Oleic acid and oleyl alcohol are commonly used permeation and penetration enhancers to facilitate topical drug delivery. Here, we aimed to better understand the mechanism of their enhancing effects in terms of their interactions with the human skin barrier using diclofenac diethylamine (DIC-DEA), a nonsteroidal anti-inflammatory drug for topical pain management. Oleic acid promoted DIC-DEA permeation through ex vivo human skin more rapidly than oleyl alcohol (both applied at 0.75%) due to fluidization of stratum corneum lipids as revealed by infrared spectroscopy. After 12 h, the effect of these enhancers on DIC-DEA permeation leveled off, fluidization was no longer evident, and skin permeabilization was mainly due to the formation of fluid enhancer-rich domains. Contrary to oleyl alcohol, oleic acid adversely affected two indicators of the skin barrier integrity, transepidermal water loss and skin electrical impedance. The content of oleyl alcohol in the stratum corneum was lower than that of oleic acid (even 12 h after the enhancers were removed from the skin surface), but it caused higher DIC-DEA retention in both epidermis and dermis compared to oleic acid. The effects of oleyl alcohol and oleic acid on DIC-DEA permeation and retention in the skin were similar after a single and repeated application (4 doses every 12 h). Thus, oleyl alcohol offers several advantages over oleic acid for topical drug delivery.

• Keywords
• diclofenac, infrared spectroscopy, lipid interactions, penetration enhancer, permeation enhancer, skin barrier, topical drug delivery,
• MeSH
• Administration, Cutaneous MeSH
• Skin Absorption * MeSH
• Skin metabolism   MeSH
• Oleic Acid * pharmacology   metabolism   MeSH
• Humans MeSH
• Fatty Alcohols metabolism   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Oleic Acid * MeSH
• Fatty Alcohols MeSH
• oleyl alcohol MeSH Browser

This study aims to document the diversity of medicinal plants used by the Cashinahua people (also known as Huni Kuin) of the Curanja River, as well as describe and compare their uses with pharmacological and phytochemical records from previously published studies. The ethnic has been studied to a limited extent from an ethnobotanical perspective. The study area is located in the Ucayali region, eastern Central Amazon, where ancestral knowledge is preserved due to the limited accessibility of the region. Between November 2010 and June 2015, a total of 11 months were spent on the survey, which included a short-term visit to complete voucher specimen collection and taxonomic identification. We conducted semi-structured interviews with 10 Cashinahua traditional healers and 10 midwives. Vernacular names, ethnomedicinal uses, plant parts used and forms of preparation and administration were recorded. Ethnopharmacological, pharmacological and phytochemical uses were checked through survey of the previously published papers indexed on Web of Science databases between 2018 and 2022. We obtained data on 467 plant taxa, among which we highlighted 79 species unreported or rarely cited for medicinal use or phytochemical analysis. These species were spread over 60 genera and 42 botanical families, with Acanthaceae being the most represented. Leaves were used the most frequently (93.56%). Among the 79 species, the most reported therapeutic activities involved pregnancy and birth disorders (13.84%), followed by poisonings, infections and infestations. The predominant application form was external (87%). Our study indicates that there are locally valuable species that have not yet been studied for their medical potential.

• Keywords
• Ethnobotany, Ethnomedicine, Indigenous people, Peru, Traditional knowledge,
• MeSH
• Ethnobotany MeSH
• Phytotherapy MeSH
• Traditional Medicine Practitioners MeSH
• Plants, Medicinal * MeSH
• Humans MeSH
• Health Knowledge, Attitudes, Practice MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Peru MeSH

Overcoming the skin barrier properties efficiently, temporarily, and safely for successful transdermal drug delivery remains a challenge. We synthesized three series of potential skin permeation enhancers derived from natural amino acid derivatives proline, 4-hydroxyproline, and pyrrolidone carboxylic acid, which is a component of natural moisturizing factor. Permeation studies using in vitro human skin identified dodecyl prolinates with N-acetyl, propionyl, and butyryl chains (Pro2, Pro3, and Pro4, respectively) as potent enhancers for model drugs theophylline and diclofenac. The proline derivatives were generally more active than 4-hydroxyprolines and pyrrolidone carboxylic acid derivatives. Pro2-4 had acceptable in vitro toxicities on 3T3 fibroblast and HaCaT cell lines with IC50 values in tens of µM. Infrared spectroscopy using the human stratum corneum revealed that these enhancers preferentially interacted with the skin barrier lipids and decreased the overall chain order without causing lipid extraction, while their effects on the stratum corneum protein structures were negligible. The impacts of Pro3 and Pro4 on an in vitro transepidermal water loss and skin electrical impedance were fully reversible. Thus, proline derivatives Pro3 and Pro4 have an advantageous combination of high enhancing potency, low cellular toxicity, and reversible action, which is important for their potential in vivo use as the skin barrier would quickly recover after the drug/enhancer administration is terminated.

• MeSH
• Administration, Cutaneous MeSH
• Hydroxyproline metabolism   MeSH
• Skin Absorption * MeSH
• Skin metabolism   MeSH
• Carboxylic Acids metabolism   MeSH
• Pharmaceutical Preparations metabolism   MeSH
• Humans MeSH
• Organic Chemicals metabolism   MeSH
• Permeability MeSH
• Proline * metabolism   MeSH
• Pyrrolidinones pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hydroxyproline MeSH
• Carboxylic Acids MeSH
• Pharmaceutical Preparations MeSH
• Organic Chemicals MeSH
• Proline * MeSH
• Pyrrolidinones MeSH

Transdermal drug delivery is an attractive non-invasive method offering numerous advantages over the conventional routes of administration. The main obstacle to drug transport is, however, the powerful skin barrier that needs to be modulated, for example, by transdermal permeation enhancers. Unfortunately, there are still only a few enhancers showing optimum properties including low toxicity and reversibility of enhancing effects. For this reason, we investigated a series of new N-alkylmorpholines with various side chains as potential enhancers in an in vitro permeation study, using three model permeants (theophylline, indomethacin, diclofenac). Moreover, electrical impedance, transepidermal water loss, cellular toxicity and infrared spectroscopy measurements were applied to assess the effect of enhancers on skin integrity, reversibility, toxicity and enhancers' mode of action, respectively. Our results showed a bell-shaped relationship between the enhancing activity and the hydrocarbon chain length of the N-alkylmorpholines, with the most efficient derivatives having 10-14 carbons for both transdermal and dermal delivery. These structures were even more potent than the unsaturated oleyl derivative. The best results were obtained for indomethacin, where particularly the C10-14 derivatives showed significantly stronger effects than the traditional enhancer Azone. Further experiments revealed reversibility in the enhancing effect, acceptable toxicity and a mode of action based predominantly on interactions with stratum corneum lipids.

• Keywords
• dermal and transdermal drug delivery, morpholine derivatives, skin barrier, skin permeation enhancers,
• Publication type
• Journal Article MeSH