Pharmaceuticals

13 pages, 10155 KiB

Open AccessArticle

Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies

by Carolina Afonso de Lima, Ian Lucas de Souza Bueno, Stanley Nunes Siqueira Vasconcelos, Juliana Mozer Sciani, Ana Lúcia Tasca Gois Ruiz, Mary Ann Foglio, João Ernesto de Carvalho and Giovanna Barbarini Longato

Pharmaceuticals 2020, 13(10), 327; https://doi.org/10.3390/ph13100327 - 21 Oct 2020

Cited by 10 | Viewed by 3543

Abstract

Multidrug resistance (MDR) is the main obstacle in anticancer therapy. The use of drug combinations to circumvent tumor resistance is a well-established principle in the clinic. Among the therapeutic targets, glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating MDR, is highlighted. [...] Read more.

Multidrug resistance (MDR) is the main obstacle in anticancer therapy. The use of drug combinations to circumvent tumor resistance is a well-established principle in the clinic. Among the therapeutic targets, glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating MDR, is highlighted. Many pharmacological studies report the ability of calcium channel blockers to reverse tumor resistance to chemotherapy drugs. Isolated for the first time from parsley, the phenylpropanoid apiole is described as a potent calcium channel inhibitor. Taking this into account, herein, the ability of apiole to potentiate the action of well-established chemotherapeutics in the clinic, as well as the compound’s relationship with the reversal of the resistance phenomenon by blocking P-gp, is reported. The association of apiole with both chemotherapeutic drugs doxorubicin and vincristine resulted in synergistic effect, in a concentration-dependent manner, as evaluated by the concentration reduction index. Molecular docking analysis demonstrated the affinity between apiole and the active site of P-gp, corroborating the inhibitory effect. Moreover, apiole demonstrated druglikeness, according to ADME analysis. In conclusion, apiole possibly blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants)

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10 pages, 1302 KiB

Open AccessCommunication

Possibility of a New Indication for Amantadine in the Treatment of Bipolar Depression—Case Series Study

by Marek Krzystanek and Artur Pałasz

Pharmaceuticals 2020, 13(10), 326; https://doi.org/10.3390/ph13100326 - 21 Oct 2020

Cited by 12 | Viewed by 6247

Abstract

Bipolar disorder is a chronic and remitting mental illness. Antidepressants are not effective in treating acute bipolar depression, and antipsychotic drugs used in the treatment of bipolar depression cause frequent side effects. This situation justifies the search for new drugs as well as [...] Read more.

Bipolar disorder is a chronic and remitting mental illness. Antidepressants are not effective in treating acute bipolar depression, and antipsychotic drugs used in the treatment of bipolar depression cause frequent side effects. This situation justifies the search for new drugs as well as the repurposing of drugs used in other indications. In an open and naturalistic serious case study, 4 patients diagnosed with bipolar I disorder, chronically treated with a mood stabilizer, in whom at least two antidepressants were ineffective in the depressive phase, were treated with amantadine. The woman received 100 mg/day and 3 men received the target dose of 200 mg/day. All patients treated with amantadine improved their depressive symptoms after 1 week of treatment. None of them experienced side effects or manic switch. To reduce the risk of a manic switch, the treatment with amantadine was discontinued 2 weeks after the improvement of depressive symptoms, and no recurrence of depressive symptoms was observed. Amantadine may be a further therapeutic option for the treatment of acute bipolar depression. The drug in this indication may act quickly and be well tolerated. Confirmation of the antidepressant efficacy of amantadine in this indication requires replication of the results and conducting clinical trials. Full article

(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)

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19 pages, 1025 KiB

Open AccessArticle

Cardiotoxicity Associated with Gemcitabine: Literature Review and a Pharmacovigilance Study

by Marc Hilmi, Stéphane Ederhy, Xavier Waintraub, Christian Funck-Brentano, Ariel Cohen, Aurore Vozy, Bénédicte Lebrun-Vignes, Javid Moslehi, Lee S. Nguyen and Joe-Elie Salem

Pharmaceuticals 2020, 13(10), 325; https://doi.org/10.3390/ph13100325 - 21 Oct 2020

Cited by 25 | Viewed by 4397

Abstract

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in [...] Read more.

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization’s global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 1 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC₀₂₅) ≥ 0, is deemed significant. Results: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC₀₂₅ ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design. Full article

(This article belongs to the Special Issue Cancer Drugs Treatment and Toxicity)

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20 pages, 1609 KiB

Open AccessArticle

Learnings from Regional Market Dynamics of Originator and Biosimilar Infliximab and Etanercept in Germany

by Evelien Moorkens, Teresa Barcina Lacosta, Arnold G. Vulto, Martin Schulz, Gabriele Gradl, Salka Enners, Gisbert Selke, Isabelle Huys and Steven Simoens

Pharmaceuticals 2020, 13(10), 324; https://doi.org/10.3390/ph13100324 - 21 Oct 2020

Cited by 23 | Viewed by 5508

Abstract

Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the [...] Read more.

Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the influence of biosimilar policies on these dynamics. This study is based on: (1) a literature review in which German biosimilar policies are identified, (2) the analysis of dispensing data (2010–2018) for the class of TNFα inhibitors, and (3) ten semi-structured interviews investigating prescribers’ and insurers’ views on factors potentially influencing biosimilar uptake. The analysis of biosimilar market shares of infliximab and etanercept revealed wide variations across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions). Quantitative analyses indicated that biosimilar market shares for infliximab and etanercept were significantly lower in former East Germany when compared to former West Germany regions. Through qualitative interview analyses, this study showed that the use of infliximab and etanercept biosimilars across Germany is primarily influenced by (1) the regional-level implementation of biosimilar quotas and the presence of monitoring/sanctioning mechanisms to ensure adherence to these quotas, (2) the different insurer-manufacturer discount contracts, and (3) gainsharing arrangements established at the insurer-prescriber level. Full article

(This article belongs to the Special Issue Biosimilars in Europe)

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28 pages, 4508 KiB

Open AccessArticle

Novel Sulfonamide-Based Analogs of Metformin Exert Promising Anti-Coagulant Effects without Compromising Glucose-Lowering Activity

by Magdalena Markowicz-Piasecka, Adrianna Sadkowska, Joanna Sikora, Marlena Broncel and Kristiina M. Huttunen

Pharmaceuticals 2020, 13(10), 323; https://doi.org/10.3390/ph13100323 - 21 Oct 2020

Cited by 10 | Viewed by 3535

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. [...] Read more.

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. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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22 pages, 744 KiB

Open AccessFeature PaperReview

Anti-stress Properties of Atypical Antipsychotics

by Alice Sanson and Marco A. Riva

Pharmaceuticals 2020, 13(10), 322; https://doi.org/10.3390/ph13100322 - 20 Oct 2020

Cited by 12 | Viewed by 3291

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)

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9 pages, 1332 KiB

Open AccessFeature PaperArticle

Antiarrhythmic Effect of Ranolazine in Combination with Selective NCX-Inhibition in an Experimental Model of Atrial Fibrillation

by Julian Wolfes, Christian Ellermann, Niklas Broer, Benjamin Rath, Kevin Willy, Patrick Robert Leitz, Philipp Sebastian Lange, Lars Eckardt and Gerrit Frommeyer

Pharmaceuticals 2020, 13(10), 321; https://doi.org/10.3390/ph13100321 - 20 Oct 2020

Cited by 6 | Viewed by 2759

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Innovative Concepts for Pharmacological Treatment of Cardiac Arrhythmias)

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24 pages, 6760 KiB

Open AccessArticle

Impact of Washingtonia robusta Leaves on Gamma Irradiation-Induced Hepatotoxicity in Rats and Correlation with STING Pathway and Phenolic Composition

by Nabil M. Selim, Seham S. El-Hawary, Soheir M. El Zalabani, Rehab Nabil Shamma, Nariman El Sayed Mahdy, Noheir H. Sherif, Hanan A. Fahmy, Mai H. Mekkawy, Abdelaziz Yasri and Mansour Sobeh

Pharmaceuticals 2020, 13(10), 320; https://doi.org/10.3390/ph13100320 - 19 Oct 2020

Cited by 8 | Viewed by 3376 | Correction

Abstract

Exposure to ionizing radiation usually results in cellular oxidative damage and may induce liver toxicity. The efficiency of the ethanol extracts of Washingtonia filifera (EWF) and Washingtonia robusta (EWR) leaves in alleviating γ-radiation-induced oxidative hepatotoxicity was herein explored. Proximate and macronutrient composition of [...] Read more.

Exposure to ionizing radiation usually results in cellular oxidative damage and may induce liver toxicity. The efficiency of the ethanol extracts of Washingtonia filifera (EWF) and Washingtonia robusta (EWR) leaves in alleviating γ-radiation-induced oxidative hepatotoxicity was herein explored. Proximate and macronutrient composition of the leaves was determined to establish reliable quality control criteria. Colorimetric estimation of total phenolic (TPC) and flavonoid (TFC) contents revealed their occurrence in larger amounts in EWR. In vitro evaluation of the antioxidant capacity by 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and ferric reducing antioxidant power (FRAP) assays confirmed higher efficiency of EWR designating a close correlation with phenolic composition. Four phenolics, viz., naringenin, kaempferol, quercetin, and gallic acid, were isolated from EWR. In vivo assessment of the extracts’ antioxidant potential was performed on γ-irradiated (7.5 Gy) female rats. EWR was found more efficient in restoring the elevated liver index, ALT, albumin, cholesterol, and reactive oxygen species (ROS) levels. Both extracts ameliorated the increase in the stimulator of interferon gene (STING) expression. Bioactivity was confirmed by immuno-histochemical examination of inflammatory and apoptotic biomarkers (TNF-α, IL-6 and caspase-3) and histopathological architecture. In addition, the interactions of the isolated compounds with STING were assessed in silico by molecular docking. Therefore, Washingtonia robusta leaves might be suggested as a valuable nutritional supplement to alleviate radiotherapy-induced hepatotoxicity. Full article

(This article belongs to the Section Natural Products)

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25 pages, 1141 KiB

Open AccessReview

Exosomes in Gliomas: Biogenesis, Isolation, and Preliminary Applications in Nanomedicine

by Eugenia Romano, Paolo Antonio Netti and Enza Torino

Pharmaceuticals 2020, 13(10), 319; https://doi.org/10.3390/ph13100319 - 19 Oct 2020

Cited by 24 | Viewed by 4110

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)

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18 pages, 4350 KiB

Open AccessArticle

Attenuation of Spatial Memory in 5xFAD Mice by Halting Cholinesterases, Oxidative Stress and Neuroinflammation Using a Cyclopentanone Derivative

by Rahim Ullah, Gowhar Ali, Nisar Ahmad, Muhammad Akram, Geeta Kumari, Muhammad Usman Amin and Muhammad Naveed Umar

Pharmaceuticals 2020, 13(10), 318; https://doi.org/10.3390/ph13100318 - 19 Oct 2020

Cited by 17 | Viewed by 4507

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 [...] Read more.

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. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 1861 KiB

Open AccessFeature PaperArticle

Effect of Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia: A Case-Control Cohort Study

by Benjamin Rossi, Lee S. Nguyen, Philippe Zimmermann, Faiza Boucenna, Louis Dubret, Louise Baucher, Helene Guillot, Marie-Anne Bouldouyre, Yves Allenbach, Joe-Elie Salem, Paul Barsoum, Arezki Oufella and Helene Gros

Pharmaceuticals 2020, 13(10), 317; https://doi.org/10.3390/ph13100317 - 17 Oct 2020

Cited by 32 | Viewed by 4632

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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10 pages, 2537 KiB

Open AccessArticle

Novel Photosensitizer β-Mannose-Conjugated Chlorin e6 as a Potent Anticancer Agent for Human Glioblastoma U251 Cells

by Yo Shinoda, Kohei Kujirai, Kohei Aoki, Mai Morita, Masato Masuda, Lihao Zhang, Zhou Kaixin, Akihiro Nomoto, Tsutomu Takahashi, Yayoi Tsuneoka, Jiro Akimoto, Hiromi Kataoka, Rioko Rachi, Atsushi Narumi, Tomokazu Yoshimura, Shigenobu Yano and Yasuyuki Fujiwara

Pharmaceuticals 2020, 13(10), 316; https://doi.org/10.3390/ph13100316 - 16 Oct 2020

Cited by 13 | Viewed by 3984

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Photodynamic Therapy 2021)

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20 pages, 3303 KiB

Open AccessCommunication

Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells

by Maritza P. Garrido, Renato Salvatierra, Manuel Valenzuela-Valderrama, Christopher Vallejos, Nicole Bruneau, Andrea Hernández, Margarita Vega, Alberto Selman, Andrew F. G. Quest and Carmen Romero

Pharmaceuticals 2020, 13(10), 315; https://doi.org/10.3390/ph13100315 - 16 Oct 2020

Cited by 12 | Viewed by 3940

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)

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20 pages, 3522 KiB

Open AccessArticle

Brain-Targeted Delivery of Pre-miR-29b Using Lactoferrin-Stearic Acid-Modified-Chitosan/Polyethyleneimine Polyplexes

by Patrícia Pereira, Maria Barreira, Carla Cruz, Joana Tomás, Ângelo Luís, Augusto Q. Pedro, João A. Queiroz and Fani Sousa

Pharmaceuticals 2020, 13(10), 314; https://doi.org/10.3390/ph13100314 - 15 Oct 2020

Cited by 20 | Viewed by 3902

Abstract

The efficacy of brain therapeutics is largely hampered by the presence of the blood–brain barrier (BBB), mainly due to the failure of most (bio) pharmaceuticals to cross it. Accordingly, this study aims to develop nanocarriers for targeted delivery of recombinant precursor microRNA (pre-miR-29b), [...] Read more.

The efficacy of brain therapeutics is largely hampered by the presence of the blood–brain barrier (BBB), mainly due to the failure of most (bio) pharmaceuticals to cross it. Accordingly, this study aims to develop nanocarriers for targeted delivery of recombinant precursor microRNA (pre-miR-29b), foreseeing a decrease in the expression of the BACE1 protein, with potential implications in Alzheimer’s disease (AD) treatment. Stearic acid (SA) and lactoferrin (Lf) were successfully exploited as brain-targeting ligands to modify cationic polymers (chitosan (CS) or polyethyleneimine (PEI)), and its BBB penetration behavior was evaluated. The intracellular uptake of the dual-targeting drug delivery systems by neuronal cell models, as well as the gene silencing efficiency of recombinant pre-miR-29b, was analyzed in vitro. Labeled pre-miR-29b-CS/PEI-SA-Lf systems showed very strong fluorescence in the cytoplasm and nucleus of RBE4 cells, being verified the delivery of pre-miR-29b to neuronal cells after 1 h transfection. The experiment of transport across the BBB showed that CS-SA-Lf delivered 65% of recombinant pre-miR-29b in a period of 4 h, a significantly higher transport ratio than the 42% found for PEI-SA-Lf in the same time frame. Overall, a novel procedure for the dual targeting of DDS is disclosed, opening new perspectives in nanomedicines delivery, whereby a novel drug delivery system harvests the merits and properties of the different immobilized ligands. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)

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17 pages, 382 KiB

Open AccessReview

Medicinal Plants to Strengthen Immunity during a Pandemic

by Olga Babich, Stanislav Sukhikh, Alexander Prosekov, Lyudmila Asyakina and Svetlana Ivanova

Pharmaceuticals 2020, 13(10), 313; https://doi.org/10.3390/ph13100313 - 15 Oct 2020

Cited by 49 | Viewed by 7668

Abstract

The development of new effective anti-coronavirus drugs and therapies is important, but it requires significant human, financial and, most importantly, time expenditures. The current pandemic is neither the first nor the last. Humanity has already accumulated considerable survival experience. We cannot do without [...] Read more.

The development of new effective anti-coronavirus drugs and therapies is important, but it requires significant human, financial and, most importantly, time expenditures. The current pandemic is neither the first nor the last. Humanity has already accumulated considerable survival experience. We cannot do without prevention and epidemiological protection measures. This study reviews medicinal plants that grow in Northeast Asia and whose antioxidant, antiviral, anti-inflammatory and immunomodulatory characteristics are already known, also in the framework of the prevention and treatment of pneumonia of various etiologies. The need for a comprehensive approach to maintaining immunodefences, including functional foods and positive emotions, is emphasized. In the period of pandemics, it is important to research various areas that allow to us accumulate a critical mass of information and cope with the next global disease. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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17 pages, 3408 KiB

Open AccessArticle

New Class of Efficient T₂ Magnetic Resonance Imaging Contrast Agent: Carbon-Coated Paramagnetic Dysprosium Oxide Nanoparticles

by Huan Yue, Ji Ae Park, Son Long Ho, Mohammad Yaseen Ahmad, Hyunsil Cha, Shuwen Liu, Tirusew Tegafaw, Shanti Marasini, Adibehalsadat Ghazanfari, Soyeon Kim, Kwon Seok Chae, Yongmin Chang and Gang Ho Lee

Pharmaceuticals 2020, 13(10), 312; https://doi.org/10.3390/ph13100312 - 15 Oct 2020

Cited by 10 | Viewed by 4118

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 [...] Read more.

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 (DYO@C) nanoparticles (core = DYO = Dy_xO_y; 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) (⁶H_15/2), the DYO@C 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. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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15 pages, 3858 KiB

Open AccessArticle

Development of a Multivariate Predictive Dissolution Model for Tablets Coated with Cellulose Ester Blends

by Eman M. Mohamed, Tahir Khuroo, Hamideh Afrooz, Sathish Dharani, Khaldia Sediri, Phillip Cook, Rajendran Arunagiri, Mansoor A. Khan and Ziyaur Rahman

Pharmaceuticals 2020, 13(10), 311; https://doi.org/10.3390/ph13100311 - 15 Oct 2020

Cited by 3 | Viewed by 3445

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 [...] Read more.

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, Y_2, 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, Y_2, 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, Y_2, 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. Full article

(This article belongs to the Section Pharmaceutical Technology)

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17 pages, 2947 KiB

Open AccessArticle

Additive Effect of a Combination of Artocarpus lakoocha and Glycyrrhiza glabra Extracts on Tyrosinase Inhibition in Melanoma B16 Cells

by Tasanee Panichakul, Teerapat Rodboon, Prasit Suwannalert, Chanchai Tripetch, Rittipun Rungruang, Nattaporn Boohuad and Piyawan Youdee

Pharmaceuticals 2020, 13(10), 310; https://doi.org/10.3390/ph13100310 - 14 Oct 2020

Cited by 21 | Viewed by 4298

Abstract

Artocarpus lakoocha (Al) and Glycyrrhiza glabra (Gg) extracts have been reported to show tyrosinase inhibitory activity and melanin pigment reduction. This is the first study to assess the combination of Al and Gg extracts in enhancing inhibition of tyrosinase and reduction of melanin [...] Read more.

Artocarpus lakoocha (Al) and Glycyrrhiza glabra (Gg) extracts have been reported to show tyrosinase inhibitory activity and melanin pigment reduction. This is the first study to assess the combination of Al and Gg extracts in enhancing inhibition of tyrosinase and reduction of melanin pigments. Al and Gg extracted by maceration in 70% and 95% ethanol were analyzed for oxyresveratrol and glabridin using Ultra High Performance Liquid Chromatography. Extracts of Al and Gg singly and combinations of Al95 and Gg95 were tested for cytotoxicity, tyrosinase inhibitory activity, and reduction of melanin pigments in melanoma B16 cells. Al95 had higher antioxidant, tyrosinase inhibitory activity and reduced more melanin pigments in B16 cells compared to Al70, and exhibited higher levels of oxyresveratrol. Gg95 inhibited oxidative stress and mushroom tyrosinase better than Gg70, and exhibited higher levels of glabridin. Combinations of Al95 and Gg95 at various ratios (concentration of 0.1 mg/mL) were not cytotoxic to B16 cells. Interestingly, Al95 and Gg95 combined at a ratio 9:1 reduced melanin pigment up to 53% in B16 cells. This combination of Al95 and Gg95 extracts exhibited the additive effect of reducing melanin pigments by suppressing the expression of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR) and tyrosinase-related protein-2 (TRP-2) in B16 cells. The combination of Al and Gg extracts could be developed as skin care products for hyperpigmentation treatment. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)

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51 pages, 882 KiB

Open AccessFeature PaperReview

Pharmacology of Herbal Sexual Enhancers: A Review of Psychiatric and Neurological Adverse Effects

by Pietro Brunetti, Alfredo Fabrizio Lo Faro, Anastasio Tini, Francesco Paolo Busardò and Jeremy Carlier

Pharmaceuticals 2020, 13(10), 309; https://doi.org/10.3390/ph13100309 - 14 Oct 2020

Cited by 14 | Viewed by 18450

Abstract

Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse [...] Read more.

Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse reactions associated with the use of aphrodisiacs are strongly expected. However, sexual enhancers of plant origin have gained popularity over recent years, as natural substances are often regarded as a safer alternative to modern medications and are easily acquired without prescription. We reviewed the psychiatric and neurological adverse effects associated with the consumption of herbal aphrodisiacs Areca catechu L., Argemone Mexicana L., Citrus aurantium L., Eurycoma longifolia Jack., Lepidium meyenii Walp., Mitragyna speciosa Korth., Panax ginseng C. A. Mey, Panax quinquefolius L., Pausinystalia johimbe (K. Schum.) Pierre ex Beille, Piper methysticum G. Forst., Ptychopetalum olacoides Benth., Sceletium tortuosum (L.) N. E. Brown, Turnera diffusa Willd. ex. Schult., Voacanga africana Stapf ex Scott-Elliot, and Withania somnifera (L.) Dunal. A literature search was conducted on the PubMed, Scopus, and Web of Science databases with the aim of identifying all the relevant articles published on the issue up to June 2020. Most of the selected sexual enhancers appeared to be safe at therapeutic doses, although mild to severe adverse effects may occur in cases of overdosing or self-medication with unstandardized products. Drug interactions are more concerning, considering that herbal aphrodisiacs are likely used together with other plant extracts and/or pharmaceuticals. However, few data are available on the side effects of several plants included in this review, and more clinical studies with controlled administrations should be conducted to address this issue. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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21 pages, 6233 KiB

Open AccessArticle

Characterization of Novel Dipeptidyl Peptidase-IV Inhibitory Peptides from Soft-Shelled Turtle Yolk Hydrolysate Using Orthogonal Bioassay-Guided Fractionations Coupled with In Vitro and In Silico Study

by Nhung Thi Phuong Nong, Yu-Kuo Chen, Wen-Ling Shih and Jue-Liang Hsu

Pharmaceuticals 2020, 13(10), 308; https://doi.org/10.3390/ph13100308 - 14 Oct 2020

Cited by 25 | Viewed by 3581

Abstract

Five novel peptides (LPLF, WLQL, LPSW, VPGLAL, and LVGLPL) bearing dipeptidyl peptidase IV (DPP-IV) inhibitory activities were identified from the gastrointestinal enzymatic hydrolysate of soft-shelled turtle yolk (SSTY) proteins. Peptides were isolated separately using reversed-phase (RP) chromatography in parallel with off-line strong cation [...] Read more.

Five novel peptides (LPLF, WLQL, LPSW, VPGLAL, and LVGLPL) bearing dipeptidyl peptidase IV (DPP-IV) inhibitory activities were identified from the gastrointestinal enzymatic hydrolysate of soft-shelled turtle yolk (SSTY) proteins. Peptides were isolated separately using reversed-phase (RP) chromatography in parallel with off-line strong cation exchange (SCX) chromatography followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to determine sequences. Among these peptides, LPSW showed the highest DPP-IV inhibitory activity with an IC₅₀ value of 269.7 ± 15.91 µM. The results of the pre-incubation experiment and the kinetic study of these peptides indicated that WLQL is a true inhibitor and its inhibition toward DPP-IV is of an uncompetitive model, while LPLF, LPSW, and VPGLAL are real-substrates and competitive inhibitors against DPP-IV. The DPP-IV inhibitory peptides derived from SSTY hydrolysate in study are promising in the management of hyperglycemia in Type 2 diabetes. Full article

(This article belongs to the Section Biopharmaceuticals)

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29 pages, 3309 KiB

Open AccessReview

Recent Progress of Chitosan and Chitosan Derivatives-Based Nanoparticles: Pharmaceutical Perspectives of Oral Insulin Delivery

by Salma Seyam, Norsyafikah Asyilla Nordin and Mulham Alfatama

Pharmaceuticals 2020, 13(10), 307; https://doi.org/10.3390/ph13100307 - 14 Oct 2020

Cited by 53 | Viewed by 8285

Abstract

Diabetes mellitus is a chronic endocrine disease, affecting more than 400 million people around the world. Patients with poorly controlled blood glucose levels are liable to suffer from life-threatening complications, such as cardiovascular, neuropathy, retinopathy and even premature death. Today, subcutaneous parenteral is [...] Read more.

Diabetes mellitus is a chronic endocrine disease, affecting more than 400 million people around the world. Patients with poorly controlled blood glucose levels are liable to suffer from life-threatening complications, such as cardiovascular, neuropathy, retinopathy and even premature death. Today, subcutaneous parenteral is still the most common route for insulin therapy. Oral insulin administration is favourable and convenient to the patients. In contrast to injection route, oral insulin delivery mimics the physiological pathway of endogenous insulin secretion. However, oral insulin has poor bioavailability (less than 2%) due to the harsh physiological environment through the gastrointestinal tract (GIT). Over the last few decades, many attempts have been made to achieve an effective oral insulin formulation with high bioavailability using insulin encapsulation into nanoparticles as advanced technology. Various natural polymers have been employed to fabricate nanoparticles as a delivery vehicle for insulin oral administration. Chitosan, a natural polymer, is extensively studied due to the attractive properties, such as biodegradability, biocompatibility, bioactivity, nontoxicity and polycationic nature. Numerous studies were conducted to evaluate chitosan and chitosan derivatives-based nanoparticles capabilities for oral insulin delivery. This review highlights strategies that have been applied in the recent five years to fabricate chitosan/chitosan derivatives-based nanoparticles for oral insulin delivery. A summary of the barriers hurdle insulin absorption rendering its low bioavailability such as physical, chemical and enzymatic barriers are highlighted with an emphasis on the most common methods of chitosan nanoparticles preparation. Nanocarriers are able to improve the absorption of insulin through GIT, deliver insulin to the blood circulation and lower blood glucose levels. In spite of some drawbacks encountered in this technology, chitosan and chitosan derivatives-based nanoparticles are greatly promising entities for oral insulin delivery. Full article

(This article belongs to the Section Pharmaceutical Technology)

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15 pages, 980 KiB

Open AccessReview

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

by Stephanie Kourakis, Cara A. Timpani, Judy B. de Haan, Nuri Gueven, Dirk Fischer and Emma Rybalka

Pharmaceuticals 2020, 13(10), 306; https://doi.org/10.3390/ph13100306 - 13 Oct 2020

Cited by 57 | Viewed by 10304

Abstract

Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, [...] Read more.

Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, driven by severe inflammation and oxidative stress. DMF, as well as monomethyl fumarate and diroximel fumarate, are commonly prescribed first-line agents with favourable safety and efficacy profiles. The potential benefits of FAEs against other diseases that appear pathogenically different but share the pathologies of oxidative stress and inflammation are currently investigated. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)

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12 pages, 472 KiB

Open AccessArticle

Prediction of Antidepressant Treatment Response and Remission Using an Ensemble Machine Learning Framework

by Eugene Lin, Po-Hsiu Kuo, Yu-Li Liu, Younger W.-Y. Yu, Albert C. Yang and Shih-Jen Tsai

Pharmaceuticals 2020, 13(10), 305; https://doi.org/10.3390/ph13100305 - 13 Oct 2020

Cited by 23 | Viewed by 3721

Abstract

In the wake of recent advances in machine learning research, the study of pharmacogenomics using predictive algorithms serves as a new paradigmatic application. In this work, our goal was to explore an ensemble machine learning approach which aims to predict probable antidepressant treatment [...] Read more.

In the wake of recent advances in machine learning research, the study of pharmacogenomics using predictive algorithms serves as a new paradigmatic application. In this work, our goal was to explore an ensemble machine learning approach which aims to predict probable antidepressant treatment response and remission in major depressive disorder (MDD). To discover the status of antidepressant treatments, we established an ensemble predictive model with a feature selection algorithm resulting from the analysis of genetic variants and clinical variables of 421 patients who were treated with selective serotonin reuptake inhibitors. We also compared our ensemble machine learning framework with other state-of-the-art models including multi-layer feedforward neural networks (MFNNs), logistic regression, support vector machine, C4.5 decision tree, naïve Bayes, and random forests. Our data revealed that the ensemble predictive algorithm with feature selection (using fewer biomarkers) performed comparably to other predictive algorithms (such as MFNNs and logistic regression) to derive the perplexing relationship between biomarkers and the status of antidepressant treatments. Our study demonstrates that the ensemble machine learning framework may present a useful technique to create bioinformatics tools for discriminating non-responders from responders prior to antidepressant treatments. Full article

(This article belongs to the Special Issue The Pharmacogenomics of Mood Stabilizers)

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12 pages, 2442 KiB

Open AccessArticle

Antibacterial Drug-Release Polydimethylsiloxane Coating for 3D-Printing Dental Polymer: Surface Alterations and Antimicrobial Effects

by Hang-Nga Mai, Dong Choon Hyun, Ju Hayng Park, Do-Yeon Kim, Sang Min Lee and Du-Hyeong Lee

Pharmaceuticals 2020, 13(10), 304; https://doi.org/10.3390/ph13100304 - 12 Oct 2020

Cited by 28 | Viewed by 4496

Abstract

Polymers are the most commonly used material for three-dimensional (3D) printing in dentistry; however, the high porosity and water absorptiveness of the material adversely influence biofilm formation on the surface of the 3D-printed dental prostheses. This study evaluated the effects of a newly [...] Read more.

Polymers are the most commonly used material for three-dimensional (3D) printing in dentistry; however, the high porosity and water absorptiveness of the material adversely influence biofilm formation on the surface of the 3D-printed dental prostheses. This study evaluated the effects of a newly developed chlorhexidine (CHX)-loaded polydimethylsiloxane (PDMS)-based coating material on the surface microstructure, surface wettability and antibacterial activity of 3D-printing dental polymer. First, mesoporous silica nanoparticles (MSN) were used to encapsulate CHX, and the combination was added to PDMS to synthesize the antibacterial agent-releasing coating substance. Then, a thin coating film was formed on the 3D-printing polymer specimens using oxygen plasma and thermal treatment. The results show that using the coating substance significantly reduced the surface irregularity and increased the hydrophobicity of the specimens. Remarkably, the culture media containing coated specimens had a significantly lower number of bacterial colony formation units than the noncoated specimens, thereby indicating the effective antibacterial activity of the coating. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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21 pages, 1545 KiB

Open AccessArticle

Terminalia bentzoë, a Mascarene Endemic Plant, Inhibits Human Hepatocellular Carcinoma Cells Growth In Vitro via G0/G1 Phase Cell Cycle Arrest

by Nawraj Rummun, Philippe Rondeau, Emmanuel Bourdon, Elisabete Pires, James McCullagh, Timothy D. W. Claridge, Theeshan Bahorun, Wen-Wu Li and Vidushi S. Neergheen

Pharmaceuticals 2020, 13(10), 303; https://doi.org/10.3390/ph13100303 - 12 Oct 2020

Cited by 15 | Viewed by 4466

Abstract

Tropical forests constitute a prolific sanctuary of unique floral diversity and potential medicinal sources, however, many of them remain unexplored. The scarcity of rigorous scientific data on the surviving Mascarene endemic taxa renders bioprospecting of this untapped resource of utmost importance. Thus, in [...] Read more.

Tropical forests constitute a prolific sanctuary of unique floral diversity and potential medicinal sources, however, many of them remain unexplored. The scarcity of rigorous scientific data on the surviving Mascarene endemic taxa renders bioprospecting of this untapped resource of utmost importance. Thus, in view of valorizing the native resource, this study has as its objective to investigate the bioactivities of endemic leaf extracts. Herein, seven Mascarene endemic plants leaves were extracted and evaluated for their in vitro antioxidant properties and antiproliferative effects on a panel of cancer cell lines, using methyl thiazolyl diphenyl-tetrazolium bromide (MTT) and clonogenic cell survival assays. Flow cytometry and comet assay were used to investigate the cell cycle and DNA damaging effects, respectively. Bioassay guided-fractionation coupled with liquid chromatography mass spectrometry (MS), gas chromatography-MS, and nuclear magnetic resonance spectroscopic analysis were used to identify the bioactive compounds. Among the seven plants tested, Terminaliabentzoë was comparatively the most potent antioxidant extract, with significantly (p < 0.05) higher cytotoxic activities. T. bentzoë extract further selectively suppressed the growth of human hepatocellular carcinoma cells and significantly halted the cell cycle progression in the G0/G1 phase, decreased the cells’ replicative potential and induced significant DNA damage. In total, 10 phenolic compounds, including punicalagin and ellagic acid, were identified and likely contributed to the extract’s potent antioxidant and cytotoxic activities. These results established a promising basis for further in-depth investigations into the potential use of T. bentzoë as a supportive therapy in cancer management. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants)

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14 pages, 1494 KiB

Open AccessArticle

Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1

by Soo Hyun Lim, Ki Hong Nam, Kyungtae Kim, Sang Ah Yi, Jaecheol Lee and Jeung-Whan Han

Pharmaceuticals 2020, 13(10), 302; https://doi.org/10.3390/ph13100302 - 12 Oct 2020

Cited by 15 | Viewed by 3561

Abstract

Rosmarinic acid methyl ester (RAME), a derivative of rosmarinic acid (RA), is reported to have several therapeutic effects, including anti-tumor effects against cervical cancer. However, its anti-tumor effects in ovarian cancer is unclear. In this study, we studied the molecular pathways associated with [...] Read more.

Rosmarinic acid methyl ester (RAME), a derivative of rosmarinic acid (RA), is reported to have several therapeutic effects, including anti-tumor effects against cervical cancer. However, its anti-tumor effects in ovarian cancer is unclear. In this study, we studied the molecular pathways associated with the anti-tumor effects of RAME in ovarian cancer. To identify the effects of RAME in ovarian cancer, RNA sequencing was performed in RAME-treated ovarian cancer cells; we found that RAME treatment downregulated the genes closely involved with the target genes of the transcription factor Forkhead box M1 (FOXM1). It was reported that FOXM1 is overexpressed in a variety of cancer cells and is associated with cell proliferation and tumorigenesis. Therefore, we hypothesized that FOXM1 is a key target of RAME; this could result in its anti-tumor effects. Treatment of ovarian cancer cells with RAME-inhibited cell migration and invasion, as shown by wound healing and transwell migration assays. To examine whether RAME represses the action of FOXM1, we performed quantitative RT-PCR and ChIP-qPCR. Treatment of ovarian cancer cells with RAME decreased the mRNA expression of FOXM1 target genes and the binding of FOXM1 to its target genes. Moreover, FOXM1 expression was increased in cisplatin-resistant ovarian cancer cells, and combination treatment with RAME and cisplatin sensitized the cisplatin-resistant ovarian cancer cells, which was likely due to FOXM1 inhibition. Our research suggests that RAME is a promising option in treating ovarian cancer patients, as it revealed a novel molecular pathway underlying its anti-tumor effects. Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods with Pharmaceutical Interest)

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12 pages, 889 KiB

Open AccessArticle

Determination of Very Low Concentration of Bisphenol A in Toys and Baby Pacifiers Using Dispersive Liquid–Liquid Microextraction by In Situ Ionic Liquid Formation and High-Performance Liquid Chromatography

by Yesica Vicente-Martínez, Manuel Caravaca and Antonio Soto-Meca

Pharmaceuticals 2020, 13(10), 301; https://doi.org/10.3390/ph13100301 - 12 Oct 2020

Cited by 17 | Viewed by 2998

Abstract

Bisphenol A (BPA) is a chemical compound used in the manufacturing of plastics and resins whose presence in the body in low concentrations can cause serious health problems. Due to this, there is a growing interest in the scientific community to develop analytical [...] Read more.

Bisphenol A (BPA) is a chemical compound used in the manufacturing of plastics and resins whose presence in the body in low concentrations can cause serious health problems. Due to this, there is a growing interest in the scientific community to develop analytical methods that allow quantifying trace concentrations of BPA in different types of samples. The determination of this compound in toys made of plastics that can be manipulated by children leads to an extra concern, because it is possible for BPA to enter the body by introducing these toys into the mouth. This work presents a novel procedure to the quickly and easily quantification of trace levels of BPA in samples of toys and pacifiers according to the current demanding regulations. The determination of very low levels of BPA was carried out by ionic liquid dispersive liquid–liquid microextraction (IL-DLLME) followed by high-performance liquid chromatography (HPLC). The formation in situ of the ionic liquid (IL) 1-octyl-3-methylimidazolium bis((trifluoromethane)sulfonyl)imide ([C₈MIm] [NTf₂]), was achieved by mixing 1-octyl-3-methylimidazolium chloride ([C₈MIm]Cl) and lithium bis(trifluoromethanesulfonyl)imide ([NTf₂]Li) aqueous solutions, reaching an instant dispersion whose cloud of microdrops allows the total extraction of BPA in the IL from aqueous solutions. After centrifugation, BPA concentration in the sedimented phase was determined by HPLC. The optimal experimental conditions for the microextraction and determination of BPA in the IL were studied. The total extraction was achieved at pH 4, heating the sample at 30 °C for 5 min, using 100 µL of IL precursor volume, and spinning after the formation of dispersion at 3000 rpm for 10 min. The enrichment factor (EF) and detection limit (LOD) reached with the procedure were 299 and 0.19 µg L⁻¹, respectively. The relative standard deviation for ten replications at the 0.5 µg L⁻¹ level was 5.2%. Recovery studies showed a mean value for BPA recovery percentage in the samples of 99%. Additionally, a hybrid model was applied to characterize the extraction kinetics. This simple, low cost and fast method simplifies traditional microextraction techniques, representing an outstanding alternative. Full article

(This article belongs to the Special Issue Applications of Liquid Chromatography in Analysis of Pharmaceuticals and Natural Products)

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20 pages, 3130 KiB

Open AccessArticle

Characterization of iRGD-Ligand Modified Arginine-Histidine-Rich Peptides for Nucleic Acid Therapeutics Delivery to αvβ3 Integrin-Expressing Cancer Cells

by Anna Egorova, Alexander Selutin, Marianna Maretina, Sergei Selkov, Vladislav Baranov and Anton Kiselev

Pharmaceuticals 2020, 13(10), 300; https://doi.org/10.3390/ph13100300 - 10 Oct 2020

Cited by 15 | Viewed by 3116

Abstract

Efficient and specific delivery of nucleic acid (NA) therapeutics to tumor cells is extremely important for cancer gene therapy. Various therapeutic strategies include delivery of DNA-therapeutics such as immunostimulatory or suicide genes and delivery of siRNA-therapeutics able to silence expression of cancer-related genes. [...] Read more.

Efficient and specific delivery of nucleic acid (NA) therapeutics to tumor cells is extremely important for cancer gene therapy. Various therapeutic strategies include delivery of DNA-therapeutics such as immunostimulatory or suicide genes and delivery of siRNA-therapeutics able to silence expression of cancer-related genes. Peptides are a promising class of non-viral vehicles which are biodegradable and can efficiently condense, protect and specifically deliver NA to the cells. Here we designed arginine-histidine-rich peptide carriers consisting of an iRGD ligand to target αvβ3 integrins and studied them as vehicles for DNA and siRNA delivery to cancer cells. Combination of iRGD-modified and unmodified arginine–histidine-rich peptides during NA complexation resulted in carriers with different ligand contents. The NA-binding and protecting properties in vitro transfection efficiency and cytotoxicity of the DNA- and siRNA-polyplexes were studied and the most efficient carrier RGD1 was determined. The ability of the peptides to mediate specific intracellular uptake was confirmed inhuman cervical carcinoma (HeLa), human kidney (293T) and human pancreatic (PANC-1) cell lines with different αvβ3 integrins surface expression. By means of RGD1 carrier, efficient delivery of the herpes simplex virus (HSV-1) thymidine kinase gene to PANC-1 cells was demonstrated. Subsequent ganciclovir treatment led to a reduction of PANC-1 cells’ viability by up to 54%. Efficient RNAi-mediated down-regulation of GFP and VEGFA gene expression was achieved in MDA-MB-231-GFP+ breast cancer and EA.hy926 endothelial cells, respectively, by means of RGD1/siRNA polyplexes. Here we demonstrated that the peptide carrier RGD1 can be considered as promising candidate for development of NA therapeutics delivery systems useful in cancer gene therapy. Full article

(This article belongs to the Special Issue Multi-Component Delivery Systems for Targeted Delivery of Nucleic Acids)

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13 pages, 940 KiB

Open AccessReview

The Principles, Mechanisms, and Benefits of Unconventional Agents in the Treatment of Biofilm Infection

by Jasminka Talapko and Ivana Škrlec

Pharmaceuticals 2020, 13(10), 299; https://doi.org/10.3390/ph13100299 - 10 Oct 2020

Cited by 26 | Viewed by 4828

Abstract

Today, researchers are looking at new ways to treat severe infections caused by resistance to standard antibiotic therapy. This is quite challenging due to the complex and interdependent relationships involved: the cause of infection–the patient–antimicrobial agents. The sessile biofilm form is essential in [...] Read more.

Today, researchers are looking at new ways to treat severe infections caused by resistance to standard antibiotic therapy. This is quite challenging due to the complex and interdependent relationships involved: the cause of infection–the patient–antimicrobial agents. The sessile biofilm form is essential in research to reduce resistance to very severe infections (such as ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, and Enterobacter spp). The purpose of this study is to elucidate the mechanisms of the occurrence, maintenance, and suppression of biofilm infections. One form of biofilm suppression is the efficient action of natural antagonists of bacteria—bacteriophages. Bacteriophages effectively penetrate the biofilm’s causative cells. They infect those bacterial cells and either destroy them or prevent the infection spreading. In this process, bacteriophages are specific, relatively easy to apply, and harmless to the patient. Antimicrobial peptides (AMPs) support the mechanisms of bacteriophages’ action. AMPs could also attack and destroy infectious agents on their own (even on biofilm). AMPs are simple, universal peptide molecules, mainly cationic peptides. Additional AMP research could help develop even more effective treatments of biofilm (bacteriophages, antibiotics, AMPs, nanoparticles). Here, we review recent unconventional agents, such as bacteriophages and AMPs, used for eradication of biofilm, providing an overview of potentially new biofilm treatment strategies. Full article

(This article belongs to the Section Biopharmaceuticals)

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14 pages, 1414 KiB

Open AccessCommunication

Impact of S1P Mimetics on Mesenteric Ischemia/Reperfusion Injury

by Francesco Potì, Carmine Giorgio, Irene Zini, Jerzy-Roch Nofer, Valentina Vivo, Simone Palese, Vigilio Ballabeni, Elisabetta Barocelli and Simona Bertoni

Pharmaceuticals 2020, 13(10), 298; https://doi.org/10.3390/ph13100298 - 9 Oct 2020

Cited by 8 | Viewed by 2274

Abstract

Mesenteric ischemia/reperfusion (I/R), following the transient deprivation of blood flow to the gut, triggers an acute flogistic process involving the disruption of endothelial and epithelial barriers integrity, the activation of immune cells, and the abundant release of inflammatory mediators. Among them, the lipid [...] Read more.

Mesenteric ischemia/reperfusion (I/R), following the transient deprivation of blood flow to the gut, triggers an acute flogistic process involving the disruption of endothelial and epithelial barriers integrity, the activation of immune cells, and the abundant release of inflammatory mediators. Among them, the lipid mediator sphingosine-1-phosphate (S1P) is involved in maintaining epithelial and endothelial barrier integrity and in governing the migration of immune cells through the interaction with S1P_1–5 receptors. Therefore, the present work aims to investigate the involvement of S1P signaling in intestinal I/R-induced injury by studying the effects of FTY720, the non-selective S1P_1,3–5 agonist, and comparing them with the responses to ozanimod, selective S1P_1,5 agonist, in a murine model of gut I/R. Intestinal edema, gut and lung neutrophil infiltration, and oxidative stress were evaluated through biochemical and morphological assays. The collected results highlight the protective action of FTY720 against the inflammatory cascade elicited by mesenteric I/R injury, mainly through the control of vascular barrier integrity. While these beneficial effects were mimicked by ozanimod and can be therefore attributed largely to the effects exerted by FTY720 on S1P₁, the recruitment of myeloid cells to the injured areas, limited by FTY720 but not by ozanimod, rather suggests the involvement of other receptor subtypes. Full article

(This article belongs to the Section Pharmacology)

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Pharmaceuticals, Volume 13, Issue 10 (October 2020) – 64 articles

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