Infusion Scheme Research Articles

The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.

We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo. Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point. The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma. Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.

Impact of humanized vancomycin infusion on kidney function and kidney injury in a translational rat model

Allometric dose scaling aims to create isometric exposures between animals and humans and is often employed in preclinical pharmacokinetic/pharmacodynamic models. Bolus-administration with allometric scaling is the most simple and commonly used strategy in pre-clinical kidney injury studies; however, it is possible to humanize drug exposures. Currently, it is unknown if dose-matched, bolus-administration with allometric scaling results in similar outcomes compared to humanized infusions in the vancomycin induced kidney injury model. We utilized a preclinical Sprague-Dawley rat model to compare traditional allometrically-scaled, dose-matched, bolus-administration of vancomycin to an infusion-pump controlled, humanized infusion scheme to assess for differences in iohexol-measured kidney function and urinary kidney injury biomarkers. Following 24 h of vancomycin administration, rats in the humanized infusion group had equivalent area under the curve exposures to animals in the dose-matched bolus group (93.7 mg·h/L [IQR 90.2-97.2] vs. 99.5 mg·h/L [IQR 95.1-104.0], P = 0.07). No significant differences in iohexol-measured kidney function nor meaningful differences in urinary kidney injury biomarkers, kidney injury molecule-1, clusterin, and osteopontin, were detected. Administration of intravenous vancomycin as either a humanized infusion or dose-matched bolus resulted in similar vancomycin exposures. No differences in iohexol-measured GFR nor meaningful differences in urinary kidney injury biomarkers were observed among male Sprague-Dawley rats.

Anaesthetic Considerations for a Seven-Month-Old Infant with Suspected Malignant Hyperthermia: A Case Report

Introduction: Malignant hyperthermia (MH) is a life-threatening pharmacogenetic skeletal muscle disorder resulting in increased myoplasmic calcium concentrations leading to sustained muscle contraction. In cases susceptible to MH, a total intravenous intravenous anaesthesia (TIVA) approach is employed to avoid the use of MH triggering agents namely volatile anaesthetics and suxamethonium. Case presentation: In this case report, we present a seven-month-old male infant with MH susceptibility that was scheduled for a rectal biopsy under general anaesthesia. The patient was managed according to MH guidelines and paediatrics dosing schemes for TIVA; using propofol and remifentanil as an adjuvant. The case was management successfully and uneventfully. Conclusion: MH is a potentially life-threatening disorder, hence following the evidence-based precautions and management of patients with suspected MH is key. Moreover, managing a paediatric patient with MH suspicion often impose additional challenges. In this case report, the perioperative considerations for infants with MH suspicion is discussed. Keywords: Malignant Hyperthermia, Total Intravenous Anaesthesia, Steur propofol infusion scheme.

NUMERICAL ANALYSIS OF INFUSION STRATEGIES IN VACUUM ASSISTED RESIN TRANSFER MOLDING (VARTM) PROCESS

The Liquid composite Molding (LCM) process, such as Vacuum Assisted Resin Transfer Molding (VARTM), offers a fast and high-quality production of composites laminates. In the VARTM process, the simulation tool is found beneficial to predict and solve composite manufacturing issues. The part quality is dependent on the resin mold filling stage in the VARTM process. The infiltration of resin into a porous fibrous medium is taken place during the resin mold filling stage. The permeability has a crucial role during the resin mold filling stage. In this study, simulation of resin infusion through multiple injection gates is discussed. The various infusion schemes are simulated to identify defect-free composite manufacturing. The simulation approach is applied to five different stacking sequences of reinforcements. In this transient simulation study, permeability and resin viscosity is essential inputs for the resin flow. The simulation approach found that a gating scheme plays a vital role in mold filling time and defect-free composite fabrication. It is found that the line gating system can be useful for fast mold filling over the point gating system.

Hematopoietic Reconstitution of Human Umbilical Cord Mesenchymal Stem Cells after Leukemia Chemotherapy: Effectiveness and Safety

Objective: As the incidence of tumors increases, more patients need chemotherapy. Patients receiving chemotherapy also inevitably suffer side effects from treatment. Damage to the immune and hematopoietic system causes the failure of therapies. Mesenchymal stem cells have excellent capabilities in immune regulation and hematopoietic support. This study preliminarily explored the safety and effectiveness and of human umbilical cord mesenchymal stem cells (UCMSC) in myelosuppressive patient-derived tumor xenograft (PDX) models of acute myeloid leukemia (AML).Methods: B-NDG mice were used to establish the PDX models. The mice were randomly divided into three groups: AML group, AML+Ara-C group and AML+Ara-C+MSC group. Mice in the AML+Ara-C group and AML+Ara-C+MSC group were injected intraperitoneally with cytarabine (Ara-C) 60mg/kg on day1-day3 to induce myelosuppression. Mice in the AML+Ara-C+MSC group were injected 3×10 6 UCMSC through the tail vein on day4. We observed the changes in peripheral blood, bone marrow signaling pathways, and AML progression in mice.Results: The experiment found that UCMSC rescued the body weight and peripheral blood. We also found that UCMSC could increase the number of bone marrow CD117 + hematopoietic stem/progenitor cells and CD41 + megakaryocytes through flow cytometry. We verified at protein level that the hematopoiesis-related signaling pathway JAK2/STAT3 was up-regulated in AML+Ara-C+MSC group compared with AML+Ara-C group through flow cytometry and immunohistochemistry. At the same time, the infusion of UCMSC after Ara-C had no influence on disease progression. On day15, the proportion of human CD45 + cells in the bone marrow of between AML+Ara-C+MSC group and AML+Ara-C group was similar, and there was no statistical difference (21.96±3.10 vs. 23.04±1.51; P=0.6792).Conclusion: Infusion of exogenous UCMSC after chemotherapy in PDX models could promote the recovery of hematopoiesis without affecting the efficacy of Ara-C. A reasonable UCMSC infusion scheme is potential to be used in the treatment of AML patients and it requires a lot of preclinical exploration in the future. DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Cytarabine (Ara-C) was administrated to mice models to induce myelosuppression.

Cytotoxic and biomechanical effects of clinical dosing schemes of paclitaxel on neurons and cancer cells.

Chemotherapy-induced peripheral neuropathy often results in a reduction in drug dose. However, the serum level of anticancer drugs varies with time after intravenous infusion, and this factor has seldom been considered in previous in vitro studies. The goals of this study were to build an automatic dosage control system and to evaluate the influence of drug infusion rate on the cells. Neurons and melanoma cells were used as the samples. The 3-h (average and peak concentration: 0.024 and 0.287μM) and 24-h infusion (average and peak concentration: 0.020 and 0.042μM) schemes were investigated. For evaluations, cell indentation tests by an atomic force microscope, serial immunofluorescent images, and cell viability analysis was performed. For the neurons, Young's modulus first increased and then remained unchanged in the 3-h scheme, but was stationary throughout the observation period in the 24-h scheme. For the cancer cells, Young's modulus increased in both infusion schemes, and the increase was larger in the 3-h scheme. Morphologically, axons swelled and shortened, and the number of their branches decreased in the 3-h scheme. In contrast, there was only slowed growth of axons without obvious morphological changes in the 24-h scheme. Viability analysis of the cancer cells revealed that the 3-h scheme had a better anticancer effect. A dosage-control system simulating the pharmacodynamic changes of drugs was successfully constructed for in vitro cell cultures. The 3-h scheme of paclitaxel showed better anticancer effects but more adverse effects on neuronal growth and morphology.

In Vitro Thermal Assessment of Vascularized Tissue Phantom in Presence of Gold Nanorods During Photo-Thermal Therapy

Abstract Nowadays, laser and nanotechnology have drawn more attention in the field of noninvasive cancer treatment with precise ablation of tumor preserving the surrounding healthy tissue. Besides, the assessment of viscoelastic deformation within the tissue can estimate the thermally induced nociceptive pain during laser therapy. This study deals with a laser-assisted in vitro thermal analysis on vascular tissue phantom doped with gold nanorods along with a comparative study with numerical results. The prediction of tissue thermomechanical response under laser heating also has been made. Both Pennes and dual-phase-lag bioheat equations coupled with equilibrium equations are solved using comsolmultiphysics (Bangalore, India). The aim is to create a comparative study between intratumoral (IT) and intravenous (IV) infusion schemes of nanoparticles in terms of thermal and mechanical behavior. The in vitro heating of tissue phantom with IT scheme provides more control over the spreading of necrotic temperature in terms of precise damage of the targeted area, preserving the surrounding nontargeted area. Predicted results show a reduced overall thermal deformation of the nanoparticle doped tissue model with the IT scheme depicting a stiffer thermoelastic response comparing the model doped with the IV scheme. The simultaneous heating and cooling shows a viscoelastic nature of biotissue. However, under cyclic heating and cooling of the tissue model embedded in a large blood vessel (LBV) depicts a smaller sized stress–strain hysteresis loop. Nevertheless, the present findings can help to understand the thermo-mechanical behavior of tissue during clinical photothermal therapy.

Bolus infusion scheme for the adjustment of steady state [11C]Flumazenil levels in the grey matter and in the blood plasma for neuroreceptor imaging

The use of hybrid PET/MR imaging facilitates the simultaneous investigation of challenge-related changes in ligand binding to neuroreceptors using PET, while concurrently measuring neuroactivation or blood flow with MRI. Having attained a steady state of the PET radiotracer using a bolus-infusion protocol, it is possible to observe alterations in ligand neuroreceptor binding through changes in distribution volumes. Here, we present an iterative procedure for establishing an administration scheme to obtain steady state [11C]flumazenil concentrations in grey matter in the human brain. In order to achieve a steady state in the shortest possible time, the bolus infusion ratio from a previous examination was adapted to fit the subsequent examination. 17 male volunteers were included in the study. Boli and infusions with different weightings were given to the subjects and were characterised by kbol values from 74 ​min down to 42 ​min. Metabolite analysis was used to ascertain the value of unmetabolised flumazenil in the plasma, and PET imaging was used to assess its binding in the grey matter. The flumazenil time-activity curves (TACs) in the brain were decomposed into activity contributions from pure grey and white matter and analysed for 12 ​vol of interest (VOIs). The curves highlighted a large variability in metabolic rates between the subjects, with kbol ​= ​54.3 ​min being a reliable value to provide flumazenil equilibrium conditions in the majority of the VOIs and cases. The distribution volume of flumazenil in all 12 VOIs was determined.

Brain-Derived Neurotrophic Factor Affects mRNA and miRNA Expression of the Appetite Regulating Centre in the Sheep Arcuate Nucleus

Abstract The neuromodulatory effects of brain-derived neurotrophic factor (BDNF) on appetite regulation centre peptide gene activity in the sheep hypothalamus have not been examined yet. The aim of this study was to determine whether BDNF participates in modulation of neuropeptide Y (npy), agouti-related peptide (agrp), cocaine and amphetamine regulated transcript (cart), and proopiomelanocortin (pomc) mRNA expression and selected microRNAs in the sheep hypothalamic arcuate (ARC) nucleus. Animals (Polish Merino sheep, n=24) were divided into three groups. The control group received a central infusion of Ringer-Locke solution (480 µl/day) whereas the experimental groups were treated with BDNF in two doses: 10 or 60 μg/480 µl/day. All sheep received four intracerebroventricular infusions (performed from 08:40 a.m. to 01:30 p.m.; infusion scheme: 4 x 50 min infusions with 30 min intervals between them) on each of three consecutive days. Immediately after the last infusion, the sheep were slaughtered, and selected structures of the hypothalamus were frozen for further real-time qPCR analysis. Central infusion of BDNF evoked dose-dependent changes in npy, agrp, cart, pomc and peptidylglicine alpha-amidating monooxygenase (pam) mRNA expression in the sheep ARC nucleus. An increase in npy, agrp and pomc mRNA expression but also a decrease in cart mRNA expression in the ARC nucleus were detected. Moreover, a decrease in pam (gene encoding an enzyme that converts POMC into α-MSH) mRNA expression, was also noted. Furthermore, after central BDNF administration, changes in miRNA-33a-5p, miRNA-33b-5p, miRNA-377-3p, miRNA-214-3p, miRNA-485 and miRNA-488 expression were observed. Based on the presented results, it can be concluded that BDNF may affect the appetite regulating centre activity through modulation of npy, agrp, cart, pomc and pam mRNA expression in the ARC nucleus. It was also revealed that BDNF modulates miRNA expression in the sheep ARC nucleus.

Clinical Study on the Effects of Different Infusion Solutions on Colloid Osmotic Pressure During Major Abdominal Surgery and Perioperative Albumin in Elderly Patients

Objective: To explore the effects of different infusion schemes on colloid osmotic pressure during major abdominal surgery and perioperative albumin in elderly patients. Methods: 140 elderly patients of 65-80 years old undergoing major abdominal surgery were divided into 4 groups according to the method of random number table , and different proportions of crystals and colloids were given to different groups (group A: whole crystal, group B: crystal-colloid ratio 1 : 1, group C: crystal-colloid ratio 2: 1, Group D: crystal-colloid ratio 1: 2). The plasma colloid osmotic pressure and level of albumin during perioperative period were monitored. Simultaneously observe the arterial blood pH, blood glucose, extubating time of endotracheal tube, postoperative feeding time, et al. Results: The total amount of liquid inputted in the group of whole crystal was 3056ml (3056 ± 253), which was significantly increased compared with other groups (P<0.01). At the same time, the colloid osmotic pressure decreased by 11.9 mmHg (11.9 ± 2.8), which was more obviously decreased than that of the other groups( B group3.9 ± 1.3, C group 1.5 ± 0.3, D group 4.7±2.1). The difference was a statistically significant(P<0.01). On the other day after surgery, the level of albumin decreased by an average of 4.3 g / L (4.5 ± 1.9) compared with that in group B before surgery, and group C decreased by 2.9 g / L (2.9 ± 1.2) in average, which was significantly different (P<0.05) from group A 10.2 g / L (10.2 ± 1.8). There was no statistically significant difference between group A and group D (P>0.05). And the other indexes were not significantly different between the two groups. Conclusion: This study found that different infusion solutions with different crystal-colloid ratios had an effect on perioperative colloid osmotic pressure and level of albumin.

Thermomechanical analysis of a triple layered skin structure in presence of nanoparticle embedding multi-level blood vessels

Concerning a target-specific malignant cell damage sparing healthy tissue, the advancements in laser and nanotechnology are one of the recent challenges in non-invasive cancer treatment processes. In addition, proper assessment of nociceptive pain induced in the ablation process by simulating the tissue thermomechanical response in a more realistic situation is a useful step prior to real clinical practice. In the present study a nanoparticle infused lesion in a 3-D triple-layered healthy skin structure embedding thermally significant multi-level small arteries and veins is chosen as the computational domain. Dual-phase-lag (DPL) and Pennes bioheat model coupled with equilibrium equations are solved using COMSOL Multiphysics (Bangalore, India) to compute the thermal and mechanical fields in the tissue. An in-vitro temperature measurement of laser irradiated agar-based tissue phantom is also performed to validate the predicted temperature. The aim is to develop a comparative analysis between Intravenous (IV) and Intratumoral (IT) infusion schemes of nanoparticles in terms of precise and uniform necrosis achieved along with stress, strain, and deformation induced in tissue during laser therapy. Numerical results show that the IT scheme offers a useful outcome in terms of precise tumor ablation with minimum thermally induced skin deformation in comparison to the IV scheme. Additionally, the DPL model predicts a more realistic temperature profile along with the induced tissue mechanical response in contrast to the Pennes bioheat model. Most importantly, the small veins have comparatively lower cooling effects than the small arteries in the composite skin structure. Nevertheless, the present study can improve the pre-operational computational modeling of the tissue damage and the nociceptive pain involved during laser therapy prior to clinical application.

1568. The Pharmacodynamic–Toxicodynamic Relationship of AUC and CMAX in Vancomycin-Induced Kidney Injury

BackgroundVancomycin induces exposure-related acute kidney injury [AKI]; yet the toxicodynamic (TD) driver for toxicity (area under the curve [AUC], vs. maximum concentration [CMAX] vs. trough concentrations [CMIN]) remains unclear. Recent vancomycin guidelines now recommend monitoring AUC over troughs. Here we employed our translational rat model with intensive dose fractionation and sensitive FDA qualified urinary biomarkers to better understand TD relationship.MethodsMale Sprague-Dawley rats received intravenous (IV) vancomycin via an internal jugular vein catheter. Total daily doses of 300 and 400 mg/kg/day were administered as a single, twice, thrice and four times a day injection over 24 hours. Controls received IV saline. Plasma sampling was conducted via a second dedicated jugular catheter, with up to 8 samples in 24 hours. Twenty-four-hour urine was collected during this time and assayed for kidney injury molecule 1 (KIM-1) and other urinary biomarkers using the MILLIPLEX MAP Rat Kidney Panel. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 hours (i.e., AUC0-24hours, CMAX0-24hours) were calculated from Bayesian posteriors. Pharmacokinetic-toxicodynamic (PK-TD) relationships were assessed with the best fit mathematic model (e.g., exposure-response curve fitting in GraphPad v.7).ResultsSixty-four vancomycin treated and control rats contributed to PK-TD data. An exposure-response (via 4-parameter Hill) model was identified for AUC0-24hoursvs KIM-1 (R2 = 0.62, Figure 1a). Convergence was not obtained for exposure-response models for CMAX0-24hours and CMIN, which was also verified visually (Figure 1b and c). Despite the intensive fractionation, AUC0-24hoursand CMAX0-24hours were highly correlated (P < 0.001, rho = 0.89) and this correlation was consistent across KIM-1 values (Figure 2).ConclusionVancomycin-induced kidney injury was driven by AUC0-24 hours and not CMIN. Continuous infusion studies are needed to understand if changing the infusion profile can improve safety; however, these studies suggest that isometric AUCs may result in similar toxicity. When using intermittent infusion schemes, clinicians should focus on AUC to prevent AKI. Disclosures All authors: No reported disclosures.

CAR22/19 Cocktail Therapy for Patients with Refractory/Relapsed B-Cell Malignancies

▪CD19 CAR T-cell (CAR-19) therapy have elicited great clinical responses in B-cell malignancies. However, CD19-negative relapse has emerged as a major challenge for the long-term disease control post CAR-19 therapy and conferred a dismal outcome to these pts. Recently, co-targeting of CD19/CD20, CD19/CD22 or CD19/CD123 has been proposed as a strategic approach to overcome antigen loss relapse after CAR-19 therapy. However, the infusion scheme has not yet been defined, the efficacy to avoid antigen escape has not been tested, and its toxicity remains to be assessed. Furthermore, the impact of genetic abnormalities on the outcome post CAR T-cell therapy has not been fully elucidated.We conducted an open-label, single-center and single-arm pilot study of sequential infusion of third generation CAR T-cell “cocktail” comprising both anti-CD22 and anti-CD19 CAR T-cells, which was registered with Chinese Clinical Trial Registry (ChiCTR, number ChiCTR-OPN-16008526).Between March 2016 and January 2018, a total of 89 eligibility pts completed CAR-22/19 “cocktail” infusion and were included for analysis. Of 89 pts (median age 36 years; range, 9-71), 51 had refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and 38 had R/R B-cell non-Hodgkin lymphoma (B-NHL). The cutoff date for data collection was April 30, 2018, with a median follow-up of 7.6 months (mos) for B-ALL and 5.4 mos for B-NHL.CAR-22 and CAR-19 cells were given separately in 2 divided doses (range, 1 to 4 for CAR-22, and 1 to 5 for CAR-19) with a dose-escalation infusion. Eighty-one pts firstly received CAR-22 infusion, and then CAR-19 infusion, while 8 pts received CAR-19 first and CAR-22 later. B-ALL pts received 2.73±1.19×106/kg CAR-22 and 2.61±1.45×106/kg CAR-19; B-NHL pts received instead higher doses, i.e. 5.28±2.44 ×106/kg CAR-22 and 5.14±2.06 ×106/kg CAR-19.Of the 50 evaluable B-ALL pts, 48 (96.0%) achieved complete remission (CR)/or CR with incomplete count recovery (CRi) at the day 30 assessment. By sensitive multi-parameter flow cytometry (MFC) assay, 47 (94.0%) achieved MRD-negative CR/CRi. At a median follow-up of 7.6 mos (range, 1.3 to 22.2), the progression-free survival (PFS) of all B-ALL pts was 12.0 mos and the overall survival (OS) was not reached. Of the 13 pts with Ph+ B-ALL, 6 of whom had T315I mutation, 11 (84.6%) achieved MRD-negative CR/CRi. The PFS was 15.4 months, and the OS was not reached at a median follow-up of 13.5 months (range, 3 to 22.5). Of the 6 pts with MLL translocations (mainly MLL-AF6), 66.7% were progression-free and the median PFS was not reached. However, among pts with Ph-like ALL, the PFS was only 4.6 months. A total of 23 pts relapsed, however, antigen loss of CD19 and CD22 was not detected by MFC. Forty-Seven pts (92.2%) experienced cytokine release syndrome (CRS) and 11 (21.6%) had severe CRS (≥ grade 3). Except for 1 pt, all the severe cases were reversible. Seven pts (13.7%) developed neurotoxicity.At a minimum follow-up of 3 months, the overall response rate (ORR) and CR rate in 36 evaluable B-NHL pts was 72.2% and 50%, respectively. At the cutoff date for data collection, 50.5% of all pts remained progression-free. A total of 8 pts (26.7%) had relapsed with a median PFS of 2.6 months. Re-biopsy and immunophenotyping was performed in 3 relapsed pts and antigen loss of CD19 or CD22 was not detected. At a median follow-up of 5.4 months (range, 3.0 to 16.2), both PFS and OS of all pts were not reached. Of the 9 pts with MYC translocation, 8 had a response and 7 maintained their responses with a median follow-up of 10.1 months, including all the 4 pts with “double-hit” lymphoma (concurrently carrying MYC and BCL2 or BCL6 translocations). Of the 10 pts with del(17p) or TP53 mutation, 8 (80.0%) had a clinical response. With a median follow-up of 5.3 months, the PFS was 3.3 months, and 45.0% of these pts were progression-free. All the B-NHL pts experienced CRS, but only 21.1% had severe (grade 3 or 4), but reversible CRS and 13.2% developed reversible neurotoxicity.In summary, our results indicated that infusion of third generation CD22/19 CAR T-cell “cocktail” is feasible and safe for pts with B-cell malignancies. Co-targeting to CD19/CD22 is a promising approach for overcoming antigen escape relapse of CAR-19 therapy, but this remain to be fully tested. The treatment response predictive value of distinct genetic subtypes for CAR T-cell therapy should be considered for selection of pts for personalized immunotherapy. DisclosuresNo relevant conflicts of interest to declare.

Development and validation of brain target controlled infusion of propofol in mice

Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice.

Reduction of 68Ga-PSMA renal uptake with mannitol infusion: preliminary results.

Urea-based prostate-specific membrane antigen (PSMA) ligands labelled with 68Ga or 177Lu are new tracers with great potential for theranostic approaches in prostate cancer. However, clinical studies have shown that the kidneys are one of the off-target organs along with the salivary and lacrimal glands. In the kidneys, PSMA is physiologically expressed in the apical epithelium of the proximal tubules, and mannitol acts as an osmotic diuretic in these tubules. We investigated the potential of mannitol to reduce renal uptake of 68Ga-PSMA. Kidney uptake (SUVmax) was calculated in nine patients undergoing 68Ga-PSMA PET/CT at baseline (b-PET/CT) and after intravenous infusion of 500ml of 10% mannitol (m-PET/CT). Two different infusion schemes for mannitol were used: (1) 500ml mannitol was infused over 40min after 68Ga-PSMA administration (A-infusion) and (2) 250ml mannitol was infused over 15min before and again after 68Ga-PSMA administration (B-infusion). In patients receiving the A-infusion, mean SUVmax increased by 11.9% and 7.4% in the right and left kidney, respectively. In patients receiving the B-infusion, mean SUVmax decreased by 24.3% and 22.4% in the right and left kidney, respectively. Our preliminary findings indicate that mannitol may play a role in reducing off-target 68Ga-PSMA renal uptake. Administration of the osmotic diuretic should be rapid and start before 68Ga-PSMA injection. These results warrant dosimetric studies in patients treated with 177Lu-PSMA to find the best scheme for mannitol administration.

An Allometric Model of Remifentanil Pharmacokinetics and Pharmacodynamics.

Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide range of age and weight. Remifentanil pharmacokinetic data were obtained from three previously published studies of adults and children, one of which also contained pharmacodynamic data from adults. NONMEM was used to estimate allometrically scaled compartmental pharmacokinetic and pharmacodynamic models. Weight, age, height, sex, and body mass index were explored as covariates. Predictive performance was measured across young children, children, young adults, middle-aged, and elderly. Overall, 2,634 remifentanil arterial concentration and 3,989 spectral-edge frequency observations from 131 individuals (55 male, 76 female) were analyzed. Age range was 5 days to 85 yr, weight range was 2.5 to 106 kg, and height range was 49 to 193 cm. The final pharmacokinetic model uses age, weight, and sex as covariates. Parameter estimates for a 35-yr-old, 70-kg male (reference individual) are: V1, 5.81 l; V2, 8.82 l; V3, 5.03 l; CL, 2.58 l/min; Q2, 1.72 l/min; and Q3, 0.124 l/min. Parameters mostly increased with fat-free mass and decreased with age. The pharmacodynamic model effect compartment rate constant (ke0) was 1.09 per minute (reference individual), which decreased with age. We developed a pharmacokinetic-pharmacodynamic model to predict remifentanil concentration and effect for a wide range of patient ages and weights. Performance exceeded the Minto model over a wide age and weight range.

Mesenchymal stem cell therapy in the treatment of hip osteoarthritis.

This study was performed to investigate the safety and efficacy of the intra-articular infusion of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (BM-MSC) to a cohort of patients with articular cartilage defects in the hip. The above rationale is sustained by the notion that MSCs express a chondrocyte differential potential and produce extracellular matrix molecules as well as regulatory signals, that may well contribute to cure the function of the damaged hip joint. A cohort of 10 patients with functional and radiological evidences of hip osteoarthritis, either in one or both legs, was included in the study. BM-MSC (the cell product) were prepared and infused into the damaged articulation(s) of each patient (60 × 106 cells in 3 weekly/doses). Before and after completion of the cell infusion scheme, patients were evaluated (hip scores for pain, stiffness, physical function, range of motion), to assess whether the infusion of the respective cell product was beneficial. The intra-articular injection of three consecutive weekly doses of ex vivo expanded autologous BM-MSC to patients with articular cartilage defects in the hip and proved to be a safe and clinically effective treatment in the restoration of hip function and range of motion. In addition, the statistical significance of the above data is in line with the observation that the radiographic scores (Tönnis Classification of Osteoarthritis) of the damaged leg(s) remained without variation in 9 out of 10 patients, after the administration of the cell product.

Factor VIII assay variability in postinfusion samples containing full length and B-domain deleted FVIII.

Although the variability in factor VIII (FVIII):C measurement is well recognized, this has not been widely reported for post-FVIII infusion samples. Three samples from haemophilia A patients were distributed in a UK National External Quality Assessment Scheme survey, each after treatment with either ReFacto AF, Kogenate FS or Advate. Fifty-two UK haemophilia centres performed FVIII assays using one-stage (n = 46) and chromogenic (n = 10) assays. Centres calibrated assays with the local plasma standard and with ReFacto AF laboratory standard for the ReFacto AF sample. Chromogenic assays gave significantly higher results than one-stage assays (P < 0.0001, 32% difference) in the post-Kogenate sample but not in the post-ReFacto AF (11% higher by chromogenic assay, ns) or post-Advate samples (3% lower by chromogenic, ns) when assays were calibrated with plasma standards. Twenty centres used all Instrumentation Laboratory (IL)-activated partial thromboplastin time reagents (Synthasil)/IL deficient plasma/reference plasma) in the one-stage assay and 15 used all Siemens reagents (Actin FS/Siemens deficient plasma/reference plasma); this made a significant difference to results post-ReFacto AF (41% higher by IL reagents, P < 0.0001) and Advate (39% higher by IL reagents, P < 0.0001), but not Kogenate (7% higher by IL, ns) when calibrated with plasma standards. Differences between results obtained with different one-stage assay reagents for monitoring Advate have implications for dosing patients. Furthermore, there was considerable inter-laboratory variation as indicated by CVs in the range 15-26% for chromogenic assay and 12-19% for one-stage assay results. This study suggests that external quality assessment schemes should offer participation in post-FVIII infusion schemes where haemophilic patients are monitored.

Strategies for the treatment of polymyxin B-resistant Acinetobacter baumannii infections

In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category using CLSI interpretive criteria. Pharmacodynamic evaluation found that for a FOF minimum inhibitory concentration (MIC) of ≤16μg/mL, treatment both by bolus dosing and prolonged infusion achieved adequate PTA, whilst for MIC=32μg/mL only infusion achieved adequate PTA. For a MEM MIC of 4μg/mL, only the bolus treatment scheme with 1.5g q6h and the infusion schemes with 1.0g q8h, 1.5g q6h and 2.0g q8h achieved PTA ≥0.9. Results of antimicrobial and pharmacodynamic analyses can assist in treating infections caused by multidrug-resistant A. baumannii. However, in vivo clinical studies are essential to evaluate the true role of these compounds, including intravenous antimicrobial FOF therapy.

COMPARATIVE CHARACTERISTICS OF THE METHODS OF CHEMODRUGS ADMINISTRATION IN THE TREATMENT OF PATIENTS WITH LOCALLY-ADVANCED BREAST CANCER

COMPARATIVE CHARACTERISTICS OF THE METHODS OF CHEMODRUGS ADMINISTRATION IN THE TREATMENT OF PATIENTS WITH LOCALLY-ADVANCED BREAST CANCER