scholarly journals Impact of CNS Diseases on Drug Delivery to Brain Extracellular and Intracellular Target Sites in Human: A “WHAT-IF” Simulation Study

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 95
Author(s):  
Mohammed A. A. Saleh ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Drug Transport ◽  
Extracellular Fluid ◽  
Drug Effects ◽  
Transport Processes ◽  
Cns Diseases ◽  
Time Profiles ◽  
Target Sites ◽  
Intracellular Target ◽  
Drug Dependent ◽  
The Impact

The blood–brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration–time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug target sites in the brain extracellular fluid (brainECF) and intracellular fluid (brainICF) that may result in changes in CNS drug effects. Here, we used our human CNS physiologically-based PK model (LeiCNS-PK3.0) to investigate the impact of altered cerebral blood flow (CBF), tight junction paracellular pore radius (pararadius), brainECF volume, and pH of brainECF (pHECF) and of brainICF (pHICF) on brainECF and brainICF PK for 46 small drugs with distinct physicochemical properties. LeiCNS-PK3.0 simulations showed a drug-dependent effect of the pathophysiological changes on the rate and extent of BBB transport and on brainECF and brainICF PK. Altered pararadius, pHECF, and pHICF affected both the rate and extent of BBB drug transport, whereas changes in CBF and brainECF volume modestly affected the rate of BBB drug transport. While the focus is often on BBB paracellular and active transport processes, this study indicates that also changes in pH should be considered for their important implications on brainECF and brainICF target site PK.

scholarly journals The 3D Brain Unit Network Model to Study Spatial Brain Drug Exposure under Healthy and Pathological Conditions

2020 ◽  
Vol 37 (7) ◽  
Author(s):  
Esmée Vendel ◽  
Vivi Rottschäfer ◽  
Elizabeth C.M. de Lange
Keyword(s):  
Brain Tissue ◽  
Network Model ◽  
Drug Exposure ◽  
Extracellular Fluid ◽  
Transport Processes ◽  
Drug Concentrations ◽  
Induced Changes ◽  
The Impact ◽  
The Brain ◽  
Unit Network

Abstract Purpose We have developed a 3D brain unit network model to understand the spatial-temporal distribution of a drug within the brain under different (normal and disease) conditions. Our main aim is to study the impact of disease-induced changes in drug transport processes on spatial drug distribution within the brain extracellular fluid (ECF). Methods The 3D brain unit network consists of multiple connected single 3D brain units in which the brain capillaries surround the brain ECF. The model includes the distribution of unbound drug within blood plasma, coupled with the distribution of drug within brain ECF and incorporates brain capillaryblood flow, passive paracellular and transcellular BBB transport, active BBB transport, brain ECF diffusion, brain ECF bulk flow, and specific and nonspecific brain tissue binding. All of these processes may change under disease conditions. Results We show that the simulated disease-induced changes in brain tissue characteristics significantly affect drug concentrations within the brain ECF. Conclusions We demonstrate that the 3D brain unit network model is an excellent tool to gain understanding in the interdependencies of the factors governing spatial-temporal drug concentrations within the brain ECF. Additionally, the model helps in predicting the spatial-temporal brain ECF concentrations of existing drugs, under both normal and disease conditions.

scholarly journals Patient-reported effectiveness and safety of Pamidronate in NSAIDs-refractory chronic recurrent multifocal osteomyelitis in children

2021 ◽  
Author(s):  
Bartłomiej Juszczak ◽  
Jerzy Sułko
Keyword(s):  
Adverse Drug Reactions ◽  
Social Life ◽  
Chronic Recurrent Multifocal Osteomyelitis ◽  
Daily Activities ◽  
Drug Reactions ◽  
Patient Reported ◽  
Multifocal Osteomyelitis ◽  
Drug Dependent ◽  
Treatment Onset ◽  
The Impact

AbstractTo evaluate patient-reported effectiveness, safety and social influence of Pamidronate in the therapy of NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis in children. Authors reviewed self-created questionnaires, which asked patients for symptoms alleviation, adverse drug reactions frequency and degree of severity and daily activities self-reliance. Only surveys with complete answers, which were returned to authors by an e-mail from juvenile patients treated for NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis at the University Children’s Hospital of Cracow were analyzed. Between 2010 and 2019, 61 children were diagnosed with NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis at our department. Out of 61 requests sent, 42 complete replies (33 females, 9 males) were gathered and analyzed. All patients included in this research were administered with at least one set of Pamidronate intravenously in the dose of 1 mg/kg/day for 3 consecutive days. Our analysis shows remarkable in terms of patient’s impressions decrease of pain intensity after 2.5 series of Pamidronate on average, and total pain resolution after 5.9 series on average. Overall number of adverse drug reaction events reported by responders was 105. One patient developed drug-dependent renal insufficiency in the course of therapy. Outcome assessment indicates that nearly 50% of the studied population was more eager to participate in social life just after the first infusion of the drug. 95% of the surveyed unanimously agreed to recommend Pamidronate therapy to cure NSAIDs-refractory CRMO. 39 out of 42 (93%) patients considered Pamidronate effective at the end of the treatment. Onset of Pamidronate’s action is gradual and differs in terms of symptoms alleviation between sexes. The therapy can induce considerable number of adverse drug reactions (2.5 per patient). Only 3 out of 42 (7%) patients were free from any ADRs. To demonstrate the impact of the use of Pamidronate on daily activities more precisely, further research with quantification of the quality of life is warranted.

The impact of fibropapillomatosis on clinical characteristics, blood gas, plasma biochemistry, and hematological profiles in juvenile green turtles ( Chelonia mydas)

2020 ◽  
Vol 96 (4) ◽  
pp. 723-734
Author(s):  
Tsung-Hsien Li ◽  
Chao-Chin Chang
Keyword(s):  
White Blood Cells ◽  
Extracellular Fluid ◽  
Chelonia Mydas ◽  
Sea Turtle ◽  
Total Carbon ◽  
Blood Gas ◽  
Green Turtles ◽  
Cell Counts ◽  
Significant Difference ◽  
The Impact

Fibropapillomatosis (FP) is a tumor- forming disease that afflicts all marine turtles and is the most common in green turtles (Chelonia mydas). In this study, the morphometric characteristics, blood gas, biochemistry, and hematological profiles of 28 (6 FP-positive and 22 FP-negative) green turtles from the coast of Taiwan were investigated. The results indicated that body weight ( P < 0.001) and curved carapace length (CCL; P < 0.001) in green turtles with FP were significantly higher than in turtles without FP. Furthermore, green turtles with FP had a significantly lower value of hemoglobin (HB; P = 0.010) and packed cell volume (PCV; P = 0.005) than turtles without FP. Blood cell counts of white blood cells (WBC; P = 0.008) and lymphocytes ( P = 0.022) were observed with significant difference; green turtles with FP had lower counts than turtles without FP. In addition, turtles with FP had significantly higher pH ( P = 0.036), base excess in extracellular fluid (BEecf; P = 0.012), bicarbonate (HCO3– ; P = 0.008), and total carbon dioxide (TCO2 ; P = 0.025) values than turtles without FP. The findings of this study provide valuable clinical parameters for the medical care of the species in sea turtle rehabilitation centers and help us to understand the physiological response of green turtles to different tumor-forming conditions.

scholarly journals Polypharmacy and Malnutrition Management of Elderly Perioperative Patients with Cancer: A Systematic Review

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1961
Author(s):  
Eiji Kose ◽  
Hidetaka Wakabayashi ◽  
Nobuhiro Yasuno
Keyword(s):  
Side Effects ◽  
Cancer Cachexia ◽  
Drug Effects ◽  
Drug Efficacy ◽  
Nutritional Management ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Induced ◽  
Anabolic Resistance ◽  
Patients With Cancer ◽  
The Impact

Malnutrition, which commonly occurs in perioperative patients with cancer, leads to decreased muscle mass, hypoalbuminemia, and edema, thereby increasing the patient’s risk of various complications. Thus, the nutritional management of perioperative patients with cancer should be focused on to ensure that surgical treatment is safe and effective, postoperative complications are prevented, and mortality is reduced. Pathophysiological and drug-induced factors in elderly patients with cancer are associated with the risk of developing malnutrition. Pathophysiological factors include the effects of tumors, cachexia, and anorexia of aging. Metabolic changes, such as inflammation, excess catabolism, and anabolic resistance in patients with tumor-induced cancer alter the body’s ability to use essential nutrients. Drug-induced factors include the side effects of anticancer drugs and polypharmacy. Drug–drug, drug–disease, drug–nutrient, and drug–food interactions can significantly affect the patient’s nutritional status. Furthermore, malnutrition may affect pharmacokinetics and pharmacodynamics, potentiate drug effects, and cause side effects. This review outlines polypharmacy and malnutrition, the impact of malnutrition on drug efficacy, drug–nutrient and drug–food interactions, and intervention effects on polypharmacy or cancer cachexia in elderly perioperative patients with cancer.

Assessing the impact of health and clinical research in British Columbia health authorities

2019 ◽  
Vol 32 (6) ◽  
pp. 280-287
Author(s):  
Dawn Waterhouse ◽  
Susan Chunick ◽  
Julia Lauzon ◽  
Lupin Battersby ◽  
Terri Fleming ◽  
...  
Keyword(s):  
British Columbia ◽  
Drug Effects ◽  
Research Impact ◽  
Research Capacity ◽  
Healthcare Research ◽  
Healthcare Organizations ◽  
Health Authorities ◽  
Academic Faculty ◽  
Health Studies ◽  
The Impact

This article describes results of a healthcare research impact survey conducted in two health authorities in British Columbia. A tailored research impact framework formed the basis for the survey created and used to collect quantitative and qualitative data from a sample of employees and academic faculty who had completed research in both health authorities. In all, 178 responses were collected for a combined response rate of 34%. Although there are differences between the two health authorities, the data confirm that the majority of respondents were successful in disseminating their research; 30% of both Island and Fraser Health studies reported improved safety, whether through avoidance of adverse drug effects, or reduced nosocomial infections, and as high as 26% of studies reported a reduction in morbidity or mortality. We conclude with recommendations that build on existing research capacity infrastructure to enhance the generation, implementation, and evaluation of research evidence within healthcare organizations.

scholarly journals Mass transport of contaminated soil released into surface water by landslides (Göta River, SW Sweden)

2012 ◽  
Vol 16 (7) ◽  
pp. 1879-1893 ◽  
Author(s):  
G. Göransson ◽  
M. Larson ◽  
D. Bendz ◽  
M. Åkesson
Keyword(s):  
Surface Water ◽  
Contaminated Soil ◽  
Suspended Particle ◽  
Transport Processes ◽  
Landslide Risk ◽  
Suspended Sediment Transport ◽  
River Stretch ◽  
Landslide Mass ◽  
Exposure Pathway ◽  
The Impact

Abstract. Landslides of contaminated soil into surface water represent an overlooked exposure pathway that has not been addressed properly in existing risk analysis for landslide hazard, contaminated land, or river basin management. A landslide of contaminated soil into surface water implies an instantaneous exposure of the water to the soil, dramatically changing the prerequisites for the mobilisation and transport of pollutants. In this study, an analytical approach is taken to simulate the transport of suspended matter released in connection with landslides into rivers. Different analytical solutions to the advection-dispersion equation (ADE) were tested against the measured data from the shallow rotational, retrogressive landslide in clayey sediments that took place in 1993 on the Göta River, SW Sweden. The landslide encompassed three distinct events, namely an initial submerged slide, followed by a main slide, and a retrogressive slide. These slides generated three distinct and non-Gaussian peaks in the online turbidity recordings at the freshwater intake downstream the slide area. To our knowledge, this registration of the impact on a river of the sediment release from a landslide is one of few of its kind in the world and unique for Sweden. Considering the low frequency of such events, the data from this landslide are highly useful for evaluating how appropriate the ADE is to describe the effects of landslides into surface water. The results yielded realistic predictions of the measured variation in suspended particle matter (SPM) concentration, after proper calibration. For the three individual slides it was estimated that a total of about 0.6% of the total landslide mass went into suspension and was transported downstream. This release corresponds to about 1 to 2% of the annual suspended sediment transport for that river stretch. The studied landslide partly involved an industrial area, and by applying the analytical solution to estimate the transport of metals in the sediments, it was found that landslides may release a significant amount of pollutants if large contaminated areas are involved. However, further studies are needed to develop more detailed descriptions of the transport processes. There is also a need to increase the knowledge on possible environmental consequences in the near and far field, in a short- and long-time perspective. In summary, the release of pollutants should not be neglected in landslide risk assessments.

scholarly journals Extracellular Acid-Base Balance and Ion Transport Between Body Fluid Compartments

Physiology ◽  
2017 ◽  
Vol 32 (5) ◽  
pp. 367-379 ◽  
Author(s):  
Julian L. Seifter ◽  
Hsin-Yun Chang
Keyword(s):  
Ion Transport ◽  
Ph Regulation ◽  
Extracellular Fluid ◽  
Transport Processes ◽  
Electrolyte Balance ◽  
Ph Homeostasis ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance ◽  
Fluid Compartments

Clinical assessment of acid-base disorders depends on measurements made in the blood, part of the extracellular compartment. Yet much of the metabolic importance of these disorders concerns intracellular events. Intracellular and interstitial compartment acid-base balance is complex and heterogeneous. This review considers the determinants of the extracellular fluid pH related to the ion transport processes at the interface of cells and the interstitial fluid, and between epithelial cells lining the transcellular contents of the gastrointestinal and urinary tracts that open to the external environment. The generation of acid-base disorders and the associated disruption of electrolyte balance are considered in the context of these membrane transporters. This review suggests a process of internal and external balance for pH regulation, similar to that of potassium. The role of secretory gastrointestinal epithelia and renal epithelia with respect to normal pH homeostasis and clinical disorders are considered. Electroneutrality of electrolytes in the ECF is discussed in the context of reciprocal changes in Cl−or non Cl−anions and [Formula: see text].

scholarly journals INFRASTRUCTURE OF LOGISTIC WALKING FLOWS IN THE CONTEXT OF THE PUSH I PULL CONCEPT

2021 ◽  
Author(s):  
Lubov Lipych ◽  
Oksana Khilukha ◽  
Myroslava Kushnir
Keyword(s):  
Personal Space ◽  
Group Behavior ◽  
Transport Processes ◽  
Social Characteristics ◽  
Cultural Norms ◽  
Pull System ◽  
Safety Issues ◽  
Current State ◽  
Pedestrian Traffic ◽  
The Impact

Due to the limited safety of pedestrians, as well as the ability to direct their movement according to the established infrastructure, the analysis of the impact of factors consistent with the concept of push/pull, seems justified and useful. The aim of the article is to try to apply the concepts of push / pull in terms of the impact of logistics infrastructure on the nature of pedestrian traffic. The components of the logistics infrastructure related to the movement of the population are public roads, roads of cities and other settlements, departmental (technological) roads, roads in private areas, providing access to external and internal vehicles and passengers. The nature of pedestrian traffic is determined by the decision-making process of a certain person when moving along a certain route. It is proved that the form and result of this process are influenced by psychological and social mechanisms. It is established the main psychological and social characteristics of pedestrian traffic: maintaining personal space, as a result of which people prefer to «move for», keeping a distance of ten or several tens of centimeters; avoidance of direct impact of discomfort (psychological and physical), ie «movement from» different intensities, depending on the scale of the projected threat; minimization of efforts that cause «movement against» the shortest way; conformism (tendency to succumb to group behavior and attitude to novelty, different levels of which determine belonging to groups of innovators, early followers, early majority, late majority and conservatives); cultural norms (modification of behavior based on the influence of learned principles). The article presents models of simple situations of pedestrian traffic, which in practice demonstrate the influence of determinants of push/pull factors. It is substantiated that simulation of pedestrian traffic allows to increase its safety. Pedestrian safety issues are particularly important due to the high risk of accidents and their impact on other transport processes. However, the current state of knowledge about the determinants of the push / pull system does not yet allow such a free and comprehensive modeling.

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