Intravenous Bolus Administration Research Articles

Glucose related endocrine and metabolic responses following bolus intravenous hypertonic dextrose administration in Iranian fat-tailed ewes at different pre and post parturition periods

Providing glucose as primary metabolic fuel for maintenance, foetal growth and milk production may be considered necessary for protection against negative energy balance and metabolic disorders. Five adult Ghezel ewes were selected 4 weeks before their parturition and followed at 2 weeks before, 2 and 4 weeks and 2, 3 and 4 months after parturition. Dextrose 50% was administered at 500 mg/kg, 10 mL/kg/hour, and blood samples were collected from all ewes prior to and 1, 2, 3 and 4 hours after 50% dextrose infusion. Serum levels of glucose, beta-hydroxybutyric acid, non-esterified fatty acids, cholesterol, triglyceride, high, low and very low density lipoproteins, insulin, triiodothyronine, thyroxine, prolactin, cortisol and insulin like growth factor-1 were evaluated. Glucose and insulin were increased significantly and immediately following intravenous dextrose administration at all studied periods. The levels of beta-hydroxybutyric acid and non-esterified fatty acids were significantly decreased following dextrose infusion at all periods. Triiodothyronine was decreased in pregnant ewes and increased in non-pregnant, lactating ones. The significant increasing cortisol patterns were detected at 2 and 4 weeks before and 2 and 4 weeks after parturition following dextrose administrations. The decreasing patterns of insulin like growth factor-1 were seen in all studied periods. Prolactin was significantly increased following dextrose administration at 4 and 2 weeks before and 2 weeks after parturition. Bolus intravenous hypertonic dextrose administration could induce the obvious endocrine and metabolic responses in Ghezel ewes via providing a source of energy and the glucose is an important direct controller of metabolic interactions in Ghezel ewes.

Case Reports: Rapid Fluid Delivery for Hypotension via a Novel Device (LifeFlow®) Leads to Improved Patient Outcome

Introduction: Critically ill patients presenting to the emergency department with shock often require a rapid intravenous fluid bolus to correct hypotension, restore tissue perfusion, and prevent cardiovascular collapse. In patients who require intravenous fluid bolus administration, a variety of barriers can limit effective resuscitation, including difficult vascular access, technically complex or slow infusion devices, and inadequate nursing resources. LifeFlow® (410 Medical, Inc., Durham, NC) is a handheld, manually-operated device that allows the user to precisely and rapidly deliver appropriately measured boluses of crystalloid fluid during resuscitation. No reports of the clinical use of LifeFlow currently exist in the literature.

“Simulect” as a model compound for assessing placental transfer of monoclonal antibodies in minipigs

The aim of this study was to directly test and measure in vivo, if placental transfer of monoclonal antibodies takes place in pregnant Göttingen Minipigs to assess their suitability for reproductive assessment of therapeutic monoclonal antibodies.Simulect®, an approved anti CD25 (anti IL-2 receptor alpha) chimeric monoclonal IgG1 antibody, was used as a model monoclonal antibody. Maternal systemic exposure and potential placental transfer of Simulect® to fetuses were investigated following 4 weekly bolus intravenous administration of 5.0 mg/kg from gestation day (GD) 79 or 80 (e.g GD 79, 86, 93 and 100) and with terminal Caesarean section on GD 108 or GD 109 respectively. Results clearly showed exposure in maternal animals, detectable compound in the amniotic fluid from one out of 9 maternal animals, but no exposure in fetuses confirming absence of placental transfer of the selected model antibody Simulect® in minipigs. The absence of Simulect® in the fetuses further supports that the presence of Simulect® in the amniotic fluid in one maternal animal was likely due to contamination with maternal blood during sampling. The demonstrated absence of fetal exposure clearly indicates that, the minipig is not a suitable species for conduct of reproductive toxicity studies with monoclonal antibodies.

Pharmacokinetics of HLDF-6-AA Peptide in the Organism of Experimental Animals

Pharmacokinetics of the promising antitumor peptide HLDF-6-AA (Ac-ThrGlyGluAsnHisArg-NH2) was studied using its uniformly tritiated derivative. Experiments were performed on male Wistar rats, Balb/c mice and Chinchilla rabbits. The tritium labeled peptide [3H]HLDF-6-AA with the molar radioactivity of 50 Ci/mmol was obtained by the reaction of high-temperature solid-state catalytic isotope exchange (HSCIE). Under intravenous bolus administration of HLDF-6-AA peptide to rats and rabbits, the characteristics of its pharmacokinetic profile in the blood were obtained and the values of the main pharmacokinetic parameters of HLDF-6-AA peptide, and its active metabolite HisArg-NH2 were calculated. It was shown that parameters of the retention time in the body and the rate of elimination for peptides HLDF-6-AA and HisArg-NH2 in rats and rabbits are close and in rats they are about 7 and 21 min, respectively. It was shown that repeated administration of the drug does not lead to a change in its regular cumulation and does not cause a change in its pharmacokinetics compared with a single administration. The linearity of the dependence of pharmacokinetic parameters on the amount of administered peptide in the range of 2–22 mg/kg was proved in experiments in rats. As a result of the study of the distribution of HLDF-6-AA peptide and its metabolite HisArg-NH2 between the blood and peripheral tissues of mice, it was shown that the maximum concentration of HLDF-6-AA peptide is observed in the kidney tissues and a somewhat smaller concentration in the omentum. It was found that 15–20 min after intraperitoneal administration of HLDF-6-AA to mice, the concentration of HisArg-NH2 peptide begins to exceed the concentration of HLDF-6-AA peptide, which is caused by its greater resistance to proteolytic hydrolysis. The highest concentration of HisArg-NH2 peptide is observed in the kidney and liver tissues.

The capability of Several Population-based Approach Software to Analyze Sparse Drug Plasma Concentration Data after Intra-Venous Bolus Injection

Monolix, NONMEM, and WinBUGS-PKBUGS are among available software package for population-based modeling. The sparse condition of drug plasma concentration versus time ( Cp-time ) data is prevalent in clinically based studies involving patients. It is not ethical in this case, to collect a many and large volumes of blood samples. This study was aimed to simulate the capability of Monolix, NONMEM, and WinBUGS-PKBUGS to analyze very sparse Cp-time data after an intravenous bolus drug administration and to estimate the minimum number of Cp-time data required for an adequate analysis. Data of Cp-time were obtained based on simulation using the pharmacokinetic one-compartment open model following an intravenous bolus administration of 50 mg of a hypothetical drug. In this respect, six random values of k (rate constant of elimination) and Vd (volume of distribution) with mean and standard deviation values of 0.3 ±0.1 per hour and 30 ± 10 L, respectively, were used to create simulated Cp-time data of 6 subjects. Simulated Cp-time data in each subject were randomly ranked to choose data based on the intended number of samples in each subject. Several sparse Cp-time data scenarios, starting from a very limited state, i.e., with a total of 6 Cp-time data (1 datum per subject) to a rich situation with 48 Cp data (8 data per subject), were examined. The goodness of fit evaluations, as well as the similarity of individual values of k and Vd to the respective real values (p>0.05), indicate that nonlinear-mixed-effect-model using Monolix, NONMEM and WinBUGS-PKBUGS can appropriately describe sparse Cp-time data even with only 2 data per subject. This fact is an important finding to support the demand of analytical tool for a limited number of Cp-time data such as obtained in therapeutic drug monitoring event.

Formation of HETE-EAs and dihydroxy derivatives in mouse kidney tissue and analysis by high-performance liquid chromatography tandem mass spectrometry

The kidneys play an important role in the long-term regulation of blood pressure by control of salt and water balance in the body through various systems including the endocannabinoid system. The endocannabinoid system consists of the two major cannabinoid receptor agonists, anandamide (AEA) and 2-arachidonylglycerol (2-AG), their hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the cannabinoid receptors, CB1 and CB2. AEA can be converted into 12- and 15(S)-hydroperoxyeicosatetraenoic acid ethanolamides by 12-LOX and 15-LOX, respectively and can form epoxyeicosatrienoic acid- (EET-EAs) (5,6-, 8,9-, 11,12-, 14,15-) and hydroxyeicosatetraenoic acid- (HETE) ethanolamides. Furthermore, the EET-EAs produce a secondary metabolism by microsomal epoxide hydrolase to form the corresponding dihydroxyeicosatetraenoic acid-EAs (DiHETE-EA). Reference material was not available for DiHETE-EA. These metabolites were synthesized by incubation of the corresponding EET-EAs with mouse liver cytosol containing epoxide hydrolases. Presented is a solid phase extraction and high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for the extraction and quantitation of AEA, 2-AG, their metabolites, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA), and the in vivo formation of the DiHETE-EAs in kidney after a single intravenous bolus administration of 20 mg/kg of anandamide in C57BL/6 J and FAAH KO mice.

Absence of Interactive Effects of trans-1,2-Cyclohexanediol, a Major Metabolite of the Side-Chain of Candesartan Cilexetil, on Digoxin-Induced Arrhythmias in Dogs

trans-1,2-Cyclohexanediol, the major metabolite of the cilexetil moiety of candesartan cilexetil (CC), has been reported to have potent pro-arrhythmic effects in dogs with congestive heart failure (CHF), especially when co-administered with digoxin. To verify this and to clarify the clinical relevance and the underlying mechanisms, a series of in vivo and in vitro experiments was conducted. When CC up to 300 mg/kg was administered orally to intact dogs, no changes in the electrocardiograms (ECG) or the required cumulative doses of ouabain to induce ventricular arrhythmias were observed. In dogs with CHF, intravenous bolus administration of trans-1,2-cyclohexanediol at 4 mg/kg followed by continuous infusion at 0.1 mg·kg-1·min-1 had no effects on the ECG parameters, the type, incidence, and onset time of digoxin-induced arrhythmias or the metabolism of digoxin. In an in vitro experiment using isolated guinea pig papillary muscle, trans-1,2-cyclohexanediol (1 – 100 μmol/L) showed no effects on any parameter of the action potentials. Because no effects were observed in these experiments where the exposure levels of trans-1,2-cyclohexanediol were extremely high compared to those in humans given the maximum therapeutic dose of CC, it is unlikely that CC would induce arrhythmias in clinical use even in patients treated with cardiac glycosides.

Effectiveness and Safety of 4-factor Prothrombin Complex Concentrate (4PCC) in Neonates With Intractable Bleeding or Severe Coagulation Disturbances: A Retrospective Study of 37 Cases.

To date, clinical experience with prothrombin complex concentrate (PCC) in the neonatal population has been limited. The objective of this study was to describe our experience regarding the effectiveness and safety of PCC administration in newborns with severe bleeding or coagulopathy resistant to conventional therapy. We retrospectively analyzed data from 37 neonates with intractable bleeding or severe coagulation disturbances. All patients received intravenous bolus administration of 20 or 30 u/kg of PCC per dose, as a rescue procedure. Hemostasis was achieved in the majority of neonates and we observed statistically significant improvement in prothrombin time, international normalized ratio, and activated partial thromboplastin time (P<0.001, P=0.044, P<0.001, respectively). Thirteen neonates survived, whereas 24 did not survive. In those who survived, PCC had been administered earlier (<24 h) in the disease process compared with those who died (P=0.043). Neither acute adverse events nor thromboembolic complications were observed in all neonates. In our study, PCC seemed to be a safe and effective intervention for hemostasis and early intervention was more effective as a rescue therapy, without any adverse event. Further prospective controlled trials are required to determine optimal dose and timing of PCC administration in neonates.

ФАРМАКОЛОГИЧЕСКАЯ КОРРЕКЦИЯ ФУНКЦИОНАЛЬНОЙ НЕДОСТАТОЧНОСТИ ЭПИФИЗА У ПАЦИЕНТОВ С ПОЛИТРАВМОЙ КАК СОСТАВНАЯ ЧАСТЬ СТРАТЕГИИ СЕДАТИВНОЙ ТЕРАПИИ

Целью исследования является выявление изменения концентрации гормонов эпифиза (серотонин и мелатонин) в плазме крови в дневное и ночное время у пациентов с политравмой с применением фармакологической коррекции выявленных нарушений препаратами мелатонина и серотонина. Вид исследования – продольное, проспективное, рандомизированное. Критерии включения больных в исследование: возраст от 20 до 50 лет; тяжесть состояния по шкале АРАСНЕ II не ниже 25 баллов. Представлены результаты обследования 70 пациентов, разделенных по виду выбора препарата для проведения седативной терапии. Была выявлена физиологическая закономерность, характеризующая функциональную активность эпифиза в виде альтернирующего характера изменения уровней серотонина и мелатонина в плазме крови здоровых добровольцев. Доказано, что функциональная активность эпифиза по уровню секреции гормонов мелатонина и серотонина снижена у пациентов, находящихся в критическом состоянии вследствие политравмы различного генеза (исключая черепно-мозговую травму). Назначение больным дополнительно мелатонина по 6 мг перорально в ночные часы в течение 5 суток позволяет снизить дозировку гипнотиков для достижения конечных значений уровня седации. Болюсное внутривенное введение серотонина адипината позволяет создавать у пациентов «неврологическое» окно через 60 минут.

Pharmacokinetic study of hepatoprotective coumarinolignoids from Cleome viscosa in mice using validated high-performance liquid chromatography-photodiode array method

Background: Three key coumarinolignoids, cleomiscosins A, B, and C of Cleome viscosa seed origin in particular ratio, are a proven hepatoprotective agent known as Cliv-92. Objectives: However, the bioavailability and pharmacokinetics of Cliv-92 are still not clear. The present study is the first validated method which deals with the assay of Cliv-92 in mouse plasma. Methods: Single-step sample preparation meets the criteria of recovery (80%–93% with relative standard deviation [RSD] 2.14%–4.80%). Reverse-phase high-performance liquid chromatography with photodiode array detection has resulted into acceptable separation and sensitivity of three structurally similar cleomiscosins – A, B, and C of Cliv-92. The analysis involved a binary gradient of mobile phase and flow rate. Quantification was done at peak area at 326 nm using linear regression curve (r2 > 0.999). The precision (0.46%–2.68% RSD) and accuracy (±2.09% bias) of Cliv-92 determination in plasma complied the criteria of the current international guidelines. We have also evaluated the matrix effect on sensitivities by spiking method. Limit of detection and limit of quantification in mouse plasma ranged between 0.13–0.24 μg/ml and 0.41–0.74 μg/ml. Results: Pharmacokinetic parameters were studied after intravenous bolus administration of Cliv-92 at 10 mg/kg dose in mice. Blood samples were collected at a predefined time up to 24 h post-injection. The Cliv-92 plasma half-life (t1/2) was 2.77 h, and the clearance was estimated as 2.38 L/h/kg. Conclusion: The method is simple, sensitive, and accurate for the determination of plasma concentration of coumarinolignoids. The present preclinical pharmacokinetic study of coumarinolignoids has been anticipated in clinical studies with scaling techniques. Abbreviations used: HPLC-PDA: High Performance Liquid Chromatography-Photodiode Array; HQC: High-Quality Control level; LOD: Limit of Detection; LOQ: Limit of Quantification; LQC: Low-Quality Control level; MQC: Medium-Quality Control level; QC: Quality Control; RT: Room Temperature.

Dopamine D1 Receptor Within Basolateral Amygdala Is Involved in Propofol Relapse Behavior Induced by Cues.

Propofol has been proven to be potentially abused by humans and laboratory animals; however, studies that have examined propofol relapse behavior are limited, and its underlying mechanism remains unclear. In this study, we examined whether basolateral amygdala-specific or systematic administration of the dopamine receptor antagonist alters cue-induced propofol-seeking behaviors in a rat model. Male Sprague-Dawley rats first received 14 days of propofol self-administration training, where active nose poke resulted in the delivery of propofol infusion paired with a tone and light cues. After 1-30 days of forced abstinence, the cue-induced propofol-seeking behaviors were tested in the operant chamber. We demonstrated, for the first time, after a few days of withdrawal from intravenous bolus administration of propofol, propofol-related cues could induce robust reinstatement of drug-seeking behavior. Systematic administration of dopamine D1 receptor antagonist (SCH-23390) or dopamine D2 receptor antagonist (spiperone) inhibited propofol relapse behavior induced by drug-related cues. Furthermore, we show that microinfusion of SCH-23390 into basolateral amygdala dose-dependently attenuated cue-induced propofol drug-seeking behavior, whereas infusion of spiperone had no effect on the propofol relapse behavior. Our results reveal the involvement of dopamine receptors within the basolateral amygdala in the cue-induced propofol relapse behavior in rats.

Supplemented Alkaline Phosphatase Supports the Immune Response in Patients Undergoing Cardiac Surgery: Clinical and Computational Evidence

Alkaline phosphatase (AP) is an enzyme that exhibits anti-inflammatory effects by dephosphorylating inflammation triggering moieties (ITMs) like bacterial lipopolysaccharides and extracellular nucleotides. AP administration aims to prevent and treat peri- and post-surgical ischemia reperfusion injury in cardiothoracic surgery patients. Recent studies reported that intravenous bolus administration and continuous infusion of AP in patients undergoing coronary artery bypass grafting with cardiac valve surgery induce an increased release of liver-type “tissue non-specific alkaline phosphatase” (TNAP) into the bloodstream. The release of liver-type TNAP into circulation could be the body's way of strengthening its defense against a massive ischemic insult. However, the underlying mechanism behind the induction of TNAP is still unclear. To obtain a deeper insight into the role of AP during surgery, we developed a mathematical model of systemic inflammation that clarifies the relation between supplemented AP and TNAP and describes a plausible induction mechanism of TNAP in patients undergoing cardiothoracic surgery. The model was validated against clinical data from patients treated with bovine Intestinal AP (bIAP treatment) or without AP (placebo treatment), in addition to standard care procedures. We performed additional in-silico experiments adding a secondary source of ITMs after surgery, as observed in some patients with complications, and predicted the response to different AP treatment regimens. Our results show a strong protective effect of supplemented AP for patients with complications. The model provides evidence of the existence of an induction mechanism of liver-type tissue non-specific alkaline phosphatase, triggered by the supplementation of AP in patients undergoing cardiac surgery. To the best of our knowledge this is the first time that a quantitative and validated numerical model of systemic inflammation under clinical treatment conditions is presented.

Single-Center Pharmacokinetic Study and Simulation of a Low Meropenem Concentration in Brain-Dead Organ Donors.

Meropenem is an ultrabroad-spectrum antibiotic of the carbapenem family. In brain-dead organ donors, administration of standard meropenem dosages does not reach therapeutic levels. Our objectives were to determine the plasma concentration of meropenem after the administration of standard meropenem dose and to estimate an improved dosage regimen for these patients. One gram of meropenem was administered as a 1-h infusion every 8 h for 1 to 3 days, and blood samples were collected. The plasma concentration of meropenem was measured and subjected to pharmacokinetic analysis. Simcyp simulation was performed to predict the optimum plasma levels and dosage based on the patients' individual pharmacokinetic parameters. The maximum plasma concentration of meropenem was 3.29 μg/ml, which was lower than four times the MIC of 8 μg/ml. Although the mean creatinine clearance of patients was moderately low (67.5 ml/min), the apparent volume of distribution at steady state (Vss) and time-averaged total body clearance (CL) of meropenem were markedly elevated (4.97 liters/kg and 2.06 liters/h/kg, respectively), owing to massive fluid loading to decrease the high sodium levels and to treat shock or dehydration. The simulation revealed that dose and infusion time of meropenem should be increased based on patients' Vss and CL, and a loading dose is recommended to reach rapidly the target concentration. In conclusion, a standard meropenem regimen is insufficient to achieve optimal drug levels in brain-dead patients, and an increase in dose and extended or continuous infusion with intravenous bolus administration of a loading dose are recommended for these patients.

Control Strategies for Nonzero Set-Point Regulation of Linear Impulsive Systems

Despite its potential use in several meaningful problems linear impulsive systems have not been extensively studied to account for dynamics in which the equilibria are out of the origin. In this work a novel characterization of the system equilibria and invariant regions—derived from the definition of two underlying discrete-time systems—is given, and based on this characterization, an unconstrained feedback control and a zone Model Predictive Control strategies are proposed. The controllers are tested in two drug administration problems: An intravenous bolus administration of Lithium ions and a nonlinear human immunodeficiency virus infection dynamics under Zidovudine treatment.

Assessment of graft perfusion and oxygenation for improved outcome in esophageal cancer surgery: Protocol for a single-center prospective observational study.

Introduction:The main cause of anastomotic leakage (AL) is tissue hypoxia, which results from impaired perfusion of the pedicle stomach graft after esophageal reconstruction. Clinical judgment is unreliable in determining graft perfusion. Therefore, an objective, validated, and reproducible method is urgently needed. Near infrared fluorescence perfusion imaging using indocyanine green (ICG) is an emerging and promising modality. This study's objectives are to evaluate the feasibility of quantification of ICG angiography (ICGA) to assess graft perfusion and to validate ICGA by comparison with hemodynamic parameters, blood and tissue expression of hypoxia-induced markers, and tissue mitochondrial respiration rates. And, second, to evaluate its ability to predict AL in patients after minimally invasive esophagectomy (MIE).Methods:Patients (N = 70) with resectable esophageal cancer will be recruited for standard MIE. ICGA will be performed after graft creation and thoracic pull-up. Dynamic digital images will be obtained starting after intravenous bolus administration of ICG. The resulting images will be subjected to curve analysis and to compartmental analysis based on the adiabatic approximation to tissue homogeneity kinetic model. The calculated perfusion parameters will be compared to intraoperative hemodynamic data to evaluate the effects of patient hemodynamics. To verify whether graft perfusion represents tissue oxygenation, ICGA perfusion parameters will be compared with systemic and serosa lactate from the stomach graft. In addition, perfusion parameters will be compared to tissue expression of hypoxia-related markers and mitochondrial chain respiratory rate. Finally, the ability of functional, histological, and cellular perfusion and oxygenation parameters to predict AL and postoperative morbidity in general will be evaluated using the appropriate univariate and multivariate statistical analyses.Discussion:The results of this project may lead to a novel, reproducible, and minimally invasive method to objectively assess perioperative anastomotic perfusion during MIE, potentially reducing the incidence of AL and its associated severe morbidity and mortality.Trial registration:Clinicaltrials.gov registration number is NCT03587532. The study was approved by the ethical committee of the Ghent University, Belgium (B670201836427).

Bolus administration of ephedrine and etilefrine induces transient vasodilation just after injection in combined epidural and general anesthesia patients: A randomized clinical study.

Hypotension commonly accompanies combined epidural and general anesthesia, and intravenous bolus ephedrine and etilefrine are widely used to correct hypotension. We have noticed that systemic vascular resistance (SVR) transiently decreases just after intravenous bolus administration of these drugs. The goal of the present study was to investigate whether bolus administration of these drugs decrease SVR just after intravenous administration in combined epidural and general anesthesia patients. We investigated 40 patients who were scheduled for elective abdominal surgery. Patients were chosen as subjects if their systolic arterial pressure decreased by 20% or to <100 mmHg at 30 min after the induction of general anesthesia. Baseline hemodynamic values were recorded, and after ephedrine 10 mg injection or etilefrine 2 mg injection (equipotent), the parameters were recorded again at 0.5 min and once each min for the next 5 min thereafter. The 40 patients were enrolled into the ephedrine (n = 20) or etilefrine (n = 20) treatment groups. Patient characteristics were comparable in both groups. After ephedrine injection, SVR decreased significantly at the 1-min time point, whereas after etilefrine injection, SVR decreased significantly at the 0.5- to 2-min time points compared with baseline values. SVR at the 0.5- to 1-min time points was lower in the etilefrine versus the ephedrine group. Both drugs transiently decreased SVR after intravenous injection, but etilefrine decreased SVR much more than ephedrine, indicating that more vasodilation occurred after the injection of etilefrine than after ephedrine. It is thus important to recognize the different characteristics of these drugs.

Клинический случай: компьютерная томография с 3D реконструкцией в планировании двухэтапной резекции печени ALPPS по поводу альвеококкоза

Purpose: To provide case report of alveococcosis of the liver, when ALPPS procedure was planned based on diagnostic information and 3D reconstructions of computed tomography. Material and methods: Computed tomography with bolus intravenous administration of 100 ml of contrast media Ultravist-370 was performed on multislice computed tomography Aquilion 64 Toshiba. Results: The preoperative planning is the crucial part of treatment to minimize or exclude liver insufficiency after resection. The minimal volume of remnant of the liver should be more than 25–30 % for normal parenchyma and more than 40 % in case of chronic pathologic diffuse process in the liver for example steatosis or cirrhosis. If the estimated volume of remnant is not enough to perform resection, two staged hepatectomy should be planned. According to CT data, the parenchyma of segment S2 and most of parenchyma S3, which together constitute the so-called lateral sector of the liver, were preserved. It allowed to plan an extended right-sided resection. However, the volume of the future liver remnant was 410 ml – about 30 % of the functioning part of the liver which was considered insufficient in view of the presence of prolonged biliary hypertension and a decreasing density of the parenchyma. Vascular elements of the left lateral sector – left hepatic artery, left hepatic vein and inferior vena cava were intact, however, there was a possibility of involving the wall of the left portal vein, due to its prolonged contact with the surface of the parasitic lesion. Using the segmentation tool on radiology workstation, a 3D surface model of the liver was built, where the localization of the pathologic lesion and its relationship with the main vessels were visually demonstrated. After preoperative preparation, a decision was made to perform ALPPS procedure. At the first stage intraoperative the adhesion of the parasitic lesion with the left portal vein was confirmed, which required its resection and plastic. Also in addition to the usual volume of the operation, an atypical resection of the S3 segment and Roux-en-Y choledochojejunostomy were performed. On the 7th day after the 1st stage, a control CT scan was performed, at which an increase in the volume of the remnant to 630 ml (46 % of the preserved parenchyma of the liver) was recorded. The hepatic artery, portal and hepatic veins of the future liver remainder were enhanced homogenously; drainage was traced in the area of parenchyma dissection after the second, l stage of the operation, CT was performed in 15 days to exclude liquid accumulations in the abdominal cavity and to assess the condition of the remnant due to a moderate increasing of the level of direct bilirubin up to 98 μmol/l. No pathological changes in the abdominal cavity were revealed, only free pleural effusion was observed in the pleural cavities with partial atelectasis of the lower lobes of the lungs. After conservative therapy the liver insufficiency was resolved. On the 20th day after the operation, the patient was discharged. Conclusion: In the described clinical case, computed tomography with 3D reconstructions made possible to obtain complete diagnostic information that was necessary for the surgeon to assess the resectability of the pathological process and to plan the type of surgical intervention.

A new method for simultaneous quantification of fosphenytoin, phenytoin and its primary metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin in whole blood by ultra-performance liquid chromatography-tandem mass spectrometry.

A method for simultaneous quantification of fosphenytoin (F-PHT), phenytoin (PHT) and its main metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in whole blood was developed and validated using ultra-performance liquid chromatography-tandem mass spectrometry. Whole blood samples were pretreated by liquid-liquid extraction with acetonitrile and methanol. Chromatographic separation was performed using a CORTECS™ UPLC® C18 (2.1 × 50 mm i.d., particle size 1.6 μm) analytical column, and water containing 10 mM ammonium formate and acetonitrile as the mobile phase. Quantification of the analytes was carried out using mass chromatography with each product ion referenced against phenytoin-d10 as an internal standard. Calibration curves exhibited good linear relationships in a range from 0.005 to 50 μg/ml with correlation coefficients exceeding 0.995. The limits of detection were estimated to be 0.002-0.01 μg/ml. The accuracies and precisions were 96.2-104.3% and 0.7-10.7%, respectively. The recovery efficiencies were in the range of 42.4-59.2%. Matrix effects were observed for PHT and HPPH, with signal suppression ranging from -6.6 to -32.2%. Matrix effect for F-PHT (-5.0 to 8.9%) was less than those for PHT and HPPH. All analytes were stable under different storage conditions. This method was successfully applied for the quantification of F-PHT, PHT and HPPH in rat whole blood samples taken after bolus intravenous administration of F-PHT.

Brain Uptake of [13C] and [14C]Sucrose Quantified by Microdialysis and Whole Tissue Analysis in Mice.

Among small, hydrophilic drug-like molecules, [14C]sucrose has long been considered the gold standard for determination of blood-brain barrier permeability. However, we have recently shown in rats that, compared with liquid chromatography-tandem mass spectrometry analysis of stable isotope (13C) of sucrose, [14C]sucrose significantly overestimates the brain tissue concentration and uptake of sucrose by a factor of 6 to 7. This discrepancy is due to the presence of small quantities of lipophilic impurities in [14C]sucrose tracer solutions. Here, we used intracranial microdialysis to measure concentrations of both sucrose variants in brain extracellular fluid (ECF) after intravenous bolus administration to mice. Both markers displayed similar plasma profiles and ECF dialysate concentrations. However, total brain tissue concentrations and apparent brain uptake clearance of [14C]sucrose were 4.1- and 3.6-fold higher, respectively, than those of [13C]sucrose. Therefore, the contaminants of [14C]sucrose with higher permeability were likely sequestered by brain cells, which renders them nondialyzable. It is concluded that although measurement of radioactivity overestimates the concentrations of intact sucrose in the brain tissue, the ECF radioactivity after microdialysis is a relatively accurate reflection of intact sucrose after the systemic administration of the [14C]sucrose marker.

Continuous low-dose infusion of patupilone increases the therapeutic index in mouse and rat tumour models.

Patupilone is a microtubule-targeted cytotoxic agent with clinical efficacy, but causes diarrhoea in more than 80% of patients. The efficacy and tolerability of patupilone delivered continuously by subcutaneous (s.c.) mini-pumps [(mini-pump dose (MPD)] or by intravenous bolus administration [intravenous bolus dose (IVBD)] were compared preclinically to determine whether the therapeutic index could be improved. The antiproliferative potency in vitro of patupilone was determined by measuring total cell protein. Tumours were grown s.c. in rats (A15) or nude mice (KB31, KB8511) or intracranially in nude mice (NCI-H460-Luc). Efficacy was monitored by measuring tumour volumes, bioluminescence or survival. Toxicity was monitored by body weight and/or diarrhoea. Total drug levels in blood, plasma, tissues or dialysates were quantified ex-vivo by liquid chromatography-mass spectroscopy/mass spectroscopy. Patupilone was potent in vitro with GI50s of 0.24-0.28 nmol/l and GI90s of 0.46-1.64 nmol/l. In rats, a single IVBD of patupilone dose dependently inhibited the growth of A15 tumours, but also caused dose-dependent body weight loss and diarrhoea, whereas MPD achieved similar efficacy, but no toxicity. In mice, MPD showed efficacy similar to that of IVBD against KB31 and KB8511 tumours, but with reduced toxicity. In a mouse intracranial tumour model, IVBD was more efficacious than MPD, consistent with patupilone concentrations in the brain. MPD provided constant plasma levels, whereas IVBD had very high C0/Cmin ratios of 70-280 (rat) or 8000 (mouse) over the dosing cycle. Overall, the correlation of plasma and tumour levels with response indicated that a Cave of at least GI90 led to tumour stasis. Continuous low concentrations of patupilone by MPD increased the therapeutic index in s.c. rodent tumour models compared with IVBD by maintaining efficacy, but reducing toxicity.