bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Pharmacokinetics of Oral Ceftibuten, Cefixime, Cefaclor, and Cefuroxime Axetil in Healthy Volunteers
Authors: Nix David E. , Symonds William T. , Hyatt Judith M. , Wilton John H. , Teal Marilyn A. , Reidenberg Pascale , Affrime Melton B. 
Published: October 2023

Study Objective. To compare the pharmacokinetics of ceftibuten, cefixime, cefuroxime axetil, and cefaclor after oral administration.Design. Randomized, four‐period, crossover study.Setting. Hospital‐based clinical research center.Subjects. Healthy adult men and women volunteers.Interventions. Single 400‐mg doses of cefixime and ceftibuten, and 500‐mg doses of cefuroxime axetil and cefaclor.Measurements and Main Results. Serum concentrations were determined by high‐performance liquid chromatography methods. The mean oral clearances of cefixime, cefuroxime axetil, and cefaclor were similar, ranging from 20.4–27.0 L/hour; clearance of ceftibuten was approximately 4‐fold less, 5.45 L/hour. The serum half‐lives of ceftibuten (2.35 hrs) and cefixime (2.38 hrs) were prolonged compared with those of cefuroxime axetil (1.30 hrs) and cefaclor (0.693 hr). These agents also differed in terms of time to maximum concentration, time to peak plasma level, area under the curve, and apparent volume of distribution, the last reflecting differences in bioavailability.Conclusion. Ceftibuten had a relatively high time to maximum concentration and long half‐life, resulting in a 3.5‐fold higher area under the curve than cefixime, cefuroxime axetil, and cefaclor. These pharmacokinetic data can be used as a basis to compare the four oral cephalosporins; however, comparative susceptibility data must also be considered.
Alteration in Indinavir Clearance During Interleukin‐2 Infusions in Patients Infected with the Human Immunodeficiency Virus
Authors: Piscitelli Stephen C. , Vogel Susan , Figg William D. , Raje Sangeeta , Forrest Alan , Metcalf Julia A. , Baseler Michael , Falloon Judith 
Published: October 2023

Study Objective. To evaluate the effect of interleukin‐2 (IL‐2) infusions on the pharmacokinetics of indinavir in patients infected with the human immunodeficiency virus.Design. Observational, noncontrolled trial and prospective, open‐label, nonrandomized, pharmacokinetic study.Setting. Government research hospital.Patients. Seventeen patients receiving indinavir 800 mg every 8 hours and a 5‐day continuous infusion of recombinant IL‐2.Interventions. Observational study: trough indinavir concentrations were measured on day 1 and day 5 of IL‐2 as part of a clinical trial. Prospective study: serial plasma samples were collected on days 1 and 5 of IL‐2 to determine indinavir concentrations. Samples were also collected over the study period to determine IL‐6 concentrations. The data were fit by a one‐compartment model that allowed clearance to change based on IL‐6 production and by standard noncompartmental equations.Measurements and Main Results. The area under the curve of indinavir increased in eight of nine patients by a mean of 88% (range −29–215%) between days 1 and 5 of IL‐2 infusion. Over this period, IL‐6 concentrations also increased in all patients and indinavir clearance significantly decreased. Observational data in eight patients from the clinical trial showed significantly increased indinavir trough concentrations from 264 ± 493 to 670 ± 677 ng/ml in the presence of IL‐2.Conclusion. Indinavir concentrations were altered during IL‐2 infusions, possibly by induction of IL‐6. Investigation into the effects of other proinflammatory cytokines is warranted.
In Unfractionated Heparin Dosing, the Combination of Patient Age and Estimated Plasma Volume Predicts Initial Antifactor Xa Activity Better than Patient Weight Alone
Authors: Rosborough Terry K. 
Published: October 2023

Study Objective. To determine whether patient factors other than body weight would better predict patients' initial antifactor Xa heparin activity (HA) after start of unfractionated heparin (UFH) therapy.Design. Case series.Setting. A 625‐bed, adults‐only private, tertiary care teaching hospital.Patients. Ninety‐two patients requiring UFH therapy.Interventions. Patients received initial UFH bolus doses of 72–80 U/kg ideal weight and initial UFH infusions of 19.1–21.2 U/kg ideal weight.Measurements and Main Results. Fifty‐five percent of the first 6‐hour HA measurements were supratherapeutic (> 0.7 U/ml antifactor Xa activity). Patient weight was inferior to a combination of age and estimated plasma volume in predicting initial HA. A predictive model including these two factors accounted for 38.5% of variation in first HA levels compared with 17.7% with actual weight alone.Conclusion. Weight‐based UFH dosing may frequently result in nontherapeutic initial HA levels. Initial UFH dosing might be improved if protocols based on patient age and estimated plasma volume were developed.
The Pharmacokinetics and Pharmacodynamics of Fludarabine in Rheumatoid Arthritis
Authors: Knebel William , Davis John C. , Sanders William D. , Fessler Barri , Yarboro Cheryl , Pucino Frank , Boumpas Dimitrios T. 
Published: October 2023

Study Objective. To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA).Design. Open‐label, staggered trial conducted in conjunction with a phase I‐II clinical trial.Setting. Government research hospital.Patients. Twenty‐six patients with refractory RA.Intervention. Fludarabine 20 or 30 mg/m2/day was administered as a 0.5‐hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo).Measurements and Main Results. Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two‐compartment model. There were no differences in pharmacokinetics between the low‐ and high‐dose groups. The mean ± SD total clearance, volume of distribution at steady state, and β‐half‐life were 13.68 ± 5.1 L/hour, 170.08 ± 86.5 L, and 10.9 ± 3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters.Conclusion. Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate‐length distribution phase (∼ 40 min), terminal half‐life of 10.9 hours, and significant amount of tissue distribution.
Pharmacokinetics of Dexamethasone and Valspodar, a P‐glycoprotein (mdr1) Modulator: Implications for Coadministration
Authors: Kovarik John M. , Purba Harpal S. , Pongowski Michele , Gerbeau Christophe , Humbert Henri , Mueller Edgar A. 
Published: October 2023

Study Objective. To assess the potential for a drug‐drug interaction between valspodar, a P‐glycoprotein (mdr1) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens.Design. Randomized, open‐label, three‐period crossover study.Setting. Clinical pharmacology research center.Subjects. Eighteen healthy men volunteers (age 25.8 ± 3.5 yrs, weight 71.6 ± 10.3 kg).Interventions. Subjects received single fasting oral doses of valspodar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2‐ to 3‐week washout phases between administrations.Measurements and Main Results. Lack of a pharmacokinetic drug‐drug interaction with respect to valspodar was conclusively demonstrated for both Cmax,b (2.3 ± 0.4 vs 2.4 ± 0.5 μg/ml) and AUCb (19.8 ± 4.8 vs 19.6 ± 4.9 μg·hr/ml) inasmuch as bioequivalence criteria were satisfied when comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (Cmax 88 ± 23 vs 91 ± 20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400 ± 87 vs 494 ± 90 ng·hr/ml). Regression analysis of valspodar Cmax,b and AUCb during coadministration versus the extent of the interaction (percentage increase in dexamethasone AUC) did not reveal a concentration‐effect relationship (p=0.7299 and 0.9718, respectively).Conclusion. Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clinical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in dexamethasone's AUC is unlikely to be relevant. Thus no alterations in valspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple‐dose experience in patients would be desirable to confirm these conclusions.
Cytochrome P450 3A4 Activity in Premenopausal and Postmenopausal Women, Based on 6‐β‐Hydroxycortisol:Cortisol Ratios
Authors: Burstein Aaron H. , Reiss William G. , Kantor Eric , Anderson Gail D. 
Published: October 2023

Study Objective. To characterize cytochrome P450 (CYP) 3A4 activity in premenopausal and postmenopausal women by evaluating the urinary 6‐β‐hydroxycortisokcortisol ratio.Design. Prospective study.Subjects. Thirteen premenopausal and 13 postmenopausal women who were healthy and not receiving drugs known to affect CYP3A4 activity.Interventions. Beginning on day 2 of menses, premenopausal women collected first morning urine samples every other day for a complete menstrual cycle. Postmenopausal women collected first morning urine every other day for 28 days.Measurements and Main Results. Mean weekly 6‐β‐hydroxycortisol:cortisol ratios did not differ during the phase (week) of the menstrual cycle. Daily ratios did not differ in postmenopausal women. No difference between premenopausal and postmenopausal women was found on comparing overall median ratios.Conclusion. Cytochrome P450 3A4 activity as measured by 6‐β‐hydroxy cortisol:cortisol ratio did not differ by week of menstrual cycle, suggesting no menstrual cycle‐related changes. Menopause does not appear to be associated with differences in CYP3A4 activity, compared with premenopause.
Patient Recall of Therapeutic Paralysis in a Surgical Critical Care Unit
Authors: Wagner Bertil K.J. , Zavotsky Kathleen Evanovich , Sweeney Janet B. , Palmeri Barbara A. , Hammond Jeffrey S. 
Published: October 2023

Study Objective. To investigate patient recall of therapeutic paralysis (TP) in a surgical critical care unit.Design. Prospectively applied structured interview of patients undergoing TP over 18 months.Setting. Surgical critical care unit with 27 beds at a tertiary care university teaching hospital.Patients. Forty patients admitted for postoperative care after coronary artery bypass graft surgery, trauma, or gastrointestinal surgery.Interventions. Patients received TP and concurrent sedation with benzodiazepines, propofol, and narcotics.Measurements and Main Results. After the end of TP patients were asked to recall the experience, and their responses were ranked on a four‐point ordinal scale. Four of 11 patients recalled mostly negative events and experiences with TP, such as sleeplessness, discomfort, pain, anxiety, and inconsistent caregiver communication. All patients with recall experienced fear, anxiety, and sleeplessness. Single‐drug therapy with propofol and inadequate benzodiazepine dosing were linked to patient recall.Conclusions. Patient recollection from TP may be more common than appreciated and is generally unpleasant. Adequate dosing with benzodiazepines and narcotics is warranted to prevent recall and discomfort.
Effect of Oral H2‐Receptor Antagonists on Left Ventricular Systolic Function and Exercise Capacity in Patients with Chronic Stable Heart Failure
Authors: Lucas B. Daniel , Williams Mark A. , Mohiuddin Syed M. , LaMadrid Lance J. , Schroeder Lisa J. , Hilleman Daniel E. 
Published: October 2023

Study Objective. To evaluate the effect of cimetidine, famotidine, ranitidine, and placebo on left ventricular systolic function, aerobic metabolic performance, and exercise capacity in patients with chronic, stable heart failure.Design. Double‐blind, randomized, placebo‐controlled, four‐way crossover study.Setting. Outpatient, university‐affiliated cardiology clinic.Patients. Twelve men with stable New York Heart Association class II or III heart failure secondary to ischemic heart disease or hypertension.Interventions. Patients received in random sequence cimetidine 400 mg twice/day, famotidine 40 mg/day, ranitidine 150 mg twice/day, and placebo. Each treatment was administered for 7 days, and the periods were separated by a 1‐week washout.Measurements and Main Results. Before and after each treatment, patients underwent a bicycle stress echocardiogram with aerobic metabolic assessment. Left ventricular function was evaluated by calculating ejection phase indexes from Doppler echocardiographic measurements. All 12 patients successfully completed the study. No patient reported any adverse effect attributed to study drugs. None of the treatments was associated with significant changes in any measure of left ventricular systolic function, aerobic metabolic performance, or exercise capacity, nor were placebo‐subtracted differences for the agents significantly different for any of the three measures.
A Comparison of Fluvastatin 40 mg Every Other Day versus 20 mg Every Day in Patients with Hypercholesterolemia
Authors: Rindone Joseph P. , Hiller Debra , Arriola Greg 
Published: October 2023

Study Objective. To assess the efficacy of fluvastatin administered every other day versus an equivalent dose given daily in patients with hypercholesterolemia.Design. Randomized, nonblinded, crossover study.Setting. Veterans Affairs Medical Center.Patients. Twenty‐three patients with low‐density lipoprotein (LDL) levels above 160 mg/dl despite diet therapy.Intervention. Patients received fluvastatin 40 mg every other day or 20 mg/day, all doses taken at bedtime. Each treatment arm was 6 weeks in duration.Measurements and Main Results. A lipid profile was determined at baseline and after each regimen. Both regimens significantly lowered total cholesterol and LDL versus baseline. The LDL levels were lowered by 24% and 21% by fluvastatin 20 mg/day and 40 mg every other day, respectively. There was no statistically significant difference in lipid components between regimens.Conclusion. Fluvastatin 40 mg every other day is effective in lowering total cholesterol and LDL in patients with hypercholesterolemia.
Comparison of Bactericidal Activities of Intermittent and Continuous Infusion Dosing of Vancomycin against Methicillin‐Resistant Staphylococcus aureus and Enterococcus faecalis
Authors: Klepser Michael E. , Patel Kalpana B. , Nicolau David P. , Quintiliani Richard , Nightingale Charles H. 
Published: October 2023

Study Objective. To describe the pharmacokinetic profiles of vancomycin administered by continuous infusion and intermittent dosing and compare the duration of activity of the regimens.Design. Randomized, open‐label, cross‐over study.Setting. Clinical research center at an academic medical center.Subjects. Twelve healthy, nonpregnant volunteers age 27.6 ± 2.3 years.Intervention. Subjects received the following intravenous vancomycin regimens: 1 g every 12 hours; 2 g continuous infusion over 24 hours; and 1 g continuous infusion over 24 hours. Dosages were administered with and without gentamicin 2 mg/kg.Measurements and Main Results. Serum samples were collected, drug concentrations determined, and bactericidal activity measured against two isolates each of methicillin‐resistant Staphylococcus aureus and Enterococcus faecalis. Subjects had poor tolerability for continuous infusions. Trough concentration for the intermittent regimen was 5.5 ± 1.9 mg/ml, and steady‐state concentrations were 8.8 ± 1.6 and 16.9 ± 1.9 mg/ml for 1 and 2 g continuous infusions, respectively. In general, all regimens provided bactericidal activity throughout the study interval. Against one isolate of E. faecalis, 2 g continuous infusion plus gentamicin provided cidal activity for a significantly greater percentage of the dosing interval (p<0.001).Conclusion. Continuous infusion does not greatly improve the activity of vancomycin and should not be routinely administered. However, it may prove useful against isolates with reduced susceptibility to the agent.
Expression of Cydin‐Dependent Kinase 5 and Associated Cyclins in Leydig and Sertoli Cells of the Testis
Authors: MUSA FATHEL RAHMAN M. , TOKUDA MASAAKI , KUWATA YOSHIHIRO , OGAWA TAKAAKI , TOMIZAWA KAZUHTTO , KONISHI RYOJI , TAKENAKA IKUMASA , HATASE OSAMU 
Published: October 2023

ABSTRACT: In this study, we examined the expression and subcellular localization of cyclin‐dependent kinase 5 (Cdk5), cyclin D1, and cyclin E in Leydig and Sertoli cell lines that were cultured with 7.5, 1.0, 0.5, or 0% serum (mixture of a 2:1 ratio of horse serum and fetal bovine serum) and in the developing rat testis to verify the possible functions of Cdk5, cyclin D1, and cyclin E in the testis. The abundance of Cdk5 and cyclin E in the Leydig cell line, TM3, was significantly reduced at low serum concentrations. In contrast, serum concentration had no effect on Cdk5 and cyclin E levels in the Sertoli cell line, TM4.Cyclin D1 was detected by western blot analysis in TM4 cells only, and its abundance was serum dose dependent. The kinase activity of Cdk5 in TM3 and TM4 cells that were cultured at various serum concentrations coincided with the levels of Cdk5 expression. Immunohistochemical staining for Cdk5 and cyclin E reealed nuclear and cytoplasmic distribution, both in TM3 and TM4 cells. Moreover, cyclin D1 immunoreactivity was only detected in TM4 cells. In the developing rat testis, Cdk5 expression was most prominent at 2 and 3 weeks after birth. Cyclin D1 was strongly expressed at 1 and 2 weeks in premature rat testes. On the other hand, cyclin E was highly expressed in the adult testis. Immunohistochemical localization of Cdk5, cyclin D1, and cyclin E in 1‐week‐old and adult rat testes revealed expression in both Leydig and Sertoli cells. Our results suggest that Cdk5 in TM3 and Leydig cells of the testis might play a role in cell cycle regulation, whereas Cdk5 in TM4 and Sertoli cells of the adult testis might have some additional functions besides control of proliferation. Key words: Kinase activity, growth control.
Effects of Cryopreservation on Bull Sperm Head Morphometry
Authors: GRAVANCE CURTIS G. , VISHWANATH R. , PITT COLIN , GARNER DUANE L. , CASEY PATRICK J. 
Published: October 2023

ABSTRACT: Artificial insemination using cryopreserved semen is a common management tool of the contemporary livestock producer. However, cryopreservation is detrimental to sperm function and fertility, killing some 50% of the spermatozoa during the process. Prediction of cryopreservation damage from prefreeze samples remains elusive. Computer‐automated sperm head morphometry was used in this study to determine the effects of cryopreservation on bovine sperm head morphometry.Semen was collected from 18 bulls and was divided. One portion was extended to 200 × 106 sperm/ml and a microscope slide was prepared, while the remaining portion was cryopreserved in a Triscitrateyolk extender. After thawing, the cryopreserved samples were prepared on microscope slides. All slides were air dried and were stained with hematoxylin and rose bengal. The morphometry dimensions for length, width, width/length, area, and perimeter for a minimum of 200 sperm heads were analyzed from each slide by computer‐aided sperm head morphometry analysis, and the mean measurements were recorded. Bull sperm heads were significantly I (P < 0.01) smaller in cryopreserved spermatozoa than in the companion extended samples for length (8.56 ± 0.07 vs. 8.63 ± 0.08 μm), width (4.39 ± 0.05 vs. 4.48 ± 0.05 μm), area (28.42 ± 0.07 vs. 29.14 ± 0.08 μm), and perimeter (23.33 ± 0.21 vs. 23.70 ± 0.23 μm) for all bulls. Width/length was also different (0.513 vs 0.519). In addition, differences (P < 0.05) were found within 14 of 18 bulls for at least four of the morphometric parameters. The percent change in measures after cryopreservation were correlated (P ± 0.05) to the variability of the extended sample. Variations in sperm head measurements were lower (P ≥ 0.05) in extended samples of the four bulls in which no changes occurred than in extended samples of the remaining 14 bulls. These data suggest that the variability in sperm head measurements of individual bulls, or ejaculates, may be an indicator of sperm cryosurvivability.
Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus
Authors: Zanner Sebastian , Goff Elliott , Ghatan Samuel , Wölfel Eva Maria , Ejersted Charlotte , Kuhn Gisela , Müller Ralph , Frost Morten 
Published: October 2023

ABSTRACTClinical studies indicate that microvascular disease (MVD) affects bone microstructure and decreases bone strength in type 2 diabetes mellitus (T2D). Osteocytes are housed in small voids within the bone matrix and lacunae and act as sensors of mechanical forces in bone. These cells regulate osteoclastic bone resorption and osteoblastic bone formation as well as osteocytic perilacunar remodeling. We hypothesized that MVD changes morphometric osteocyte lacunar parameters in individuals with T2D. We collected iliac crest bone biopsies from 35 individuals (10 female, 25 male) with T2D with MVD (15%) or without MVD (21%) with a median age of 67 years (interquartile range [IQR] 62–72 years). The participants were included based on c‐peptide levels >700 pmol L−1, absence of anti‐GAD65 antibodies, and glycated hemoglobin (HbA1c) levels between 40 and 82 mmol mol−1 or 5.8% and 9.7%, respectively. We assessed osteocyte lacunar morphometric parameters in trabecular and cortical bone regions using micro‐computed tomography (micro‐CT) at a nominal resolution of 1.2 μm voxel size. The cortical osteocyte lacunar volume (Lc.V) was 7.7% larger (p = 0.05) and more spherical (Lc.Sr, p < 0.01) in the T2D + MVD group. Using linear regression, we found that lacunar density (Lc.N/BV) in trabecular but not cortical bone was associated with HbA1c (p < 0.05, R2 = 0.067) independently of MVD. Furthermore, Lc.V was larger and Lc.Sr higher in the center than in the periphery of the trabecular and cortical bone regions (p < 0.05). In conclusion, these data imply that MVD may impair skeletal integrity, possibly contributing to increased skeletal fragility in T2D complicated by MVD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.