An aquaporin 4 antisense oligonucleotide loaded, brain targeted nanoparticulate system design.

Aquaporins (AQPs), members of the water-channel protein family, are highly expressed in brain tissue especially in astrocytic end-feet. They are important players for water hemostasis during development of cytotoxic as well as vasogenic edema. Increased expression of AQPs is important in pathophysiology of neurological diseases such as neuroinflammation and ischemia. Unfortunately, there are a few pharmacological inhibitors of AQP4 with several side effects limiting their translation as a drug for use in clinical conditions. Another therapeutic approach is using antisense oligonucleotides (ASOs) to block AQP4 activity. These are short, synthetic, modified nucleic acids that bind RNA to modulate its function. However, they cannot pass the blood brain barrier (BBB). To overcome this obstacle we designed a nanoparticulate system made up of chitosan nanoparticles surface modified with PEG and conjugated with monoclonal anti transferrin receptor-1 antibody via streptavidin-biotin binding. The nanocarrier system could be targeted to the transferrin receptor-1 at the brain endothelial capillaries through monoclonal antibodies. It is hypothesized that the nanoparticles could pass the BBB via receptor mediated transcytosis and reach brain parenchyma. Particle size, zeta potential, loading capacity and release profiles of nanoparticles were investigated. It was observed that all types of chitosau (CS) nanoparticles had positive zeta potential values and nanoparticle particle size distribution varied between 100 and 800 nm. The association efficiency of ASOs into the nanoparticles was between 80-97% and the release profiles of the nanoparticles exhibited an initial burst effect followed by a controlled release. The results showed that the designed chitosan based nanocarriers could be a promising carrier system to transport nucleic acid based drugs to brain parenchyma.

The influence of technological parameters on the physicochemical properties of blank PLGA nanoparticles.

In this work, PLGA nanoparticles were prepared by an emulsification-diffusion technique. The main objective was to optimize the preparation of formulations by evaluating the influence of the technological parameters on the physicochemical properties of PLGA nanoparticles. The effects of variations in polymer and emulsifier concentrations, and homogenization duration, rate and type on the particle size distribution, surface charge and morphology of nanoparticles were assessed. The smallest nanoparticles (177.53 +/- 2.78 nm) were obtained with a 2% PLGA (w/v) concentration in the organic phase and 3% PVA (w/v) in the aqueous phase and were prepared by an emulsification-diffusion method via ultrasonic homogenization at a power of 80 W applied for 30 s. It was observed that nanoparticles prepared by Ultra Turrax were more spherical but larger. In addition, increasing the PVA concentration in the aqueous phase, increasing the PLGA concentration in the organic phase and increasing the homogenization rate decreased the zeta potential values of PLGA nanoparticles.

Bipolar rapid cycling: focus on depression as its hallmark.

The phenomenon of frequent cycling in bipolar disorder was first recognized by Emil Kraepelin in 1913. More recently, rapid cycling has been reported to be a predictor of nonresponse to treatment. At the time of presentation, most patients with DSM-IV-defined rapid cycling appear to be in the depressed phase of their illness. Frequent and more severe episodes of depression appear to be the hallmark of rapid cycling. Reported in this article are recent preliminary data suggesting that the combination of lithium and divalproex sodium administered continuously over 6 months appears to result in marked acute and continuation antimanic efficacy in 85% of patients and marked antidepressant efficacy in 60%. However, only one half of patients experienced bimodal stabilization. Comorbid alcohol, cannabis, and/or cocaine abuse and/or dependence did not appear to directly affect the spectrum of efficacy of lithium and divalproex or response rates in compliant patients. Comorbidity appeared to alter prognosis by increasing the prevalence of poor compliance. The majority of patients receiving lithium and divalproex who required additional treatment were depressed, suggesting that the frequent recurrence of depression is the primary unmet need in patients with rapid cycling. The use of antidepressants in this population has been discouraged because of concerns about the possibility of cycle acceleration. There exists a need for a pharmacotherapy that not only possesses marked acute antidepressant properties, but that does so without inducing switching or cycle acceleration. A double-blind, placebo-controlled trial of lamotrigine monotherapy in bipolar I depression has demonstrated efficacy without causing switching at a rate exceeding placebo; however, this initial study excluded patients with rapid cycling. To explore the efficacy of lamotrigine in rapid cycling, a recent multicenter study has examined lamotrigine as a maintenance therapy for this population. The results indicate that lamotrigine may be a useful treatment for patients with rapid-cycling bipolar II disorder and that this drug has begun to address this unmet need.

Current research on rapid cycling bipolar disorder and its treatment.

Rapid cycling is a pattern of presentation of bipolar disorder that specifies the course of the illness and is associated with a greater morbidity. The validity of rapid cycling as a distinct course modifier for bipolar disorder has been demonstrated and the term has been incorporated into the DSM-IV. The phenomenon of rapid cycling tends to appear late in the course of the disorder, occurs more frequently among females, and is more frequently seen in patients with bipolar type II disorder. Stimulants such as cocaine may also play some role in rapid-cycling. It is generally accepted that a recent history of rapid cycling predicts non-response to monotherapy with lithium and probably carbamazepine as well; however it is also possible that concurrent use of antidepressants may play a role in destabilizing the illness course under these agents. Thus, clinical considerations suggest that discontinuing antidepressants may facilitate the recovery process. Among clinically available monotherapies, valproate and lamotrigine appear to be the most useful clinically. However, other treatments such as lithium, carbamazepine, the atypical antipsychotic agents, thyroid hormone, and bupropion are frequently needed augmentation strategies. Electroconvulsive therapy may also prove efficacious in selected cases. The present paper provides a critical review of the evidence for the foregoing clinical issues in rapid cycling.