bluuebunny/crossref_metadata_2025 huggingface dataset:
AICA‐Riboside: Safety, Tolerance, and Pharmacokinetics of a Novel Adenosine‐Regulating Agent
Authors: Dixon Ross , Gourzis James , McDermott Daniel , Fujitaki James , Dewland Peter , Gruber Harry
Published: March 2013

AICA‐riboside (5‐amino‐4‐imidazole carboxamide ribonucleoside) is a novel adenosine‐regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo‐controlled, double‐blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1‐week wash‐out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post‐infusion plasma concentrations of AICA‐riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean tt/2β of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady‐state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5′‐monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA‐riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P > .05) in the mean estimates of t1/2β, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (<5%) when administered orally in solution.
Induction of Fluconazole Metabolism by Rifampin: In Vivo Study in Humans
Authors: Apseloff Glen , Hilligoss Donald M. , Gardner Mark J. , Henry Eugenia B. , Inskeep Philip B. , Gerber Nicholas , Lazar Jeffrey D.
Published: March 2013

The effects of rifampin on the pharmacokinetics of fluconazole were analyzed in an open‐label, placebo‐controlled, parallel study. Sixteen healthy male volunteers, randomized into two groups, received 200 mg of oral fluconazole on days 1 and 22. On days 8 through 27, group I received oral rifampin, 600 mg/d, and group II received placebo. Fluconazole in serum was analyzed by HPLC. On days 1 and 22, respectively, the AUC (μg · hr/mL) (mean ± SD) was 160.5 ± 19.5 and 124 ± 22.2 in group I, 152 ± 25 and 152.8 ± 33.9 in group II; the Kel (hr−1) was .0211 ± .0030 and .0264 ± .0040 in group I, .0219 ± .0036 and .0216 ± .0053 in group II. Cmax and Tmax did not change significantly in either group. Urinary 6β‐hydroxycortisol/cortisol increased from 3.47 ± 1.04 to 15.2 ± 5.07 in group I, but was unchanged (3.54 ± 1.33–4.26 ± 2.36) in group II on days 1 and 22, respectively. The findings in this study indicate that rifampin induces the metabolism of fluconazole.
Pharmacokinetics of Cefprozil in Healthy Subjects and Patients with Hepatic Impairment
Authors: Shyu Wen Chyi , Wilber Richard B. , Pittman Kenneth A. , Garg Dyal C. , Barbhaiya Rashmi H.
Published: March 2013

The pharmacokinetics of cefprozil were studied in 12 (9 men, 3 women) subjects with hepatic impairment and in 12 healthy subjects who were matched for age, sex, and weight. Each subject received a single 1000 mg oral dose of cefprozil, which consists of cis and trans isomers in approximately a 90:10 ratio. Serial blood and urine samples were collected and analyzed using validated HPLC/UV methods for the concentration of each isomer. The results of the plasma and urine analyses were subjected to noncompartmental pharmacokinetic analysis. The values for the peak plasma concentrations (Cmax), area under the plasma concentration versus time curve (AUC0–∞), apparent total body clearance (Clt/F), renal clearance (Clr), and percent of drug excreted in urine (% UR) of each isomer were not significantly different in healthy subjects and patients with hepatic impairment. The only parameters that were significantly (P ≤ .05) longer in patients with hepatic impairment were mean residence time in the body (MRT) and half‐life; the MRT for the cis isomer in healthy subjects and subjects with hepatic impairment were 3.33 hr and 3.88 hr, respectively, and for the trans isomer 3.17 hr and 3.68 hr; the half‐life for the cis isomer was 1.62 hr and 2.22 hr, respectively, and for the trans isomer 1.21 hr and 1.54 hr. The pharmacokinetics of the cis and trans isomers of cefprozil were virtually identical in healthy subjects as well as those with hepatic impairment. The results of the study showed that the pharmacokinetics of cefprozil are not significantly affected in patients with hepatic dysfunction, and as a result, the dosage of cefprozil does not require adjustment in patients with hepatic dysfunction.
Fluoxetine‐Induced Tricyclic Toxicity: Extent and Duration
Authors: Westermeyer Joseph
Published: March 2013

Combined fluoxetine‐tricyclic medication has been recommended for patients who are partial responders or nonresponders to tricyclic medication alone. Three cases were encountered in which the addition of fluoxetine to tricyclic medication resulted in toxic, potentially dangerous elevations in tricyclic blood level amounting to approximately 100–300% increases over recent tricyclic levels. In reducing the tricyclic dosage after fluoxetine, blood level decreases were behind dosage decreases; and blood level and dosage decreases were not well correlated with each other. Symptoms associated with toxic levels are described. Due to the long half‐life of fluoxetine, such increases in tricyclic medication must be anticipated well in advance of initiating treatment with these two compounds. Based on these few cases, a procedure is tentatively recommended for patients on combined fluoxetine‐tricyclic regimens, until such time as a definitive regimen can be developed.
Serum Digoxin Levels Related to Plasma Propafenone Levels During Concomitant Treatment
Authors: Bigot Marie‐Claire , Debruyne Danièle , Bonnefoy Laurent , Grollier Gilles , Moulin Maurice , Potier Jean‐Claude
Published: March 2013

Nine patients with supraventricular rhythm disorders were treated during 5‐day periods with different oral doses (300, 450, 600, and 900 mg daily) of propafenone concomitantly to long‐term digoxin treatment. A poor correlation (r = .398; P <.05) was obtained when the difference between the mean digoxin serum level (calculated with the Cmin data determined each of the 5 days) observed during a given propafenone dose and the mean digoxin serum level observed before propafenone treatment, was correlated with the dose of propafenone; but an evident correlation (r = .778; P <.01) was found when the difference in digoxin level was correlated with the plasma propafenone concentration. The propafenone effect of increasing digoxin blood levels was thus concluded to be poorly dose dependent but strongly concentration dependent. The association of propafenone to a long‐term digoxin treatment can be considered with a low risk of toxicity when plasma propafenone concentration does not exceed about 1000 ng/mL. Propafenone plasma levels are unpredictable in view of their wide interindividual variation for a given dose, so their measurement is advised to detect high levels and consequently to prevent a rise in digoxin serum concentrations with the possibility of toxicity. In clinical practice, when propafenone concentration determinations are not readily available, digoxin serum levels at least have to be carefully monitored.
Short‐Term Effects of Estrogen and Progestin on Blood Pressure of Normotensive Postmenopausal Women
Authors: Regensteiner Judith G. , Hiatt William R. , Byyny Richard L. , Pickett Cheryl K. , Woodard W. Donald , Moore Lorna Grindlay
Published: March 2013

Blood pressure rises in women with increasing age, possibly related to the decrease in production of female hormones that accompanies menopause. Although estrogen or progestin administration alone consistently does not lower blood pressure in postmenopausal women, possible interactions of these two hormones in affecting blood pressure are not well understood. We studied 12 surgically postmenopausal, normotensive women, aged 51 ±2 years (SEM). Treatment for each subject consisted of 1 week each of placebo, estrogen (conjugated equine estrogens, 2.5 mg/day), progestin (medroxyprogesterone acetate, 60 mg/day), and combined estrogen and progestin, given in varied order. At the end of each week, auscultatory blood pressures were measured while patients were seated. Neither estrogen nor progestin alone either increased or decreased blood pressure significantly, whereas combined estrogen and progestin lowered systolic, diastolic, and mean blood pressures 6 to 7 mm Hg (P <.05). Treatment order was unrelated to the change in blood pressure values. The authors suggest that administering progestin with estrogen may be more effective in lowering blood pressure than either hormone alone in postmenopausal women.
Nonsteroidal Anti‐Inflammatory Drugs: Effects on Kidney Function
Authors: Whelton Andrew , Hamilton Cindy W.
Published: March 2013

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are capable of inducing a variety of renal function abnormalities, particularly in high‐risk patients with decreased renal blood perfusion who depend on prostaglandin synthesis to maintain normal renal function. Fluid retention is the most common NSAID‐related renal complication, occurring to some degree in virtually all exposed individuals; however, clinically detectable edema occurs in less than 5% of patients and is readily reversible on discontinuation of the NSAID. Other electrolyte complications, notably hyperkalemia, are seen infrequently and occur in specific at‐risk patients. The next most worrisome complication is acute deterioration of renal function, which occurs in high‐risk patients and is also reversible. Nephrotic syndrome with interstitial nephritis is a rare problem of NSAID use and is reversible. Papillary necrosis is the only permanent complication of NSAIDs and is very rare. Altogether, these renal function abnormalities, with the exception of mild fluid retention, are clinically detectable in approximately 1% of exposed patients. Given the number of patients who take NSAIDs on a prescription or over‐the‐counter basis, the absolute number of at‐risk patients is relatively large. Consequently, an appreciation for the risk factors and pathophysiology of NSAID‐induced renal function abnormalities is required for optimal use of these drugs.
Relapsing Native‐Valve Enterococcal Endocarditis: A Unique Cure with Oral Ciprofloxacin Combination Drug Therapy
Authors: Sacher Howard L. , Miller William C. , Landau Stuart W. , Sacher Michael L. , Dixon William A. , Dietrich Kathleen A.
Published: March 2013

Enterococcal endocarditis is the third most common presentation in native valves, and it is the most refractory. Unique among the streptococci, enterococci are relatively resistant to beta‐lactam antibiotics requiring a combination aminoglycoside regimen for cure. Relapse is common even after apparently adequate therapy and may be seen in up to 25% of cases that involve streptomycin‐resistant strains. This problem is magnified by the recent appearance of beta—lactamase‐producing strains of S. faecalis resistant to both ampicillin and gentamicin. Ciprofloxacin is being investigated with a number of antimicrobials in the attempt to identify superior protocols against troublesome pathogens. However, little published data is available concerning the clinical efficacy of this drug in enterococcal endocarditis. In vitro studies and preliminary trials with animal models have generally been disappointing with broth macrodilution time‐kill or agar dilution proving the most reliable in vitro methods for predicting in vivo outcomes. The urgent need to identify new combination drug regimens is underscored not only by the development of new resistance patterns, but by the well‐documented toxicities of conventional therapies. The authors present a case of relapsing enterococcal endocarditis caused by a non—beta—lactamase‐producing strain of S. faecalis, which demonstrated high‐level resistance to streptomycin but not to gentamicin. Relapses occurred despite favorable laboratory data and aggressive beta—lactam‐gentamicin therapies. Cure was achieved using oral ciprofloxacin in a combination drug regimen, which is reported here for the first time.
Pharmacokinetics of Ceftriaxone in Liver‐Transplant Recipients
Authors: Toth Ann , Abdallah Hisham Y. , Venkataramanan Raman , Teperman Lewis , Halsf Glen , Rabinovitch Mordechai , Burckart Gilbert J. , Starzl Thomas E.
Published: March 2013

The disposition of ceftriaxone was studied after a single 2 g intravenous dose in seven patients 3 to 5 days after liver transplantation. Ceftriaxone concentrations in plasma, urine, and bile were measured by HPLC, and plasma protein binding was determined by equilibrium dialysis. Plasma protein binding was nonlinear, and the unbound fraction varied between 0.05 and 0.56. Both capacity and affinity were markedly different from reported values for normal subjects. The pharmacokinetic parameters obtained were: total body clearance (TBC), 11.2 ± 7.8 mL/hr/kg total and 44.8 ± 29.1 mL/hr/kg unbound; volume of distribution (Varea), 224 ± 76 mh/kg total and 767 ± 432 mL/kg unbound; steady‐state volume of distribution (Vss), 212 ± 68 mh/kg total and 651 ± 368 mL/kg unbound; terminal disposition half‐life (t1/2), 21.6 ± 14.3 hour total and 16.3 ±11.1 hour unbound. TBC for both total and free drug was considerably lower than literature values for normal subjects. Varea for total drug was greater than normal whereas the corresponding value for free drug was smaller than normal. The plasma ceftriaxone concentrations at 12 and 24 hours were above the reported minimum inhibitory concentration (MIC). The fraction of the administered dose excreted in urine over 24 hours was 38 ± 29% and did not differ markedly from that reported for normal subjects. Less than 2% of the administered dose was excreted in 24‐hour bile; however, biliary concentrations were always above MIC. Ceftriaxone can be administered once or twice daily at a dose of 2 g/day for prophylaxis in liver transplant recipients.
A Double‐Blind, Randomized, Placebo‐Controlled Comparison of the Metabolic Effects of Low‐Dose Hydrochlorothiazide and Indapamide
Authors: Elliott William J. , Weber Roy R. , Murphy Michael B.
Published: March 2013

To compare the metabolic effects of indapamide (I) and hydrochlorothiazide (HCTZ) at equivalent hypotensive doses, 11 hypertensive patients (5 male, 8 black, aged 56 ± 8 yr — mean ± SEM) having serum uric acid concentrations >8.0 mg/dL while receiving previous therapy with thiazides, received 28‐day courses of placebo, indapamide (2.5 mg/d), and HCTZ (25 mg/d) in randomized, double‐blind, double‐crossover design. Supine and standing blood pressures, weight, pulse rates and sera were obtained after each 28 day period. Blood pressures and weights were lowered (P <.001 and 0.01, respectively) equally by the diuretics: supine blood pressures fell from 168 ± 4/104 ± 2 (placebo) to 153 ± 4/93 ± 2 (HCTZ) and 155 ± 4/94 ± 2 mm Hg (I); standing blood pressures (after 2 minutes upright) also decreased: 171 ± 5/104 ± 2 (placebo) to 156 ± 5/93 ± 2 (HCTZ) and 157 ± 4/94 ± 2 mm Hg (I). There was a statistically significant difference (P <.05) across treatments by analysis of variance in both uric acid and potassium concentrations: serum urate (in mg/dL) was lowest with placebo (7.1 ± 0.3), and rose to 8.3 ± 0.2 with HCTZ (P <.001 compared with placebo by paired t test), and 8.1 ± 0.2 with I (P <.005 vs. placebo). The urate concentration with I was significantly lower than that with HCTZ (P <.02), but the magnitude of the difference was small (0.2 mg/dL). Serum potassium (mmol/L) was lower on each diuretic than that with placebo (4.2 ± 0.1, P <.005 for each), but not different between diuretics (HCTZ: 3.8 ±0.1; I: 3.9 ±0.1). No other significant differences were found in biochemical indices between therapies. Thus, at equihypotensive (i.e., low) doses in patients known to have elevated serum‐urate concentrations with thiazides, indapamide may cause less hyperuricemia than HCTZ. Although statistically significant, this difference is of questionable clinical importance, since both diuretics raise serum‐urate concentrations relative to placebo.
Drug‐Food Interaction Potential of Clarithromycin, A New Macrolide Antimicrobial
Authors: Chu Sou‐yie , Park Y. , Locke Charles , Wilson David S. , Cavanaugh J. C.
Published: March 2013

To evaluate the effect of food on bioavailability, clarithromycin and 14‐hydroxy clarithromycin (active metabolite) pharmacokinetics were assessed in 26 healthy adult volunteers after ingestion of a single oral 500‐mg dose of clarithromycin in a fasting state (2 hours before breakfast after an overnight fast) and a nonfasting state (0.5 hours after the start of breakfast). Clarithromycin and 14‐hydroxy metabolite plasma concentrations were measured using a high‐performance liquid chromatographic technique. Food intake immediately before dosing increased the extent of absorption from the 500‐mg tablet formulation by approximately 25%. The mean increase in metabolite area under the plasma concentration‐time curve was approximately 9%. These results suggest that clarithromycin can be taken without regard to timing in relation to meals.
Evaluation of Quinapril on Regional Blood Flow and Cardiac Function in Patients with Congestive Heart Failure
Authors: Munger Mark A. , Chance Michael , Nair Ravi , Prescott Amanda W. , Nara Andrew R. , Simonson Michael S. , Green Jeffrey A. , Posvar Edward L.
Published: March 2013

Quinapril, a nonsulfhydryl ACE inhibitor, was evaluated in ten New York Heart Association (NYHA) functional class (FC) II‐III CHF patients to determine its effects on regional blood flow [effective renal plasma flow (ERPF), renal blood flow (RBF), renal vascular resistance (RVR), hepatic blood flow (HBF), hepatic vascular resistance (HVR), segmental limb pressure (SLP), creatinine clearance (CRCL)] and cardiac function [left ventricular ejection fraction (LVEF)]. Previous vasodilator therapy was withdrawn 2 weeks before baseline measurements. Stable regimens of digoxin and diuretics were continued throughout the study. ERPF was assessed using p‐aminohippurate (PAH), HBF by indocyanine green (ICG) clearance, and LVEF by radionuclide scintography. Segmental limb pressures were measured by Doppler flow detection. Measurements were performed at baseline (B) and after 4 weeks of quinapril therapy (10 mg BID). Quinapril increased renal (P <0.05) and hepatic blood flow (P = 0.06) and significantly reduced renal and hepatic vascular resistance. Glomerular titration rate and left ventricular ejection fraction were unchanged. Mean arterial pressure and brachial segmental pressures decreased without change in heart rate. Noninvasive cardiovascular assessments indicate that quinapril improves regional blood flow while exhibiting no change in left ventricular ejection fraction, in patients with NYHA FC II‐III CHF.
Single‐Dose Pharmacokinetics of Pravastatin and Metabolites in Patients with Renal Impairment
Authors: Halstenson Charles E. , Triscari Joseph , DeVault Arthur , Shapiro Bruce , Keane William , Pan Henry
Published: March 2013

The disposition of a single 20‐mg oral dose of pravastatin was assessed in subjects with various degrees of renal function. Sixteen subjects (13 males, 3 females) with creatinine clearance values ranging from 15 to 112 mL/min/1.73 m2 completed the study. Area under the serum concentration‐time curve, maximum serum concentration, time to maximum serum concentration, terminal serum elimination half‐life, apparent clearance, and apparent volume of distribution for pravastatin were not affected by renal impairment, whereas the renal clearance of pravastatin decreased as creatinine clearance decreased (r2 = 0.697, P <.001). The area under the serum concentration‐time curve and time to maximum serum concentration of SQ 31,945 (a hepatic metabolite) increased in patients with renal impairment, whereas the terminal elimination rate constant and renal clearance of SQ 31,945 significantly decreased as a function of creatinine clearance. The renal clearance of another metabolite (SQ 31,906) also significantly declined with decreasing renal function. This single‐dose study demonstrates that pravastatin pharmacokinetics were not affected in patients with renal impairment, probably because of its dual route of elimination.
Single‐Dose Pharmacokinetics of Ibuprofen and Acetaminophen in Febrile Children
Authors: Brown R. Don , Wilson John T. , Kearns Gregory L. , Eichler Valarie F. , Johnson Virginia A. , Bertrand Karl M.
Published: March 2013

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one‐compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUC0→∞) of ibuprofen 10 mg/kg were less than expected for a two‐fold increase in dose. For acetaminophen, the tlog was less than ibuprofen, Ka was more than ibuprofen, and β was less than ibuprofen. The ibuprofen β was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUC0→∞ was higher in the older (≥ 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUC0→∞ and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.
Sustained‐Release Verapamil Formulations for Treating Hypertension
Authors: Frishman William H. , Lazar Eliot J.
Published: March 2013

Verapamil, the first calcium‐channel blocker to be introduced for clinical use, is a major drug used for the treatment of systemic hypertension. During the past 10 years, the use of verapamil for hypertension has produced a considerable clinical database to support the efficacy and safety of the agent in many patients. Because of its short half‐life, verapamil was originally administered 3 to 4 times daily. During the past decade, a sustained‐release formulation of verapamil has been marketed in the US. This product allows for once‐daily dosing up to 240 mg/d; however, when higher doses are needed, this sustained‐release formulation should be administered twice daily. In addition, the medicine should be taken with food to avoid the high peak blood levels of verapamil, which appears to be related to the delivery system. A new pellet‐filled capsule formulation of verapamil (Verelan, Lederle, Wayne, NJ and Wyeth‐Ayerst, Philadelphia, PA) is available and provides controlled absorption, 24‐hour blood pressure control, improved peak‐to‐trough plasma levels, and once‐daily dosing regardless of dosage size. Prolonged‐release verapamil can be taken without food.
No Influence of Single Intravenous Doses of Omeprazole on Theophylline Elimination Kinetics
Authors: Oosterhuis Berend , Jonkman Jan HG , Andersson Tommy , Zuiderwijk Peter BM
Published: March 2013

The influence of single intravenous doses of omeprazole on the pharmacokinetics of intravenously administered theophylline was studied in eight healthy male volunteers. In a partially randomized three‐period crossover design, an IV infusion of theophylline (400 mg over 30 min) was combined with IV omeprazole (either 40 mg over 2.5 min or 80 mg over 5 min) or with IV placebo (over 2.5 min). Theophylline and omeprazole plasma concentrations were measured over 24 hours after the start of the infusions and pharmacokinetic parameters were calculated. The theophylline plasma concentration‐time proxies after omeprazole coadministration were virtually identical to the corresponding profile after placebo administration. For each of the pharmacokinetic parameters of theophylline, the 90% confidence intervals of the omeprazole coadministrations were within the 80 to 120% bioequivalence range with respect to the placebo coadministration. Omeprazole plasma concentrations indicated a biexponential decline in most subjects, with a more rapid elimination after the 40‐mg than after the 80‐mg dose (P < .01). Doubling the dose caused an almost three‐fold increase of AUC resulting in a difference in clearance (P < .02), whereas the volume of distribution was similar. The results of this study indicate that the metabolism of theophylline is not affected by single intravenous doses of omeprazole. The nonlinear pharmacokinetics of omeprazole are ascribed to saturation of its main metabolizing enzyme, S‐mephenytoin hydroxylase.
Single‐Dose Antibiotic Therapy: What Has the Past Taught Us?
Authors: Carbón Claude
Published: March 2013

The proper dosage schedule of antibiotics has generally been determined empirically, due to the difficulty of clinical trials. Initially, the dosage was chosen to allow high sustained levels > MIC in the blood. Antibiotics (β lactams, tetracyclins, macrolides) were given at high doses three to six times daily, whatever their kinetic properties. The data obtained by Eagle with β lactams in animal models of streptococcal and treponemal infections outlined the importance of interval between doses on the in vivo efficacy. They also showed that increasing the dose of penicillin had a positive effect on the bactericidal activity only through the persistence of effective levels (>MIC) at the site of infection. Further illustrations were given through experimental and clinical studies with β lactams or other compounds on different types of infections: LRTIs, UTIs, meningitis, and endocarditis. The importance of both dynamic (i.e., pattern of bactericidal effect) and kinetic (elimination half‐life) parameters was thus further identified. Information on toxicity with some compounds with a narrow therapeutic index, such as aminoglycosides, indicated that increasing the dose to enhance efficacy had some limitations. This led to numerous studies on the relations between concentration and toxicity, stating that nephro‐ or ototoxicity were not directly related to peak level in serum. Experimental studies showed that OD administration of aminoglycosides was both more efficient and less toxic than the multiple‐dose regimen of the same daily amount. Economic considerations progressively justified attempts to both reduce the dose and the work load related to multiple administrations. Development of oral compounds able to be given as initial therapy or as a quick alternative to parenteral administration raised the question of applicability to oral route of OD dosing. High bioavailability is required to ensure efficacy. Oral OD dosing may be discussed in more or less severe infectious processes and in some difficult‐to‐cure chronic infections.
Introduction of a Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O‐Desmethyl Metabolite
Authors: Klamerus Karen J. , Moloney Kathleen , Rudolph Richard L. , Sisenwine Samuel F. , Jusko William J. , Chiang Soong T.
Published: March 2013

Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three‐period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O‐desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady‐state elimination half‐life was 3 to 4 hours for venlafaxine and 10 hours for O‐desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral‐dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O‐desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O‐desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor · AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high‐clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose‐proportionality.
Oral Absolute Bioavailability and Intravenous Dose‐Proportionality of Cefprozil in Humans
Authors: Shyu W. C. , Shah V. R. , Campbell D. A. , Wilber R. B. , Pittman K. A. , Barbhaiya R. H.
Published: March 2013

The absolute bioavailability (F) and dose proportionality of cefprozil were investigated in a parallel design study with an embedded two‐way crossover leg. Twenty‐four healthy male subjects divided into 3 dosing groups received a single 250‐, 500‐, or 1000‐mg dose of cefprozil by a 30‐minute intravenous infusion. Subjects assigned to the 500‐mg dose group also received a 500‐mg oral dose of cefprozil in crossover manner with a wash‐out period of 7 days between each treatment. Cefprozil consists of cis and trans isomers in an approximate 90:10 ratio. Serial blood and urine samples were collected and analyzed for the concentrations of the cis and trans isomers of the cephalosporin using high‐pressure liquid chromatographic assay with UV detection methods. After the 250‐, 500‐, and 1000‐mg intravenous administration of cefprozil, the peak concentrations were 13.2, 26.0, and 48.5 μg/mL, and area under the plasma concentration versus time proxies were 17.2, 31 A, and 58.1 μg · hour/mL, respectively, for the cis isomer increasing in a dose proportional manner. Total body clearance, renal clearance, and volume of distribution at steady state, adjusted for body weight, were not significantly different among all groups. Mean residence time, elimination half‐life, and urinary recovery were invariant with the dose. Based on the plasma and urine data, the estimates of F were 89% and 94% for the cis isomer, respectively. The plasma concentrations of the trans isomer were about 1/10th of the cis isomer, and all parameters were similar to those observed for the cis isomer. In summary, cefprozil exhibits linear pharmacokinetics and is essentially completely absorbed after oral administration.
Sustained Antihypertensive Activity of Diltiazem SR: Double‐Blind, Placebo‐Controlled Study with 24‐Hour Ambulatory Blood Pressure Monitoring
Authors: Whelton Andrew , Eff Jack , Magner David J.
Published: March 2013

A new polymeric matrix technology provides a sustained‐release formulation of diltiazem hydrochloride (diltiazem SR) suitable for once‐daily therapy. The efficacy and safety of diltiazem SR were evaluated in a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study. After a single‐blind, placebo lead‐in period, 275 patients with mild to moderate essential hypertension were assigned to receive placebo or diltiazem SR 120, 240, 360, or 480 mg once daily for 4 weeks. The efficacy evaluation was based on office and 24‐hour ambulatory blood pressure monitoring. Twenty‐four hours after the last dose in the 4‐week, double‐blind treatment period, the mean reduction from baseline in supine diastolic blood pressure ranged from 5.1 to 10.6 mm Hg in the diltiazem SR 120‐to 480‐mg groups, resulting in a significant linear trend across all treatments (P < .001). Reductions in systolic blood pressure were similar. Ambulatory blood pressure monitoring, performed in 138 patients, confirmed the dose‐response relationship and showed consistent antihypertensive activity throughout the 24‐hour dosing interval. The percentage of patients reporting adverse events was similar in the placebo‐ and active‐treated groups. The results of this study indicate that diltiazem SR is well tolerated, lowers blood pressure in a dose‐related manner, and provides sustained activity throughout the 24‐hour dosing interval.
Circadian Changes of Valproate Kinetics Depending on Meal Condition in Humans
Authors: Ohdo Shigehiro , Nakano Shigeyuki , Ogawa Nobuya
Published: March 2013

The objective of this study was to examine the effect of meal condition on circadian changes in valproic acid (VPA) kinetics. Two experiments were performed in 16 healthy men that were synchronized with diurnal activity and nocturnal rest as their routine life. In both experiments, four 200‐mg tablets of VPA were given orally on two occasions in the morning (8:30 am) or in the evening (8:30 pm). In each study, a randomized, single‐dose, two‐way crossover design was used, and 2 weeks elapsed between morning and evening trials. In experiment 1, eight subjects took a light meal as breakfast between 8:00 and 8:15 am and a heavy meal as dinner between 6:00 and 6:30 pm to fit the subject's usual food amount. The mean peak plasma concentration (Cmax) was significantly higher (P < .01), the time to peak concentration (tmax) was shorter (P < .05), and the absorption rate (Ka) was larger (P < .05) after the morning dose than after the evening dose. In experiment 2, the size and contents of meal in breakfast and dinner were prepared in the same manner as the standard breakfast for the subjects. Namely, eight subjects took the same light meal between 8:00 and 8:15 am in the morning and between 8:00 and 8:15 pm in the evening. There was no significant circadian change in VPA kinetics under this same meal condition. These results suggest that the differences of meal condition between morning and evening in our daily life play a major role in the mechanism underlying the circadian changes of VPA absorption in man.
Retinoids in Cancer Treatment
Authors: Tallman Martin S. , Wiernik Peter H.
Published: March 2013

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis‐retinoic acid in patients with acute promyelocyte leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all‐trans‐retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocyte leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinogenesis.
Labetalol in Hypertension During the Third Trimester of Pregnancy: Its Antihypertensive Effect and Pharmacokinetic‐Dynamic Analysis
Authors: Saotome Tomoko , Minoura Shigeki , Terashi Keiko , Sato Takashi , Echizen Hirotoshi , Ishizaki Takashi
Published: March 2013

The hypotensive effect, kinetics, and concentration‐response relationship of labetalol, a β‐ and α1‐adrenoceptor blocking drug, were studied in seven women with a moderate‐to‐severe hypertension (averaged diastolic blood pressure [DBP] of 100 to 120 mm Hg measured during a 1‐ to 2‐day hospitalization period) during the third trimester of pregnancy who received the oral twice‐daily doses of 150 to 450 mg. These dosages were individually selected by attaining a therapeutic goal of DBP ≤ 100 mm Hg or systolic blood pressure (SBP)/DBP reduction of > 30/15 mm Hg, as compared with the pretreatment value, at any time during the 12‐hour dosing interval for a 3‐ to 5‐day dosage escalation period. Labetalol concentrations in plasma were measured by a high‐performance liquid chromatography with fluorescence detection, and the plasma drug concentration‐response relationship was analyzed by a sigmoidal Emax model. Labetalol decreased significantly (P < 0.05 to 0.01) the pretreatment SBP/DBP (166.3 ± 5.2/110.3 ± 3.0 mm Hg, mean ± SEM) without any recognizable side‐effects during the twice‐daily dosing period in the mothers. Peaked concentrations occurred at 1 hour postdose in all patients. The elimination half‐lives ranged from 4.3 to 6.9 hours, and the apparent oral clearance from 31.9 to 73.3 mL/min/kg. The pharmacodynamic parameters (Emax and EC50) analyzed by the Emax model revealed a 3‐ to 5‐fold interindividual variability. The gestational ages at delivery ranged from 34 to 37 weeks, and the birth weights were < 2000 g in 6 of the 7 neonates. Four neonates developed respiratory distress syndrome after delivery, and one infant died of pulmonary hypoplasia 3 months later. The results indicate that 1) labetalol orally administered in a twice‐daily regimen as done in this study is an effective antihypertensive drug in women with hypertension during late pregnancy, and 2) interindividual variability in the kinetic factor (e.g., oral clearance) as well as that in the pharmacodynamic factor (e.g., EC50) appear to be related to the overall variability in the hypotensive responsiveness to the drug. However, whether labetalol and/or hypertension per se would have been related to the fetal outcome remains unanswered from the present study.
The Relationship Between the Degradation of Prostacyclin in Blood and Antiplatelet Drug Effects in Patients with Atherosclerosis
Authors: Akopov Sergey E. , Gabrielian Emil S.
Published: March 2013

Blood and plasma from 109 patients with atherosclerosis and 70 healthy volunteers were tested to study the rate of prostacyclin (PGI2) hydrolysis. It has been reported that patients with atherosclerosis have the enhanced velocity of PGI2 degradation. The increase in the velocity was more marked in blood than in plasma. The significant negative correlation between antiaggregation effects of pentoxifylline, nifedipine, and dipyridamole and the velocity of PGI2 degradation in the patients was found. These data suggest that the increase of PGI2 biosynthesis by the drugs studied can enhance their antiaggregation effect if processes of PGI2 degradation in blood are not accelerated.
A One‐Month Drug Analysis Laboratory Rotation for Doctor of Pharmacy Students
Authors: MacKichan Janis J. , Shields Brenda J.
Published: March 2013

A one‐month drug analysis laboratory rotation for PharmD students is described. The students gain hands‐on experience through the performance of a structured sequence of laboratory experiments covering topics such as calibration standards, the calibration curve, extraction recovery, chromatographic resolution, HPLC detectors, and plasma protein binding. The self‐paced, independent study approach to the rotation was cited by students to be an effective method for teaching a large number of new concepts in a short time. The course was a good aid in helping students to decide if they wanted to pursue postdoctoral research training.
Inhibition of Gentamicin Uptake into Cultured Mouse Proximal Tubule Epithelial Cells by L‐Lysine
Authors: Kaunitz Jonathan D. , Cummins Vierka P. Smith , Mishler Delta , Nagami Glenn T.
Published: March 2013

Gentamicin uptake and toxicity was studied in a nontransformed cell line obtained from the S1 segment of the proximal tubule epithelium of a transgenic mouse. Cytotoxicity was assayed using the dye 3‐(4,‐5dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT). Gentamicin uptake was assayed by a fluorescence polarization assay. No differences in toxicity were found among cells incubated for 4 hours in complete culture medium, enriched Kreb's buffer alone, or enriched Krebs' buffer with added 300 μg/mL gentamicin, 0.5 mmol/L L‐lysine, or gentamicin plus L‐lysine. Uptake of 300 μg/mL gentamicin was minimal at zero time and increased as a function of time. Uptake of gentamicin at 4 hours was positively correlated with medium gentamicin concentration. Addition of 0.5 mmol/L L‐lysine inhibited uptake of 300 μg/mL gentamicin 38.9 ± 10.2%. No other amino acid, including D‐lysine or arginine, significantly changed gentamicin uptake. The authors conclude that gentamicin and L‐lysine share a specific uptake mechanism located in the apical membrane of renal proximal tubule cells.
Pharmacokinetics and Bioavailability of the RRR and All Racemic Stereoisomers of Alpha‐Tocopherol in Humans After Single Oral Administration
Authors: Ferslew Kenneth E. , Acuff Robert V. , Daigneault Ernest A. , Woolley Thomas W. , Stanton Paul E.
Published: March 2013

The plasma and red blood cell pharmacokinetics and bioavailability of the natural source (RRR, d) and all racemic (all rac, dl) stereoisomers of alpha‐tocopherol were studied in 12 men in a double‐blind randomized crossover study. Subjects were administered two 400‐mg soft‐gelatin capsules of either RRR or all rac alpha‐tocopherol. Plasma alpha‐tocopherol concentrations were determined by high‐performance liquid chromatography at various time intervals for up to 96 hours postadministration. Pharmacokinetic modeling of the data showed that alpha‐tocopherol was absorbed after a 2 to 4 hour lagtime and maximum plasma concentration occurred from 12 to 14 hours postadministration. There were no significant differences in the Ka, t1/2 α, β, or t1/2 β between RRR and all rac. Mean plasma alpha‐tocopherol concentrations were greater for RRR than all rac from 10 to 96 hours postadministration and significantly greater at 24 hours (P < .05). The red blood cell alpha‐tocopherol concentration from the RRR preparation was significantly greater than from the all rac preparation from 24 to 96 hours postadministration with Cmax for RRR (4.8 μg/mL) significantly greater than for all rac (4.0 μg/mL, P < .05). The RRR AUC0–96 for both plasma and red blood cells were significantly greater than the all rac AUC0–96 (P < .05) indicating a greater bioavailability of RRR versus all rac alpha‐tocopherol. This difference in overall bioavailability was apparently not due to a single pharmacokinetic component.
Iron Management During Treatment with Recombinant Human Erythropoietin in Chronic Renal Failure
Authors: Watson Alan
Published: March 2013

The anemia of chronic renal failure often contributes to the poor functional status in patients with renal insufficiency and results primarily from decreased erythropoietin production. Recombinant human erythropoietin (rHuEpo) results in clinical and symptomatic improvements in patients with anemia of chronic renal failure. Treatment with rHuEpo also improves the quality of life in these patients. Resistance to rHuEpo therapy is not uncommon, however, and often is related to iron deficiency resulting from rapid erythropoiesis during rHuEpo therapy. Interestingly, rHuEpo‐treated patients may continue to develop iron deficiency while receiving oral iron. Alternatively, parenteral iron is effective in replenishing iron stores and sustaining erythropoiesis in patients treated with rHuEpo.
Computer‐Assisted Molecular Modeling: Indispensable Tools for Molecular Pharmacology
Authors: Bowen J. Phillip , Charifson Paul S. , Fox Peter C. , Kontoyianni Maria , Miller Aaron B. , Schnur Dora , Stewart Eugene L. , Van Dyke Christopher
Published: March 2013

Ball‐and‐stick mechanical models, typically associated with chemists, have been helpful in understanding structural problems and the relationship between structure and biologic activity. With progress in computer speed, graphics performance, and software innovation, molecules of biological interest can be subjected to rigorous calculations. Computational chemistry and biology are rooted in the belief that theoretical physics can be used to calculate accurate molecular structures. Although in its infancy, computer‐assisted molecular modeling is gaining attention and acceptability as an increasing number of researchers turn their attention toward rational molecular design. The trend to use theoretical methods can be traced to the greater availability of computer graphics workstations, decreasing computer costs, faster central processing units, more robust algorithms, and “user‐friendly” software codes. Every major pharmaceutical company has invested in these resources to reduce the time it takes to design and develop pharmaceutical agents. Because of the vast financial and manpower investments needed to introduce a single drug, medicinal chemists and pharmacologists are interested in understanding and predicting drug action at the molecular level. Although drug action is still poorly understood, molecular modeling should reduce some of the labor in the development of pharmaceutical agents.