Клинико-фармакоэкономический анализ антигеликобактерной терапии в стационарных и амбулаторно-поликлинических условиях

ГЕЛИКОБАКТЕРИОЗ /ЛЕК ТЕРЭКОНОМИКА ФАРМАЦЕВТИЧЕСКА

Correction to: Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017

After publication of the article [1], it has been brought to our attention that there are some errors in the formatting of names in the final version of the article

On The Rate and Extent of Drug Delivery to the Brain

To define and differentiate relevant aspects of blood–brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologically active drug molecule. Drug delivery to the brain can be comprehensively described using three parameters: Kp,uu (concentration ratio of unbound drug in brain to blood), CLin (permeability clearance into the brain), and Vu,brain (intra-brain distribution). The permeability of the blood–brain barrier is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a continuous (repeated) basis. Kp,uu can differ between CNS-active drugs by a factor of up to 150-fold. This range is much smaller than that for log BB ratios (Kp), which can differ by up to at least 2,000-fold, or for BBB permeabilities, which span an even larger range (up to at least 20,000-fold difference). Methods that measure the three parameters Kp,uu, CLin, and Vu,brain can give clinically valuable estimates of brain drug delivery in early drug discovery programmes

Microdialysis as an Important Technique in Systems Pharmacology : a Historical and Methodological Review

Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident

Perspectives on Nanodelivery to the Brain : Prerequisites for Successful Brain Treatment

Nanocarriers (NCs) are promising tools to improve drug delivery across the blood-brain barrier (BBB) for more effective treatment of brain disorders, although there is a scarcity of clinical translation of brain-directed NCs. In order to drive the development of brain-oriented NCs toward clinical success, it is essential to understand the prerequisites for nanodelivery to be successful in brain treatment. In this Perspective, we present how pharmacokinetic/pharmacodynamic (PK/PD), formulation and nanotoxicity factors impact the therapeutic success of brain-specific nanodelivery. Properties including high loading efficiency, slow in vivo drug release, long systemic circulation, an increase in unbound brain-to-plasma concentration/exposure ratio (K-p,K-uu,K-brain), high drug potency, and minimal nanotoxicity are prerequisites that should preferably be combined to maximize the therapeutic potential of a brain-targeted NC. The PK of brain-directed NCs needs to be evaluated in a more therapeutically relevant manner, focusing on the released, unbound drug. It is more crucial to increase the K-p,K-uu,K-brain than to improve the ability of the NC to cross the BBB in its intact form. Brain-targeted NCs, which are mostly developed for treating brain tumors, including metastases, should aim to enhance drug delivery not just to tumor regions with disrupted BBB, but equally important to regions with intact BBB where the drugs themselves have problems reaching. This article provides critical insights into how a brain-targeted nanoformulation needs to be designed and optimized to achieve therapeutic success in the brain

The brain slice method for studying drug distribution in the CNS

The high-throughput brain slice method is a precise and robust technique for estimating the overall uptake of drugs into brain tissue through determination of the unbound volume of distribution in the brain (Vu,brain; ml·g brain-1). Vu,brain describes the relationship between the total drug concentration in the brain and the concentration of unbound drug in the brain interstitial fluid, regardless of blood–brain barrier function. The brain slice method is more physiologically based than the brain homogenate method with respect to the assessment of drug distribution in the brain because the cell-cell interactions, pH gradients and active transport systems are all conserved. The method provides information that is directly relevant to issues such as nonspecific binding to brain tissue, lysosomal trapping, and active uptake into the cells. For these reasons, the brain slice method is recommended for estimation of target-site pharmacokinetics in the early drug discovery process and fundamental pharmacological studies. This article provides a detailed protocol for the rat and mouse brain slice methods, with the aim of enabling simple, cost-effective profiling of compounds with diverse physicochemical properties. The procedure for assessing the viability of the brain slices after the 5 h incubation period is also described. The results are interpreted for a set of compounds covering a wide range of physicochemical properties and various pharmacological targets. Application of the method for evaluating the unbound intracellular-to-extracellular concentration ratio (Kp,uu,cell) and the unbound brain-to-plasma concentration ratio (Kp,uu,brain) is discussed

Active Uptake of Oxycodone at Both the Blood-Cerebrospinal Fluid Barrier and The Blood-Brain Barrier without Sex Differences : A Rat Microdialysis Study

Background: Oxycodone active uptake across the blood-brain barrier (BBB) is associated with the putative proton-coupled organic cation (H+/OC) antiporter system. Yet, the activity of this system at the blood-cerebrospinal fluid barrier (BCSFB) is not fully understood. Additionally, sex differences in systemic pharmacokinetics and pharmacodynamics of oxycodone has been reported, but whether the previous observations involve sex differences in the function of the H+/OC antiporter system remain unknown. The objective of this study was, therefore, to investigate the extent of oxycodone transport across the BBB and the BCSFB in female and male Sprague-Dawley rats using microdialysis. Methods: Microdialysis probes were implanted in the blood and two of the following brain locations: striatum and lateral ventricle or cisterna magna. Oxycodone was administered as an intravenous infusion, and dialysate, blood and brain were collected. Unbound partition coefficients (K-p,K-uu) were calculated to understand the extent of oxycodone transport across the blood-brain barriers. Non-compartmental analysis was conducted using Phoenix 64 WinNonlin. GraphPad Prism version 9.0.0 was used to perform t-tests, one-way and two-way analysis of variance followed by Tukey's or Sidak's multiple comparison tests. Differences were considered significant at p < 0.05. Results: The extent of transport at the BBB measured in striatum was 4.44 +/- 1.02 (K-p,K-uu,K-STR), in the lateral ventricle 3.41 +/- 0.74 (K-p,K-uu,K-LV) and in cisterna magna 2.68 +/- 1.01 (K-p,K-uu,K-CM). These K-p,K-uu values indicate that the extent of oxycodone transport is significantly lower at the BCSFB compared with that at the BBB, but still confirm the presence of active uptake at both blood-brain interfaces. No significant sex differences were observed in neither the extent of oxycodone delivery to the brain, nor in the systemic pharmacokinetics of oxycodone. Conclusions: The findings clearly show that active uptake is present at both the BCSFB and the BBB. Despite some underestimation of the extent of oxycodone delivery to the brain, CSF may be an acceptable surrogate of brain ISF for oxycodone, and potentially also other drugs actively transported into the brain via the H+/OC antiporter system

AND HAMMALUND-UDENAES, M.: Quantification of effect delay and acute tolerance development to morphine in the rat

ABSTRACT ABBREVIATIONS: M3G, morphine-3-glucuronide; M6G, morphine-6-glucuronlde; AUC, area under concentration-tIme curve from time zero to infinity; AUMC, area under the first moment curve from time zero to infinity

In vivo blood-brain barrier transport of oxycodone in the rat-indications for active influx and implications for PK/PD. Drug Metab Dispos

ABSTRACT: The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL in and K p,uu . CL in describes the clearance of oxycodone across the BBB into the brain, whereas K p,uu describes the extent of drug equilibration across the BBB. CL in across the BBB was estimated to 1910 l/min ⅐ g brain. K p,uu was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids. The blood-brain barrier (BBB) is composed of capillary endothelial cells connected by tight junctions. Its main function is to be a physical and active barrier to restrict and regulate the penetration of compounds into and out from the brain to maintain brain homeostasis. Transport into the brain across the BBB is essential for drugs that act within the central nervous system (CNS), whereas BBB penetration needs to be minimized for drugs with potential CNS side effects. Brain distribution can be described with respect to the rate and extent of equilibration of a drug molecule across the BBB (Hammarlund-Udenaes, 2000). The rate of equilibration can be expressed as clearances into and out of the brain, CL in and CL out , respectively. The extent of equilibration across the BBB can be expressed as the ratio of the steady-state concentration of unbound drug in brain over unbound drug in blood, K p,uu Conclusions on the bidirectional transport properties of the BBB can be drawn based on the unbound concentrations in brain and bloo