Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing-Part 2.

Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17ß-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17ß-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing.

Increasing bioavailability of (R)-alpha-lipoic acid to boost antioxidant activity in the treatment of neuropathic pain.

a-lipoic acid (a-LA) is a potent natural antioxidant because it has a broad spectrum of action towards a great many free radical species and boosts the endogenous antioxidant systems.Although it is a multi-functional molecule, its pharmacokinetic characteristics pose restrictions to its use in the treatment of oxidative stress-dependent illnesses. Formulations that increase the bioavailability of a-LA have a better potential efficacy as adjuvants for the treatment of these conditions.This objective was achieved with a liquid formulation for oral use containing only R-aLA, the natural enantiomeric and most active form of a-lipoic acid.For the first time, the effects of this formulation were evaluated on neuropathic pain, a symptom caused by an increase in oxidative stress, regardless of the underlying cause. Neuropathic patients who have used this dietary supplement noticed an improvement in their quality of life and a significant reduction was observed in a number of certain descriptive pain parameters (intensity, burning, unpleasantness, superficial pain).Undoubtedly further, more in-depth, studies need to be conducted; however, this first investigation confirms the role of R-aLA as an anti-oxidant for the aetiological treatment of peripheral neuropathy. Increasing its plasma bioavailability even after a non-invasive administration through the oral route is a good starting point for proposing a valid adjuvant for the treatment of pain symptoms.

(R)-α-lipoic acid oral liquid formulation: pharmacokinetic parameters and therapeutic efficacy.

Despite its numerous potentials, oral administration of α-lipoic acid (ALA) is characterised by pharmacokinetic limitations that reduce its therapeutic efficacy. Indeed, phenomena such as reduced solubility, lack of gastric stability and hepatic degradation determine a bioavailability of around 30% and a short half-life of ALA. The innovative oral formulation has the potential to overcome these pharmacokinetic limitations as it uses only the R enantiomer of α-lipoic acid, the natural and more active form, whose solubility and stability in gastric environment are ensured by the patented liquid solution. Analysis of the pharmacokinetic profile showed that, with this formulation, the absorption of R-ALA is accelerated with high plasmatic concentrations and prolonged stability. Therefore, the bioavailability, which tends towards intravenous bioavailability, is markedly greater than that recorded with a solid R-ALA formulation. To overcome the pharmacokinetic limitations of current solid oral formulations, one potentiates the biological efficacy of ALA: indeed, in animal models, R-ALA in a liquid formulation amplifies the recovery of the conduction velocity of sensory and motor nerves altered by diabetic neuropathy. These results highlight that the characteristics of R-ALA in the liquid formulation lead to a more effective and faster biological response suggesting a new therapeutic scenario for numerous oxidative stress-dependent pathologies (diabetic complications, peripheral neuropathies, neurodegenerative and cardiovascular diseases, etc.) requiring chronic treatment.

Novel locally active estrogens accelerate cutaneous wound healing. A preliminary study.

New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2's ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.