Improving Cognition with Nutraceuticals Targeting TGF-ß1 Signaling.

Rescue of cognitive function represents an unmet need in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Nutraceuticals deliver a concentrated form of a presumed bioactive(s) agent(s) that can improve cognitive function alone or in combination with current approved drugs for the treatment of cognitive disorders. Nutraceuticals include different natural compounds such as flavonoids and their subclasses (flavan-3-ols, catechins, anthocyanins, and flavonols), omega-3, and carnosine that can improve synaptic plasticity and rescue cognitive deficits through multiple molecular mechanisms. A deficit of transforming growth factor-ß1 (TGF-ß1) pathway is an early event in the pathophysiology of cognitive impairment in different neuropsychiatric disorders, from depression to AD. In the present review, we provide evidence that different nutraceuticals, such as Hypericum perforatum (hypericin and hyperforin), flavonoids such as hesperidin, omega-3, and carnosine, can target TGF-ß1 signaling and increase TGF-ß1 production in the central nervous system as well as cognitive function. The bioavailability of these nutraceuticals, in particular carnosine, can be significantly improved with novel formulations (nanoparticulate systems, nanoliposomes) that increase the efficacy and stability of this peptide. Overall, these studies suggest that the synergism between nutraceuticals targeting the TGF-ß1 pathway and current approved drugs might represent a novel pharmacological approach for reverting cognitive deficits in AD patients.

Development of advanced phospholipid vesicles loaded with Lippia citriodora pressurized liquid extract for the treatment of gastrointestinal disorders.

Pressurized liquid extraction was performed to obtain a phytocomplex from Lippia citriodora leaves rich in bioactive compounds. The extract was loaded in phospholipid vesicles to improve its protective effect against oxidative stress in the intestine. The phytochemicals were identified and quantified by HPLC-ESI-TOF-MS. The extract was incorporated in liposomes and penetration enhancer-containing vesicles (PEVs) modified with glucidex, a dextrin, and a biopolymer obtained from Chimaera monstrosa. The PEVs were smaller than liposomes (~150 vs 370 nm) and more stable, according to accelerated aging tests. The integrity of the vesicles in acidic or neutral pH and high ionic strength or in milk whey was assessed. The cytocompatibility of the formulations and their ability to protect Caco-2 cells against oxidative stress were confirmed in vitro and compared with two commercial extracts of L. citriodora. The results confirmed the suitability of formulations to be used in functional foods to protect the intestine from oxidative stress.

Ferulic Acid-NLC with Lavandula Essential Oil: A Possible Strategy for Wound-Healing?

Nowadays, an increasing interest in combinatorial drug delivery systems is emerging, highlighting the possibility of exploiting essential oils (EO) for topical applications. This work aimed at developing nanostructured lipid carriers (NLC) for the combined delivery of ferulic acid and Lavandula EO, whose beneficial effects in wound-healing processes have been widely reported. Homogeneous (polydispersity index, PDI < 0.2) nanoparticles with a small size (<150 nm) and a high encapsulation efficiency (>85%) were obtained. The co-presence of ferulic acid and Lavandula EO, as compared to synthetic isopropyl myristate-based NLC, increased nanoparticles' stability, due to higher ordering chains, as confirmed by morphological and physicochemical studies. An enhanced cytocompatibility was observed when combining ferulic acid and Lavandula EO, as confirmed by in vitro studies on fibroblasts. Furthermore, the combined delivery of ferulic acid and Lavandula EO significantly promoted cell migration with higher effectiveness in respect to the free drug solution and the carrier without the EO. Taken all together, our results suggest a potential combined effect of the antioxidant ferulic acid and Lavandula EO co-delivered in lipid nanoparticles in promoting cell proliferation and migration, representing a promising strategy in the treatment of wounds.

Clotrimazole-Loaded Mediterranean Essential Oils NLC: A Synergic Treatment of Candida Skin Infections.

The increasing development of resistance of Candida species to traditional drugs represents a great challenge to the medical field for the treatment of skin infections. Essential oils were recently proposed to increase drug effectiveness. Herein, we developed and optimized (23 full factorial design) Mediterranean essential oil (Rosmarinus officinalis, Lavandula x intermedia "Sumian", Origanum vulgare subsp. hirtum) lipid nanoparticles for clotrimazole delivery, exploring the potential synergistic effects against Candida spp. Small sized nanoparticles (<100 nm) with a very broad size distribution (PDI < 0.15) and long-term stability were successfully prepared. Results of the in vitro biosafety on HaCaT (normal cell line) and A431 (tumoral cell line), allowed us to select Lavandula and Rosmarinus as anti-proliferative agents with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases. Results of calorimetric studies on biomembrane models, confirmed the potential antimicrobial activity of the selected oils due to their interaction with membrane permeabilization. Nanoparticles provided a prolonged in vitro release of clotrimazole. In vitro studies against Candida albicans, Candida krusei and Candida parapsilosis, showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming nanostructured lipid carriers (NLC) containing Mediterranean essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis.

Combination of argan oil and phospholipids for the development of an effective liposome-like formulation able to improve skin hydration and allantoin dermal delivery.

Allantoin is traditionally employed in the treatment of skin ulcers and hypertrophic scars. In the present work, to improve its local deposition in the skin and deeper tissues, allantoin was incorporated in conventional liposomes and in new argan oil enriched liposomes. In both cases, obtained vesicles were unilamellar, as confirmed by cryo-TEM observation, but the addition of argan oil allowed a slight increase of the mean diameter (∼130nm versus ∼85nm). The formulations, especially those containing argan oil, favoured the allantoin accumulation in the skin, in particular in the dermis (∼8.7µg/cm(2)), and its permeation through the skin (∼33µg/cm(2)). The performances of vesicles as skin delivery systems were compared with those obtained by water dispersion of allantoin and the commercial gel, Sameplast(®). Moreover, in this work, for the first time, the elastic and viscous moduli of the skin were measured, underlining the different hydrating/moisturizing effects of the formulations. The application of ARG liposomes seems to provide a softening and relaxing effect on the skin, thus facilitating the drug accumulation and passage into and trough it.

Randomised phase II trial (NCT00637975) evaluating activity and toxicity of two different escalating strategies for pregabalin and oxycodone combination therapy for neuropathic pain in cancer patients.

PURPOSE: Neuropathic pain is commonly associated with cancer. Current treatments include combination opioid and adjuvant therapies, but no guidelines are available for dose escalation strategies. This phase II study compared the efficacy and tolerability of two dose escalation strategies for oxycodone and pregabalin combination therapy. METHODS: Patients (N = 75) with oncological neuropathic pain, previously untreated with pregabalin, were recruited in 5 Italian institutions between 2007 and 2010. Patients were randomised to two different dose escalation strategies (arm A; N = 38) oxycodone at a fixed dose with increasing pregabalin doses; (arm B; N = 37) pregabalin at a fixed dose with increasing oxycodone doses. Patients were evaluated from daily diaries and follow-ups at 3, 7, 10, and 14 days after beginning treatment with a numerical rating scale (NRS), neuropathic pain scale (SDN), and well-being scale (ESAS). The primary endpoint was a ≥1/3 reduction in pain (NRS); secondary endpoints included the time to analgesia and adverse effects. The study had a 90% probability of detecting the best strategy for a true difference of at least 15%. RESULTS: More patients in arm A (76%) than arm B (64%) achieved ≥1/3 overall pain reduction even after controlling for baseline factors (gender, baseline pain). Group A reported fewer side effects than group B; constipation 52.8% vs. 66.7%; nausea: 27.8% vs. 44.4%; drowsiness: 44.4% vs. 55.6%; confusion: 16.7% vs. 27.8%; itching: 8.3% vs. 19.4%. CONCLUSIONS: Both strategies effectively controlled neuropathic pain, but according to the adopted selection design arm A is preferable to arm B for pain control. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637975.

Idebenone-loaded solid lipid nanoparticles for drug delivery to the skin: in vitro evaluation.

Idebenone (IDE), a synthetic derivative of ubiquinone, shows a potent antioxidant activity that could be beneficial in the treatment of skin oxidative damages. In this work, the feasibility of targeting IDE into the upper layers of the skin by topical application of IDE-loaded solid lipid nanoparticles (SLN) was evaluated. SLN loading different amounts of IDE were prepared by the phase inversion temperature method using cetyl palmitate as solid lipid and three different non-ionic surfactants: ceteth-20, isoceteth-20 and oleth-20. All IDE loaded SLN showed a mean particle size in the range of 30-49 nm and a single peak in size distribution. In vitro permeation/penetration experiments were performed on pig skin using Franz-type diffusion cells. IDE penetration into the different skin layers depended on the type of SLN used while no IDE permeation occurred from all the SLN under investigation. The highest IDE content was found in the epidermis when SLN contained ceteth-20 or isoceteth-20 as surfactant while IDE distribution into the upper skin layers depended on the amount of IDE loaded when oleth-20 was used as surfactant. These results suggest that the SLN tested could be an interesting carrier for IDE targeting to the upper skin layers.