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La presente invenzione si riferisce a particelle micrometriche comprendenti il decanoato di cetile, al loro metodo di preparazione e a loro usi. In particolare, le particelle dell’invenzione sono utili per favorire l’assorbimento transpiteliale di principi attivi scarsamente solubili e/o permeabili.

Dairy products represent an important source of beneficial substances for humans. At the same time, they can expose the consumers to environmental contaminants ingested by animals through their diet, influencing their health negatively. This experiment aims to evaluate the risk and benefits related to the consumption of typical stretched cheeses, considering their fatty acid (FA) profile and persistent organic pollutants (POPs) content. Six representative farms, two of them organic, raising Cinisara cattle were selected, considering the typical extensive management systems, based on feeding of natural pasture integrated with concentrate and hay depending on the availability of forage on pastures. A total of 18 cheeses produced in winter, spring and summer with bulk milk of each farm were sampled and analyzed. The chemical composition of cheeses was influenced by farm management, and the FA profile mainly by the season. In particular, cheeses made in spring showed a healthier FA profile with the content of polyunsaturated fatty acids (PUFA), of omega3-PUFA and omega6/omega3 ratio pair to 7.29%, 1.44% and 1.32, respectively, while in winter 5.44%, 0.98% and 2.55, respectively, and in summer 4.77% 0.49% and 3.04, respectively. Due to high levels of feeding integration, cheese made in winter presented unhealthier characteristics compared to the cheeses made in spring and summer, showing high levels of saturated FA (66.2%, 64.2% and 65.5%, respectively), and large contents of polycyclic aromatic hydrocarbons (PAH) (57.07 ng/g fat, 36.25 ng/g fat and 10.22 ng/g fat, respectively) and polychlorinated biphenyls (PCBs) (36.19 ng/g fat, 4.68 ng/g fat and 3.73 ng/g fat, respectively), mainly in those from non-organic farms. Levels of PCBs considered to be hazardous to human health were found in nine samples.

The comparison of grapefruit IntegroPectin powders isolated via spray drying and via freeze drying in terms of phenolic content, quantification of the most representative flavonoids (naringin and hesperidin), radical scavenging activity, total protein content and pH of the aqueous solutions provides relevant information. Except for the protein content and the antioxidant power, the two drying methods afford similar pectins. Optimization of the spray drying parameters allowed to maximize the yield of isolated pectin that nearly approached (>95%) the quantitative yield obtained via freeze drying.

Resveratrol (RSV) is a natural polyphenol with several interesting broad-spectrum pharmacological properties. However, it is characterized by poor oral bioavailability, extensive first-pass effect metabolism and low stability. Indeed, RSV could benefit from the advantage of the sublingual route of administration. In this view, RSV attitudes to crossing the porcine sublingual mucosa were evaluated and promoted both by six different chemical permeation enhancers (CPEs) as well as by preparing four innovative fast-disintegrating sublingual mini-tablets by spray drying followed by direct compression. Since RSV by itself exhibits a low permeation aptitude, this could be significantly enhanced by the use of CPEs as well as by embedding RSV in a spray-dried powder to be compressed in order to prepare fast-disintegrating mini-tablets. The most promising observed CPEs (menthol, lysine and urea) were then inserted into the most promising spray-dried excipients’ compositions (RSV-B and RSV-C), thus preparing CPE-loaded mini-tablets. However, this procedure leads to unsatisfactory results which preclude the possibility of merging the two proposed approaches. Finally, the best spray-dried composition (RSV-B) was further evaluated by SEM, FTIR, XRD and disintegration as well as dissolution behavior to prove its effectiveness as a sublingual fast-disintegrating formulation.

The management of critical-size bone defects is still demanding. Recently, autologous platelet concentrates in combination with bone substitute have been applied and reported in a few studies. Our aim is to report the healing of a critical-size alveolar bone defect treated with a new bone regeneration technique by means of L-PRF and L-PRF blocks. A 45-year-old woman presented a large cystic lesion; the extraction of three teeth, a cyst removal procedure, and bone regeneration procedures with L-PRF and L-PRF blocks were planned. The L-PRF block was prepared by mixing a bone substitute with a piece of L-PRF membrane and liquid fibrinogen. Additionally, after bone healing an implant-based rehabilitation was optimally performed. On the basis of the positive results, in terms of bone healing and tissue regeneration in a large bone defect, the application of L-PRF and L-PRF blocks, in agreement with the scarce literature, is suggested as a feasible procedure in selected cases.

The restoration and prosthetic rehabilitation of missing teeth are commonly performed using dental implants, which are extremely effective and long-lasting techniques due to their osteointegration ability with the preimplant tissues. Quercetin is a phytoestrogen-like flavonoid well known for its several positive effects on human health, mostly linked to the anti-inflammatory, antioxidant, and antibacterial activities against both Gram-positive and Gram-negative bacteria. Moreover, many studies in dentistry and the maxillofacial fields have highlighted the positive effects of quercetin on osteogenesis, acting on osteoblast activity and angiogenetic process, and promoting soft and hard tissue regeneration. This review focuses on the role of quercetin on the healing and restoration of bony defects, considering the experimental findings of its application both in vitro and in vivo as a mere compound or in association with scaffolds and dental implants having functionalized surfaces.

Background: The research on the improvement of epilepsy therapy is constantly growing. Valproyl-LPhenylalanine (VPA-Phen) and N-valproyl-L-tryptophan (VPA-Tryp) were synthesized to increase the antiepileptic efficacy of valproic acid. Methods: VPA-Phen and VPA-Tryp were comparatively tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 mM) of VPA-Phen or VPA-Tryp. Both burst duration and interburst frequency, during and after treatment, were off-line compared with baseline values. For both parameters, either the latency or the duration of drug-induced statistically significant responses was calculated, as well as the response magnitude. Results: VPA-Phen significantly reduced both burst frequency and duration. Comparative analyses show that VPA-Phen and VPA-Tryp exert almost equivalent actions on both latency and magnitude of the observed inhibitory effects. The main observed difference between the two tested molecules concerned the duration of inhibitory effects, since VPA-Phen-dependent actions on both burst rate and duration were significantly shorter than the VPA-Tryp-induced ones. In addition, in some slices the above reported inhibitory responses were preceded by a “paradoxical” transient increase, more present at lower drug concentrations. Conclusions: Both VPA-Phen and VPA-Tryp exert significant inhibitory effects on hippocampal burst activity parameters. Although of comparable magnitude, VPA-Phen-dependent effects have a shorter duration than VPATryp- induced ones. Nevertheless, the present results confirm that the conjugation between VPA and aminoacids represents a valid tool to improve the efficacy of antiepileptic drugs and, as well as for VPA-Tryp, propose VPAPhen as a novel VPA derivative with enhanced pharmacological features.

Immediate implant placement is a single-stage restorative approach for missing teeth widely used to overcome the ridge remodeling process occurring after dental extractions. The success of this procedure relies on opportune osseointegration in the surrounding tissues. To support this process, a multifunctional nanocomposite, to be applied in the fresh post-extraction socket, was here designed, prepared, and characterized. This formulation consists of quercetin (QRC)-loaded nanostructured lipid carriers (NLCs) entrapped in a chitosan-based solid matrix containing ciprofloxacin (CPX). QRC-NLCs were prepared by homogenization followed by high-frequency sonication, and thereafter this dispersion was trapped in a chitosan-based CPX-loaded gel, obtaining the nanocomposite powder (BioQ-CPX) by lyophilization. BioQ-CPX displayed desirable properties such as high porosity (94.1 ± 0.5%), drug amounts (2.1% QRC and 3.5% CPX). and low swelling index (100%). Moreover, the mechanism of drug release from BioQ-CPX and their ability to be accumulated in the target tissue were in vitro and ex vivo elucidated, also by applying mathematical models. When trapped into the nanocomposite, QRC stressed under UV light exposure (50 W) was shown to maintain its antioxidant power, and CPX and QRC under natural light were stable over nine months. Finally, both the measured antioxidant power and the antimicrobial and antibiofilm properties on Staphylococcus aureus demonstrated that BioQ-CPX could be a promising platform to support the single-stage dental restorative treatment.

The mesolimbic dopamine (DA) system plays a key role in drug reinforcement and is involved in the development of alcohol addiction. Manipulation of the DAergic system represents a promising strategy to control drug-seeking behavior. Previous studies on 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) showed in vivo effects as a DA-ergic modulator. This study was aimed at investigate DA-Phen effects on operant behavior for alcohol seeking behavior, during reinstatement following subsequent periods of alcohol deprivation. For this purpose, male Wistar rats were tested in an operant paradigm of self-administration; behavioral reactivity and anxiety like-behavior during acute abstinence were evaluated. A characterization of DA-Phen CNS targeting by its quantification in the brain was also carried out. Our findings showed that DA-Phen administration was able to reduce relapse in alcohol drinking by 50% and reversed the alterations in behavioral reactivity and emotionality observed during acute abstinence. In conclusion, DA-Phen can reduce reinstatement of alcohol drinking in an operant-drinking paradigm following deprivation periods and reverse abstinence-induced behavioral phenotype. DA-Phen activity seems to be mediated by the modulation of the DAergic transmission. However further studies are needed to characterize DA-Phen pharmacodynamic and pharmacokinetic properties, and its potential therapeutic profile in alcohol addiction.

Nowadays, chemoprevention by administering natural supplements is considered an attractive strategy to reverse, suppress, or prevent the evolution of premalignant oral lesions. In particular, Barbaloin exhibits anti-proliferative, anti-inflammatory, and anti-cancer properties, and it results useful in multi-therapy with classic chemotherapeutics. Therefore, in this work, mucoadhesive buccal films, as locoregional drug delivery system able to provide a targeted and efficient therapeutic delivery of Barbaloin, are proposed. Thus, Aloin extract-loaded Eudragit (R) RL100 or Eudragit (R) RS100-based buccal films were designed in order to obtain an easily self-administrable formulation capable of promoting Barbaloin penetration into buccal mucosa and assuring high patient compliance. Large amounts of extract (44%) were loaded into the polymer matrix and six formulations were prepared varying polymers and plasticizers ratios. For all formulations, physical form (thermogravimetric analysis-differential scanning calorimetry, TGA-DSC), swelling degree, mucoadhesiveness, drug release, and ability to promote drug penetration in mucosa have been investigated. After a sequential selection process, Eudragit RS 100-based film, with low PVP and high plasticizers amounts, emerged as the most promising. It results appropriately flexible, uniform in terms of weight, thickness and drug content, as well as characterized by suitable surface pH, good mucoadhesiveness, and low swelling degree. It displays a Higuchian drug release behavior up to 89% of Barbaloin released, thus demonstrating that diffusion through the matrix is the main release mechanism. Remarkable penetration enhancer properties of film were demonstrated by evidence of Barbaloin accumulation into buccal mucosa up to 10-fold higher than those obtained following administration of Aloin solution.

In many mucocutaneous disorders, corticosteroids therapy is currently central. Systemic therapy is restricted to severe disorders whereas topical applications are considered as the first-line treatment. The oral cavity environment, the medication form and other factors related to the delivery method are key factors for the therapy efficiency and effectiveness. Current marketed medications are not able to avoid wrong drug exposure and scarce patients’ compliance. Innovative in situ delivery systems are able to prolong the drug retention time on the mucosa and to avoid the drawbacks of conventional formulations. This review is intended to give a general overview of oral mucocutaneous pathologies and highlight the potential of new technologies in designing innovative delivery systems able to release corticosteroids in situ for the treatment of various oral cavity disorders.

Administered by an oral route, Furosemide (FUR), a diuretic used in several edematous states and hypertension, presents bioavailability problems, reported as a consequence of an erratic gastrointestinal absorption due to various existing polymorphic forms and low and pH-dependent solubility. A mucoadhesive sublingual fast-dissolving FUR based film has been developed and evaluated in order to optimize the bioavailability of FUR by increasing solubility and guaranteeing a good dissolution reproducibility. The Differential Scanning Calorimetry (DSC) analyses confirmed that the film prepared using the solvent casting method entrapped FUR in the amorphous state. As a solid dispersion, FUR increases its solubility up to 28.36 mg/mL. Drug content, thickness, and weight uniformity of film were also evaluated. The measured Young’s Modulus, yield strength, and relative elongation of break percentage (EB%) allowed for the classification of the drug-loaded film as an elastomer. Mucoadhesive strength tests showed that the force to detach film from mucosa grew exponentially with increasing contact time up to 7667 N/m2. FUR was quickly discharged from the film following a trend well fitted with the Weibull kinetic model. When applied on sublingual mucosa, the new formulation produced a massive drug flux in the systemic compartment. Overall, the proposed sublingual film enhances drug solubility and absorption, allowing for the prediction of a rapid onset of action and reproducible bioavailability in its clinical application.

The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate. The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) − a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-mediated metabolism of drug-like molecules. Wistar rats, subjected to two different behavioural studies in which DA-Phen was intraperitoneally administrated at a dose equal to 0.03 mmol/kg, were sacrificed after the experimental protocols and their major organs were analysed to quantify the drug uptake. The data obtained were integrated with in silico prediction of potential metabolites of DA-Phen using the SmartCYP predictive tool. DA-Phen reached quantitatively the Central Nervous System and the results showed that the amide bond of the DA-Phen is scarcely hydrolysed as it was found intact in analyzed organs. As a consequence, it is possible to assume that DA-Phen acts as dopaminergic modulator per se and not as a Dopamine prodrug, thus avoiding peripheral release and toxic side effects due to the endogenous neurotransmitter. Furthermore the identification of potential metabolites related to biotransformation of the drug candidate leads to a more careful evaluation of the appropriate route of administration for future intended therapeutic aims and potential translation into clinical studies.

A major challenge in the development of novel neuro-therapeutic agents is to effectively overcome the blood-brain barrier (BBB), which acts as a 'working dynamic barrier'. The core problem in the treatment of neurodegenerative diseases is failed delivery of potential medicines due to their inadequate permeation rate. Areas covered: The present review gives a summary of endogenous moieties used in synthesizing prodrugs, derivatives and bioisosteric drugs appositely designed to structurally resemble physiological molecular entities able to be passively absorbed or carried by specific carrier proteins expressed at BBB level. In particular, this overview focuses on aminoacidic, glycosyl, purinergic, ureic and acidic fragments derivatives, most of which can take advantage from BBB carrier-mediated transporters, where passive diffusion is not permitted. Expert opinion: In the authors ’ perspective, further progress in this field could expedite successful translation of new chemical entities into clinical trials. Careful rationalization of the linkage between endogenous molecular structures and putative transporters binding sites could allow to useful work-flows and libraries for synthesizing new BBB-crossing therapeutic substances and/or multifunctional drugs for treatments of central disorders.

The dopamine-amino acid conjugate DA-Phen was firstly designed to obtain a useful prodrug for the therapy of Parkinson's disease, but experimental evidence shows that it effectively interacts with D1 dopamine receptors (D1DRs), leading to an enhancement in cognitive flexibility and to the development of adaptive strategies in aversive mazes, together with a decrease in despair-like behavior. In this paper, homology modelling, molecular dynamics, and site mapping of D1 receptor were carried out with the aim of further performing docking studies on other dopamine conjugates compared with D1 agonists, in the attempt to identify new compounds with potential dopaminergic activity. Two new conjugates (DA-Trp 2C, and DA-Leu 3C) have been identified as the most promising candidates, and consequently synthesized. Preliminary evaluation in terms of distribution coefficient (DpH7.4), stability in rat brain homogenate, and in human plasma confirmed that DA-Trp (2C), and DA-Leu (3C) could be considered as very valuable candidates for further in vivo studies as new dopaminergic drugs.

Tumor derived exosomes are vesicles which contain proteins and microRNAs that mediate cell-cell communication and are involved in angiogenesis and tumor progression. Curcumin derived from the plant Curcuma longa, shows anticancer effects. Exosomes released by CML cells treated with Curcumin contain a high amount of miR-21 that is shuttled into the endothelial cells in a biologically active form. The treatment of HUVECs with CML Curcu-exosomes reduced RhoB expression and negatively modulated endothelial cells motility. We showed that the addition of CML control exosomes to HUVECs caused an increase in IL8 and VCAM1 levels, but Curcu-exosomes reversed these effects thus attenuating their angiogenic properties. This antiangiogenic effect was confirmed with in in vitro and in vivo vascular network formation assays. SWATH analysis of the proteomic profile of Curcu-exosomes revealed that Curcumin treatment deeply changes their molecular properties, in particular, Curcumin induces a release of exosomes depleted in pro-angiogenic proteins and enriched in proteins endowed with anti-angiogenic activity. Among the proteins differential expressed we focused on MARCKS, since it was the most modulated protein and a target of miR-21. Taken together our data indicated that also Curcumin attenuates the exosome's ability to promote the angiogenic phenotype and to modulate the endothelial barrier organization.

The aptitude of ropinirole to permeate the buccal tissue was tested using porcine mucosa mounted on Franz-type diffusion cells as ex vivo model. Drug permeation was also evaluated in presence of various penetration enhancers and in iontophoretic conditions. Ropinirole, widely used in treatment of motor fluctuations of Parkinson's disease, passes the buccal mucosa. Flux and permeability coefficient values suggested that the membrane does not appear a limiting step to the drug absorption. Nevertheless, an initial lag time is observed but the input rate can be modulated by permeation enhancement using limonene or by application of electric fields. Absorption improvement was accompanied by the important reduction of the lag time; at once the time required to reach the steady state plasma concentration was drastically decreased. On the basis of these results we could assume that clinical application of ropinirole by buccal delivery is feasible.

5-Fluorouracil (5-FU) is currently used for treatment of oral squamous cell carcinoma (OSCC). 5-FU is given by i.v. although the systemic administration is associated with severe toxic effects and no topical formulations of 5-FU for buccal drug delivery have been reported. In this study we would report the development of buccal tablets suitable for direct application of low-doses of 5-FU on cancer lesions. The topical administration could be effective on tumor area while systemic undesired side effects are avoided. Preliminarily, the limited tendency of 5-FU to cross the buccal tissue was established using reconstituted human oral epithelium (RHOE, in vitro) and porcine buccal mucosa (ex vivo) as mucosal models. The values of steady-state flux and permeability coefficient suggested the scarce aptitude of 5-FU to reach the systemic circulation. Matrix buccal tablets, were designed for 5-FU local delivery, developed and prepared. Release tests showed a highly reproducible Higuchian drug discharge. After tablet administration on buccal tissue specimens, the occurrence of histomorphological effects of 5-FU was highlighted. Apoptotic events were registered in all samples treated while only negligible amounts of 5-FU permeated the buccal membrane and reached the simulated plasma. The results suggest that loaded matrix tablets containing 5% of 5-FU could be a useful means in topical treatment of OSCC.

The transbuccal delivery of drugs could assist several categories of chronic, especially elderly, patients in adhering to a correct dosage regimen. In particular, patients suffering from dementia have several difficulties in following the prescribed dosage, in addition to problems associated with swallowing tablets. Galantamine is currently used for treating patients with mild to moderate Alzheimer's-type dementia. The transbuccal delivery of this drug could be an interesting non- invasive and safe administration route. Several studies have been performed in vitro and ex vivo within the framework of a European Commission funded Project (IntelliDrug-FP6), aimed at developing a device which would be fitted for controlled delivery of drugs by an electronic and software-driven system. The primary objective of this study was to evaluate the efficacy of a prototype of the IntelliDrug device in vivo on 6 pigs, following a single Galantamine dose to be delivered through the buccal mucosae, as compared to intravenous drug injection. The secondary objectives were: a) to verify Galantamine bioavailability through buccal delivery; b) to evaluate the permeation enhancement effect of iontophoresis; and, finally, c) to assess any histomorphological changes in the buccal mucosae after transbuccal delivery. The results suggested that transbuccal delivery has the potential to cause long-lasting and controlled blood levels of Galantamine. The latter crosses the entire buccal mucosae, reaching systemic circulation after about 30 minutes and its plasmatic peak approximately 120 minutes after administration. The histological analysis of the buccal mucosae did not reveal any evidence of flogosis or tissue injury. Our results have clearly confirmed that the buccal delivery of Galantamine is a reliable tool with which to overcome the drawbacks associated with the conventional administration route. In general, transbuccal drug delivery has been shown to be an interesting, non-invasive and safe administration route for delivering systemically-acting drugs.

Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of the blood-brain barrier (BBB). Condensation of dopamine with neutral amino acids could afford potential pro- drugs able to interact with the BBB endogenous transporters and easily enter the brain. To improve the bio-availability of the dopamine prodrug, 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DOPH), it was encapsulated in unilamellar liposomes of dimiristoylphosphatidylcholine (DMPC)and cholesterol. Vesicles were characterized by dynamic light scattering in order to evaluate their dimensions and vesicle stability, by zeta-potential measurements, by means of electronic microscopy after freeze-fracture and differential scanning calorimetry. The influence of vesicle composition on DOPH chemical and enzymatic stability was also evaluated. The formulated liposome suspensions were found to be stable, monodisperse systems with a negative zeta potential. From the obtained results, it is possible to conclude that, in studied samples, DOPH inclusion in liposomes offers the possibility of preventing photodegradation and of enhancing in vitro plasma stability. These studies suggest the potential of these formulations as a method to prevent DOPH chemical degradation and enzymatic metabolism.

Transbuccal drug delivery has got several well-known advantages especially with respect to peroral way. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800 microm thick was investigated using Franz type diffusion cells and compared with in vitro data previously obtained by reconstituted human oral epithelium 100 microm thick. Both fluxes (Js) and permeability coefficients (K(p)) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhancers or iontophoresis. No significant differences in penetration rate were observed using chemical enhancers; in contrast, Js and K(p) were extensively affected by application of electric fields. Tablets, designed for Naltrexone hydrochloride (NLX) administration on buccal mucosa, were developed and prepared by direct compression of drug loaded (56%) poly-octylcyanocrylate (poly-OCA) matrices. NLX is slowly discharged from buccal tablets following Higuchian kinetic. Histologically, no signs of flogosis ascribable to NLX and/or poly-OCA were observed, while cytoarchitectural changes due to iontophoresis were detected. Buccal tablets containing NLX may represent a potential alternative dosage form in addiction management.

2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-PHEN) has been previously synthesized to obtain a potential prodrug capable of release dopamine (DA) into CNS. However, DA-PHEN could act per se as a dopaminergic drug. In this study, the permeability transport (Pe), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (Pe = 0.32 ± 0.01 × 10(-6 )cm/s). Using the Caco-2 cell system, the Papp AP-BL in absorptive direction (3.36 ± 0.02 × 10(-5 )cm/s) was significantly higher than the Papp BL-AP in secretive direction (1.75 ± 0.07 × 10(-5 )cm/s), suggesting a polarized transport. The efflux ratio (Papp AP-BL/Papp BL-AP = 0.52 ± 0.02) indicated a low affinity of DA-PHEN to efflux carriers. The forced swim test highlighted a reduction of immobility time in both pre-test and test sessions (p 0.0001), with an exacerbation in the number of headshakes and divings in the pretest (p 0.0001). Morris water maze strengthened the hypothesis that DA-PHEN induces adaptive responses to environmental challenges which are involved on cognitive functions (DA-PHEN versus CTR: escape latency; p 0.001; distance swum p 0.001, time spent on target quadrant p 0.001), without any change in locomotor activity for the administered dose. The molecular docking revealed the interaction of DA-PHEN with the identified D1 site mapping human brain receptor.

Rewarding and reinforcing properties of alcohol are mediated by activation of the mesolimbic dopaminergic system1. This neurosystem is hypofunctional in the addicted brain, even beyond somatic and psychological signs of withdrawal. Boosting strategy on the dopaminergic tone could represent a valid approach to alcohol addiction treatment2. The effects of a new dopamine conjugate3 (2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide, DA-Phen) on operant behaviour and on withdrawal behaviour, following alcohol deprivation, were evaluated. The concentration of acetaldehyde (ACD), ethanol's first metabolite, as an indirect measure of the possible DA-Phen modulation in alcohol consumption, was also assessed. Male Wistar rats were tested in an operant paradigm, made by different phases: Habituation (Ethanol 5%), Training (Ethanol 20%), Extinction and Deprivation/Relapse (3 cycles). Rats were treated with DA-Phen (0.03 mmol/kg i.p) during abstinence, or during relapse. Behavioural reactivity and anxiety-like behaviour during withdrawal were also evaluated. At the end of described paradigm, animals were sacrificed, and DA-Phen distribution in organ homogenates was detected and quantified. Da-Phen promoted a reduction in alcohol intake by 50% from the second day of relapse (p

Context: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose. Objective: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system. Materials and Methods: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudragit® RS 100 as, biocompatible, low permeable, pH-independent, and non-swelling polymer. The prepared tablets were evaluated for drug-polymer compatibility, weight variation, drug uniformity content, diameter, thickness, hardness, friability, swelling, mucoadhesive strength, and drug release. Results: Aloin has low tendency to cross buccal mucosa, permeation is marginal, and high drug amounts remain entrapped into the epithelium. Matrix tablets characteristics were in agreement with pharmacopoeial requirements. Drug release showed highly reproducible Higuchian profile. Delivery through matrix tablets promoted drug accumulation in the mucosal tissue. Discussion and conclusion: Following application of matrix tablets on porcine buccal mucosa, the amount of discharged drug recovered in the tissue should be sufficient to produce the desired effects, providing therapeutic drug levels directly at the site of action. Aloin loaded tablets are valid candidates for prevention/treatment of potentially malignant disorders and oral cancer and could potentially lead to clinically relevant drug delivery system as coadjuvant of conventional chemotherapy/radiation therapy.

The need for more rapid onset of action and improved absorption of medications has resulted in great development of drug delivery technologies. Transmucosal drug delivery offers a convenient route of administration for a variety of clinical indications. Unfortunately, the wide variability in structure of the oral mucosal tissues could constitute a key factor in drug penetration and absorption. To circumvent this obstacle and to increase the drug flux through the mucosal membranes, different approaches to permeation enhancement are used. This chapter describes the most significant aspects of the physical techniques widely used such as sonophoresis, iontophoresis, and electroporation. These physical methods are extensively used to enhance drug permeation through the skin, nevertheless, they have some infrequent applications on the mucosae of the oral cavity despite are very promising. In the future, these methods could be further developed and improved.

Epilepsy, affecting at least 50 million persons worldwide, is one of the most common neurological disorders. Despite the significant advances in understanding epileptogenic mechanisms and in counteracting their pathological consequences, this clinical condition still has to be faced of treating more effectively the symptoms (epileptic seizures) and of preventing their unfavourable evolution. So far, research has been unsuccessful involved in developing effective antiepileptic drugs (AEDs) capable of preventing the development of the pathogenic process, set in motion by different etiological factors, that leads ultimately to chronic epilepsies .[1, 2] So, a substantial need remains to develop new AEDs with better safety, less toxicity, and higher efficacy [3, 4]. Valproic acid, VPA, is one of the four most widely prescribed AEDs. Besides its wide use in both generalized and partial epilepsies, VPA has also gained widespread use in recent years for the treatment of bipolar disorders, neuropathic pain and for prophylactic treatment of migraine. [5,6] However the use of VPA is limited by two rare but potentially life-threatening side effects, hepatotoxicity, induced from the formation of metabolite(s) with a terminal double bond, specifically 4-ene-VPA, [7] and teratogenicity, associated with the parent compound itself [8]. In a previous work we reported the synthesis of aminoacidic ester derivatives of VPA as resulted of chemical conjugation of VPA with esters of essential neutral aminoacids, with the aim of modifying the physicochemical properties relevant to bioavailability, such as solubility or lipophilicity, improving the efficacy and reducing unwanted side or toxic effects of VPA [9]. We had reported also the synthesis of N-valproyl-L-tryptophan, that has shown adequate physicochemical characteristics to permeate biological membranes and antiepileptic activity at lower concentration than VPA. [10,11] In this paper, we focused our research on synthesis and characterization of new aminoacidic compounds with potential antiepileptic activity: N-Valproyl-L-Leucine (ValLeu), N-Valproyl-L-methionine (ValMet) and N-Valproyl-L-Histidine (ValHist). The conjugation could consent to obtain VPA derivatives, lacking of structural characteristics usually implicated on VPA teratogenicity, and avoiding formation of possible hepatotoxic metabolites. The aminoacidic derivatives of VPA was successfully obtained covalent linking carboxyl group of drug with aminic group of L-aminoacids, by synthesis involving two main steps. The first step, described in our previous work [9] was modified by adding DMAP as further coupling agent together with DCC. The structures of obtained compounds were assigned on the basis of respective analytical data-sets, FT-IR, MS and 1H and 13C-NMR spectral data. Since the drug lipophilicity is an important factor conditioning brain uptake, the apparent partition coefficient (Papp) could be used as simple descriptor of ability to cross the BBB: values of log Papp within -0.2 to 1.3 have been described as optimal for cerebral transport; on the other hand higher values than these could reduce the rate of transport inside the membrane [12, 13]. Apparent partition coefficient (Papp) of ValLeu, ValMet and ValHist were determined in n-octanol /phosphate buffer pH 7.4 solution and expressed as Log Papp. The determined Log Papp resulted -0.11,- 1,02 and -1,61 respectively. The Log DpH7.4 values indicate that ValLeu, ValMet are adequate to cross biological membranes and in particular BBB barrier while ValHist value is too low, probably due to the fact that was obtained as hydrochloride. Compared to others drug administration routes, the oral one remains the most preferred as it implies ease of administration as well as high patient compliance. However, the transit through the gastrointestinal tract could constitute a limiting step to bioavailability as a consequence of degradation correlated to the environmental pH. In view of a possible administration of ValLeu, ValMet and ValHist by oral route, studies on their chemical stability were performed in simulated gastro-intestinal buffer (37°C, pH 1.2 to 8.0) and monitored by HPLC analysis. The experiments demonstrated that ValLeu, ValMet and ValHist remained unchanged up to 24 h, and didn’t produce degradation products or potential metabolites. This behaviour indicates high stability at pH conditions of gastro-intestinal tract. Since compounds containing amide functional group could be susceptible of hydrolysis by plasma and/or cerebral enzymes, our experiments were focused on the evaluation of stability of ValLeu, ValMet and ValHist in these biological environments. Otherwise, plasma stability of drug candidates plays an important role in drug discovery and development; it is essential for maintaining acceptable drug concentration and half-life in order to achieve desirable pharmacological effects [14]. Experimental data highlighted that ValLeu, ValMet and ValHist remained unmodified up to 24 h in plasma environment. In rat brain homogenate ValLeu, ValMet and ValHist didn’t undergo cleavage after 24 h, indicating that synthetized compounds have also good stability to cerebral enzymes. References [1] Arroyo S, Brodie MJ, Avanzini G, Baumgartner C, Chiron C, Dulac O, French JA, Serratosa JM Is refractory epilepsy preventable? Epilepsia, (2002) 43, 437–444. [2] Walker MC, White HS, Sander JWAS. Disease modification in partial epilepsy. Brain, (2002) 125, 1937–1950 [3] Bialer M, Yagen B, Valproic Acid: Second Generation, Neurotherapeutics (2007) 4, 130-137 [4] Shimshoni J A, Bialer M, Yagen B, Synthesis and anticonvulsant activity of aromatictetramethylcyclopropanecarboxamide derivatives, Bioorg. Med. Chem. (2008) 16, 6297-6305. [5] Lennkh C, Simhandl C, Current aspects of valproate in bipolar disorder, Int Clin Psychopharmacol. (2000) 15, 1-11. [6] Guidotti A, Dong E, Kundakovic M, Satta R, Grayson DR, Costa E Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodelling, Trends Pharmacol. Sci. (2008) 30, 55–60., 7]. [7] Silva MFB, Aires CC, Luis PB, Ruiter JP, Ijlst L, Duran M, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. 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[11] Sardo P, Rizzo V, Friscia S, Carletti F, De Caro V, Scaturro AL, Giandalia G, Giannola LI, Ferraro G Inhibitory effects of N-valproyl-L-tryptophan on high potassium, low calcium and low magnesium-induced CA1 hippocampal epileptiform bursting activity in rat brain slices, J Neural Transm. (2012) 119, 1249–1259. [12] Trojnar MK; Weirzchowska-Cioch E, Krzyzanowski M; Jargiello M, Czuzczwar SJ. New generation of valproic acid. Pol. J. Pharmacol., (2004) 56, 283–288. [13] Gimenez F, Fernandez C, Mabondzo A. Transport of HIV protease inhibitors through the bloodbrain barrier and interactions with the efflux proteins, P-glycoprotein and multidrug resistance proteins. J. Acquir. Immune Defic. Syndr. (2004) 36, 649-658 [14] Di L, Kerns EH, HongY, Chen H. Development and application of high throughput plasma stability assay for drug discovery. Int. J. Pharm., (2005) 297, 110–119

Ionizing radiation can be used as a drug sterilization technique, provided that the drug itself is not modified and that no toxic products are produced; moreover, if the irradiated product is a drug delivery system, the drug release characteristics must not be significantly altered by radiation. The aim of this work was to study the effects of sterilization by ionizing radiation on hydroxyethylcellulose/trehalose spherical micromatrices, containing the antibiotic vancomycin. Our experimental results showed that gamma-rays did not alter the chromophore groups of vancomycin (UV measurements), and did not modify the kinetic behavior of drug release from microspheres. Moreover, no significant changes in the shape and in the size distribution of microspheres were found after irradiation. The electron spin resonance (ESR) spectroscopy was proven to be a valid identification method of the executed radiation treatment, even after 5 years. The experimental results showed that the therapeutic application of the pharmacological system investigated was not compromised by irradiation, and that ESR spectroscopy can be used to distinguish irradiated from non-irradiated products.

The buccal mucosa is the stratified squamous epithelial tissue inside lining of the cheeks. It is a favorable site of drug absorption since the tissue is non-keratinized, relatively immobile and strongly supplied with blood by a dense capillary-vessel network; moreover, it is highly tolerant to allergens, resistant to potentially harmful agents and has a relatively low enzymatic activity. The tissue consents quick onset of effect, offers an easily accessible and generally well-accepted site for drug delivery, is a useful route of administration in patients in an unconscious state (e.g., when swallowing is impaired), and is suitable for retentive dosage forms of administration. Buccal mucosa allows drug delivery for both locoregional and systemic treatments. Locoregional delivery has a number of applications, including treatment of local conditions, such as mucositis, bacterial and fungal infections, aphthous stomatitis, vesiculobullous diseases, and potentially malignant disorders and oral cancer. On the other hand, the tissue is appropriate for delivering systemically acting drugs. The actives directly enter general circulation through capillary vessels, bypassing the first-pass metabolism in the intestine and liver, avoiding presystemic drug elimination or chemical/enzymatic degradation within the gastrointestinal tract thus leading to high bioavailability. “If low concentrations of drug are required to gain access to the blood, transbuccal drug delivery may be very satisfactory for safe and well-accepted future clinical applications” [1–3]. Controlled delivery of drugs through the buccal mucosa should be considered like a slow intravenous infusion. These characteristics contribute to optimal pharmacokinetic behavior of drugs after administration of smaller doses than in conventional oral formulations [4]. Nevertheless, similar to other mucosal membranes, the buccal mucosa has some disadvantages, including short residence time and small absorption area. The major limitation to buccal drug delivery is the barrier property of the tissue which has inadequate permeability for certain molecules, resulting in low drug bioavailability. Drug absorption is very satisfactory only for those actives that possess adequate physicochemical properties and the ability to permeate across the tissue. Accordingly, the formulative approach alone could be not sufficient for an effective control of drug delivery through the mucosa, and limited rate of absorption should be adjusted by simultaneous chemical and physical enhancement, including supersaturation and eutectic formation [4,5]. Buccal dosage forms reside in a tastesensing organ, and organoleptic aspects of formulation could become crucial limiting factors for drug application. Suitable palatal properties are often required to get optimal acceptability of dosage form or for masking less desirable properties of the active component [6]. Despite offering the possibility of improved systemic drug delivery, buccal administration has been utilized for relatively few pharmaceutical products so far. Conventional dosage forms, such as solutions, are commercially available for Buccal drug delivery: what’s new and what does the future hold?

Rewarding and reinforcing properties of alcohol have been shown to be mediated by activation of the mesolimbic dopaminergic system. Experimental evidences suggest that mesolimbic dopamine system is hypofunctional in addicted brain; further, reduced dopaminergic activity outlasts somatic signs of withdrawal and may drive craving and relapse. Boosting strategy on dopaminergic neurons could represent a valid therapy. Effects of pharmacological manipulation of brain Dopaminergic receptors by a new dopamine conjugate, Phenylalanine-β(3,4dihydroxyphenyl)-etilamide (DA-Phen), on operant behaviour and on both acute and prolonged withdrawal symptoms during ethanol abstinence have been evaluated. Male Wistar rats were tested in an operant conditioning task: they were subjected to Habituation (Ethanol 5%), Training (Ethanol 20%), and Extinction sessions. Then, three cycles of Deprivation/Relapse were performed. Rats were administered with DA-Phen (0.03mmol/kg i.p) during abstinence, or during relapse, 2h prior the operant task session. Locomotor activity and anxiety-like behaviour during withdrawal were also evaluated. Da-Phen, administered during abstinence phase, or during relapse, was able to reduce alcoholic intake pattern by 50% from the second day of operant conditioning task (p