Current Drug Delivery - Volume 7, Issue 4, 2010

Long term prevention of smooth muscle cell migration and proliferation inside the lumen of coronary arteries after stent implantation remains a challenge in medicine. Vascular stents have been coated with anti-proliferative drugs such as paclitaxel and rapamycin to improve the stents' efficacy. Maintaining adequate drug concentration on coronary stents presents an obstacle which magnetic nanoparticle (MNP) drug delivery could potentially overcome. Biodegradable, super-paramagnetic nanoparticles guided by high gradient magnetic fields have been proposed as transport vehicles for redosing stents with anti-proliferative drugs. The current study determined the characteristics of a number of candidate MNP formulations in terms of their size, surface charge, efficiency of magnetite and drug loadings, drug release profiles as well as their anti-proliferative effect on the relevant vascular cells. MNPs containing near 30% (w/w) magnetite and 12% (w/w) paclitaxel were formulated from polylactide and poly(lactide-co-glycolide) polymers using an emulsificationsolvent evaporation methodology. Drug release patterns correlated well with cell growth inhibition in cultured aortic smooth muscle cells and bovine aortic endothelial cells treated with varying MNP doses. Cell viability assays revealed MNP dose-dependent cell growth inhibition over an 8-day time span for paclitaxel-loaded formulations resulting in near 80% and 100% of cell growth arrest in cultured vascular smooth muscle cells and endothelial cells respectively, while unloaded with drug formulations showed negligible variation from the non treated cells. It is concluded, that biodegradable polymeric superparamagnetic nanoparticles loaded with a relatively high level of magnetite and drug could serve as efficient carriers in vascular stent targeting applications and potentially allow re-dosing the depleted stents, thereby prolonging the lifecycle of the implant.

It has been proposed that endothelial progenitor cells (EPC), originating from the bone marrow contribute to neo-angiogenesis in vivo by forming endothelial cells. Once released in the bloodstream, EPC home at the site of vascular damage where they participate in endothelium regeneration. In this process CXCR4 plays a key role. Recently we demonstrated that a prolonged therapy with phosphodiesterase-5 (PDE5) inhibitors does improve endothelial function and increases circulating EPC, suggesting a role of PDE5 in EPC physiology. Here we tested the expression of PDE5 and CXCR4 on cultured, circulating, and bone marrow resident EPC, and we studied the effect in vivo and in vitro of PDE5 inhibition after administration of a PDE5 inhibitor (tadalafil) on EPC, in term of CXCR4 expression. We documented that in vivo and in vitro EPC express both PDE5 and CXCR4, and that tadalafil administration induced a significant increase in EPC number and the relative CXCR4 expression. This effect is inhibited by selective CXCR4 antagonist. We thus demonstrated that PDE5 inhibition acts on CXCR4 signalling in EPC and we can suppose an involvement of cGMP second messenger system in both EPC release from the bone marrow and EPC-mediated peripheral re-endothelization.

Skin disease (dermatological conditions') affects at least one-third of the US population and has been cited as one of the top 15 medical conditions for which prevalence and healthcare spending increased in the last decade. The outcome of topical dermatological drug treatment is significantly influenced by the choice of vehicle or delivery system. Advancements in the life sciences coupled with a growing market for dermatologicals have facilitated the emergence of improved topical formulations and drug delivery systems. The current and emerging approaches of optimizing the topical delivery of dermatological agents (small and large molecules) include the use of chemical enhancers, bio-polymers (e.g. sodium hyaluronate), liposomes, particulate carriers (microspheres and lipid nanoparticles), topical sprays and foams, occlusion (via dressings and patches) topical peels, temperature (heat), iontophoresis and ultrasound. These delivery approaches (when used solely or in a synergistic manner) are a significant improvement over conventional systems (creams, lotions, ointments and pastes) and have the potential to enhance efficacy and tolerability, improve patient compliance (including dermatology life quality), and also fulfil other unmet needs of the topical dermatological market.

The aim of the present work was to evaluate alginate hydrogels in the form of spherical beads as carrier for antithrombotic drugs for future use in artificial grafts. The ionotropic gelation technique was employed to prepare beads from the L. hyperborea stipe of alginate with two different alginate concentrations and two different guluronic to manuronic acid ratios. The beads were loaded, via soaking, with three different types of low molecular weight model molecules representing drugs with antithrombotic action and their release characteristics were subsequently evaluated. The entire release process of the negatively charged model drugs under study (Salicylic acid and Hirudin), was found to be governed by diffusion, while additional electrostatic interactions between drug molecule and alginate matrix was indicated to influence the release rate of the analyzed positively charged drug molecule (Dipyridamole). It was found that the alginate hydrogel matrix imposed a decrease of the drug diffusion rate on the molecules under study as compared to the corresponding diffusion rates in water. All diffusion coefficients decreased slightly with increasing concentration of alginate and with increasing guluronic to manuronic acid ratio. The results show on the potential use of alginate gel beads when developing vehicles for release of low molecular weight antithrombotic drugs.

Coronary atherosclerosis is the largest cause of mortality and morbidity in industrialised countries. Despite recent advances in medical therapies, the prevention and treatment of atherosclerosis remain suboptimal. Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall, involving the accumulation of macrophages and excess low density lipoproteins (LDL), the formation of foam cells which create the atheromatous plaque, resulting in stenosis, aneurysm and plaque rupture leading to acute coronary events. Every step in the atherogenesis process is a potential therapeutic target for both the prevention and regression of atherosclerosis. A novel approach is the use of nanoparticles containing drugs, providing new perspectives in targeted modification of these pathways. Nanoparticles are ultrafine particles sized between 1-100 nm. By using specific methods, nanoparticles can be filled with drugs and achieve targeted drug delivery near the diseased area. In this review article we describe the basic actions of nanoparticles, and we discuss their potential applications in atherosclerosis. We also discuss their advantages and we expose the existing toxicity issues, making it clear however, that the use of nanoparticles is one of the most promising therapeutic strategies against atherosclerosis.

Malaria has been, and remains, one of the biggest global health concerns as far as infectious diseases are concerned, with yearly incidence and mortality figures running into millions. One of the major drawbacks to the control of this disease has been the emergence of drug resistant strains of the causative agent, which limits the successful use of many clinically available antimalarial drugs. This review discusses chloroquine resistance; it highlights some of the proposed molecular mechanisms of chloroquine resistance, but dwells more on efforts at reversing chloroquine resistance and the concept of chloroquine resistance-reversal agents.

The systemic use of non-steroidal anti-inflammatory drugs (NSAIDs) which act by inhibiting cyclooxygenase (COX) is severely hampered by gastric and peptic ulcers. The topical delivery of NSAIDs has the advantages of avoiding gastric and peptic ulcers and delivering the drug to the inflammation site. Importance of aceclofenac as a new generational NSAID has inspired the development of topical dosage forms. This mode of administration may help to avoid typical side effects of NSAIDs associated with oral and systemic administration such as gastric irritation, particularly diarrhoea, nausea, abdominal pain and flatulence. The aim of this study was to formulate topical gel containing 1% of aceclofenac in carbopol and PEG base and to evaluate it for analgesic and antiinflammatory activity using carrageenan-induced thermal hyperalgesia and paw oedema in rats. Carrageenan administration into the hind paw produced a significant inflammation associated with hyperalgesia as shown by decreased rat paw withdrawal latency in response to a thermal stimulus (47±0.5°C) 4 h after carrageenan injection. Topical application of AF1 significantly attenuated the development of hypersensitivity to thermal stimulus as compared to control (P<0.05) and other formulation treated groups (P<0.05). All the AF semisolid formulations, when applied topically 2 h before carrageenan administration, inhibited paw edema in a timedependent manner with maximum percent edema inhibition of 80.33±2.52 achieved with AF1 after 5 h of carrageenan administration However, topical application of AF2 markedly prevented the development of edema as compared to other formulation (AF2 and AF3) treated groups (P<0.05). Among all the semisolid formulations, Carbopol gel base was found to be most suitable dermatological base for aceclofenac.

The purpose of the present study was to explore the combined effect of chemical enhancers and iontophoresis on the in vitro permeation of acyclovir gel across porcine skin. Acyclovir gel was formulated using carbopol 940 and hydroxypropyl methylcellulose K4M (HPMC K4M). Effect of drug concentration on the delivery of acyclovir was examined. Increasing drug concentration of acyclovir enhanced its flux across the skin. Incorporation of permeation enhancers (menthol, n-methyl-2-pyrrolidone and polyethylene glycol 400) into the gel resulted in enhanced acyclovir permeation when combined with iontophoresis. Menthol showed the highest drug permeation and when combined with iontophoresis it significantly increased the acyclovir skin permeation.

The purpose of this research was to develop and evaluate different sustained release preparations, using swellable polymers as carriers in the form of matrices and three-layer tablets. These preparations may offer a number of therapeutic advantages over immediate release dosage forms in drug delivery. The materials used for the fabrication of these systems were hydrophilic swellable polymers namely Metolose, Polyox, Xanthan gum and an erodible material Gantrez, acting as drug(diclofenac sodium) carriers. The powder characteristics determined for these polymers suggest good flowability with the exception of Gantrez. The addition of 1% of magnesium stearate resulted in improved flow properties for all polymers including Gantrez. Tablets were prepared by direct compression whereas three-layer tablets were prepared by compressing polymer barrier layers on both sides of the core containing the drug. Our findings show that both preparations exhibit sustained release characteristics; also the structure of the device considerably affects the drug release and the release rate. Furthermore erosion and swelling greatly influence the overall behavior, function and performance of the systems. Finally kinetic analysis studies indicated that the drug release mechanisms were also affected by these effects.