Current pharmaceutical design [journal]
- Circulating microRNAs as novel potential diagnostic and prognosis biomarkers in pancreatic cancer. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 16.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis, and excessive resistance to chemotherapy. MicroRNAs have been shown to play important roles in PDAC oncogenesis as they can act as both oncogenes and tumor suppressor molecules. Altered expression of specific microRNAs in PDAC has diagnostic and prognostic implications. There is growing body of evidence showing the important role of miR-486-5p and miR-938 for discrimination of PDAC patients from healthy subjects and those with chronic pancreatitis. Additionally the diagnostic features of miR-486-5p were comparable with CA 19-9 for the detection of PDAC patients, suggesting its diagnostic value as a blood-based miRNA in PDAC, although further investigations are warranted for validation of these markers. In addition to these applications, several studies have suggested therapeutic potential of some miRNAs in PDAC. In particular, modulations of let-7, miR-29a, miR-17-5p, miR-365, miR-181b, miR-21, miR-221 and miR-96 are reported to be associated with chemotherapy resistance/sensitivity. Moreover, enforced expression of miR-17-92 inhibits tumourigenicity and increased chemoresistance in PDAC cancer stem cells via TGF-β1 pathway, while miR-96 could targets KRAS. In this review we attempt to give an overview about recent preclinical and clinical studies that have addressed the potential use of circulating microRNAs as diagnostic and prognostic biomarkers, their use as therapeutic agents and finally, we discuss the possible role of microRNAs in PDAC chemoresistance.
- Editorial (Thematic Issue: Current and Perspective Therapeutic Strategies for Alzheimer's Disease). [Editorial]
- Curr Pharm Des 2016; 22(26):3935-6.
- Evaluation of the performance of an ophthalmic thermosensitive hydrogel containing combination of Suramin and Bevacizumab. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 11.
Suramab (SUM) is a new pharmaceutical combination made up of suramine (SUR) and bevacizumab (BVM), which showed a high synergistic effect when administered jointly. As the pharmaceutical vehicle, poloxamer aqueous dispersions were used since this system is able to maintain their fluidity at low temperatures (<15ºC) but which become gel in the corporal environment (>35ºC).In the present study we aimed at evaluating the effect of Poloxamer to prolong the effect of SUM. These formulations were characterized using rheological, biopharmaceutical (drug release) and morphological (SEM) technique. Corneal NV was induced in Sprague Dawley rats Corneal . At 15 days of follow up animals were sacrificed and perfused with black drawing ink. Digital photographs were taken and the area of neovascularisation (ANV) was calculated using the image programmed. The rheological behavior was influenced by the addition of drugs, resulting in a decrease in the gelation temperature (Tsol/gel). Both drugs were released from poloxamer gels by means of an anomalous mechanism. However, BVM was released faster than SUR, with their combination (SUM) to appearing to reduce delivery, probably due to interactions between the drugs or with the polymeric matrix. The in vivo studies showed that SUM-poloxamer gel was able to increase the corneal antiangiogenic effect compared to the SUM solution and BVM alone at 15 days of follow-up. Furthermore no injurious effects were observed in the histological tissue examination after drug administration.The presence of Poloxamer, known to modulate control release of biological agents, seems to have a favorable effect on SUM subconjunctival administered.
- Cannabis Epidemiology: A Selective Review. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 13.
Globally, the most widely used set of compounds among the internationally regulated drugs is cannabis.To review evidence from epidemiological research on cannabis, organized in relation to this field's five main rubrics: quantity, location, causes, mechanisms, and prevention/control.The review covers a selection of evidence from standardized population surveys, official statistics, and governmental reports, as well as published articles and books identified via MEDLINE, Web of Science, and Google Scholar as of July 2016.In relation to quantity, an estimated 3% to 5% of the world population is thought to have tried a cannabis product, with at least one fairly recent use, mainly extra-medical and outside boundaries of prescribed use. Among cannabis users in the United States, roughly one in 7-8 have engaged in medical marijuana use. In relation to location, prevalence proportions reveal important variations across countries and between subgroups within countries. Regarding causes and mechanisms of starting to use cannabis, there is no compelling integrative and replicable conceptual model or theoretical formulation. Most studies of mechanisms have focused upon a 'gateway sequence' and person-to-person diffusion, with some recent work on disability-adjusted life years. A brief review of cannabis use consequences, as well as prevention and control strategies is also provided.At present, we know much about the frequency and occurrence of cannabis use, with too little replicable definitive evidence with respect to the other main rubrics. Given a changing regulatory environment for cannabis products, new institutions such as an independent International Cannabis Products Safety Commission may be required to produce evidence required to weigh benefits versus costs. It is not clear that government-sponsored research will be sufficient to meet consumer demand for balanced points of view.
- Potential Role of Cardiovascular Imaging in Improving Cardiovascular Outcome in Coronary Artery Disease. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 13.
There is increasing interest in cardiovascular imaging modalities in the detection of subclinical and clinically-manifest coronary artery disease (CAD) to improve cardiovascular outcome in these patients.SPECT/CT and PET/CT can be applied for the assessment of myocardial perfusion and myocardial blood flow (MBF) quantification in CAD detection and characterization, while CT is predominantly used to identify coronary plaque burden and epicardial narrowing. In addition, PET/CT plays an increasing role in the detection of the "vulnerable" plaque in the epicardial artery.Imaging of myocardial perfusion with SPECT, SPECT/CT and PET/CT is a mainstay in clinical practice for the identification of flow-limiting epicardial lesions and risk stratification of patients with suspected or known CAD. In this direction, The concurrent ability of PET/CT to determine regional myocardial blood flow (MBF) in ml/g/min at rest and during pharmacologically-induced hyperemic flows allows the calculation of the myocardial flow reserve (MFR) that may unravel reductions in coronary vasodilator capacity, as functional precursor of the CAD process, monitor its response to preventive medical intervention, yield important prognostic information in subclinical - and clinically-manifest CAD, and contributes to identify the flow-limiting effect of single lesions in multivessel CAD. Adding non-contrast computed-tomography (CT) measurements of coronary artery calcifications has further improved the reclassification of cardiovascular risk in asymptomatic individuals with intermediate probability of the presence of CAD. With contrast CT, the non-invasive visualization of coronary vessels, CAD-related plaque burden and stenosis has become feasible. Yet, a definite identification of the "vulnerable plaque" is still a matter of ongoing research. PET/CT in conjunction with various positron-emitting radiotracer yields promise in the detection of the "vulnerable plaque," that, however, needs further clinical evaluation in CAD patients.Multimodality imaging in cardiovascular disease is likely to further advances and refine the identification and characterization of cardiovascular pathology in the near future.
- Insulin-like growth factor-1, a potential predicative biomarker for postoperative delirium among elderly patients with open abdominal surgery. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 13.
Delirium is commonly observed among elderly surgical subjects during the postoperative period, and the incidence of postoperative delirium (POD) in elderly patients (≥65 years) ranges widely from 10% to 70%. This study aimed at investigating potential serum predicative factors for POD in elderly patients after open abdominal surgery.140 subjects scheduled to undergo elective gastrointestinal tumor resection via laparotomy from March, 2013 to May, 2015 were enrolled in this study. Participants enrolled were evaluated for delirium and delirium severity on preoperative day, postoperative days 2 and 3. Non-fasting blood samples were collected in the morning on the day before surgery for the detection of serum cytokines expressions by enzyme-linked immunesorbent assays (ELISA).A total of 140 patients were finally enrolled in this study and 36 of them occurred POD, with a POD incidence of 25.7%. In comparison with non-POD group, the serum levels of insulin-like growth factor-1 (IGF-1) demonstrated significantly decreased of patients in POD group (P<0.01). The receiver operating characteristic (ROC) curve analysis revealed that serum IGF-1 levels as potential predicative factor for POD with the area under the ROC curve (AUC) values of 0. 805, with 95 % confidence interval (CI) of 0.719-0.891 (P<0.001). Univariate and multivariate logistic regression analysis resulted in serum IGF-1 level as a non-invasive predicative factor for POD (OR=2.52, 95%CI: 1.19-5.43, P=0.019).Our results showed that serum IGF-1 level was a potential predicative biomarker for POD among patients undergoing elective gastrointestinal tumor resection via laparotomy.
- A New Direction in Ophthalmic Development: Nanoparticle Drug Delivery Systems. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 13.
The purpose of each dosage form is to provide an optimal therapeutic effect with a minimum dose and with minimal side effects. This is particularly relevant for drugs that require systemic administration, higher dosing and/or show lower bioavailability. Тhe eye as an anatomical structure is an extremely protected organ. In this regard, providing an optimal bioavailability in the eye tissues, resulting in the desired therapeutic effect represents a major challenge. This is particularly true for the treatment of diseases, affecting the posterior segment after topically administered drug formulations. The use of nano- and microcarriers of drug substances may be an appropriate technological approach, to provide a high bioavailability of the drug substance for a certain interval of time at the right place. The purpose of this review is to indicate how nano- and microcarriers of drug substances can solve the problems with the drug delivery in the ocular tissues, to indicate the possible hazards and side effects, depending on the polymer nature and route of administration, and to visualize the future potential of these carriers in the pharmaceutical practice.
- Pleiotropic effects of simvastatin on some calcium regulatory and myofibrillar proteins in ischemic/reperfused heart: causality of statins cardioprotection? [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 13.
It is known that statins possess beneficial cardioprotective effects irrespective of lipid-lowering action and that cardiac injury due ischemia/reperfusion is associated with Ca2+ dysregulation resulting in contractile dysfunction.With this background, we tested a hypothesis that simvastatin influences signaling of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), a protein kinase regulating both Ca2+ homeostasis and thick filament function, and thereby might underlie the mitigation of ischemia/reperfusion (I/R)-induced cardiac dysfunction.Isolated hearts of control and simvastatin-treated (p.o. 10 mg/kg, 5 days) rats were subjected to global I and R and Western blotting was used to study the expression/activation of certain signaling proteins.Simvastatin treatment did not modify the plasma lipid levels; however, it recovered depressed cardiac performance and reduced reperfusion arrhythmias without affecting the activation of CaMKIIδ through phosphorylation of Thr287. Activation of its downstreams, such as phospholamban (PLN) and cardiac myosin-binding protein C (cMyBP-C) at Thr17 and Ser282, respectively, was in accordance with the levels of pThr287-CaMKIIδ.Total expression of these proteins, however, did not follow the same pattern and was either unchanged (CaMKIIδ, cMYBP-C) or increased (PLN). Likewise, PLN/SERCA2a (sarco/endoplasmic reticulum Ca2+-ATPase 2a) ratio in I/R hearts was unaffected by the treatment. On the other hand, simvastatin reversed the increased protein expression of protein phosphatase 1β (PP1β), but not protein phosphatase 2A (PP2A), in I/R hearts.A lower rate of dephosphorylation and thereby a delay in inactivation of phosphorylated proteins due to a decrease in PP1β, rather than effects on phosphorylation of CaMKIIδ and its downstreams, such as PLN and cMyBP-C, may underlie beneficial effects of simvastatin in I/R hearts.
- Determing Effective Diabetic Care: A Multicentre - Longitudinal Interventional Study. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 13.
Prevalence of chronic diseases are on the rise with majority occurring in developing countries where the projected death caused by chronic diseases will reach 50 million by the year 2020.The aim of the study is to evaluate and compare the outcomes of wireless mobile device (Telemonitoring) with Pharmacist intervention and usual care on glycemic control and clinical outcomes.This study is a six-month parallel groups interventional longitudinal multi-center study with a control arm. The study participants consist of patient diagnosed with type 2 diabetes mellitus and attending the outpatient department (OPD) for diabetic treatment. The study protocol is approved from ministry of health Malaysia and clinical research committee (CRC). Data analysis was made using IBM SPSS Statistics, version 22 (Armok, NY).A total of 150 participants were selected to enroll in this study. Initial baseline comparison showed 'No significant difference' between the two intervention arms and control group. Findings showed that baseline dataset have no significant change among all three-arms. However last week of study showed significant (p<0.001) improvement among pharmacist intervention arm as compared to telemonitoring and control arm. Glycemic control seems well tolerated and managed among pharmacist intervention arm as compared to telemonitoring and control arm (p<0.001). The study findings also showed reduction of mean 2.72 % (HbA1c) as compare to baseline in six months. The proportion of participants experiencing hypoglycemic/hyperglycemic events was significantly lower in the pharmacist intervention group compared to telemonitoring and control arm (odds ratio: 2.1381; 95% CI: 3.0267-1.6059, p<0.001).The Pharmacist educational focus-home care program improves the patient knowledge, self-care practices and also significantly reduce the adverse events over study duration.
- Altered Steroid Metabolism And Insulin Signaling In Pcos Endometria: Impact In Tissue Function. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Aug 10.
Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine/metabolic disorder characterized by hyperandrogenemia and in most cases, by hyperinsulinemia in addition to obesity. Besides ovarian dysfunction, endometrial physiology is also disrupted since this tissue is highly dependent on the action of steroids; in case of conception cycles, high percentage of abortion is observed. Because of the endocrine/metabolic alterations, PCOS-women present high probability to develop hyperplasia and endometrial cancer, where an imbalance of cell proliferation/apoptosis processes is detected. Additionally, insulin pathway and the endometrial energetic homeostasis are also compromised.The aim of this review was to report molecular alterations related to insulin-resistance and/or obesity in PCOS-women endometria that could drive to infertility. For this, several methods were employed: immunohistocytochemistry, qPCR, western-blot, glucose-uptake, cell cultures, among others.Diminished levels and activity of several insulin signaling pathway molecules, like IRS-1/AS160/PKCζ, were detected. Concomitantly, a defect in the synthesis and GLUT4 translocation to cell surface is induced. Oral administration of metformin (insulin sensitizer) to PCOS-patients increases GLUT4 endometrial levels, improving fertility of those patients. Another relevant feature is the high percentage of obesity in PCOS-women; adiponectin is an obesity marker and elicits an insulin-sensitizer action, being diminished in plasma of obese PCOS-women similar to its endometrial level, adiponectin-receptors and APPL1, an adapter molecule of adiponectin pathway. Moreover, obesity and PCOS can induce a pro-inflammatory environment, exaggerating the alterations in insulin pathway.The evidences obtained in PCOS-endometria clearly indicate that these molecular defects could partially explain the reproductive failures of these patients.