Current Medicinal Chemistry - Volume 20, Issue 14, 2013

RNA interference (RNAi) is an efficient process of posttranscriptional gene silencing. In recent years it has been developed into a new technology in biopharmaceutical fields of science. RNAi products include short interference RNA (siRNA) but also short hairpin RNA (shRNA), bifunctional short hairpin RNA (bi-shRNA) and microRNA (miRNA). They combine with homologous fragments of the mRNA and cause its degradation. It results in inhibition of protein synthesis, or in mutation in the gene encoding it. RNAi has been used in analysis of genomes and creation of new animal models to test drugs. From the pharmaceutical point of view, what is the most important is its therapeutic application. So far the basic and clinical research has been focused on the following targets: macular degeneration, cancer and antiviral therapy. But there are also reports on clinical trials in asthma, hypercholesterolemia and genetic diseases such as inherited skin disorders and amyloidosis. Among over 20 therapeutics that reached clinical trials, only few are still investigated. Another few are clinical candidates. The review focuses on RNAi products under clinical evaluation and their most promising new applications.

Chronic stable angina pectoris (CSAP) is the most common manifestation of coronary artery disease (CAD). Angina pectoris occurs as a result of an imbalance between myocardial perfusion and the demands of the myocardium. Elevated heart rate (HR) is an important pathophysiological variable that increases myocardial oxygen demand, and also limits tissue perfusion by reducing the duration of diastole during which most myocardial perfusion occurs. Elevated resting HR represents a significant predictor of all-cause and cardiovascular mortality in the general population and patients with cardiovascular disease (CVD) because it assists the progression of CVD through the development of atherosclerosis, plaque destabilization, and initiation of arrhythmias. Since βblockers have been found to reduce HR, therefore, they are currently viewed as the first line therapy for CSAP and are associated with an improved prognosis after acute myocardial infarction (AMI) or congestive heart failure (CHF). The classical treatments for HR reduction have shown negative aspects, such as β-blockers therapy which exerts negative effects on regional myocardial blood flow and function when HR reduction is eliminated by atrial pacing. Calcium channel antagonists functionally antagonize coronary vasoconstriction mediated through α-adrenoreceptors, and are thus devoid of this undesired effect, but the compounds are nevertheless negative inotrope. Ivabradine (IVA), a pure HR lowering drug, reduces the demand of myocardial oxygen during exercise, contributes to the restoration of oxygen balance and is therefore benefitial in chronic CVD. No relevant negative effects have been observed on cardiac conduction, contractility, relaxation, repolarization or blood pressure (BP). Beneficial effects of IVA have been noticedin CSAP and CHF, with optimal tolerability profile due to selective interaction with If channel of sino atrial node cells. More recently, IVA has been highly recommended to be used in patients with CAD in association with β-blockers. This review highlights the importance of IVA in the treatment of ischemic heart disease.

Endocannabinoid hydrolases are nowadays increasingly considered as potential therapeutic targets for treating several pathological states. So far, numerous classes of endocannabinoid hydrolase inhibitors have been described. We herein review the medicinal chemistry of these inhibitors with a particular emphasis on the basis of their design, chemical structure, structure-activity relationships, and inhibition mechanisms.

NSAIDs are the most commonly prescribed category of drugs for the treatment of musculoskeletal pain and inflammation associated with many conditions. Topical administration of these drugs is always the best choice since adverse effects occur commonly with systemic NSAID therapy. Colloidal drug delivery systems (CDDS) are interesting systems, which are able to improve the duration of drug residence in the skin and to allow an achievable drug sustained and controlled release compared to conventional topical formulations. This review focuses on micro and nanoemulsions, vesicular carriers and nanoparticles as novel high efficiency delivery systems of NSAIDs in topical applications.

Histone deacetylases are able to catalyze the hydrolysis of N-acetyl lysine residues of histones which package chromosomal DNA. Therefore they play an important role in mediating gene expression and cell proliferation. HDAC inhibitors have not only shown promise as antiparasitic, antineurodegenerative, antirheumatologic agents and immunosuppressant, but as potent anticancer agents by inducing cell cycle arrest, differentiation and apoptosis. This review highlights recent development in design, synthesis and biological evaluation of HDAC inhibitors for cancer therapy.

Histone deacetylase inhibitors (HDACi) have been enthusiastically investigated as a novel generation of chemotherapeutics for cancers usually called as epigenetic therapeutics. Histone deacetylases have been found to influence cellular function by catalyzing the removal of acetyl groups from ε-N-acetylated lysine residues of several protein substrates including histones, transcription factors, α-tubulin, and nuclear importers. Cyclic peptides represent the most structurally complicated and diverse class of histone deacetylase inhibitors. Each subtype of the Histone Deacetylase (HDAC) family perform a distinct role in the gene expression and cyclic peptides with their plentiful set of surface contacts, zinc binding group and macrocyclic cap, can target enzyme precisely through adequate modulation of the amino acid configurational and structural assortment. The present article summarizes current status of different peptide based macrocyclic compounds being developed as HDACi for the treatment of cancer.

For some time Photodynamic Therapy and electrochemotherapy have been used as alternative therapies against skin cancer. The primary aim of this work was to develop, characterize, and evaluate the in vitro cytotoxic activity of new drug delivery systems based on chitosan nanoparticles containing aminolevulinic acid derivatives such as prodrug (5-ALA and its ester derivative 8-ALA). The second goal of this study was to evaluate the synergistic effect of a combination of classical Photodynamic Therapy and electrochemotherapy, which is routinely utilized to modulate and enhance the permeation of photosensitizers, prodrugs, and other active compounds through the skin, improving the efficiency of PDT in the treatment of cutaneous neoplasms.

Platelet hyperaggregability might contribute to vascular complications associated with type 2 diabetes mellitus (DM2).Experimental evidence supports a direct link between altered Ca2+ entry and hyperaggregability in DM2 patients. Objectives: We aimed to investigate whether altered immunophilin expression and function are involved in the abnormal Ca2+ entry observed in platelets from DM2 patients. Results: Inhibition of immunophilins by tacrolimus (FK506) and sirolimus (rapamycin) reduced Ca2+ entry in platelets from healthy donors and DM2 patients. Similarly, immunophilin inhibitors reduced platelet degranulation in both healthy and DM2 subjects. Nevertheless,α-granule secretion reduction was greater than that observed for dense granules in platelets from DM2 patients. However, no difference was observed in the inhibition of secretion in platelets from healthy subjects. Additionally, altered expression of FK506 binding protein-52 (FKBP52) and coupling to Ca2+ channels were found in platelets from DM2 patients compared to healthy subjects. Finally, reduction in platelet function from healthy subjects and DM2 patients in the presence of immunophilin antagonists was observed, being this dysfunction more evident in platelets from DM2 patients. Conclusions: We suggest that, among others, FKBP52 expression and function are altered in platelets from DM2 patients, contributing to the altered Ca2+ entry and hyperaggregability in these cells.