Perfluoropolyether phosphate: skin exfoliation after a topical pre-treatment, TEWL and skin elasticity, by in-vivo non-invasive methods.

Glycolic acid (GA) and other alpha-hydroxyacids (AHAs) are common ingredients of products designed to accelerate exfoliation of the skin. It is known that acidic pHs are essential in order to increase the efficacy of AHA-based products. The formulator is, therefore, obliged to achieve a difficult balance between performance (skin exfoliation) and risks (skin irritation). In order to overcome this problem, many common organic acids, and combinations of them, have been proposed, with marginal improvements. The need for a new chemistry, in order to achieve better results, was evident, particularly from the point of view of safety. We decided, therefore, to investigate the efficacy of perfluoropolyether (PFPE) phosphate, a new acidic material, already proposed for lowering the pH without increasing skin irritation. Two gels containing PFPE phosphate at different pH values (3 and 7), an acidic gel containing GA at pH 3, and a neutral gel, without an active compound, were applied on 20 healthy volunteers and evaluated with regard to effects on the skin: *Exfoliation after a topical pre-treatment with these gels *Transepidermal water loss (TEWL) and elasticity The main conclusion of the investigation was that PFPE phosphate has effects, particularly skin exfoliation rate, quite independent of the pH, and comparable to the gel containing GA at pH 3, apparently without the typical drawbacks of AHAs.

Alpha-tocopherol pro-vitamins: synthesis, hydrolysis and accumulation in rabbit ear skin.

We synthesized esters of alpha-tocopherol (VE) with the aim to develop new pro-vitamins, easily reconverted by enzymes in the skin and able to release another active moiety such as an amino acid, in order to obtain a synergic effect. In particular, the attention was dedicated to the amino acids glycine and alanine and to pyroglutamic acid. The sensitivity of pro-vitamins to enzymatic hydrolysis was evaluated in vitro using porcine liver esterase. Permeation experiments were performed using rabbit ear skin, for the quantification of pro-vitamins and derived VE in the epidermis and dermis. The new derivatives synthesized, and in particular the glycine and alanine derivatives, accumulated in rabbit skin in a significant extent and originated substantial amounts of alpha-tocopherol. In comparison with the acetate derivative (VEAc), the amounts accumulated are comparable or higher. Moreover, the new derivatives, being more hydrophilic, allow the use of vehicles such as the mixture water/propylene glycol/ethanol widely employed for the preparation of creams and gels. Finally, the enzymatic metabolism of these new derivatives generates not only VE, but also components that can have a further advantageous action on skin.

Research on heterocyclic compounds, XLI. 2-Phenylimidazo

The synthesis of a group of 2-phenylimidazo[1,2-b]pyridazine-3-acetic esters and acids is described. The structures of the new compounds are supported by 1H-NMR spectra. These compounds were tested in vivo for their anti-inflammatory, analgesic and ulcerogenic activity. All new compounds showed remarkable anti-inflammatory action in the carrageenan rat paw oedema (one third of that for indomethacin) but no significant analgesic activity in the acetic acid writhing test together with negligible ulcerogenic action, and were also found to be lacking inhibitory activity on cyclooxygenase in vitro.

Ionized prodrugs of dehydroepiandrosterone for transdermal iontophoretic delivery.

PURPOSE: The aim of this work was to synthesize ionized dehydroepiandrosterone (DHEA) prodrugs with higher water solubility, useful for iontophoretic transdermal application. METHODS: The synthesized derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Solid state and solution stability was also determined. Transdermal iontophoretic anodal transport in vitro was studied using excised rabbit skin. RESULTS: Two DHEA ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a quaternary ammonium salt. The two derivatives possess higher water solubility and lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to enzymatic hydrolysis; in particular the primary amine was hydrolyzed faster than the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of the two prodrugs was slightly higher than the parent drug. In the case of passive diffusion, only DHEA was found in the receptor compartment, indicating the complete breakdown of the prodrug in the skin. Current application gave higher drug flux and a significant amount of prodrug was found in the receptor. CONCLUSIONS: The use of ionized prodrugs of DHEA can increase the flux attainable during transdermal anodal iontophoresis by up to 7 times, but they are useful for passive transport as well.

Research on heterocyclic compounds. XXXVIII. Synthesis and pharmacological activity of imidazo[1,2-b]pyridazine-2-carboxylic derivatives.

A series of imidazo[1,2-b]pyridazine-2-carboxylic acids, esters and amides was synthesized and tested for antiinflammatory, analgesic and ulcerogenic activities. The ethyl esters were prepared by cyclocondensation of some 3-aminopyridazines with ethyl bromopyruvate, followed by hydrolysis or ammonolysis in order to obtain the corresponding acids and amides. The inhibitory activity on the carrageenan-induced edema in the rat paw and on writhes induced by acetic acid in mice was evaluated, as well as the ulcerogenic action on the rat gastric mucosa. The pharmacological activity was discussed in terms of structure-activity relationships. In particular, the analgestic activity shown by these carboxylic derivatives was compared with that found in other series of imidazo[1,2-b]pyridazine analogues previously examined.

Research on heterocyclic compounds. XXXIII--Synthesis and analgesic activity of imidazo[1,2-b]pyridazine-2-acetic acid derivatives.

A series of imidazo[1,2-b]pyridazine-2-acetic esters, acids and amides was synthesized and tested for antiinflammatory, analgesic and ulcerogenic activities. The ethyl esters were prepared by cyclocondensation of some 3-aminopyridazines with ethyl 4-chloroacetoacetate, followed by hydrolysis or ammonolysis in order to obtain the corresponding acids and amides. The capacity of inhibiting the carrageenan-induced edema in the rat paw and the writhes induced by acetic acid in mice were evaluated, as well as the ulcerogenic action in rats. The acidic derivatives showed significant analgesic activity which is comparable to that found in other series of imidazo[1,2-b]pyridazine analogs previously examined.