Medium-chain fatty acid esters-Optimising their efficacy as anti-Malassezia agents.

BACKGROUND: For fatty acid esters of monohydric alcohols, cleavage by exo-enzymes of Malassezia (M.) spp. and release of fatty acids with antimicrobial activity have been shown recently. On skin surface, this selective activation of antimicrobial activity might result in a 'self-kill' targeted locally at the site with the highest M. density. OBJECTIVES: As for the disadvantage of strong odour, use of these esters for topical therapy is limited to low concentrations. Therefore, cleavage was also tested for monoesters of octanoic and undec-10-enoic acid with the bihydric alcohol propane-1,3-diol or the trihydric glycerol. METHODS: In an agar dilution test, the minimal inhibitory concentrations of these compounds were determined for M. furfur, M. globosa, M. sympodialis and M. restricta, respectively. GC analysis of parent compounds and liberated fatty acids was used to reveal ester cleavage. RESULTS: Ester cleavage started immediately. MICs for the test compounds ranged between ~1000-8000 ppm after 14 days of incubation. 1,3-propanediol esters, especially 3-hydroxypropyl octanoate and 3-hydroxypropyl undecylenate were most effective, binary combinations exerted synergistic effects. CONCLUSIONS: The new substances are advantageous in terms of odour and substantivity and have also beneficial skin caring properties if not hydrolysed by M. spp. As a different panel of hydrolases of each single M. species is responsible for variation in efficacy among the test substances, tailored products to treat preferentially single species or blends with a broader effectivity can be designed. In vivo verification will be the next step for the successful development of this new therapeutical concept for M.-associated diseases.

Dihydroavenanthramide D inhibits mast cell degranulation and exhibits anti-inflammatory effects through the activation of neurokinin-1 receptor.

Chronic pruritus is difficult to treat. Current treatment options are frequently ineffective and new therapeutic approaches are urgently needed. Avenanthramides are active substances in oats that exhibit anti-inflammatory effects. Their potential to interrupt pruritus mechanisms was investigated in this study. It was found that the synthetic analog dihydroavenanthramide D (DHAvD) can interact with the neurokinin-1 receptor (NK1R) and inhibit mast cell degranulation. DHAvD also affects inflammatory processes and reduces secretion of the cytokine interleukin-6. Our findings indicate that DHAvD may act as a NK1R inhibitor and could be a promising candidate for topical treatments of chronic pruritus.

Inhibition of TRPV1 for the treatment of sensitive skin.

During the past years, the topic sensitive skin became one of the most important fields in dermatology. The tremendous interest is based on several studies showing that about 50% of the population declares to have sensitive skin. The human thermoreceptor hTRPV1 was previously identified to contribute to this skin condition while facilitating neurogenic inflammation leading to hyperalgesia. Furthermore, skin sensitivity towards capsaicin, a natural activator of TRPV1, was shown to correlate with sensitive skin. In a screening campaign based on recombinant HEK293-cells stably transfected with hTRPV1, the selective antagonist trans-4-tert-butylcyclohexanol was identified. This antagonist is able to inhibit capsaicin-induced hTRPV1 activation with an IC(50) value of 34 ± 5 µm tested in HEK293-cells as well as in electrophysiological recordings performed in oocytes expressing hTRPV1. Strikingly, in a clinical study with 30 women using topical treatment with o/w emulsions containing 31.6 ppm capsaicin, we were able to show that 0.4% of this inhibitor significantly reduces capsaicin-induced burning (P < 0.0001) in vivo. Thus trans-4-tert-butylcyclohexanol has the potential as a novel bioactive for the treatment of sensitive skin.

Modulation of dihydroavenanthramide D release and skin penetration by 1,2-alkanediols.

If a semisolid vehicle does not allow for the sufficient penetration of the incorporated drug, the addition of enhancers, e.g. glycols, is an option. Propylene glycol is most frequently applied in dermal products. Other 1,2-alkanediols like pentylene glycol were found to exhibit moisturizing effects and good anti-microbial activity. In the present study, the influence of propylene glycol and mainly butylene glycol (BuG) and pentylene glycol (PeG) on release and skin penetration of Dihydroavenanthramide D (DHAvD) was investigated. DHAvD release increased twice up to fourfold within 30 min if 2% of a mixture of BuG and PeG was added to a lipophilic as well as to a hydrophilic cream. Incorporation of single 1,2-alkanediols into the hydrophilic cream resulted in a linear slope of the released DHAvD amount with increasing chain length of the glycol. Trends found in the release model were also reflected in penetration studies on full thickness human breast skin using Franz diffusion cells. Here, the hydrophilic cream containing the BuG/PeG mixture was compared to the glycol-free reference. Already within 30 min the amount that penetrated into the viable skin layers doubled using the glycol-containing vehicle. After 300 min 12% of the applied dose was detected in the viable epidermis and dermis following application of the pure cream compared to 41% from the improved formulation. Dermal availability was further enhanced by administration of a polymer-stabilized hydrodispersion gel which also contained the glycol mixture. Due to their favorable biopharmaceutical and technological properties, longer chain 1,2-alkanediols represent a valuable class of ingredients for dermal products.

Thesinine-4'-O-beta-D-glucoside the first glycosylated plant pyrrolizidine alkaloid from Borago officinalis.

The glycosylated pyrrolizidine alkaloid, thesinine-4'-O-beta-D-glucoside, has been isolated from the aqueous methanol extract of dried, defatted seeds of Borago officinalis (Boraginaceae). The structure was established by means of spectroscopic and chemical analysis.