Skin permeability data: anomalous results

Analysis of published skin permeation data has shown that a few compounds appear to have anomalous skin permeability coefficients. These include penetrants such as naproxen, atropine and nicotine. The permeabilities of these materials were re-determined together with aspirin, benzoic acid, diclofenac, ibuprofen and methyl nicotinate. The results are discussed in conjunction with published regression analyses and compared with values predicted by estimating the octanol–water partition coefficients using commercial software packages.     

草乌甲素脂质体的皮肤渗透性及抗炎镇痛作用

目的：考察草乌甲素脂质体的皮肤渗透性及抗炎镇痛效果。方法：采用正交设计详细考察了处方中各因素对透皮速率的影响；比较了脂质体与饱和水溶液的经皮渗透性；研究了脂质体对二甲苯所致急性炎症以及醋酸所致扭体反应的影响。结果：处方中磷脂、油酸、油酸钠对透皮速率有极显著性影响。脂质体可以明显加快草乌甲素的透皮吸收，缩短时滞。本品对炎症和疼痛均有明显的抑制作用，优于双氯芬酸钠乳胶剂对照组。结论：脂质体是草乌甲素透皮吸收的优良载体，有利于充分发挥药物的疗效。     

Skin permeability enhancement by low frequency sonophoresis: lipid extraction and transport pathways

The objective of this study was to shed light on the mechanism(s) by which low-frequency ultrasound (20 KHz) enhances the permeability of the skin. The physical effects on the barrier and the transport pathway, in particular, were examined. The amount of lipid removed from the intercellular domains of the stratum corneum following sonophoresis was determined by infrared spectroscopy. Transport of the fluorescent probes nile red and calcein, under the influence of ultrasound, was evaluated by laser-scanning confocal microscopy. The results were compared with the appropriate passive control data and with data obtained from experiments in which the skin was exposed simply to the thermal effects induced by ultrasound treatment. A significant fraction ( approximately 30%) of the intercellular lipids of the stratum corneum, which are principally responsible for skin barrier function, were removed during the application of low-frequency sonophoresis. Although the confocal images from the nile red experiments were not particularly informative, ultrasound clearly and significantly (again, relative to the corresponding controls) facilitated transport of the hydrophilic calcein via discrete permeabilized regions, whereas other areas of the barrier were apparently unaffected. Lipid removal from the stratum corneum is implicated as a factor contributing the observed permeation enhancement effects of low-frequency ultrasound. However, microscopic observations imply that sonophoresis induces localized (aqueous?) permeation pathways at discrete sites.     

Skin toxicology of lead species evaluated by their permeability and proteomic profiles: A comparison of organic and inorganic lead

Lead compounds are known to cause cytotoxicity and genotoxicity. Lead absorption by the skin is an important route through which this metal enters the body. The purpose of this work was to evaluate the skin permeability and toxicological profiles of two lead species, lead acetate and lead nitrate. This study assessed lead-induced toxicity mechanisms by focusing on the histopathology, proteomics, cell growth, and cellular ATP. In vitro skin permeation assays showed that there was no significant difference of lead accumulation within and across the skin between the two lead species. The presence of simulated sweat reduced the skin uptake of lead. The skin deposition of lead acetate was greater than that of lead nitrate with in vivo topical application. On the other hand, lead nitrate produced greater changes in the skin's histology and proteomic profiles compared to lead acetate. Four protein spots which showed significant changes were identified and are discussed in this study. These included glucose-related protein precursor (GRP) 78, K14, α-actin, and Rho GDP-dissociation inhibitor 2 (RhoGDI2). These proteins are respectively associated with oxidative stress, apoptosis, wound healing, and proliferation. Lead presented a biphasic pattern on cell growth and intracellular ATP content, with a stimulating effect at low concentrations and an inhibitory effect on cell proliferation at higher concentrations.     

皮肤微生态与皮肤疾病研究进展

皮肤是人体最大的器官,其结构从内到外依次为皮下组织、真皮层和表皮层。皮肤表面及腺体等部位定植着众多微生物,统称为皮肤微生物组。不同微生物其组成和分布在一定范围内维持动态平衡,并通过增殖、分泌等方式与宿主的皮肤及免疫系统进行相互调节,构成了皮肤微生态系统。当皮肤菌群失调时,会引发微生态紊乱,导致疾病的发生。通过微生态角度进行治疗,不仅能有效减少病症,还可避免细菌耐药性扩散等情况。综述了皮肤微生态相关的近期研究成果,并着重介绍皮肤微生物与皮肤疾病的关联,以及微生态治疗在皮肤疾病中的应用,旨在为相关研究提供参考。     

Prediction of human intestinal permeability using artificial membrane permeability

The purpose of the present study was to examine a correlation between the human intestinal permeability (P(eff)) and the bio-mimetic artificial membrane permeability corrected by the paracellular pathway model based on the Renkin function (P(PAMPA-PP-RF)) and to construct a prediction scheme. The effect of the unstirred water layer was incorporated to the prediction scheme. Eighteen P(eff) values of passively absorbed drugs were employed for the analysis. The correlation coefficient (CC) between the predicted and observed logP(eff) was 0.91. P(eff) of furosemide, hydrochlorothiazide and creatinine were underestimated by P(PAMPA-PP-RF). When these compounds were excluded, CC was 0.97. Without the correction for the paracellular pathway, P(eff) of small, cationic and hydrophilic compounds were underestimated. Therefore, P(PAMPA-PP-RF) was found to be an adequate in vitro surrogate for P(eff).     

头孢菌素类药物皮肤过敏的试验及皮试方法的研究

目的观察和分析头孢菌素类药物皮肤过敏的实验以及皮试方法。方法选择我院2010年1月至2011年1月接收的治疗过程中使用头孢菌素类药物的500例住院患者,随机平均分成皮试组与非皮试组,分别观察患者用药后的情况。结果有青霉素过敏史的患者占19.80%,皮试阳性占有率中,其他物质过敏史的占12.02%,无过敏史的占0.55%;皮试阴性组用药后发生的不良用药反应以及过敏反应明显低于非皮试组患者,两组数据差异显著,具有统计学意义。结论影响头孢菌素类药物出现不良药物反应以及皮试阳性发生率的主要因素是患者的过敏史,因此,对具有过敏史患者用药前应该对患者进行采取拟用药皮试。     

基于皮肤微生态的炎症性皮肤病和衰老治疗策略

皮肤微生态在调控微生物和内稳态方面发挥着关键作用,与炎症性皮肤病及皮肤衰老存在密切联系。本文总结了皮肤微生态的组成与作用、皮肤疾病与微生态之间的关系、炎症性皮肤病和皮肤衰老的微生态调节治疗策略,为皮肤疾病的临床治疗及药物开发提供参考。     

Predicting Skin Permeability

Published permeability coefficient (K _p) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (K _oct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of K _p upon MV (or MW) and K _oct. It is found that the existence of an aqueous-polar (pore) pathway across the SC is not necessary to explain the K _p values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected K _p. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log K _oct ranging from –3 to + 6), the postulated upper limiting value of K _p for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal K _p values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of K _p upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.     

Skin deep.

Over the past 30 or so years there has been a considerable advance in our knowledge of the mechanisms of skin permeation. This has largely been brought about by the development of sophisticated biophysical techniques and increased computing powers. The advanced technology has clearly provided indications, at a molecular level, about routes of permeation and how the barrier function can be modulated by excipients with which actives are formulated. This publication reviews some of the advances that have been made and mathematical models that have been constructed to predict percutaneous penetration and transdermal delivery. The models also indicate the various enhancement strategies that can be used in dermal penetration. In the past, it has been difficult to identify precise mechanisms of action of the different classes of enhancer but a combination of appropriate biophysical techniques, mathematical modelling and chemometric analysis can help identify the contributing processes. The models can also be used to indicate rate control in transdermal delivery, whether it is in the applied delivery device or in the skin.     

Warfarin-Induced Skin Necrosis

Background:

Warfarin is a frequently used oral anticoagulant in the treatment and prevention of various medical conditions. One uncommon adverse effect that can occur following the initiation of therapy is warfarin-induced skin necrosis. Because it is a rare effect with an undetermined pathophysiology of disease, the treatment is not well established.

Case:

A 52-year-old female was prescribed warfarin and enoxaparin for a newly diagnosed deep vein thrombosis (DVT) in the left lower extremity. On day 4 of therapy, the patient had a supra-therapeutic international normalized ratio (INR), prompting the discontinuation of enoxaparin and a decrease in the warfarin dose. The patient returned to the emergency department on day 7 of treatment with a purple, cold, and extremely painful right foot with punctate areas of necrosis and petechiae proximal to the discoloration. The patient’s INR was found to be 10.64. Following the diagnosis of warfarin-induced skin necrosis, the patient was administered vitamin K intravenously and fresh frozen plasma (FFP) to reverse the effects of warfarin and promote protein C and S synthesis. Once the patient’s INR was no longer supratherapeutic, subcutaneous enoxaparin was re-started as treatment for the known recent DVT. The patient’s necrotic foot began to improve and she was discharged home with an anticipated full recovery.

Conclusions:

Based on the proposed pathophysiology of disease, adequate bridge therapy may decrease the likelihood of developing this life-threatening condition. Early recognition and treatment with intravenous vitamin K, FFP or 4-factor prothrombin complex concentrate, and continued wound care are essential to prevent further complications.