Current Drug Therapy - Volume 3, Issue 2, 2008

In modern medicine technologies the oral administration of solid forms is the preferred route for drug delivery. Thus, in pharmaceutical applications, size, shape and morphology of the solid particles are important because they can affect the solubility as well as bioavailability of the drug particles. Since the bioavailability of orally applied drugs depends on the rates of dissolution and absorption, methods to increase such rates are often essential to reach significant levels (concentrations) in the blood. A very suitable way to increase the rate of dissolution is the reduction of the particle size. Particle design, in particular the design of micron, submicron, or nanoparticles, is thus critical. There are several methods for the production of drug particles of decreased sizes such as pulverization of large particles using a ball or jet mill, solidification of emulsions by in-water drying methods, spray freezing, spray drying and supercritical antisolvent technique (SAS), etc. These methods are reviewed here with a focus on the production of micro/nano-sized drug particles with or without water soluble materials. Such particles are used in oral, pulmonary and transdermal drug delivery of water insoluble or poorly water soluble drugs. Especially, our review concentrates on spray drying methods for the synthesis of drug particles with or without water soluble materials that show a faster rate and higher extent of dissolution and enhanced bioavailability in comparison with commercial preparations containing the normal form of the drug. This review provides an update and insights on recent and relevant studies in this area, highlights our work in this field and attempts to provide a future outlook on this research.

Multiresistant Gram-positive cocci, including Staphylococcus aureus, the group of coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium, as well as Streptococcus pneumoniae and other streptococci, represent emerging pathogens in the community, but especially in the setting of immunocompromised, hospitalized patients. In these last subjects, it happens in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are of concern, and broad-spectrum antibiotics are widely used in the environment. The spectrum of antimicrobial compounds now available for an effective management and treatment of these relevant infections is significantly threatened by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant microbial strains. The streptogramine association represented by quinupristin/dalfopristin, the oxazolidinone derivative linezolid, and the recently licensed daptomycin and tigecycline, together with a number of glycopeptides, quinolones, and other experimental compounds on the pipeline, represent an effective response to the majority of these problems, due to their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic/pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also to compromised patients. The main problems related to the epidemiology of multiresistant gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of all these compounds, are updated and outlined based on an extensive review of all available, recent evidences from the international literature.

Glitazones were introduced into clinical use to offer type II diabetic patients an alternative to oral hypoglycaemic agents. Unlike traditional agents based on β-pancreatic overstimulation, glitazones raise peripheral insulin sensitivity allowing the patient to efficiently use his own insulin. Although glitazones are only approved for the treatment of diabetes, their beneficial effects extend to every symptom of the so-called metabolic syndrome: they protect against atherosclerosis, inhibit blood coagulation, decrease hypertension and improve vascular endothelial function. Moreover, glitazones counteract activation of macrophages and brain microglia, attenuate the expression of pro-inflammatory genes, and inhibit various signalling events involved in inflammation. In addition, glitazones are able to induce cell differentiation and apoptosis in several cancer cells, suggesting possible use of these drugs for the treatment of gliomas and other tumors. The molecular basis of such a vast array of glitazone actions is necessarily complex. Glitazone effects were originally attributed to activation of peroxisome proliferator activated receptor-γ (PPARγ). However, several properties of glitazones are unrelated to PPARγ. We review here the emerging actions of glitazones focusing on their antihypertensive and anti-tumoral effects, PPARγ-dependent and -independent, and also emphasizing the contribution of mitochondria and reactive oxygen and nitrogen species to these actions.

Treatment resistant patients with Obsessive-Compulsive Disorder (OCD) are those who undergo adequate trials of first-line therapies without a satisfactory response. Two major options are available for those patients: 1) augmentation with cognitive-behavioral therapy (CBT) or pharmacotherapy, and 2) switch to another compound or to another formulation. The first approach is to augment the serotonin reuptake inhibitor (SRI) with CBT or with another drug. In the first case preliminary data indicate that exposure and response prevention is effective. Pharmacological augmentation has been tried with several drugs; the effectiveness of antipsychotic (first and second generation) augmentation is well documented and subjects with comorbid tic may be particularly responsive to haloperidol. A second, although less established, augmentation strategy consists in adding another SRI. Other drugs like pindolol and morphine have shown efficacy in few controlled studies. The second approach, less studied, is switching from a serotonergic compound to another one (generally from a selective serotonin reuptake inhibitor to clomipramine or vice-versa), or to venlafaxine or mirtazapine. Finally, patients that failed to respond to oral clomipramine might benefit from switching to the IV clomipramine. The augmentation strategy should be considered in case of partial response while the switch strategy in absence of any minimal improvement.

Sensorineural hearing loss (SNHL) is one of the most common disabilities in our society. Experimentally, many candidates for use as therapeutic molecules have been discovered. However, a considerable obstacle to clinical application is the lack of an effective method for drug delivery to the cochlea. In order to overcome this obstacle, there needs to be development of a local cochlear drug delivery system. Advances in pharmacological technology have provided various drug delivery systems that use biomaterials, and which can be utilized for local drug delivery to the cochlea. Indeed, recent studies have demonstrated the potential of synthetic and natural biomaterials for local drug delivery to the cochlea, indicating that the clinical application of such local drug delivery systems could be used in the near future for therapeutic treatments. Recent progress in cell therapy research also offers a novel drug delivery method for the cochlea. In addition, transplantation of stem cells into the cochlea has been demonstrated to provide protective effects for the auditory function. Transplantation of genetically engineered cells has also resulted in the sustained delivery of aimed therapeutic molecules within the inner ear. Although problems involving clinical application still need to be resolved, these drug delivery systems for the inner ear may hold the future therapeutic options for treatment of SNHL.

A growing body of evidence has shown that critical illness and associated treatments can lead to de novo neurological degradation manifesting as delirium or acute brain dysfunction. Many survivors further suffer from long-term cognitive impairment (LTCI), months to years after their critical illness, affecting their functional quality of life. Recent data have demonstrated that delirium is an independent risk factor for increased morbidity and mortality in the critically ill and may also predispose patients to long-term cognitive impairment. Delirium, therefore, may represent a critical point for intervention and treatment in critically ill patients. The pathogenesis of delirium is multifactorial and is considered to be related to several physiological and possibly iatrogenic processes. Due to its complexity, the optimum pharmacological treatment by which to manage delirium is not fully understood; however, recent investigations have proposed several plausible protocols. In this review, we examine evidence pertaining to the pharmacological treatment of delirium in the context of acute critical illness.