Farhaan Hafeez

Transungual delivery of ketoconazole using novel lacquer formulation.

Onychomycosis, a common fungal infection of the nail, can have a substantial impact on quality of life. The success of topical therapy for onychomycosis depends on effective penetration, which can be enhanced using an appropriate delivery method. This study evaluated the effectiveness of a novel topical lacquer on enhancing [(14)C]-ketoconazole penetration by comparing nail absorption, nail distribution, and nail penetration of [(14)C]-ketoconazole dissolved in the novel lacquer versus a commercial ketoconazole cream. Using the in vitro finite dose model, the formulations were applied daily to human nail plates for 7 days. Drug absorption was measured by monitoring rate of appearance in each nail layer and the supporting bed. After the multiple day treatment, cumulative concentrations of ketoconazole formulated in novel lacquer in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of commercial ketoconazole (p<0.05), as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of causative dermatophytic and yeast species. These results suggest that this novel ketoconazole lacquer has the potential to be an effective topical treatment for onychomycosis.

Skin lesion metrics: role of photography in acne

Accurate assessment of acne severity is essential for determining the appropriate treatment required. This paper reviews photographic methods for such assessment. Literature included met the following criteria: proposed photographic standards to assess acne, evaluated such standards, or offered photographic methods to improve visualization and assessment. Validity was evaluated by comparing given photographic grading methods to other methods, such as lesion counting. Many photographic standards were shown to be objective, time-efficient, and have intra-grader and inter-grader consistency. Photography also documents progress for retrospective verification. Drawbacks include not allowing determination of depth, minimization of small lesions and erythema, and difficulty in maintaining consistent settings. Fluorescence and polarized photography improve visualization beyond clinical observation alone. Advances such as computer alignment, imaging segmentation, and three-dimensional analysis methods track lesions and measure objective characteristics. The combined experience summarized here strongly promotes the use of a photographic standard in assessing acne severity. Cooks method can also be used to train and qualify graders. Photographic advancements improve accuracy of assessment by solving problems with consistent settings and depth visualization. Further advancements can improve image analysis through analysis of objective attributes.

Is Ki-67 Expression Prognostic for Local Relapse in Early-Stage Breast Cancer Patients Treated With Breast Conservation Therapy (BCT)?

PURPOSE Ki-67 is a human nuclear protein whose expression is strongly up-regulated in proliferating cells and can be used to determine the growth fraction in clonal cell populations. Although there are some data to suggest that Ki-67 overexpression may be prognostic for endpoints such as survival or postmastectomy recurrence, further elucidation of its prognostic significance is warranted. Specifically after breast conservation therapy (BCT) (defined in this setting as breast-conserving surgery and adjuvant radiation therapy), whether Ki-67 predicts for locoregional recurrence has not been investigated. The purpose of this study was to assess Ki-67 expression in a cohort of early-stage breast cancer patients to determine whether a significant independent association between Ki-67 and locoregional relapse exists. METHODS AND MATERIALS Ki-67 staining was conducted on a tissue microarray of 438 patients previously treated with BCT, and expression was analyzed with clinicopathologic features and outcomes from our database. RESULTS Ki-67 expression was more prevalent in black patients (37% of black patients vs 17% of white patients, P<.01), younger patients (27% of patients aged ≤50 years vs 15% of patients aged >50 years, P<.01), estrogen receptor (ER)-negative tumors (25% of ER-negative tumors vs 17% of ER-positive tumors, P=.04), human epidermal growth factor receptor 2 (HER2)/neu-positive tumors (35% of HER2-positive tumors vs 18% of HER2-negative tumors, P=.01), and larger tumors (26% of T2 tumors vs 16% of T1 tumors, P=.03). On univariate/multivariate analysis, Ki-67 did not predict for overall survival (74.4% vs 72.6%), cause-specific survival (82.9% vs 82.1%), local relapse-free survival (83.6% vs 88.5%), distant metastasis-free survival (76.1% vs 81.4%), recurrence-free survival (65.5% vs 74.6%), and locoregional recurrence-free survival (81.6% vs 84.7%): P>.05 for all. CONCLUSIONS Ki-67 appears to be a surrogate marker for aggressive disease and significantly correlates with known prognostic features such as age, race, hormone receptor status, and HER2 status but independently does not predict for locoregional outcomes after BCT when these other prognostic clinicopathologic features are taken into consideration. The independent associations of Ki-67 with race and age appear to be novel to our study.

Dermal exposure to methamphetamine hydrochloride contaminated residential surfaces II. Skin surface contact and dermal transfer relationship.

This in vitro investigation evaluated [(14)C] - d-methamphetamine hydrochloride ([(14)C]-meth HCl) transfer from contaminated vinyl tile (non-porous and smooth) and upholstery fabric (rough and loose) to human skin. (14)C-Meth HCl transfer rate from vinyl to skin was rapid; a contact duration as brief as 15s resulted in measurable radioactivity in the skin and receptor fluid samples. In contrast, the transfer from fabric occurred more slowly: the amount of [(14)C]-meth HCl that was transferred from dry fabric after 2-h skin contact was one-fifth the amount transferred from vinyl after 5-min contact time. With moistened fabric, the transfer efficiency to skin after 2-h contact was seven times greater than that of dry fabric. While the duration of surface-skin contact appeared to affect the total dermal absorption of [(14)C]-meth HCl, it had little effect on the time point of maximum transdermal absorption. [(14)C]-meth HCl retained in skin continued to be absorbed after the contaminated material was removed. Mass balance in these studies was approximately 96%. In conclusion, [(14)C]-meth HCl penetrates into/through human skin quickly following skin contact with contaminated materials. The porosity of the contact surface and the moisture content appears to alter the degree of transfer and dermal penetration.

Ciclopirox delivery into the human nail plate using novel lipid diffusion enhancers

Abstract Context: Onychomycosis is a common fungal infection of the nail plate and bed that affects up to 14% of the population and can have a substantial impact on the quality of life of those affected. Objective: This study compared the onychopharmacokinetics, nail absorption, nail distribution, and nail penetration of [14C]-ciclopirox dissolved in novel lipid diffusion enhancers with that of a commercial ciclopirox nail lacquer using the in vitro finite dose model. Materials and methods: The penetration rate of ciclopirox was determined by applying doses of topical formulation twice daily to human nail plates for 11 d. Drug absorption was then measured by monitoring its rate of appearance in each nail layer and in the cotton pad/nail supporting bed. Results: After a multiple day treatment, cumulative concentrations of ciclopirox formulated with lipid enhancers in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of the commercial ciclopirox lacquer (p < 0.001) as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of the causative dermatophyte species. Conclusion: When formulated with lipid enhancers, the amount of ciclopirox in the ventral/intermediate layer and supporting bed dramatically exceed the inhibitory concentration of ciclopirox for the most common onychomycosis organisms. These results suggest that topical ciclopirox with lipid enhancers has the potential to be an effective topical treatment for onychomycosis, and the lipidic pathway of the nail can be utilized as a means of effective transungual delivery.

Stratum corneum reservoir as a predictive method for in vitro percutaneous absorption.

Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short‐term (30 min) SC reservoir predict long‐term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate‐limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright

Role of partition coefficients in determining the percutaneous penetration of salicylic acid and formaldehyde under varying occlusion durations

Abstract Context: Occlusion is widely utilized to enhance the percutaneous penetration of applied drugs in clinical practice; however, occlusion does not increase the penetration of all chemicals. Objective: This study determines: (1) whether occlusion enhances the percutaneous penetration of the lipophilic salicylic acid or the hydrophilic formaldehyde when compared to non-occlusion, (2) evaluate whether occlusion duration affects the penetration of compounds and (3) establish to what extent occlusive films in clinical practice interact with topically-applied chemicals and possibly hinder penetration. Materials and methods: Separately, single doses of [14C]-formaldehyde and [14C]-salicylic acid were applied onto human skin overlying diffusion cells under non-occlusion as well as various occlusive time periods (1, 4 and 8 h). The percent dose penetrating into each compartment as well the percent dose adhering to the plastic wrap were determined. Results: The radioactivity recovery as percent of applied dose of [14C]-salicylic acid was significantly higher under occlusion versus non-occlusion in the epidermis, dermis and receptor fluid after 24 h (p < 0.05). For [14C]-formaldehyde, no significant statistical differences were observed between occlusion versus non-occlusion. The plastic wrap often used to enhance the penetration of topically applied drugs does not itself substantially adhere to the tested chemicals. Conclusion: Occlusion duration, previously undocumented for in vitro studies, impacted the percutaneous penetration of the lipophilic salicylic acid more so than the hydrophilic formaldehyde. A strong correlation between occlusion-enhanced penetration and partition coefficients was observed, but we do not wish to overgeneralize these results until more compounds of varying physical--chemical properties are studied.

Do partition coefficients (liphophilicity/hydrophilicity) predict effects of occlusion on percutaneous penetration in vitro: a retrospective review.

Abstract Context: Skin occlusion influences percutaneous penetration by limiting penetrant evaporation, but also through impeding loss of water from skin and increasing the hydration state of the stratum corneum, thus dramatically altering the physiological nature of the stratum corneum. In general, occlusion is widely utilized to enhance penetration of applied drugs in clinical practice; however, occlusion does not increase the percutaneous absorption of all chemicals. Objective: We focus on what effect occlusion has on the in vitro percutaneous absorption of compounds of varying lipophilicities/hydrophilicities. Methods: Studies and prior reviews of the effects of occlusion on the in vitro percutaneous penetration of penetrants of varying lipophilicities/hydrophilicities were identified in the MEDLINE, PubMED, Embase and Science Citation Index databases using the terms occlusive, occluded, occlusion, in vitro, skin and percutaneous absorption/penetration to generate as broad of a search as possible. From the results generated, abstracts were subsequently scrutinized to identify articles dealing primarily with in vitro models of the skin involving occlusion. Moreover, after the identification of relevant articles, their references were examined to find additional sources of information. Results: After examining the research articles generated by the search results, five original research articles were obtained that used in vitro occlusion models and provided insight regarding the role of partition coefficients in predicting occlusion’s effects on percutaneous penetration; articles that dealt with occlusion and percutaneous penetration but did not shed light on how the lipophilicity/hydrophilicity of a compound could affect occlusion efficacy were excluded. Some of the studies bolster the notion that occlusion-enhanced hydration of the stratum corneum increases the percutaneous absorption of lipophilic molecules more than hydrophilic molecules, which seems to confirm some in vivo studies. However, this effect was not consistent; many studies reviewed did not find that the penetrant’s liphophilicity/hydrophilicity reliably predicted occlusion’s effect on penetration. In these studies, lipophilic compounds did not demonstrate increased percutaneous absorption under occlusion. Conclusion: Thus, it does not seem that partition coefficients can reliably predict the effect of occlusion on percutaneous penetration in vitro. This suggests skin occlusion may be more complex than previously thought.