bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple‐Dose Pharmacokinetics and Safety of Two Regimens of Quinupristm/Dalfopristin (Synercid®) in Healthy Volunteers
Authors: Chevalier Paul , Rey Jacques , Pasquier Olivier , Rouzier‐Panis Régine , Harding Neasa , Montay Guy
Published: July 2003

Quinupristin/dalfopristin (Q/D) is a novel streptogramin antibiotic for the treatment of severe gram‐positive infections. The purpose of this open, nonrandomized, parallel‐group, phase I trial was to evaluate Q/D pharmacokinetics after single and repeated doses under the two different dosing regimens corresponding to the effective doses and to evaluate tolerability. Two groups of 10 healthy volunteers received multiple 1‐hour intravenous infusions of 7.5 mg/kg Q/D either every 8 or 12 hours for 4 or 5 days, respectively. Plasma concentrations of Q, D, and metabolites were determined using high‐performance liquid chromatography and selective microbiological assays. The two regimens q8h and q12h lead to the same disposition profile after single and repeated ad‐ministration. Single‐dose data confirmed the high plasma clearances of Q and D (about 0.90 l/h/kg) obtained previously. Unchanged drugs were the main components in plasma, with each of the three metabolites representing about 20% (in terms of the AUC ratio) of the parent drugs. Comparable steady‐state concentrations were reached from day 2 of both regimens. A similar moderate increase in Cmax and AUC (about 20%) of parent drugs was observed between the first and last day of treatment. This phenomenon, which was also observed for the metabolites, was not expected considering the short terminal disposition half‐lives of the parent drugs and trough plasma concentrations of all components mostly below the limits of quantitation at steady state, whatever the dosing regimen. The clearances of parent drugs at steady state were about 20% lower as compared with that observed following the first drug administration (statistically significant difference). No trend suggesting a treatment effect on any laboratory parameter, vital signs, or electrocardiographic parameters was identified. However, 80% of subjects reported venous adverse events probably related to treatment.
Pharmacokinetics and Pharmacodynamics of Dexamethasone Sodium‐m‐Sulfobenzoate (DS) after Intravenous and Intramuscular Administration: A Comparison with Dexamethasone Phosphate (DP)
Authors: Hochhaus Günther , Barth Jürgen , Al‐Fayoumi Suliman , Suarez Sandra , Derendorf Hartmut , Hochhaus Renate , Möllmann Helmut
Published: July 2003

The pharmacokinetics (PK) and pharmacodynamics (effects on blood lymphocytes) of dexamethasone (D) after intravenous (i.v.) administration of dexamethasone phosphate (DP, 10 mg, equivalent to 8.3 mg of dexamethasone) and after intravenous and intramuscular (i.m.) administration of dexamethasone sulfobenzoate sodium (DS, 9.15 mg, equivalent to 6 mg of dexamethasone) were assessed. Only 25% of DS was converted into dexamethasone with a half‐life for DS of 5.4 hours and 7.4 hours after i.v. and i.m. administration, respectively. Consequently, the mean residence time of D after both i.m. and i.v. administration of DS (10.4–11.6 h) was longer than that after DP administration (6.1 h). The smaller lymphocyte suppression induced by DS (50% of that after DP administration) was shown to be related to differences in the pharmacokinetics. This study revealed significant differences in the pharmacokinetics of D after administration of DS and DP and stresses the importance of the prodrug for the pharmacological response. Because of the slow and incomplete conversion of DS into dexamethasone, its use in emergency medicine situations should be critically evaluated.
Fundamentals of Positron Emission Tomography and Applications in Preclinical Drug Development
Authors: Cherry Simon R.
Published: July 2003

Positron emission tomography (PET) is a nuclear imaging technique that can dynamically image trace amounts of positron‐labeled radiopharmaceuticals in vivo. Tracer concentrations can be determined quantitatively, and by application of appropriate tracer kinetic models, the rates of a wide range of different biological processes can be measured noninvasively in humans. PET has been used as a research tool for more than 25 years and has also found clinical applications, particularly in oncology, neurological disorders, and cardiovascular disease. Recently, there has been tremendous interest in applying PET technology to in vivo small‐animal imaging. Significant improvements in the imaging technology now permit a wide range of PET studies in mice and rats, using compact, relatively low‐cost, dedicated small‐animal PET scanners. This article reviews the fundamental basis of PET imaging and discusses the development of small‐animal PET scanners and their possible application in preclinical drug development.
Pharmacokinetics and Bioavailability of Quercetin Glycosides in Humans
Authors: Graefe Eva U. , Wittig Joerg , Mueller Silke , Riethling Anne‐Kathrin , Uehleke Bernhard , Drewelow Bernd , Pforte Holger , Jacobasch Gisela , Derendorf Hartmut , Veit Markus
Published: July 2003

Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four‐way crossover study. Each subject received an onion supplement or quercetin‐4′‐O‐glucoside (both equivalent to 100 mg quercetin), as well as quercetin‐3‐O‐rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12‐channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailabilityand pharmacokinetic parameters between the onion supplement and quercetin‐4′‐O‐glucoside. Peak plasma concentrations were 2.3 ± 1.5 μg•mL−1 and 2.1 ± 1.6 μg•mL−1 (mean ± SDJ and were reached after 0.7 ± 0.2 hours and 0.7 ± 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were—despite the higher dose—only 0.6 ± 0.7 μg•mL−1 and 0.3 ± 0.3 μg•mL−1, respectively. Peak concentrations were reached 4.3 ± 1.8 hours after administration of buckwheat tea and 7.0 ± 2.9 hours after ingestion of rutin. The terminal elimination half‐life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin‐4′‐O‐glucoside and quercetin‐3‐O‐rutinoside. The significance of specific carriers on the absorption of quercetin glycosides, as well as specific intestinal b‐glucosidases, needs to be further evaluated.
Single‐Dose Gabapentin Pharmacokinetics and Safety in Healthy Infants and Children
Authors: Haig George M. , Bockbrader Howard N. , Wesche David L. , Boellner Samuel W. , Ouellet Daniele , Brown Richard R. , Randinitis Edward J. , Posvar Edward L.
Published: July 2003

Gabapentin (Neurontin®) is a gamma‐aminobutyric acid analogue indicated in adults for adjunctive treatment of partial seizures with or without secondary generalization. Two studies were conducted to determine the single‐dose pharmacokinetics of gabapentin in healthy subjects age 1 month to 12 years and to guide dose selection in safety and efficacy trials in pediatric patients. Forty‐eight subjects were given single oral doses of gabapentin (10 mg/kg) while fasting. Enrollment was homogeneously distributed throughout the age range. Plasma samples were drawn predose and then serially for 24 hours postdose. Single doses of gabapentin were well tolerated by healthy pediatric subjects. Plots of pharmacokinetic parameters versus age suggested significant differences between younger (1 month to < 5 years) and older (∞5 to 12 years) subjects. Mean area under the plasma concentration‐time curve from zero to infinity (AUC (0‐∞)) was 25.6 μg•h/mL in younger subjects and 36.0 μg•h/mL in older subjects (p < 0.001). Corresponding mean peak plasma concentrations (Cmax) were 3.74 and 4.52 μg/ml (p < 0.05). Oral clearance (normalized for body weight) was 7.40 and 4.41 mL/min/kg in younger subjects and older subjects, respectively (p < 0.001). It was concluded that children between 1 month and < 5 years of age require approximately 30% higher daily doses of gabapentin than those ≥ 5 to 12 years of age.
Pharmacokinetics and Rectal Bioavailability of Hydrocortisone Acetate after Single and Multiple Administration in Healthy Subjects and Patients
Authors: Tromm Andreas , Möllmann Helmut , Barth Jürgen , Hochhaus Günther , Krieg Michael , Bigalke Christiane , Möllmann Anja , Derendorf Hartmut
Published: July 2003

The pharmacokinetics and bioavailability of hydrocortisone after rectal administration of a hydrocortisone acetate foam were determined after single and multiple dosing in healthy subjects as well as in patients with inflammatory bowel disease. Endogenous hydrocortisone was suppressed by dexa‐methasone administration. Plasma levels were compared with those observed after intravenous administration of hydrocortisone. Only a very small part of the rectal dose (100 mg) was absorbed; the mean absolute bioavailability was 3.1% in healthy volunteers and 4.5% in patients. There was substantial intersubject variability. Although maximum hydrocortisone levels after single or multiple doses were significantly higher (about 70%) in the patient group, the systemic bioavailability is very low so that the risk of systemic side effects after rectal administration of hydrocortisone acetate foam has to be considered very low.
Clinical Utility of Monitoring Tacrolimus Blood Concentrations in Liver Transplant Patients
Authors: Venkataramanan Raman , Shaw Leslie M. , Sarkozi Laszlo , Mullins Richard , Pirsch John , MacFarlane Gordon , Scheller Dan , Ersfeld Diana , Frick Mary , Fitzsimmons William E. , Virji Mohammed , Jain Ashok , Brayman Kenneth L. , Shaked Abraham
Published: July 2003

The relationship between the dose of tacrolimus, trough tacrolimus blood concentration, and selected clinical endpoints (acute rejection, nephrotoxicity, and other toxicities) were examined in a prospective, multicenter clinical trial to validate the use of an enzyme‐linked immunosorbent assay (ELISA) for monitoring whole‐blood concentrations of tacrolimus in liver transplant patients. A total of 111 subjects from six transplant centers were evaluated over 12 weeks posttransplantation. In addition to trough tacrolimus blood concentrations, hematocrit, ALT, AST, GGTP, alkaline phosphatase, total bilirubin, serum creatinine, BUN, serum potassium, serum magnesium, blood glucose, and serum albumin were also measured. The relationship between trough tacrolimus blood concentrations and clinical endpoints was analyzed using both a logistic regression model and a Cox proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between increasing trough tacrolimus blood concentrations and decreasing risk of acute rejection was demonstrated over a 7‐day time window. Nephrotoxicity and other toxicities also demonstrated statistically significant relationships with trough tacrolimus blood concentrations. The results of the Cox analysis were consistent with the logistic regression analysis. Using receiver operator characteristic curves, trough tacrolimus concentrations as measured by the ELISA method were able to differentiate the occurrence of nephrotoxicity and toxicity from nonevents. To minimize nephrotoxicity of tacrolimus, it is necessary to maintain trough blood concentrations below 15 ng/ml. This study demonstrates that the ELISA method used to measure tacrolimus blood concentrations in this study provides information of predictive value for managing the risk of nephrotoxicity, other toxicity, and rejection in liver transplant patients.
Lack of Effect of Rosiglitazone on the Pharmacokinetics of Oral Contraceptives in Healthy Female Volunteers
Authors: Inglis Anne Marie L. , Miller Ann K. , Culkin Kathleen Thompson , Finnerty Dana , Patterson Scott D. , Jorkasky Diane K. , Freed Martin I.
Published: July 2003

The effect of rosiglitazone (Avandia® [BRL 49653C]) on the pharmacokinetics of ethinylestmdiol and norethindrone was evaluated after repeat dosing of rosiglitazone with an oral contraceptive (OC; Ortho‐Novum® 1/35 containing norethindrone 1 mg and ethinylestradiol 0.035 mg) in a randomized, doubleblind, placebo‐controlled crossover study. Thirty‐four healthy female volunteers received oral rosiglitazone (RSG) 8 mg + OC or matched placebo (P) + OC daily on days 1 to 14 of a 28‐day OC dosing cycle; the alternate regimen was administered during a second cycle. Ethinylestradiol and norethindrone pharmacokinetics were determined from plasma concentrations on day 14. Lack of pharmacokinetic effect was prospectively defined as 90% CI for the point estimate (PE) of the ratio (RSG + OC):(P + OC) contained within a 20% equivalence range for both ethinylestradiol and norethindrone (analyzed by ANOVA). For RSG + OC and P + OC, respectively, mean ethinylestradiol AUC(024) was 1126 and 1208 pg·h/mL (PE: 0.92; 90% CI: 0.88‐0.97), and mean norethindrone AUC(0_24) was 178 and 171 ng·h/mL (PE: 1.04;90% CI: 1.00–1.07). Thus, rosiglitazone had no significant effects on the pharmacokinetics of ethinylestradiol or norethindrone. Coadministration of rosiglitazone with OCs does not induce metabolism of these synthetic sex steroids and is not expected to impair the efficacy of OCs or hormone replacement therapy.
Role of Veterinary Medicine in Public Health: Antibiotic Use in Food Animals and Humans and the Effect on Evolution of Antibacterial Resistance
Authors: Lathers Claire M.
Published: July 2003

Veterinary public health is another frontier in the fight against human disease. The veterinary public health scope includes the control and eradication of zoonoses, diseases that are naturally transmitted between vertebrate animals and man. These diseases pose a continuous hazard to the health and welfare of the public. More than 100 diseases are categorized as zoonoses, including salmonellosis. It is important to understand how antibiotics are used in humans and in food animals and how these uses affect the evolution of antibacterial resistance. Appropriate use of antibiotics for food animals will preserve the long‐term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. An understanding of the epidemiology of antimicrobial resistance allows development of preventive strategies to limit existing resistance and to avoid emergence of new strains of resistant bacteria. Risk assessments are being used by the Center for Veterinary Medicine at the U.S. Food and Drug Administration as regulatory tools to assess potential risk to humans resulting from antibiotic use in food‐producing animals and to then develop microbial safety policies to protect the public health. The veterinary public health scope, in addition to the control and eradication of zoonoses, also includes the development and supervision of food hygiene practices, laboratory and research activities, and education of the public. Thus, it may be seen that there are many ways in which veterinary medicine plays a very important role in public health.
Caffeine Metabolism in Premature Infants
Authors: Al‐Alaiyan Saleh , Al‐Rawithi Sameer , Raines Dale , Yusuf Ahmed , Legayada Erlinda , Shoukri Mohamed M. , El‐Yazigi Adnan
Published: July 2003

Caffeine has been used frequently in the treatment and prevention of apnea of prematurity. The metabolism of caffeine depends on the activities of the hepatic enzymes that vary from one infant to another. The objective of this study was to determine the influence of postnatal age (PNA), birth weight (BW), study weight (SW), gestational age (GA), postconceptual age (PCA), and gender on the maturation of caffeine metabolism in premature infants. The caffeine base was administered orally as a loading dose of 10 mg/kg, followed by a maintenance dose of 2 mg/kg every 24 hours. The steady‐ state concentration of caffeine and metabolites was measured in plasma taken on the 5th‐day postloading dose. The molar concentration ratios for the N3 (N3‐), N7 (N7‐), N1 (N1‐), and all methyl (N‐) demethylation processes; clear‐ance (CL); and the percentage of molar concentration of caffeine found in plasma to that of the total caffeine and metabolites (%CAF) were calculated from samples collected from 80 neonatal infants. The 48 male and 32 female premature infants had median (range) BW (g), GA (weeks), SW (g), PCA (weeks), and PNA (days) of 1300 (650–2260), 30 (24–34), 1630 (980–2670), 34 (29–40), and 28 (5–60), respectively. The median (range) of the ratios for the %CAF, CL, and the N3‐, N7‐, N1‐, and Nall‐ were 86.9 (52.9–99.0), 0.127 (0.046‐0.503) ml·kg−1 ·min−1, 0.032 (0‐0.438), 0.070 (0.007‐0.471), 0.026 (0‐0.283), and 0.0463 (0.003‐0.303), respectively. When the patients were stratified into four PNA age groups, each older group showed a consistently higher level of caffeine metabolic activity for the N3‐, N7‐, and Nall‐‐ pathways with a corresponding decrease in the %CAF, whereas no significant differences were seen for the N1‐pathway or for CL. No pattern of significant differences between the demethylation process ratios, %CAF, or CL was seen between groups of infants when they were stratified according to BW, SW, PCA, or GA. The female infants were found to have significantly higher rates of caffeine metabolism as shown by %CAF, N1‐, N3‐, and Nall‐ processes but not the N7‐. Multivariate linear regression analysis by two methods demonstrated that PNA is significantly related to %CAF and Nall‐, whereas the female patients had higher levels of metabolic activity for the %CAF and N1‐ process. The authors conclude that the N7‐demethy‐ lation process is the predominate caffeine metabolic process in premature infants. Furthermore, the maturation of the caffeine metabolism in premature infants with a PNA of less than 60 days increases with postnatal age, regardless of birth weight, gestational age, postconceptual age, and study weight. The female neonatal patients demonstrated a higher rate of caffeine metabolism than the males.
The Pharmacokinetics of Colistin in Patients with Cystic Fibrosis
Authors: Reed Michael D. , Stern Robert C. , O'Riordan Mary Ann , Blumer Jeffrey L.
Published: July 2003

The safety and pharmacokinetics ofcolistin were determined after first dose (n = 30) and again under steady‐state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half‐life (t1/2), mean residence time (MRT), steady‐state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first‐dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first‐dose and steady‐state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty‐one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin‐induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin‐induced nephrotoxicity. No relationship between the occurrence of any colistin‐associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.
Thalidomide Dose Proportionality Assessment following Single Doses to Healthy Subjects
Authors: Teo Steve K. , Scheffler Michael R. , Kook Karin A. , Tracewell William G. , Colburn Wayne A. , Stirling David I. , Thomas Steve D.
Published: July 2003

Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy. The present study determined the single‐dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgene's commercial Thalomid® thalidomide formulation in an open‐label, single‐dose, three‐way crossover study. Fifteen healthy subjects were given 50,200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using noncompartmental methods, and dose proportionality was assessed by linear regression of dosenormalized Cmax and AUC0‐∞. No serious or unexpected adverse events occurred. The most common adverse events were dizziness, somnolence, headache, and nausea. One patient was discontinued because of pharyngitis. There was a significant deviation from proportionality for Cmax with increases being less than proportional than changes in dose. AUC0‐∞ increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as its clearance, is independent of dose over the range used. V/F was found to increase with dose. This was most likely due to the terminal rate constant, which is used to calculate V/F, actually representing the absorption process rather than elimination (i.e., flip‐flop phenomenon). The terminal rate constant (absorption rate constant) for the highest dose was 50% less than for the other two lower doses. The less than proportional increases in Cmax were most likely due to thalidomide's low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.
The Effects of Converting from Simvastatin to Atorvastatin on Plasminogen Activator Inhibitor Type‐1
Authors: Ito Matthew K.
Published: July 2003

Plasminogen activator inhibitor type‐1 (PAI‐1) is an important regulatory component of fibrinolysis and is elevated in the presence of endothelial dysfunction. Endothelial dysfunction and PAI‐1 in patients with coronary artery disease (CAD) have been demonstrated to improve following simvastatin therapy. The effect of converting from simvastatin to atorvastatin on PAI‐1 has not been reported and may be an additional consideration when making a formulary medication switch. Fourteen adult patients with hypercholesterolemia and CAD who were receiving simvastatin fora minimum of 3 months were randomized to continue on simvastatin or be converted to atorvastatin. Doses were adjusted to achieve or sustain a low‐density lipoprotein (LDL) cholesterol of 100 mg/dL. A fasting lipid panel and PAI‐1 were obtained at baseline and following 10 weeks of treatment. Mean SD LDL cholesterol at baseline (95.6 13.8 vs. 87.012.3 dL, p = 0.24) and following 10 weeks of simvastatin or atorvastatin (96.6 8.9 vs. 87.4 20.3 mg/dL, p = 0.29) were similar. No differences in PAI‐1 were observed at baseline (47.7 19.3 vs. 64.6 22.2 ng/mL, p = 0.15) or at 10 weeks (51.1 32.5 vs. 63.9 26.9 ng/mL, p = 0.44). These data suggest that the conversion from simvastatin to atorvastatin does not adversely affect PAI‐1 plasma concentrations in patients with CAD.
Pharmacokinetics of Buspirone Extended‐Release Tablets: A Single‐Dose Study
Authors: Sakr Adel , Andheria Mahalaxmi
Published: July 2003

The objective of this study is to evaluate the absorption of buspirone and its biotransformation to 1‐(2‐pyrimidinyl) piperazine (1‐PP) from two different extended‐release (ER) formulations of buspirone HCl tablets (12‐hour and 24‐hour in vitro release) and from a commercially available immediate‐release (IR) tablet. A single dose of the 30 mg ER tablets was compared with two doses of the 15 mg IR tablet administered 12 hours apart. Eighteen healthy male subjects participated in this randomized, open‐label, three‐treatment crossover study. Blood samples were obtained at 22 time points from predose (0 hour) until 36 hours postdose, and plasma concentration of buspirone and 1‐PP was determined by LC/tandem mass spectrometry method. The pharmacokinetic parameters AUC0‐t_ AUC0‐∞, CMax tmax, and t1/2 were calculated and statistically analyzed. The results indicated extended release of buspirone from the two test products in vivo with a 70% to 90% greater bioavailability in comparison with the IR formulation. The bioavailability of 1‐PP from ER formulations appears to be equal to that from the IR formulation. Both buspirone ER tablets successfully delivered bioavailable buspirone with a reduction in peak drug and metabolite plasma levels, prolonged buspirone plasma concentrations, and decreased ratio of 1‐PP to buspirone concentration with less intersubject variation when evaluated as a single‐dose study in healthy human subjects.
Pharmacokinetics of Zidovudine and Lamivudine in Neonates following Coadministration of Oral Doses Every 12 Hours
Authors: Moodley Daya , Pillay Kuben , Naidoo Kogie , Moodley Jack , Johnson Mark A. , Moore Katy H. P. , Mudd Paul N. , Pakes Gary E.
Published: July 2003

A phase I, repeat‐dose, open‐label study was conducted to determine the pharmacokinetics and safety of zidovudine and lamivudine, coadministered orally every 12 hours, in 16 neonates whose mothers were infected with human immunodeficiency virus type 1 (HIV‐1). The prospective mothers had been stabilized on a zidovudine/lamivudine regimen since week 36 of pregnancy to prevent mother‐to‐child transmission of HIV During 1 week postpartum, the mothers received zidovudine 300 mg plus lamivudine 150 mg every 12 hours and breastfed. Neonatal treatment was initiated 12 hours following birth with 4 mg/kg of zidovudine suspension plus 2 mg/kg of lamivudine solution every 12 hours; this regimen was continued for 1 week. Between days 1 and 7 of neonatal treatment, the neonatal oral clearance (CL/F) of zidovudine and lamivudine increased by 2‐fold (p < 0.001) and 1.6‐fold (p = 0.004), respectively, possibly reflecting maturation of intestinal hepatic and renal function occurring during the first week of life. Day 7/day 1 ratios for exposure (area under the serum concentration‐time curve [AUC]) and maximum observed serum concentration (Cmax) were 0.48 and 0.63, respectively, for zidovudine and 0.64 and 0.73, respectively, for lamivudine. At the time of delivery, the geometric mean cord/maternal concentration ratio was 1.24 for zidovudine and 1.12 for lamivudine, indicating free passage of each drug across the placenta. The maternal and neonatal treatment regimens were well tolerated. The results of this study confirm that in the neonate, a convenient regimen combining zidovudine 4 mg/kg and lamivudine 2 mg/kg, administered orally every 12 hours, provides zidovudine serum exposure very similar to that reported with the standard neonatal zidovudine regimen of 2 mg/kg every 6 hours, as well as lamivudine serum exposure within the range reported in adults receiving lamivudine 15 0mg twice a day and children receiving 4 mg/kg twice a day.
The Pharmacokinetics of Irbesartan in Hypertensive Children and Adolescents
Authors: Sakarcan Abdullah , Tenney Frank , Wilson John T. , Stewart John J. , Adcock Kim G. , Wells Thomas G. , Vachharajani Nimish N. , Hadjilambris Ophelia W. , Slugg Peter , Ford Neville F. , Marino Maria R.
Published: July 2003

An open‐label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1–12 years) and adolescents (13–16 years) with hypertension. Patients received single once‐daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high‐performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day1, and up to 48 hours after the final dose. The plasma concentration‐time profiles were similar between the 6‐ to 12‐year and the 13‐ to 16‐year age groups and to that previously determined from a study of adult subjects receiving 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and maybe a treatment option for pediatric hypertensive patients.
Acid‐Suppressive Therapy Use Associated with Antihypertensive Agents
Authors: Chow Sheryl L. , Luzier Aileen B. , DiTusa Lisanne , Snyder Brian D. , Izzo Joseph L.
Published: July 2003

Nitrates and calcium channel blockers (CCBs) have been shown to decrease lower esophageal sphincter pressure and theoretically may precipitate or aggravate gastroesophageal reflux. Thus, the authors hypothesized that patients who receive these agents would have greater use of acid‐suppressive drug use, defined as histamine2 antagonists or proton pump inhibitors. A retrospective cohort design was used to assess the use of acid‐suppressive drug use in hypertensive patients with respect to both nitrates and antihypertensive therapy. Of 15,662 treated hypertensive patients, 20% received acid‐suppressive therapy. An increased use of acid‐suppressive therapy was associated with nitrate (odds ratio [OR] = 1.71), CCB (OR = 1.46), and alpha1 antagonist (OR = 1.32) treatment, which appeared to be additive when patients received two or more of the agents. Within the class of CCBs, there was no significant difference among the individual agents. As the clinical and economic burden maybe substantial, further study is warranted.
Oral Bioavailability and Disposition of [14C]Omapatrilat in Healthy Subjects
Authors: Malhotra Bimal K. , Iyer Ramaswamy A. , Soucek Kathy M. , Behr Douglas , Liao Wei‐chi , Mitroka James G. , Kaul Sanjeev , Cohen Marvin B. , Knupp Catherine A.
Published: July 2003

The objective of this study was to determine the absolute oral bioavailability and disposition of omapatrilat. This singledose, randomized, crossover study of 20 mg intravenous and 50 mg oral [14C]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailability of omapatrilat, an orally active vasopeptidase inhibitor. Blood samples were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, plasma, urine, and feces was determined by liquid scintillation counting. Urinary excretion of radioactivity averaged 80% and 64% of intravenous and oral doses, respectively; < 1% of oral dose was excreted unchanged in urine. The absolute oral bioavailability of omapatrilat averaged 31%. Total body clearance of omapatrilat (80 L/h) exceeded liver plasma flow. Apparent steady‐state volume of distribution of omapatrilat (21 L/kg) was extremely high compared with total body water. Omapatrilat undergoes substantial presystemic first‐pass metabolism after oral administration. Omapatrilat is eliminated primarily by metabolism, and its metabolites are eliminated primarily in urine. Extrahepatic organs may be involved in the elimination of omapatrilat. Plasma concentrations of omapatrilat exhibit a prolonged terminal elimination phase, which represents elimination from a deep compartment.
The Risk of Liver Damage Associated with Minocycline: A Comparative Study
Authors: Seaman Helen E. , Lawrenson Ross A. , Williams Tim J. , MacRae Kenneth D. , Farmer Richard D. T.
Published: July 2003

Using the General Practice Research Database, the authors performed (1) a cohort analysis comparing the incidence of liver dysfunction in new users of minocycline with new users of oxytetracycline/tetracycline and (2) a case control study assessing antibiotic exposure in new cases of liver dysfunction and controls without liver dysfunction. In new users, the incidence of liver dysfunction in those exposed to minocycline was 1.04 cases/10,000 exposed person months (EPM)and 0.69 cases/10,000 EPM in those exposed to oxytetracycline/tetracycline (relative risk 1.51 [CI95: 0.63, 3.65]). The risk in both groups was greatest in the first month of use. The adjusted odds ratio (ORadj) of liver dysfunction associated with exposure to minocycline compared with nonuse was 2.10 (CI95: 1.30, 3.40); for oxytetracycline/tetracycline, the ORadj was 1.46 (CI95: 0.81, 2.64); and for exposure to erythromycin, the ORadj was 1.64 (CI95: 0.71, 3.80). The authors thus support a weak association between the use of oral antibiotics and liver dysfunction in patients with acne. The risk associated with exposure to minocycline appears to be very small. The cohort analysis demonstrated that any risk associated with minocycline was not significantly greater than that associated with oxytetracycline/tetracycline exposure.
Cardiac Adverse Effects of Early Dexamethasone Treatment in Preterm Infants: A Randomized Clinical Trial
Authors: Zecca Enrico , Papacci Patrizia , Maggio Luca , Gallini Francesca , Elia Serena , de Rosa Gabriella , Romagnoli Costantino
Published: July 2003

This study evaluates the effects of early administration of dexamethasone on left ventricle dimensions and their clinical significance in preterm infants. Fifty preterm infants with birth weight ≤ 1250 g and gestational age ≤ 30 weeks were randomly assigned after 72 hours of life to the dexamethasone group (n = 25) or to the control group (n = 25). The treated infants received dexamethasone intravenously from the 4th day of life for 7 days (0.5 mg/kg/day for the first 3 days, 0.25 mg/kg/day for the next 3 days, and 0.125 mg/kg/day for the 7th day). Serial echocardiographic measurements of end systolic interventricular septum thickness, end diastolic interventricular septum thickness, end systolic left ventricle posterior wall thickness, end diastolic left ventricle posterior wall thickness, left ventricle end diastolic diameter, and left ventricle end systolic diameter were taken before starting dexamethasone, on days 3 and 7 of treatment, 7 days after the interruption of treatment, and at the 28th day of life. Five infants of each group were excluded by the final analysis because of the lack of a complete cardiac evaluation, leaving 20 treated and 20 control infants. Infants receiving dexamethasone had a significantly larger increase in mean septal and left posterior wall thickness during the treatment and 7 days after the dexamethasone weaning. The mean left ventricle diameter of treated infants was significantly lower than that of control infants from the 7th day of treatment to the 28th day of life. Four neonates (20%) in the dexamethasone group developed left ventricular myocardial hypertrophy without left ventricle outflow tract obstruction, showing signs of decreased cardiac output and ischemic changes on ECG. The daily fluid intake was increased to 200 ml/kgto ensure an adequate preload volume, and the complete resolution of left ventricle hypertrophy was obtained within the 2nd to 3rd week after dexamethasone weaning. Preterm infants receiving an early (< 96 hours of life) short course of dexamethasone develop a left ventricular myocardial hypertrophy that can be symptomatic and clinically significant. Preterm infants included in future studies with the goal to find the minimum dose and duration of dexamethasone treatment should be strictly monitored echocardiographically for this side effect.
Pharmacokinetic‐Pharmacodynamic Modeling of Rivastigmine, a Cholinesterase Inhibitor, in Patients with Alzheimer's Disease
Authors: Gobburu J.V.S. , Tammara V , Lesko L , Jhee S. S. , Sramek J. J. , Cutler N. R. , Yuan Ruihua
Published: July 2003

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics‐pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114–666, also called NAP 226‐90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed‐effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose‐disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half‐life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114–666 concentration of about 5.4 μg/L required for half‐maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK‐PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.
Pharmacokinetics and Pharmacodynamics of Thalidomide in HIV Patients Treated for Oral Aphthous Ulcers: ACTG Protocol 251
Authors: Aweeka Francesca , Trapnell Carol , Chernoff Miriam , Jayewardene Anura , Spritzler John , Bellibas S. Eralp , Lizak Patricia , Jacobson Jeffrey
Published: July 2003

Thalidomide has increasing clinical benefits, including the healing of aphthous ulcers in patients with HIV. Unfortunately, pharmacological information addressing the pharmacokinetics (PK) of this compound in HIV patients is limited. Concern exists as to whether thalidomide may alter its own metabolism owing to in vitro data previously reported. Furthermore, no information is available defining the relationship between drug exposure and clinical response. This study evaluated the PK and pharmacodynamics (PD) of thalidomide in patients enrolled in AIDS Clinical Trials Group Protocol 251. Study patients had HIV infection and oral aphthous ulcers of at least 2 weeks' duration. Pharmacologic studies were completed in those subjects randomized to receive active thalidomide at a dose of 200 mg daily for the 4‐ week study period. PK studies involving serial sampling were carried out in 7 subjects following multiple dosing during study weeks 1 and 4. In addition, trough measurements were done in 20 subjects during each of the 4 study weeks to explore the relationship between time‐averaged trough values and extent of clinical response. All samples were analyzed using a validated HPLC method, and parameters were determined using noncompartmental PK analysis. Thalidomide oral clearance averaged 0.14 ± 0.08 and 0.12 ± 0.05 l/h/kg on weeks 1 and 4 (p = 0.72), while the terminal elimination half‐life averaged 5.7 ± 1.5 and 7.3 ± 1.7hours (p = 0.12). The median time‐averaged trough value for subjects deemed complete responders was 0.60, while the median value for noncomplete responders was 0.54. Adjusting for baseline CD4 count and initial index ulcer area, no significant effects were observed of increased thalidomide levels on response. In summary, this study provides steady‐state PK data in HIV patients managed with thalidomide and suggests negligible effect of chronic dosing on drug clearance (comparing results from weeks 1 and 4). Furthermore, variable trough measurements between patients do not directly influence the effectiveness of thalidomide for oral aphthous ulcers.
Effects of Oral Prasterone (Dehydroepiandrosterone) on Single‐Dose Pharmacokinetics of Oral Prednisone and Cortisol Suppression in Normal Women
Authors: Meno‐Tetang GuyM. L. , Blum Robert A. , Schwartz Kenneth E. , Jusko William J.
Published: July 2003

This study sought to determine effects of multiple dosing of prasterone (DHEA, dehydroepiandrosterone) on the pharmacokinetics of prednisolone and endogenous cortisol secretion. These drugs are likely to be coadministered to patients with systemic lupus erythematosus. Fourteen normal women (ages 30.1 ± 5.4 years) received single‐dose oral prednisone (20 mg) before and after200 mg/day of oral prasterone for one menstrual cycle (approximately 28 days). Identical assessments, timed to onset of menses, were conducted pretreatment (baseline) and at days 28 and 29 of prasterone treatment and included serum total and free prednisolone, prednisone, DHEA, DHEA‐S (dehydro‐epiandrosterone sulfate), ACTH‐stimulated cortisol, and sex hormones and 24‐hour urine free cortisol. Pharmacokinetic parameters of prednisolone as assessed by Cmax, t1/2, AUC, or serum protein binding were not affected by prasterone. The ACTH‐stimulated plasma cortisol concentrations were mildly reduced, but 24‐hour urine free cortisol excretion was unchanged during prasterone administration. Serum androstenedione and testosterone increased, while no changes in serum estradiol or estrone occurred. The administration of 200 mg oral prasterone produced serum concentrations of DHEA and DHEA‐S significantly greater than endogenous levels. Chronic dosing with 200 mg/day of prasterone did not alter either prednisolone pharmacokinetics or inhibition of cortisol secretion by prednisolone.
Bioavailability and Pharmacokinetics of Lorazepam after Intranasal, Intravenous, and Intramuscular Administration
Authors: Wermeling Daniel Paul H. , Miller Jodi Lynn , Archer Sanford Mitchell , Manaligod Jose M. , Rudy Anita C.
Published: July 2003

The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1‐week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (%CV) bioavailability of 77.7 (11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration. Elimination profiles were comparable between all three routes. The concentration‐time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.
P‐glycoprotein (P‐gp) Is Upregulated in Peripheral T‐Cell Subsets from Solid Organ Transplant Recipients
Authors: Donnenberg Ms. Vera S. , Burckart Gilbert J. , Griffith Bartley P. , Jain Ashok B. , Zeevi Adriana , Donnenberg Albert D.
Published: July 2003

Immunosuppressive agents such ascyclosporine, tacrolimus, sirolimus, and corticosteroids are substrates for the transmembrane multidrug resistance pump P‐glycoprotein (P‐gp). Experience in oncology has suggested that chronic exposure to P‐gp substrates induces upregulation of P‐gp activity, which could result in resistance to immunosuppressive drugs. The authors investigated P‐gp function in CD4+ and CD8+ T cells from the peripheral blood of solid organ transplant recipients (SOTX). Subjects included 14 stable SOTX (10 liver, 4 lung) and 16 healthy controls. Four‐color flow cytometry was used to simultaneously measure intracellular concentration of the fluorescent P‐gp substrate Rhodamine 123 (Rh123) and surface expression of CD45RO (nominal memory/effector), CD45RA (naive), and either CD4 or CD8. P‐glycoprotein function was measured by a dye efflux assay in which activity was inferred from a decrease in Rh123 fluorescence. CD4+ and CD8+ T cells from patients and control subjects eliminated Rh123, and this activity was inhibited by verapamil, a known P‐gp substrate. CD8+ T cells had greater P‐gp activity than CD4+ cells, and naive and transitional T cells displayed greater activity than memory T cells. Activity wasbimodalin CD8+ CD45RO+ T cells, with a subset of these cells expressing the greatest P‐gp activity. Patient CD8+ naive and transitional T cells had upregulated P‐gp activity compared to control subjects. We conclude that (1) P‐gp activity is significantly upregulated in specific T‐cell subsets (CD8+/CD45RA+) in the peripheral blood of SOTX, and (2) the bimodal nature of P‐gp response in CD8+ T cells complicates analysis of the effect of chronic administration of P‐gp substrates to SOTX.