Vol. 26, No. 2, 2013
Issue release date: April 2013
Skin Pharmacol Physiol 2013;26:85–91
(DOI:10.1159/000346273)
Review
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Occlusion Effect on in vivo Percutaneous Penetration of Chemicals in Man and Monkey: Partition Coefficient Effects

Hafeez F. · Maibach H.
Dermatology Department, University of California, San Francisco, Calif., USA
email Corresponding Author


 Outline


 goto top of outline Key Words

  • Barrier function
  • Occlusion
  • Percutaneous absorption-penetration in vivo
  • Stratum corneum
  • Octanol-water partition coefficient
  • Hydrophilicity
  • Liphophilicity

 goto top of outline Abstract

Background/Aim: Skin occlusion can increase the hydration of the stratum corneum up to 50%, which can have substantial effects on the percutaneous absorption of penetrants by altering skin barrier physiology. Though occlusion is widely utilized to enhance the penetration of applied drugs in clinical practice, it is not well known for which chemicals occlusion enhances the penetration through skin. In this review, we focus on what effect occlusion has on the percutaneous absorption of compounds of varying lipophilicities/hydrophilicities in vivo in the monkey and man. Methods: Studies and prior reviews of the effects of occlusion on the in vivo percutaneous penetration of penetrants of varying liphophilicities/hydrophilicities were identified in the Medline, Pubmed, Embase and Science Citation Index databases. Results: After examining the research articles generated by the search results, 7 original research studies were obtained that used in vivo occlusion models and provided insight regarding the role of partition coefficients in predicting the effects of occlusion on percutaneous penetration. From these studies, one can conclude the following: (1) occlusion enhances the percutaneous absorption of many but not all compounds, (2) penetration can increase as the amount of time of occlusion increases, (3) occlusion seems to enhance the penetration of very lipophilic compounds more than that of very hydrophilic compounds, but (4) a relationship between a compound’s octanol-water partition coefficient and its occlusion-induced enhancement has not been determined. Conclusion: These in vivo studies reinforce the conclusions drawn from in vitro studies that partition coefficients incompletely predict the effect of occlusion on percutaneous penetration.

Copyright © 2013 S. Karger AG, Basel


goto top of outline Introduction

Occlusion refers to the impervious-to-water covering of the skin directly or indirectly by various means, including tape, gloves, impermeable dressings, or even transdermal devices [1]. Certain topical vehicles, e.g. petrolatum or paraffin, contain fats and/or polymer oils that may generate occlusive effects by reducing water loss [2]. The epidermis of healthy skin provides an efficient barrier against the infiltration of exogenous and potentially harmful substances, and the stratum corneum typically has a water content of 10–20%. Skin occlusion increases the water content of the stratum corneum up to 50%, and even a short-time occlusion (30 min) results in significantly increased hydration [3,4,5]. By increasing stratum corneum hydration, occlusion influences percutaneous absorption by altering the partitioning between the chemical penetrant and the skin, swelling corneocytes and possibly altering the intercellular lipid phase organization, increasing skin surface temperature, and increasing blood flow [4,6].

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 [3,4]. In fact, evidence suggests skin occlusion is more complex than previously thought as it can induce changes in epidermal lipid content, DNA synthesis, epidermal turnover, skin pH, epidermal morphology, sweat glands, and Langerhans cell stresses [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21]. This overview focuses on what effect occlusion has on the percutaneous absorption of compounds of varying lipophilicities/hydrophilicities in vivo in the monkey and man; a companion review discusses the effect occlusion has on the in vitro percutaneous absorption of compounds of varying partition coefficients [submitted].

 

goto top of outline Methods

Studies and prior reviews of the effects of occlusion on the in vivo percutaneous penetration of penetrants of varying liphophilicities/hydrophilicities were identified in the Medline, Pubmed, Embase and Science Citation Index databases using the terms ‘occlusive’, ‘occluded’, ‘occlusion’, ‘in vivo’, ‘skin’ and ‘percutaneous absorption/penetration’ to generate as broad a search as possible. The search occurred between August 15, 2012, and August 24, 2012. From the results generated, abstracts were subsequently scrutinized to identify articles dealing primarily with in vivo skin experiments involving occlusion. Moreover, after the identification of relevant articles, their references were examined to find additional information sources.

 

goto top of outline Results

After examining the research articles generated by the search results, 7 original research studies were obtained that used in vivo occlusion models and provided insight regarding the role of partition coefficients in predicting occlusion effects on percutaneous penetration; 6 studies were excluded that dealt with occlusion and percutaneous penetration but did not shed light on how the lipophilicity/hydrophilicity of a compound could affect occlusion efficacy.

Feldmann and Maibach [22] were the first to correlate the increased pharmacological effect of hydrocortisone under occlusive conditions with the pharmacokinetics of the penetration of 14C hydrocortisone through normal skin. Following the topical application of 14C hydrocortisone to the ventral forearm of human volunteers, the rate and extent of 14C-labeled excretion was measured. The application site was either nonoccluded or occluded with plastic wrap. For the nonoccluded condition, the application site was washed 24 h after application, while for the occluded skin condition, the plastic wrap was left in place for 96 h after application before the site was washed. The urine for both conditions was collected for 10 days. The percentage of the applied dose excreted into the urine after 10 days was 0.46 ± 0.2 (mean ± SD) for the nonoccluded condition and 4.48 ± 2.7 for the occluded condition (table 1). The occlusive condition significantly increased (10-fold) the cumulative absorption of hydrocortisone compared to the nonoccluded condition (p = 0.01). The authors noted that the difference in application duration (24 h of exposure for the nonoccluded site versus 96 h for the occluded site) could affect absorption as measured by the cumulative amount of drug excreted into urine, but the significant difference observed in percent dose absorbed at 12 and 24 h between occluded and nonoccluded conditions could not be explained by differences in application duration.

TAB01
Table 1. Total excretion data summary for topical application of 14C hydrocortisone to the ventral forearm of human volunteers

Maibach and Feldmann [23 ] then later studied the effect of occlusion on the percutaneous penetration of pesticides. They applied 14C-radiolabeled pesticides to the forearm of volunteers, and the rate and extent of 14C-labeled urinary excretion was determined using sensitive methods that allowed the doses to be in micrograms, far below the toxic range of any pesticide. From their experiments, it is evident occlusion has a variable effect on penetration; at a minimum, occlusion increased the penetration of azodrin approximately 3-fold while at the other extreme, it increased the penetration of malathion almost 10-fold (table 2; fig. 1). In general, as the octanol-water partition coefficients increased, occlusion had a greater effect on enhancing penetration, though enhancement by occlusion peaked for malathion and then decreased as the octanol-water partition coefficients further increased. In order to understand how occlusion duration affects penetration, these authors documented the effects of occluding malathion under variable amounts of time (table 3). As the occlusion duration increased, the penetration of malathion increased as well, and that by 2 h of occlusion, the penetration had almost doubled, and that by 8 h, penetration almost increased by 4-fold. There have been few, if any experiments, besides this one, that have documented the effect of occlusion duration on percutaneous penetration.

TAB02
Table 2. Effect of occlusion on the penetration of pesticides

TAB03
Table 3. Effect of occlusion duration on penetration of malathion

FIG01
Fig. 1. Logarithmic octanol-water partition coefficient (log Kow) versus enhancement ratio (ER) of pesticides. This figure plots the enhancement ratios of the various pesticides as a function of their log octanol-water partition coefficients. Data from Maibach and Feldmann [23].

Guy et al. [24] studied how occlusion impacts the percutaneous absorption of a variety of steroids (progesterone, testosterone, estradiol, and hydrocortisone) in vivo. In the control studies, they applied the 14C-radiolabeled steroids dissolved in acetone to the ventral forearm of volunteers and then tracked the elimination of the compounds into urine. In the occlusive studies, after evaporation of the acetone vehicle, the site of application was covered with a plastic (Hill Top) chamber. In all cases, the application sites were washed after 24 h using a standardized procedure [25,26]. In the occlusive studies, the authors covered the administration site again with a new chamber after the washing. These studies reveal that occlusion significantly increased the percutaneous absorption of estradiol, testosterone, and progesterone but not that of hydrocortisone, which had the lowest octanol-water partition coefficient amongst the steroids used (table 4; fig. 2). Moreover, under both occlusion and nonocclusion, percutaneous absorption increased with increasing octanol-water partition coefficient up to testosterone but declined for progesterone.

TAB04
Table 4. Effects of occlusion on percutaneous absorption of steroids in man as a function of penetrant octanol-water partition coefficient

FIG02
Fig. 2. Logarithmic octanol-water partition coefficient (log Kow) versus enhancement ratio (ER) of stereoids. This figure plots the enhancement ratios of the various stereoids as a function of their log octanol-water partition coefficients. Data from Guy et al. [24] and Bucks and Maibach [26].

Bucks et al. [27 ] measured the percutaneous absorption of these same 4 steroids (hydrocortisone, estradiol, testosterone, and progesterone) in vivo in man under occluded and ‘protected’ (i.e. covered but nonocclusive) conditions. Using the same methodology as Guy et al. [24], the 14C-labeled chemicals were applied in acetone to the ventral forearm of volunteers. After vehicle evaporation, the application sites were covered with a semirigid polypropylene chamber for 24 h; intact chambers were used as the occlusive condition, while the ‘protected’ condition was created by boring several small holes through the chamber. Urine was then collected for 7 days after application. In excellent agreement with the previous study by Guy et al. [24], steroid absorption under occlusion increased with increasing lipophilicity up to a point, but the penetration of progesterone (the most hydrophobic of the steroids) did not continue the trend. With the exception of hydrocortisone, 24-hour occlusion significantly increased (p < 0.01) percutaneous absorption of the steroids. From these studies, it seemed occlusion enhanced the percutaneous absorption of the more liphophilic steroids but not that of hydrocortisone, the most water-soluble steroid.

Bucks and his group then investigated the effect of occlusion on the in vivo percutaneous absorption of phenols in man [26,28,29]. Nine 14C-ring-labeled para-substituted phenols (4-aminophenol, 4-acetamidophenol, 4-propionylamidophenol, phenol, 4-cyanophenol, 4-nitrophenol, 4-iodophenol, 4-heptyloxyphenol, and 4-pentyloxyphenol) were applied in ethanol to the ventral forearm of male volunteers. After vehicle evaporation, the application site was covered with either an occlusive or protective chamber. After 24 h, the chamber was removed, and the site washed. The application site was then recovered with a new chamber of the same type. Urine was collected for 7 days. On the seventh day, the second chamber was removed, the application site washed, and the upper layers of stratum corneum removed from the application site by tape stripping. These studies indicate that occlusion significantly increased (p < 0.05) the absorption of phenol, heptyloxyphenol, and pentyloxyphenol, but occlusion did not significantly increase the absorption of aminophenol, acetaminophen, propionylamidophenol, cyanophenol, nitrophenol, and iodophenol (table 5). The two compounds with the lowest octanol-water partition coefficients demonstrated the least enhancement in absorption under occlusion.

TAB05
Table 5. Percutaneous absorption of phenols in humans under occluded and protected conditions

Bronaugh et al. [30] investigated the effect of occlusion on the percutaneous absorption of 6 additional volatile compounds (benzyl acetate, benzamide, benzoin, benzophenone, benzyl benzoate, and benzyl alcohol) in vivo in rhesus monkeys and humans for 24 h employing 2 occlusion methods, plastic wrap and glass chamber. In general, occlusion enhanced the absorption of these compounds. However, differences in absorption were observed between the plastic wrap and glass chamber occlusive conditions. Benzoin and benzyl acetate absorptions were lower under the plastic wrap condition compared to the nonocclusive conditions; the authors conjectured that this discrepancy may be due to compound sequestration by the plastic. Glass chamber occlusion resulted in greater absorption than the nonoccluded and plastic wrap occlusion conditions for all the compounds except benzyl benzoate and benzophenone (benzyl benzoate had greater absorption under plastic wrap occlusion than glass chamber occlusion while benzophenone had the same magnitude increase in percent dose absorbed for both occlusive conditions). The authors attempted to correlate the compounds’ octanol-water partition coefficients with their occlusion-enhanced skin absorption, but surprisingly, no apparent trends were found. One explanation for this lack of correlation could be that the volatile chemicals evaporated prior to application of the occluding device, which can influence subsequent measures of penetration [31].

Pellanda et al. [32] investigated the effect before and after occlusion on the penetration of triamcinolone acetonide (log Kow = 2.53) into the stratum corneum. Their two experiments involved the forearms of 10 healthy volunteers. In experiment 1, they applied triamcinolone acetonide (TACA) in acetone to 3 sites per arm with one arm being preoccluded for 16 h. In experiment 2, the same dose of TACA in acetone was applied on 2 sites per arm with one arm being occluded after application till skin sampling. Then, stratum corneum samples were removed by tape stripping at 0.5, 4 and 24 h for experiment 1 and at 4 and 24 h for experiment 2. The amounts of corneocytes adhering to the tape strips were quantified directly using a spectrophotometer, and the amount of TACA adhering to each tape was quantified using high-performance liquid chromatography. They found that preocclusion produced no significant effect on TACA penetration into the stratum corneum, while occlusion after application enhanced TACA penetration significantly by a factor of 2.

 

goto top of outline Discussion

Skin occlusion can increase the hydration of the stratum corneum up to 50%, which can have substantial effects on the percutaneous absorption of penetrants by altering the partitioning between the chemical penetrant and the skin, swelling corneocytes, and promoting the uptake of water into the intercellular lipid domains [3,4,5,6]. Though occlusion is widely utilized to enhance the penetration of applied drugs in clinical practice, occlusion does not increase the percutaneous absorption of all chemicals; it is not well understood for which chemicals occlusion enhances the penetration through the skin [3,4]. Here we focus on what effect occlusion has on the percutaneous absorption of compounds of varying lipophilicities/hydrophilicities in the monkey and man. In a companion overview, we examined how occlusion affects the in vitro percutaneous absorption of penetrants of varying lipophilicities/hydrophilicities [submitted]. From these in vitro studies, it seems that partition coefficients cannot reliably predict the effect of occlusion on percutaneous penetration. However, in vitro studies are not as effective as in vivo studies in mimicking the physiology occurring in man; this verity served as the impetus to examine the available in vivo data.

First, occlusion enhances the percutaneous absorption of many but not all compounds. For example, Guy et al. [24] and Bucks et al. [27] found that when measuring the effects of occlusion on the penetration of steroids, the most hydrophilic steroid of the ones being tested, hydrocortisone, did not demonstrate a statistically significant enhanced penetration under occlusion. Moreover, Bucks et al. [28] and Bucks [29] also demonstrated that occlusion did not significantly enhance the penetration of many phenols being tested.

Second, occlusion seems to enhance the penetration of very lipophilic compounds more than that of very hydrophilic compounds. Bucks et al. and Guy et al. showed that occlusion enhanced the penetration of the most lipophilic steroids (as measured by the octanol-water partition coefficient) more than that of the least lipophilic ones [24,27]. In addition, Bucks et al. [28] and Bucks [29] demonstrated that the phenols with the lowest octanol-water partition coefficients had the least enhancement in penetration under occlusion.

Third, though occlusion enhances the penetration of the most lipophilic compounds and often fails to enhance the penetration of the least lipophilic steroids, a relationship between a compound’s octanol-water partition coefficient and its occlusion-induced enhancement cannot be delineated. With regard to steroid penetration through skin, these studies showed that while a positive relationship exists between a penetrant’s octanol-water partition coefficient and its occlusion-enhanced penetration, this relationship is not a linear one [24,27]. However, with regard to the effects of occlusion on the penetration of phenols, no relationship was found between the octanol-water partition coefficient of the penetrant and the extent of its penetration under occlusion [28,29]. After investigating the effect of occlusion on the penetration of volatile compounds in vivo in rhesus monkeys, Bronaugh et al. [30] failed to correlate the penetrant’s octanol-water partition coefficients with occlusion-enhanced skin penetration.

Finally, the general shape of the figures plotting the enhancement ratios (the ratio of occlusion-enhanced penetration over nonoccluded penetration) as a function of the logarithms of octanol-water partition coefficients suggests that the enhancement in penetration afforded by occlusion increases up to a point as the partition coefficients increase, but then this enhancement declines as the partition coefficients further rise (fig. 1, 2). Occlusion may enhance the penetration of lipophilic compounds more than that of hydrophilic ones due to the rich lipid composition of the stratum corneum, but as the partition coefficients further increase, penetration may be hindered for these very lipophilic compounds as the water content present in the epidermis, which occlusion only increases, assumes a larger role in limiting the penetration of liphophilic compounds.

Moreover, though the data regarding the effect of time on occlusion’s effect on penetration is limited, it seems penetration increases with increasing duration of occlusion. However, the study that was presented only documented the effect of occlusion duration for one chemical, the lipophilic compound malathion. More experiments investigating the effect of occlusion duration on a range of chemicals, both liphophillic and hydrophilic, are needed.

In conclusion, occlusion does not universally enhance percutaneous penetration in vivo. Occlusion may enhance the penetration of the most lipophilic compounds but often fails to increase the penetration of compounds that are relatively hydrophilic. These in vivo studies reinforce the conclusions drawn from in vitro studies that partition coefficients cannot reliably predict the effect of occlusion on percutaneous penetration. It seems the degree of penetration enhancement provided by occlusion is compound specific and may be influenced by vehicle selection, temperature, humidity, and method of occlusion. As in many areas of skin biology, what seems to be a simple issue may, in fact, be complex – which seems to be the case for the effect of partition coefficients and occlusion on penetration.

 

goto top of outline Disclosure Statement

No conflicts of interest to report.


 goto top of outline References
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    External Resources

  18. Denda M, Sato J, Tsuchiya T, Elias PM, Feingold KR: Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: implication for seasonal exacerbations of inflammatory dermatoses. J Invest Dermatol 1998;111:873–878.
  19. Kömüves LG, Hanley K, Jiang Y, Katagiri C, Elias PM, Williams ML, Feingold KR: Induction of selected lipid metabolic enzymes and differentiation-linked structural proteins by air exposure in fetal rat skin explants. J Invest Dermatol 1999;112:303–309.
  20. Fluhr JW, Lazzerini S, Distante F, Gloor M, Berardesca E: Effects of prolonged occlusion on stratum corneum barrier function and water holding capacity. Skin Pharmacol Appl Skin Physiol 1999;12:193–198.
  21. Warner RR, Boissy YL, Lilly NA, Spears MJ, McKillop K, Marshall JL, Stone KJ: Water disrupts stratum corneum lipid lamellae: damage is similar to surfactants. J Invest Dermatol 1999;113:960–966.
  22. Feldmann RJ, Maibach HI: Penetration of 14C hydrocortisone through normal skin: the effect of stripping and occlusion. Arch Dermatol 1965;91:661–666.
  23. Maibach HI, Feldmann RJ: Systemic absorption of pesticides through the skin of man; in Task Group on Occupational Exposure to Pesticides (eds): Occupational Exposure to Pesticides. Report to the Federal Working Group on Pest Management from the Task Group on Occupational Exposure to Pesticides. Washington, Federal Working Group on Pest Management, 1974, pp 120–127.
  24. Guy RH, Bucks DAW, McMaster JR, Villaflor DA, Roskos KV, Hinz RS, Maibach HI: Kinetics of drug absorption across human skin in vivo; in Shroot B, Schaefer H (eds): Skin Pharmacokinetics. Basel, Karger, 1987, pp 70–76.
  25. Bucks DAW, Maibach HI, Guy RH: Percutaneous absorption of steroids: effect of repeated application. J Pharm Sci 1985;74:1337–1339.
  26. Bucks D, Maibach HI: Occlusion does not uniformly enhance penetration in vivo; in Bronaugh RL, Maibach HI (eds): Percutaneous Absorption: Drugs, Cosmetics, Mechanisms, Methodology, ed 3. New York, Dekker, 1999, pp 81–105.
  27. Bucks DA, McMaster JR, Maibach HI, Guy RH: Bioavailability of topically administered steroids: a ‘mass balance’ technique. J Invest Dermatol 1988;91:29–33.
  28. Bucks DA, McMaster JR, Maibach HI, Guy RH: Percutaneous absorption of phenols in vivo. Clin Res 1987;35:672A.
  29. Bucks DA: Prediction of Percutaneous Absorption; PhD dissertation, University of California, San Francisco, 1989.
  30. Bronaugh RL, Wester RC, Bucks D, Maibach HI, Sarason R: In vivo percutaneous absorption of fragrance ingredients in rhesus monkeys and humans. Food Chem Toxicol 1990;28:369–373.
  31. Gilpin SJ, Hui X, Maibach HI: Volatility of fragrance fhemicals: patch testing implications. Dermatitis 2009;20:200–207.
  32. Pellanda C, Strub B, Figuiredo V, Rufli T, Imanidis G, Surber C: Topical bioavailability of triamcinolone acetonide: effect of occlusion. Skin Pharmacol Physiol 2007;20:50–56.

 goto top of outline Author Contacts

Farhaan Hafeez
Dermatology Department, University of California, San Francisco
90 Medical Center Way, Surge Bldg., Room 110
San Francisco, CA 94143-0989 (USA)
E-Mail farhaanhafeez@gmail.com


 goto top of outline Article Information

Received: September 12, 2012
Accepted after revision: November 29, 2012
Published online: January 16, 2013
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 5, Number of References : 32


 goto top of outline Publication Details

Skin Pharmacology and Physiology (Journal of Pharmacological and Biophysical Research)

Vol. 26, No. 2, Year 2013 (Cover Date: April 2013)

Journal Editor: Lademann J. (Berlin)
ISSN: 1660-5527 (Print), eISSN: 1660-5535 (Online)

For additional information: http://www.karger.com/SPP


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