The presence of a blood-brain barrier (BBB) and a blood-cerebrospinal fluid barrier presents a huge challenge for effective delivery of therapeutics to the central nervous system (CNS). Many ...potential drugs, which are effective at their site of action, have failed and have been discarded during their development for clinical use due to a failure to deliver them in sufficient quantity to the CNS. In consequence, many diseases of the CNS are undertreated. In recent years, it has become clear that the blood-CNS barriers are not only anatomical barriers to the free movement of solutes between blood and brain but also transport and metabolic barriers. The cell association, sometimes called the neurovascular unit, constitutes the BBB and is now appreciated to be a complex group of interacting cells, which in combination induce the formation of a BBB. The various strategies available and under development for enhancing drug delivery to the CNS are reviewed.
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier to the free diffusion of many polar solutes into the brain. Many metabolites that are ...polar have their brain entry facilitated by specific inwardly-directed transport mechanisms. In general the more lipid soluble a molecule or drug is, the more readily it will tend to partition into brain tissue. However, a very significant number of lipid soluble molecules, among them many useful therapeutic drugs have lower brain permeability than would be predicted from a determination of their lipid solubility. These molecules are substrates for the ABC efflux transporters which are present in the BBB and BCSB and the activity of these transporters very efficiently removes the drug from the CNS, thus limiting brain uptake. P-glycoprotein (Pgp) was the first of these ABC transporters to be described, followed by the multidrug resistance-associated proteins (MRP) and more recently breast cancer resistance protein (BCRP). All are expressed in the BBB and BCSFB and combine to reduce the brain penetration of many drugs. This phenomenon of "multidrug resistance" is a major hurdle when it comes to the delivery of therapeutics to the brain, not to mention the problem of cancer chemotherapy in general. Therefore, the development of strategies for bypassing the influence of these ABC transporters and for the design of effective drugs that are not substrates and the development of inhibitors for the ABC transporters becomes a high imperative for the pharmaceutical industry.
Abstract Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the ...blood–brain barrier (BBB), blood–CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood–CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.
This study aimed to describe how video laryngoscopy is used outside the operating room within the hospital setting. Specifically, we aimed to summarise the evidence for the use of video laryngoscopy ...outside the operating room, and detail how it appears in current clinical practice guidelines. A literature search was conducted across two databases (MEDLINE and Embase), and all articles underwent screening for relevance to our aims and pre-determined exclusion criteria. Our results include 14 clinical practice guidelines, 12 interventional studies, 38 observational studies. Our results show that video laryngoscopy is likely to improve glottic view and decrease the incidence of oesophageal intubations; however, it remains unclear as to how this contributes to first-pass success, overall intubation success and clinical outcomes such as mortality outside the operating room. Furthermore, our results indicate that the appearance of video laryngoscopy in clinical practice guidelines has increased in recent years, and particularly through the COVID-19 pandemic. Current COVID-19 airway management guidelines unanimously introduce video laryngoscopy as a first-line (rather than rescue) device.
Summary
Worldwide, about 65 million people are estimated to have epilepsy. Epidemiologic studies are necessary to define the full public health burden of epilepsy; to set public health and health ...care priorities; to provide information needed for prevention, early detection, and treatment; to identify education and service needs; and to promote effective health care and support programs for people with epilepsy. However, different definitions and epidemiologic methods complicate the tasks of these studies and their interpretations and comparisons. The purpose of this document is to promote consistency in definitions and methods in an effort to enhance future population‐based epidemiologic studies, facilitate comparison between populations, and encourage the collection of data useful for the promotion of public health. We discuss: (1) conceptual and operational definitions of epilepsy, (2) data resources and recommended data elements, and (3) methods and analyses appropriate for epidemiologic studies or the surveillance of epilepsy. Variations in these are considered, taking into account differing resource availability and needs among countries and differing purposes among studies.
Mucopolysaccharidosis (MPS) disorders are caused by deficiencies in lysosomal enzymes, leading to impaired glycosaminoglycan (GAG) degradation. The resulting GAG accumulation in cells and connective ...tissues ultimately results in widespread tissue and organ dysfunction. The seven MPS types currently described are heterogeneous and progressive disorders, with somatic and neurological manifestations depending on the type of accumulating GAG. Heparan sulfate (HS) is one of the GAGs stored in patients with MPS I, II, and VII and the main GAG stored in patients with MPS III. These disorders are associated with significant central nervous system (CNS) abnormalities that can manifest as impaired cognition, hyperactive and/or aggressive behavior, epilepsy, hydrocephalus, and sleeping problems. This review discusses the anatomical and pathophysiological CNS changes accompanying HS accumulation as well as the mechanisms believed to cause CNS abnormalities in MPS patients. The content of this review is based on presentations and discussions on these topics during a meeting on the brain in MPS attended by an international group of MPS experts.
The brain is in many ways an immunologically and pharmacologically privileged site. The blood–brain barrier (BBB) of the cerebrovascular endothelium and its participation in the complex structure of ...the neurovascular unit (NVU) restrict access of immune cells and immune mediators to the central nervous system (CNS). In pathologic conditions, very well-organized immunologic responses can develop within the CNS, raising important questions about the real nature and the intrinsic and extrinsic regulation of this immune privilege. We assess the interactions of immune cells and immune mediators with the BBB and NVU in neurologic disease, cerebrovascular disease, and intracerebral tumors. The goals of this review are to outline key scientific advances and the status of the science central to both the neuroinflammation and CNS barriers fields, and highlight the opportunities and priorities in advancing brain barriers research in the context of the larger immunology and neuroscience disciplines. This review article was developed from reports presented at the 2011 Annual Blood-Brain Barrier Consortium Meeting.
Understanding mechanisms associated with flavonoid neuroprotection is complicated by the lack of information on their ability to enter the CNS. This study examined naringenin and quercetin ...permeability across the blood–brain barrier (BBB), using in vitro (ECV304/C6 coculture) and in situ (rat) models. We report measurable permeabilities (
P
app) for both flavonoids across the in vitro BBB model, consistent with their lipophilicity. Both flavonoids showed measurable in situ BBB permeability. The rates of uptake (
K
in) into the right cerebral hemisphere were 0.145 and 0.019 ml min
−1 g
−1 for naringenin and quercetin, respectively. Quercetin
K
in was comparable to that of colchicine (0.006 ml min
−1 g
−1), a substrate for P-glycoprotein (P-gp). Preadministration of the P-gp inhibitor PSC833 or GF120918 (10 mg/kg body wt) significantly increased colchicine
K
in, but only GF120918 (able to inhibit breast cancer resistance protein, BCRP) affected
K
in for quercetin. Naringenin
K
in was not affected. The influence of efflux transporters on flavonoid permeability at the BBB was further studied using MDCK-MDR1 and immortalized rat brain endothelial cells (RBE4). Colchicine, quercetin, and naringenin all showed measurable accumulation (distribution volume,
V
d (μl/mg protein)) in both cell types. The
V
d for colchicine increased significantly in both cell lines following coincubation with either PSC833 (25 μM) or GF120918 (25 μM). Both inhibitors also caused an increase in naringenin
V
d; by contrast only GF120918 coincubation significantly increased quercetin
V
d. In conclusion, the results demonstrate that flavonoids are able to traverse the BBB in vivo. However, the permeability of certain flavonoids in vivo is influenced by their lipophilicity and interactions with efflux transporters.
Thrombocytopenia is a common medical problem for which the main treatment is platelet transfusion. Given the increasing use of platelets and the declining donor population, identification of a safe ...and effective platelet growth factor could improve the management of thrombocytopenia. Thrombopoietin (TPO), the c-Mpl ligand, is the primary physiologic regulator of megakaryocyte and platelet development. Since the purification of TPO in 1994, 2 recombinant forms of the c-Mpl ligand—recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF)—have undergone extensive clinical investigation. Both have been shown to be potent stimulators of megakaryocyte growth and platelet production and are biologically active in reducing the thrombocytopenia of nonmyeloablative chemotherapy. However, neither TPO has demonstrated benefit in stem cell transplantation or leukemia chemotherapy. Other clinical studies have investigated the use of TPO in treating chronic nonchemotherapy-induced thrombocytopenia associated with myelodysplastic syndromes, idiopathic thrombocytopenic purpura, thrombocytopenia due to human immunodeficiency virus, and liver disease. Based solely on animal studies, TPO may be effective in reducing surgical thrombocytopenia and bleeding, ex vivo expansion of pluripotent stem cells, and as a radioprotectant. Ongoing and future studies will help define the clinical role of recombinant TPO and TPO mimetics in the treatment of chemotherapy- and nonchemotherapy-induced thrombocytopenia.
The restrictive nature of the blood-brain barrier means that cellular machinery must be in place to deliver macromolecules to the brain. This is achieved by transcytosis which is more complex than ...initially supposed, both in terms of structure and regulation. Brain endothelial cells have relatively few pinocytotic vesicles compared to peripheral endothelia but can still deliver macromolecules via one of the three main types of vesicles: the most numerous clathrin-coated vesicles containing adaptor protein complex-2, the smaller caveolae formed from lipid raft domains of the plasma membrane, and the large fluid engulfing macropinocytotic vesicles. Both clathrin-coated vesicles and, to a lesser extent caveolae, endocytose plasma membrane receptors and their specific ligands which include insulin, transferrin, and lipoproteins. This receptor-mediated transcytosis (RMT) delivers the ligands to the brain and enables their receptors to be recycled back to the plasma membrane. However, once endocytosed, the ligands and/or receptors must be directed toward the correct plasma membrane and avoid degradation. How this is achieved has not been well studied although there is an important role for Rab GTPases in targeting vesicles to their correct location and enabling exocytosis. In this chapter, we discuss what is known about regulation of transcytosis in related cells such as the MDCK cell line and where are the gaps in our knowledge of brain endothelial transcytotic regulation. We discuss how RMT has been exploited to deliver therapeutic drugs to the brain and the importance of further investigation in this area to improve drug delivery.
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