Time Course Of Concentration Research Articles

Hydrogen Respiratory Test: Pilot Examinations for Evaluation of the Small Intestinal Colonization by Normal Microflora

Respiration hydrogen analyzer H2Rate has been used in pilot examinations of a group of students. This method for noninvasive diagnosis of small intestinal diseases promotes proper interpretation of the results. Free hydrogen level in the exhaled air increases as a result of lactulose (diagnostic agent) cleavage by enteric microflora within about 3 h. Based on the experimental data, the main groups with characteristic curves reflecting the time course of hydrogen concentrations have been distinguished. Excessive bacterial colonization of the intestine can correspond to emergence of characteristic peaks of hydrogen concentrations in the curve. Hydrogen concentrations in exhaled air can also be analyzed to evaluate the rate of the substrate propulsion in the middle compartment of the intestine.

Metabolome Response to Glucose in the β-Cell Line INS-1 832/13

Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is triggered by metabolism of the sugar to increase ATP/ADP ratio that blocks the KATP channel leading to membrane depolarization and insulin exocytosis. Other metabolic pathways believed to augment insulin secretion have yet to be fully elucidated. To study metabolic changes during GSIS, liquid chromatography with mass spectrometry was used to determine levels of 87 metabolites temporally following a change in glucose from 3 to 10 mM glucose and in response to increasing concentrations of glucose in the INS-1 832/13 β-cell line. U-[(13)C]Glucose was used to probe flux in specific metabolic pathways. Results include a rapid increase in ATP/ADP, anaplerotic tricarboxylic acid cycle flux, and increases in the malonyl CoA pathway, support prevailing theories of GSIS. Novel findings include that aspartate used for anaplerosis does not derive from the glucose fuel added to stimulate insulin secretion, glucose flux into glycerol-3-phosphate, and esterification of long chain CoAs resulting in rapid consumption of long chain CoAs and de novo generation of phosphatidic acid and diacylglycerol. Further, novel metabolites with potential roles in GSIS such as 5-aminoimidazole-4-carboxamide ribotide (ZMP), GDP-mannose, and farnesyl pyrophosphate were found to be rapidly altered following glucose exposure.

Effect of food intake on the pharmacokinetics of sarpogrelate and its active metabolite following oral administration to beagle dogs

1. The objectives of this study were to develop a pharmacokinetic model for sarpogrelate and its metabolite M-1 and to identify the effect of food on sarpogrelate and M-1 pharmacokinetics in beagle dogs.2. A single 100 mg oral dose of sarpogrelate was administered to fasted and fed beagle dogs and the plasma concentrations of sarpogrelate and M-1 were measured simultaneously by liquid chromatography tandem mass spectrometry. The resultant data were analyzed by modeling approaches using ADAPT5.3. The plasma concentration time course of sarpogrelate and M-1 were described using a parent-metabolite compartment model with first-order absorption and elimination. The systemic exposure of sarpogrelate and its metabolite after the administration of a single 100 mg oral dose was significantly decreased under the fed condition compared to that under the fasting condition. Modeling approaches have sufficiently explained the food effect of sarpogrelate, i.e. an increased Vc and decreased Ka, in fed dogs. The food effect of sarpogrelate was due to its pH-dependent dissolution.4. These findings suggest that food intake affects both the rate and extent of absorption of sarpogrelate, and that the pharmacological effect of sarpogrelate can differ significantly according to food intake.

Oxidation of non-steroidal anti-inflammatory drugs with aqueous permanganate

Potassium permanganate is a strong oxidant widely used in drinking water treatment, that can react with organic micropollutants. Thus, the oxidation kinetics and transformation route of seven non-steroidal anti-inflammatory drugs (NSAIDs) upon reaction with potassium permanganate was investigated. A liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-Q-TOF-MS) system was used to follow the time course of pharmaceuticals concentrations and for the identification of their by-products. Under strong oxidation conditions (2 mg L−1 KMnO4, 24 h), only two NSAIDs were significantly degraded: indomethacine and diclofenac. The degradation kinetics of these two drugs was investigated at different concentrations of permanganate, chlorides, phosphates and sample pH by means of a full factorial experimental design. Depending on these factors, half-lives were in the range: 2–270 h for indomethacine and 3–558 h for diclofenac, equivalent to apparent second order constants between 0.65 and 9.5 M−1 s−1 and 0.27 and 7.4 M−1 s−1, respectively. Permanganate concentration was the most significant factor on NSAIDs oxidation kinetics, but the pH also played a significant role in diclofenac reaction, being faster at acidic pH. In the case of indomethacine, the dose of permanganate seemed also to play an autocatalytic effect. The use of an accurate-mass high resolution LC-Q-TOF-MS system permitted the identification of a total of 13 by-products. The transformation path of these drugs consisted mainly of hydroxylations, decarboxylations and oxidation of aromatic double bonds, with ring opening. The software predicted toxicity of these products indicates that they are expected not to be more toxic than the NSAIDs, with the exception of two indomethacine by-products. Reaction in real samples was slower and/or incomplete for both pharmaceuticals, depending on the organic matter content of the sample. However, still all transformation products could be detected for indomethacine in permanganate treated surface water samples, and two out of five in the case of diclofenac.

Pharmacokinetic–pharmacodynamic modeling of antipsychotic drugs in patients with schizophrenia Part I: The use of PANSS total score and clinical utility

BackgroundTo develop a pharmacokinetic–pharmacodynamic (PK–PD) model using individual-level data of Positive and Negative Syndrome Scale (PANSS) total score to characterize the antipsychotic drug effect taking into account the placebo effect and dropout rate. In addition, a clinical utility (CU) criterion that describes the usefulness of a drug therapy was calculated using the efficacy of the drug and dropout rates. MethodsData from 12 clinical trials in schizophrenia patients was used to quantify the effects of the antipsychotic drugs (APs), namely, haloperidol, risperidone, olanzapine, ziprasidone and paliperidone. Compartmental PK models were used to describe the time course of plasma drug concentrations. The combination of an Emax and the Weibull model was used to describe the drug and placebo effects. The steady-state drug concentrations were assumed to be the drivers of the exposure–response relationship. An exponential model was utilized to identify the predictors of probability of dropout. Simulations were performed to check the predictability of the model, and to calculate the CU of the drugs based on PANSS scores and dropout rates. ResultsThe maximal drug effect (Emax) was highest for olanzapine whilst it was lowest for ziprasidone. Higher observed PANSS scores resulted in a greater likelihood of dropout. Taking into account the efficacy and the drop-out rate, all APs possessed a comparable CU at the therapeutic doses. The resulting PK–PD model parameters were used to compute the effective concentration and dose required to produce a clinically meaningful 30% drop in PANSS score from the baseline. ConclusionsThe developed PK–PD model and the associated CU score allow the evaluation of the time course of the PANSS scores of the different APs and a proper comparison of their clinically relevant treatments effects.

Influence of genetic polymorphisms in UGT1A1, UGT1A7 and UGT1A9 on the pharmacokynetics of irinotecan, SN-38 and SN-38G

To evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. Plasma concentrations of irinotecan, SN-38 and SN- 38G from 72 patients were pooled to develop a population pharmacokinetic model using NONMEM VII. M3 method was used to account for plasma concentrations below the limit quantification. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. The model was internally validated using normalized visual predictive check (NVPC) and normalized predictive distribution errors (NPDE). The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. The presence of UGT1A1*28, UGT1A7*3, UGT1A9*22 genotypes decreases SN-38 clearance between 20 and 36%. Internal validation confirms the population pharmacokinetic model describe the time course of irinotecan, SN-38 and SN-38G plasma concentration and their associated variability in cancer patients. The inclusion of pharmacokinetic-pharmacogenomic information can add value to the individualized dose adjustment of irinotecan, because it will let quantitatively handle dose reductions in patients with iatrogenic toxicity due to UGT1A1 genetic polymorphisms.

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?

二酸化マンガンを用いたホルマリン燻蒸後の残留ホルムアルデヒドガスの酸化分解に関する研究

F ig .1 Schemat ic v iew of the process ing un i t (p rototype) emp loy ing MnO2 honeycomb f i l te r fo r the ox idat ive decompos i t ion o f fo rma ldehyde gas , used in th is study Fig.5 Effect of initial concentration of evaporated formaldehyde gas on the time courses of air concentrations of formaldehyde (left) and carbon dioxide (right) during the operation of the processing unit employing MnO2 filter in the full-scale chamber (Experiment cases of 4 and 5, 6, 7, temperature: 25 °C, RH: 50 %) 0.01 0.1 1 10 10

Method for Individualized Evaluation of Antiemetic Effect Induced by 5-HT<sub>3</sub> Receptor Antagonist

5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 ± 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.

非小細胞肺がん患者に対する簡易懸濁法を用いた‌エルロチニブ投与に関する検討

Erlotinib, a reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is orally available and used for the treatment of non-small cell lung cancer (NSCLC). The simple suspension method is recognized as being useful in patients with dysphagia. In this study, we aimed to clarify the solubility and stability of erlotinib tablets against the temperature and pH of the solvent used for the simple suspension method. In addition, we evaluated the pharmacokinetic profile of erlotinib in three NSCLC patients who received erlotinib by this method. Erlotinib tablets were suspended in water at three different temperatures (25, 55 and 80℃) or beverages with three different pHs (3.62, 6.97 and 8.96) at 55℃. Concentrations of erlotinib in suspension samples, which were collected at 1, 2, 5, 10, 30 and 60 minutes after the start of suspending, were determined using a high performance liquid chromatography method. The concentrations of erlotinib were not significantly affected by the temperature and pH at 10 minutes and after the start of suspending, and erlotinib was stable, at least, for 60 minutes in each water solution examined. The plasma concentration time-courses of erlotinib at a steady-state in the three patients who received erlotinib by the simple suspension method were similar to those in the phase 1 study. These findings suggest that the simple suspension method for erlotinib is a treatment option for NSCLC patients with dysphagia.

Measurement of blood flow and xenon solubility coefficient in the human liver by xenon‐enhanced computed tomography

The goal of this work was to develop a method of calculating blood flow and xenon solubility coefficient (λ) in the hepatic tissue by xenon-enhanced computed tomography (Xe-CT) and to demonstrate λ can be used as a measure of fat content in the human liver. A new blood supply model is introduced which incorporates both arterial blood and portal venous blood which join and together flow into hepatic tissue. We applied Fick's law to the model. It was theoretically derived that the time course of xenon concentration in the inflow blood (the mixture of the arterial blood and the portal venous blood) can be approximated by a monoexponential function. This approximation made it possible to obtain the time-course change rate (K(I)) of xenon concentration in the inflow blood using the time course of xenon concentration in the hepatic tissue by applying the algorithm we had reported previously. K(I) was used to calculate blood flow and λ for each pixel in the CT image of the liver. Twenty-six patients (49.2 ± 18.3 years) with nonalcoholic steatohepatitis underwent Xe-CT abdominal studies and liver biopsies. Steatosis of the liver was evaluated using the biopsy specimen and its severity was divided into ten grades according to the fat deposition percentage [(severity 1) ≤ 10%, 10 % <(severity 2) ≤ 20%, [ellipsis (horizontal)], 90% < (severity 10) ≤ 100%]. For each patient, blood flow and λ maps of the liver were created, and the average λ value (λ) was compared with steatosis severity and with the CT value ratio of the liver to the spleen (liver∕spleen ratio). There were good correlations between λ and steatosis severity (r = 0.914, P < 0.0001), and between λ and liver∕spleen ratio (r = -0.881, P < 0.0001). Ostwald solubility for xenon in the hepatic tissue (tissue Xe solubility), which is calculated using λ and the hematocrit value of the patient, also showed a good correlation with steatosis severity (r = 0.910, P < 0.0001). λ ranged from 0.86 to 7.81, and tissue Xe solubility ranged from 0.12 to 1.16. This range of solubility is reasonable considering the reported Ostwald solubility coefficients for xenon in the normal liver and in the fat tissue are 0.10 and 1.3, respectively, at 37 °C. The average blood flow value ranged from 15.3 to 53.5 ml∕100 ml tissue∕min. A method of calculating blood flow and λ in the hepatic tissue was developed by means of Xe-CT. This method would be valid even if portosystemic shunts exist; it is shown that λ maps can be used to deduce fat content in the liver. As a noninvasive modality, Xe-CT would be applicable to the quantitative study of fatty change in the human liver.

Assessing metal bioaccumulation from estuarine sediments: comparative experimental results for the polychaete Arenicola marina

The purpose of this paper is to compare three approaches for providing information on the bioaccumulation potential of metals from contaminated sediments to the deposit-feeding polychaete Arenicola marina. We present metal (Ag, As, Cd, Cu, Pb and Zn) bioaccumulation results from field-collected sediments quantified through direct measurements of bioaccumulated concentrations in A. marina over a period of 30 days under controlled laboratory exposures and compare these results with bioaccumulated metal concentrations in field-collected organisms from the same sites of collection of the sediments used in the laboratory exposures. For the metals for which model parameters are available (Ag, As, Cd and Zn), we also compare these results with biodynamic model predictions. We considered three UK estuaries characterised by a well-reported history of trace metal contamination and bioavailability in addition to the (control) site of collection of the worms. The results from laboratory-exposed organisms showed that the standard 28-day exposure duration may be adequate to identify the potential for metal bioaccumulation in this polychaete at the sites considered here. However, the time course of bioaccumulated concentrations and the comparison with measured concentrations in field-collected worms show that a steady state has not been reached, confirming the need for extended exposure periods. The worms showed symptoms of stress in feeding and growth during the initial 10 days of exposure and subsequent partial recovery during the following 20 days, suggesting that stress was not always caused by sediment contamination but that it was likely associated with handling and acclimation. At this last stage of the exposure, a generalised biodynamic model was used to provide estimates of bioaccumulated metal concentrations and net accumulation rates in worms. The results of this study highlight the number of factors that should be considered for the interpretation of bioaccumulated metal concentrations in A. marina under laboratory exposures for contaminated sediment assessment, factors that appear to be common to most deposit-feeding polychaetes. A general biodynamic model proved to be a cost-effective method for an initial estimation of the extent and pattern of metal bioaccumulation under specified exposure conditions.

Measurement of Drug Concentration in the Stomach After Intragastric Administration of Drug Solution to Healthy Volunteers: Analysis of Intragastric Fluid Dynamics and Drug Absorption

To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution. Eight healthy volunteers were intragastrically administered 150mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2mL) were sampled for 2h through the catheter. Rate constants for secretion and emptying of the fluid were obtained by fitting the time-course of atenolol concentration to the simple gastric fluid transit model. Absorption of salicylic acid from the stomach was estimated by comparing its gastric concentration with that of atenolol. Kinetic analysis of atenolol concentration in the stomach indicated a rapid emptying of the fluid with an average half-life of 4.2min. Steady-state intragastric fluid volume in 8 volunteers was estimated as 4-133mL with an average of 42mL. Intragastric concentration (normalized by dose) of salicylic acid was always lower than that of atenolol, showing approximately 40% of salicylic acid was absorbed from the stomach before emptying to the intestine. This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.

Relative oral bioavailability of 3-MCPD from 3-MCPD fatty acid esters in rats

In order to quantify the relative oral bioavailability of 3-chloropropane-1,2-diol (3-MCPD) from 3-MCPD fatty acid diesters in vivo, 1,2-dipalmitoyl-3-chloropropane-1,2-diol (3-MCPD diester) and 3-MCPD were orally applied to rats in equimolar doses. In both cases, the time courses of 3-MCPD concentrations were measured in blood, various organs, tissues and intestinal luminal contents. The results show that 3-MCPD is released by enzymatic hydrolysis from the 3-MCPD diester in the gastrointestinal tract and distributed to blood, organs and tissues. Based on the measurements in blood, the areas under the curve (AUC) for 3-MCPD were calculated. By comparing both AUC, the relative amount of 3-MCPD bioavailable from the 3-MCPD diester was calculated to be 86% on average of the amount bioavailable following administration of 3-MCPD. In view of limited experimental data, it is justified for the purpose of risk assessment to assume complete hydrolysis of the diesters in the gastro-intestinal tract. Therefore, assessment of the extent of exposure to 3-MCPD released from its fatty acid esters should be performed in the same way as exposure to the same molar quantity of 3-MCPD.

Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis

This study was performed to describe clindamycin, administered either orally or intravenously, concentration-time courses to patients with osteomyelitis, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme. Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58 from oral administration and 64 from i.v. infusion). A population pharmacokinetic model was developed with MONOLIX 4 software. A one compartment model adequately described the data. Clindamycin clearance increased significantly with body weight (BW). The typical population estimates (interindividual variability) for clearance, volume of distribution and absorption rate constant were 16.2 l h(-1) (0.39), 70.2 l and 0.92 h(-1) , respectively. The bioavailability of the oral form was estimated to be 87.6%. According to BW, theoretical doses needed to reach a C(min) of 2 mg l(-1) were then calculated. The current recommendation of 600 mg three times daily seems to be effective up to 75 kg but the dose should be raised to 900 mg three times daily thereafter. These assumptions should be prospectively confirmed.

The Clinical Relevance of Plasma Protein Binding Changes

Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients. Given that the unbound concentration is responsible for drug efficacy and potential drug toxicity, this area is of significant interest to clinicians and academics worldwide. The present uncertainty means that many questions relating to this area exist, including "How important is protein binding?", "Is protein binding always constant?", "Do pH and temperature changes alter binding?" and "How do protein binding changes affect dosing requirements?". In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using examples from the critical care area. The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill. Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (V(d)), may be dramatic. Drugs with high protein binding, high intrinsic clearance (e.g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context. Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected. In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic/pharmacodynamic characteristics of the drug. We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding.

Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass

Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both. After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

Pharmacokinetic and Pharmacodynamic Modeling for the Effect of Sodium–Glucose Cotransporter Inhibitors on Blood Glucose Level and Renal Glucose Excretion in db/db Mice

The purpose of this study is to characterize the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) of sodium-glucose cotransporter (SGLT) inhibitors. PK-PD studies of SGLT inhibitors (CH4941527 and T-1095), which have different half-life and selectivity to SGLT2, were performed using db/db mice. The time courses of compound concentration in plasma, blood glucose (BG), and renal glucose excretion were measured after a single oral administration of each SGLT inhibitor. An indirect-response PK-PD model was developed, in which it was assumed that an SGLT inhibitor enhances renal glucose excretion and the enhanced glucose excretion reduces BG. In the PK-PD study, both SGLT inhibitors increased renal glucose excretion and reduced BG in a dose-dependent manner. The present PK-PD model could suitably capture the effect of SGLT inhibitors and the effect shown suggested that the BG reduction could be explained by the enhanced renal glucose excretion. There were no great differences in the estimated PD parameters between the two inhibitors and they were comparable to the data from previously reported pharmacological studies. The present PK-PD model is helpful for understanding the plasma concentration-dependent effect of SGLT inhibitors on renal glucose excretion and BG.

Pilot Investigation on Long-Term Subcutaneous Microdialysis: Proof of Principle in Humans

Reliable drug concentration measurements at the target site are increasingly demanded and can be achieved by microdialysis. The aim of this pilot study was to demonstrate the proof of principle of long-term subcutaneous microdialysis in humans. For long-term microdialysis, a special setting implementing both concentric and linear catheters has been developed ensuring good clinical practice compliance, tolerability, and convenience for participants and personnel. As a model compound, moderately lipophilic voriconazole was selected as a well-characterized drug in in vitro microdialysis experiments. Multiple in vivo relative recovery (RR) determinations for microdialysis were performed by retrodialysis during the entire study (n = 48 samples). Continuous microdialysis was successfully applied and well tolerated over 87 h in three adults for the first time. RR revealed low intra-individual (coefficient of variation (CV) = 4.4-12.5%) and inter-individual variability (CV = 4.3-12.5%) across all samples and catheters. Lower RR values were consistently determined for linear catheters. One catheter leakage was managed without an impact on the reliability of the RR values. Overall, RR values were calculated to be 73.3% (linear: CV = 18.5%, n = 23) and 84.9% (concentric: CV = 5.6%, n = 23). Long-term microdialysis application over almost 4 days was feasible by reliable multiple RR (proof of principle), well tolerated, and reduced the burden in humans avoiding several catheter insertions, thereby allowing to monitor concentration-time courses continuously. Moreover, a moderately lipophilic drug has been proven suitable for in vivo microdialysis, as previously suggested by in vitro microdialysis.

Broadband continuous-wave technique to measure baseline values and changes in the tissue chromophore concentrations

We present a broad-band, continuous-wave spectral approach to quantify the baseline optical properties of tissue and changes in the concentration of a chromophore, which can assist to quantify the regional blood flow from dynamic contrast-enhanced near-infrared spectroscopy data. Experiments were conducted on phantoms and piglets. The baseline optical properties of tissue were determined by a multi-parameter wavelength-dependent data fit of a photon diffusion equation solution for a homogeneous medium. These baseline optical properties were used to find the changes in Indocyanine green concentration time course in the tissue. The changes were obtained by fitting the dynamic data at the peak wavelength of the chromophore absorption, which were used later to estimate the cerebral blood flow using a bolus tracking method.