Pharmaceuticals

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ISSN / EISSN : 1424-8247 / 1424-8247
Current Publisher: MDPI (10.3390)
Total articles ≅ 1,371
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Magdalena Markowicz-Piasecka, Adrianna Sadkowska, Joanna Sikora, Marlena Broncel, Kristiina Huttunen
Published: 21 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100323

Abstract:
Metformin, one of the most frequently prescribed oral anti-diabetic drugs, is characterized by multidirectional activity, including lipid lowering, cardio-protective and anti-inflammatory properties. This study presents synthesis and stability studies of 10 novel sulfonamide-based derivatives of metformin with alkyl substituents in the aromatic ring. The potential of the synthesized compounds as glucose-lowering agents and their effects on selected parameters of plasma and vascular hemostasis were examined. Compounds with two or three methyl groups in the aromatic ring (6, 7, 9, 10) significantly increased glucose uptake in human umbilical vein endothelial cells (HUVECs), e.g., 15.8 µmol/L for comp. 6 at 0.3 µmol/mL versus 11.4 ± 0.7 µmol/L for control. Basic coagulation studies showed that all examined compounds inhibit intrinsic coagulation pathway and the process of fibrin polymerization stronger than the parent drug, metformin, which give evidence of their greater anti-coagulant properties. Importantly, synthesized compounds decrease the activity of factor X, a first member of common coagulation pathway, while metformin does not affect coagulation factor X (FX) activity. A multiparametric clot formation and lysis test (CL-test) revealed that the examined compounds significantly prolong the onset of clot formation; however, they do not affect the overall potential of clot formation and fibrinolysis. Erythrotoxicity studies confirmed that none of the synthesized compounds exert an adverse effect on erythrocyte integrity, do not contribute to the massive hemolysis and do not interact strongly with the erythrocyte membrane. In summary, chemical modification of metformin scaffold into benzenesulfonamides containing alkyl substituents leads to the formation of potential dual-action agents with comparable glucose-lowering properties and stronger anti-coagulant activity than the parent drug, metformin.
Julian Wolfes, Christian Ellermann, Niklas Broer, Benjamin Rath, Kevin Willy, Patrick Leitz, Philipp Lange, Lars Eckardt, Gerrit Frommeyer
Published: 20 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100321

Abstract:
The aim of this study was to investigate the effects of a combination of ranolazine with different selective inhibitors of the Na+/Ca2+-exchanger (NCX) in an established experimental model of atrial fibrillation (AF). Eighteen hearts of New Zealand white rabbits were retrogradely perfused. Atrial catheters were used to record monophasic action potentials (aPRR). Hearts were paced at three different cycle lengths. Thereby, atrial action potential durations (aAPD90), atrial effective refractory periods (aERP) and atrial post-repolarization refractoriness were obtained. Isoproterenol and acetylcholine were employed to increase the occurrence of AF. Thereafter, the hearts were assigned to two groups (n = 9 each group) and additionally perfused with a combination of 10 µM ranolazine and 1 µM of the selective NCX-inhibitor ORM-10103 (group A: Rano-ORM) or 10 µM ranolazine and 1 µM of another NCX-inhibitor, SEA0400 (group B: Rano-SEA). The infusion of Iso/ACh led to a shortening of aAPD90, aERP, aPRR and the occurrence of AF episodes was significantly increased. Additional perfusion with ranolazine and ORM-10103 (group A) significantly prolonged the refractory periods and aPRR and AF episodes were effectively reduced. In group B, Rano-SEA led to a slight decrease in aAPD90 while aERP and aPRR were prolonged. The occurrence of AF episodes was consecutively reduced. To our knowledge, this is the first study investigating the effect of ranolazine combined with different selective NCX-inhibitors in an isolated whole-heart model of AF. Both combinations prolonged aERP and aPRR and thereby suppressed the induction of AF.
Alice Sanson, Marco A. Riva
Published: 20 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100322

Abstract:
Stress exposure represents a major environmental risk factor for schizophrenia and other psychiatric disorders, as it plays a pivotal role in the etiology as well as in the manifestation of disease symptomatology. It may be inferred that pharmacological treatments must be able to modulate the behavioral, functional, and molecular alterations produced by stress exposure to achieve significant clinical outcomes. This review aims at examining existing clinical and preclinical evidence that supports the ability of atypical antipsychotic drugs (AAPDs) to modulate stress-related alterations. Indeed, while the pharmacodynamic differences between AAPDs have been extensively characterized, less is known on their ability to regulate downstream mechanisms that are critical for functional recovery and patient stabilization. We will discuss stress-related mechanisms, spanning from neuroendocrine function to inflammation and neuronal plasticity, which are relevant for the manifestation of schizophrenic symptomatology, and we will discuss if and how AAPDs may interfere with such mechanisms. Considering the impact of stress in everyday life, we believe that a better understanding of the potential effects of AAPDs on stress-related mechanisms may provide novel and important insights for improving therapeutic strategies aimed at promoting coping mechanisms and enhancing the quality of life of patients affected by psychiatric disorders.
Eugenia Romano, Paolo Netti, Enza Torino
Published: 19 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100319

Abstract:
Exosomes are phospholipid-based particles endogenously produced by both normal and tumor cells. Initially identified as a pathway for shuttling cellular waste, for a long time they were thought to act as “garbage bags”, and only in the past few years have they emerged as a promising drug delivery system. In this review, we provide an overview of the knowledge about exosome architecture and biogenesis and the recent progress in isolation methods. Furthermore, we describe the mechanisms involved in both extra- and intracellular communication with a focus on glioma brain tumors. Glioma is considered a rare disease and is the most prominent aggressive brain malignancy. How exosomes target glial tumoral cells in vivo remains largely unknown. However, they are able to influence numerous physio-pathological aspects. Here, we discuss the role they play in this heterogeneous and complex microenvironment and their potential applications.
Rahim Ullah, Gowhar Ali, Nisar Ahmad, Muhammad Akram, Geeta Kumari, Muhammad Amin, Muhammad Umar
Published: 19 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100318

Abstract:
Alzheimer’s disease (AD) is an irreversible and chronic neurological disorder that gradually destroys memory and thinking skills. The research study was designed to investigate the underlying molecular signaling involved in the neuroprotective effects of cyclopentanone derivative i.e., 2-(hydroxyl-(3-nitrophenyl)methyl)cyclopentanone (3NCP) as a therapeutic agent for AD. In this study, In vivo studies were carried out on a well-known 5xFAD mice model using different behavioural test models such as open field, rotarod, Morris water maze (MWM), and Y-maze tests. Furthermore, in vitro cholinesterase inhibition activity assays were carried out. The frontal cortex (FC) and hippocampus (HC) homogenates were tested for the levels/activities of cholinesterases, glutathione (GSH), glutathione S-transferase (GST), and catalase. Furthermore, the hippocampal expression of inflammatory cytokines was observed via RT-PCR and western blot. The results of in vivo studies show an enhancement in the learning behavior. The 3NCP treatment reduced latency time in MWM and Y-maze tests, also increase spontaneous alternation indicate significant effect of 3NCP on memory. Furthermore, open field and rotarod studies revealed that 3NCP does not cause motor coordination deficit. The results of the in vitro studies revealed that the IC50 values of the 3NCP against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were 16.17 and 20.51 µg/mL, respectively. This decline in AChE and BChE was further supported by ex vivo studies. Further, the 3NCP mitigates the GSH level, GST, and catalase activities in HC and FC. The mRNA and protein expression of inflammatory cytokines (IL-1β, IL-6, TNF-α) markedly declined in RT-PCR and western blotting. The results of the current study conclusively demonstrate that 3NCP reduces oxidative stress and mitigates neuroinflammation in 5xFAD mice, implying that 3NCP may be a potential therapeutic candidate for AD treatment in the future.
Benjamin Rossi, Lee S. Nguyen, Philippe Zimmermann, Faiza Boucenna, Louis Dubret, Louise Baucher, Helene Guillot, Marie-Anne Bouldouyre, Yves Allenbach, Joe-Elie Salem, et al.
Published: 17 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100317

Abstract:
Tocilizumab, an anti-interleukin-6 receptor, administrated during the right timeframe may be beneficial against coronavirus-disease-2019 (COVID-19) pneumonia. All patients admitted for severe COVID-19 pneumonia (SpO2 ≤ 96% despite O2-support ≥ 6 L/min) without invasive mechanical ventilation were included in a retrospective cohort study in a primary care hospital. The treatment effect of a single-dose, 400 mg, of tocilizumab was assessed by comparing those who received tocilizumab to those who did not. Selection bias was mitigated using three statistical methods. Primary outcome measure was a composite of mortality and ventilation at day 28. A total of 246 patients were included (106 were treated with tocilizumab). Overall, 105 (42.7%) patients presented the primary outcome, with 71 (28.9%) deaths during the 28-day follow-up. Propensity-score-matched 84 pairs of comparable patients. In the matched cohort (n = 168), tocilizumab was associated with fewer primary outcomes than the control group (hazard ratio (HR) = 0.49 (95% confidence interval (95%CI) = 0.3–0.81), p-value = 0.005). These results were similar in the overall cohort (n = 246), with Cox multivariable analysis yielding a protective association between tocilizumab and primary outcome (adjusted HR = 0.26 (95%CI = 0.135–0.51, p = 0.0001), confirmed by inverse probability score weighting (IPSW) analysis (p < 0.0001). Analyses on mortality only, with 28 days of follow-up, yielded similar results. In this study, tocilizumab 400 mg in a single-dose was associated with improved survival without mechanical ventilation in patients with severe COVID-19.
Maritza P. Garrido, Renato Salvatierra, Manuel Valenzuela-Valderrama, Christopher Vallejos, Nicole Bruneau, Andrea Hernández, Margarita Vega, Alberto Selman, Andrew F. G. Quest, Carmen Romero
Published: 16 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100315

Abstract:
Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, β-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.
Yo Shinoda, Kohei Kujirai, Kohei Aoki, Mai Morita, Masato Masuda, Lihao Zhang, Zhou Kaixin, Akihiro Nomoto, Tsutomu Takahashi, Yayoi Tsuneoka, et al.
Published: 16 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100316

Abstract:
A photosensitizer is a molecular drug for photodynamic diagnosis and photodynamic therapy (PDT) against cancer. Many studies have developed photosensitizers, but improvements in their cost, efficacy, and side effects are needed for better PDT of patients. In the present study, we developed a novel photosensitizer β-mannose-conjugated chlorin e6 (β-M-Ce6) and investigated its PDT effects in human glioblastoma U251 cells. U251 cells were incubated with β-M-Ce6, followed by laser irradiation. Cell viability was determined using the Cell Counting Kit-8 assay. The PDT effects of β-M-Ce6 were compared with those of talaporfin sodium (TS) and our previously reported photosensitizer β-glucose-conjugated chlorin e6 (β-G-Ce6). Cellular uptake of each photosensitizer and subcellular distribution were analyzed by fluorescence microscopy. β-M-Ce6 showed 1000× more potent PDT effects than those of TS, and these were similar to those of β-G-Ce6. β-M-Ce6 accumulation in U251 cells was much faster than TS accumulation and distributed to several organelles such as the Golgi apparatus, mitochondria, and lysosomes. This rapid cellular uptake was inhibited by low temperature, which suggested that β-M-Ce6 uptake uses biological machinery. β-M-Ce6 showed potent PDT anti-cancer effects compared with clinically approved TS, which is a possible candidate as a next generation photosensitizer in cancer therapy.
Eman Mohamed, Tahir Khuroo, Hamideh Afrooz, Sathish Dharani, Khaldia Sediri, Phillip Cook, Rajendran Arunagiri, Mansoor Khan, Ziyaur Rahman
Published: 15 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100311

Abstract:
The focus of the present investigation was to develop a predictive dissolution model for tablets coated with blends of cellulose acetate butyrate (CAB) 171-15 and cellulose acetate phthalate (C-A-P) using the design of experiment and chemometric approaches. Diclofenac sodium was used as a model drug. Coating weight gain (X1, 5, 7.5 and 10%) and CAB 171-15 percentage (X2, 33.3, 50 and 66.7%) in the coating composition relative to C-A-P and were selected as independent variables by full factorial experimental design. The responses monitored were dissolution at 1 (Y1), 8 (Y2), and 24 (Y3) h. Statistically significant (p < 0.05) effects of X1 on Y1 and X2 on Y1, Y2, and Y3 were observed. The models showed a good correlation between actual and predicted values as indicated by the correlation coefficients of 0.964, 0.914, and 0.932 for Y1, Y2, and Y3, respectively. For the chemometric model development, the near infrared spectra of the coated tablets were collected, and partial least square regression (PLSR) was performed. PLSR also showed a good correlation between actual and model predicted values as indicated by correlation coefficients of 0.916, 0.964, and 0.974 for Y1, Y2, and Y3, respectively. Y1, Y2, and Y3 predicted values of the independent sample by both approaches were close to the actual values. In conclusion, it is possible to predict the dissolution of tablets coated with blends of cellulose esters by both approaches.
Huan Yue, Ji Park, Son Ho, Mohammad Yaseen Ahmad, Hyunsil Cha, Shuwen Liu, Tirusew Tegafaw, Shanti Marasini, Adibehalsadat Ghazanfari, Soyeon Kim, et al.
Published: 15 October 2020
by MDPI
Pharmaceuticals, Volume 13; doi:10.3390/ph13100312

Abstract:
Nanoparticles are considered potential candidates for a new class of magnetic resonance imaging (MRI) contrast agents. Negative MRI contrast agents require high magnetic moments. However, if nanoparticles can exclusively induce transverse water proton spin relaxation with negligible induction of longitudinal water proton spin relaxation, they may provide negative contrast MR images despite having low magnetic moments, thus acting as an efficient T2 MRI contrast agent. In this study, carbon-coated paramagnetic dysprosium oxide ([email protected]) nanoparticles (core = DYO = DyxOy; shell = carbon) were synthesized to explore their potential as an efficient T2 MRI contrast agent at 3.0 T MR field. Since the core DYO nanoparticles have an appreciable (but not high) magnetic moment that arises from fast 4f-electrons of Dy(III) (6H15/2), the [email protected] nanoparticles exhibited an appreciable transverse water proton spin relaxivity (r2) with a negligible longitudinal water proton spin relaxivity (r1). Consequently, they acted as a very efficient T2 MRI contrast agent, as proven from negative contrast enhancements seen in the in vivo T2 MR images.
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