Enhanced Transdermal Peptide Delivery and Stability by Lipid Conjugation: Epidermal Permeation,Stereoselectivity and Mechanistic Insights

Purpose

Efficient delivery of therapeutic peptides to the skin will facilitate better outcomes in dermatology. The tetrapeptide AAPV, an elastase inhibitor with potential utility in the management of psoriasis was coupled to short chain lipoamino acids (Laa: C6-C10) to enhance the peptide permeation into and through human epidermis.

Methods

AAPV was conjugated to Laas by solid phase synthesis. Peptide stability, skin distribution and permeation, elastase activity and surface activity were determined.

Results

Laas increased peptide permeation into the skin. The permeation lag time and amount of peptide remaining in the skin increased with the carbon chain length of the Laa conjugate. We also demonstrated stereoselective permeation enhancement in favour of the D-diastereomer. Importantly, the elastase inhibition activity of the peptide was largely retained after coupling to the Laa conjugates, showing potential therapeutic utility. The Laa-peptide structures were shown to be surface active, suggesting that this surfactant-like activity coupled with enhanced lipophilicity may contribute to their interaction with and permeation through the lipid domains of the stratum corneum.

Conclusions

This study suggests that the Laa conjugation approach may be useful for enhancing the permeation of moderately sized peptide drugs with potential application in the treatment of skin disorders.     

Use of a glyphosate-based herbicide-induced nephrotoxicity model to investigate a panel of kidney injury biomarkers

Accidental or intentional ingestion of glyphosate surfactant-based herbicides, like Roundup^®, leads to nephrotoxicity as well as death. In this study, a panel of kidney injury biomarkers was evaluated in terms of suitability to detect acute kidney injury and dysfunction. The Roundup^® intoxication model involved oral administration of glyphosate to rats at dose levels of 250, 500, 1200 and 2500 mg/kg. Urinary and plasma biomarker patterns were investigated at 8, 24 and 48 h after dosing. Biomarkers were quantified by absolute concentration; by normalising to urine creatinine; and by calculating the excretion rate. The diagnostic performances of each method in predicting of acute kidney injury were compared. By Receiver Operating Characteristic (ROC) analysis of the selected biomarkers, only urinary kidney injury molecule-1 (KIM-1) best predicted histological changes at 8 h (best cut-off point > 0.00029 μg/ml). Plasma creatinine performed better than other biomarkers at 24 h (best cut-off point > 0.21 mg/dl). Urinary KIM-1 was the best early biomarker of kidney injury in this glyphosate-induced nephrotoxicity model.     

Concentration Dependent Viscosity of Monoclonal Antibody Solutions: Explaining Experimental Behavior in Terms of Molecular Properties

Purpose

Early identification of monoclonal antibody candidates whose development, as high concentration (≥100 mg/mL) drug products, could prove challenging, due to high viscosity, can help define strategies for candidate engineering and selection.

Methods

Concentration dependent viscosities of 11 proprietary mAbs were measured. Sequence and structural features of the variable (Fv) regions were analyzed to understand viscosity behavior of the mAbs. Coarse-grained molecular simulations of two problematic mAbs were compared with that of a well behaved mAb.

Results

Net charge, ξ-potential and pI of Fv regions were found to correlate with viscosities of highly concentrated antibody solutions. Negative net charges on the Fv regions of two mAbs with poor viscosity behaviors facilitate attractive self-associations, causing them to diffuse slower than a well-behaved mAb with positive net charge on its Fv region. An empirically derived equation that connects aggregation propensity and pI of the Fv region with high concentration viscosity of the whole mAb was developed.

Conclusions

An Fv region-based qualitative screening profile was devised to flag mAb candidates whose development, as high concentration drug products, could prove challenging. This screen can facilitate developability risk assessment and mitigation strategies for antibody based therapeutics via rapid high throughput material-free screening.     

社会、经济与环境因素对老年健康和死亡的影响——基于中国22省份的抽样调查

基于全国22省市886个县15 973位老人2002—2005年跟踪调查数据,本文应用多水平多元logit模型,对社会、经济和环境因素对老年健康和死亡的影响进行了分析。结果表明,控制了个人层面相关变量后,空气污染显著增加了老人ADL（日常生活自理能力）残障、认知功能差与累计健康亏损指数上升的可能性。降雨量的增加则显著降低了老人ADL残障和认知功能差的风险。极低的气温显著增加了老人ADL残障的风险与死亡风险,而极高的气温显著增加了老人认知功能差和累计健康亏损指数上升的可能性。居住在山区的老人ADL残障风险较低,累计健康亏损指数亦较低。此外,人均GDP、15～64岁人口的劳动参与率以及文盲率对中国老年人的生理健康、心理健康、整体健康水平以及死亡风险有显著的、作用方向不同的影响。最后,得出如下结论：保护自然环境、改善社会经济状况的干预措施将有利于改善老人健康、降低老人死亡风险。     

Hepatitis C Virus Epitope Immunodominance and B Cell Repertoire Diversity

Despite the advent of effective, curative treatments for hepatitis C virus (HCV), a preventative vaccine remains essential for the global elimination of HCV. It is now clear that the induction of broadly neutralising antibodies (bNAbs) is essential for the rational design of such a vaccine. This review details the current understanding of epitopes on the HCV envelope, characterising the potency, breadth and immunodominance of antibodies induced against these epitopes, as well as describing the interactions between B-cell receptors and HCV infection, with a particular focus on bNAb heavy and light chain variable gene usage. Additionally, we consider the importance of a public repertoire for antibodies against HCV, compiling current knowledge and suggesting that further research in this area may be critical to the rational design of an effective HCV vaccine.     

Anatomic predictors of recurrence after cryoablation for atrial fibrillation: a computed tomography based composite score

Journal of Interventional Cardiac Electrophysiology - Effective pulmonary vein isolation (PVI) with cryoablation depends on adequate occlusion of pulmonary veins (PV) by the cryoballoon and is...