bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Pharmacodynamics of Tepoxalin after Single Oral Dose Administration to Healthy Volunteers
Authors: Waldman Scott A. , Vitow Cheryl , Osborne Barbara , Gillen Lisa , Argentieri Dennis C. , Wong Francis A. , Smith Ian L. , Chow Andrew T. , Misiti John , Bjornsson Thorir D.
Published: March 2013

This study was conducted to examine the pharmacokinetics and pharmacodynamics of tepoxalin in healthy volunteers, an antiinflammatory compound that inhibits cyclooxygenase and lipoxygenase. Tepoxalin was absorbed after oral administration of single doses from 35 to 300 mg, after which it was rapidly converted to an acidic metabolite, RWJ 20142, which inhibits cyclooxygenase but not lipoxygenase. The areas under the concentration‐time curve (AUC) of tepoxalin and RWJ 20142 in plasma increased in a dose‐dependent fashion. Administration of the lowest dose of tepoxalin completely inhibited whole blood cyclooxygenase for the entire period of observation. This inhibition correlated closely with that of secretion and aggregation induced by collagen of platelets obtained from these subjects. Similarly, administration of tepoxalin was associated with significant inhibition of lipoxygenase in whole blood. Lipoxygenase was inhibited a maximum of 60% in a time‐dependent fashion, and the duration of inhibition was dose‐dependent. These studies demonstrate that tepoxalin inhibits whole blood cyclooxygenase, lipoxygenase, and platelet function after oral administration in humans.
Chiral Kinetics and Dynamics of Ketorolac
Authors: Mroszczak Edward , Combs Daniel , Chaplin Melvin , Tsina Irene , Tarnowski Thomas , Rocha Cynthia , Tam Yuen , Boyd Aileen , Young John , Depass Linval
Published: March 2013

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (‐)S and (+)R enantiomers, resides primarily with (‐)S ketorolac and that the ulcerogenic activity of this agent also resides in (‐)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (‐)S and (+)R KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (‐)S KT was administered, 71% of the area under the concentration‐time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (‐)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (‐)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (‐)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (‐)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (‐)S ketorolac). When (+)R KT was administered, (‐)S ketorolac was not detectable and interconversion was essentially 0%. When (‐)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half‐life was shorter and clearance greater for (‐)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (‐)S was observed, and interconversion of (‐)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (‐)S ketorolac and a different mechanism of interconversion.
Pharmacokinetics of Methylprednisolone and Prednisolone After Single and Multiple Oral Administration
Authors: Rohatagi Shashank , Barth Jürgen , Möllmann Helmut , Hochhaus Günther , Soldner Andrea , Möllmann Carsten , Derendorf Hartmut
Published: March 2013

The pharmacokinetics of methylprednisolone and prednisolone were evaluated in 24 healthy men after oral administration of single and multiple doses for 3 days. For each drug, 6 different administration regimens with doses ranging from 1 to 80‐mg of methylprednisolone and 1.25 to 100‐mg of prednisolone, and administration intervals ranging from 3 to 24 hours for both were investigated. Plasma was assayed using a normal phase high‐performance liquid chromatography (HPLC) method. Methylprednisolone showed linear pharmacokinetics with no apparent dose or time dependency. Prednisolone showed marked dose dependency with higher clearance and volume of distribution for higher doses. This can be explained by its saturable protein binding of plasma, because unbound clearance and unbound volume of distribution were not dose‐dependent. After multiple administration, prednisolone showed significant time‐dependent pharmacokinetics with increased unbound clearance and increased unbound volume of distribution. Due to the complicated pharmacokinetic properties of prednisolone, it is extremely difficult to determine the dose needed to obtain a desired target concentration. The pharmacokinetics of methylprednisolone are more predictable because methylprednisolone concentrations are proportional to dose, and no determination of plasma protein binding is needed. J Clin Pharmacol 1997;37:916–925.
Effect of Age and Gender on Azimilide Pharmacokinetics After a Single Oral Dose of Azimilide Dihydrochloride
Authors: Corey Alfred , Agnew Jeffrey , Bao James , Bryson Philip , Comer Patrick , Griffith Susan , Li Junfang
Published: March 2013

Azimilide is a new class III antiarrhythmic drug that blocks K+ channels. To determine the effects of age and gender on azimilide pharmacokinetics, a single 150‐mg oral dose was administered to 66 healthy volunteers in a 3 × 2 factorial design (age groups of 18–40, 41–64, and ≥65 years). Blood and urine were analyzed for azimilide and metabolites. The single dose was well‐tolerated. Azimilide was 94% plasma protein bound, and binding was not affected by age or gender. Age does not affect azimilide pharmacokinetics. The renal clearance of azimilide was significantly higher in women than in men (19%), but oral clearance did not differ between genders. Although the maximum azimilide concentration (Cmax) was 27% higher in women, time to maximum concentration or area under the azimilide concentration—time curve were not different from those for men. Body weight—adjusted Cmax did not differ between genders. Dosing adjustments based on either age or gender are not required. J Clin Pharmacol 1997;37:946–953.
Pharmacokinetics and Effect of Food on The Bioavailability of Orally Administered Venlafaxine
Authors: Troy Steven M. , Parker Vernon P. , Hicks David R. , Pollack Gary M. , Chiang Soong T.
Published: March 2013

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two‐period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model‐dependent calculation of the first‐order absorption rate constant, and a model‐independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration—time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O‐demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50‐mg tablet. A standard, medium‐fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation. J Clin Pharmacol 1997;37:954–961.
Pharmacokinetic Interaction Between Butorphanol Nasal Spray and Oral Metoclopramide in Healthy Women
Authors: Vachharajani Nimish N. , Shyu Wen Chyi , Barbhaiya Rashmi H.
Published: March 2013

The pharmacokinetics of butorphanol nasal spray, with and without the coadministration of metoclopramide, were studied in 24 healthy women. In this crossover study all volunteers received 3 treatments: a single, 1‐mg dose of butorphanol nasal spray, a single, 10‐mg oral dose of metoclopramide, and a combination of a single, 1‐ mg dose of butorphanol nasal spray and a single, 10‐ mg oral dose of metoclopramide. There was at least a one‐week washout period between sessions. Serial blood samples were collected and plasma samples analyzed using a validated radioimmunoassay to determine the concentration of butorphanol, or a high‐performance liquid chromatography/ultraviolet procedure was used to determine the concentration of metoclopramide. There were no statistically significant differences in the pharmacokinetic parameters, Cmax, tmax, AUC, and t1/2, for butorphanol with or without metoclopramide. Similarly, except for a delay in tmax of metoclopramide with coadministration of butorphanol, the pharmacokinetic parameters of metoclopramide were not significantly different between two treatments. Thus, the pharmacokinetics of both butorphanol and metoclopramide were not significantly altered when administered in combination. The incidence of nausea/vomiting after butorphanol administration was substantially reduced by coadministration of metoclopramide. Based on the pharmacokinetic and safety results, it can be concluded that butorphanol nasal spray and metoclopramide can be administered in combination without altering the dose regimen of either drug. J Clin Pharmacol 1997;37:979–985.
Matrix Metalloproteinases and Coronary Artery Disease: A Novel Therapeutic Target
Authors: Celentano Diane C. , Frishman William H.
Published: March 2013

Matrix metalloproteinases (MMP) are a family of enzymes that selectively digest individual components of the extracellular matrix. Their function has been studied in both normal physiologic processes and pathologic states. In the blood vessel, MMPs play an important role in maintaining the vessel's integrity by breaking down extracellular matrix while new matrix is being synthesized. This is necessary to avoid weakening from continuous mechanical stresses. However, in certain environments, these MMPs may contribute to cardiovascular pathologic processes. The purpose of this review is to first discuss the role of MMPs in coronary vascular disease. Evidence suggests that MMPs contribute to the development of de novo atherosclerotic plaques and postangioplasty restenotic plaques by allowing smooth muscle cells to migrate from the vascular media to the intima. Evidence also suggests that MMPs contribute to the rupture of these plaques by degrading the fibrous cap that surrounds them. With this increased molecular information that concerns the pathogenesis of coronary vascular disease, new molecular therapies aimed at altering these processes are being investigated. The rationale, mode of delivery, and prospects for success of these therapies will also be discussed here.
Single‐Dose Pharmacokinetics of Isepamicin in Young and Geriatric Volunteers
Authors: Nomeir Amin A. , Radwanski Elaine , Cutler David , Affrime Melton , Christopher David , Korduba Chryzanta , Batra Vijay , Lin Chin‐chung , Cayen Mitchell N.
Published: March 2013

Isepamicin is a new aminoglycoside antibiotic with activity against both gram‐negative and gram‐positive bacteria. The pharmacokinetics of isepamicin were evaluated after a 0.5‐hour intravenous infusion of a 15‐mg/kg dose to groups of young adults and geriatric volunteers. Isepamicin was safe and well tolerated. No adverse events related to the infusion were reported. As age increased, there were increases in the elimination phase half‐life (t1/2β) and the area under the plasma concentration—time curve extrapolated to infinity (AUC0‐∞), and decreases in systemic (Cl) and renal clearance (Clr). The changes seen in Cl with age were a result of changes in renal function estimated by creatinine clearance (Clcr). There were no apparent correlations between age and maximum plasma concentration (Cmax), half‐life of the τ‐phase (t1/2τ), volume of distribution at steady‐state (Vdss), or the amount of isepamicin excreted in urine within 24 hours after dose administration (Ae24 hrs). When comparing the elderly (61–80 years old) with the younger (21–60 years) volunteers, the (AUC0‐∞), and t1/2β values were higher in the elderly and the Cl and Clr values were lower, but Cmax, t1/2τ and Vdss were similar in the two age groups. The contribution of the τ‐phase to the overall AUC was minimal and similar for the two age groups. Also, there were no gender effects on the pharmacokinetics of isepamicin in both the young and elderly volunteers. These results demonstrate that changes in the pharmacokinetics of isepamicin in the elderly are attributable to changes in renal function, whereas age, per se, is not a significant factor.
Effect of Repeated Dosing on the Pharmacokinetics of Oral Fluconazole in Bone Marrow Transplant Patients
Authors: El‐Yazigi Adnan , Ellis Michael , Ernst Peter , Hussein Rajaa , Baillie Fiona J.
Published: March 2013

We examined the pharmacokinetics of fluconazole in 11 bone marrow transplant patients after multiple oral daily dose of 200 mg of this drug. Blood was sampled at different intervals on day 1, day 13, and day 27. No dose was given on day 2, day 14, and day 28 to allow the concentration—time data to be collected over 48 hours. The 24 hour urine was also collected, and fluconazole was analyzed in both plasma and urine by a high performance liquid chromatography. The plasma concentration—time data were best described by the one‐compartment model with first‐order absorption. The overall inter‐day change and the difference between day 1 and day 27 in the rate constant for absorption (ka), peak plasma concentration (Cmax), trough plasma concentration (Cmin), time‐to‐peak (tmax), area‐under‐the‐curve 0–24 (AUC0–24), rate constant for elimination (ke), mean residence time after oral administration (MRTor), and fraction of the dose excreted unchanged in urine 24 hours (fu24) were significant (P ≤ 0.0029 and P ≤ 0.01, respectively). However, the difference between day 1 and day 13 was significant (P ≤ 0.05) only in ka, tmax, Cmax, Cmin, and AUC0–24, and between day 13 and day 27 was significant (P ≤ 0.05) only in ka, Cmin, ke, and MRTor. There was no significant inter‐day change in the renal clearance. The significant (P ≤ 0.05) increases in Cmax, Cmin, and AUC0–24 after the dose given on day 13 as compared with day 1, and in Cmin on day 27 as compared with day 13 indicate that, in contrast to volunteers, the steady state condition was not reached on day 13 and possibly not on day 27 in these patients. This perhaps should be taken into account when prescribing fluconazole to seriously ill patients.
Atorvastatin Does Not Alter the Anticoagulant Activity of Warfarin
Authors: Stern Ralph , Abel Robert , Gibson Gordon L. , Besserer Judith
Published: March 2013

Twelve patients chronically maintained on warfarin were administered 80 mg atorvastatin for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of the two‐week treatment period. Thus atorvastatin had no consistent effect on the anticoagulant activity of warfarin and adjustments in warfarin dosing should not be necessary.
Prevention and Treatment of Osteoporosis: Does the Future Belong to Hormone Replacement Therapy?
Authors: Gibaldi Milo
Published: March 2013

Estrogen replacement therapy (ERT) after menopause prevents the development of osteoporosis and reduces the risk of fracture. Other potential benefits are cardioprotection—probably related to the effects of estrogen on lipid profile and fibrinogen levels—and a delay in the onset of Alzheimer's disease and perhaps amelioration of the disease. ERT, however, increases the risk of endometriosis and endometrial cancer unless given with a progestin for at least 10 days per menstrual cycle. It also results in a small but real increase in breast cancer. Alendronate, a bisphosphonate, is the first serious competitor of conjugated equine estrogen for the treatment of osteoporosis. Nearing FDA approval are so‐called designer estrogens (e.g., raloxifene), which may selectively prevent osteoporosis with little or no effects on endometrial and breast tissue.
Effects of Theophylline on Respiratory Drive in Patients with Chronic Obstructive Pulmonary Disease
Authors: Ashutosh Kumar , Sedat Mohammad , Fragale‐Jackson Jody
Published: March 2013

Effects of theophylline administration on the respiratory drive were studied in seven patients with chronic obstructive pulmonary disease (COPD). End tidal CO2 (PetCO2), minute ventilation (Ve), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), oxygen consumption (VO2), carbon dioxide output (VCO2), serum theophylline level (STL), ventilatory response (VeR), and mouth occlusion pressure response (OPR) to rise in PetCO2 on rebreathing were measured before and at 2‐hour intervals after oral administration of 5 mg/kg anhydrous theophylline or placebo. Mouth occlusion pressure response and VeR showed a significant increase after theophylline but not after placebo. Significant positive correlation between changes (Δ) in STL and OPR (ΔOPR = 0.025 + 0.8 ΔSTL; SEE = 1; r = 0.4; P < 0.005) and between STL and VeR (VeR = 0.82 + 0.055 STL ± SEE = 0.7; r = 0.46; P < 0.01) and an inverse correlation between ΔSTL and ΔPetCO2 (ΔPetCO2 = 13.8 − 0.59 ΔSTL; SEE = 9.1; r = 0.61; P < 0.001) were noted. There was no correlation between the indices of respiratory drive and FEV1, Ve, VO2, or VCO2. It is concluded that theophylline increases respiratory drive in clinically employed doses independently of its bronchodilator or metabolic effects.
Testosterone Pharmacokinetics after Application of an Investigational Transdermal System in Hypogonadal Men
Authors: Yu Zhiling , Gupta Suneel K. , Hwang Stephen S. , Kipnes Mark S. , Mooradian Arshag D. , Snyder Peter J. , Atkinson Linda E.
Published: March 2013

This open‐label, randomized, placebo lead‐in, three‐treatment crossover study in 19 hypogonadal men (27–82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.
Effect of Diltiazem on Intraarterial Blood Pressure and Heart Rate During Stress Testing in Patients with Angina: A Gender Comparison Study
Authors: Klassen Gerald A. , Yeung Pollen K. F. , Barclay Katherine D. , Pollak P. Timothy , Hung Orlando R. , Buckley Susan J.
Published: March 2013

The purpose of this study was to measure the blood pressure and electrocardiographic responses of a small, matched group of women (n = 8) and men (n = 9) who experienced typical, effort angina during an exercise on the treadmill (up to the second stage of a Bruce protocol). These responses were measured before and after therapy with diltiazem (60 mg four times daily for 1 week). Reports of previous studies have described significant gender differences in blood pressure responses to diltiazem in healthy volunteers tested with the same protocol. In contrast to the data in healthy individuals, gender differences in blood pressure responses to exercise before and after diltiazem administration were not observed. Results of analysis of pulse pressure responses to exercise were also similar in male and female patients with angina. A significant postexercise drop in blood pressure was observed, which was augmented by diltiazem. These data suggest that gender differences in drug action may be difficult to demonstrate in patients with vascular disease.
Effect of Intravenous Fenoldopam on Intraocular Pressure in Ocular Hypertension
Authors: Everitt Daniel E. , Boike Steven C. , Piltz‐Seymour Jody R. , VanCoevorden Rosita , Audet Patricia , Zariffa Nevine , Jorkasky Diane
Published: March 2013

Intravenous fenoldopam, a selective dopamine‐1 receptor agonist, was compared with placebo in this randomized, double‐blind, two‐period crossover study to evaluate its effects on intraocular pressure, aqueous dynamics, and macular blood flow in patients with elevated intraocular pressure or primary open‐angle glaucoma. Doses of fenoldopam were titrated up to a maximum of 0.5 μg/kg/min. Intraocular pressure, measured by pneumotonometry, was the primary outcome variable. Other outcomes included macular blood flow assessed by blue field examination, visual field examined by automated perimetry, aqueous outflow facility measured by tonography, and aqueous humor production determined by fluorophotometry. During infusions of fenoldopam, intraocular pressure increased from a mean baseline level of 29.2 mmHg to a mean maximum level of 35.7 mmHg. During the placebo infusions, pressure increased from a mean baseline of 28.4 mmHg to a mean of 29.0 mmHg at the time point that corresponded to the mean maximum intraocular pressure on the day intravenous fenoldopam was administered, to yield a mean difference in pressure between study days of 6.7 mmHg (P <0.05). There were no apparent changes in macular blood flow, visual fields, or production or outflow of aqueous humor associated with fenoldopam infusion. The increase in intraocular pressure seen in this population of patients with ocular hypertension during infusions of fenoldopam is consistent with fenoldopam‐associated increases in intraocular pressure reported in previous studies of healthy volunteers and of patients with accelerated systemic hypertension. These results further suggest that dopamine‐1 receptors play a role in the regulation of intraocular pressure.
Pharmacokinetics and Psychomotor Performance of Alprazolam: Concentration—Effect Relationship
Authors: Wright C. Eugene , Sisson Theresa Lasher , Fleishaker Joseph C. , Antal Edward J.
Published: March 2013

The relationship between the pharmacokinetics of alprazolam and dose and the relationship between the concentration of alprazolam and psychomotor performance in healthy male volunteers were investigated in this double‐blind, placebo‐controlled, modified crossover study. Twenty‐four volunteers received placebo in Phase I and then received single 2‐mg, 4‐mg, 8‐mg, and 10‐mg doses of a sustained‐release formulation in Phases II through V, according to a crossover design. Blood samples were collected at several times throughout each phase to 48 hours after the dose; the harvested plasma was assayed for concentrations of alprazolam, 4‐hydroxyalprazolam, and α‐hydroxyalprazolam by high‐performance liquid chromatography. Sedation was rated at each blood‐sampling time and psychomotor performance tests, consisting of digit—symbol substitution and card‐sorting tasks, were conducted at several times after each dose. Area under the concentration—time curve and peak concentration for alprazolam increased proportionally with each higher dose; clearance did not differ significantly between treatments. The concentrations of 4‐hydroxyalprazolam and α‐hydroxyalprazolam increased proportionally with dose and the combined plasma concentrations of the metabolites were less than 15% of unchanged concentrations of alprazolam for all doses. Maximum sedation increased with each increase in dose up to 8 mg, and psychomotor performance decreased with each increase in dose. Performance versus concentration curves for alprazolam exhibited a clockwise hysteresis loop in contrast to the counterclockwise hystereses previously reported for both intravenous and oral doses of immediate‐release tablets. Data through 6 hours after dose were well described by a sigmoid Emax model. Alprazolam exhibits linear pharmacokinetics after single oral doses of sustained‐release tablets between 2 mg and 10 mg. Reversal of the concentration—effect curve to a clockwise loop suggests the counterclockwise hystereses of rapidly absorbed doses was caused by the differing distribution rates into the systemic circulation and effect site and not by metabolite activity.
Effects of Vasodilators Guanethidine, Nicardipine, Nitroglycerin, and Prostaglandin E1 on Primary Afferent Nociceptors in Humans
Authors: Mashimo Takashi , Pak Myon , Choe Huhu , Inagaki Yoshimi , Yamamoto Mitsuaki , Yoshiya Ikuto
Published: March 2013

Although vasodilator agents have been used to alleviate the pain of complex regional pain syndromes, the precise mechanism of pain relief is not well known. In this study the effects of various kinds of vasodilators on primary afferent nociceptors were investigated by measuring the thermal pain threshold. Evaluated in the study were the effects of guanethidine (2 mg/mL), nicardipine (0.2 mg/mL), Nitroglycerin (0.3 mg/mL), and prostaglandin E1 (1 μg/mL) on the cutaneous pain threshold and blood flow at 7‐day intervals in six healthy volunteers. Each aliquot of 0.5 mL of the test vasodilator or lidocaine (10 mg/mL) and saline (control) were intradermally injected at three sites each on both forearms. The pricking‐pain threshold and skin tissue blood flow were determined using a radiant heat—stimulating system and a laser‐Doppler tissue—blood flowmeter, respectively. The pain threshold increased with lidocaine, guanethidine, and nicardipine; remained unchanged with Nitroglycerin; but decreased with prostaglandin E1. In contrast, the skin tissue blood flow increased by four to nine times with all vasodilators. These results indicate that the effect of vasodilators on primary afferent nociceptors is not related to the vasodilating effect and may not involve a common mechanism of action for pain relief in complex regional pain syndromes.
Cyclosporine and Nonsteroidal Antiinflammatory Drugs: Exploring Potential Drug Interactions and Their Implications for the Treatment of Rheumatoid Arthritis
Authors: Kovarik J. M. , Mueller E. A. , Gerbeau C. , Tarral A. , Francheteau P. , Guerret M.
Published: March 2013

A series of clinical pharmacology studies was performed to screen for possible pharmacokinetic/dynamic contributions to drug interactions reported in rheumatoid arthritis patients receiving cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs). No clinically relevant pharmacokinetic changes in any of the drugs were noted when single‐dose cyclosporine was coadministered during a steady‐state regimen of aspirin, indomethacin, or piroxicam in healthy volunteers. Only with diclofenac was an interaction observed whereby the diclofenac area under the concentration—time curve was doubled in the presence of cyclosporine. Based on the outcomes of the screening studies, steady‐state coadministration of both diclofenac and cyclosporine was assessed in rheumatoid arthritis patients, confirming the drug interaction of diclofenac with cyclosporine. Although the drug interaction was accompanied by a significant rise in serum creatinine, there was no apparent concentration—effect relationship, inasmuch as the increase in diclofenac exposure was not related to the magnitude of increase in serum creatinine. Based on the results of these five drug—drug interaction studies and the known biotransformation pathways of nonsteroidal antiinflammatory drugs, it is speculated that the pharmacokinetic interaction, which is unique to diclofenac, is caused by inhibition by cyclosporine of diclofenac's first‐pass metabolism. Caution and appropriate clinical monitoring are recommended whenever cyclosporine and NSAIDs are coadministered; however, diclofenac in particular should be administered near the lower end of its therapeutic range when it is initially combined with cyclosporine in the treatment of rheumatoid arthritis.
Adulteration by Synthetic Therapeutic Substances of Traditional Chinese Medicines in Taiwan
Authors: Huang Weng F. , Wen Kuo‐Ching , Hsiao Mei‐Ling
Published: March 2013

The adulteration by synthetic therapeutic substances of traditional Chinese medicines has been reported on various occasions and has been a public health concern in Taiwan over the past several years. A large‐scale effort was initiated in 1992 to screen traditional Chinese medicines that were suspected of adulteration with synthetic therapeutic substances. The term “adulteration” refers to traditional Chinese medicines that are tested and found to contain chemical substances not prescribed or labeled as part of the intended use. A total of 2,609 samples were collected by eight major general hospitals in Taiwan. Samples were collected through physicians' referrals during patient visits. The samples were analyzed by hospital pharmacists following the established standard procedures in comparison to references by thin‐layer chromatography. An average of 23.7% (n = 618) of the samples collected from the eight hospitals were adulterated. Four samples with either a rheumatoid or an antiinflammatory indication contained six different kinds of adulterants. More than half (52.8%) of the adulterated traditional Chinese medicines contained two or more adulterants. The sources of adulterated samples and their claimed indications, as well as the most frequently detected synthetic therapeutic substances, are presented in this report. The controversies regarding the combination of synthetic therapeutic substances and traditional Chinese medicines without adequate labeling should be resolved through regulatory actions for better safety of drug use.
New Dimensions in the Pharmacologic Treatment of Schizophrenia and Related Psychoses
Authors: Buckley Peter F.
Published: March 2013

During the past 5 years unprecedented advances have taken place in the psychopharmacology of schizophrenia and related psychoses. Clozapine and risperidone, two prototypic novel antipsychotic drugs, have had a significant impact on the treatment of psychotic disorders. Additionally, they have ushered in another generation of antipsychotic drugs with complex pharmacologic profiles, potentially enhanced efficacy, and more benign side‐effect profiles than previously associated with conventional antipsychotic medications. This review highlights these developments, implications for the management of psychotic disorders, and the use of novel antipsychotic drugs in specific clinical subgroups.
Pharmacokinetics of Zileuton and Its Metabolites in Patients with Renal Impairment
Authors: Awni Walid M. , Wong Shekman , Chu Sou‐yie , Patterson Karen , Hansen Robert , Machinist Joseph M. , Drajesk Jeff , Keane William F. , Halstenson Charles E.
Published: March 2013

The pharmacokinetics of zileuton and its conjugated metabolites were evaluated in patients with chronic renal impairment. Five healthy volunteers (creatinine clearance >90 mL/min), five patients with renal failure requiring hemodialysis, six with mild (creatinine clearance, 60–90 mL/min), eight with moderate (creatinine clearance, 30–59 mL/min), and six with severe (creatinine clearance <30 mL/min) renal impairment participated in the study. Zileuton was well tolerated by all participants including those with severe renal impairment and those receiving hemodialysis. The pharmacokinetics of zileuton were similar in healthy volunteers; in patients with mild, moderate and severe renal impairment; and in patients with renal failure requiring hemodialysis. The mean metabolite/parent‐area ratios for the pharmacologically inactive zileuton glucuronides progressively increased with the decline in renal function. A very small percentage of the administered zileuton dose (<0.5%) was removed by hemodialysis. Therefore, adjustment in the dose regimen of zileuton does not appear to be necessary for patients with various degrees of renal impairment and patients with renal failure requiring hemodialysis.
Influence of Oral Contraceptive Use and Cigarette Smoking, Alone and Together, on Antipyrine Pharmacokinetics
Authors: Scavone Joseph M. , Greenblatt David J. , Abernethy Darrell R. , Luna Becki G. , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

The pharmacokinetics of antipyrine following a single 1‐g intravenous dose was determined in 63 healthy women. Subjects were divided into 4 groups as follows: 1) cigarette smokers using low‐dose oral contraceptives (n = 15); 2) nonsmokers using low‐dose oral contraceptives (n = 12); 3) cigarette smokers not using oral contraceptives (n = 10); and 4) controls, neither cigarette smokers nor oral contraceptive users. Plasma antipyrine concentrations during 24 to 48 hours after dosage were measured by high‐performance liquid chromatography. Mean kinetic variables in the nonsmoking, non—oral contraceptive using control group were: volume of distribution, 37.7 L; elimination half‐life, 13.2 hours; and clearance, 34.4 mL/min. In cigarette smoking, non—oral contraceptive users versus controls, elimination half‐life was reduced (8.0 vs. 13.2 hours, P <0.05) and clearance increased (56.0 vs. 34.4 mL/min, P <0.05). In nonsmoker oral contraceptive users, the reverse was true (elimination half‐life was significantly increased: 16.6 vs. 13.2 hours, P <0.05; and clearance was significantly decreased: 24.8 vs. 34.4 mL/min, P <0.05). In smokers who were using oral contraceptives, values were not significantly different from controls (elimination half‐life, 11.2 hours; clearance, 39.5 mL/min). Volume of distribution did not differ among the four groups. Thus the opposing effects on antipyrine clearance of the induction of metabolism by cigarette smoking and the inhibition due to low dose oral contraceptive use in effect negate each other when combined in humans.
The Pharmacologic Approach to the Treatment of Obesity
Authors: Weiser Mitchell , Frishman William H. , Michaelson M. Dror , Abdeen M. Anwar
Published: March 2013

Obesity is a major risk factor for morbidity and mortality, and a series of pharmacologic approaches are available for helping to manage the problem. Obesity is caused by an imbalance between caloric intake and energy expenditure, which is influenced by both environmental and genetic factors. Pharmacologic treatments include anorexigenic agents, which fall into two broad categories: those that act via brain catecholamine pathways and those that act via serotonin pathways. The most recent oral agents approved are dexfenfluramine, which is currently being marketed, and sibutramine. Both agents inhibit the control reuptake of serotonin but in addition may have effects on thermogenesis. Under investigation are agents that increase energy expenditure: the β3‐adrenergic receptor agonists and drugs that prevent the intestinal absorption of free fatty acids and cholesterol. In development are innovative approaches to influence leptin and its receptors, various obesity genes, and biologic substances thought to influence satiety (neuropeptide Y, enterostatin, cholecystokinin, bombesin, and amylin). Obesity has now become a major target for drug development not only for affecting obesity per se but also for managing and preventing comorbid conditions such as diabetes and cardiovascular disease.
Pharmacokinetics of Pirmenol Enantiomers and Pharmacodynamics of Pirmenol Racemate in Patients with Premature Ventricular Contractions
Authors: Janiczek Nancy , Smith David E. , Chang Tsun , Sedman Allen J. , Stringer Kathleen A.
Published: March 2013

The pharmacokinetics and pharmacodynamics of pirmenol were investigated in 12 patients with premature ventricular contractions (PVCs) after oral administration of racemic pirmenol, 100 mg and 200 mg every 12 hours. Holter monitoring was performed and serial blood samples were collected after the seventh doses. Plasma concentrations of pirmenol enantiomer were determined using a stereospecific liquid chromatographic assay. Clearance of total (–)‐pirmenol was 20% higher than that of total (+)‐pirmenol, and the difference in unbound clearance was 45% between enantiomers. Total pirmenol showed a smaller difference because of stereoselective protein binding, with 25% (100‐mg dose) or 27% (200‐mg dose) higher fraction unbound for (+)‐pirmenol than for (–)‐pirmenol. Distribution volume was similar for both enantiomers. Dose‐dependent clearance was observed for unbound pirmenol enantiomers, as both enantiomers showed 20% lower unbound clearance at the higher dose. Antiarrhythmic effect (% reduction in PVCs from baseline) was correlated with plasma concentrations of pirmenol using a sigmoid maximum drug effect model, and patients showed a large variability in their antiarrhythmic response to plasma concentrations of pirmenol. The median value for minimum effective plasma concentration of racemic pirmenol was 1.5 μg/mL.
Postabsorption Concentration Peaks with Brand‐Name and Generic Verapamil: A Double‐Blind, Crossover Study in Elderly Hypertensive Patients
Authors: Saseen Joseph J. , Porter Julie A. , Barnette Debra J. , Bauman Jerry L. , Zajac Edward J. , Carter Barry L.
Published: March 2013

The pharmacokinetic actions, bioequivalence, and cardiovascular effects of two verapamil products were studied in a randomized, double‐blind, crossover study in eight elderly hypertensive patients (median age, 69.5 years; range, 60–79 years) given brand‐name or generic immediate‐release verapamil in 120‐mg twice‐daily doses for 14 days. Blood pressures, heart rates, P—R intervals, and serum concentrations of R‐/S‐verapamil and norverapamil were measured multiple times in patients during the last day of each therapy. Median blood pressure decreased more with generic verapamil than with the brand‐name drug, with the largest difference occurring at 0.5 hours (137/74 mmHg versus 144.5/80.5 mmHg; P = 0.05 and 0.091, respectively). Pharmacokinetic parameters were not different for the two products (P < 0.10). However, the generic product, compared with the brand‐name drug, had mean area under the concentration—time curve (time 0 to 12 hours) ratios (90% CI) of 1.09 (0.78–1.52), 1.16 (0.87–1.55) and 1.11 (0.81–1.52) for R‐, S‐, and total verapamil. Seventy concentration peaks (31 with the brand‐name drug, 39 with the generic drug) appeared between 8 and 24 hours. Median percentages of increase of these peaks, compared with those of previous concentrations, were 48.3% and 36.3% for brand‐name and generic drugs, respectively. Fifty of the 70 peaks (71%) were associated with a stereospecific concentration peak of norverapamil and, temporally, with meals. Our findings suggest that whereas the two verapamil products may not be bioequivalent by Food and Drug Administration criteria, the observed differences in effects were not clinically significant in this elderly population. Multiple concentration peaks after absorption were observed in all patients with both verapamil products and were perhaps related to enterohepatic recirculation.
Pharmacokinetics of the Liver‐Specific Contrast Agent Gd‐EOB‐DTPA in Relation to Contrast‐Enhanced Liver Imaging in Humans
Authors: Schuhmann‐Giampieri Gabriele , Mahler Marianne , Röll Gabriele , Maibauer Renate , Schmitz Stephan
Published: March 2013

This study was performed to evaluate the effect of dose on the pharmacokinetics and efficacy of the gadolinium‐based contrast medium gadoxetic acid, disodium, [gadolinium (4S)‐4‐(4‐ethoxybenzyl)‐3,6,9‐tris(carboxylatomethyl)‐3,6,9‐triazaundecandioic acid‐disodium salt] (Gd‐EOB‐DTPA) as a liver‐specific hepatobiliary contrast medium for computed tomography. Pharmacokinetics in serum and the pattern of elimination were investigated in 18 healthy volunteers up to 6 days after a 10‐minute infusion of 0.2 mmol, 0.35 mmol, and 0.5 mmol of gadolinium per kilogram of body weight. Pharmacokinetic behavior was compared with the compute tomographic attenuation data in the liver parenchyma after the same doses in patients. Urinary and fecal excretion accounted for approximately equal portions of the administered dose. The degree of renal elimination increased with increasing doses, whereas renal clearance and half‐life from urine data were not affected by dose. Dose‐normalized area under the concentration—time curve was significantly increased with increasing doses indicating saturation in liver uptake for the highest dose. This finding was in agreement with the measured net increase in liver attenuation by computed tomography. Hepatic disposition revealed slight saturation phenomena for the highest dose (0.5 mmol gadolinium/kg). Nevertheless, this dose resulted in sufficient uptake by human liver, allowing for computed tomographic imaging.
Inhibition of Platelet Monoamine Oxidase Type B by Selegiline
Authors: Heinonen Esa H. , Anttila Markku I. , Nyman Leena M. , Pyykkö Kaija A. , Vuorinen Jouni A. , Lammintausta Risto A. S.
Published: March 2013

Selegiline is an irreversible inhibitor of monoamine oxidase type B (MAO‐B). No comparative data are available on the MAO‐B inhibition caused by orally and intravenously administered selegiline. This study aimed to clarify this matter and to investigate the dose—response of MAO inhibition caused by orally administered selegiline. Sixteen healthy volunteers were given selegiline as a single intravenous dose (0.5 mg) and in three low oral doses (0.5 mg, 1.0 mg, and 1.5 mg) in an open‐label randomized crossover trial. The MAO‐B inhibition after the 0.5‐mg intravenous dose was 79.6 ± 15.1%. The dose—response of the three oral doses causing MAO‐B inhibition was logistic. To check whether this equation could be applied to higher doses, eight of the volunteers were given 5‐mg and 10‐mg oral doses. The MAO‐B inhibition after these doses (84.9 ± 11.9% and 95.6 ± 4.5%, respectively) fitted well with the logistic model. With this equation obtained, it was calculated that a 3.4‐mg oral dose of selegiline would be needed to obtain the same degree of MAO‐B inhibition as after the intravenous dose of 0.5 mg. Therefore, the ratio of MAO‐B inhibitory potential of intravenously and orally given selegiline is approximately 7 to 1, which fits well with the low bioavailability of the drug after oral administration.
Pharmacokinetics of Mesna and Dimesna After Simultaneous Intravenous Bolus and Infusion Administration in Patients Undergoing Bone Marrow Transplantation
Authors: El‐Yazigi Adnan , Ernst Peter , Al‐Rawithi Sameer , Legayada Erlinda , Raines Dale A.
Published: March 2013

This study was undertaken to examine the pharmacokinetics of mesna and its dimer form, dimesna, in the plasma and urine of patients undergoing bone marrow transplantation who received 130 mg/kg of mesna divided intravenously into a 30‐mg/kg bolus dose followed immediately by 100 mg/kg infused over 12 hours for uroprotection. The relationship between and urinary excretion of mesna and dimesna also was examined by comparing the data obtained in patients who developed hemorrhagic cystitis versus those who did not. Blood and urine samples were collected at different time intervals after administration, and the plasma or urine was analyzed by liquid chromatography with electrochemical detection. Dimesna was analyzed in these samples after reduction back to mesna with sodium borohydride. The concentration—time data of mesna exhibited the characteristics of the two‐compartment model well, and the mean ± SD values of the distributive phase half‐life (t1/2α), postdistributive phase half‐life (t1/2β), volume of distribution of the central compartment (Vdc), volume of distribution at steady state (Vdss), volume of distribution during the postdistributive phase (Vdβ), total clearance (Cl), and mean residence time (MRT) observed were 0.12 ± 0.15 hours, 2.12 ± 1.61 hours, 0.324 ± 0.336 L/kg, 1.09 ± 1.18 L/kg, 2.09 ± 3.0 L/kg, 0.755 ± 0.507 L/hr · kg, and 6.77 ± 0.72 hours, respectively. The mean ± SD values of t1/2 and MRT of dimesna were 1.29 ± 0.6 hours and 6.68 ± 1.05 hours, respectively, and the ratio of the area under the concentration—time curve (AUC) of mesna to that of dimesna was 1.21 ± 0.57. The fractions of dose excreted in urine in the form of mesna and dimesna in 20 hours (fu) were 0.361 ± 0.15 and 0.482 ± 0.25, and the renal clearance (ClR) values were 0.244 ± 0.201 L/hr · kg and 0.157 ± 0.156 L/hr · kg, respectively. The urinary excretion of mesna in these patients was higher than that required for uroprotection for the whole duration of infusion, and there was no significant difference in the pharmacokinetics of mesna between patients who developed hemorrhagic cystitis and those who did not. This was not the case with dimesna, in which patients with hemorrhagic cystitis excreted in urine less than 50% of the amount of dimesna excreted by those without hemorrhagic cystitis.
Bioavailability of Oral Cyclosporine in Healthy Mexican Volunteers: Evidence for Interethnic Variability
Authors: Palma‐Aguirre J. Antonio , González‐Llaven José , Flores‐Murrieta Francisco J. , Castañeda‐Hernández Gilberto
Published: March 2013

The existence of population variations in cyclosporine pharmacokinetics could be expected, as this drug, similar to nifedipine, is biotransformed by cytochrome P‐450 subfamily 3A4, and the existence of interethnic variability in nifedipine disposition has been demonstrated previously. The bioavailability of oral cyclosporine was studied in 23 healthy Mexican volunteers receiving 7.5‐mg/kg doses of cyclosporine. Blood samples were drawn over 24 hours, and concentration of cyclosporine in whole blood was determined by a radioimmunoassay using monoclonal antibodies specific for the unchanged drug. The bioavailability of cyclosporine exhibited wide interindividual variability. Maximum concentration (Cmax) ranged from 528 ng/mL to 2,689 ng/mL, area under the concentration—time curve (AUC) ranged from 6,550 ng · hr/mL to 18,562 ng · hr/mL, and time to reach Cmax (tmax) ranged from 1 to 8 hours. Half‐life (t1/2) exhibited less important variations, ranging from 4.4 to 9.1 hours. The bioavailability of oral cyclosporine in Mexicans was higher than that reported for white populations under similar conditions. The present results suggest the existence of interethnic variability in the pharmacokinetics of cyclosporine, as is the case with nifedipine.