Pharmaceuticals

13 pages, 1267 KiB

Open AccessArticle

In Vitro Effects of Low Doses of β-Caryophyllene, Ascorbic Acid and d-Glucosamine on Human Chondrocyte Viability and Inflammation

by Elena Mattiuzzo, Alessia Faggian, Rina Venerando, Andrea Benetti, Elisa Belluzzi, Giovanni Abatangelo, Pietro Ruggieri and Paola Brun

Pharmaceuticals 2021, 14(3), 286; https://doi.org/10.3390/ph14030286 - 23 Mar 2021

Cited by 9 | Viewed by 3140

Abstract

β-caryophyllene (BCP), a plant-derived sesquiterpene, has been reported to have anti-inflammatory and antioxidant effects. The purpose of this study is to evaluate the effects of BCP in combination with ascorbic acid (AA) and d-glucosamine (GlcN) against macrophage-mediated inflammation on in vitro primary [...] Read more.

β-caryophyllene (BCP), a plant-derived sesquiterpene, has been reported to have anti-inflammatory and antioxidant effects. The purpose of this study is to evaluate the effects of BCP in combination with ascorbic acid (AA) and d-glucosamine (GlcN) against macrophage-mediated inflammation on in vitro primary human chondrocytes. Changes in cell viability, intracellular ROS generation, gene expression of pro-inflammatory mediators, metalloproteinases (MMPs), collagen type II and aggrecan were analyzed in primary human chondrocytes exposed to the conditioned medium (CM) of activated U937 monocytes and subsequently treated with BCP alone or in combination with AA and GlcN. The CM-induced chondrocyte cytotoxicity was reduced by the presence of low doses of BCP alone or in combination with AA and GlcN. The exposure of cells to CM significantly increased IL-1β, NF-κB1 and MMP-13 expression, but when BCP was added to the inflamed cells, alone or in combination with AA and GlcN, gene transcription for all these molecules was restored to near baseline values. Moreover, chondrocytes increased the expression of collagen type II and aggrecan when stimulated with AA and GlcN alone or in combination with BCP. This study showed the synergistic anti-inflammatory and antioxidative effects of BCP, AA and GlcN at low doses on human chondrocyte cultures treated with the CM of activated U937 cells. Moreover, the combination of the three molecules was able to promote the expression of collagen type II and aggrecan. All together, these data could suggest that BCP, AA and GlcN exert a chondro-protective action. Full article

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

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22 pages, 2479 KiB

Open AccessArticle

The Influence of Oxidative Stress on Serum Albumin Structure as a Carrier of Selected Diazaphenothiazine with Potential Anticancer Activity

by Małgorzata Maciążek-Jurczyk, Beata Morak-Młodawska, Małgorzata Jeleń, Wiktoria Kopeć, Agnieszka Szkudlarek, Aleksandra Owczarzy, Karolina Kulig, Wojciech Rogóż and Jadwiga Pożycka

Pharmaceuticals 2021, 14(3), 285; https://doi.org/10.3390/ph14030285 - 23 Mar 2021

Cited by 23 | Viewed by 2649

Abstract

Albumin is one of the most important proteins in human blood. Among its multiple functions, drug binding is crucial in terms of drug distribution in human body. This protein undergoes many modifications that are certain to influence protein activity and affect its structure. [...] Read more.

Albumin is one of the most important proteins in human blood. Among its multiple functions, drug binding is crucial in terms of drug distribution in human body. This protein undergoes many modifications that are certain to influence protein activity and affect its structure. One such reaction is albumin oxidation. Chloramine T is a strong oxidant. Solutions of human serum albumin, both non-modified and modified by chloramine T, were examined with the use of fluorescence, absorption and circular dichroism (CD) spectroscopy. 10H-3,6-diazaphenothiazine (DAPT) has anticancer activity and it has been studied for the first time in terms of binding with human serum albumin—its potential as a transporting protein. Using fluorescence spectroscopy, in the presence of dansylated amino acids, dansyl-l-glutamine (dGlu), dansyl-l-proline (dPro), DAPT binding with two main albumin sites—in subdomain IIA and IIIA—has been evaluated. Based on the conducted data, in order to measure the stability of DAPT complexes with human (HSA) and oxidized (oHSA) serum albumin, association constant (K_a) for ligand-HSA and ligand-oHSA complexes were calculated. It has been presumed that oxidation is not an important issue in terms of 10H-3,6-diazaphenothiazine binding to albumin. It means that the distribution of this substance is similar regardless of changes in albumin structure caused by oxidation, natural occurring in the organism. Full article

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14 pages, 2869 KiB

Open AccessArticle

The 25(OH)D3, but Not 1,25(OH)2D3 Levels Are Elevated in IBD Patients Regardless of Vitamin D Supplementation and Do Not Associate with Pain Severity or Frequency

by Anna Zielińska, Aleksandra Sobolewska-Włodarczyk, Maria Wiśniewska-Jarosińska, Anita Gąsiorowska, Jakub Fichna and Maciej Sałaga

Pharmaceuticals 2021, 14(3), 284; https://doi.org/10.3390/ph14030284 - 22 Mar 2021

Cited by 4 | Viewed by 2215

Abstract

Due to its immunomodulatory effect, vitamin D has been associated with clinical parameters and outcomes in inflammatory bowel diseases (IBDs) which are chronic conditions of the gastrointestinal tract. Upon synthesis or digestion, vitamin D is metabolized in the liver to form 25(OH)D3, the [...] Read more.

Due to its immunomodulatory effect, vitamin D has been associated with clinical parameters and outcomes in inflammatory bowel diseases (IBDs) which are chronic conditions of the gastrointestinal tract. Upon synthesis or digestion, vitamin D is metabolized in the liver to form 25(OH)D3, the major circulating metabolite. Further renal hydroxylation generates 1,25(OH)2D3, the most potent metabolite. Our aim was to examine the association between vitamin D levels, and its supplementation and pain intensity in 39 IBD patients and 33 healthy individuals. 25(OH)D3 and 1,25(OH)2D3 serum levels were measured. Each subject filled out visual analog scale (VAS) and Laitinen’s pain assessment scales. Laboratory results were obtained, and disease activity was assessed. Linear regression was employed to investigate the correlation between 25(OH)D3, 1,25(OH)2D3 and pain intensity, clinical activity parameters, C-reactive protein, disease duration, and dietary habits. In IBD patients, 25(OH)D3 was increased, whereas 1,25(OH)2D3 was not. Vitamin D3 supplementation did not influence their levels. No correlation was found between pain scores, disease activity, inflammatory status, disease duration or dietary habits and both forms of vitamin D. Elevated 25(OH)D3 and normal 1,25(OH)D3 were found in IBD patients as compared to the controls. We discovered no effect from supplementation and no association between pain severity and vitamin D. Full article

(This article belongs to the Special Issue Drugs and Treatments for Inflammatory Bowel Diseases)

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15 pages, 361 KiB

Open AccessReview

Barriers to Biosimilar Prescribing Incentives in the Context of Clinical Governance in Spain

by Félix Lobo and Isabel Río-Álvarez

Pharmaceuticals 2021, 14(3), 283; https://doi.org/10.3390/ph14030283 - 22 Mar 2021

Cited by 8 | Viewed by 3295

Abstract

Incentives contribute to the proper functioning of the broader contracts that regulate the relationships between health systems and professionals. Likewise, incentives are an important element of clinical governance understood as health services’ management at the micro-level, aimed at achieving better health outcomes for [...] Read more.

Incentives contribute to the proper functioning of the broader contracts that regulate the relationships between health systems and professionals. Likewise, incentives are an important element of clinical governance understood as health services’ management at the micro-level, aimed at achieving better health outcomes for patients. In Spain, monetary and non-monetary incentives are sometimes used in the health services, but not as frequently as in other countries. There are already several examples in European countries of initiatives searching the promotion of biosimilars through different sorts of incentives, but not in Spain. Hence, this paper is aimed at identifying the barriers that incentives to prescribe biosimilars might encounter in Spain, with particular interest in incentives in the framework of clinical governance. Both questions are intertwined. Barriers are presented from two perspectives. Firstly, based on the nature of the barrier: (i) the payment system for health professionals, (ii) budget rigidity and excessive bureaucracy, (iii) little autonomy in the management of human resources (iv) lack of clinical integration, (v) absence of a legal framework for clinical governance, and (vi) other governance-related barriers. The second perspective is based on the stakeholders involved: (i) gaps in knowledge among physicians, (ii) misinformation and distrust among patients, (iii) trade unions opposition to productivity-related payments, (iv) lack of a clear position by professional associations, and (v) misalignment of the goals pursued by some healthcare professionals and the goals of the public system. Finally, the authors advance several recommendations to overcome these barriers at the national level. Full article

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

17 pages, 3342 KiB

Open AccessArticle

Marine-Derived Natural Products as ATP-Competitive mTOR Kinase Inhibitors for Cancer Therapeutics

by Shraddha Parate, Vikas Kumar, Gihwan Lee, Shailima Rampogu, Jong Chan Hong and Keun Woo Lee

Pharmaceuticals 2021, 14(3), 282; https://doi.org/10.3390/ph14030282 - 21 Mar 2021

Cited by 17 | Viewed by 3861

Abstract

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase portraying a quintessential role in cellular proliferation and survival. Aberrations in the mTOR signaling pathway have been reported in numerous cancers including thyroid, lung, gastric and ovarian cancer, thus making it a therapeutic [...] Read more.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase portraying a quintessential role in cellular proliferation and survival. Aberrations in the mTOR signaling pathway have been reported in numerous cancers including thyroid, lung, gastric and ovarian cancer, thus making it a therapeutic target. To attain this objective, an in silico investigation was designed, employing a pharmacophore modeling approach. A structure-based pharmacophore (SBP) model exploiting the key features of a selective mTOR inhibitor, Torkinib directed at the ATP-binding pocket was generated. A Marine Natural Products (MNP) library was screened using SBP model as a query. The retrieved compounds after consequent drug-likeness filtration were subjected to molecular docking with mTOR, thus revealing four MNPs with better scores than Torkinib. Successive refinement via molecular dynamics simulations demonstrated that the hits formed crucial interactions with key residues of the pocket. Furthermore, the four identified hits exhibited good binding free energy scores through MM-PBSA calculations and the subsequent in silico toxicity assessments displayed three hits deemed essentially non-carcinogenic and non-mutagenic. The hits presented in this investigation could act as potent ATP-competitive mTOR inhibitors, representing a platform for the future discovery of drugs from marine natural origin. Full article

(This article belongs to the Special Issue In Silico Approaches in Drug Design)

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26 pages, 389 KiB

Open AccessReview

Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review

by Francesco Oddone, Luca Rossetti, Mariacristina Parravano, Diego Sbardella, Massimo Coletta, Lucia Ziccardi, Gloria Roberti, Carmela Carnevale, Dario Romano, Gianluca Manni and Vincenzo Parisi

Pharmaceuticals 2021, 14(3), 281; https://doi.org/10.3390/ph14030281 - 20 Mar 2021

Cited by 14 | Viewed by 5127

Abstract

Cytidine 5’-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial [...] Read more.

Cytidine 5’-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials). Full article

(This article belongs to the Special Issue Pharmacology and Medical Uses of Citicoline)

35 pages, 1113 KiB

Open AccessReview

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

by Rita Rebelo, Bárbara Polónia, Lúcio Lara Santos, M. Helena Vasconcelos and Cristina P. R. Xavier

Pharmaceuticals 2021, 14(3), 280; https://doi.org/10.3390/ph14030280 - 20 Mar 2021

Cited by 11 | Viewed by 4753

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials. Full article

(This article belongs to the Collection Old Pharmaceuticals with New Applications)

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9 pages, 591 KiB

Open AccessReview

Clinical Evidence for the Choice of the Direct Oral Anticoagulant in Patients with Atrial Fibrillation According to Creatinine Clearance

by Riccardo Vio, Riccardo Proietti, Matteo Rigato and Lorenzo Arcangelo Calò

Pharmaceuticals 2021, 14(3), 279; https://doi.org/10.3390/ph14030279 - 19 Mar 2021

Cited by 8 | Viewed by 3613

Abstract

Atrial fibrillation (AF) often coexists with chronic kidney disease (CKD), which confer to the patient a higher risk of both thromboembolic and hemorrhagic events. Oral anticoagulation therapy, nowadays preferably with direct oral anticoagulants (DOACs), represents the cornerstone for ischemic stroke prevention in high-risk [...] Read more.

Atrial fibrillation (AF) often coexists with chronic kidney disease (CKD), which confer to the patient a higher risk of both thromboembolic and hemorrhagic events. Oral anticoagulation therapy, nowadays preferably with direct oral anticoagulants (DOACs), represents the cornerstone for ischemic stroke prevention in high-risk patients. However, all four available DOACs (dabigatran, apixaban, rivaroxaban and edoxaban) are eliminated by the kidneys to some extent. Reduced kidney function facilitates DOACs accumulation and, therefore, different dose reductions are required, with slight differences between American and European recommendations especially in case of severe renal impairment (creatinine clearance < 30 mL/min). Overall, the use of DOACs in patients with non-end stage CKD and AF is effective similarly to warfarin, showing a better safety profile. The management of thromboembolic risk among patients with AF on dialysis remains challenging, as warfarin effectiveness for stroke prevention in this population is questionable and retrospective data on apixaban need to be confirmed on a larger scale. In kidney transplant recipients, DOACs may provide a potentially safer option compared to warfarin, but co-administration with immunosuppressants is a matter of concern. Full article

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9 pages, 1093 KiB

Open AccessArticle

Analytical Characterization of an Inulin-Type Fructooligosaccharide from Root-Tubers of Asphodelusramosus L

by Valentina Noemi Madia, Daniela De Vita, Antonella Messore, Chiara Toniolo, Valeria Tudino, Alessandro De Leo, Ivano Pindinello, Davide Ialongo, Francesco Saccoliti, Anna Maria D’Ursi, Manuela Grimaldi, Pietro Ceccobelli, Luigi Scipione, Roberto Di Santo and Roberta Costi

Pharmaceuticals 2021, 14(3), 278; https://doi.org/10.3390/ph14030278 - 19 Mar 2021

Cited by 5 | Viewed by 2797

Abstract

Plant-based systems continue to play a pivotal role in healthcare, and their use has been extensively documented. Asphodelus L. is a genus comprising various herbaceous species, known by the trivial name Asphodelus. These plants have been known since antiquity for both food and [...] Read more.

Plant-based systems continue to play a pivotal role in healthcare, and their use has been extensively documented. Asphodelus L. is a genus comprising various herbaceous species, known by the trivial name Asphodelus. These plants have been known since antiquity for both food and therapeutic uses, especially for treating several diseases associated with inflammatory and infectious skin disorders. Phytochemical studies revealed the presence of different constituents, mainly anthraquinones, triterpenoids, phenolic acids, and flavonoids. Although extensive literature has been published on these constituents, a paucity of information has been reported regarding the carbohydrate composition, such as fructans and fructan-like derivatives. The extraction of water-soluble neutral polysaccharides is commonly performed using water extraction, at times assisted by microwaves and ultrasounds. Herein, we reported the investigation of the alkaline extraction of root-tubers of Asphodelus ramosus L., analyzing the water-soluble polysaccharides obtained by precipitation from the alkaline extract and its subsequent purification by chromatography. A polysaccharide was isolated by alkaline extraction; the HPTLC study to determine its composition showed fructose as the main monosaccharide. FT-IR analysis showed the presence of an inulin-type structure, and NMR analyses allowed us to conclude that A. ramosus roots contain polysaccharide with an inulin-type fructooligosaccharide with a degree of polymerization of 7–8. Full article

(This article belongs to the Special Issue Plant and Marine-Derived Natural Product Research in Drug Discovery: Strengths and Perspective)

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19 pages, 4522 KiB

Open AccessFeature PaperArticle

Species Differences in Microsomal Metabolism of Xanthine-Derived A₁ Adenosine Receptor Ligands

by Daniela Schneider, Dirk Bier, Marcus Holschbach, Andreas Bauer and Bernd Neumaier

Pharmaceuticals 2021, 14(3), 277; https://doi.org/10.3390/ph14030277 - 18 Mar 2021

Cited by 3 | Viewed by 1815

Abstract

Tracer development for positron emission tomography (PET) requires thorough evaluation of pharmacokinetics, metabolism, and dosimetry of candidate radioligands in preclinical animal studies. Since variations in pharmacokinetics and metabolism of a compound occur in different species, careful selection of a suitable model species is [...] Read more.

Tracer development for positron emission tomography (PET) requires thorough evaluation of pharmacokinetics, metabolism, and dosimetry of candidate radioligands in preclinical animal studies. Since variations in pharmacokinetics and metabolism of a compound occur in different species, careful selection of a suitable model species is mandatory to obtain valid data. This study focuses on species differences in the in vitro metabolism of three xanthine-derived ligands for the A₁ adenosine receptor (A₁AR), which, in their ¹⁸F-labeled form, can be used to image A₁AR via PET. In vitro intrinsic clearance and metabolite profiles of 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX), an established A₁AR-ligand, and two novel analogs, 8-cyclobutyl-3-(3-fluoropropyl)-1-propylxanthine (CBX) and 3-(3-fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine (MCBX), were determined in liver microsomes from humans and preclinical animal species. Molecular mechanisms leading to significant differences between human and animal metabolite profiles were also examined. The results revealed significant species differences regarding qualitative and quantitative aspects of microsomal metabolism. None of the tested animal species fully matched human microsomal metabolism of the three A₁AR ligands. In conclusion, preclinical evaluation of xanthine-derived A₁AR ligands should employ at least two animal species, preferably rodent and dog, to predict in vivo behavior in humans. Surprisingly, rhesus macaques appear unsuitable due to large differences in metabolic activity towards the test compounds. Full article

(This article belongs to the Special Issue Molecular Imaging in Neurology and Oncology: Radiopharmaceuticals for PET and SPECT)

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18 pages, 984 KiB

Open AccessFeature PaperReview

Respiratory Manifestations in Systemic Lupus Erythematosus

by Salvatore Di Bartolomeo, Alessia Alunno and Francesco Carubbi

Pharmaceuticals 2021, 14(3), 276; https://doi.org/10.3390/ph14030276 - 18 Mar 2021

Cited by 19 | Viewed by 7234

Abstract

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by a wide spectrum of clinical manifestations. The respiratory system can be involved in up to 50–70% of patients and be the presenting manifestation of the disease in 4–5% of cases. Every [...] Read more.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by a wide spectrum of clinical manifestations. The respiratory system can be involved in up to 50–70% of patients and be the presenting manifestation of the disease in 4–5% of cases. Every part of the respiratory part can be involved, and the severity can vary from mild self-limiting to life threatening forms. Respiratory involvement can be primary (caused by SLE itself) or secondary (e.g., infections or drug toxicity), acute or chronic. The course, treatment and prognosis vary greatly depending on the specific pattern of the disease. This review article aims at providing an overview of respiratory manifestations in SLE along with an update about therapeutic approaches including novel biologic therapies. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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18 pages, 4386 KiB

Open AccessArticle

Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products

by Hwangseo Park, Jinwon Jeon, Kewon Kim, Soyeon Choi and Sungwoo Hong

Pharmaceuticals 2021, 14(3), 275; https://doi.org/10.3390/ph14030275 - 18 Mar 2021

Cited by 12 | Viewed by 2976

Abstract

Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. Methods: to identify effective PIM1 kinase inhibitors, structure-based virtual [...] Read more.

Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. Methods: to identify effective PIM1 kinase inhibitors, structure-based virtual screening of natural products of plant origin and de novo design were carried out using the protein–ligand binding free energy function improved by introducing an adequate dehydration energy term. Results: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2H)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines. Conclusions: these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine. Full article

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

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16 pages, 2794 KiB

Open AccessArticle

A Comprehensive Approach to Compatibility Testing Using Chromatographic, Thermal and Spectroscopic Techniques: Evaluation of Potential for a Monolayer Fixed-Dose Combination of 6-Mercaptopurine and Folic Acid

by Edvin Brusač, Mario-Livio Jeličić, Matija Cvetnić, Daniela Amidžić Klarić, Biljana Nigović and Ana Mornar

Pharmaceuticals 2021, 14(3), 274; https://doi.org/10.3390/ph14030274 - 17 Mar 2021

Cited by 4 | Viewed by 2330

Abstract

In this work, a systematical compatibility investigation of 6-mercaptopurine and folic acid, two commonly used medications in the treatment of inflammatory bowel disease, for the needs of a fixed-dose combination development strategy is shown. Various techniques and approaches, such as differential scanning calorimetry, [...] Read more.

In this work, a systematical compatibility investigation of 6-mercaptopurine and folic acid, two commonly used medications in the treatment of inflammatory bowel disease, for the needs of a fixed-dose combination development strategy is shown. Various techniques and approaches, such as differential scanning calorimetry, isothermal stress testing, attenuated total reflectance–Fourier-transform infrared spectroscopy, dissolution medium stability and forced degradation studies, were used to elucidate the possible interactions from different aspects. The results predominantly point to the absence of physicochemical interactions between the examined substances in a variety of possible conditions. However, the forced degradation of the blend of substances and excipients in basic conditions showed a drastic degradation of 6-mercaptopurine, signifying that attention needs to be directed to the careful selection of the excipients for the formulation. To sum up, our findings indicate that a fixed-dose combination of 6-mercaptopurine and folic acid could be produced using one formulation blend, immensely simplifying its manufacture. Full article

(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)

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11 pages, 3143 KiB

Open AccessArticle

Evaluation of Hydroxychloroquine Blood Concentrations and Effects in Childhood-Onset Systemic Lupus Erythematosus

by Noël Zahr, Saik Urien, Christian Funck-Brentano, Hélène Vantomme, Nicolas Garcelon, Isabelle Melki, Margaux Boistault, Olivia Boyer and Brigitte Bader-Meunier

Pharmaceuticals 2021, 14(3), 273; https://doi.org/10.3390/ph14030273 - 17 Mar 2021

Cited by 12 | Viewed by 2345

Abstract

Background: Hydroxychloroquine (HCQ) is an antimalarial agent given to patients with systemic lupus erythematosus (SLE) as first-line therapy. It alleviates childhood-onset systemic lupus erythematosus cSLE skin and musculoskeletal disease, decreasing disease activity and flares. HCQ concentration–effect relationships in children remains unknown. This study [...] Read more.

Background: Hydroxychloroquine (HCQ) is an antimalarial agent given to patients with systemic lupus erythematosus (SLE) as first-line therapy. It alleviates childhood-onset systemic lupus erythematosus cSLE skin and musculoskeletal disease, decreasing disease activity and flares. HCQ concentration–effect relationships in children remains unknown. This study aimed to investigate the pharmacokinetics of HCQ and possible concentration–effect relationships. Methods: HCQ blood concentrations and effects were obtained during clinical follow-up on different occasions. cSLE flares were defined using the SLE Disease Activity Index (SLEDAI); flare was denoted by a SLEDAI score > 6. Blood concentration was measured using high-performance liquid chromatography with fluorometric detection. Statistical analysis was performed using a nonlinear mixed-effect approach with the Monolix software. Results: A total of 168 blood samples were obtained from 55 pediatric patients. HCQ apparent blood clearance (CL/F) was dependent on patients’ bodyweight and platelet count. Patients with active cSLE had a lower mean blood HCQ concentration compared with inactive cSLE patients (536 ± 294 vs. 758 ± 490 ng/mL, p = 5 × 10⁻⁶). Among patients with HCQ blood concentration ≥750 ng/mL, 87.6% had inactive cSLE. Moreover, HCQ blood concentration was a significant predictor of disease status. Conclusion: We developed the first HCQ blood concentration–effect relationship for cSLE associated with active or non-active disease status. A prospective randomized study is necessary to confirm these results. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 1629 KiB

Open AccessArticle

Pharmacokinetics and Pharmacogenetics of Cyclophosphamide in a Neonate and Infant Childhood Cancer Patient Population

by Shelby Barnett, Julie Errington, Julieann Sludden, David Jamieson, Vianney Poinsignon, Angelo Paci and Gareth J. Veal

Pharmaceuticals 2021, 14(3), 272; https://doi.org/10.3390/ph14030272 - 16 Mar 2021

Cited by 8 | Viewed by 2990

Abstract

Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients [...] Read more.

Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients administered cyclophosphamide at doses ranging from 100–1500 mg/m² (5–75 mg/kg), with various infusion times as determined by the standard treatment regimen that each patient was receiving. Polymorphisms in genes including CYP2B6 and CYP2C19 were investigated. Data generated for cyclophosphamide were analysed using a previously published population pharmacokinetic model. Cyclophosphamide pharmacokinetics was assessed in 111 samples obtained from 25 patients ranging from 4–23 months of age. The average cyclophosphamide clearance for the patients was 46.6 mL/min/m² (ranging from 9.4–153 mL/min/m²), with marked inter-patient variability observed (CV 41%). No significant differences in cyclophosphamide clearance or exposure (AUC) were observed between patient groups as separated by age or body weight. However, marked differences in drug clearance and metabolism were noted between the current data in children <2 years of age and recently published results from a comparable study conducted by our group in older children, which reported significantly lower cyclophosphamide clearance values and metabolite exposures using the same population pharmacokinetic model for analysis. Whilst this study demonstrates no significant differences in cyclophosphamide clearance in patients <2 years, it highlights large differences in dosing protocols across tumour types. Furthermore, the study suggests marked differences in cyclophosphamide clearance in children less than two years of age as compared to older patients. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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19 pages, 1659 KiB

Open AccessArticle

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

by Mafalda Campeão, Luciana Fernandes, Inês R. Pita, Cristina Lemos, Syed F. Ali, Félix Carvalho, Paulo Rodrigues-Santos, Carlos A. Fontes-Ribeiro, Edna Soares, Sofia D. Viana and Frederico C. Pereira

Pharmaceuticals 2021, 14(3), 271; https://doi.org/10.3390/ph14030271 - 16 Mar 2021

Cited by 2 | Viewed by 2713

Abstract

3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, [...] Read more.

3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, C57BL/6J mice were exposed to a binge MDPV or METH regimen (four intraperitoneal injections every 2 h, 10 mg/kg). Locomotor, exploratory, and emotional behavior, in addition to striatal neurotoxicity and glial signature, were assessed within 18–24 h, a known time-window encompassing classical amphetamine dopaminergic neurotoxicity. MDPV resulted in unchanged locomotor activity (open field test) and emotional behavior (elevated plus maze, splash test, tail suspension test). Additionally, striatal TH (METH neurotoxicity hallmark), Iba-1 (microglia), GFAP (astrocyte), RAGE, and TLR2/4/7 (immune modulators) protein densities remained unchanged after MDPV-exposure. Expectedly, and in sheer contrast with MDPV, METH resulted in decrease general locomotor activity paralleled by a significant striatal TH depletion, astrogliosis, and microglia arborization alterations (Sholl analysis). This comparative study newly highlights that binge MDPV-exposure comes without evident behavioral, neurochemical, and glial changes at a time-point where METH-induced striatal neurotoxicity is clearly evident. Nevertheless, neuropharmacological MDPV signature needs further profiling at different time-points, regimens, and brain regions. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics of Psychoactive Substances: Clinical and Forensic Aspects)

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16 pages, 5670 KiB

Open AccessArticle

Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating

by Magdalena Kotańska, Kamil Mika, Małgorzata Szafarz, Monika Kubacka, Christa E. Müller, Jacek Sapa and Katarzyna Kieć-Kononowicz

Pharmaceuticals 2021, 14(3), 270; https://doi.org/10.3390/ph14030270 - 16 Mar 2021

Cited by 7 | Viewed by 2702

Abstract

GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass [...] Read more.

GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising. Full article

(This article belongs to the Special Issue Searching for New Therapeutic Targets with Anti-obesity Potential)

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21 pages, 765 KiB

Open AccessReview

Plant Phenolics and Extracts in Animal Models of Preeclampsia and Clinical Trials—Review of Perspectives for Novel Therapies

by Marcin Ożarowski, Tomasz M. Karpiński, Michał Szulc, Karolina Wielgus, Radosław Kujawski, Hubert Wolski and Agnieszka Seremak-Mrozikiewicz

Pharmaceuticals 2021, 14(3), 269; https://doi.org/10.3390/ph14030269 - 16 Mar 2021

Cited by 16 | Viewed by 3613

Abstract

The current health requirements set the direction in pharmacological research, especially as regards diseases that require improvement of existing therapeutic regimens. Such diseases include preeclampsia, which is a hypertensive disorder of pregnancy during which there occurs progressive increasing activation of the immune system [...] Read more.

The current health requirements set the direction in pharmacological research, especially as regards diseases that require improvement of existing therapeutic regimens. Such diseases include preeclampsia, which is a hypertensive disorder of pregnancy during which there occurs progressive increasing activation of the immune system through elevation of pro-inflammatory cytokines and antiangiogenic factors, which is dangerous for the mother and fetus. A promising field of research for new drugs to treat this disease is the study of natural phenolic compounds of plant origin and herbal extracts, which are complex matrices of chemical compounds with broad biological activities. Many plant substances with anti‑inflammatory and anti‑hypertensive properties are known, but studies in animal models of preeclampsia and clinical trials concerning this disease constitute a new and developing research trend of significant medical importance. The aim of our research review was to identify and analyze the results of already available studies on baicalin, curcumin, epigallocatechin gallate, punicalagin, quercetin, resveratrol, salvianolic acid A (danshensu), silibinin, and vitexin, as well as plant extracts from Brassica oleracea L., Euterpe oleracea Mart., Moringa oleifera Lam., Punica granatum L., Silybum marianum (L.) Gaertner, Thymus schimperi Ronniger, Uncaria rhynchophylla (Miq.) Miq. ex Havil., and Vitis vinifera L., which are potential and promising candidates for further research and for potential new therapies. Full article

(This article belongs to the Section Natural Products)

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9 pages, 998 KiB

Open AccessFeature PaperArticle

Pipecolisporin, a Novel Cyclic Peptide with Antimalarial and Antitrypanosome Activities from a Wheat Endophytic Nigrospora oryzae

by Ignacio Fernández-Pastor, Victor González-Menéndez, Frederick Annang, Clara Toro, Thomas A. Mackenzie, Cristina Bosch-Navarrete, Olga Genilloud and Fernando Reyes

Pharmaceuticals 2021, 14(3), 268; https://doi.org/10.3390/ph14030268 - 16 Mar 2021

Cited by 11 | Viewed by 3795

Abstract

A novel cyclic antimalarial and antitrypanosome hexapeptide, pipecolisporin (1), was isolated from cultures of Nigrospora oryzae CF-298113, a fungal endophyte isolated from roots of Triticum sp. collected in a traditional agricultural land of Montefrío, Granada, Spain. The structure of this compound, [...] Read more.

A novel cyclic antimalarial and antitrypanosome hexapeptide, pipecolisporin (1), was isolated from cultures of Nigrospora oryzae CF-298113, a fungal endophyte isolated from roots of Triticum sp. collected in a traditional agricultural land of Montefrío, Granada, Spain. The structure of this compound, including its absolute configuration, was elucidated by HRMS, 1-D and 2-D NMR spectroscopy, and Marfey’s analysis. This metabolite displayed interesting activity against Plasmodium falciparum and Trypanosoma cruzi, with IC₅₀ values in the micromolar range, and no significant cytotoxicity against the human cancer cell lines A549, A2058, MCF7, MIA PaCa-2, and HepG2. Full article

(This article belongs to the Special Issue Antiparasitics)

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22 pages, 3811 KiB

Open AccessFeature PaperArticle

Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice

by Geng-Ruei Chang, Po-Hsun Hou, Wei-Cheng Yang, Chao-Min Wang, Pei-Shan Fan, Huei-Jyuan Liao and To-Pang Chen

Pharmaceuticals 2021, 14(3), 267; https://doi.org/10.3390/ph14030267 - 16 Mar 2021

Cited by 10 | Viewed by 8759

Abstract

Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, [...] Read more.

Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes. Full article

(This article belongs to the Section Pharmacology)

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18 pages, 20061 KiB

Open AccessArticle

Antioxidant and Antiproliferative Potentials of Ficus glumosa and Its Bioactive Polyphenol Metabolites

by Moses Mutuse Mutungi, Felix Wambua Muema, Festus Kimutai, Yong-Bing Xu, Hui Zhang, Gui-Lin Chen and Ming-Quan Guo

Pharmaceuticals 2021, 14(3), 266; https://doi.org/10.3390/ph14030266 - 15 Mar 2021

Cited by 11 | Viewed by 3052

Abstract

Ficus glumosa Delile (Moraceae), a reputed plant that is used in herbal medicine, is of high medicinal and nutritional value in local communities primarily ascribed to its phytochemical profile. Currently, there are hardly any fine details on the chemical profiling and pharmacological evaluation [...] Read more.

Ficus glumosa Delile (Moraceae), a reputed plant that is used in herbal medicine, is of high medicinal and nutritional value in local communities primarily ascribed to its phytochemical profile. Currently, there are hardly any fine details on the chemical profiling and pharmacological evaluation of this species. In this study, the flavonoids and phenolics contents of the ethanol extracts and four extracted fractions (petroleum ether (PE), ethyl acetate (EA), n-butanol, and water) of the stem bark of Ficus glumosa were firstly quantified. Further, their antioxidant and antiproliferative potentials were also evaluated. The quantitative determination indicated that the EA and n-butanol fractions possessed the highest total flavonoids/phenolics levels of 274.05 ± 0.68 mg RE/g and 78.87 ± 0.97 mg GAE/g, respectively. Similarly, for the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and ferric-reducing antioxidant power (FRAP) assays, the EA fraction exhibited high potency in both DPPH and ABTS⁺ scavenging activities with IC₅₀ values of 0.23 ± 0.03 mg/mL, 0.22 ± 0.03 mg/mL, and FRAP potential of 2.81 ± 0.01 mg Fe²⁺/g, respectively. Furthermore, the EA fraction displayed high cytotoxicity against human lung (A549) and colon (HT-29) cancer cells. Additionally, the liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was employed in order to characterize the chemical constituents of the EA fraction of Ficus glumosa stem bark. Our findings revealed 16 compounds from the EA fraction that were possibly responsible for the strong antioxidant and anti-proliferative properties. This study provides edge-cutting background information on the exploitation of Ficus glumosa as a potential natural antioxidant and anti-cancer remedy. Full article

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

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18 pages, 20140 KiB

Open AccessArticle

Novel Selective IDO1 Inhibitors with Isoxazolo[5,4-d]pyrimidin-4(5H)-one Scaffold

by Ana Dolšak, Tomaž Bratkovič, Larisa Mlinarič, Eva Ogorevc, Urban Švajger, Stanislav Gobec and Matej Sova

Pharmaceuticals 2021, 14(3), 265; https://doi.org/10.3390/ph14030265 - 15 Mar 2021

Cited by 6 | Viewed by 3219

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a [...] Read more.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC₅₀ values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators. Full article

(This article belongs to the Section Medicinal Chemistry)

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15 pages, 1525 KiB

Open AccessArticle

Safety and Tolerability of Mass Diethylcarbamazine and Albendazole Administration for the Elimination of Lymphatic Filariasis in Kenya: An Active Surveillance Study

by Christabel Khaemba, Abbie Barry, Wyckliff P. Omondi, Kefa Bota, Sultani Matendechero, Cecilia Wandera, Fred Siyoi, Elvis Kirui, Margaret Oluka, Pamela Nambwa, Parthasarathi Gurumurthy, Sammy M. Njenga, Anastacia Guantai and Eleni Aklillu

Pharmaceuticals 2021, 14(3), 264; https://doi.org/10.3390/ph14030264 - 15 Mar 2021

Cited by 8 | Viewed by 3917

Abstract

Preventive chemotherapy with diethylcarbamazine citrate (DEC) and albendazole (ALB) is the core intervention strategy to eliminate lymphatic filariasis (LF). We conducted a large-scale prospective active safety surveillance study to identify the incidence, type, severity, and risk factors for adverse events (AEs) following mass [...] Read more.

Preventive chemotherapy with diethylcarbamazine citrate (DEC) and albendazole (ALB) is the core intervention strategy to eliminate lymphatic filariasis (LF). We conducted a large-scale prospective active safety surveillance study to identify the incidence, type, severity, and risk factors for adverse events (AEs) following mass drug administration (MDA) of single-dose DEC and ALB in 10,010 participants from Kilifi County, Kenya. AEs were actively monitored and graded at 24 h, 48 h, and on day 7 Post-MDA. Out of 10,010 enrolled study participants, 1621 participants reported a total of 3102 AEs during a seven-day follow-up. The cumulative incidence of AEs was 16.2% (95% CI, 15.5–16.9%). The proportion of participants who experienced one, two, or ≥three types of AEs was 9.2%, 4.6%, 2.4%, respectively. AEs were mild (87.3%), moderate (12.4%), and severe (0.3%) and resolved within 72 h. The five most common AEs were dizziness (5.9%), headache (5.6%), loss of appetite (3.3%), fever (2.9%), and drowsiness (2.6%). Older age, taking concurrent medications, ≥three tablets of DEC, and type of meal taken before MDA were significant predictors of AEs. One in six participants experienced systemic mild-to-moderate severity grading and transient AEs. DEC and ALB co-administration for the elimination of LF is generally safe and well-tolerated. Full article

(This article belongs to the Special Issue Pharmacoepidemiology and Pharmacovigilance in Drug-Therapy: New Issues, Challenges, and Applications)

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15 pages, 3349 KiB

Open AccessCommunication

Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart

by Duncan Horlock, David M. Kaye, Catherine E. Winbanks, Xiao-Ming Gao, Helen Kiriazis, Daniel G. Donner, Paul Gregorevic, Julie R. McMullen and Bianca C. Bernardo

Pharmaceuticals 2021, 14(3), 263; https://doi.org/10.3390/ph14030263 - 15 Mar 2021

Cited by 3 | Viewed by 3249

Abstract

Cardiac fibrosis is associated with most forms of cardiovascular disease. No reliable therapies targeting cardiac fibrosis are available, thus identifying novel drugs that can resolve or prevent fibrosis is needed. Tilorone, an antiviral agent, can prevent fibrosis in a mouse model of lung [...] Read more.

Cardiac fibrosis is associated with most forms of cardiovascular disease. No reliable therapies targeting cardiac fibrosis are available, thus identifying novel drugs that can resolve or prevent fibrosis is needed. Tilorone, an antiviral agent, can prevent fibrosis in a mouse model of lung disease. We investigated the anti-fibrotic effects of tilorone in human cardiac fibroblasts in vitro by performing a radioisotopic assay for [³H]-proline incorporation as a proxy for collagen synthesis. Exploratory studies in human cardiac fibroblasts treated with tilorone (10 µM) showed a significant reduction in transforming growth factor-β induced collagen synthesis compared to untreated fibroblasts. To determine if this finding could be recapitulated in vivo, mice with established pathological remodelling due to four weeks of transverse aortic constriction (TAC) were administered tilorone (50 mg/kg, i.p) or saline every third day for eight weeks. Treatment with tilorone was associated with attenuation of fibrosis (assessed by Masson’s trichrome stain), a favourable cardiac gene expression profile and no further deterioration of cardiac systolic function determined by echocardiography compared to saline treated TAC mice. These data demonstrate that tilorone has anti-fibrotic actions in human cardiac fibroblasts and the adult mouse heart, and represents a potential novel therapy to treat fibrosis associated with heart failure. Full article

(This article belongs to the Collection Old Pharmaceuticals with New Applications)

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15 pages, 3695 KiB

Open AccessArticle

Effect of Methyl–β–Cyclodextrin and Trehalose on the Freeze–Drying and Spray–Drying of Sericin for Cosmetic Purposes

by Lorella Giovannelli, Andrea Milanesi, Elena Ugazio, Letizia Fracchia and Lorena Segale

Pharmaceuticals 2021, 14(3), 262; https://doi.org/10.3390/ph14030262 - 15 Mar 2021

Cited by 19 | Viewed by 3993

Abstract

Sericin is a protein extracted from Bombyx mori silk cocoons. Over the last decade, this wastewater product of the textile industry has shown many interesting biological properties. This protein is widely used in the cosmetic and biomedical fields. In this study, sericin has [...] Read more.

Sericin is a protein extracted from Bombyx mori silk cocoons. Over the last decade, this wastewater product of the textile industry has shown many interesting biological properties. This protein is widely used in the cosmetic and biomedical fields. In this study, sericin has been obtained via a High–Temperature High–Pressure degumming process, and was dried using the freeze–drying (fd) and spray–drying (sd) techniques. Proteins tend to collapse during drying, hence, sericin has been dried in the presence of two selected carrier agents: methyl–β–cyclodextrin and trehalose. The obtained powders have been analyzed using thermal investigation, microscopy (optical, SEM), and granulometric and spectroscopic analyses. Moreover, the percentage yield of the spray–drying process has been calculated. Both the agents were able to significantly improve the drying process, without altering the physico–chemical properties of the protein. In particular, the co–spray–drying of sericin with methyl–β–cyclodextrin and trehalose gave good process yields and furnished a powder with low moisture content and handling properties that are better than those of the other studied dried products. These characteristics seem to be appropriate and fruitful for the manufacturing of cosmetic raw materials. Full article

(This article belongs to the Special Issue New Frontiers in Cyclodextrin Technologies)

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15 pages, 2149 KiB

Open AccessArticle

Identification of Lactate as a Cardiac Protectant by Inhibiting Inflammation and Cardiac Hypertrophy Using a Zebrafish Acute Heart Failure Model

by Elijah R. Haege, Hui-Chi Huang and Cheng-chen Huang

Pharmaceuticals 2021, 14(3), 261; https://doi.org/10.3390/ph14030261 - 15 Mar 2021

Cited by 5 | Viewed by 2337

Abstract

Acute heart failure (AHF) commonly arises from decompensated chronic heart failure or sudden structural and functional breakdown causing a decrease in cardiac contractility and consequently fluid accumulation and systemic congestion. Current treatment for AHF aims at reducing fluid overload and improving hemodynamic which [...] Read more.

Acute heart failure (AHF) commonly arises from decompensated chronic heart failure or sudden structural and functional breakdown causing a decrease in cardiac contractility and consequently fluid accumulation and systemic congestion. Current treatment for AHF aims at reducing fluid overload and improving hemodynamic which results in quick symptom relief but still poor prognostic outcome. This study utilizes a zebrafish AHF model induced by aristolochic acid (AA) to look for natural products that could attenuate the progression of AHF. The project started off by testing nearly seventy herbal crude extracts. Two of the positive extracts were from Chinese water chestnuts and are further studied in this report. After several rounds of chromatographical chemical fractionation and biological tests, a near pure fraction, named A2-4-2-4, with several hydrophilic compounds was found to attenuate the AA-induced AHF. A2-4-2-4 appeared to inhibit inflammation and cardiac hypertrophy by reducing MAPK signaling activity. Chemical analyses revealed that the major compound in A2-4-2-4 is actually lactate. Pure sodium lactate showed attenuation of the AA-induced AHF and inflammation and cardiac hypertrophy suppression as well, suggesting that the AHF attenuation ability in A2-4-2-4 is attributable to lactate. Our studies identify lactate as a cardiac protectant and a new therapeutic agent for AHF. Full article

(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)

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14 pages, 4629 KiB

Open AccessArticle

Potential Antimetastatic Effect of Timosaponin AIII against Human Osteosarcoma Cells through Regulating the Integrin/FAK/Cofilin Axis

by Yi-Hsien Hsieh, Wen-Hung Hsu, Shun-Fa Yang, Chung-Jung Liu, Ko-Hsiu Lu, Pei-Han Wang and Renn-Chia Lin

Pharmaceuticals 2021, 14(3), 260; https://doi.org/10.3390/ph14030260 - 14 Mar 2021

Cited by 12 | Viewed by 2127

Abstract

Timosaponin AIII (TSAIII) is a steroidal saponin which demonstrates anti-tumour activities. However, the effect of TSAIII on human osteosarcoma cells remains largely unknown. In this study, we demonstrated that TSAIII exerted a significant inhibitory effect on the distribution of cytoskeletal F-actin and cytoskeletal-related [...] Read more.

Timosaponin AIII (TSAIII) is a steroidal saponin which demonstrates anti-tumour activities. However, the effect of TSAIII on human osteosarcoma cells remains largely unknown. In this study, we demonstrated that TSAIII exerted a significant inhibitory effect on the distribution of cytoskeletal F-actin and cytoskeletal-related proteins, which contributed to the suppression of cell migration and invasion, without inhibiting cell growth or apoptosis. In the synergistic inhibitory analysis, cotreatment of TSAIII with αVβ3 integrin inhibitor [Cyclo(RGDyK)] or focal adhesion kinase (FAK) inhibitor (PF-573228) exerted greater synergistic inhibitory effects on the expression of Intergin αVβ3/FAK/cofilin axis, thus inhibiting the migration and invasion capacities of human osteosarcoma cells. TSAIII was demonstrated to significantly inhibit the pulmonary metastasis formation of human osteosarcoma cells in vivo in metastasis animal models. These findings reveal the inhibitory effects of TSAIII on the metastasis progression of human osteosarcoma cells and the regulation of integrin-αVβ3-FAK-Src and TESK1/p-cofilin mediated cytoskeletal F-actin pathway. Therefore, TSAIII might represent a novel strategy for the auxiliary treatment of human osteosarcoma cells. Full article

(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)

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14 pages, 1434 KiB

Open AccessArticle

Validation of an LC-MS/MS Method to Quantify the New TRPC6 Inhibitor SH045 (Larixyl N-methylcarbamate) and Its Application in an Exploratory Pharmacokinetic Study in Mice

by Xiao-Ning Chai, Friedrich-Alexander Ludwig, Anne Müglitz, Michael Schaefer, Hai-Yan Yin, Peter Brust, Ralf Regenthal and Ute Krügel

Pharmaceuticals 2021, 14(3), 259; https://doi.org/10.3390/ph14030259 - 13 Mar 2021

Cited by 3 | Viewed by 2032

Abstract

TRPC6 (transient receptor potential cation channels; canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is [...] Read more.

TRPC6 (transient receptor potential cation channels; canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is still at the beginning stages. Recently, by chemical diversification of (+)-larixol originating from Larix decidua resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was obtained and identified in functional assays as a highly potent, subtype-selective inhibitor of TRPC6. To pave the way for use of SH045 in animal disease models, this study aimed at developing a capable bioanalytical method and to provide exploratory pharmacokinetic data for this promising derivative. According to international guidelines, a robust and selective LC-MS/MS method based on MRM detection in positive ion mode was established and validated for quantification of SH045 in mice plasma, whereby linearity and accuracy were demonstrated for the range of 2–1600 ng/mL. Applying this method, the plasma concentration time course of SH045 following single intraperitoneal administration (20 mg/kg body weight) revealed a short half-life of 1.3 h. However, the pharmacological profile of SH045 is promising, as five hours after administration, plasma levels still remained sufficiently higher than published low nanomolar IC₅₀ values. Summarizing, the LC-MS/MS method and exploratory pharmacokinetic data provide essential prerequisites for experimental pharmacological TRPC6 modulation and translational treatment of TRPC6 channelopathies. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 3816 KiB

Open AccessArticle

Safflower Seed Extract Attenuates the Development of Osteoarthritis by Blocking NF-κB Signaling

by Seong Jae Han, Min Ju Lim, Kwang Min Lee, Eunjeong Oh, Yu Su Shin, Seokho Kim, Joong Sun Kim, Seung Pil Yun and Li-Jung Kang

Pharmaceuticals 2021, 14(3), 258; https://doi.org/10.3390/ph14030258 - 12 Mar 2021

Cited by 10 | Viewed by 2592

Abstract

Although safflower seed extract exhibits pharmacological activity against various diseases, the effects of its individual compounds on osteoarthritis (OA) have not been elucidated. Here, we evaluated the effects of these extracts and their single compounds on OA. N-(p-Coumaroyl) serotonin and N-feruloyl serotonin, main [...] Read more.

Although safflower seed extract exhibits pharmacological activity against various diseases, the effects of its individual compounds on osteoarthritis (OA) have not been elucidated. Here, we evaluated the effects of these extracts and their single compounds on OA. N-(p-Coumaroyl) serotonin and N-feruloyl serotonin, main components of safflower seed extract, were isolated by high-performance liquid chromatography. Under in vitro OA mimic conditions, the expression of the matrix metalloproteinases (MMPs) MMP3/13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) ADAMTS5 were reduced in mouse chondrocytes treated with safflower seed extract. Furthermore, the oral administration of safflower seed extract attenuated cartilage destruction in a mouse OA model induced by destabilization of the medial meniscus. N-(p-Coumaroyl) serotonin and N-feruloyl serotonin, but not serotonin, reduced MMP3, MMP13, and ADAMTS5 expression in IL-1β-treated chondrocytes. Additionally, they significantly blocked the nuclear factor-κB (NF-κB) pathway by inhibiting IκB degradation and p65 phosphorylation. Our results suggest that safflower seed extract and its single compounds can attenuate cartilage destruction by suppressing MMP and ADMATS5 expression. The anti-arthritic effects are mediated by NF-κB signaling and involve the inhibition of IκB degradation and p65 phosphorylation. These results indicate that safflower seed extract may serve as a novel therapeutic agent against OA. Full article

(This article belongs to the Special Issue Drug and Therapy for Osteoarthritis (OA))

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16 pages, 24263 KiB

Open AccessArticle

The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease

by Elisabeth Singer, Lilit Hunanyan, Magda M. Melkonyan, Jonasz J. Weber, Lusine Danielyan and Huu Phuc Nguyen

Pharmaceuticals 2021, 14(3), 257; https://doi.org/10.3390/ph14030257 - 12 Mar 2021

Viewed by 2643

Abstract

Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 [...] Read more.

Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT. Full article

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

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