Piera Sozio

Potential antibacterial activity of carvacrol-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles against microbial biofilm.

The ability to form biofilms contributes significantly to the pathogenesis of many microbial infections, including a variety of ocular diseases often associated with the biofilm formation on foreign materials. Carvacrol (Car.) is an important component of essential oils and recently has attracted much attention pursuant to its ability to promote microbial biofilm disruption. In the present study Car. has been encapsulated in poly(dl-lactide-co-glycolide (PLGA) nanocapsules in order to obtain a suitable drug delivery system that could represent a starting point for developing new therapeutic strategies against biofilm-associated infections, such as improving the drug effect by associating an antimicrobial agent with a biofilm viscoelasticity modifier.

Drug delivery strategies for Alzheimer's disease treatment

Introduction: Current Alzheimers disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence. Areas covered: In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems. Expert opinion: The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.

New drug delivery strategies for improved Parkinson's disease therapy

Increasing interest has been addressed toward the introduction of new therapeutic approaches to obtaining continuous dopaminergic stimulation (CDS). The goal of this therapeutic strategy is to reduce the occurrence and severity of L-DOPA (LD)-associated motor fluctuations and dyskinesia, and provide good long-term safety and tolerability. CDS can be achieved by the administration of oral dopamine (DA) agonists with a long half-life, transdermal or subcutaneous delivery of DA agonists, or intestinal LD infusion. To allow higher concentrations of LD to reach the brain and to reduce peripheral side effects, the therapeutic approach provides the concomitant administration of LD, carbidopa and entacapone that have been developed in tablet form, standard LD/carbidopa, LD/benserazide, LD/entacapone, LD/tolcapone associations or long-acting controlled release formulations, LD/carbidopa and LD/benserazide. Alternatively to solid formulations, LD/carbidopa liquid forms have been developed. Furthermore, the authors examine a series of new LD codrugs and non-dopaminergic drugs for Parkinsons disease treatment, together with a variety of experimental delivery strategies including transdermal therapeutic systems, liposomes, solid lipid nanoparticles and biocompatible microparticles. This review provides an overview of progress in anti-Parkinson therapy, mainly focused on delivery strategies and codrug approach for treatment of this neurological disorder.

Codrugs linking L-dopa and sulfur-containing antioxidants: new pharmacological tools against Parkinson's disease.

A series of multifunctional codrugs (1-6) were synthesized to overcome the pro-oxidant effect associated with L-dopa (LD) therapy. Target compounds release LD and dopamine (DA) in human plasma after enzymatic hydrolysis, displaying an antioxidant effect superior to that of N-acetylcysteine (NAC). After intracerebroventricular injection of codrug 4, the levels of DA in the striatum were higher than those in LD-treated groups, indicating that this compound has a longer half-life in brain than LD.

Ibuprofen and Lipoic Acid Diamides as Potential Codrugs with Neuroprotective Activity

Current evidences support the hypothesis that non‐steroidal anti‐inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimers disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimers disease, and (R)‐α‐lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)‐α‐lipoic acid and ibuprofen via an amide bond. These new entities might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimers disease. Our study included the synthesis of conjugates 1–3 and the evaluation of their physicochemical and in‐vitro antioxidant properties. The new compounds are extremely stable in aqueous buffer solutions (pH = 1.3 and 7.4), and in rat and human plasma they showed a slow bioconversion to ibuprofen and (R)‐α‐lipoic acid. Codrugs 1–3 displayed in vitro free radical scavenging activity and were hydrolyzed more rapidly in brain tissue than in rat serum indicating that these new entities might allow targeted delivery of the parent drugs to neurons. The immunohistochemical analysis of Aβ (1‐40) protein showed that Aβ‐injected cerebral cortices treated with ibuprofen or compound 1 showed few plaques within capillary vessels and, in particular, Aβ (1‐40) protein was less expressed in codrug‐1‐treated than in ibuprofen‐treated cerebral cortex.

Dimeric L-Dopa Derivatives as Potential Prodrugs

A series of dimeric derivatives (+)-1, and (+)-2, and (+)-3a-d of L-Dopa diacetyl esters was synthesized and evaluated as potential L-Dopa prodrugs with improved physicochemical properties. All the new compounds showed chemical stability in aqueous buffer solutions (pH 1.3 and 7.4). A relatively slow release of L-Dopa in human plasma was observed.

Ibuprofen and Glutathione Conjugate as a Potential Therapeutic Agent for Treating Alzheimer's Disease

Non‐steroidal anti‐inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimers disease (AD). In the present work, we synthesized a molecular combination of glutathione (GSH) and ibuprofen (IBU) via an amide bond and investigated its potential for targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation are related to AD. Evaluation of its physicochemical and in‐vitro antioxidant properties indicated that compound 1 exhibits good stability toward human plasma enzymatic activity, and, like GSH, displays in‐vitro free radical scavenging activity in a time and concentration‐dependent manner. The new compound was also assessed by infusion in a rat model for Alzheimers disease for its potential to antagonize the deleterious structural and cognitive effects of β‐amyloid(1‐40). In behavioral tests of long‐term spatial memory, animals treated with codrug 1 performed significantly better than those treated with β‐amyloid (Aβ) peptide. Histochemical findings confirmed the behavioral data, revealing that Aβ protein was less expressed in cerebral cortex treated with 1 than that treated with IBU. Taken together, the present findings suggest that conjugate 1 treatment may protect against the oxidative stress generated by reactive oxygen species (ROS) and the cognitive dysfunction induced by intracerebroventricular (i.c.v.) infusion of Aβ(1‐40) in rats, and thus that codrug 1 could prove useful as a tool for controlling AD induced cerebral amyloid deposits and behavioral deterioration.

Viscoelastic properties of Staphylococcus aureus and Staphylococcus epidermidis mono-microbial biofilms

The viscoelastic properties of mono‐microbial biofilms produced by ocular and reference staphylococcal strains were investigated. The microorganisms were characterized for their haemolytic activity and agr typing and the biofilms, grown on stainless steel surface under static conditions, were analysed by Confocal Laser Scanning Microscopy. Static and dynamic rheometric tests were carried out to determine the steady‐flow viscosity and the elastic and viscous moduli. The analysed biofilms showed the typical time‐dependent behaviour of viscoelastic materials with considerable elasticity and mechanical stability except for Staphylococcus aureus ATCC 29213 biofilm which showed a very fragile structure. In particular, S. aureus 6ME biofilm was more compact than other staphylococcal biofilms studied with a yield stress ranging between 2 and 3 Pa. The data obtained in this work could represent a starting point for developing new therapeutic strategies against biofilm‐associated infections, such as improving the drug effect by associating an antimicrobial agent with a biofilm viscoelasticity modifier.

Preparation and characterization of poly(lactic-co-glycolic acid) microspheres loaded with a labile antiparkinson prodrug.

L-dopa-α-lipoic acid (LD-LA) is a new multifunctional prodrug for the treatment of Parkinsons disease. In human plasma, LD-LA catechol esters and amide bonds are chemically and enzymatically cleaved, respectively, resulting in a half-life time of about fifty minutes. In the present work, the unstable LD-LA was entrapped into biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres designed as depot systems to protect this prodrug against degradation and to obtain a sustained release of the intact compound. The microspheres were prepared by an oil-in-water emulsion/solvent evaporation technique and the effect of formulation and processing parameters (polymer concentration in the organic solvent, volumes ratio of the phases, rate of the organic solvent evaporation) on microspheres characteristics (size, loading, morphology, release) was investigated. Also emphasis was given on the stability of the drug before and after release as well as on the underlying mass transport mechanisms controlling LD-LA release. Interestingly, when encapsulated in appropriate conditions into PLGA microspheres, the labile prodrug was stabilized and released via Fickian diffusion up to more than one week.

New L‐Dopa Codrugs as Potential Antiparkinson Agents

This paper reports the synthesis and preliminary evaluation of new L‐dopa (LD) conjugates (1 and 2) obtained by joining LD with two different natural antioxidants, caffeic acid and carnosine, respectively. The antioxidant efficacy of compounds 1 and 2 was assessed by evaluating plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the rat. Rat striatal concentration of LD and dopamine (DA), and central nervous effects were evaluated after oral administration of the codrugs 1 and 2. The results suggest that, though our codrugs are devoid of significant antioxidant activity, they are able to induce sustained delivery of DA in rat striatum and can improve LD and DA release in the brain.