A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in human RABEP2 modulates ischemic stroke outcomes.

Ischemic stroke, caused by vessel blockage, results in cerebral infarction, the death of brain tissue. Previously, quantitative trait locus (QTL) mapping of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified RAB GTPase-binding effector protein 2 (Rabep2) as the casual gene. However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice by using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 knockout ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in human RABEP2. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke.

Preliminary Evaluation of in vivo Reflectance Confocal Microscopy Features of Neonatal Lupus Erythematosus.

INTRODUCTION: Neonatal lupus erythematosus (NLE) is a rare autoimmune disease, which needs to be distinguished from eczema, congenital syphilis, and tinea corporis in newborns. Reflectance confocal microscopy (RCM) could be a helpful noninvasive diagnostic tool, which has been used to evaluate several inflammatory skin conditions. The aim of this study was to describe the RCM characteristics of NLE. METHODS: Eleven NLE patients were included in the study, and all patients were evaluated clinically with RCM. We also evaluated RCM images from 11 eczema patients as controls. RESULTS: Some major key diagnostic features of NLE can be observed by RCM: an enlarged honeycomb pattern (9/11, 81.8%), round-to-oval cyst-like structures were present (6/11, 54.5%), the normal ring-like structures were totally or partially obliterated (11/11, 100%) at the level of the dermo-epidermal junction, medium refractivity collagen fibers that were disorganized (10/11, 90.9%), numerous high refractivity round cells (11/11, 100%) in the dermis. CONCLUSION: RCM allows the visualization of major key diagnostic features of NLE and serves as a complementary diagnostic tool for NLE.

Biofunctionalization of surfaces to minimize undesirable effects in cardiovascular assistance devices.

BACKGROUND: The reactivity of blood with non-endothelial surface is a challenge for long-term Ventricular Assist Devices development, usually made with pure titanium, which despite of being inert, low density and high mechanical resistance it does not avoid the thrombogenic responses. Here we tested a modification on the titanium surface with Laser Induced Periodic Surface Structures followed by Diamond Like Carbon (DLC) coating in different thicknesses to customize the wettability profile by changing the surface energy of the titanium. METHODS: Four different surfaces were proposed: (1) Pure Titanium as Reference Material (RM), (2) Textured as Test Sample (TS), (3) Textured with DLC 0.3µm as (TSA) and (4) Textured with 2.4µm DLC as (TSB). A single implant was positioned in the abdominal aorta of Wistar rats and the effects of hemodynamic interaction were evaluated without anticoagulant drugs. RESULTS: After twelve weeks, the implants were extracted and subjected to qualitative analysis by Scanning Electron Microscopy under low vacuum and X-ray Energy Dispersion. The regions that remained in contact with the wall of the aorta showed encapsulation of the endothelial tissue. TSB implants, although superhydrophilic, have proven that the DLC coating inhibits the adhesion of biological material, prevents abrasive wear and delamination, as observed in the TS and TSA implants. Pseudo- neointimal layers were heterogeneously identified in higher concentration on Test Surfaces.

Transdermal drug delivery of rizatriptan using microneedles array patch: preparation, characterization and ex-vivo/in-vivo study.

Given the extensive first pass metabolism of rizatriptan in oral administration and its delayed absorption during a migraine attack as a result of gastric stasis, focus has been on transdermal delivery. The main purpose of this study is to prepare and assess transdermal formulation of rizatriptan, loaded on hydrogel microneedles delivery system, to avoid first pass metabolism and also improve its percutaneous permeation rate. Rizatriptan hydrogel microneedles were prepared using micromolding method and evaluated in terms of mechanical strength, encapsulation efficiency, permeation and in-vivo skin absorption. Different formulations of rizatriptan microneedles (F1-F5) were successfully prepared using different concentrations of carboxymethyl cellulose and gelatin type A. Rizatriptan hydrogel microneedles demonstrated favorable mechanical properties, including withstanding insertion forces, thereby enhancing its skin insertion ability. In permeation study, the percent cumulative drug released after 24 h ranged between 93.1-100% which means that microneedles were able to deliver the drug effectively. For in-vivo study, F3 formulation was selected due to its superior characteristics over other formulations as it exhibited the highest swelling capacity, and demonstrated favorable mechanical properties. Furthermore, F3 showcased the most controlled drug release over a 24-hour period. Relative bioavailability of F3 microneedles was 179.59% compared to oral administration based on the AUC0-24. The observed AUC0-24 in F3 microneedles was statistically significant and 1.80 times greater than that in oral administration. The higher rizatriptan level in the microneedle demonstrated adequate drug permeability through the rat skin, suggesting the potential of microneedles for enhanced therapeutic effectiveness.

Synthesis and preclinical evaluation of a selective MET kinase positron emission tomography tracer.

The tyrosine kinase MET (hepatocyte growth factor receptor) is activated or mutated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (1) formed the basis for a bioisosteric replacement, leading to the deoxyfluorinated analog [18 F]2. [18 F]2 could be synthesized with a "hydrous fluoroethylation" protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/µmol. In vitro autoradiography indicated that [18 F]2 selectively binds to MET in PC3 tumor tissue, and in vivo biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs.

Artesunate Dry Emulsion Formulation Combined with Antibiotics for Treatment of Helicobacter pylori Infections: In Vitro/In Vivo Evaluation.

Helicobacter pylori is the primary pathogen responsible for causing gastroduodenal ulcers and stomach cancer. The standard treatment for H. pylori typically involves a combination of antibiotics and acid-reducing medications. However, the recurrence of ulcers is closely linked to the emergence of antibiotic resistance in H. pylori, necessitating the development of alternative drugs. This report focuses on the investigation of artesunate as a potential alternative to reduce antibiotic use and enhance effectiveness against H. pylori. Unfortunately, commercial artesunate is available in an acid form, which has poor solubility, especially in gastric acid fluid. The aim of this study is to utilize a water-soluble formulation of artesunate called dry emulsion formulation (ADEF) and combine it with amoxicillin to eradicate H. pylori. In vitro studies were conducted to evaluate the activity of ADEF against H. pylori and determine its inhibitory concentrations. In addition, pharmacokinetic parameters of orally administered ADEF and native artesunate were investigated in rats for in vivo studies. The results showed that when combined with amoxicillin and pantoprazole, ADEF exhibited effectiveness against H. pylori. It is worth noting that the solubility of ADEF in gastric acid appears to be a critical factor for achieving successful treatment. Consequently, ADEF could be considered a promising candidate for H. pylori therapy.

The Bioavailability of Drugs-The Current State of Knowledge.

Drug bioavailability is a crucial aspect of pharmacology, affecting the effectiveness of drug therapy. Understanding how drugs are absorbed, distributed, metabolized, and eliminated in patients' bodies is essential to ensure proper and safe treatment. This publication aims to highlight the relevance of drug bioavailability research and its importance in therapy. In addition to biochemical activity, bioavailability also plays a critical role in achieving the desired therapeutic effects. This may seem obvious, but it is worth noting that a drug can only produce the expected effect if the proper level of concentration can be achieved at the desired point in a patient's body. Given the differences between patients, drug dosages, and administration forms, understanding and controlling bioavailability has become a priority in pharmacology. This publication discusses the basic concepts of bioavailability and the factors affecting it. We also looked at various methods of assessing bioavailability, both in the laboratory and in the clinic. Notably, the introduction of new technologies and tools in this field is vital to achieve advances in drug bioavailability research. This publication also discusses cases of drugs with poorly described bioavailability, providing a deeper understanding of the complex challenges they pose to medical researchers and practitioners. Simultaneously, the article focuses on the perspectives and trends that may shape the future of research regarding bioavailability, which is crucial to the development of modern pharmacology and drug therapy. In this context, the publication offers an essential, meaningful contribution toward understanding and highlighting bioavailability's role in reliable patient treatment. The text also identifies areas that require further research and exploration.

A review of nondairy kefir products: their characteristics and potential human health benefits.

Functional foods are foods that, in addition to having nutrients, contain in their composition ingredients that act specifically on body functions associated with the control and reduction of the risk of developing some diseases. In this sense, kefir, a group of microorganisms in symbiosis, mainly yeasts and lactic acid bacteria, stands out. The trend of ingesting kefir has been focused on the development of products that serve specific consumers, such as those who are lactose-intolerant, vegans and vegetarians, and consumers in general who seek to combine the consumption of functional products with the improvement of their health and lifestyle. This overview provides an insight into kefir, presenting the technological process to produce a nondairy beverage and evidence of the benefits of its use to reduce the risk of disease. We also discuss regulatory aspects of products fermented using kefir. Until now, the use of kefir (isolated microorganism, kefiran, or fermented product) has demonstrated the potential to promote an increase in the number of bifidobacteria in the colon and an increase in the glycemic control while reducing the blood cholesterol and balancing the intestinal microbiota, which helps in reducing constipation and diarrhea, improving intestinal permeability, and stimulating and balancing the immune system. However, the literature still has gaps that need to be clarified, such as the consumption dose of kefir or its products to cause some health benefit.

Nanoformulation of Seaweed Eisenia bicyclis in Albumin Nanoparticles Targeting Cardiovascular Diseases: In Vitro and In Vivo Evaluation.

Natural products, especially those derived from seaweeds, are starting to be seen as effective against various diseases, such as cardiovascular diseases (CVDs). This study aimed to design a novel oral formulation of bovine albumin serum nanoparticles (BSA NPs) loaded with an extract of Eisenia bicyclis and to validate its beneficial health effects, particularly targeting hypercholesterolemia and CVD prevention. Small and well-defined BSA NPs loaded with Eisenia bicyclis extract were successfully prepared exhibiting high encapsulation efficiency. Antioxidant activity and cholesterol biosynthesis enzyme 3-hydroxy-3 methylutaryl coenzyme A reductase (HMGR) inhibition, as well as reduction of cholesterol permeation in intestinal lining model cells, were assessed for the extract both in free and nanoformulated forms. The nanoformulation was more efficient than the free extract, particularly in terms of HMGR inhibition and cholesterol permeation reduction. In vitro cytotoxicity and in vivo assays in Wistar rats were performed to evaluate its safety and overall effects on metabolism. The results demonstrated that the Eisenia bicyclis extract and BSA NPs were not cytotoxic against human intestinal Caco-2 and liver HepG2 cells and were also safe after oral administration in the rat model. In addition, an innovative approach was adopted to compare the metabolomic profile of the serum from the animals involved in the in vivo assay, which showed the extract and nanoformulation's impact on CVD-associated key metabolites. Altogether, these preliminary results revealed that the seaweed extract and the nanoformulation may constitute an alternative natural dosage form which is safe and simple to produce, capable of reducing cholesterol levels, and consequently helpful in preventing hypercholesterolemia, the main risk factor of CVDs.

A Case Study in Breast Density Evaluation Using Bioimpedance Measurements.

(1) Background: As breast cancer studies suggest, a high percentage of breast density (PBD) may be related to breast cancer incidence. Although PBD screening is one of the strongest predictors of breast cancer risk, X-ray-based mammography evaluation is subjective. Therefore, new objective PBD measuring techniques are of interest. A case study analyzing the PBD of thirteen female participants using a bioimpedance-based method, the anomalies tracking circle (ATC), is described in this paper. (2) Methods: In the first stage, the breast bioimpedance of each participant was measured. Then, the participant breast density was determined by applying a mammogram just after the breast bioimpedance measurement stage. In the third stage, the ATC algorithm was applied to the measured bioimpedance data for each participant, and a results analysis was done. (3) Results: An ATC variation according to the breast density was observed from the obtained data, this allowed the use of classification techniques to determine the PBD. (4) Conclusions: The described breast density method is a promising approach that might be applied as an auxiliary tool to the mammography in order to obtain precise and objective results for evaluation of breast density and with that determine potential breast cancer risk.

Poloxamer 407/188 Binary Thermosensitive Gel as a Moxidectin Delivery System: In Vitro Release and In Vivo Evaluation.

Moxidectin (MXD) is an antiparasitic drug used extensively in veterinary clinics. In this study, to develop a new formulation of MXD, a thermosensitive gel of MXD (MXD-TG) was prepared based on poloxamer 407/188. Furthermore, the gelation temperature, the stability, in vitro release kinetics and in vivo pharmacokinetics of MXD-TG were evaluated. The results showed that the gelation temperature was approximately 27 °C. MXD-TG was physically stable and can be released continuously for more than 96 h in vitro. The Korsmeyer−Peppas model provided the best fit to the release kinetics, and the release mechanism followed a diffusive erosion style. MXD-TG was released persistently for over 70 days in sheep. Part of pharmacokinetic parameters had a difference in female and male sheep (p < 0.05). It was concluded that MXD-TG had a good stability, and its release followed the characteristics of a diffusive erosion style in vitro and a sustained release pattern in vivo.

Assessment of Binary Agarose-Carbopol Buccal Gels for Mucoadhesive Drug Delivery: Ex Vivo and In Vivo Characterization.

Agarose (AG) is a naturally occurring biocompatible marine seaweed extract that is converted to hydrocolloid gel in hot water with notable gel strength. Currently, its mucoadhesion properties have not been fully explored. Therefore, the main aim of this study was to evaluate the mucoadhesive potential of AG binary dispersions in combination with Carbopol 934P (CP) as mucoadhesive gel preparations. The gels fabricated via homogenization were evaluated for ex vivo mucoadhesion, swelling index (SI), dissolution and stability studies. The mucoadhesive properties of AG were concentration dependent and it was improved by the addition of CP. Maximum mucoadhesive strength (MS) (27.03 g), mucoadhesive flow time (FT) (192.2 min), mucoadhesive time in volunteers (MT) (203.2 min) and SI (23.6% at 4 h) were observed with formulation F9. The mucoadhesive time investigated in volunteers (MT) was influenced by AG concentration and was greater than corresponding FT values. Formulations containing 0.3%, w/v AG (F3 and F9) were able to sustain the release (~99%) for both drugs till 3 h. The optimized formulation (F9) did not evoke any inflammation, irritation or pain in the buccal cavity of healthy volunteers and was also stable up to 6 months. Therefore, AG could be considered a natural and potential polymer with profound mucoadhesive properties to deliver drugs through the mucosal route.

Evaluating Candida albicans biofilm formation in silkworms.

Candida albicans is a pathogenic fungus that causes deep mycosis in immunocompromised patients and forms a biofilm on catheter surfaces. Here we showed that C. albicans infection of silkworms led to biofilm formation on the surface of polyurethane fibers, a catheter substrate material, while inside the silkworm body. Silkworms inserted with polyurethane fibers survived for at least 48 hours. When silkworms inserted with polyurethane fibers were subsequently infected with C. albicans, biofilm formed on the surface of the polyurethane fiber within 24 hours in the silkworm body. These results suggest that silkworms can be used to evaluate C. albicans biofilm formation.

miR-143 Regulates Lysosomal Enzyme Transport across the Blood-Brain Barrier and Transforms CNS Treatment for Mucopolysaccharidosis Type I.

During brain maturation, cation-independent mannose-6-phosphate receptor (CI-MPR), a key transporter for lysosomal hydrolases, decreases significantly on the blood-brain barrier (BBB). Such a phenomenon leads to poor brain penetration of therapeutic enzymes and subsequent failure in reversing neurological complications in patients with neuropathic lysosomal storage diseases (nLSDs), such as Hurler syndrome (severe form of mucopolysaccharidosis type I [MPS I]). In this study, we discover that upregulation of microRNA-143 (miR-143) contributes to the decline of CI-MPR on the BBB during development. Gain- and loss-of-function studies showed that miR-143 inhibits CI-MPR expression and its transport function in human endothelial cells in vitro. Genetic removal of miR-143 in MPS I mice enhances CI-MPR expression and improves enzyme transport across the BBB, leading to brain metabolic correction, pathology normalization, and correction of neurological functional deficits 5 months after peripheral protein delivery at clinically relevant levels that derived from erythroid/megakaryocytic cells via hematopoietic stem cell-mediated gene therapy, when otherwise no improvement was observed in MPS I mice at a parallel setting. These studies not only uncover a novel role of miR-143 as an important modulator for the developmental decline of CI-MPR on the BBB, but they also demonstrate the functional significance of depleting miR-143 for "rescuing" BBB-anchored CI-MPR on advancing CNS treatment for nLSDs.

Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent.

(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC90 = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8 g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.

Fucoidan from Ascophyllum nodosum Suppresses Postprandial Hyperglycemia by Inhibiting Na+/Glucose Cotransporter 1 Activity.

We previously demonstrated that fucoidan with a type II structure inhibited postprandial hyperglycemia by suppressing glucose uptake, but the mechanism remains elusive. Here, we aimed to assess whether the effect of glucose absorption inhibition was related to the basic structure of fucoidans and preliminarily clarified the underlying mechanism. Fucoidans with type II structure and type I structure were prepared from Ascophyllumnodosum (AnF) or Laminariajaponica (LjF) and Kjellmaniellacrassifolia (KcF), respectively. The effects of various fucoidans on suppressing postprandial hyperglycemia were investigated using in vitro (Caco-2 monolayer model), semi-in vivo (everted gut sac model), and in vivo (oral glucose tolerance test, OGTT) assays. The results showed that only AnF with a type II structure, but not LjF or KcF with type I structure, could inhibit the glucose transport in the Caco-2 monolayer and everted gut sac models. A similar result was seen in the OGTT of Kunming mice and leptin receptor-deficient (db/db) mice, where only AnF could effectively inhibit glucose transport into the bloodstream. Furthermore, AnF (400 mg/kg/d) treatment decreased the fasting blood glucose, HbA1c, and fasting insulin levels, while increasing the serum glucagon-like peptide-1 (GLP-1) level in obese leptin receptor-deficient (db/db) mice. Furthermore, surface plasmon resonance (SPR) analysis revealed the specific binding of AnF to Na+/glucose cotransporter 1 (SGLT1), which indicated the effect of AnF on postprandial hyperglycemia could be due to its suppression on SGLT1 activity. Taken together, this study suggests that AnF with a type II structure can be a promising candidate for hyperglycemia treatment.

New supersaturating drug delivery system as strategy to improve apparent solubility of candesartan cilexetil in biorelevant medium.

Candesartan cilexetil (CC) is a poorly soluble antihypertensive drug with in vivo absorption limited by its low aqueous solubility. Aiming to generate CC supersaturation as strategy to improve its absorption and bioavailability, amorphous solid dispersions (ASDs) of CC with hydroxypropylmethylcellulose acetate succinate type M (HPMCAS M) were developed and evaluated by in vitro and in vivo techniques. The ASDs were characterized by several solid-state techniques and evaluated regarding the supersaturation generation and maintenance under non-sink conditions in biorelevant medium. Stability studies at different storage conditions and in vivo pharmacodynamics studies were performed for the best formulation. The ASD developed presented appropriate drug amorphization, confirmed by solid state characterization, and CC apparent solubility increases around 85 times when compared to the pure crystalline drug. Supersaturation was maintained for up to 24 h in biorelevant medium. The in vivo pharmacodynamics studies revealed that ASD of CC with the polymer HPMCAS M presented an onset of action about four times faster when compared to the pure crystalline drug. The CC-HPMCAS ASD were successfully developed and demonstrated good physical stability under different storage conditions as well as promising results that indicated the ASD potential for improvement of CC biopharmaceutical properties.

Development of Valsartan Floating Matrix Tablets Using Low Density Polypropylene Foam Powder: In vitro and In vivo Evaluation.

The main purpose of the study was to develop valsartan floating tablets (VFT) via non-effervescent technique using low density polypropylene foam powder, carbopol, and xanthan gum by direct compression. Before compression, the particulate powdered mixture was evaluated for pre-compression parameters. The prepared valsartan tablets were evaluated for post-compression parameters, swelling index, floating lag time, in vitro buoyancy studies, and in vitro and in vivo X-ray imaging studies in albino rabbits. The result of all formulations for pre- and post-compression parameters were within the limits of USP. FTIR and DSC studies revealed no interaction between the drug and polymers used. The prepared floating tablets had good swelling and floating capabilities for more than 12 h with zero floating lag time. The release of valsartan from optimized formulation NF-2 showed sustained release up to 12 h; which was found to be non-Fickian release. Moreover, the X-ray imaging of optimized formulation (NF-2) revealed that tablet was constantly floating in the stomach region of the rabbit, thereby indicating improved gastric retention time for more than 12 h. Consequently, all the findings and outcomes have showed that developed valsartan matrix tablets could be effectively used for floating drug delivery system.

In Vitro Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice.

Influenza viruses of the H1N1, H2N2, and H3N2 subtypes have caused previous pandemics. H2 influenza viruses represent a pandemic threat due to continued circulation in wild birds and limited immunity in the human population. In the event of a pandemic, antiviral agents are the mainstay for treatment, but broadly neutralizing antibodies (bNAbs) may be a viable alternative for short-term prophylaxis or treatment. The hemagglutinin stem binding bNAbs CR6261 and CR9114 have been shown to protect mice from severe disease following challenge with H1N1 and H5N1 and with H1N1, H3N2, and influenza B viruses, respectively. Early studies with CR6261 and CR9114 showed weak in vitro activity against human H2 influenza viruses, but the in vivo efficacy against H2 viruses is unknown. Therefore, we evaluated these antibodies against human- and animal-origin H2 viruses A/Ann Arbor/6/1960 (H2N2) (AA60) and A/swine/MO/4296424/06 (H2N3) (Sw06). In vitro, CR6261 neutralized both H2 viruses, while CR9114 only neutralized Sw06. To evaluate prophylactic efficacy, mice were given CR6261 or CR9114 and intranasally challenged 24 h later with lethal doses of AA60 or Sw06. Both antibodies reduced mortality, weight loss, airway inflammation, and pulmonary viral load. Using engineered bNAb variants, antibody-mediated cell cytotoxicity reporter assays, and Fcγ receptor-deficient (Fcer1g-/-) mice, we show that the in vivo efficacy of CR9114 against AA60 is mediated by Fcγ receptor-dependent mechanisms. Collectively, these findings demonstrate the in vivo efficacy of CR6261 and CR9114 against H2 viruses and emphasize the need for in vivo evaluation of bNAbs.IMPORTANCE bNAbs represent a strategy to prevent or treat infection by a wide range of influenza viruses. The evaluation of these antibodies against H2 viruses is important because H2 viruses caused a pandemic in 1957 and could cross into humans again. We demonstrate that CR6261 and CR9114 are effective against infection with H2 viruses of both human and animal origin in mice, despite the finding that CR9114 did not display in vitro neutralizing activity against the human H2 virus. These findings emphasize the importance of in vivo evaluation and testing of bNAbs.

Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the Challenge of Preclinical to Clinical Translation.

Topical delivery of therapeutics to the posterior segment of the eye remains the "holy grail" of ocular drug delivery. As an example, anti-vascular endothelial growth factor biologics, such as ranibizumab, aflibercept, and bevacizumab, are delivered by intravitreal injection to treat neovascular age-related macular degeneration and, although these drugs have revolutionized treatment of the disease, less invasive alternatives to intravitreal injection are desired. Multiple reports in the literature have demonstrated topical delivery of both small and large molecules to the back of the eye in small animal models. Despite this progress, successful translation to larger species, and ultimately humans, has yet to be demonstrated. Selection of animal models with relevant ocular anatomy and physiology, along with appropriate experimental design, is critical to enable more relevant feasibility assessments and increased probability of successful translation.