Use of Shed Snake Skin as a Model Membrane for in Vitro Percutaneous Penetration Studies: Comparison with Human Skin

The potential usefulness of shed snake skin as a model membrane for transdermal research was examined. There are similarities between shed snake skin and human stratum corneum in terms of structure, composition, lipid content, water permeability, etc. The permeability of various compounds and the contribution of several functional groups to the permeability were also found to be similar between shed snake skin and human skin. Moreover, the permeability of compounds through shed snake skin was increased by Azone, one of the most extensively studied transdermal penetration enhancers. Considering the similarities between shed snake skin and human skin, ease of storage and handling, and low cost, shed snake skin may offer a good model membrane for transdermal research.     

Dog Colonoscopy Model for Predicting Human Colon Absorption

PURPOSE: This study was conducted to develop and validate a dog colon model that predicts colon permeability in humans. METHODS: The following compounds were studied: Class 1 highly soluble (HS)/highly permeable (HP): aminophylline, propranolol, CP-409092; Class 2 LS/HP: nifedipine; trovafloxacin, sertraline; Class 3 HS/LP: azithromycin, atenolol, CP-331684, CP-424391; Class 4 LS/LP: CJ-13610. Administration to dogs was made 30 cm cranial to the anal sphincter with a lubricated Schott Model VFS-5 flexible endoscope. The bioavailability of the compound following the colon administration in dogs, relative to the same formulation administered orally (relative bioavailability), was determined. RESULTS: Except for atenolol, a small hydrophillic molecule, the relative bioavailability from administration to the colon of the dog correlated well with the following compound properties: high solubility and high, passive permeability > high solubility, low permeability > low solubility, high, passive permeability approximately low solubility, low permeability. CONCLUSION: The dog colon model is proposed as a surrogate for human intubation studies when the controlled release candidate falls in BCS Classes 2 (LS/HP), 3 (HS/LP), and 4 (LS/LP). However, no human intubation or dog colon studies are required for Class 1 (HS/HP), as these compounds are likely to be well absorbed from the colon.     

Impedance Spectroscopy in Human Skin. A Refined Model

Pharmaceutical Research -     

Clinical Potential of a Silk Sericin-Releasing Bioactive Wound Dressing for the Treatment of Split-Thickness Skin Graft Donor Sites

Purpose

An ethyl alcohol-precipitated silk sericin/PVA scaffold that controlled the release of silk sericin was previously developed and applied for the treatment of full-thickness wounds in rats and demonstrated efficient healing. In this study, we aimed to further evaluate the clinical potential of this scaffold, hereafter called “silk sericin-releasing wound dressing”, for the treatment of split-thickness skin graft donor sites by comparison with the clinically available wound dressing known as “Bactigras®”.

Methods

In vitro characterization and in vivo evaluation for safety of the wound dressings were performed. A clinical trial of the wound dressings was conducted according to standard protocols.

Results

The sericin released from the wound dressing was not toxic to HaCat human keratinocytes. A peel test indicated that the silk sericin-releasing wound dressing was less adhesive than Bactigras®, potentially reducing trauma and the risk of repeated injury upon removal. There was no evidence of skin irritation upon treatment with either wound dressing. When tested in patients with split-thickness skin graft donor sites, the wounds treated with the silk sericin-releasing wound dressing exhibited complete healing at 12?±?5.0 days, whereas those treated with Bactigras® were completely healed at 14?±?5.2 days (p?=?1.99?×?10^?4). In addition, treatment with the silk sericin-releasing wound dressing significantly reduced pain compared with Bactigras® particularly during the first 4 postoperative days (p?=?2.70?×?10^?5 on day 1).

Conclusion

We introduce this novel silk sericin-releasing wound dressing as an alternative treatment for split-thickness skin graft donor sites.     

A Model for Improving Medication Use in Home Health Care Patients

Objectives(1) To develop a model for the identification and resolution of problems associated with suboptimal medication use in elderly patients receiving home health care; (2) To select the most important identifiable problems and develop structured procedures for their resolution.DesignExpert panel review, problem selection, and development of a problem resolution model and guidelines.SettingHome health care.ParticipantsA panel with expertise in home health nursing, pharmacy, clinical pharmacology, gerontology, pharmacoepidemiology, and health services research.InterventionsA list of potential problems associated with the most frequently used classes of drugs was compiled for review by the panel. Problems that were controversial or that could not be identified in the home care setting were excluded. Panel members individually ranked the remainder. Detailed procedures for identification and resolution of the 15 top-ranking problems were developed.Main Outcome MeasuresNot applicable.ResultsPotential medication problems were defined by both drug use and symptoms or clinical signs associated with specific adverse effects, to ensure that clinically relevant problems would be identified. The model developed for problem assessment and resolution was centered on the drug utilization review (DUR) coordinator and the attending home health nurse. Following guidelines developed by the panel, the DUR coordinator advises the home health nurse about identified problems and how to resolve them. One of these practitioners, usually the nurse, then contacts the attending physician to explain their concerns, offer potential solutions, and request instructions.ConclusionA potentially useful model for the identification and resolution of medication problems in the home health care setting was developed. This model is currently being evaluated in a randomized controlled trial.     

Skin Tumorigenic Potential of Crude and Refined Coal Liquids and Analogous Petroleum Products

Skin Tumorigenic Potential of Crude and Refined Coal Liquidsand Analogous Petroleum Products. WITSCHI, H. P., SMITH, L.H., FROME, E. L., PECQUET-GOAD, M. E., GRIEST, W. H., HO. C.-H.,AND GUERIN, M. R. (1987). Fundam. Appl. Toxicol 9, 297–303.The skin tumorigenic potential of seven complex hydrocarbonmixtures was determined: a coal-derived raw blend composed oflight and heavy oils, a low- and high-severity hydrotreatedproduct of that blend, and naphthas and fuel oils from the rawblend or from natural petroleum. Male and female C3H/Bd_f micewere exposed three times per week to each test mixture by dermalapplication of 50 µl of neat, 50, or 25% (w/v) preparations.Room, vehicle, and benzo[a] control groups were run concurrently.The raw blend produced an almost 100% incidence of skin tumorsat all three doses while tuniorigenicity was considerably decreasedby hydrotreating the blend both in terms of incidence and onset.The tumongenicities of the naphthas and fuel oils derived fromthe raw blend or from petroleums were low relative to that ofthe parent mixture. Although tumorigens in the raw blend weremuch reduced by hydrotreatment, tumori genicity of the otheragents did not parallel the content of polycyclic aromatic hydrocarbonsknown to be good tumor initiators.     

A Model for Predicting the Interindividual Variability of Drug-Drug Interactions

Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96–1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc?=?1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.     

Use of In Vitro Human Skin Models to Assess Potential Immune Activation In Response to Biotherapeutic Attributes and Process-related Impurities

Subcutaneous (SubQ) injection is a common administration route for biotherapeutics. However, limited tools are available for understanding the dynamic relationships between drug products and resident cells following injection. Advances in tissue engineering have enabled the production of in vitro skin models that recapitulate the morphological structure and functional activity of human skin. Here we explore the use of a commercially available skin model to investigate potential immune activation in response to subcutaneously injected biotherapeutics. Exposure to high levels of a mixture of process-related impurities (that are known potent immune system activators) induced a robust immune response from the skin model, as indicated by enhanced metabolic activity and increased secretion of 19 cytokines and chemokines. The skin model also responded to aggregated antibodies (generated by extreme mechanical stirring and pH-jump stress, which resulted in orders of magnitude higher particle numbers than that found in products), as shown by the secretion of several signature cytokines (GM-CSF, RANTES, and MCP-1). However, the magnitude of the responses to the aggregates were significantly lower than the response to the impurities. These results highlight the promising utility of in vitro skin models for investigating the potential immune response to process-related impurities and biotherapeutic attributes in a subcutaneous environment. The use of skin models for assessing drug safety may provide new insights to help guide drug product and process development, and potentially mitigate the risk of injection site reactions and systemic immunogenic responses that may compromise the safety and efficacy of subcutaneously administered drugs.     

1例葡萄球菌性烫伤样皮肤综合征患儿的药学服务实践

目的 通过临床药师对1例葡萄球菌性烫伤样皮肤综合征患儿的药学服务实践,阐明临床药师参与药物治疗决策的重要性和必要性。方法 临床药师参与治疗方案的制定,根据患者病情变化及时提出药物治疗方案调整意见,同时与患儿家长沟通,做好用药教育。结果 在临床药师参与下,临床医师调整治疗方案,使患者得到合理、有效治疗。结论 临床药师与医师密切配合并及时做好患者用药教育的工作模式科学合理,可优化药物治疗方案、确保临床用药合理、安全、有效。     

Dual Characteristics of Skin Care Creams Evaluated by Two In-Vivo Human Experimental Models

The use of skin care creams is a well documented protection measure to reduce the risk of barrier damage and contact dermatitis from exogenous contact with skin irritants. Before choosing a skin care cream two aspects should be considered: a) Is the product able to reduce irritant reactions caused by the irritant, and b) is the product well tolerated, also on damaged skin. Both aspects can be evaluated by experimental models in human volunteers. We used two standard experimental designs to compare six commercially available skin care products: a) the chamber scarification test, designed to assess the irritancy potential, and b) the repeated short-time occlusive irritation test (ROIT), developed to evaluate the efficacy of skin care creams. The results showed that a high score in the chamber scarification test for skin irritation was not necessarily correlated to the products' ability to impede sodium lauryl sulfate (SLS)-induced irritant skin reactions. Three products were shown to both have a low irritancy potential and be capable of reducing skin barrier damage induced by SLS, and one product had both an irritant potential on scarified skin and also a modest capability to reduce skin irritation induced by SLS. The use of both test methods, chamber scarification and ROIT, gives valuable information on skin compatibility and efficacy of skin care creams. The clinical relevance of the test results can only be determined by comparing products with high and low scores in both tests in controlled clinical experiments with subjects at risk of developing irritant contact dermatitis.     

Committee for Medicinal Products for Human Use (CHMP) assessment on efficacy of antidepressants

Background: Recent publications have raised questions over the efficacy and clinically relevant effects of antidepressants that have been approved for the treatment of major depression. In this context, the European Commission requested that the European Medicines Agency (EMEA) and its scientific committee (CHMP) issue an opinion on these data under Article 5(3) of Regulation (EC) No 726/2004. Findings: Results from a recent meta-analysis [Kirsch, I., Deacon, B.J. et al., (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 5(2), e45.] have questioned the clinical relevance of the use of some antidepressants in treating major depression. This analysis focused only on statistically significant mean differences versus placebo in changes in a rating scale (such as the Hamilton Depression Rating Scale). This, however, would not be an adequate basis for the evaluation of clinical relevance and, from a regulatory perspective, would not be sufficient to grant an antidepressant the approval needed to allow it onto the market. Improvements that are both statistically significant (based on improvements in validated rating scales between baseline and study end) and clinically relevant (based on responder rates) need to be shown in short-term studies. In addition, these short-term results need to be confirmed in a randomised withdrawal study to demonstrate the maintenance of an antidepressant's effects. Conclusions: The CHMP concluded that the approval of antidepressants for the treatment of patients with major depression is based on data that provide robust and sufficient evidence of clinically meaningful benefits for patients with major depression. Therefore, the CHMP is of the opinion that, as no public health concerns have been identified, no regulatory action is necessary on the basis of Kirsch et al.'s findings.     

欧盟人用药品风险管理制度指南（三）

药品风险管理制度体系在欧美药品监管中发挥的作用越来越大。关注药品的安全，并从安全风险管理的角度来梳理药品监管的整体制度安排，对于面临药品“风险高发期和事故凸显期”的我国药品监管状况而言应当具有重要的意义。本译文旨在介绍欧盟药品风险管理的制度规划与相关背景，期望能对我国药品风险管理发挥一定的借鉴作用。     

欧盟人用药品风险管理制度指南（四）

药品风险管理制度体系在欧美药品监管中发挥的作用越来越大，关注药品的安全，并从安全风险管理的角度来梳理药品监管的整体制度安排，对于面临药品“风险高发期和事故凸显期”的我国药品监管状况而言应当具有重要的意义。本译文旨在介绍欧盟药品风险管理的制度规划与相关背景，期望能对我国药品风险管理发挥一定的借鉴作用。     

欧盟人用药品风险管理制度指南（五）

药品风险管理制度体系在欧美药品监管中发挥的作用越来越大。关注药品的安全,并从安全风险管理的角度来梳理药品监管的整体制度安排,对于面临药品“风险高发期和事故凸显期”的我国药品监管状况而言应当具有重要的意义。本译文旨在介绍欧盟药品风险管理的制度规划与相关背景,期望能对我国药品风险管理发挥一定的借鉴作用。     

欧盟人用药品风险管理制度指南（六）

药品风险管理制度体系在欧美药品监管中发挥的作用越来越大。关注药品的安全,并从安全风险管理的角度来梳理药品监管的整体制度安排,对于面临药品“风险高发期和事故凸显期”的我国药品监管状况而言应当具有重要的意义。本译文旨在介绍欧盟药品风险管理的制度规划与相关背景,期望能对我国药品风险管理发挥一定的借鉴作用。     

A Model for Predicting Field-Directed Particle Transport in the Magnetofection Process

Purpose  

To analyze the magnetofection process in which magnetic carrier particles with surface-bound gene vectors are attracted to target cells for transfection using an external magnetic field and to obtain a fundamental understanding of the impact of key factors such as particle size and field strength on the gene delivery process.     

A Mechanistic Model for Predicting the Physical Stability of Amorphous Solid Dispersions

In this paper, we establish a mechanistic model for the prediction of amorphous solid dispersion (ASD) stability. The novel approach incorporates fundamental physical parameters, principally supersaturation, diffusivity, and interfacial energy, to model crystallization in ASDs accounting for both kinetic and thermodynamic drivers. API dependent decoupling coefficients were also considered which allowed dynamic mechanical analysis to probe molecular mobility, with viscosity measurements, across an exceptionally broad range of temperatures to support ASD stability simulations. ASDs are multicomponent systems in which the amorphous form of active pharmaceutical ingredients (APIs) are molecularly dispersed within a carrier. This gives rise to a transiently supersaturated API solution upon dissolution which increases the driving force for oral absorption and results in increased bioavailability as compared to that of the crystalline API. A major shortcoming of ASDs, however, is that there is the potential for amorphous APIs to revert to their more stable crystalline form during storage, despite the use of polymer carriers to stabilize formulations and limit recrystallization. Hot melt extrusion (HME) has been employed as the preparation method for ASDs used in this study as it is well-suited for the formation of uniform dispersions. The ASDs were stored under controlled temperature conditions, in the absence of humidity, to determine recrystallization kinetics. Our mechanistic model, considering both crystal nucleation and growth processes, describes temporal ASD stability through a system of coupled differential equations that connect the physiochemical properties of the ASD system to drug recrystallization. The model and prolonged time scale of crystallization observed highlight the importance of considering both thermodynamic and kinetic factors in the preparation of stable ASDs. Experimental observations were found to be in good agreement with predictions of the model confirming its utility in predicting the temporal physical stability of amorphous solid dispersions through a mechanistic lens.     

标准化皮肤护理对乳腺癌放疗后皮损的疗效评价

目的探究标准化皮肤护理对乳腺癌放疗后皮损的临床效果。方法本次选取乳腺癌放疗后皮损患者120例作为研究对象,收治时间2015年6月17日至2017年9月17日,分为对照组(给予常规护理)、观察组(在对照组的基础上给予标准化皮肤护理);并对120例患者的皮肤护理效果及总体健康状况评分、生活质量(心理职能、生理功能、疾病治疗、社会功能)进行观察及评估。结果两组乳腺癌放疗后皮损患者在皮肤护理效果对比中存在一定差异,P<0.05。两组乳腺癌放疗后皮损患者在总体健康状况评分对比中存在一定差异,P<0.05。观察组与对照组患者在生活质量评估对比中存在明显差异,即观察组数据高于对照组数据,P值<0.05。结论标准化皮肤护理对乳腺癌放疗后皮损具有较高的应用价值,不仅可以改善皮肤损伤程度,并且还能提高患者的生活质量及耐受性,临床上值得应用及推广。     

Use of Animal Eye Test Data and Human Experience for Determining the Ocular Irritation Potential of Shampoos

Abstract

Human experience can be used in combination with animal test data to determine the safety of consumer products. Results of rabbit low-volume eye irritation testing and human experience were evaluated to determine the ocular safety of shampoos. These data were reviewed for four marketed shampoos and show that the shampoos have a low eye irritation potential. This review supports the use of the rabbit low-volume eye irritation test in determining human ocular irritation potential of new shampoo formulations and the use of consumer accidental exposure information in product safety assessment.     

Distribution and Visualisation of Chlorhexidine Within the Skin Using ToF-SIMS: A Potential Platform for the Design of More Efficacious Skin Antiseptic Formulations

Purpose

In order to increase the efficacy of a topically applied antimicrobial compound the permeation profile, localisation and mechanism of action within the skin must first be investigated.

Methods

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to visualise the distribution of a conventional antimicrobial compound, chlorhexidine digluconate, within porcine skin without the need for laborious preparation, radio-labels or fluorescent tags.

Results

High mass resolution and high spatial resolution mass spectra and chemical images were achieved when analysing chlorhexidine digluconate treated cryo-sectioned porcine skin sections by ToF-SIMS. The distribution of chlorhexidine digluconate was mapped throughout the skin sections and our studies indicate that the compound appears to be localised within the stratum corneum. In parallel, tape strips taken from chlorhexidine digluconate treated porcine skin were analysed by ToF-SIMS to support the distribution profile obtained from the skin sections.

Conclusions

ToF-SIMS can act as a powerful complementary technique to map the distribution of topically applied compounds within the skin.