bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclosporine Absorption Following Orthotopic Liver Transplantation
Authors: Burckart Gilbert J. , Venkataramanan Raman , Ptachcinski Richard J. , Starzl Thomas E. , Gartner J. Carlton , Zitelli Basil J. , Malatack Jeffrey J. , Shaw Byers W. , Iwatsuki Shunzaburo , VAN Thiel David H.
Published: March 2013

Blood concentrations of cyclosporine were determined in adult and pediatric patients following orthotopic liver transplantation to quantitate cyclosporine blood clearance and oral absorption. Seventeen bioavailability studies were performed following transplantation surgery in nine children and seven adults. The intravenous cyclosporine study was performed following an average dose of 2.1 mg/kg. The patients were again studied when they received the same intravenous dose plus an oral dose of cyclosporine of 8.6 mg/kg or an oral dose alone. Blood samples were collected and analyzed for cyclosporine using high‐performance liquid chromatography. Cyclosporine blood clearance ranged from 29 to 203 mL/min (1.9–21.5 mL/min/kg) in children and from 253 to 680 mL/min (3.2–7.6 mL/min/kg) in adults. The mean cyclosporine clearance value was 9.3 mL/min/kg in the pediatric patients and 5.5 mL/min/kg in the adults. Cyclosporine bioavailability was less than 5% in six studies on five pediatric patients in the immediate postoperative period. The bioavailability varied from 8% to 60% in adult liver transplant patients (mean, 27%). We conclude that: (1) cyclosporine clearance is highly variable between patients, (2) pediatric patients clear the drug more rapidly than adults and therefore need a higher cyclosporine dose on a body weight basis, (3) cyclosporine is poorly and variably absorbed in liver transplant patients, and (4) cyclosporine blood concentration monitoring is essential following orthotopic liver transplantation.
Cyclosporine Serum Concentrations Soon After Heart or Heart‐Lung Transplantation
Authors: Aziz Salim , Oyer Philip E. , Kates Robert E.
Published: March 2013

The accumulation of cyclosporine was evaluated in 11 patients following either heart or heart‐lung transplantation. Blood samples were drawn frequently for the first few postoperative days, and the plasma was analyzed by both radioimmunoassay (RIA) and high‐performance liquid chromatography (HPLC). The levels determined by RIA were higher than those assessed by HPLC, and it is hypothesized that the difference is due to antibody reactive metabolites of cyclosporine, which are measured by the RIA procedure. We did not find any consistent trends in the accumulation of these metabolites. Analysis of early clinical data did not suggest any relationship between levels of cyclosporine or its metabolites and clinical outcome.
Renal Cyclosporine Clearance in Marrow Transplant Recipients: Age‐Related Variation
Authors: Yee Gary C. , Mills Greg , Schaffer Randy , Lennon Thomas P. , Kennedy Michael S. , Deeg H. Joachim
Published: March 2013

Cyclosporine is extensively metabolized in the liver and is subject to biliary elimination. Although only a small amount of the drug is eliminated unchanged in the urine, urine concentrations of the drug are much higher than blood or serum concentrations known to be associated with renal toxicity. Renal clearance (CL) of cyclosporine may be a sensitive correlate of nephrotoxicity, but renal CL studies of cyclosporine have not been reported in transplant patients. Therefore, we studied the renal CL of cyclosporine in 21 patients (median age, 27 yr) with hematologic malignancies undergoing allogeneic bone marrow transplantation. All patients received cyclosporine for prophylaxis or treatment of acute graft vs host disease. At the time of the study, all patients had normal renal function, as determined by serum creatinine concentration. Urine and serum cyclosporine concentrations were measured by high‐performance liquid chromatography. Renal cyclosporine CL in different patients ranged from 1.8 to 79.8 mL/min. However, serial renal CL studies performed one week apart in two patients showed minimal intrapatient variability. Patients 25 years old or younger had a higher mean renal cyclosporine CL (39.7 mL/min) than older patients (17.9 mL/min) (P < .05). These data show that renal cyclosporine CL is related to age and that renal CL in marrow transplant recipients is higher than the reported mean value in non‐marrow‐transplant patients. Further clinical studies are needed to evaluate renal cyclosporine CL in solid organ transplant recipients and the correlation between urinary cyclosporine (or cyclosporine metabolite) concentrations and renal dysfunction.
Parkinson's Disease: Follow‐up After “Drug Holiday”
Authors: Feldman Robert G. , Kaye Jeffrey A. , Lannon Margaret C.
Published: March 2013

Long‐term management of patients with Parkinson's disease includes close monitoring and frequent dose adjustment. In a small selected group of patients, complete withdrawal of l‐dopa (drug holiday) and slow reintroduction of lower doses of this drug assured continued benefit for six to 24 months. We studied 45 drug holidays in 45 patients with idiopathic Parkinson's disease. Average preholiday l‐dopa dose was 2,970 mg/d; at 24 months, it was 263 mg/d. The drug holiday resulted in reduced adverse drug effects (dyskinesias, “on‐off” phenomenon, hallucinations, and confusion), and improved functional ratings at one, six, 12, and 24 months after the drug holiday.
Accumulation and Washout Kinetics of Valproic Acid and Its Active Metabolites
Authors: Pollack Gary M. , McHugh William B. , Gengo Francis M. , Ermer James C. , Shen Danny D.
Published: March 2013

There is growing evidence that the metabolites of valproic acid (VPA) may be pharmacologically active and could contribute to both the therapeutic and toxic effects of the drug. The accumulation and washout kinetics of VPA and its oxidative metabolites were, therefore, examined in five healthy volunteers. Valproic acid (250‐mg capsules) was administered bid for 15 days. Blood samples were obtained periodically during the 15 days of drug administration and for seven days following termination of treatment. Urine was also collected over the final dosing interval. Steady‐state serum concentrations of VPA were achieved within three to four days of treatment. The accumulation of all metabolites in serum lagged behind that of the parent compound, with the mono‐desaturated metabolites accumulating more slowly than the hydroxylated species. Furthermore, the apparent washout half‐life of each metabolite was longer than the elimination half‐life of VPA. In general, the unsaturated metabolites were eliminated more slowly than the hydroxylated metabolites. The serum and urinary metabolite profiles of VPA observed in the healthy volunteers were comparable with those reported for epileptic patients. The differences in the disposition kinetics of VPA and of its potentially active metabolites may explain the previously observed dissociation between the pharmacokinetics and pharmacodynamics of the drug in epileptic patients.
Clinical Pharmacology of Muscle Relaxants in Patients With Burns
Authors: Martyn Jeevendra , Goldhill David R. , Goudsouzian Nishan G.
Published: March 2013

Pathophysiologic changes accompanying burn trauma can alter the pharmacokinetics and pharmacodynamic responses to neuromuscular relaxants. Pathophysiologic changes that can potentially affect kinetics in the hypermetabolic phase of burn injury include increased hepatic blood flow, increased glomerular filtration, and increased protein binding. Except for d‐tubocurarine, the pharmacokinetics of neuromuscular relaxants relative to burn trauma have not been studied. The unbound volume of distribution, clearance, and half‐life of d‐tubocurarine were not significantly different from controls, but the plasma binding and renal elimination at 24 hours was increased in burn patients. The aberrant pharmacodynamic responses to neuromuscular relaxants in burn patients include the potential for lethal hyperkalemia with the administration of depolarizing relaxant, succinylcholine, and a 2.5‐ to 5.0‐fold increase in the dose or plasma concentration requirement for nondepolarizing relaxant, including d‐tubocurarine, metocurine, pancuronium, and atracurium. The altered pharmacodynamic responses are probably related to an increase in nicotinic acetylcholine receptor number. An alternative to succinylcholine to produce rapid‐onset neuromuscular paralysis include the administration of 3XED95 doses of pancuronium and metocurine in combination (but recovery from paralysis is prolonged). Vecuronium and atracurium have good cardiovascular stability and faster recovery times even in high dosages in healthy patients, but the pharmacokinetics and pharmacodynamics of these drugs in patients with burns have not been fully characterized.
Continuous Arteriovenous Hemofiltration of Aminoglycoside Antibiotics in Critically Ill Patients
Authors: Zarowitz Barbara J. , Anandan J. V. , Dumler Francis , Jayashankar J. , Levin Nathan
Published: March 2013

The effect of continuous arteriovenous hemofiltration on the clearance of either tobramycin or gentamicin (mean dose, 1.65 ± 0.36 mg/kg) was studied in eight critically ill patients. Mean aminoglycoside clearance by hemofiltration was 3.47 ± 1.93 mL/min and total body clearance was 11.92 ± 3.51 mL/min. Hemofiltration clearance (HFCL) was directly correlated with hemofiltration flow rate (HFQR): HFCL (mL/min) = 1.03 HFQR (mL/min) − 0.88 (R = .89). Mean volume of distribution was 0.31 ± 0.08 L/kg, and the elimination rate constant was 0.020 ± 0.01 hr−1. Continuous arteriovenous hemofiltration was responsible for the removal of between 3% and 36% of each aminoglycoside dose in 24 hours. In critically ill patients with changing hemofiltration flow rates, measurement of multiple serum aminoglycoside concentrations is necessary to accurately assess dosing requirements and avoid ototoxicity and nephrotoxicity.
Aminoglycoside Dosage in Hemodialysis Patients
Authors: Keller Frieder , Wagner Karl , Borner Klaus , Kemmerich Bernd , Lode Hartmut , Offermann Gerd , Distler Armin
Published: March 2013

Regulating aminoglycoside dosage in patients undergoing hemodialysis is difficult because its elimination depends entirely on renal function and because the therapeutic margin is narrow. Guidelines for aminoglycoside dosage were derived from published population‐based kinetics and investigated in a prospective clinical study over a 12‐month period in 50 consecutive patients undergoing hemodialysis with acute (70%) or chronic (30%) renal failure. Based on body weight, each patient received one loading dose (1.5 mg/kg) and a daily maintenance dose (0.5 mg/kg) of netilmicin. The dosage interval was 24 hours. On each hemodialysis day, the dose of netilmicin was given immediately after hemodialysis. Each posthemodialysis dose (1.3 mg/kg) was the sum of the daily maintenance dose plus a supplementary dose to replace the amount of the drug removed during hemodialysis. A blood sample was taken at the start and the end of each hemodialysis and one hour after the start of the posthemodialysis dosage. Netilmicin plasma concentrations were determined by substrate‐labeled fluorescence immunoassay. The mean (± standard deviation) peak plasma concentration of the pooled data for all patients was 7.5 ± 2.7 mg/L, and the mean trough level was 3.6 ± 1.3 mg/L. The theoretically postulated range of therapeutic peak levels (5–10 mg/L) was the same as in patients with normal renal function, whereas the theoretically postulated range of therapeutic trough levels (2.2–5.0 mg/L) was considerably higher than in healthy persons. Peak and trough levels within the postulated range were achieved in 81% of the patients. Peaks and troughs were significantly lower in the 23 patients who did not respond than in the 27 patients who responded to antibiotic treatment (54%). Ototoxicity developed in three of 18 investigated patients (17%). Thus, efficacy and toxicity of aminoglycosides in patients undergoing hemodialysis are comparable with those of patients with normal renal function, and the dosage can be derived from one‐compartment pharmacokinetics.
The Effect of Rifampin on Theophylline Kinetics
Authors: Boyce Eric G. , Dukes George E. , Rollins Douglas E. , Sudds Thomas W.
Published: March 2013

The effect of rifampin on the pharmacokinetics of theophylline was studied in ten healthy nonsmoking men (age, 23–42 years). Each subject received 5.9‐6.8 mg/kg of aminophyl‐line intravenously over 20 minutes before and at the end of two weeks of oral rifampin therapy (600 mg/d). Theophylline serum concentrations were measured serially over the 24 hours following each aminophylline infusion. In every subject, rifampin caused an increase in total clearance (from 0.88 ± 0.21 to 1.21 ± 0.29 mL/min/kg) and terminal elimination rate constant (from 0.104 ± 0.023 to 0.148 ± 0.030 hr−1) and a decrease in the area under the theophylline concentration‐time curve (from 104 ± 29 to 76 ± 19 hr‐mg/L) and half‐life of theophylline (from 7.0 ± 1.7 to 4.8 ± 0.9 hr). All of these changes were significant (P < .02, Wilcoxon matched‐pair, signed‐rank, two‐tailed test). The apparent volume of distribution of theophylline did not consistently change following rifampin administration (mean change, −4%; range, −18‐+20%, P > .20). Patients should be monitored for signs of decreased theophylline efficacy when rifampin is added, or of increased theophylline toxicity when rifampin is discontinued from maintanence therapy.
A Multiple‐Dose Comparison of Ketorolac Tromethamine with Diflunisal and Placebo in Postmeniscectomy Pain
Authors: Honig W. J. , VAN Ochten J.
Published: March 2013

The efficacy of oral ketorolac 5 mg and 10 mg taken qid was compared in a randomized double‐blind study with that of oral diflunisal 500 mg bid (interleaved with placebo twice daily) and of placebo, in 120 patients suffering at least moderate pain following meniscectomy. The trial comprised two phases: (1) an acute phase (the first postoperative day) and (2) a chronic phase (days 2–5 postoperatively). Acutely, pain was assessed before drug administration, and then 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 9.0 hours after the first dose. The second of the four daily doses was administered at four hours after the first dose. During the chronic phase, pain was assessed using visual analogue scales at 8 am and 4 pm daily. The acute phase results show that all the active treatments were statistically significantly superior to placebo but were not distinguished from each other. Over the chronic phase, ketorolac 5 mg and placebo showed similar results, with diflunisal showing the least pain relief and ketorolac 10 mg the most. All the active treatments showed a low incidence of side effects and, in an overall evaluation, no one treatment was distinguishable. Ketorolac would seem to be an acceptable therapy for acute postoperative pain.
A Double‐Blind, Parallel Comparison of Ketoprofen, Aspirin, and Placebo in Patients With Postpartum Pain
Authors: Sunshine Abraham , Zighelboim Itic , Laska Eugene , Siegel Carole , Olson Nancy Z. , de Castro Ana
Published: March 2013

Our purpose was to evaluate the analgesic efficacy of single oral doses of ketoprofen 25, 50, and 100 mg compared with aspirin 650 mg and placebo in the relief of moderate to severe postepisiotomy, uterine cramping, or cesarean section pain. One hundred and fifty‐six patients participated in a randomized, double‐blind, stratified, parallel‐group study. They were observed over a six‐hour period by one nurse‐observer. Several of the standard summary measures of analgesia were derived from the interview data, including the sum of pain intensity differences (SPID) and the sum of the hourly relief values (TOTAL). The study showed significant differences between aspirin and placebo for four‐hour SPID and several other parameters and between ketoprofen at all dose levels and placebo for the four‐ and six‐hour SPID and many other parameters. The two higher doses of ketoprofen were significantly more effective than aspirin as assessed by the four‐ and six‐hour SPID, TOTAL, and other summary measures. The low dose of ketoprofen, although not significantly different from aspirin for SPID and TOTAL, showed a significantly faster onset of relief and had a better global rating. This study suggests that 50 mg of ketoprofen may be the clinical dose of choice as an analgesic. There were no adverse effects reported.
Protein‐Bound Homocyst(e)ine in Patients With Rheumatoid Arthritis Undergoing D‐Penicillamine Treatment
Authors: Kang Soo‐Sang , Wong Paul W. K. , Glickman Paul B. , MacLeod Catherine M. , Jaffe Israeli A.
Published: March 2013

Protein‐bound homocyst(e)ine was measured in the plasma of 38 nonhomocystinuric patients with rheumatoid arthritis. Nineteen of them were treated orally with d‐penicillamine 100‐1,500 mg/d for a period of one month to 15 years. For these patients, the mean ± standard deviation level of plasma protein‐bound homocyst(e)ine was 1.95 ± 1.07 nmol/mL. In contrast, the mean plasma level of protein‐bound homocyst(e)ine was 4.72 ± 1.11 nmol/mL in the 19 patients who had not been treated with oral d‐penicillamine. There was a statistically significant difference (P < .0001) in the plasma protein‐bound homocyst(e)ine concentrations between patients with and without oral d‐penicillamine therapy. Thus, it may be speculated that oral d‐penicillamine may be beneficial in protecting patients from the development of thromboembolism and arteriosclerosis.
Absence of Response to Histamine1Blockade
Authors: Giannini A. James , Price William A. , Giannini Matthew C. , Lazarus Howard D. , Loiselle Robert H.
Published: March 2013

Absence of Response to Histamine1 Blockade in Phencyclidine Toxicity
Controversy I: Patients or Healthy Volunteers for Pharmacokinetic Studies?
Authors: Brazzell Romulus K. , Colburn Wayne A.
Published: March 2013

Many factors should be considered when choosing an appropriate population for a pharmacokinetic trial. Although there are some generalities that apply to most studies, each investigation must be judged separately, since the relevant considerations will vary depending on the particular study, the nature of the drug, and the population that will receive it for therapeutic benefit. Some of the most important information that is generated from pharmacokinetic studies concerns the pharmacokinetic variability among patients and the factors that can influence this variability under the conditions that the drug will be used. This information can best be obtained from a combination of baseline studies to define the variability within the patient population(s) and comparative studies to determine the impact of specific variables on the disposition of the drug and its pharmacokinetic variability. These data can provide valuable information to the clinician that can be used to individualize drug dosage and optimize therapy as well as to identify populations who may be at high risk of therapeutic failure or drug toxicity. It is our feeling that baseline studies in patients are necessary for understanding the pharmacokinetics of a drug, whereas the objectives of most comparative studies can be achieved using healthy volunteers. For most comparative studies, the data obtained from healthy volunteers will reflect what will occur in patients, especially if the variable of interest is drug absorption. This is particularly important when practical and ethical considerations preclude the use of patients. When considering studies in the elderly, one must decide whether the variable of interest may be influenced by age. Baseline pharmacokinetic studies in both patients and healthy volunteers should be conducted, whenever possible, before undertaking comparative studies in order that the data generated can provide a basis for choosing the population for subsequent, more rigorous studies. It is imperative to sufficiently understand the pharmacokinetics of the drug so that one can judge whether a given population will provide information that can be applied to patients who will use the drug for therapy. If the study objective can be successfully fulfilled without the need for a specific patient population, and if the data from healthy volunteers can be extrapolated to patients, practical considerations would suggest that healthy subjects should be used.
Rising Multiple‐Dose Pharmacokinetics of Labetalol in Hypertensive Patients
Authors: Chung Menger , Leitz Frederick H. , Maier Gary , Patrick James E. , Gural Richard P. , Symchowicz Samson
Published: March 2013

Labetalol a drug possessing both alpha‐ and beta‐adrenergic blocking activities, is used in the treatment of hypertension. The current study was undertaken to elucidate the steady‐state pharmacokinetics of labetalol following a rising oral multiple‐dosage regimen. Twelve patients received oral labetalol every 12 hours for 18 days. An initial dose of 100 mg was increased at three‐day intervals to 200, 300, 400, and 600 mg q12h. Selected blood samples were taken at various times following drug administration at each dose level and analyzed for labetalol levels by a specific high‐performance liquid chromography assay. The pharmacokinetics of labetalol are best described by a two‐compartment open model with first‐order absorption. The half‐lives of the absorption, distribution, and elimination phases are 0.6, 1.3, and 8.3 hours, respectively. The steady‐state plasma drug concentrations are predictable from the pharmacokinetic data and are in good agreement with the observed values. Steady‐state levels are reached by the third day at each dose level studied and increase proportionally with dose.
Dose‐ and Time‐Dependent Binding and Kinetics of Pindolol in Patients With Congestive Heart Failure
Authors: Lima John J. , Binkley Philip F. , Johnson Julie , Leier Carl V.
Published: March 2013

Dose‐ and time‐dependent pharmacokinetics and plasma protein binding of pindolol were studied in patients with idiopathic cardiomyopathy who had mild to moderate congestive heart failure. The binding and plasma concentrations of pindolol at various times following the oral administration of single 5‐ and 10‐mg doses and multiple 10‐mg doses were determined. The binding of pindolol to plasma protein was time‐dependent, increasing from 26% on the first day to 31% during the third day of treatment (P < .05); this was probably due to increased alpha‐1‐acid glycoprotein concentration. Analysis of the plasma concentration‐time data indicated dose‐independent pharmacokinetics. Pindolol pharmacokinetics were time‐dependent in one patient. Absorption and elimination half‐lives ranged between 0.05 to 0.6 and 1.6 to 7.2 hours, respectively.
The Influence of Pindolol and Hydrochlorothiazide on Blood Pressure, and Plasma Renin and Plasma Lipid levels
Authors: Johnson Brian F. , Weiner Bonnie , Marwaha Raj , Johnson Johanna
Published: March 2013

After three weeks' administration of placebo, three groups of eight patients with moderate hypertension were randomly assigned to single daily dose, double‐blind treatment with either pindolol 15 mg, hydrochlorothiazide 50 mg, or a combination of both for eight weeks. All determinations were made 24 hours after ingestion of a dose. Reductions in supine, sitting, and standing systolic and diastolic blood pressure were greater in patients receiving hydrochlorothiazide than in those administered pindolol; however, the greatest reductions were registered in individuals receiving combination therapy. Mean basal plasma renin activity rose significantly from 0.45 ± 0.44 to 1.42 ± 1.31 ng/mL/hr and from 0.67 ± 0.46 to 1.27 ± 0.83 ng/mL/hr in patients receiving hydrochlorothiazide and combination therapy, respectively, but there was no change in those administered pindolol. Hydrochlorothiazide and combination therapy increased mean total cholesterol levels from 247 ± 25 to 263 ± 37 mg/dL and 198 ± 36 to 211 ± 33 mg/dL, respectively, at eight weeks, and both increased mean triglyceride concentrations at two weeks. Pindolol did not show any tendency to alter lipid levels. Pindolol should be given twice daily. At 15 mg daily, it has little or no effect on basal plasma renin activity or plasma lipid levels.
Pharmacokinetics of Captopril in Elderly Healthy Male Volunteers
Authors: Creasey William A. , Funke Phillip T. , McKinstry Doris N. , Sugerman A. Arthur
Published: March 2013

The pharmacokinetics of captopril were studied in 12 healthy male volunteers aged 65 to 76 years, who each received a single 100‐mg oral dose. Blood and urine samples were collected over a 24‐hour period, and assayed for unchanged captopril (CAP), S‐methyl captopril (Me‐CAP, plasma concentrations from 2 subjects only), and total captopril levels (TOT, a mixture of CAP and its dimer and mixed disulfides with endogenous thiolcontaining compounds such as glutathione and cysteine). Mean values for the maximum concentration (Cmax) were 803 and 66.3 ng/mL for CAP and Me‐CAP, respectively. Mean time to maximum concentration (tmax) was determined as 1.0, 1.4, and 1.0 for CAP, TOT, and Me‐CAP, respectively. Mean areas under the plasma concentration‐time curve (AUC) were 1,394 hr‐ng/mL (CAP, 0–8 hr) and 17,316 hr‐ng/mL (TOT, 0–24 hr). The mean estimated half‐life (t1/2) for CAP was 1.4 hr, and its renal clearance was 187 mL/hr/kg. Mean urinary excretion over 24 hr was 20.8 and 53.1 for CAP and TOT, respectively. Cmax, and AUC for CAP were 9% less and 13% greater, respectively, than in a historical control group of 18–35‐year‐old men, treated in the same clinic, by the same personnel, using the same analytic procedures, whereas the 24‐hour urinary excretion was 25% lower and eight‐hour renal clearance 36% lower in the older population. Since the values for Cmax, AUC, and t1/2 were similar in the two populations, it does not appear that the pharmacokinetics of CAP are altered markedly with age alone.
The Effect of Etodolac Administration on Renal Function in Patients With Arthritis
Authors: Shand David G. , Epstein Carol , Kinberg‐Calhoun Judy , Mullane John F. , Sanda Marie
Published: March 2013

The effect of etodolac 50–600 mg/d on renal function was assessed in four‐ to 52‐week trials in 1,382 patients with arthritides. No patient was withdrawn from treatment due to an abnormal renal function test related to etodolac administration. There were no significant differences in the incidence of definite renal function abnormalities between patients receiving etodolac and those receiving placebo. Both etodolac and placebo groups had a significantly lower incidence of deviant BUN results than either aspirin‐ or sulindac‐treated patients. Fewer than 2% of patients receiving etodolac showed either a persistent or variably persistent pattern of deviant renal function tests. The results in these studies indicate that chronic etodolac therapy did not adversely affect renal function in patients with arthritis.
Intravenous Dezocine for Postoperative Pain: A Double‐Blind, Placebo‐Controlled Comparison With Morphine
Authors: Pandit Uma A. , Kothary Sarla P. , Pandit Sujit K.
Published: March 2013

Dezocine, a new mixed agonist‐antagonist opioid analgesic, and morphine were compared in a double‐blind study in 206 patients with postoperative pain. The analgesic efficacy of single intravenous injections of dezocine (2.5, 5.0, and 10.0 mg), morphine (5.0 mg), and placebo was assessed by verbal and visual scales at regular intervals for six hours after administration. All active treatments provided greater pain relief than placebo. Pain relief with dezocine 5 and 10 mg was significantly greater (P < .05) than with placebo for up to four and five hours, respectively, and with morphine up to one hour. Pain relief scores were significantly higher (P < .05) with morphine than with placebo at all observations except that of the fifth hour, and higher with dezocine 2.5 mg than with placebo for the first 30 minutes. Doses of 5 and 10 mg of dezocine produced approximately the same peak analgesic effect, with the larger dose having a longer duration of effect. All active treatments produced mild to moderate sedation. Side effects were few and mild or moderate with all of the treatments. The physician's and the patients' evaluations favored dezocine in a dose‐dependent order, with morphine 5 mg rated lower than dezocine 5 mg and higher than dezocine 2.5 mg.
Absence of Tachyphylaxis in Gastric Acid Secretion During Pentagastrin Infusion
Authors: Chin T. W. F. , MacLeod S. M. , Mahon W. A.
Published: March 2013

Tachyphylaxis to stimulation of gastric juice secretion during intravenous pentagastrin (PG) infusion has been reported in animal studies. We assessed the course of gastric response to PG 2 μg/kg/hr over eight hours in eight healthy subjects. Peak H+, pepsin, and volume secretions occurred during the second half hour of stimulation. Peak H+ output was 11.6 ± 1.3 mmol/0.5 hr or 7.6 ± 0.8% of the total eight‐hour secretion. During subsequent half‐hour collection intervals, there was no significant decline in response, and the average output was 10.3 ± 0.4 mmol/0.5 hr (6.5 ± 0.1%). Peak pepsin and volume secretions were respectively 10.0 ± 1.4% (74.8 ± 11.6 mg/0.5 hr) and 8.8 ± 1.1% (146.3 ± 17.4 mL/0.5 hr) of the total eight‐hour secretion. Although there was a significant decline in pepsin and volume response subsequent to the peak output, the decline was not continuous, and pepsin and volume secretions were maintained, respectively, at 6.0 ± 0.2% (46.1 ± 2.5 mg/0.5 hr) and 6.2 ± 0.1% (107.5 ± 3.0 mL/0.5 hr) of the total eight‐hour secretion. Our study did not demonstrate any tachyphylaxis in H+ response to continuous PG stimulation. This model appears to be a valid tool for the assessment of histamine‐H2 antagonist effects on stimulated gastric juice secretion over 8 hours in humans.
Pharmacokinetics of Ranitidine in Patients With Renal Failure
Authors: Garg Dyal C. , Baltodano Neyton , Jallad Nader S. , Perez Guido , Oster James R. , Eshelman Fred N. , Weidler Donald J.
Published: March 2013

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6–54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378–808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half‐life following oral administration was 8.5 ± 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% ± 10.5%. After IV administration, the elimination half‐life, plasma clearance, renal clearance, and volume of distribution were 7.0 ± 1.0 hours, 170 ± 38 mL/min, 36.0 ± 25.0 mL/min, and 1.3 ± 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P < .05) after IV administration. The elimination half‐life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2‐blocking activity.
Pharmacokinetics and Clinical Effects of Alprazolam Following Single and Multiple Oral Doses in Patients With Panic Disorder
Authors: Ciraulo Domenic A. , Barnhill Jamie G. , Boxenbaum Harold G. , Greenblatt David J. , Smith Randall B.
Published: March 2013

The anxiolytic triazolobenzodiazepine alprazolam was administered to six male patients, aged 26 to 46 years, with panic disorder or agoraphobia (with panic attacks) to assess clinical effects and steady‐state pharmacokinetics following multiple dosing at three levels: 3.0 mg/d, 6.0 mg/d, and 9.0 mg/d. Multiple‐dose kinetics of alprazolam were compared with alprazolam disposition after a 1.0‐mg oral dose in the same patients. Kinetic variables after the single dose were very similar to those reported previously for healthy young male volunteers. Mean values were peak plasma concentration, 19 ng/mL; time of peak, 1.33 hours after dosage; elimination half‐life, 10.0 hours; total oral clearance, 1.11 mL/min/kg. During multiple dosage, mean steady‐state plasma concentrations (Css) was proportional to dosing rate, and steady‐state clearance was independent of dosage. Clinical improvement was rapid, with the greatest decrement in symptoms at the 3‐mg/d dosage, at a mean Css of 30 ng/mL. Further improvement was not seen at 6 mg/d (Css 62 ng/mL), or at 9 mg/d (Css, 103 ng/mL). Side effects, however, were directly related to dosage and plasma level, and increased progressively in number at the 3‐, 6‐, and 9‐mg/d dosage levels. Thus, the disposition of alprazolam in young male patients with panic disorder is essentially identical to that in healthy male volunteers of similar age. Alprazolam clearance is independent of dose and plasma concentration up to daily doses of at least 9 mg/d, with steady‐state plasma level proportional to dosing rate.
Interaction of Diazepam With Famotidine and Cimetidine, Two H2‐Receptor Antagonists
Authors: Locniskar Ann , Greenblatt David J. , Harmatz Jerold S. , Zinny Michael A. , Shader Richard I.
Published: March 2013

Famotidine is currently under investigation as an H2‐receptor antagonist. Eleven healthy male volunteers received a single 10 mg intravenous dose of diazepam on three occasions: once during coadministration of famotidine 40 mg bid, once during coadministration of cimetidine 300 mg qid, and once without other drug treatment (control). Multiple blood samples were drawn during the seven days after each diazepam dose. Diazepam and desmethyldiazepam plasma concentrations were measured by electron capture gas chromatography. There were no significant differences among the three treatment conditions in diazepam central compartment volume or total volume of distribution. During the cimetidine as compared with the control treatment, diazepam elimination half‐life was significantly increased (72 vs 55 hr, P < .05), total area under the curve (AUC) increased (11.8 vs 9.8 hr‐μg/mL, P < .05), and total clearance reduced (0.20 vs 0.28 mL/min/kg, P < .05). Seven‐day AUC for desmethyldiazepam also increased (4.6 vs 3.8 hr‐μg/mL, P < .05). However, there were no significant differences between famotidine and control treatment conditions in diazepam elimination half‐life (53 vs 55 hr), total AUC (9.5 vs 9.8 hr‐μg/mL), or total clearance (0.28 vs 0.28 mL/min/kg) or in seven‐day AUC for desmethyldiazepam (3.9 vs 3.8 hr‐μg/mL). Thus, therapeutic doses of cimetidine significantly impair the clearance of diazepam and desmethyldiazepam. Therapeutic doses of famotidine do not impair diazepam and desmethyldiazepam kinetics, suggesting that there is no significant kinetic interaction when diazepam and famotidine are administered concurrently in clinical practice.
Noninteraction of Digoxin and Nifedipine in Cardiac Patients
Authors: Garty M. , Shamir E. , Ilfeld D. , Pitlik S. , Rosenfeld J.B.
Published: March 2013

Digoxin and calcium antagonists are frequently used together in the treatment of cardiac diseases. There are elevated digoxin levels in patients receiving digoxin together with presently available or investigational calcium antagonists, such as verapamil, diltiazem, gallopamil, nicardipine, and tiapamil. However, reports of possible nifedipine‐digoxin interactions have yielded controversial results. This study was undertaken to determine if an interaction between nifedipine and digoxin does exist and, if so, to determine its pharmacokinetic basis.
Bioanalytic Considerations for Pharmacokinetic and Biopharmaceutic Studies
Authors: Pachla Lawrence A. , Wright D. Scott , Reynolds Donald L.
Published: March 2013

The correct evaluation of pharmacokinetic and biopharmaceutic data can only be achieved if accurate analytic data are obtained. The accuracy of analytic data depends on the criteria used to validate the method. Consequently, careful scrutiny of drug stability, assay sensitivity, selectivity, recovery, linearity, precision, and accuracy is necessary for the proper interpretation of data. The importance of method validation and its influence on pharmacokinetic and biopharmaceutic data evaluation and interpretation will be discussed.
Pharmacokinetic and Pharmacodynamic Modeling of Cibenzoline Plasma Concentrations and Antiarrhythmic Effect
Authors: Holazo Alice A. , Brazzell Romulus K. , Colburn Wayne A.
Published: March 2013

The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total‐data set, average‐data set, and grouped‐data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average‐data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.
Labetalol in the Treatment of Essential Hypertension: A Single‐Blind Dose Ranging Study
Authors: Dux Shlomo , Grosskopf Itamar , Boner Geoffrey , Rosenfeld Joseph B.
Published: March 2013

The hypotensive efficacy of labetalol was evaluated in 29 patients with essential hypertension in a single‐blind dose ranging study. After a two‐week period of placebo treatment, labetalol was given in oral doses of 0.6 g/d, 0.8 g/d, and 0.8 g/d combined with 25–50 mg/d of hydrochlorothiazide. Each regimen lasted four weeks. The decrease in blood pressure was dose dependent: 90% of patients showed a significant reduction in diastolic blood pressure and 75% showed a significant reduction in systolic blood pressure. In 69% of the patients, side effects of the drug were noted, and in five patients (17%), treatment was discontinued because of the side effects. Seven patients received labetalol intravenously before the oral treatment. Their heart rate and blood pressure reductions were similar to those found in patients only taking the medication orally. We conclude that labetalol is an efficient and safe antihypertensive agent in both oral and intravenous administration. However, the high incidence of side effects makes labetalol a drug of second choice in uncomplicated hypertensive patients.
Cardiovascular and Neuromuscular Effects of Esmolol During Induction of Anesthesia
Authors: Murthy V. Shrinivas , Patel Kita D. , Elangovan Rakki G. , Hwang Tsae‐Fung , Solochek Sheldon M. , Steck James D. , Laddu Atul R.
Published: March 2013

Sixteen subjects scheduled for surgical procedures under general anesthesia participated in an investigation of the effects of esmolol on the transient hypertension and tachycardia that was observed during endotracheal intubation and on the duration of succinylcholine‐induced neuromuscular blockade. In eight subjects, infusion of esmolol was begun five minutes before induction of anesthesia and continued for 12 minutes after induction. In the remaining subjects, an equivalent volume of solvent (D5W) was infused for 12 minutes. Infusion of esmolol significantly attenuated the cardioacceleration observed during intubation without any significant effect on the pressor effects of the procedure. Esmolol delayed the recovery from succinylcholine‐induced neuromuscular blockade by less than three minutes. The mechanism of this delay remains to be investigated, although such a delay does not have clinical significance. Esmolol‐induced attenuation of the tachycardia seen during intubation may offer a protective effect on the myocardium, especially in elderly subjects and patients with coronary artery disease.
Cyclosporine Concentration Determinations for Monitoring and Pharmacokinetic Studies
Authors: Ptachcinski Richard J. , Burckart Gilbert J. , Venkataramanan Raman
Published: March 2013

The availability of the immunosuppressant cyclosporine has led to significant improvements in the recent success of clinical organ transplantation. Problems associated with cyclosporine therapy include serious adverse reactions, such as nephrotoxicity, wide variability in the drug's pharmacokinetics, and several complex drug interactions. Monitoring of drug concentrations is accepted as a part of the routine care of patients receiving cyclosporine. However, cyclosporine concentrations can be determined in different biologic fluids by either radioimmunoassay or high‐performance liquid chromatographic techniques. Controversy exists regarding the optimal analytic technique to be used for cyclosporine monitoring and pharmacokinetic studies. This commentary addresses factors including: (1) why the monitoring of cyclosporine concentrations is important, (2) the differences between the biologic fluids and analytic techniques, (3) when monitoring and special pharmacokinetic studies are indicated, (4) what some major transplant centers have established as a “therapeutic range” for cyclosporine concentrations, and (5) provides guidelines for the optimal clinical monitoring of cyclosporine concentrations.
Cyclosporine Blood Concentrations Determined by Specific Versus Nonspecific Assay Methods
Authors: Blyden Gershwin T. , Franklin Cass , Cho Sang I. , Kaplan Marshall M. , Hirsch Carl A. , Greenblatt David J.
Published: March 2013

Cyclosporine blood concentrations were simultaneously determined by radioimmunoassay (RIA) and high‐performance liquid chromatography (HPLC) at multiple points in time in two patients receiving cyclosporine for immunosuppression following liver transplantation. Radioimmunoassay levels always exceed those determined by HPLC; however, the divergence between the two methods increased as serum bilirubin concentration increased, with HPLC:RIA ratios generally less than 0.3 when serum bilirubin concentrations exceeded 10.0 mg/dL. These preliminary results suggest that retention of immunoactive cyclosporine metabolites due to impaired liver function may account for RIA‐determined cyclosporine concentrations that greatly exceed those measured by HPLC.
Inhibition of Tolbutamide Elimination by Cimetidine but not Ranitidine
Authors: Cate Emily W. , Rogers John F. , Powell J. Robert
Published: March 2013

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on tolbutamide pharmacokinetics. Twelve healthy men were given a 1‐g oral dose of tolbutamide on three occasions. Subjects were randomly assigned to three treatments in a crossover fashion: cimetidine 1,200 mg/d, ranitidine 300 mg/d, and placebo. Cimetidine significantly increased the tolbutamide area under the plasma concentration‐time curve by 20% (range, −5% to 42%), increased the elimination half‐life by 17%, and decreased the carboxytolbutamide:tolbutamide plasma ratio from 0.042 to 0.036. Ranitidine did not significantly alter tolbutamide pharmacokinetics.
Stable Isotopes: Origins and Safety
Authors: Klein Peter D. , Klein E. Roseland
Published: March 2013

Fundamental studies of the atomic elements in the first quarter of the 20th century resulted in the recognition of the isotopes of oxygen, carbon, nitrogen, and finally hydrogen. The unique character of a hydrogen isotope led quickly to its enrichment, to the investigation of its biologic effects, and ultimately to its use as a tracer in biologic transformations. As a tracer, deuterium provided a totally new appreciation of the living organism: as one in constant flux. Together with 15N, 13C, and 18O, the foundation of modern biochemistry was laid. The milestones in stable isotope history, their architects and their impact on the research of that time are reviewed.
Isotope Effects: Definitions and Consequences for Pharmacologic Studies
Authors: Van Langenhove Agnes
Published: March 2013

The use of stable isotope‐labeled compounds for pharmacologic studies requires careful consideration of the nature of the stable isotope label (2H, 13C, 15N, 18O) and its position of incorporation in the molecule. When deuterium is used, improper positioning can lead to significant primary isotope effects. Primary isotope effects occur when the breaking of the bond to the heavy isotope is the rate‐limiting step in a reaction (or metabolic transformation). A reaction will proceed slower for the molecule with the heavy isotope label because of the mass difference between the light and the heavy isotope. In addition to these primary isotope effects, smaller but nevertheless important secondary isotope effects, physicochemical isotope effects, active hydrogen/deuterium exchange, or isotope effects associated with either the enzyme‐catalyzed biotransformation or the mass spectrometric ionization and fragmentation can be operative. In mechanistic studies, isotope effects are used to their advantage; however, in pharmacokinetic studies, the occurrence of isotope effects can lead to grossly misleading biologic and analytic results: the metabolism of the drug will differ when ‘in vivo’ isotope effects are operative, and isotope effects occurring during the analysis procedure will obscure the true metabolic profile of the drug.
Fundamentals of Present‐Day Mass Spectrometry
Authors: Costello Catherine E.
Published: March 2013

Mass spectral analysis offers much to the field of clinical pharmacology: specificity, sensitivity, reliability, and potential for the structural determination of unknown compounds, even when they are present at very low concentrations as part of complex mixtures. In order to employ mass spectrometry effectively, the researcher or analyst must acquire an understanding of the fundamental processes involved in the technique and some overview of the strengths and limitations of the different options now available. This brief summary is presented as an introduction to the field and should provide the impetus for further reading by the interested investigator.
Applications to Analytic Chemistry: An Evaluation of Stable Isotopes in Mass Spectral Drug Assays
Authors: Garland W.A. , Barbalas M.P.
Published: March 2013

We evaluated stable isotope analogues (SIAs) as internal standards in mass spectral drug assays on the analytic parameters of accuracy, precision, specificity, and limit of quantitation. Only one literature report suggests that the use of an SIA made an assay more accurate, although theoretic considerations strongly support their use. There is substantial evidence, however, that their use made assays more precise. Potentially, the chromatographic peak shape and retention time of the SIA can be compared with those of the analyte to support assay specificity, and this type of comparison has been implemented as a new computer program (QSIMPS). There is some evidence that SIAs can serve in “carrier” substances to increase recoveries and thus lower the limit of quantitation of an assay. However, the use of large amounts of an SIA (relative to the analyte) leads to analytic imprecision, because of memory effects, large blank values, and unacceptable confidence limits.