Current Pharmaceutical Design - Volume 25, Issue 2, 2019

Doxorubicin (DOX) is a cytostatic antibiotic from the class of anthracyclines widely used in chemotherapeutic cancer treatments. Despite the efficiency against several types of cancer, the use of DOX remains limited due to the side effects, especially cardiotoxicity. Among the DOX administration strategies, there are the “classic players” such as nanoparticles and polymers, which are capable of DOX delivery directly to interesting neoplastic regions. On the other hand, the “new players” such as phytochemicals and probiotics emerged with the proposal to react with DOX free radicals, reducing the oxidative stress, inflammatory and apoptotic process. Thus, this review aims to report the studies involving these classics and new players along the years that focus on improved administration and reduction of DOX-induced cardiotoxicity.

In the last few years, great importance has been given to natural materials (such as walnuts, peanuts, chestnuts) due to their medicinal and pharmaceutical uses induced by the presence of natural agents, including polyphenols. Juglans regia is a traditional plant that has been used since ancient times in traditional medicine for the treatment of various diseases like microbial infections, stomach ache, thyroid dysfunctions, cancer, heart diseases and sinusitis. Recently, scientific attention for the phytochemical profile of walnut by-products is increasing due to their valuable active constituents. Natural polyphenols are important compounds present in walnut with valuable properties that have been studied for the treatment of inflammation, cancer or anti-ageing effect. The use of nanocarriers as a drug delivery system is now a promising strategy to get more stable products and is easier to apply in a medical, therapeutic and pharmaceutical environment. The aim of this work was to review the latest information provided by scientific investigators regarding the nutritional value, bioactive compounds, antioxidant and antitumor activity of walnut by-product extracts. Moreover, this review provides comprehensive information on the nanoencapsulation of bioactive constituents for application in clinical medicine, particularly in cancer research.

Drug delivery systems are created to achieve the desired therapeutic effect of a specific pharmaceutical compound. Numerous drawbacks and side effects such as unfavorable pharmacokinetics, lack of tissue selectivity, immunogenicity, increased systemic clearance and toxicity, have been observed for currently available drug delivery systems (DDSs). The use of natural and artificial extracellular vesicles (EVs) in drug delivery may help to solve the aforementioned problems faced by different DDSs. Due to their self-origin, small size, flexibility, the presence of multiple adhesive molecules on their surfaces as well as their function as biomolecules carriers, EVs are the perfect candidates for DDSs. Currently, several drug delivery systems based on EVs have been proposed. While the great potential of these particles in targeted drug delivery has been recognized in cancer, hepatitis C, neurodegenerative diseases, inflammatory states etc., this field is still in the early stage of development. Unfortunately, the use of EVs from natural sources (cell cultures, body fluids) results in numerous problems in terms of the heterogeneity of isolated vesicle population as well as the method of isolation thereof, which may influence vesicle composition and properties. Therefore, there is a significant need for the synthesis of artificial EV-based DDSs under strictly controlled laboratory conditions and from well-defined biomolecules (proteins and lipids). Vesicle-mimetic delivery systems, characterized by properties similar to natural EVs, will bring new opportunities to study the mechanisms of DDS internalization and their biological activity after delivering their cargo to a target cell.

Rheumatoid Arthritis (RA) is a systemic autoimmune disease accompanied by chronic inflammation. Due to the long-term infiltration in inflammatory sites, joints get steadily deteriorated, eventually resulting in functional incapacitation and disability. Despite the considerable effect, RA sufferers treated with current drug therapeutic efficacy are exposed to severe side effects. Application of Drug Delivery Systems (DDS) has improved these situations while the problem of limited drug exposure remains untackled. Stimuli-responsive DDS that are responsive to a variety of endogenous and exogenous stimuli, such as pH, redox status, and temperature, have emerged as a promising therapeutic strategy to optimize the drug release. Herein, we discussed the therapeutic regimes and serious side effects of current RA therapy, as well as focused on some of the potential stimuliresponsive DDS utilized in RA therapy. Besides, the prospective room in designing DDS for RA treatment has also been discussed.

Background: Insulin is essential for the treatment of Type 1 diabetes mellitus (T1DM) and is necessary in numerous cases of Type 2 diabetes mellitus (T2DM). Prolonged administration of anti-diabetic therapy is necessary for the maintenance of the normal glucose levels and thereby preventing vascular complications. A better understanding of the disease per se and the technological progress contribute to the development of new approaches with the aim to achieve better glycemic control. Objective: Current therapies for DM are faced with some challenges. The purpose of this review is to analyze in detail the current trends for insulin delivery systems for diabetes treatment. Results: Contemporary ways have been proposed for the management of both types of diabetes by adequate application of drug via subcutaneous, buccal, oral, ocular, nasal, rectal and pulmonary ways. Development of improved oral administration of insulin is beneficial regarding mimicking physiological pathway of insulin and minimizing the discomfort of the patient. Various nanoparticle carriers for oral and other ways of insulin delivery are currently being developed. Engineered specific properties of nanoparticles (NP): controlling toxicity of NP, stability and drug release, can allow delivery of higher concentration of the drug to the desired location. Conclusions: The successful development of any drug delivery system relies on solving three important issues: toxicity of nanoparticles, stability of nanoparticles, and desired drug release rate at targeted sites. The main goals of future investigations are to improve the existing therapies by pharmacokinetic modifications, development of a fully automatized system to mimic insulin delivery by the pancreas and reduce invasiveness during admission.

Background: Protein kinases are the enzymes involved in phosphorylation of different proteins which leads to functional changes in those proteins. They belong to serine-threonine kinases family and are classified into the AGC (Protein kinase A/ Protein kinase G/ Protein kinase C) families of protein and Rho-associated kinase protein (ROCK). The AGC family of kinases are involved in G-protein stimuli, muscle contraction, platelet biology and lipid signaling. On the other hand, ROCK regulates actin cytoskeleton which is involved in the development of stress fibres. Inflammation is the main signal in all ROCK-mediated disease. It triggers the cascade of a reaction involving various proinflammatory cytokine molecules. Methods: Two ROCK isoforms are found in mammals and invertebrates. The first isoforms are present mainly in the kidney, lung, spleen, liver, and testis. The second one is mainly distributed in the brain and heart. Results: ROCK proteins are ubiquitously present in all tissues and are involved in many ailments that include hypertension, stroke, atherosclerosis, pulmonary hypertension, vasospasm, ischemia-reperfusion injury and heart failure. Several ROCK inhibitors have shown positive results in the treatment of various disease including cardiovascular diseases. Conclusion: ROCK inhibitors, fasudil and Y27632, have been reported for significant efficiency in dropping vascular smooth muscle cell hyper-contraction, vascular inflammatory cell recruitment, cardiac remodelling and endothelial dysfunction which highlight ROCK role in cardiovascular diseases.

Objective: To investigate changes in retinal nerve fiber layer, ganglion cell-inner plexiform layer, and choroidal thickness in the macular area in patients with neovascular age-related macular degeneration who received repeated intravitreal ranibizumab and aflibercept treatments. Methods: This retrospective study included 90 eyes of 90 treatment-naive patients. Fifty eyes were treated with intravitreal injections of aflibercept, and 40 were treated with intravitreal injections of ranibizumab. Unaffected fellow eyes (71 eyes) were used as controls. The dosage was one injection per month for 3 consecutive months as an initial treatment. The patients were examined monthly for 6 months following the initial injection. Additional intravitreal injections were given reactively in an optical coherence tomography-guided “pro re nata” protocol. Measurements of the retinal nerve fiber layer, ganglion cell-inner plexiform layer, full retina, and choroidal thickness were simultaneously obtained via swept-source optical coherence tomography in the nine Early Treatment Diabetic Retinopathy Study subfields. Results: The retinal nerve fiber layer thickness in the nine Early Treatment Diabetic Retinopathy Study subfields did not differ significantly among the three study groups (aflibercept vs. ranibizumab vs. control). The ganglion cell-inner plexiform layer thickness was significantly reduced in the aflibercept group, while the choroidal thickness was reduced in both the aflibercept and ranibizumab groups. Conclusion: Excessive long-term vascular endothelial growth factor inhibition by an anti-vascular endothelial growth factor agent that is trapped by neuronal and retinal pigment epithelium cells may adversely affect the function of physiological vascular endothelial growth factor and harm retinal cells and vessels.

Background and objective: Familial hypercholesterolemia (FH) is a severe genetic hyperlipidemia characterized by increased levels of low-density lipoprotein cholesterol (LDL-C), leading to premature atherosclerosis. Angiopoietin-like protein (ANGPTL3) is a hepatocyte-specific protein that can be used to lower LDL in FH. However, it was unknown whether ANGPTL3 variants are present in FH patients. This study was performed to identify ANGPTL3 variants in unrelated Chinese Han patients with FH. Methods and Results: We screened 80 patients with FH (total cholesterol >7.8mmol/L, LDL-cholesterol >4.9mmol/L) and 77 controls using targeted next-generation sequencing (NGS) of six FH candidate genes (LDLR, ApoB100, PCSK9, ABCG5, ABCG8, and ANGPTL3). Candidate pathogenic variants identified by NGS were validated by Sanger sequencing. Mutant and wild-type plasmids containing the variant sequence were constructed and verified by Sanger sequencing. The gene expression profile was analyzed by an expression profile chip in transfected HepG2 cells using quantitative real-time (qRT)-PCR. We identified 41 variants in 28 FH patients, including two ANGPTL3 mutations: one exonic (c.A956G: p.K319R) and one in the untranslated region (c.*249G>A). Gene ontology analyses found that the cholesterol metabolic process and ANGPTL3 expression were significantly up-regulated in the ANGPTL3 K319R mutation group compared with the wild-type group. qRT-PCR findings were consistent with the expression profile analysis. Conclusion: Rare ANGPTL3 variants were identified in Chinese patients with FH, including ANGPTL3: p.(Lys319Arg) which affected the expression of ANGPTL3 and the cholesterol metabolic process as determined by bioinformatics analysis. Clinical Trial Registration: Chinese Clinical Trial Registration (ChiCTR-ROC-17011027) http://www.chictr.org.cn/listbycreater.aspx

Background: Insulin resistance, dyslipidemia and chronic inflammation are important risk factors for cardiovascular diseases (CVD). Hence, vitamin D supplementation might be an appropriate approach to decrease the complications of CVD. This systematic review and meta-analysis aimed to determine the effects of vitamin D supplementation on glycemic control, lipid profiles, and C-reactive protein among patients with coronary artery disease. Methods: Two independent authors systematically searched online databases including EMBASE, Scopus, Pub- Med, Cochrane Library, and Web of Science until 20th September 2018. Cochrane Collaboration risk of bias tool was applied to assess the methodological quality of included trials. The heterogeneity among the included studies was assessed using Cochran’s Q test and I-square (I2) statistic. Data were pooled using a random-effects model and weighted mean difference (WMD) was considered as the overall effect size. Results: A total of eight trials (305 participants in the intervention group and 325 in placebo group) were included in the current meta-analysis. Pooling effect sizes from studies revealed a significant reduction in fasting glucose (WMD): -15.67; 95% CI: -29.32, -2.03), insulin concentrations (WMD: -3.53; 95% CI: -4.59, -2.46) and homeostatic model assessment of insulin resistance (WMD: -1.07; 95% CI: -1.49, -0.66), and significant increase in the quantitative insulin-sensitivity check index (WMD: 0.02; 95% CI: 0.01, 0.03) following the administration of vitamin D. In addition, pooled analysis revealed a significant increase in serum HDL-cholesterol concentrations following vitamin D therapy (WMD: 3.08; 95% CI: 1.42, 4.73). Additionally, vitamin D supplementation significantly reduced C-reactive protein (CRP) levels (WMD: -0.75; 95% CI: -1.28, -0.23). Conclusion: This meta-analysis demonstrated the beneficial effects of vitamin D supplementation on improving glycemic control, HDL-cholesterol and CRP levels among patients with CVD, though it did not affect triglycerides, total- and LDL-cholesterol levels.