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Pharmaceuticals, Volume 14, Issue 1 (January 2021) – 74 articles

Cover Story (view full-size image): COVID-19 pathogenesis is underscored by immune dysregulation which induces a cytokine storm that potentiates hyperinflammation and oxidative stress that can cause multi-organ damage and failure and, ultimately, death. Thus, therapeutic options that address this systemic dysfunction are critical. Severe cases of COVID-19 share similar pathogenic processes with multiple sclerosis and psoriasis, both of which are currently treated with dimethyl fumarate. Thus, we propose repurposing dimethyl fumarate, an immune-modulatory, anti-inflammatory, and anti-oxidative drug as a treatment option for severe cases of COVID-19. This perspective highlights the known effects of dimethyl fumarate and outlines the potential positive impact its clinical utilization could have for COVID-19. View this paper
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Article
Monosubstituted Acetophenone Thiosemicarbazones as Potent Inhibitors of Tyrosinase: Synthesis, Inhibitory Studies, and Molecular Docking
Pharmaceuticals 2021, 14(1), 74; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010074 - 18 Jan 2021
Cited by 2 | Viewed by 1119
Abstract
A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions [...] Read more.
A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC50) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Article
Hot-Melt Extruded Amorphous Solid Dispersion for Solubility, Stability, and Bioavailability Enhancement of Telmisartan
Pharmaceuticals 2021, 14(1), 73; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010073 - 18 Jan 2021
Cited by 3 | Viewed by 937
Abstract
Telmisartan (TEL, an antihypertensive drug) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its poor aqueous solubility. In this study, we enhanced the solubility, bioavailability, and stability of TEL through the fabrication of TEL-loaded pH-modulated solid dispersion (TEL pH [...] Read more.
Telmisartan (TEL, an antihypertensive drug) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its poor aqueous solubility. In this study, we enhanced the solubility, bioavailability, and stability of TEL through the fabrication of TEL-loaded pH-modulated solid dispersion (TEL pHM-SD) using hot-melt extrusion (HME) technology. We prepared different TEL pHM-SD formulations by varying the ratio of the drug (TEL, 10–60% w/w), the hydrophilic polymer (Soluplus®, 30–90% w/w), and pH-modifier (sodium carbonate, 0–10% w/w). More so, the tablets prepared from an optimized formulation (F8) showed a strikingly improved in vitro dissolution profile (~30-fold) compared to the free drug tablets. The conversion of crystalline TEL to its amorphous state is observed through solid-state characterizations. During the stability study, F8 tablets had a better stability profile compared to the commercial product with F8, showing higher drug content, low moisture content, and negligible physical changes. Moreover, compared to the TEL powder, in vivo pharmacokinetic studies in rats showed superior pharmacokinetic parameters, with maximum serum concentration (Cmax) and area under the drug concentration–time curve (AUC0) of the TEL pHM-SD formulation increasing by 6.61- and 5.37-fold, respectively. Collectively, the results from the current study showed that the inclusion of a hydrophilic polymer, pH modulator, and the amorphization of crystalline drugs in solid dispersion prepared by HME can be an effective strategy to improve the solubility and bioavailability of hydrophobic drugs without compromising the drug’s physical stability. Full article
(This article belongs to the Section Pharmaceutical Technology)
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Review
Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy
Pharmaceuticals 2021, 14(1), 72; https://doi.org/10.3390/ph14010072 - 18 Jan 2021
Cited by 2 | Viewed by 1359
Abstract
Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require [...] Read more.
Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure. Full article
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Review
COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection
Pharmaceuticals 2021, 14(1), 71; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010071 - 17 Jan 2021
Cited by 9 | Viewed by 3090
Abstract
In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute [...] Read more.
In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential. Full article
(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)
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Review
Endogenous Retroviruses in Nervous System Disorders
Pharmaceuticals 2021, 14(1), 70; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010070 - 16 Jan 2021
Cited by 6 | Viewed by 973
Abstract
Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of [...] Read more.
Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies. Full article
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
Review
Activatable Nanoparticles: Recent Advances in Redox-Sensitive Magnetic Resonance Contrast Agent Candidates Capable of Detecting Inflammation
Pharmaceuticals 2021, 14(1), 69; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010069 - 16 Jan 2021
Viewed by 720
Abstract
The emergence of activatable magnetic resonance (MR) contrast agents has prompted significant interest in the detection of functional markers of diseases, resulting in the creation of a plethora of nanoprobes capable of detecting these biomarkers. These markers are commonly dysregulated in several chronic [...] Read more.
The emergence of activatable magnetic resonance (MR) contrast agents has prompted significant interest in the detection of functional markers of diseases, resulting in the creation of a plethora of nanoprobes capable of detecting these biomarkers. These markers are commonly dysregulated in several chronic diseases, specifically select cancers and inflammatory diseases. Recently, the development of redox-sensitive nanoparticle-based contrast agents has gained momentum given advances in medicine linking several inflammatory diseases to redox imbalance. Researchers have pinpointed redox dysregulation as an opportunity to use activatable MR contrast agents to detect and stage several diseases as well as monitor the treatment of inflammatory diseases or conditions. These new classes of agents represent an advancement in the field of MR imaging as they elicit a response to stimuli, creating contrast while providing evidence of biomarker changes and commensurate disease state. Most redox-sensitive nanoparticle-based contrast agents are sensitive to reductive glutathione or oxidative reactive oxygen species. In this review, we will explore recent investigations into redox-activatable, nanoparticle-based MR contrast agent candidates. Full article
(This article belongs to the Special Issue Next Generation of MRI Agents)
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Article
Formulation and Optimization of Nanospanlastics for Improving the Bioavailability of Green Tea Epigallocatechin Gallate
Pharmaceuticals 2021, 14(1), 68; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010068 - 15 Jan 2021
Cited by 2 | Viewed by 901
Abstract
The present study aimed to investigate the potential of nanospanlastics for boosting the bioavailability of epigallocatechin gallate (EGCG). EGCG has valuable effects like anti-inflammation, anti-oxidation, and anti-tumorigenesis. Unfortunately, it has a low oral bioavailability due to its limited permeation and poor stability. To [...] Read more.
The present study aimed to investigate the potential of nanospanlastics for boosting the bioavailability of epigallocatechin gallate (EGCG). EGCG has valuable effects like anti-inflammation, anti-oxidation, and anti-tumorigenesis. Unfortunately, it has a low oral bioavailability due to its limited permeation and poor stability. To overcome these pitfalls, EGCG was fabricated as a nanospanlastic. Nanospanlastics are flexible nanovesicles that are composed of surfactants and edge activators (EAs). EAs improve the deformability of spanlastics by acting as a destabilizing factor of their vesicular membranes. EGCG-loaded spanlastics were prepared by an ethanol injection method, according to 23 factorial design, to explore the impact of different independent variables on entrapment efficiency (EE%), % drug released after 12 h (Q12h), and particle size (PS). In vitro characterization, ex vivo intestinal permeation test, and pharmacokinetic study of the optimized formula were performed. A newly developed RP-HPLC technique was adopted for the estimation of EGCG. The optimized formula (F4) demonstrated more prolonged drug release and a significant improvement in the EE%, permeability, deformability and stability than the corresponding niosomes. The pharmacokinetic study investigated that F4 had a more sustained drug release and a higher bioavailability than the conventional niosomes and free drugs. Nanospanlastics could be a promising approach for improving the bioavailability of EGCG. Full article
(This article belongs to the Special Issue Nano Drug Carriers 2021)
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Article
Drug–Drug Interactions and Pharmacogenomic Evaluation in Colorectal Cancer Patients: The New Drug-PIN® System Comprehensive Approach
Pharmaceuticals 2021, 14(1), 67; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010067 - 15 Jan 2021
Cited by 3 | Viewed by 967
Abstract
Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage [...] Read more.
Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3–G4 toxicity. Drug-PIN® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients. Full article
(This article belongs to the Special Issue Development of Colon Targeted Drug Delivery System)
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Article
In Situ-Forming Microparticles for Controlled Release of Rivastigmine: In Vitro Optimization and In Vivo Evaluation
Pharmaceuticals 2021, 14(1), 66; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010066 - 14 Jan 2021
Cited by 2 | Viewed by 967
Abstract
In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situ-forming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal [...] Read more.
In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situ-forming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal phase, containing the drug and the matrix former(s), into an external oily phase containing a stabilizer. The statistical design, Central Composite Design (CCD), was adopted as a quality by design (QbD) approach to optimize the formulation of RV-ISM systems. The fabricated RV-ISM systems was designed to minimize the initial burst drug release and maximize the sustainment of RV release from the ISM and ease of injection. The influence of critical formulation variables such as the matrix-former to drug (MF/D) ratio and SAIB to PLGA (S/P) ratio in the internal phase with respect to critical quality attributes (CQAs), such as the percentage drug release within the first day (Q1), the time required for 50% drug release (T50%) and the rate of injection, were studied using the CCD. The optimal RV-ISM system with the highest desirability value (0.74) was predicted to have an MF/D ratio of 11.7:1 (w/w) and an S/P ratio of 1.64:1 (w/w). The optimal RV-ISM system was assessed for its release profile, injectability, rheological properties, morphology, effect on cell viability, tolerance to γ-sterilization and in vivo performance in male albino rabbits. In vitro release studies revealed that the optimal RV-ISM system released 100% of its drug content throughout a release period of 30 days with only 15.5% drug release within the first day (Q1) and T50% of 13.09 days. Moreover, the optimal system showed a high injection rate of 1.012 mL/min, pseudoplastic flow, uniform spherical globules with homogenous particle size, minimal cytotoxicity and high tolerability to γ-sterilization. In vivo pharmacokinetic (PK) studies revealed that the rate of absorption of RV from the optimal RV-ISM system was controlled compared to a drug solution following either intramuscular (IM) or subcutaneous (SC) injection. Furthermore, the optimal RV-ISM was found to follow flip-flop PK with poor correlation between in vitro release and in vivo findings. These findings suggest that the optimal RV-ISM is a promising tool to achieve a sustained release therapy for RV; however, further investigation is still required to optimize the in vivo performance of RV-ISM. Full article
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Review
Chinese Herbal Medicine for the Treatment of Depression: Effects on the Neuroendocrine-Immune Network
Pharmaceuticals 2021, 14(1), 65; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010065 - 14 Jan 2021
Viewed by 1146
Abstract
The neuroimmune and neuroendocrine systems are two critical biological systems in the pathogenesis of depression. Clinical and preclinical studies have demonstrated that the activation of the neuroinflammatory response of the immune system and hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis of the neuroendocrine system [...] Read more.
The neuroimmune and neuroendocrine systems are two critical biological systems in the pathogenesis of depression. Clinical and preclinical studies have demonstrated that the activation of the neuroinflammatory response of the immune system and hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis of the neuroendocrine system commonly coexist in patients with depression and that these two systems bidirectionally regulate one another through neural, immunological, and humoral intersystem interactions. The neuroendocrine-immune network poses difficulties associated with the development of antidepressant agents directed toward these biological systems for the effective treatment of depression. On the other hand, multidrug and multitarget Chinese Herbal Medicine (CHM) has great potential to assist in the development of novel medications for the systematic pharmacotherapy of depression. In this narrative essay, we conclusively analyze the mechanisms of action of CHM antidepressant constituents and formulas, specifically through the modulation of the neuroendocrine-immune network, by reviewing recent preclinical studies conducted using depressive animal models. Some CHM herbal constituents and formulas are highlighted as examples, and their mechanisms of action at both the molecular and systems levels are discussed. Furthermore, we discuss the crosstalk of these two biological systems and the systems pharmacology approach for understanding the system-wide mechanism of action of CHM on the neuroendocrine-immune network in depression treatment. The holistic, multidrug, and multitarget nature of CHM represents an excellent example of systems medicine in the effective treatment of depression. Full article
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Article
Did the Introduction of Biosimilars Influence Their Prices and Utilization? The Case of Biologic Disease Modifying Antirheumatic Drugs (bDMARD) in Bulgaria
Pharmaceuticals 2021, 14(1), 64; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010064 - 14 Jan 2021
Viewed by 809
Abstract
The aim of this study is to evaluate the effect of the introduction of biosimilars in Bulgaria on the prices and utilization of biologic disease modifying antirheumatic drugs (bDMARD). It is a combined qualitative and quantitative analysis of time of entry of biosimilars [...] Read more.
The aim of this study is to evaluate the effect of the introduction of biosimilars in Bulgaria on the prices and utilization of biologic disease modifying antirheumatic drugs (bDMARD). It is a combined qualitative and quantitative analysis of time of entry of biosimilars on the national market and the respective changes in the prices and utilization during 2015–2020. We found 58 biosimilars for 16 reference products authorized for sale on the European market by the end of 2019, but for 2 of the reference products biosimilars were not found on the national market. Only inflammatory joint disease had more than one biosimilar molecule indicated for therapy. Prices of the observed bDMARD decreased by 17% down to 48%. We noted significant price decreases upon biosimilar entrance onto the market. In total, the reimbursed expenditures for the whole therapeutic group steadily increased from 72 to 99 million BGN. Utilization changed from to 0.5868 to 2.7215 defined daily dose (DDD)/1000inh/day. Our study shows that the entrance of biosimilars in the country is relatively slow because only half of the biosimilars authorized in Europe are reimbursed nationally. Introduction of biosimilars decreases the prices and changes the utilization significantly but other factors might also contribute to this. Full article
(This article belongs to the Special Issue Biosimilars in Europe)
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Review
Mycosporine-Like Amino Acids (MAAs): Biology, Chemistry and Identification Features
Pharmaceuticals 2021, 14(1), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010063 - 14 Jan 2021
Cited by 3 | Viewed by 1355
Abstract
Mycosporines and mycosporine-like amino acids are ultra-violet-absorbing compounds produced by several organisms such as lichens, fungi, algae and cyanobacteria, especially upon exposure to solar ultraviolet radiation. These compounds have photoprotective and antioxidant functions. Mycosporine-like amino acids have been used as a natural bioactive [...] Read more.
Mycosporines and mycosporine-like amino acids are ultra-violet-absorbing compounds produced by several organisms such as lichens, fungi, algae and cyanobacteria, especially upon exposure to solar ultraviolet radiation. These compounds have photoprotective and antioxidant functions. Mycosporine-like amino acids have been used as a natural bioactive ingredient in cosmetic products. Several reviews have already been developed on these photoprotective compounds, but they focus on specific features. Herein, an extremely complete database on mycosporines and mycosporine-like amino acids, covering the whole class of these natural sunscreen compounds known to date, is presented. Currently, this database has 74 compounds and provides information about the chemistry, absorption maxima, protonated mass, fragments and molecular structure of these UV-absorbing compounds as well as their presence in organisms. This platform completes the previous reviews and is available online for free and in the public domain. This database is a useful tool for natural product data mining, dereplication studies, research working in the field of UV-absorbing compounds mycosporines and being integrated in mass spectrometry library software. Full article
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Article
Annurca Apple Polyphenol Extract Affects Acetyl- Cholinesterase and Mono-Amine Oxidase In Vitro Enzyme Activity
Pharmaceuticals 2021, 14(1), 62; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010062 - 14 Jan 2021
Cited by 3 | Viewed by 807
Abstract
In this study, we explored the ability of Annurca apple flesh polyphenol extract (AFPE) to affect the activity of key enzymes involved in neurodegenerative disorders—in particular, Acetyl- and Butirryl-cholinesterases, and type A and B monoamine oxidase. The effect of AFPE on enzyme activity [...] Read more.
In this study, we explored the ability of Annurca apple flesh polyphenol extract (AFPE) to affect the activity of key enzymes involved in neurodegenerative disorders—in particular, Acetyl- and Butirryl-cholinesterases, and type A and B monoamine oxidase. The effect of AFPE on enzyme activity was analyzed by in vitro enzyme assays, and the results showed concentration-dependent enzyme inhibition, with IC50 values corresponding to 859 ± 18 µM and 966 ± 72 µM for AChE and BuChE respectively, and IC50 corresponding to 145 ± 3 µM and 199 ± 7 µM for MAO-A and MAO-B, respectively, with a preference for MAO-A. Moreover, in this concentration range, AFPE did not affect the viability of human neuroblastoma SH-SY5Y and fibroblast BJ-5ta cell lines, as determined by an MTT assay. In conclusion, our results demonstrate that AFPE shows the new biological properties of inhibiting the activity of enzymes that are involved in brain functions, neurodegenerative disorders, and aging. Full article
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Review
Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP
Pharmaceuticals 2021, 14(1), 61; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010061 - 13 Jan 2021
Cited by 1 | Viewed by 863
Abstract
Cyclic guanosine-3′,5′-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with [...] Read more.
Cyclic guanosine-3′,5′-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a “gold rush” for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer’s disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive. More trials with a dose-finding design on selected AD patient’s cohorts, possibly investigating also combination therapies, are still needed to evaluate the clinical potential of cGMP enhancers. Full article
(This article belongs to the Special Issue Treatment of Alzheimer Disease)
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Review
Cancer Stem Cells and Nucleolin as Drivers of Carcinogenesis
Pharmaceuticals 2021, 14(1), 60; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010060 - 13 Jan 2021
Cited by 2 | Viewed by 1547
Abstract
Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth [...] Read more.
Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth and plasticity of cancer cells. The activation of epithelial-to-mesenchymal transition and its molecular players are widely correlated with the presence of cancer stem cells in tumors. Moreover, the acquisition of certain oncological features may be partially attributed to alterations in the levels, location or function of nucleolin, a multifunctional protein involved in several cellular processes. This review aims at integrating the established hallmarks of cancer with the plasticity of cancer cells as an emerging hallmark; responsible for tumor heterogeneity; therapy resistance and relapse. The discussion will contextualize the involvement of nucleolin in the establishment of cancer hallmarks and its application as a marker protein for targeted anticancer therapies Full article
(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)
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Article
Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis
Pharmaceuticals 2021, 14(1), 59; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010059 - 13 Jan 2021
Cited by 5 | Viewed by 1326
Abstract
Inhalation by vaporization is a useful application mode for medical cannabis. In this study, we present the disposition of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, and their metabolites in serum, oral fluid, and urine together with the acute pharmacological effects in 14 [...] Read more.
Inhalation by vaporization is a useful application mode for medical cannabis. In this study, we present the disposition of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, and their metabolites in serum, oral fluid, and urine together with the acute pharmacological effects in 14 healthy individuals treated with vaporized medical cannabis. THC and CBD peaked firstly in serum and then in oral fluid, with higher concentrations in the first biological matrices and consequent higher area under the curve AUCs. Acidic precursors Δ-9-tetrahydrocannabinolic acid A (THCA) and cannabidiolic acid (CBDA) showed a similar time course profile but lower concentrations due to the fact that vaporization partly decarboxylated these compounds. All THC and CBD metabolites showed a later onset with respect to the parent compounds in the absorption phase and a slower decrease to baseline. In agreement with serum kinetics, THC-COOH-GLUC and 7-COOH-CBD were the significantly most excreted THC and CBD metabolites. The administration of vaporized medical cannabis induced prototypical effects associated with the administration of cannabis or THC in humans, with a kinetic trend overlapping that of parent compounds and metabolites in serum. The pharmacokinetics of cannabinoids, their precursors, and their metabolites in biological fluids of individuals treated with vaporized medical cannabis preparations showed a high interindividual variability as in the case of oral medical cannabis decoction and oil. Inhaled medical cannabis was absorbed into the organism earlier than decoction and oil. Cannabinoids reached higher systemic concentrations, also due to the fact that the acid precursors decarboxylated to parent cannabinoids at high temperatures, and consequently, the physiological and subjective effects occurred earlier and resulted with higher intensity. No serious adverse effects were observed. Full article
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Review
A Perspective on Natural and Nature-Inspired Small Molecules Targeting Phosphodiesterase 9 (PDE9): Chances and Challenges against Neurodegeneration
Pharmaceuticals 2021, 14(1), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010058 - 13 Jan 2021
Cited by 2 | Viewed by 764
Abstract
As life expectancy increases, dementia affects a growing number of people worldwide. Besides current treatments, phosphodiesterase 9 (PDE9) represents an alternative target for developing innovative small molecules to contrast neurodegeneration. PDE inhibition promotes neurotransmitter release, amelioration of microvascular dysfunction, and neuronal plasticity. This [...] Read more.
As life expectancy increases, dementia affects a growing number of people worldwide. Besides current treatments, phosphodiesterase 9 (PDE9) represents an alternative target for developing innovative small molecules to contrast neurodegeneration. PDE inhibition promotes neurotransmitter release, amelioration of microvascular dysfunction, and neuronal plasticity. This review will provide an update on natural and nature-inspired PDE9 inhibitors, with a focus on the structural features of PDE9 that encourage the development of isoform-selective ligands. The expression in the brain, the presence within its structure of a peculiar accessory pocket, the asymmetry between the two subunits composing the protein dimer, and the selectivity towards chiral species make PDE9 a suitable target to develop specific inhibitors. Additionally, the world of natural compounds is an ideal source for identifying novel, possibly asymmetric, scaffolds, and xanthines, flavonoids, neolignans, and their derivatives are currently being studied. In this review, the available literature data were interpreted and clarified, from a structural point of view, taking advantage of molecular modeling: 3D structures of ligand-target complexes were retrieved, or built, and discussed. Full article
(This article belongs to the Section Medicinal Chemistry)
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Review
Targeting Loss of Heterozygosity: A Novel Paradigm for Cancer Therapy
Pharmaceuticals 2021, 14(1), 57; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010057 - 13 Jan 2021
Cited by 1 | Viewed by 1109
Abstract
Loss of heterozygosity (LOH) is a common genetic event in the development of cancer. In certain tumor types, LOH can affect more than 20% of the genome, entailing loss of allelic variation in thousands of genes. This reduction of heterozygosity creates genetic differences [...] Read more.
Loss of heterozygosity (LOH) is a common genetic event in the development of cancer. In certain tumor types, LOH can affect more than 20% of the genome, entailing loss of allelic variation in thousands of genes. This reduction of heterozygosity creates genetic differences between tumor and normal cells, providing opportunities for development of novel cancer therapies. Here, we review and summarize (1) mutations associated with LOH on chromosomes which have been shown to be promising biomarkers of cancer risk or the prediction of clinical outcomes in certain types of tumors; (2) loci undergoing LOH that can be targeted for development of novel anticancer drugs as well as (3) LOH in tumors provides up-and-coming possibilities to understand the underlying mechanisms of cancer evolution and to discover novel cancer vulnerabilities which are worth a further investigation in the near future. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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Article
Contact System Activation in Plasma from Dengue Patients Might Harness Endothelial Virus Replication through the Signaling of Bradykinin Receptors
Pharmaceuticals 2021, 14(1), 56; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010056 - 12 Jan 2021
Cited by 1 | Viewed by 816
Abstract
Since exacerbated inflammation and microvascular leakage are hallmarks of dengue virus (DENV) infection, here we interrogated whether systemic activation of the contact/kallikrein-kinin system (KKS) might hamper endothelial function. In vitro assays showed that dextran sulfate, a potent contact activator, failed to generate appreciable [...] Read more.
Since exacerbated inflammation and microvascular leakage are hallmarks of dengue virus (DENV) infection, here we interrogated whether systemic activation of the contact/kallikrein-kinin system (KKS) might hamper endothelial function. In vitro assays showed that dextran sulfate, a potent contact activator, failed to generate appreciable levels of activated plasma kallikrein (PKa) in the large majority of samples from a dengue cohort (n = 70), irrespective of severity of clinical symptoms. Impaired formation of PKa in dengue-plasmas correlated with the presence of cleaved Factor XII and high molecular weight kininogen (HK), suggesting that the prothrombogenic contact system is frequently triggered during the course of infection. Using two pathogenic arboviruses, DENV or Zika virus (ZIKV), we then asked whether exogenous BK could influence the outcome of infection of human brain microvascular endothelial cells (HBMECs). Unlike the unresponsive phenotype of Zika-infected HBMECs, we found that BK, acting via B2R, vigorously stimulated DENV-2 replication by reverting nitric oxide-driven apoptosis of endothelial cells. Using the mouse model of cerebral dengue infection, we next demonstrated that B2R targeting by icatibant decreased viral load in brain tissues. In summary, our study suggests that contact/KKS activation followed by BK-induced enhancement of DENV replication in the endothelium may underlie microvascular pathology in dengue. Full article
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Article
Extract of Herba Anthrisci cerefolii: Chemical Profiling and Insights into Its Anti-Glioblastoma and Antimicrobial Mechanism of Actions
Pharmaceuticals 2021, 14(1), 55; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010055 - 12 Jan 2021
Cited by 1 | Viewed by 794
Abstract
Anthriscus cerefolium (L.) Hoffm. is a plant traditionally used around the globe since antiquity. Although widely used in many traditional medicines in different cultures, from the scientific point of view it is poorly investigated. Glioblastoma, a tumor type with poor prognosis, is the [...] Read more.
Anthriscus cerefolium (L.) Hoffm. is a plant traditionally used around the globe since antiquity. Although widely used in many traditional medicines in different cultures, from the scientific point of view it is poorly investigated. Glioblastoma, a tumor type with poor prognosis, is the most common and lethal brain tumor in adults. Current therapeutic strategies for glioblastoma include surgery, radiation and chemotherapy. On the other hand, it has been revealed that patients with cancers are highly susceptible to microbial infections due to the invasive nature of cancer treatment approaches. This study was designed to investigate the chemical profile of herba Anthriscii cerefoli methanolic extract by applying UHPLC-LTQ OrbiTrap MS4 analysis and to analyze its anti-glioblastoma and antimicrobial activities. This study revealed that methanolic extract of herba Anthrisc cerefolii contained phenolic acids and flavonoids, with 32 compounds being identified. Anti-glioblastoma activity was investigated in vitro using A172 glioblastoma cell line. The cytotoxic effects of the extract on A172 cells were compared to the same effect on primary human gingival fibroblast (HGF-1) cells. Decreased rate of proliferation and changes in cell morphology were detected upon treatment of A172 cells with the extract. The antimicrobial activity of extract was tested against Staphylococcus aureus and Candida species. The extract was active against the tested bacterium and yeasts, inhibiting free floating cells and microbial biofilms. This study is the first one to provide a detailed description of the chemical profile of A. cerefolium extract dealing with scientific insights into its anti-glioblastoma and antimicrobial activities. Full article
(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants)
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Article
Sugar Matters: Improving In Vivo Clearance Rate of Highly Glycosylated Recombinant Plasma Proteins for Therapeutic Use
Pharmaceuticals 2021, 14(1), 54; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010054 - 11 Jan 2021
Viewed by 762
Abstract
Correct glycosylation of proteins is essential for production of therapeutic proteins as glycosylation is important for protein solubility, stability, half-life and immunogenicity. The heavily glycosylated plasma protein C1-inhibitor (C1-INH) is used in treatment of hereditary angioedema attacks. In this study, we used C1-INH [...] Read more.
Correct glycosylation of proteins is essential for production of therapeutic proteins as glycosylation is important for protein solubility, stability, half-life and immunogenicity. The heavily glycosylated plasma protein C1-inhibitor (C1-INH) is used in treatment of hereditary angioedema attacks. In this study, we used C1-INH as a model protein to propose an approach to develop recombinant glycoproteins with the desired glycosylation. We produced fully functional recombinant C1-INH in Chinese hamster ovary (CHO) cells. In vivo we observed a biphasic clearance, indicating different glycosylation forms. N-glycan analysis with mass spectrometry indeed demonstrated heterogeneous glycosylation for recombinant C1-INH containing terminal galactose and terminal sialic acid. Using a Ricinus Communis Agglutinin I (RCA120) column, we could reduce the relative abundance of terminal galactose and increase the relative abundance of terminal sialic acid. This resulted in a fully active protein with a similar in vivo clearance rate to plasmaderived C1-INH. In summary, we describe the development of a recombinant human glycoprotein using simple screening tools to obtain a product that is similar in function and in vivo clearance rate to its plasma-derived counterpart. The approach used here is of potential use in the development of other therapeutic recombinant human glycoproteins. Full article
(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)
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Article
Morphological Changes and Prognostic Factors before and after Photodynamic Therapy for Central Serous Chorioretinopathy
Pharmaceuticals 2021, 14(1), 53; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010053 - 11 Jan 2021
Cited by 1 | Viewed by 637
Abstract
Central serous chorioretinopathy (CSC) is a disease of unknown etiology, but half-dose photodynamic therapy (hPDT) is well known to be effective for CSC. Infrared reflectance (IR) has been shown to be effective for detecting retinal pigmented epithelial and choroidal lesions, but no reports [...] Read more.
Central serous chorioretinopathy (CSC) is a disease of unknown etiology, but half-dose photodynamic therapy (hPDT) is well known to be effective for CSC. Infrared reflectance (IR) has been shown to be effective for detecting retinal pigmented epithelial and choroidal lesions, but no reports have focused on chorioretinal changes using IR images after as compared to before hPDT. This study aimed to clarify the features of IR images as well as retinal and choroidal morphological changes before and after treatment with verteporfin hPDT for CSC. We also examined prognostic factors associated with CSC treatment. This was a retrospective study that included 140 eyes of 140 patients (male/female ratio 122:18, mean age 53.4 ± 10.8 years) diagnosed with CSC who underwent hPDT in our hospital during the period from April 2015 to December 2018. We determined changes in visual acuity, therapeutic efficacy, central retinal thickness (CRT), central choroidal thickness (CCT), and IR images at one and three months after hPDT as compared to before treatment. Dry macula was defined as a complete resolution of serous retinal detachment after hPDT. History of smoking, disease duration, presence of drusen, presence of retinal pigment epithelium abnormalities, type of fluorescein angiographic leakage, and presence of choroidal vascular hyperpermeability were investigated as prognostic factors associated with treatment efficacy. CRT and CCT were measured using optical coherence tomography (Spectralis HRA-2; Heidelberg Engineering), and IR images after versus before treatment were compared using ImageJ software (version 1.52) to calculate the mean luminance for a 3 × 3 mm area in the macula. Compared with the values before treatment, CCT, CRT, and visual acuity showed significant improvements at one and three months after treatment, and the mean luminance of IR images was also significantly increased. Furthermore, the luminance on IR images tended to rise, though the values at one month and three months after treatment did not differ significantly. Disease duration was significantly associated with dry macula one month after treatment, and visual acuity and CRT before hPDT were both significantly related to dry macula three months after treatment. IR images tended to improve over time, from before treatment through one and three months after hPDT. Full article
(This article belongs to the Special Issue Pharmacotherapy for Macular Diseases)
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Review
The Neuronal Actions of Leptin and the Implications for Treating Alzheimer’s Disease
Pharmaceuticals 2021, 14(1), 52; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010052 - 11 Jan 2021
Cited by 2 | Viewed by 1459
Abstract
It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has [...] Read more.
It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has a significant impact on hippocampal synaptic function. Thus, cellular and behavioural studies support a cognitive enhancing role for leptin as excitatory synaptic transmission, synaptic plasticity and glutamate receptor trafficking at hippocampal Schaffer collateral (SC)-CA1 synapses are regulated by leptin, and treatment with leptin enhances performance in hippocampus-dependent memory tasks. Recent studies indicate that hippocampal temporoammonic (TA)-CA1 synapses are also a key target for leptin. The ability of leptin to regulate TA-CA1 synapses has important functional consequences as TA-CA1 synapses are implicated in spatial and episodic memory processes. Moreover, degeneration is initiated in the TA pathway at very early stages of Alzheimer’s disease, and recent clinical evidence has revealed links between plasma leptin levels and the incidence of Alzheimer’s disease (AD). Additionally, accumulating evidence indicates that leptin has neuroprotective actions in various AD models, whereas dysfunctions in the leptin system accelerate AD pathogenesis. Here, we review the data implicating the leptin system as a potential novel target for AD, and the evidence that boosting the hippocampal actions of leptin may be beneficial. Full article
(This article belongs to the Special Issue Treatment of Alzheimer Disease)
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Review
Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma
Pharmaceuticals 2021, 14(1), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010051 - 11 Jan 2021
Cited by 1 | Viewed by 1215
Abstract
Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment [...] Read more.
Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA. Full article
(This article belongs to the Special Issue Clinical Development of Cancer Treatment)
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Article
A Safe GDNF and GDNF/BDNF Controlled Delivery System Improves Migration in Human Retinal Pigment Epithelial Cells and Survival in Retinal Ganglion Cells: Potential Usefulness in Degenerative Retinal Pathologies
Pharmaceuticals 2021, 14(1), 50; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010050 - 11 Jan 2021
Viewed by 914
Abstract
We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF; GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) [...] Read more.
We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF; GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) cells, primate choroidal endothelial (RF/6A) cells, and the survival of isolated mouse retinal ganglion cells (RGCs). The morphology of the MSs, particle size, and encapsulation efficiencies of the active substances were evaluated. In vitro release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability, terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labelling (TUNEL) apoptosis, functional wound healing migration (ARPE-19; migration), and (RF/6A; angiogenesis) assays were conducted. The safety of MS intravitreal injection was assessed using hematoxylin and eosin, neuronal nuclei (NeuN) immunolabeling, and TUNEL assays, and RGC in vitro survival was analyzed. MSs delivered GDNF and co-delivered GDNF/BDNF in a sustained manner over 77 days. The BDNF/GDNF combination increased RPE cell migration, whereas no effect was observed on RF/6A. MSs did not alter cell viability, apoptosis was absent in vitro, and RGCs survived in vitro for seven weeks. In mice, retinal toxicity and apoptosis was absent in histologic sections. This delivery strategy could be useful as a potential co-therapy in retinal degenerations and glaucoma, in line with future personalized long-term intravitreal treatment as different amounts (doses) of microparticles can be administered according to patients’ needs. Full article
(This article belongs to the Special Issue Advances in Ocular Pharmacology)
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Article
Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells
Pharmaceuticals 2021, 14(1), 49; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010049 - 10 Jan 2021
Cited by 3 | Viewed by 951
Abstract
The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable [...] Read more.
The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models. Full article
(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)
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Article
Effectiveness of Riboflavin and Rose Bengal Photosensitizer Modified Adhesive Resin for Orthodontic Bonding
Pharmaceuticals 2021, 14(1), 48; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010048 - 10 Jan 2021
Cited by 1 | Viewed by 640
Abstract
This study aimed to evaluate the effect of riboflavin (RF) and Rose Bengal (RB) photosensitizer modified adhesive resin on the degree of conversion (DC), and antimicrobial capacity after bonded to tooth surface. Different concentrations of RB and RF were prepared by homogenization method. [...] Read more.
This study aimed to evaluate the effect of riboflavin (RF) and Rose Bengal (RB) photosensitizer modified adhesive resin on the degree of conversion (DC), and antimicrobial capacity after bonded to tooth surface. Different concentrations of RB and RF were prepared by homogenization method. An ultraviolet light source A (UVA) (375 nm wavelength, 3 mW/cm2 power) was used for 30 min irradiation. FTIR was performed for control and test adhesives to analyze the DC. Antibacterial testing was performed using the MTT assay. Metal brackets were bonded using the modified adhesives and subjected for SEM examination. The surfaces of teeth and metal brackets were examined at ×10 magnification for assessing adhesive remnant index (ARI) after PDT, 24 h and thermocycling. For DC, control group, 0.1% RB and RF after PDT showed the highest value. SEM imaging indicated lowest growth of Streptococcus mutans over 0.5% of RB-PDT and RF-PDT as compared to the control group. The MTT assay outcomes reported that the activity of S. mutans substantially decreased with the addition of a high amount of either RB or RF (p < 0.01). Mean ARI scores showed a significant difference between all groups. This study concluded that 0.1% of either RB or RF after PDT can be used for bonding orthodontic brackets to the tooth surface with substantial antibacterial properties. Full article
(This article belongs to the Special Issue Photodynamic Therapy 2021)
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Article
The Influence of Body Composition on the Systemic Exposure of Paclitaxel in Esophageal Cancer Patients
Pharmaceuticals 2021, 14(1), 47; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010047 - 09 Jan 2021
Cited by 1 | Viewed by 736
Abstract
Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with [...] Read more.
Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with esophageal cancer. Skeletal muscle index (SMI), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were measured at the third lumbar vertebra on computed tomography (CT) scans performed before treatment. Paclitaxel PK data were collected from a prospective study performed between May 2004 and January 2014. Non-linear mixed-effects modeling was used to fit paclitaxel PK profiles and evaluate the covariates body surface area (BSA), SMI, VAT, and SMD using a significance threshold of p < 0.001. Paclitaxel was administered to 184 patients in a dose range of 50 to 175 mg/m2. Median BSA was 1.98 m2 (range of 1.4 to 2.8 m2). SMI, VAT, and SMD were not superior to BSA in predicting paclitaxel PK. The additive value of SMI, VAT, and SMD to BSA was also negligible. We did not find evidence that paclitaxel dosing could be further optimized by correcting for SMI, VAT, or SMD. Full article
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Case Report
Combining Sorafenib and Immunosuppression in Liver Transplant Recipients with Hepatocellular Carcinoma
Pharmaceuticals 2021, 14(1), 46; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010046 - 09 Jan 2021
Cited by 3 | Viewed by 983
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approximately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) sorafenib. However, sorafenib and many immunosuppressants are substrates [...] Read more.
Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approximately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) sorafenib. However, sorafenib and many immunosuppressants are substrates of the same enzymatic pathways (e.g., CYP3A4), which may potentially result in altered SMKI or immunosuppressant plasma levels. Therefore, we investigated changes in drug exposure of both sorafenib and immunosuppressants over time in four patients with systemic immunosuppressant and sorafenib treatment after HCC recurrence. In this study, sorafenib exposure declined over time during combined treatment with immunosuppressants, while two patients also experienced declining tacrolimus plasma levels. Importantly, patients were unable to increase the sorafenib dose higher than 200 mg b.i.d. without experiencing significant toxicity. We recommend to treat patients using both sorafenib and immunosuppressants with a sorafenib starting dose of 200 mg b.i.d. Full article
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Review
Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player
Pharmaceuticals 2021, 14(1), 45; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010045 - 08 Jan 2021
Cited by 2 | Viewed by 941
Abstract
The melanocortin system encompasses melanocortin peptides, five receptors, and two endogenous antagonists. Besides pigmentary effects generated by α-Melanocytic Hormone (α-MSH), new physiologic roles in sexual activity, exocrine secretion, energy homeostasis, as well as immunomodulatory actions, exerted by melanocortins, have been described recently. Among [...] Read more.
The melanocortin system encompasses melanocortin peptides, five receptors, and two endogenous antagonists. Besides pigmentary effects generated by α-Melanocytic Hormone (α-MSH), new physiologic roles in sexual activity, exocrine secretion, energy homeostasis, as well as immunomodulatory actions, exerted by melanocortins, have been described recently. Among the most common and burdensome consequences of chronic inflammation is the development of fibrosis. Depending on the regenerative capacity of the affected tissue and the quality of the inflammatory response, the outcome is not always perfect, with the development of some fibrosis. Despite the heterogeneous etiology and clinical presentations, fibrosis in many pathological states follows the same path of activation or migration of fibroblasts, and the differentiation of fibroblasts to myofibroblasts, which produce collagen and α-SMA in fibrosing tissue. The melanocortin agonists might have favorable effects on the trajectories leading from tissue injury to inflammation, from inflammation to fibrosis, and from fibrosis to organ dysfunction. In this review we briefly summarized the data on structure, receptor signaling, and anti-inflammatory and anti-fibrotic properties of α-MSH and proposed that α-MSH analogues might be promising future therapeutic candidates for inflammatory and fibrotic diseases, regarding their favorable safety profile. Full article
(This article belongs to the Special Issue Lung Injury and Repair)
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