent of the radioactivity was recovered, with 70.3 per cent in the urine and 22.5 per cent in the feces. 14C‐indapamide was shown to be extensively metabolized, with only 7.3 per cent of the dose excreted as unchanged drug in the urine. Systemic and renal clearances of total radioactivity were 12.8 ± 1.3 and 8.6 ± 0.8 ml/min, respectively, while the renal clearance of unchanged indapamide, determined for one subject, was substantially lower (1.71 ml/min).
Suprofen Concentrations in Human Breast Milk
Authors: CHAIKIN PHILIP , CHASIN MARK , KENNEDY BARBARA , SILVERMAN BENJAMIN K.
Published: March 2013

Abstract: Six healthy females who had been nursing their infants for 6 to 11 months received a single, 200‐mg oral dose of suprofen, an analgesic which has been evaluated clinically. Blood and milk samples were collected at discrete times over an 8‐hour period and suprofen concentrations in milk and plasma were determined by HPLC. The binding of suprofen to milk and plasma proteins was determined by equilibrium dialysis. The maximum concentrations of suprofen in the milk ranged from 0.118 to 0.232 μg/ml and occurred from 1 to 2 hours after dose administration. The maximum plasma suprofen concentrations ranged from 13.8 to 28.3 μ/ml and occurred from 0.5 to 2 hours after dosing. Within any subject, the peak suprofen concentration in milk was 0.5 to 0.9 per cent of the peak concentration in plasma. Suprofen was extensively bound to plasma proteins (99.4 per cent) and minimally bound to milk proteins (10 per cent). The average milk/plasma ratio based on area‐under‐the‐curve measurements was approximately 0.014, or 1.4 per cent. This ratio agrees well with an estimated value of 1.2 per cent for the pH‐dependent, passive diffusion of suprofen from plasma into milk. From these data, it appears that there would be minimal suprofen exposure to a nursing infant after administration of recommended doses to the nursing mother.
Is Volume of Distribution at Steady State a Meaningful Kinetic Variable?
Authors: GREENBLATT DAVID J. , ABERNETHY DARRELL R. , DIVOLL MARCIA
Published: March 2013

Abstract: Pharmacokinetic volumes of distribution (Vd) are commonly calculated either by the steady‐state method (Vdss) or the area method (Vdarea). Vdss is traditionally perceived as the least biased and most reliable indicator of the extent of distribution, but Vdss in fact has far greater practical and theoretical limitation than does Vdarea. After single doses or multiple discrete doses of a drug, Vdarea correctly relates plasma concentration to amount of drug in the body at all times after distribution equilibrium is attained. Vdss, on the other hand, is a correct proportionality constant only during continuous intravenous infusion or at a single instant in time after discrete dosing. Furthermore, calculated values of Vdss are strongly dependent on the precise configuration of the initial distributional phase of the plasma concentration curve, which may be difficult or impossible to delineate because of variance arising from methodologic artefacts or unexplained causes. Such variance can lead to large nonphysiologic within‐ and between‐individual variability in Vdss Vdarea, on the other hand, is relatively independent of artefactual changes in the initial distribution profile. Finally, experimental observations indicate that elimination depends physiologically on distribution in the absence of changes in clearance, not the reverse. The relation of distribution and elimination holds whether the steady‐state method or the area method is used to calculate Vd. Thus, Vdarea is a more reliable and generally valid descriptor of the extent of drug distribution than is Vdss.
Augmentation of Renal Citrate Excretion by Oral Potassium Citrate Administration: Time Course, Dose Frequency Schedule, and Dose—Response Relationship
Authors: PAK CHARLES Y.C. , SKURLA CAROLYN , BRINKLEY LINDA , SAKHAEE KHASHAYAR
Published: March 2013

Abstract: The time course, dose frequency schedule, and dose—response relationship of the citraturic response to orally administered potassium citrate was examined in 22 normal volunteers and 21 patients with uric acid or calcium nephrolithiasis. The slow‐release (wax matrix) preparation of potassium citrate produced a rapid and sustained rise in urinary citrate lasting for up to 12 hours following a single oral administration. Probably owing to this prolonged action, the slow‐release preparation when given in a twice‐daily or thrice‐daily schedule at a dosage of 60 meq or 3.78 Gm citrate/day virtually eliminated the normally wide circadian fluctuation in urinary citrate and maintained urinary citrate at a higher, more constant level throughout the day. The liquid preparation of potassium citrate was less effective in this regard. However, the two preparations of potassium citrate caused an equivalent rise in total 24‐hour urinary citrate. When 24‐hour excretions of citrate were examined, urinary citrate was shown to reach its peak level by the second day of potassium citrate treatment and to return to the pretreatment level by the second day after the treatment was stopped. The rise in urinary citrate produced by treatment was directly proportional to the dose of potassium citrate. In most hypocitraturic patients with renal stones, potassium citrate 60 meq/day restored normal urinary citrate (>320 mg/day).
Analgesic Efficacy After Single and Repeated Doses of Codeine and Acetaminophen
Authors: QUIDING HANS , OIKARINEN VALLE , SANE JUHA , SJÖBLAD ANNE‐MARIE
Published: March 2013

Abstract: A double‐blind randomized analgesic trial was carried out in patients suffering from pain after removal of a third molar tooth. In a two‐dose regimen, 108 patients received either 60 mg codeine, 500 mg acetaminophen, or 1000 mg acetaminophen. On the day of surgery, the patients assessed their pain intensity hourly on a visual analog scale. The evaluation was carried out during the 10‐hour period after first medication. The best pain reducing effects were achieved with 1000 mg acetaminophen. Both the category and position of each tooth were examined in relation to pain intensity; however, the statistical analysis did not reveal any significant correlation. In all treatment groups, the efficacy of the second dose was superior to that of the first, and the most pronounced difference was obtained in patients taking codeine, who increased their pain reduction from 20 to 60 per cent. Clinical comparisons including codeine may therefore be better carried out in a repeated‐dose regimen.
The Relative Analgesic Efficacy of Propiram Fumarate, Codeine, Aspirin, and Placebo in Post‐impaction Dental Pain
Authors: DESJARDINS PAUL J. , COOPER STEPHEN A. , GALLEGOS THOMAS L. , ALLWEIN JOHN B. , REYNOLDS DONALD C. , KRUGER GUSTAV O. , BEAVER WILLIAM T.
Published: March 2013

Abstract: To evaluate the analgesic efficacy of orally administered 50 mg propiram fumarate, 650 mg aspirin, 60 mg codeine phosphate, and placebo in acute post‐impaction dental pain, 159 patients with moderate or severe pain were randomly allocated to the four treatments in this single‐dose double‐blind, stratified, parallel‐group study. A research nurse questioned the patients at 1/2 hour and hourly for 6 hours after medicating. A standard format was used to question subjects about their pain intensity and relief from the starting pain. Propiram, 50 mg, produced a level of analgesia approaching that of 650 mg aspirin in peak effect, total effect, and duration of action and was statistically superior to 60 mg codeine and placebo for every measure of analgesic efficacy. Several mild adverse effects were observed; however, they appeared to be evenly distributed among the active treatments.
Influence of Ascites on Tobramycin Pharmacokinetics
Authors: SAMPLINER RICHARD , PERRIER DONALD , POWELL ROBERT , FINLEY PAUL
Published: March 2013

Abstract: The influence of ascites on the disposition of tobramycin was examined in eight subjects with cirrhosis of the liver. Five of these subjects had resolution of ascites so they could be used as their own controls. While there was no significant effect of ascites on the clearance and half‐life of tobramycin, the volume of distribution of tobramycin was significantly larger when ascites was present, 0.32 versus 0.26 liter/kg (P < 0.01). There was a trend for the volume of distribution to be larger in those patients with larger ascitic fluid volume.
Pharmacokinetics of Compound 58–112, a Potential Skeletal Muscle Relaxant, in Man
Authors: TSE FRANCIS L. S. , JAFFE JAMES M. , DAIN JEREMY G.
Published: March 2013

Abstract: The pharmacokinetics of 4‐[(3‐methoxyphenyl)methyl]‐2,2,6,6‐tetramethyl‐1‐oxa‐4‐aza‐2,6‐disilacyclohexane (Sandoz compound 58–112), a new chemical entity with a unique myotonolytic effect, was studied in 12 healthy male volunteers who received an oral dose of 50 or 100 mg of the 14C‐labeled drug. Serial blood and breath samples and complete urine and feces were collected for 120 hours after dosing. All samples were analyzed for total radioactivity while the blood and urine were also assayed for unchanged compound 58–112. Measurable blood radioactivity levels were observed at 0.5 hour, and peak concentrations were attained at 1 to 2 hours after dosing. The absorption of the radioactive doses was complete and appeared linear in the 50–100 mg range, as indicated by blood 14C levels that were proportional to the dose. The 50‐ and 100‐mg doses also resulted in virtually identical excretion patterns, with 95 per cent of the administered radioactivity recovered within 9 hours, almost exclusively in the urine. However, the disproportionately higher blood concentrations of unchanged compound 58–112 after the 100‐mg dose could suggest saturable presystemic metabolism in the liver. Simultaneous fitting of all data in the 100‐mg dose study to a pharmacokinetic model showed that unchanged compound 58–112 was distributed into a central and a peripheral compartment and was eliminated entirely by metabolism, the distribution and elimination half‐lives being 0.5 and 3.9 hours, respectively. The metabolite(s) was distributed into one homogeneous space, and its elimination half‐life was 0.1 hour, with a renal:fecal clearance ratio of ∼96:4.
Is Temazepam an Accumulating Hypnotic?
Authors: OCHS HERMANN R. , GREENBLATT DAVID J. , HEUER HEINZ
Published: March 2013

Abstract: Ten healthy volunteers aged 22 to 30 years received a single 20‐mg oral dose of temazepam. Serum temazepam concentrations were measured by gas chromatography at multiple times during the next 48 hours. Mean kinetic variables were: volume of distribution, 1.45 liter/kg; elimination half‐life, 8.6 hours; total clearance, 2.33 ml/min/kg. The subjects then received 20 mg temazepam once daily for seven consecutive days. Serum concentrations were measured just prior to each dose and at multiple time points after the last dose. Predose serum levels increased during the first three days of dosage, then increased no further. Mean values measured 24 hours after doses 1 through 6, respectively, were 33, 43, 55, 47, 53, and 51 ng/ml. Based on the area under the serum concentration curve after the last dose compared with that after the first dose, the mean accumulation ratio was 1.32, which was significantly greater than unity. The extent of accumulation was consistent with that predicted from the single‐dose study. Postdosage washout half‐life averaged 10.2 hours. Thus, temazepam has a pharmacokinetic profile of an intermediate half‐life benzodiazepine that produces an intermediate degree of accumulation with multiple dosage.
Central Effects of Zomepirac on Pain Evoked by Intraneural Stimulation in Man
Authors: SCHADY W. , TOREBJÖRK H. E.
Published: March 2013

Abstract: The central analgesic activity of zomepirac was studied in six healthy subjects by means of intraneural electrical stimulation. Pain elicited by selective activation of nociceptive fibers was inhibited by the administration of a single oral dose of 100 mg zomepirac. Pain relief in this double‐blind crossover study was significantly greater after zomepirac than after placebo. Maximal analgesic effect was observed between 30 and 90 minutes after ingestion. Since peripheral receptors are bypassed by this technique, it is postulated that the observed effect reflects a central action of zomepirac, possibly as a result of inhibition of prostaglandin systhesis in the central nervous system.
Comparison of Long‐Term Renal Hemodynamic Effects of Methyldopa and Propranolol in Patients with Hypertension and Renal Insufficiency
Authors: LOWENSTEIN INGE , ALTERMAN LLOYD , ZELEN RANDY , BANK DAVID E. , BANK NORMAN
Published: March 2013

Abstract: Studies were carried out in 15 patients with renal insufficiency and hypertension to compare the long‐term effects of methyldopa and propranolol on renal hemodynamics. Inulin and PAH clearance measurements were made under baseline conditions and four to six months of antihypertensive therapy with each of the two drugs. Eight of the 15 patients (group I) were started on methyldopa and then switched to propranolol; and in the other seven (group II), the sequence was reversed. There were no statistical differences in blood pressure or inulin or PAH clearances under baseline conditions between the two groups of patients. Blood pressure was controlled equally with the two drugs in combination with furosemide. In group I, there was no significant effect of either antihypertensive drug on inulin clearance, but PAH clearance was significantly higher during methyldopa than propranolol therapy. In group II, the same higher PAH clearance was found with methyldopa, even though the sequence of drug administration was opposite to that of group I. Challenge with iv furosemide resulted in a greater 3‐hour natriuresis during methyldopa than propranolol treatment. The observations indicate that glomerular filtration rate (GFR) is not significantly affected by long‐term treatment with methyldopa or propranolol but that renal plasma flow (RPF) is higher during treatment with methyldopa in patients with renal insufficiency and hypertension. The higher RPF apparently enhances the acute natriuretic effect of iv furosemide.
Comparative Single‐Dose Kinetics of Oxazolam, Prazepam, and Clorazepate: Three Precursors of Desmethyldiazepam
Authors: OCHS HERMANN R. , GREENBLATT DAVID J. , VERBURG‐OCHS BIRGITT , LOCNISKAR ANN
Published: March 2013

Abstract: Twelve healthy volunteers received a single 40‐mg oral dose of the benzodiazepine derivative oxazolam, which serves primarily as a precursor of the active substance desmethyldiazepam (DMDZ). Concentrations of DMDZ were measured in multiple serum samples drawn for up to two weeks after the dose. Peak serum DMDZ concentrations averaged 115 ng/ml, measured at 8.6 hours after dosage. Mean DMDZ elimination half‐life averaged 61 hours. Three of the subjects also received 40 mg each of prazepam and clorazepate, two other DMDZ precursors, on separate occasions. Although DMDZ elimination half‐life was similar, total area under the curve (AUC) for DMDZ was larger for clorazepate, known to be completely transformed into DMDZ, than for oxazolam or prazepam the extent of whose conversion to DMDZ has not been previously established. After correcting for the different molar equivalent of DMDZ available from each preparation, the DMDZ ratio averaged 0.22 for oxazolam vs. clorazepate and 0.51 for prazepam vs. clorazepate. Thus, both oxazolam and prazepam lead to slow appearance of DMDZ in the systemic circulation. Furthermore the extent of DMDZ formation from oxazolam and prazepam is either incomplete or the drugs are incompletely absorbed. Equivalent doses of oxazolam, prazepam, and clorazepate should not be interchanged in clinical practice.
Pharmacokinetics and Urinary Excretion of Clavulanic Acid After Oral Administration of Amoxicillin and Potassium Clavulanate
Authors: FERSLEW KENNETH E. , DAIGNEAULT ERNEST A. , ATEN EDWARD M. , ROSEMAN JAMES M.
Published: March 2013

Abstract: Clavulanic acid is a β‐lactamase inhibitor which prevents microbial lactamase inactivation of β‐lactam antibiotics. The pharmacokinetics and urinary excretion of clavulanic acid were studied in eight healthy adult volunteers after oral administration of 500 mg amoxicillin and 125 mg potassium clavulanate. Serum and urine clavulanic acid concentrations were assayed using high‐performance liquid chromatography. Pharmacokinetic parameters were: t1/2β = 1.019 ± 0.090 hour, t1/2α = 0.276 ± 0.031 hour, lag time = 0.321 ± 0.018 hour, tmax = 1.042 ± 0.80 hour, Cmax = 2.098 ± 0.441 μg/ml, and AUC = 4.897 ± 0.979 μg · hr/ml. Cumulative urinary excretion of clavulanic acid (as percentage of dose administered) was: 14.05 ± 2.87 within 2 hours, 25.77 ± 3.98 within 4 hours, and 27.85 ± 4.27 within 6 hours after administration.