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Crossing the Blood–Brain Barrier: Recent Advances in Drug Delivery to the Brain
CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood–brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.
Journal Article
الطب والأبحاث العلمية
أصبحت التقنيات الحديثة كالحواسيب والهواتف الجوالة والبطاقات الذكية والتقنيات البيولوجية والأبحاث الجينية تؤثر بشكل كبير على الطريقة التي ننهج فيها حياتنا في مطلع القرن 21 ومحاطين بهذه المجموعة المذهلة من التقنيات الحديثة أصبح من السهل أن نتوه فيها. من هنا تأتي أهمية سلسلة \"التطورات العلمية في القرن 21\" المبنية على المقالات الشهيرة التي نشرت أساسا في مجلة Scientific American والتي تهدف إلى رصد أسرار التكنولوجيات المعقدة التي تشكل عالمنا الحديث وتسيره وكشف طرق عملها. كما تهدف أيضا إلى تسليط الضوء على عالم التقنيات الحديثة، حيث تأخذك مستعينة بالرسوم المذهلة الفوتوغرافية الدقيقة إضافة إلى النصوص الموثوقة والسهلة الفهم، إلى عالم التقنيات الملموسة والغير ملموسة، بدءا من منزلك ووصولا إلى الفضاء الخارجي، حيث يتم الكشف عن طريقة عمل مجموعة كبيرة من الأشياء والأنظمة، من البطاقات الذكية والساعات الذرية إلى التصوير الرقمي الطبي والأفلام الرقمية وذلك على صفحات ملونة كاملة الوضوح وفي هذا الكتاب \"الطب والأبحاث العلمية\" سيتم شرح أكثر من 19 موضوعا تدور حول الطب والأبحاث العلمية بكلمات مبسطة وبصور فوتوغرافية ثلاثية الأبعاد عالية الدقة وذلك بعد تدوينه لمقدمة قصيرة عن كل موضوع ؛ قدم فيها وصفا عاما للتقنية أو الشيء قد الشرح ؛ هذا بالإضافة إلى التعريف بآخر التطورات والاختراعات في حقل الطب وذلك ليكشف للقارئ عن أحدث طرق التشخيص وأساليب العلاج والعقاقير وبشكل عام يحتوي هذا الكتاب على رصيد للموضوعات التالية : الصوت الفائق، الأشعة السينية والمسح الشعاعي الطبقي المبرمج، التصوير بالرنين المغناطيسي والمسح بابتعاث البوزترون، تصميم العقاقير الحديثة، أساليب إيصال الدواء، الجراحة بالمنظار الداخلي، صناعة السيراميك (الخزف)، تكنولوجيا زراعة الأعضاء، الروابط، الهندسة الوراثية، مشروع المجين البشري، تكنولوجيا تقدير الأعمار، الاستكشاف الجيولوجي الليزر، التصوير، التجسيمي (الهولوغرام)، الساعة الذرية، المجاهر الإلكترونية، التلسكوبات البصرية، معجلات الجسيمات.
Book
New Drug Delivery Systems Developed for Brain Targeting
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (B
CSF
) are two of the most complex and sophisticated concierges that defend the central nervous system (CNS) by numerous mechanisms. While they maintain the neuro-ecological homeostasis through the regulated entry of essential biomolecules, their conservative nature challenges the entry of most of the drugs intended for CNS delivery. Targeted delivery challenges for a diverse spectrum of therapeutic agents/drugs (non-small molecules, small molecules, gene-based therapeutics, protein and peptides, antibodies) are diverse and demand specialized delivery and disease-targeting strategies. This review aims to capture the trends that have shaped the current brain targeting research scenario. This review discusses the physiological, neuropharmacological, and etiological factors that participate in the transportation of various drug delivery cargoes across the BBB/B
CSF
and influence their therapeutic intracranial concentrations. Recent research works spanning various invasive, minimally invasive, and non-invasive brain- targeting approaches are discussed. While the pre-clinical outcomes from many of these approaches seem promising, further research is warranted to overcome the translational glitches that prevent their clinical use. Non-invasive approaches like intranasal administration, P-glycoprotein (P-gp) inhibition, pro-drugs, and carrier/targeted nanocarrier-aided delivery systems (alone or often in combination) hold positive clinical prospects for brain targeting if explored further in the right direction.
Journal Article
Childhood Intussusception: A Literature Review
Postlicensure data has identified a causal link between rotavirus vaccines and intussusception in some settings. As rotavirus vaccines are introduced globally, monitoring intussusception will be crucial for ensuring safety of the vaccine programs.
To obtain updated information on background rates and clinical management of intussusception, we reviewed studies of intussusception in children <18 years of age published since 2002. We assessed the incidence of intussusception by month of life among children <1 year of age, seasonality, method of diagnosis, treatment, and case-fatality.
We identified 82 studies from North America, Asia, Europe, Oceania, Africa, Eastern Mediterranean, and Central & South America that reported a total of 44,454 intussusception events. The mean incidence of intussusception was 74 per 100,000 (range: 9-328) among children <1 year of age, with peak incidence among infants 5-7 months of age. No seasonal patterns were observed. A radiographic modality was used to diagnose intussusception in over 95% of the cases in all regions except Africa where clinical findings or surgery were used in 65% of the cases. Surgical rates were substantially higher in Africa (77%) and Central and South America (86%) compared to other regions (13-29%). Case-fatality also was higher in Africa (9%) compared to other regions (<1%). The primary limitation of this review relates to the heterogeneity in intussusception surveillance across different regions.
This review of the intussusception literature from the past decade provides pertinent information that should facilitate implementation of intussusception surveillance for monitoring the postlicensure safety of rotavirus vaccines.
Journal Article
Effect of Hospital Volume on Outcomes of Transcatheter Aortic Valve Implantation
Transcatheter aortic valve implantation (TAVI) is associated with a significant learning curve. There is paucity of data regarding the effect of hospital volume on outcomes after TAVI. This is a cross-sectional study based on Healthcare Cost and Utilization Project's Nationwide Inpatient Sample database of 2012. Subjects were identified by International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes, 35.05 (Trans-femoral/Trans-aortic Replacement of Aortic Valve) and 35.06 (Trans-apical Replacement of Aortic Valve). Annual hospital TAVI volumes were calculated using unique identification numbers and then divided into quartiles. Multivariate logistic regression models were created. The primary outcome was inhospital mortality; secondary outcome was a composite of inhospital mortality and periprocedural complications. Length of stay (LOS) and cost of hospitalization were assessed. The study included 1,481 TAVIs (weighted n = 7,405). Overall inhospital mortality rate was 5.1%, postprocedural complication rate was 43.4%, median LOS was 6 days, and median cost of hospitalization was $51,975. Inhospital mortality rates decreased with increasing hospital TAVI volume with a rate of 6.4% for lowest volume hospitals (first quartile), 5.9% (second quartile), 5.2% (third quartile), and 2.8% for the highest volume TAVI hospitals (fourth quartile). Complication rates were significantly higher in hospitals with the lowest volume quartile (48.5%) compared to hospitals in the second (44.2%), third (39.7%), and fourth (41.5%) quartiles (p <0.001). Increasing hospital volume was independently predictive of shorter LOS and lower hospitalization costs. In conclusion, higher annual hospital volumes are significantly predictive of reduced postprocedural mortality, complications, shorter LOS, and lower hospitalization costs after TAVI.
Journal Article
Leptogenesis and fermion mass fit in a renormalizable SO(10) model
A
bstract
A non-supersymmetric renormalizable SO(10) model is investigated for its viability in explaining the observed fermion masses and mixing parameters along with the baryon asymmetry produced via thermal leptogenesis. The Yukawa sector of the model consists of complex 10
H
and
126
¯
H
scalars with a Peccei-Quinn like symmetry and it leads to strong correlations among the Yukawa couplings of all the standard model fermions including the couplings and masses of the right-handed (RH) neutrinos. The latter implies the necessity to include the second lightest RH neutrino and flavor effects for the precision computation of leptogenesis. We use the most general density matrix equations to calculate the temperature evolution of flavoured leptonic asymmetry. A simplified analytical solution of these equations, applicable to the RH neutrino spectrum predicted in the model, is also obtained which allows one to fit the observed baryon to photon ratio along with the other fermion mass observables in a numerically efficient way. The analytical and numerical solutions are found to be in agreement within a factor of
O
1
. We find that the successful leptogenesis in this model does not prefer any particular value for leptonic Dirac and Majorana CP phases and the entire range of values of these observables is found to be consistent. The model specifically predicts (a) the lightest neutrino mass
m
v
1
between 2–8 meV, (b) the effective mass of neutrinoless double beta decay
m
ββ
between 4–10 meV, and (c) a particular correlation between the Dirac and one of the Majorana CP phases.
Journal Article
Gender, Race, and Health Insurance Status in Patients Undergoing Catheter Ablation for Atrial Fibrillation
Catheter ablation for atrial fibrillation (AF) has emerged as a popular procedure. The purpose of this study was to examine whether there exist differences or disparities in ablation utilization across gender, socioeconomic class, insurance, or race. Using the Nationwide Inpatient Sample (2000 to 2012), we identified adults hospitalized with a principal diagnosis of AF by ICD 9 code 427.31 who had catheter ablation (ICD 9 code–37.34). We stratified patients by race, insurance status, age, gender, and hospital characteristics. A hierarchical multivariate mixed-effect model was created to identify the independent predictors of AF ablation. Among an estimated total of 3,508,122 patients (extrapolated from 20% Nationwide Inpatient Sample) hospitalized with a diagnosis of AF in the United States from the year 2000 to 2012, 102,469 patients (2.9%) underwent catheter ablations. The number of ablations was increased by 940%, from 1,439 in 2000 to 15,090 in 2012. There were significant differences according to gender, race, and health insurance status, which persisted even after adjustment for other risk factors. Female gender (0.83 [95% CI 0.79 to 0.87; p <0.001]), black (0.49 [95% CI 0.44 to 0.55; p <0.001]), and Hispanic race (0.64 [95% CI 0.56 to 0.72; p <0.001]) were associated with lower likelihoods of undergoing an AF ablation. Medicare (0.93, 0.88 to 0.98, <0.001) or Medicaid (0.67, 0.59 to 0.76, <0.001) coverage and uninsured patients (0.55, 0.49 to 0.62, <0.001) also had lower rates of AF ablation compared to patients with private insurance. In conclusion we found differences in utilization of catheter ablation for AF based on gender, race, and insurance status that persisted over time.
Journal Article
Gauged SU(3)F and loop induced quark and lepton masses
A
bstract
We investigate a local SU(3)
F
flavour symmetry for its viability in generating the masses for the quarks and charged leptons of the first two families through radiative corrections. Only the third-generation fermions get tree-level masses due to specific choice of the field content and their gauge charges. Unprotected by symmetry, the remaining fermions acquire non-vanishing masses through the quantum corrections induced by the gauge bosons of broken SU(3)
F
. We show that inter-generational hierarchy between the masses of the first two families arises if the flavour symmetry is broken with an intermediate SU(2) leading to a specific ordering in the masses of the gauge bosons. Based on this scheme, we construct an explicit and predictive model and show its viability in reproducing the realistic charged fermion masses and quark mixing parameters in terms of not-so-hierarchical fundamental couplings. The model leads to the strange quark mass,
m
s
≈ 16 MeV at
M
Z
, which is ~2
.
4
σ
away from its current central value. Large flavour violations are a generic prediction of the scheme which pushes the masses of the new gauge bosons to 10
3
TeV or higher.
Journal Article
Electroweak triplet scalar contribution to SO(10) leptogenesis
A
bstract
We show that electroweak triplet scalar can significantly impact baryogenesis via leptogenesis in concrete and predictive SO(10) GUTs, even when light neutrino masses arise predominantly from the type-I seesaw mechanism. This is illustrated within a minimal renormalisable SO(10) model with
10
and
126
¯
scalars in the Yukawa sector and a global Peccei-Quinn-like symmetry. The quark-lepton unification and the flavour structure of the fundamental Yukawa couplings enforce type-I dominance in the light neutrino masses, also suppressing the triplet-induced CP asymmetries in the right-handed neutrino decays. However, the triplet’s own decays introduce a new CP-violating source, which can enhance or suppress the total baryon asymmetry. For triplet mass near the right-handed neutrino mass scale, this contribution can dominate, making it essential in assessing the viability of SO(10) leptogenesis scenarios.
Journal Article