Current Pharmaceutical Design - Volume 25, Issue 14, 2019

Background: Leishmania are sandfly-transmitted protozoan parasites that harbour within the macrophages of a mammalian host and cause leishmaniasis, a serious zoonotic disease that threatens the lives of millions worldwide. Its numerous forms (cutaneous, mucocutaneous, and visceral) are currently treated with a sparse arsenal of drugs, specifically antimonials, amphotericin B, miltefosine, and paromomycin, for which drug resistance and clinical failure are rampant. Medicine is presently trending towards nanotechnology to aid in the successful delivery of drugs. Vehicles such as lipid-based nanocarriers, polymer-based nanoparticles, and metal ions and oxides have been previously demonstrated to improve bioavailability of drugs and decrease toxicity for the patient. These cutting-edge solutions can be combined with existing active molecules, as well as novel drugs or plant extracts with promising antileishmanial activity. Conclusion: This review explores the current evidence for the treatment of leishmaniases using nanoscale drug delivery systems (specifically lipid-, polymer- and metal-based systems) and encourages further development of the aforementioned nanotechnologies for treatment of Leishmania.

Background: Leishmaniasis is a major health problem mainly in tropical and subtropical areas worldwide, although in the last decades it has been treated with the use of conventional drugs such as amphotericin, the emergence of multidrug-resistant strains has raised a warning signal to the public health systems thus a new call for the creation of new leishmanicidal drugs is needed. Methods: The goal of this review was to explore the potential use of antimicrobial peptides-based nanostructured delivery systems as an approach for leishmaniasis treatment. Results: Within these new potential drugs, human host defense peptides (HDP) can be included given their remarkable antimicrobial activity and their outstanding immunomodulatory functions for the therapy of leishmaniasis. Conclusion: Though several approaches have been done using these peptides, new ways for delivering HDPs need to be analyzed, such is the case for nanotechnology.

Background: Plant extracts loaded in nanostructured drug delivery systems (NDDSs) have been reported as an alternative to current therapies for treating parasitic and antimicrobial diseases. Among their advantages, plant extracts in NDSSs increase the stability of the drugs against environmental factors by promoting protection against oxygen, humidity, and light, among other factors; improve the solubility of hydrophobic compounds; enhance the low absorption of the active components of the extracts (i.e., biopharmaceutical classification II), which results in greater bioavailability; and control the release rate of the substances, which is fundamental to improving the therapeutic effectiveness. In this review, we present the most recent data on NDDSs using plant extracts and report results obtained from studies related to in vitro and in vivo biological activities.

Leishmaniasis is one of the most neglected diseases in the world. Its most severe clinical form, called visceral, if left untreated, can be fatal. Conventional therapy is based on the use of pentavalent antimonials and includes amphotericin B (AmB) as a second-choice drug. The micellar formulation of AmB, although effective, is associated with acute and chronic toxicity. Commercially-available lipid formulations emerged to overcome such drawbacks, but their high cost limits their widespread use. Drug delivery systems such as nanoemulsions (NE) have proven ability to solubilize hydrophobic compounds, improve absorption and bioavailability, increase efficacy and reduce toxicity of encapsulated drugs. NE become even more attractive because they are inexpensive and easy to prepare. The aim of this work was to incorporate AmB in NE prepared by sonicating a mixture of surfactants, Kolliphor® HS15 (KHS15) and Brij® 52, and an oil, isopropyl myristate. NE exhibited neutral pH, conductivity values consistent with oil in water systems, spherical structures with negative Zeta potential value, monomodal size distribution and average diameter of drug-containing droplets ranging from 33 to 132 nm. AmB did not modify the thermal behavior of the system, likely due to its dispersion in the internal phase. Statistically similar antileishmanial activity of AmB-loaded NE to that of AmB micellar formulation suggests further exploring them in terms of toxicity and effectiveness against amastigotes, with the aim of offering an alternative to treat visceral leishmaniasis.

Triazenes are a very useful and diverse class of compounds that have been studied for their potential in the treatment of many tumors including brain tumor, leukemia and melanoma. Novel compounds of this class continue to be developed as either anticancer compounds or even with other therapeutic applications. This review focused on several types of triazenes from the simplest ones like 1,3-dialkyl-3-acyltriazenes to the more complex ones like combi-triazenes with an emphasis on how triazenes have been developed as effective antitumor agents.

Breast adenocarcinoma (BAC) in glandular tissue cells have excessive metastasis and invasion capability. The major challenges for the chemotherapy used for the management of BAC include chemoresistance and auto-immunosuppression in BAC. The 5-fluro uracil (5-FU) based therapy promotes the immune activation in BAC by targeting the regulatory T cells and myeloid-derived suppressor cells (MDSC). The beneficial effect of the combination of L-Arginine with 5-FU strives to be established in different pre-clinical and clinical conditions and explored in the scientific literature. L-Arginine induces NO production and potentiates the anticancer effect of 5-FU. NO-mediated signaling is regulated by nuclear factor erythroid 2-related factor 2 (NRF-2) mediated antioxidant response. NRF-2 mediated antioxidant mechanism always suppresses the formation of superoxide (O2 -) as well as other reactive oxygen species (ROS). Thus the utilization of NO by O2 - will be minimum in this combination therapy. The regulatory role of NRF-2 in regulation to Antioxidant Response Element (ARE) mediated cytoprotective gene expression in BAC remains unexplored. The present review summarizes the role of NRF-2 mediated antioxidant response on the synergistic antitumor effect of L-Arginine and 5-FU in BAC. This review brought new insight into the management of BAC and in the same context, a hypothesis is raised on the use of reduced glutathione (GSH) or N-Acetyl Cysteine as it may be an added adjuvant in the combination of 5- FU and L-Arginine for management of BAC.

Background: Glucocorticoid (GC)-induced osteoporosis and fractures have become a serious problem for Eastern Asians. Bisphosphonates (BPs), vitamin D and a combination treatment are effective methods to prevent and treat GC-induced osteoporosis. Objective: The study aimed to compare the efficacy of BPs, vitamin D and a combination treatment for preventing and managing GC-induced osteoporosis in Eastern Asians. Methods: A comprehensive search in the PubMed, EMBASE, Web of Science and Cochrane CENTRAL databases was undertaken for randomized controlled trials (RCTs) on the effect of BPs, vitamin D and the combination treatment on GCs-induced osteoporosis in Eastern Asian populations. Primary outcome measures were the change in bone mineral density (BMD) and bone turnover markers. The final search was performed in March 2019. Results: Nine RCTs were included. A total of 545 patients met the inclusion criteria. Compared with vitamin D, BPs and the combination treatment significantly alleviated osteoporosis of the spine and femoral neck in Eastern Asians with GC-induced osteoporosis. At the same time, the change in serum bone-specific alkaline phosphatase (BAP) and serum C-telopeptide of type I collagen (CTX) levels was observed to be significantly less with BPs and the combination treatment with vitamin D alone. No significant difference was found between BPs and the combination treatment in the markers mentioned above. Conclusion: Compared with vitamin D alone, BPs alone and the combination treatment were significantly effective on Eastern Asians with GC-induced osteoporosis. Compared with the combination treatment, BPs alone were observed to be effective enough to increase the BMDs of the spine and femoral neck on both sides and thus prevent GC-induced osteoporosis in Eastern Asians.

Background: Certain patients experience muscle-related adverse effects after taking atorvastatin. Genetic factors play an important role in the occurrence of statin-induced myopathy. Aim: We aimed to identify genetic variants associated with statin-induced myotoxicity. Methods: We prospectively enrolled 1,102 acute ischemic stroke patients who underwent atorvastatin treatment for the first time after admission. Patients were separated into case and control groups after a follow-up of 3 months. We used a biochemical definition of myopathy consisting of serum creatine kinase values more than ten times the upper limit of normal for the reference laboratory (150 U/L). Fifty single nucleotide polymorphisms (SNPs) from seven genes of ABCB1, CoQ2, HTR3B, RYR2, CYP3A5, HTR7 and SLCO1B1 were selected and genotyped. The effects of genetic polymorphisms on myopathy were observed. Results: 61 cases and 110 controls were recruited in the study. Compared with the controls, the cases had a significant higher mutant frequency of the allele A (ABCB1, rs2373588) (OR = 2.01, 95%CI = 1.10-3.67, P = 0.001) and a significant lower mutant frequency of the allele A (SLCO1B1, rs976754) (OR = 1.85, 95%CI = 1.12-3.03, P = 0.042). Genotypes or alleles of the other SNPs had no significant difference between the two groups (P > 0.05). Conclusion: Our findings reveal that SLCO1B1 and ABCB1 genetic variants are associated with statin-induced myopathy. These are valuable biomarkers for the evaluation of atorvastatin safety.

Background: Cardiac resynchronization therapy (CRT) is a valuable intracardiac device-based treatment option for a subgroup of patients with advanced heart failure (HF) and QRS prolongation. However, still a significant proportion of patients do not benefit from CRT implantation, labeled as non-responders. Objectives: The aim of the present study was to evaluate the N-terminal prohormone of brain natriuretic peptide (NT-pro BNP) and high sensitivity troponin T (cTnThs) value as predictors of CRT response in a 12-month observation. Materials and Methods: The study included 46 patients with HF and implanted CRT-D. Levels of NT-pro BNP and cTnThs were assessed during a 12 month follow up. Results: 46 consecutive patients (76% men) with a mean age of 64±8 were observed for 12 months. The CRT response criteria was met by 26 patients (56,5%). A significant decline in the NT-pro BNP concentrations was documented in responders (p=0.001). Moreover, ΔNT-pro BNP by at least 579 pg/ml had high sensitivity and specificity for identifying the CRT responders. There were no statistically significant differences in the results of cTnThs between the two study groups. Conclusion: The relative change in the level of NT-pro BNP by at least 43,5% allows to identify the responders to CRT after 12 months of follow-up. Serial measurements of NT-pro BNP can be a valuable tool for monitoring the effectiveness of CRT.