Current Pharmaceutical Design - Volume 24, Issue 30, 2018

Reducing infant mortality due to infectious diseases is one of the most important public health goals worldwide. Several approaches have been implemented to reach this goal and vaccination has been an effective strategy for reducing infant and newborn mortality. However, the immunological features of neonates and infants represent a significant barrier to the effectiveness of vaccination. Since regulatory T cells (Treg cells) are known to play an active role in contributing to various mechanisms of suppression of the immune cell function. It has been proposed that these immune cells could decrease the immunogenicity of vaccines administered in newborns and infants. In this article, we discuss the various types of Treg cells, along with their suppressing and inhibitory mechanisms, which are used by these cells in the context of infectious and immunization processes in newborns and infants.

Background: Erectile dysfunction (ED) affects 30 million men in the US with a decrease in quality of life. Thirty percent of hypertensive men suffer from ED. Objective: This review will debate the interplay between hypertension and ED, discovering novel insights concerning hypertension-linked ED, as well as the influence of antihypertensive medications on patients with ED. Method: Total number of records screened from PubMed yielded by the search which performed from January 2000 - June 2018. Results: Hypertension can cause ED as a consequence of high blood pressure or antihypertensive treatment. Both hypertension and ED have endothelial dysfunction as a common base mechanism, which can lead to an increase in vascular smooth muscle contraction. Also, some phosphodiesterase (PDE)-5 inhibitors used to treat ED can recover blood pressure. Conclusion: Understanding of common mechanisms involved in ED accompanied with hypertension and the research on antihypertensive drugs that impact ED will bring important approaches for identifying novel therapeutic strategies that will improve quality of life in patients with these conditions.

Objective: The present meta-analysis was designed to assess the effects of vitamin C supplementation on serum C-reactive Protein (CRP) levels. Methods: We conducted a comprehensive systematic search of the literature in Scopus, PubMed and Google Scholar until May 2018. The pooled Weighted Mean Difference (WMD) and its 95% Confidence Interval (CI) in baseline and at the end of the trial were calculated to assess the net change in serum CRP by using random-effects model. The heterogeneity was assessed by I2 test. Combined and stratified analyses were used in the metaanalysis. Results: From 306 articles found and screened in our initial search, 12 studies were included with 446 participants in supplementation groups and 447 in control groups. The pooled effect size analysis showed a significant reducing effect of vitamin C supplementation on circulating CRP level (−0.23 mg/L, 95% CI, −0.44, -0.03, p=0.02), with a significant heterogeneity effect across the studies involved. Subgroup analyses showed that vitamin C supplementation significantly lowered CRP among trials. The most significant effect was found 1) on hs- CRP as the representative inflammatory marker (-0.43 mg/L, 95% CI -0.76, -0.1) 2) in subjects with a baseline CRP≥3 (-1.48 mg/L, 95% CI -2.84, -0.11) 3) in subjects under <60 years old of age (-0.23 mg/L, 95% CI -0.44,- 0.01) 4) or using intravenous administration of vitamin C (-0.89 mg/L, 95% CI -1.49,-0.3). Conclusion: The present meta-analysis shows that vitamin C supplementation reduces serum CRP level, particularly in younger subjects, with higher CRP baseline level, at a lower dosage and intravenous administration.

Background: Andrographolide (Andro) is a main active ingredient of the natural plant Andrographis paniculata, which has special effects on bacterial infections and inflammatory diseases. Objective: We previously synthesized Andrographolide derivatives AL-1 and investigated its anti-inflammatory activity. For further research, we decided to modify the structure of AL-1 and expected to have better antiinflammatory activity. Methods: By conjugating with anti-inflammatory and anti-bacterial group, we designed and synthesized the andrographolide derivative AL-2, AL-3 and AL-4. The anti-inflammatory activity of AL-2, AL-3 and AL-4 was also evaluated by detecting cell activity and Nitric Oxide (NO) release. Results: The new compounds AL-2, AL-3 and AL-4 increased cell viability in lipopolysaccharide (LPS)-induced RAW 264.7 cell, which could have a certain anti-inflammatory activity, and inhibited the release of NO in cells to reduce the inflammatory response of cells. Conclusion: The new compounds AL-2, AL-3 and AL-4 may be candidates of anti-inflammatory drugs in the future.

Purpose: Pituitary adenylate Cyclase-Activating Polypeptide (PACAP) is a neuroprotective peptide that has been shown to exert protective effects in different models of neurodegenerative diseases, including retinal degenerations. Data obtained from PACAP-deficient (PACAP KO) mice provide evidence that endogenous PACAP has a neuroprotective role in different pathologies. PACAP KO mice show enhanced sensitivity to different insults, such as oxidative stress, hypoxia and inflammation. The aim of the present study was to investigate the protective effects of endogenous PACAP in retinal inflammation. Methods: Endotoxin-induced eye inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS) in PACAP KO and wild-type (Wt) mice. After LPS treatment, retinas were processed for histological examination. To detect the alterations of different proteins and cytokines, immunohistochemical, western blot and cytokine array were used. We also performed dark-adapted electroretinography (ERG) to detect the functional differences. Results: The thickness of nearly all layers was significantly less in LPS-injected PACAP KO mice compared to Wt animals. Increased expression of Glial Fibrillary Acidic Protein (GFAP) was induced in Müller glial cells after LPS treatment, which was more intense in PACAP KO mice. The levels of pAkt and pGSK were decreased in PACAP KO group during inflammation. LPS treatment significantly increased cytokines (sICAM-1, JE, TIMP-1) in both treated groups, but it was more expressed in PACAP KO animals. Furthermore, ERG responses were disturbed after LPS injection in PACAP KO mice. Conclusion: Our results showed that endogenous PACAP has a protective role in LPS-caused retinal inflammation.

Purpose: Filgrastim, a recombinant human granulocyte colony-stimulating factor (rhG-CSF) produced in Escherichia coli, is indicated for treatment of neutropenia-related conditions in cancer patients. It has been marketed as Neupogen since 1991. In 2006, biosimilar rhG-CSF products have been approved in the European Union (EU). The aim of this study was to compare quality attributes of the originator filgrastim with its three biosimilars which came from the EU market in 2014 to verify whether their similarity is maintained since their market approval. Materials/Methods: Spectrophotometric analysis was used to determine protein content in analyzed products. Chromatographic and electrophoretic analyses were applied to verify the presence of high and low-molecular weight impurities. Secondary and tertiary structure of the drugs were investigated with circular dichroism and intrinsic fluorescence. Finally, biological activity of the drugs was assessed using cell proliferation assay. Results: All products displayed protein content close to the label concentration with a ±6% variation. Two oxidized forms and a deamidated form were present at <0.5%. Levels of dimers and other high molecular-weight impurities were similar except for one product, which contained higher amount of the dimer. Profiles and levels of process-related impurities were comparable. The three-dimensional conformation of the molecules with respect to exposed tryptophan residues was similar. The relative potencies of the products were comparable to the reference standard with a ±2% variation. Conclusion: This study shows that a high level of similarity is maintained among originator and three biosimilar filgrastims up to 5 years from their first registration in the EU.

Purpose: The emerging evidence has recently shown an evident dependence between recently identified salusin peptides and atherosclerosis, and their important roles as endogenous modulators of atherogenesis. It was reported that the development of atherosclerosis could also be affected by endogenous salusin- β overproduction in vascular lesions. Materials/Methods: This prospective cohort study was conducted in two groups of children: HT – 58 patients with essential hypertension (HT); R - 30 participants with white-coat HT (R). We analysed the relationship between serum salusin- α and salusin- β levels and ADMA, SDMA and hs- CRP in children and adolescents with essential hypertension. Results: Serum level of salusin- #145; in each sample was under the sensitivity of method. Serum level of salusin-β was statistically significantly higher in hypertension group when compared to the reference group (p<0.05) and correlated positively with serum hs-CRP [rho=0.47; p<0.01] and asymmetric dimethylarginine (ADMA) [rho=0.32; p<0.05]. There was no significant association between salusin-β and symmetric dimethylarginine (SDMA) [rho=0.27; p>0.05]. Conclusion: This preliminary study showed that the concentration of salusin-β is associated with circulating level of hs-CRP and ADMA in teenagers with hypertension. Further studies are needed to find out if salusin-β levels may indicate for endothelial dysfunction and form the basis for the development of new therapeutic agent.

Background: New Oral Anticoagulants (NOACs) are effective and widely used to prevent and treat thromboembolic diseases, but the response to NOACs differs according to ABCB1 genotypes. Objective: We investigated the effects of ABCB1 genotypes on the pharmacokinetics and clinical outcomes of NOACs. Methods: We searched PubMed, Embase, and the Cochrane Library for studies on ABCB1 genotypes published from the inception of these databases until May 23, 2018. The Weighted Mean Difference (WMD) and Odds Ratio (OR) with 95% Confidence Interval (CI) were calculated for continuous and dichotomous data, respectively. Summary results were calculated using a random effects model. Results: Ten studies involving 2609 individuals were included in the systematic review, and three studies involving 535 individuals were included in the meta-analysis. Overall, four ABCB1 single-nucleotide polymorphisms were identified in the review. Carriers of the ABCB1 rs1045642 CC genotype had lower maximum plasma concentration (Cmax) than those of TT (WMD = −16.99 ng/mL; 95% CI = −33.39 to −0.59; P = 0.04), and carriers of the rs2032582 GG genotype showed lower Cmax than those of the A/T allele (WMD = −19.21 ng/mL; 95% CI = −36.62 to −1.80; P = 0.03). Carriers of the rs1045642 CC genotype showed lower area under the curve from time 0 to infinity (AUC0–∞) than those of the T allele (WMD = −78.58 ng·h/mL; 95% CI = −151.14 to −6.01; P = 0.03). ABCB1 rs4148738 genotypes did not affect the risks of ischemic stroke or systemic embolism (OR = 0.88), ischemic events (OR = 0.98), bleeding (OR = 0.94), major bleeding (OR = 1.14), or minor bleeding (OR = 0.94) in patients treated with dabigatran. Conclusion: Cmax was lower in carriers of ABCB1 rs1045642 CC than in those of TT and in carriers of rs2032582 GG than in those of the A/T allele, and AUC0–∞ was lower in carriers of rs1045642 CC than in those of TT. Conversely, ABCB1 rs4148738 genotypes did not affect primary clinical endpoints in dabigatran-administered patients. Future studies should analyze the relationships of ABCB1 genotypes with the pharmacokinetics and clinical outcomes of specific NOACs.

TP53 is a tumor suppressor gene which is commonly mutated in various cancers including breast cancer. Alterations in the gene lead to an altered expression of various genes that are directly or indirectly under the transcriptional control of p53. This results in malfunctioning of DNA damage repair pathways, cell-cycle arrest, chromatin remodeling and apoptosis. Different mutations in TP53 gene have been reported in different ethnic groups and exon 4 and intron 3 are reported to be frequently mutated in breast cancer patients especially triplenegative breast cancer. Increased global burden of TP53 mutated breast tumors has paved the path for various therapies targeting p53/TP53. Numerous molecules including nutilins, MI series, RO5693, PRIMA-1, RITA, etc. have been developed. Majority of these restore p53/TP53 function by targeting negative regulators of p53/TP53, wtp53/TP53 (wild-type) and mtp53/TP53 (mutant). Most of these molecules are in the preclinical phase except for two APR-246 and COTI-2 that have progressed to clinical trials. The current review has been compiled with an aim to give an overview of mutations in p53 across various ethnic groups, the effect of these alterations on TP53 function and the therapeutic strategies developed till date targeting p53/TP53 especially in breast cancer.

The present study focused to optimize dual coated multiparticulates using Box-Behnken Experimental Design and in-silico simulation using GastroPlusTM software. The optimized formulations (OB1 and OB2) were comparatively evaluated for particle size, morphological, in vitro drug release, and in vivo permeation studies. In silico simulation study predicted the in vivo performance of the optimized formulation based on in-vitro data. Results suggested that optimized formulation was obtained using maximum content of Eudragit FS30D and minimum drying time (2 min). In vitro data corroborated that curcumin release was completely protected from premature drug release in the proximal part of gastro intestinal tract and successfully released to the colon (95%) which was closely predicted (90.1 %) by GastroPlusTM simulation technique. Finally, confocal laser scanning microscopy confirmed the in-vitro findings wherein maximum intensity was observed with OB1 treated group suggesting successful delivery of OB1 to the colon for enhanced absorption as predicted in regional absorption profile in ascending colon (30.9%) and caecum (23.2%). Limited drug absorption was predicted in small intestine (1.5-8.7%). The successful outcomes of the research work minimized the release of curcumin in the upper gastric tract and the maximized drug access to the colon (pH 7.4) as prime concern.

Purpose: Ultrasound contrast agents involving a therapeutic drug applied during enhanced imaging can be used for targeted therapy. The preparation of contrast agents is a precondition and basis for the use of multifunctional contrast agents in molecular imaging. Methods: This study uses thin-film hydration-mechanical vibration to carry out the preliminary preparation of a cationic contrast agent (CCA); characterizes the particle diameter, potential, distribution, and concentration of the agents; and optimizes the factors affecting the preparation of the agents. Results: This study found that thin-film hydration-mechanical vibration methods offer a better preparation effectiveness and achieve smaller particle diameters and more even distributions, as well as give better imaging performance. Different concentrations of CCA and plasmid and different gene transfection methods can produce different degrees of sonoporation to achieve optimal transfection efficiency. Ultrasound parameters have a great influence on transfection efficiency and plasmid integrity. A previous study confirmed that the ultrasound parameters of 1 MHz, 1 W/cm2, a duty cycle controller (DC) of 20%, and irradiation for 1 min can well deliver genes to tumor cells, with little impact on cell survival. Conclusion: Our findings indicate that ultrasound-targeted microbubble destruction (UTMD)-mediated CCA destruction facilitates gene transfection and may represent an effective gene delivery method for cervical cancer therapy.