Vancomycin Pharmacokinetics in a Pregnancy Rat Model.

Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding the mass transit of vancomycin to the fetus is important in pregnancy. We aimed to (i) identify a relevant population pharmacokinetic (PK) model for vancomycin in pregnancy and (ii) estimate PK parameters and describe the mass transit of vancomycin from mother to pup kidneys. Pregnant Sprague-Dawley rats (i.e., trimester 1 and trimester 3) received 250 mg/kg vancomycin once daily for three days through intravenous injection via an internal jugular vein catheter. Vancomycin concentrations in maternal plasma and pup kidneys were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple compartment models were fitted and assessed using a nonparametric approach with Pmetrics. A total of 10 vancomycin-treated rats and 48 pups contributed PK data. A 3-compartment model adjusted for trimester fit the data well (maternal plasma Bayesian, observed versus predicted R2 = 0.978; pup kidney Bayesian, observed versus predicted R2 = 0.999). The mean rate constant for vancomycin mass transit to the pup kidney was 0.72 h-1 for trimester 1 dams and 0.75 h-1 for trimester 3 dams. Median vancomycin concentrations in pup kidneys from trimester 3 were significantly higher than those in trimester 1 (8.62 versus 0.36 µg/mL, P < 0.001). Vancomycin transited to the fetus from the mother and was; kidney accumulation differed by trimester. This model may be useful for a translational understanding of vancomycin distribution in pregnancy to ensure efficacious and safe doses to both mother and fetus.

Faculty satisfaction and perception regarding emergency remote teaching : An exploratory study.

Background: The COVID 19 pandemic which made its presence felt by March 2020 made the educators and administrators, both of whom had very little experience with alternate teaching and learning methods, look for alternate methods of delivering the teaching learning. Because of the mandates from apex bodies, faculty members were forced to delve into an unknown territory of Emergency Remote Teaching (ERT). This study aimed to explore the factors that contributed to faculty satisfaction for ERT, the challenges faced, and suggestions for improving online teaching. Method: A modified survey tool to suit ERT was developed which demonstrated favourable preliminary factor analysis (Bartlett's Test of Sphericity (p < .001) and the Kaiser- Mayer- Olkin measure of sampling adequacy, KMO = 0.811). Results: The EFA identified four factors, such as faculty-student interaction, faculty and IT-related, faculty training and faculty preparedness with heavy loading on faculty training, as important factors for improving faculty satisfaction for online teaching. Most of the faculty members were satisfied with the ERT. A trend of shared opinion was observed in capacity building and empowering the faculty community with full IT and course development support from the institution in the form of faculty development programmes and infrastructure development in order to equip them with emergency academic transitions. Conclusion: The modified Survey tool was valid in identifying the faculty perceptions regarding the ERT. Faculty felt that they managed to quickly move to online teaching due to the pandemic but felt that they needed better IT support and faculty development programmes to effectively adapt to online teaching. Students, too, need to be trained for online learning, as per faculty members.

Evaluation of Fetal and Maternal Vancomycin-Induced Kidney Injury during Pregnancy in a Rat Model.

Previous literature suggests that maternal vancomycin crosses the placental barrier to the fetus. Further, early animal studies indicated that kidney injury was not observed in the progeny. These studies were conducted prior to the availability of sensitive biomarkers for kidney injury. Therefore, a previous finding of no renal damage to the infant may be misleading. Vancomycin was administered intravenously to pregnant rats at a dose of 250 mg/kg of body weight/day (N = 6 per trimester) on three consecutive gestational days (GD) during trimesters 1, 2, and 3 (T1, T2, and T3, respectively) in three independent cohorts. The dams carried to term and delivered vaginally on GD 21. Kidneys were harvested from dams and pups and homogenized. Samples were prepared by protein precipitation and injected in a liquid chromatography tandem mass spectrometer, and vancomycin was quantified. The kidney tissue homogenate from dams and pups were analyzed for kidney injury molecule-1 (KIM-1). As trimesters progressed, the quantity of vancomycin increased linearly in the kidneys of both rat dams and pups (P < 0.0001 for T1 and T3, P < 0.0001 for T2 and T3, and P < 0.0001 for T3 and T3 control for both rat dams and pups). KIM-1 concentrations in pup kidneys were significantly higher when dams were administered vancomycin in trimesters 1 (P = 0.0001) and 2 (P = 0.0024) than in controls in trimester 3. Data demonstrate persistence of vancomycin in maternal and rat pup kidneys in all three trimesters of pregnancy with associated damage to the kidney, as indicated by expression of KIM-1.

Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model.

OBJECTIVES: To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury. METHODS: Male Sprague-Dawley rats received intravenous (iv) vancomycin. Doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice-daily injection over 24 h (total protocol duration). Controls received iv saline. Plasma was sampled with up to eight samples in 24 h per rat. Twenty-four hour urine was collected and assayed for kidney injury molecule 1 (KIM-1), osteopontin and clusterin. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 h (i.e. AUC0-24h, Cmax 0-24h and Cmin 0-24h) were calculated. PK/TD relationships were assessed with Spearman's rank coefficient (rs) and the best-fit mathematical model. RESULTS: PK/TD data were generated from 45 vancomycin-treated and 5 control rats. A two-compartment model fit the data well (Bayesian: observed versus predicted R2 = 0.97). Exposure-response relationships were found between AUC0-24h versus KIM-1 and osteopontin (R2 = 0.61 and 0.66) and Cmax 0-24h versus KIM-1 and osteopontin (R2 = 0.50 and 0.56) using a four-parameter Hill fit. Conversely, Cmin 0-24h was less predictive of KIM-1 and osteopontin (R2 = 0.46 and 0.53). A vancomycin AUC0-24h of 482.2 corresponded to a 90% of maximal rise in KIM-1. CONCLUSIONS: Vancomycin-induced kidney injury as defined by urinary biomarkers is driven by vancomycin AUC or Cmax rather than Cmin. Further, an identified PK/TD target AUC0-24h of 482.2 mg·h/L may have direct relevance to human outcomes.

24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury.

Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (Cmax), and the minimum concentration. Spearman's rank correlation coefficient (rs ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and Cmax were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for Cmax). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or Cmax.

Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function.

Unresolved inflammation is a major contributor to the development of heart failure following myocardial infarction (MI). Pro-resolving lipid mediators, such as resolvins (e.g. RvD1), are biosynthesized endogenously. The role of RvD1 in resolving post-MI inflammation has not been elucidated due to its unstable nature. Here, we have tested the role for two forms of RvD1, after incorporation into liposomes (Lipo-RvD1) and its free acid form (RvD1) in the left ventricle (LV) and splenic remodeling post-MI. 8 to 12-week old male, C57BL/6J-mice were subjected to coronary artery ligation and Lipo-RvD1 or RvD1 (3 µg/kg/day) was injected 3h post-MI for day (d)1 or until d5. No-MI mice and saline-injected MI mice served as controls. RvD1 injected groups showed improved fractional shortening post-MI; preserving transient changes in the splenic reservoir compared to MI-saline. RvD1-groups showed an early exit of neutrophils from LV and spleen at d5 post-MI with an increased expression of lipoxin A4 receptor (ALX; synonym formyl peptide receptor; FPR2) compared to the MI-saline group. The levels of pro-resolving mediators RvD1, RvD2, Maresin 1 (MaR1) and Lipoxin A4 (LXA4) were increased in spleens from RvD1 injected mice at d5 post-MI. RvD1 administration reduced macrophage density, ccr5 and cxcl5 levels at d5 post-MI compared to saline injected mice (both, p < 0.05). Increased transcripts of mrc-1, arg-1 and Ym-1 (all, p < 0.05) suggest macrophage-mediated clearance of necrotic cells in RvD1-groups. RvD1 reduced the pro-fibrotic genes (colla1, coll2a1 and tnc (all; p < 0.05)) and decreased collagen deposition, thereby reducing post-MI fibrosis and thus stabilizing the extracellular matrix. In summary, RvD1 and Lipo-RvD1 promote the resolution of acute inflammation initiated by MI, thereby delaying the onset of heart failure.

Nanocarrier-based approaches for treatment and detection of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurological disorder in people over the age of 65. It has been estimated that in 2010 there were 4.7 million individuals aged 65 years or older with AD dementia, and it is projected that the total number of individuals with AD dementia in 2050 will be 13.8 million. The most commonly believed cause and most frequently studied aspect of AD is the aggregation of beta amyloid (Abeta), both as soluble Abeta and in the form of extracellular plaque. Treatment options are limited mainly due to the inability of drugs to cross the blood-brain barrier. Nanoparticulate drug carriers that have been targeted to the brain are able to pass through by virtue of their size, surface potential, surface coatings (e.g., polyethylene glycol, polysorbate), surface decoration with ligands or antibodies attached toward the receptors on the blood-brain barrier. Herein, we discuss the current front-runner nanocarriers under investigation for effective delivery of pharmaceuticals active in the treatment and detection of AD and their mechanisms and discuss a few of the outstanding studies.

International trends in health science librarianship part 12: South Asia (India, Pakistan and Sri Lanka).

This is the 12th in a series of articles exploring international trends in health science librarianship. This issue describes developments in health science librarianship in the first decade of the 21st century in South Asia. The three contributors report on challenges facing health science librarians in India, Pakistan and Sri Lanka. There is consensus as to the need for education, training and professional development. Starting in the next issue, the focus will turn to Africa, starting with countries in southern Africa. JM.

Bibliometric indicators for evaluating the quality of scientifc publications.

Evaluation of quality and quantity of publications can be done using a set of statistical and mathematical indices called bibliometric indicators. Two major categories of indicators are (1) quantitative indicators that measure the research productivity of a researcher and (2) performance indicators that evaluate the quality of publications. Bibliometric indicators are important for both the individual researcher and organizations. They are widely used to compare the performance of the individual researchers, journals and universities. Many of the appointments, promotions and allocation of research funds are based on these indicators. This review article describes some of the currently used bibliometric indicators such as journal impact factor, crown indicator, h-index and it's variants. It is suggested that for comparison of scientific impact and scientific output of researchers due consideration should be given to various factors affecting theses indicators.

Pharmacokinetic and Biomarker Quantification Studies on Vancomycin-Loaded PEGylated Liposomes and Its Potential to Reduce Vancomycin-Induced Kidney Injury: A Rat Study.

Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To attempt to reduce vancomycin-induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol-coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study, we have dosed male adult rats with PEG-VANCO-lipo or vancomycin HCl and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine. Male Sprague Dawley rats (350 ± 10 g) were administered vancomycin (n = 6) or PEG-VANCO-lipo (n = 6) 150 mg/kg/day for three days using an IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240, and 1440 min after the first and the last IV dose. Urine was collected 0-2, 2-4, 4-8, and 8-24 h after the first and the last IV infusions using metabolic cages. The animals were observed for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit. Three days after the last dose, under terminal anesthesia with IP ketamine (65-100 mg/kg) and xylazine (7-10 mg/kg), rats were euthanized. Vancomycin urine and kidney concentrations and KIM-1 were lower on day three in the PEG-Vanco-lipo group compared to the vancomycin group (p < 0.05, ANOVA and/or t-test). There was a significant reduction in plasma vancomycin concentration on day one and day three (p < 0.05, t-test) in the vancomycin group compared to the PEG-VANCO-lipo group. Vancomycin-loaded PEGylated liposomes resulted in lower levels of kidney injury, as noted by a decrease in KIM-1 values. Moreover, longer circulation in plasma with increased concentration in plasma as opposed to the kidney was observed with the PEG-VANCO-lipo group. The results indicate the high potential of PEG-VANCO-lipo in decreasing the nephrotoxicity of vancomycin clinically.

Stress-induced severe transient hypercortisolism with reversible bilateral adrenal enlargement after cardiogenic shock.

Summary: Acute illness-related stress can result in severe hypercortisolism and bilateral adrenal enlargement in certain patients. We report a case of stress-induced hypercortisolism and bilateral adrenal enlargement in a patient admitted for acute respiratory distress and cardiogenic shock. Bilateral adrenal enlargement and hypercortisolism found during hospitalization for acute illness resolved 3 weeks later following the resolution of acute illness. Acute illness can be a precipitating factor for stress-induced hypercortisolism and bilateral adrenal enlargement. We hypothesize that increased adrenocorticotrophic hormone mediated by corticotrophin-releasing hormone from physical stress resulted in significant adrenal hyperplasia and hypercortisolism. This mechanism is downregulated once acute illness resolves. Learning points: Adrenal enlargement with abnormal adrenal function after stress is uncommon in humans; however, if present, it can have self-resolution after the acute illness is resolved. Stress induces enlargement of the adrenals, and the degree of cortisol elevation could be very massive. This process is acute, and the absence of cushingoid features is expected. Treatment efforts should be focused on treating the underlying condition.

Intravenous ß-artemether formulation (ARM NLC) as a superior alternative to commercial artesunate formulation.

OBJECTIVES: To compare the in vivo pharmacodynamic efficacy of intravenously administered artemether nanostructured lipid carrier (ARM NLC) with commercial artesunate (C-AST) at different dose levels. METHODS: The study compared the in vivo pharmacodynamic efficacy of ARM NLC with C-AST in a murine model. For this study, the Peters 4 day suppressive test was adopted. Plasmodium berghei was the causative organism for inducing malaria in mice. The efficacies of the formulations were evaluated on the basis of percentage parasitaemia in, and survival of, mice. RESULTS: In comparison with the C-AST formulation, ARM NLC demonstrated superior activity in terms of reduction in parasitaemia and increased survival. CONCLUSIONS: Although both formulations were found to be effective in reducing parasitaemia in the murine model, ARM NLC was found to be superior. The study clearly demonstrates the effectiveness of this novel alternative to existing artesunate dosage forms.

Course design, delivery, and assessment strategies for pharmaceutical calculations course in a doctor of pharmacy program: A review.

BACKGROUND: Pharmaceutical calculations is a fundamental course taken by doctor of pharmacy students in United States schools and colleges of pharmacy. To minimize medical errors and increase the accuracy with which future pharmacists perform calculations, a comprehensive training during the program is deemed. This review attempts to summarize research outcomes of interventions described thus far in the literature concerning the improvement of course design, delivery, and assessment strategies. METHODS: A detailed literature review of various educational resources was conducted using pharmaceutical calculations and related terms. RESULTS: The literature review outcomes were divided into three major categories: educational interventions in design, delivery, and assessment of pharmaceutical calculations courses. The research findings of course design describe a standalone course vs. an integrated course, a computer-aided course, use of compact disc read-only memory, and implementation of Gagne's Nine Events of Instructions. Findings in course delivery include the use of self-paced vs. integrated courses, flipped classroom vs. traditional lecture, Keller's Personalized System of Instruction, condensed videos, and podcasts. Finally, different types of assessments are presented such as those based on selected- vs. constructed-response questions, collaborative quizzes, the approach of repeated testing, and the use of technology. IMPLICATIONS: While the review intends to present educational interventions available to construct and/or modify an existing pharmaceutical calculations course, the choice of design, delivery, and assessment approaches depends upon various factors such as the purpose of course modification, resources available, and the number of students in class.

In Vitro Nephrotoxicity and Permeation of Vancomycin Hydrochloride Loaded Liposomes.

Drugs can be toxic to the fetus depending on the amount that permeates across the maternal-fetal barrier. One way to limit the amount which penetrates this barrier is to increase the molecular size of the drug. In this study, we have achieved this by encapsulating our model antibiotic (vancomycin hydrochloride, a known nephrotoxic agent) in liposomes. PEGylated and non-PEGylated liposomes encapsulating vancomycin hydrochloride were prepared using two different methods: thin-film hydration followed by the freeze-thaw method and the reverse-phase evaporation method. These liposomes were characterized by their hydrodynamic size and zeta potential measurements, CryoTEM microscopy, loading and encapsulation efficiency studies, in vitro release measurements and in vitro cytotoxicity assays using NRK-52 E rat kidney cells. We also determined the in vitro permeability of these liposomes across the human placental cell and dog kidney cell barriers. Vancomycin hydrochloride-loaded PEGylated liposomes (VHCL-lipo) of a size less than 200 nm were prepared. The VHCL-lipo were found to have the faster release of vancomycin hydrochloride and resulted in greater viability of NRK-52E cells. In vitro, the VHCL-lipo permeated the human placental cell and dog kidney cell barriers to a lesser extent than the free vancomycin hydrochloride. The data suggest a reduction in nephrotoxicity and permeability of vancomycin hydrochloride after encapsulation in PEGylated liposomes.

Pharmacokinetic Disposition of Amiodarone When Given with an Intralipid Rescue Strategy.

While the antiarrhythmic drug amiodarone is commonly used in clinical practice, it has a narrow therapeutic index that can lead to acute overdose. One proposed method to deal with this toxicity is lipid emulsion therapy, which may potentially quench the free amiodarone in blood and prevent its further distribution to target organs and tissues. In this study, we utilize an established swine model to examine the effects of Intralipid™ (IL) administration for acute amiodarone toxicity. A total of 14 pigs received an overdose of intravenous amiodarone. After twenty minutes, half of the pigs (n = 7) received IL while the control group (n = 7) received normal saline. Serum concentrations of amiodarone were then analyzed using a validated high-performance liquid chromatography (HPLC) method. Noncompartmental pharmacokinetic analyses were performed on the observed concentrations. There were no statistical differences in the area under the concentration time curve (6 h) or clearance, but there was a difference in the half-life between the two groups (3.12 vs. 0.85 h, p = 0.01). The administration of IL did not statistically change the overall exposure of amiodarone in the blood in the first 6 h; however, trends toward prolonged blood retention in the IL group were seen.

An Online, Self-directed Pharmacy Bridging Course for Incoming First-Year Students.

Objective. To evaluate the short-term effectiveness of an online bridging course to increase the knowledge of struggling incoming students' in crucial content areas within the Doctor of Pharmacy (PharmD) curriculum. Methods. An assessment was administered to all incoming first-year pharmacy students (N=180) during orientation to determine their foundational knowledge in key areas. Students who scored <70% on the assessment (N=137) were instructed to complete a 10-module, online, self-directed bridging course focusing on physiology, biochemistry, math, and medical terminology during the first two weeks of the quarter to prepare them for first-quarter coursework. After completing the bridging course, participants completed the same assessment to determine content knowledge acquisition and retention. At the end of the quarter, the assessment was again administered to all first-year students, regardless of whether they had completed the bridging course. Results. The average assessment score of students who completed the bridging course modules improved significantly (53% vs 76%). All students demonstrated significant improvement in assessment scores between orientation and the end of the quarter; however, bridging course participants achieved a greater increase in assessment scores (53% vs 73%) than nonparticipants (76% vs 81%). Significant relationships were found between assessment scores following completion of the bridging course and pass rates in first-quarter courses. Conclusion. The online, self-directed bridging course offered at Midwestern University, Chicago College of Pharmacy proved successful as a method of knowledge acquisition and as a system for early identification (within the first two weeks of the quarter) of students in need of additional academic support.

Fabrication of Nanostructured Lipid Carriers (NLC)-Based Gels from Microemulsion Template for Delivery Through Skin.

Nanostructured lipid carriers (NLC) represent the novel and widely explored generation of lipid nanoparticles. These are the second-generation solid lipid nanoparticles (SLN) developed with the aim to overcome limitations of SLN mainly with respect to limited drug loading and drug leakage during its storage. NLC are fabricated by mixing solid lipids with spatially incompatible (liquid) lipids leading to nanoparticulate structures with improved drug loading and controllable release properties. Out of the numerous methods reported to prepare NLC, microemulsion template (ME) technique is the most simple and preferred method. This methodology of preparation of lipid nanoparticles obviates the need for specialized equipment and energy to generate NLC, enables achieving desirable particle size of nanoparticles by modulating the size of the emulsion droplet, and is also feasible for easy scale-up. This chapter describes microemulsion template technique for fabrication of NLC based gel for topical delivery, particularly with respect to its method of preparation and product analysis.

A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid and Plasma Concentrations of Cefepime.

This study sought to define the transit of cefepime between plasma and cerebral spinal fluid (CSF) in a rat model. Male Sprague-Dawley rats received cefepime intravenously. A total daily dose of 150 mg/kg of body weight/day was administered as a single injection every 24 h for 4 days. Plasma samples were obtained via a second dedicated intravenous catheter. CSF sampling occurred via an intracisternal catheter. Cefepime levels in plasma and CSF were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic (PK) analyses were conducted using Pmetrics for R. PK parameters and exposures during the first 24 h (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration of drug in serum from 0 to 24 h [Cmax 0-24]) were calculated from Bayesian posteriors. CSF penetration was estimated by comparing the exposure profiles between plasma and the CSF. Eleven rats contributed PK data. A four-compartmental model with a lag compartment for CSF fit the data well for both plasma (Bayesian [R2 = 0.956]) and CSF (Bayesian [R2 = 0.565]). Median parameter values (with the coefficient of variation percentage [CV%] in parentheses) for the rate constants to CSF from the lag compartment (K34), to the central compartment from the CSF compartment (K41), and to the lag compartment from the central compartment (K13) were 2.96 h-1 (116.27%), 0.47 h-1 (54.86%), and 0.13 h-1 (23.42%), respectively. The elimination rate constant (kel) was 3.15 h-1 (7.5%). Exposure estimation revealed a plasma median (with interquartile range [IQR] in parentheses) half-life, AUC0-24, and Cmax 0-24, of 1.7 (1.5 to 1.9) h, 111.3 (95.7 to 136.5) mg · 24 h/liter, and 177.8 (169.7 to 236.4) µg/ml, from the first dose, respectively. Exposure estimation of CSF demonstrated a median (with IQR in parentheses) AUC0-24 and Cmax 0-24 of 26.3 (16.6 to 43.1) mg · 24 h/liter and 6.8 (5.2 to 9.4) µg/ml, respectively. The median CSF/blood percentage of penetration was 19%. Cefepime transit to the CSF is rapid and predictable in the rat model. This model will be highly useful for understanding the therapeutic window for cefepime and neurotoxicity.IMPORTANCE This study defines the transit of cefepime between plasma and cerebral spinal fluid (CSF) in a rat model. Male Sprague-Dawley rats received cefepime intravenously. Plasma samples were obtained via a second dedicated intravenous catheter. CSF sampling occurred via an intracisternal catheter. Drug exposures and transfer from the plasma to the CSF during the first 24 h were calculated. The median CSF/blood percentage of penetration was 19%. Cefepime transit to the CSF is rapid and predictable in the rat model. This model will be highly useful for understanding the therapeutic window for cefepime and neurotoxicity.

Towards long-acting adrenaline for cardiopulmonary resuscitation: Production and characterization of a liposomal formulation.

The use of adrenaline in cardiopulmonary resuscitation is a long-standing medical procedure, recommended by several international guidelines. However, its unspecific action on adrenergic receptors and the need for repeated administrations pose serious concerns about its safety, the balance between benefits and risks being still under debate. To address this issue, a sustained release nano-formulation of adrenaline was developed. Adrenaline was encapsulated into PEGylated, anionic liposomes by a pH-driven loading technique. Particular attention was devoted to the prevention of oxidation of adrenaline by optimizing the preparative process and including an optimal amount of antioxidants in the formulation. The vesicles obtained were then characterized for size, zeta-potential, and lamellarity, while their morphology was described by cryo-TEM. The controlled release properties were confirmed by two different in vitro release-testing methods, and the biocompatibility was assayed on human endothelial cells in vitro.