Pharmaceuticals

15 pages, 2062 KiB

Open AccessReview

The Antiviral Role of Galectins toward Influenza A Virus Infection—An Alternative Strategy for Influenza Therapy

by Chih-Yen Lin, Zih-Syuan Yang, Wen-Hung Wang, Aspiro Nayim Urbina, Yu-Ting Lin, Jason C. Huang, Fu-Tong Liu and Sheng-Fan Wang

Pharmaceuticals 2021, 14(5), 490; https://doi.org/10.3390/ph14050490 - 20 May 2021

Cited by 10 | Viewed by 3829

Abstract

Animal lectins are proteins with carbohydrate recognition activity. Galectins, the β-galactoside binding lectins, are expressed in various cells and have been reported to regulate several immunological and physiological responses. Recently, some galectins have been reported to regulate some viral infections, including influenza A [...] Read more.

Animal lectins are proteins with carbohydrate recognition activity. Galectins, the β-galactoside binding lectins, are expressed in various cells and have been reported to regulate several immunological and physiological responses. Recently, some galectins have been reported to regulate some viral infections, including influenza A virus (IAV); however, the mechanism is still not fully understood. Thus, we aim to review systemically the roles of galectins in their antiviral functions against IAVs. The PRISMA guidelines were used to select the eligible articles. Results indicated that only Galectin-1, Galectin-3, and Galectin-9 were reported to play a regulatory role in IAV infection. These regulatory effects occur extracellularly, through their carbohydrate recognition domain (CRD) interacting with glycans expressed on the virus surface, as well as endogenously, in a cell–cell interaction manner. The inhibition effects induced by galectins on IAV infection were through blocking virus–host receptors interaction, activation of NLRP-3 inflammasome, augment expression of antiviral genes and related cytokines, as well as stimulation of Tim-3 related signaling to enhance virus-specific T cells and humoral immune response. Combined, this study concludes that currently, only three galectins have reported antiviral capabilities against IAV infection, thereby having the potential to be applied as an alternative anti-influenza therapeutic strategy. Full article

(This article belongs to the Special Issue Recent Strategies in Anti-influenza Therapeutics)

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21 pages, 9308 KiB

Open AccessArticle

Neuropeptide S-Mediated Modulation of Prepulse Inhibition Depends on Age, Gender, Stimulus-Timing, and Attention

by Wei Si, Xiaobin Liu, Hans-Christian Pape and Rainer K. Reinscheid

Pharmaceuticals 2021, 14(5), 489; https://doi.org/10.3390/ph14050489 - 20 May 2021

Cited by 2 | Viewed by 2792

Abstract

Conflicting reports about the role of neuropeptide S (NPS) in animal models of psychotic-like behavior and inconsistent results from human genetic studies seeking potential associations with schizophrenia prompted us to reevaluate the effects of NPS in the prepulse inhibition (PPI) paradigm in mice. [...] Read more.

Conflicting reports about the role of neuropeptide S (NPS) in animal models of psychotic-like behavior and inconsistent results from human genetic studies seeking potential associations with schizophrenia prompted us to reevaluate the effects of NPS in the prepulse inhibition (PPI) paradigm in mice. Careful examination of NPS receptor (NPSR1) knockout mice at different ages revealed that PPI deficits are only expressed in young male knockout animals (<12 weeks of age), that can be replicated in NPS precursor knockout mice and appear strain-independent, but are absent in female mice. PPI deficits can be aggravated by MK-801 and alleviated by clozapine. Importantly, treatment of wildtype mice with a centrally-active NPSR1 antagonist was able to mimic PPI deficits. PPI impairment in young male NPSR1 and NPS knockout mice may be caused by attentional deficits that are enhanced by increasing interstimulus intervals. Our data reveal a substantial NPS-dependent developmental influence on PPI performance and confirm a significant role of attentional processes for sensory-motor gating. Through its influence on attention and arousal, NPS appears to positively modulate PPI in young animals, whereas compensatory mechanisms may alleviate NPS-dependent deficits in older mice. Full article

(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)

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20 pages, 1274 KiB

Open AccessReview

Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi

by Lucie Peyclit, Hanane Yousfi, Jean-Marc Rolain and Fadi Bittar

Pharmaceuticals 2021, 14(5), 488; https://doi.org/10.3390/ph14050488 - 20 May 2021

Cited by 35 | Viewed by 5728

Abstract

Immunodepression, whether due to HIV infection or organ transplantation, has increased human vulnerability to fungal infections. These conditions have created an optimal environment for the emergence of opportunistic infections, which is concomitant to the increase in antifungal resistance. The use of conventional antifungal [...] Read more.

Immunodepression, whether due to HIV infection or organ transplantation, has increased human vulnerability to fungal infections. These conditions have created an optimal environment for the emergence of opportunistic infections, which is concomitant to the increase in antifungal resistance. The use of conventional antifungal drugs as azoles and polyenes can lead to clinical failure, particularly in immunocompromised individuals. Difficulties related to treating fungal infections combined with the time required to develop new drugs, require urgent consideration of other therapeutic alternatives. Drug repurposing is one of the most promising and rapid solutions that the scientific and medical community can turn to, with low costs and safety advantages. To treat life-threatening resistant fungal infections, drug repurposing has led to the consideration of well-known and potential molecules as a last-line therapy. The aim of this review is to provide a summary of current antifungal compounds and their main resistance mechanisms, following by an overview of the antifungal activity of non-traditional antimicrobial drugs. We provide their eventual mechanisms of action and the synergistic combinations that improve the activity of current antifungal treatments. Finally, we discuss drug repurposing for the main emerging multidrug resistant (MDR) fungus, including the Candida auris, Aspergillus or Cryptococcus species. Full article

(This article belongs to the Special Issue Advances in Antifungal Development: Discovery of New Drugs and Drug Repurposing)

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15 pages, 2029 KiB

Open AccessReview

The Influence of Pharmacogenetics on the Clinical Relevance of Pharmacokinetic Drug–Drug Interactions: Drug–Gene, Drug–Gene–Gene and Drug–Drug–Gene Interactions

by Martina Hahn and Sibylle C. Roll

Pharmaceuticals 2021, 14(5), 487; https://doi.org/10.3390/ph14050487 - 20 May 2021

Cited by 35 | Viewed by 6940

Abstract

Drug interactions are a well-known cause of adverse drug events, and drug interaction databases can help the clinician to recognize and avoid such interactions and their adverse events. However, not every interaction leads to an adverse drug event. This is because the clinical [...] Read more.

Drug interactions are a well-known cause of adverse drug events, and drug interaction databases can help the clinician to recognize and avoid such interactions and their adverse events. However, not every interaction leads to an adverse drug event. This is because the clinical relevance of drug–drug interactions also depends on the genetic profile of the patient. If inhibitors or inducers of drug metabolising enzymes (e.g., CYP and UGT) are added to the drug therapy, phenoconcversion can occur. This leads to a genetic phenotype that mismatches the observable phenotype. Drug–drug–gene and drug–gene–gene interactions influence the toxicity and/or ineffectivness of the drug therapy. To date, there have been limited published studies on the impact of genetic variations on drug–drug interactions. This review discusses the current evidence of drug–drug–gene interactions, as well as drug–gene–gene interactions. Phenoconversion is explained, the and methods to calculate the phenotypes are described. Clinical recommendations are given regarding the integratation of the PGx results in the assessment of the relevance of drug interactions in the future. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)

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14 pages, 2693 KiB

Open AccessArticle

Hydrotalcite–Niclosamide Nanohybrid as Oral Formulation towards SARS-CoV-2 Viral Infections

by Goeun Choi, Huiyan Piao, N. Sanoj Rejinold, Seungjin Yu, Ki-yeok Kim, Geun-woo Jin and Jin-Ho Choy

Pharmaceuticals 2021, 14(5), 486; https://doi.org/10.3390/ph14050486 - 19 May 2021

Cited by 17 | Viewed by 7359

Abstract

COVID-19 has been affecting millions of individuals worldwide and, thus far, there is no accurate therapeutic strategy. This critical situation necessitates novel formulations for already existing, FDA approved, but poorly absorbable drug candidates, such as niclosamide (NIC), which is of great relevance. In [...] Read more.

COVID-19 has been affecting millions of individuals worldwide and, thus far, there is no accurate therapeutic strategy. This critical situation necessitates novel formulations for already existing, FDA approved, but poorly absorbable drug candidates, such as niclosamide (NIC), which is of great relevance. In this context, we have rationally designed NIC-loaded hydrotalcite composite nanohybrids, which were further coated with Tween 60 or hydroxypropyl methyl cellulose (HPMC), and characterized them in vitro. The optimized nanohybrids showed particle sizes <300 nm and were orally administrated to rats to determine whether they could retain an optimum plasma therapeutic concentration of NIC that would be effective for treating COVID-19. The pharmacokinetic (PK) results clearly indicated that hydrotalcite-based NIC formulations could be highly potential options for treating the ongoing pandemic and we are on our way to understanding the in vivo anti-viral efficacy sooner. It is worth mentioning that hydrotalcite–NIC nanohybrids maintained a therapeutic NIC level, even above the required IC₅₀ value, after just a single administration in 8–12 h. In conclusion, we were very successfully able to develop a NIC oral formulation by immobilizing with hydrotalcite nanoparticles, which were further coated with Tween 60 or HPMC, in order to enhance their emulsification in the gastrointestinal tract. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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10 pages, 2242 KiB

Open AccessCommunication

Synthesis of Novel Fluorinated Xanthine Derivatives with High Adenosine A_2B Receptor Binding Affinity

by Marcel Lindemann, Sladjana Dukic-Stefanovic, Sonja Hinz, Winnie Deuther-Conrad, Rodrigo Teodoro, Cathleen Juhl, Jörg Steinbach, Peter Brust, Christa E. Müller and Barbara Wenzel

Pharmaceuticals 2021, 14(5), 485; https://doi.org/10.3390/ph14050485 - 19 May 2021

Cited by 1 | Viewed by 3525

Abstract

The G protein-coupled adenosine A_2B receptor is suggested to be involved in various pathological processes accompanied by increased levels of adenosine as found in inflammation, hypoxia, and cancer. Therefore, the adenosine A_2B receptor is currently in focus as a novel target [...] Read more.

The G protein-coupled adenosine A_2B receptor is suggested to be involved in various pathological processes accompanied by increased levels of adenosine as found in inflammation, hypoxia, and cancer. Therefore, the adenosine A_2B receptor is currently in focus as a novel target for cancer therapy as well as for noninvasive molecular imaging via positron emission tomography (PET). Aiming at the development of a radiotracer labeled with the PET radionuclide fluorine-18 for imaging the adenosine A_2B receptor in brain tumors, one of the most potent and selective antagonists, the xanthine derivative PSB-603, was selected as a lead compound. As initial biodistribution studies in mice revealed a negligible brain uptake of [³H]PSB-603 (SUV_3min: 0.2), structural modifications were performed to optimize the physicochemical properties regarding blood–brain barrier penetration. Two novel fluorinated derivatives bearing a 2-fluoropyridine (5) moiety and a 4-fluoro-piperidine (6) moiety were synthesized, and their affinity towards the four adenosine receptor subtypes was determined in competition binding assays. Both compounds showed high affinity towards the adenosine A_2B receptor (K_i (5) = 9.97 ± 0.86 nM; K_i (6) = 12.3 ± 3.6 nM) with moderate selectivity versus the other adenosine receptor subtypes. Full article

(This article belongs to the Special Issue Medicinal Chemistry of Adenosine Receptor Antagonists)

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17 pages, 96674 KiB

Open AccessArticle

Human Salivary Histatin-1-Functionalized Gelatin Methacrylate Hydrogels Promote the Regeneration of Cartilage and Subchondral Bone in Temporomandibular Joints

by Changjing Shi, Yu Yao, Lei Wang, Ping Sun, Jianying Feng and Gang Wu

Pharmaceuticals 2021, 14(5), 484; https://doi.org/10.3390/ph14050484 - 19 May 2021

Cited by 10 | Viewed by 3603

Abstract

The avascular structure and lack of regenerative cells make the repair of osteochondral defects in the temporomandibular joint (TMJ) highly challenging in the clinic. To provide a viable treatment option, we developed a methacrylated gelatin (Gel-MA) hydrogel functionalized with human salivary histatin-1 (Hst1). [...] Read more.

The avascular structure and lack of regenerative cells make the repair of osteochondral defects in the temporomandibular joint (TMJ) highly challenging in the clinic. To provide a viable treatment option, we developed a methacrylated gelatin (Gel-MA) hydrogel functionalized with human salivary histatin-1 (Hst1). Gel-MA is highly biocompatible, biodegradable, and cost-effective. Hst1 is capable of activating a series of cell activities, such as adhesion, migration, differentiation, and angiogenesis. To evaluate the efficacy of Hst1/Gel-MA, critical-size osteochondral defects (3 mm in diameter and 3 mm in depth) of TMJ in New Zealand white rabbits were surgically created and randomly assigned to one of the three treatment groups: (1) control (no filling material); (2) Gel-MA hydrogel; (3) Hst1/Gel-MA hydrogel. Samples were retrieved 1, 2, and 4 weeks post-surgery and subjected to gross examination and a series of histomorphometric and immunological analyses. In comparison with the control and Gel-MA alone groups, Hst1/Gel-MA hydrogel was associated with significantly higher International Cartilage Repair Society score, modified O’Driscoll score, area percentages of newly formed bone, cartilage, collagen fiber, and glycosaminoglycan, and expression of collagen II and aggrecan. In conclusion, Hst1/Gel-MA hydrogels significantly enhance bone and cartilage regeneration, thus bearing promising application potential for repairing osteochondral defects. Full article

(This article belongs to the Special Issue Cell-Based Therapies for Bone and Cartilage Regeneration)

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13 pages, 528 KiB

Open AccessFeature PaperReview

Roles of Neuropeptide S in Anesthesia, Analgesia, and Sleep

by Tetsuya Kushikata, Kazuyoshi Hirota, Junichi Saito and Daiki Takekawa

Pharmaceuticals 2021, 14(5), 483; https://doi.org/10.3390/ph14050483 - 19 May 2021

Cited by 9 | Viewed by 3691

Abstract

Neuropeptide S (NPS) is an endogenous peptide that regulates various physiological functions, such as immune functions, anxiety-like behaviors, learning and memory, the sleep–wake rhythm, ingestion, energy balance, and drug addiction. These processes include the NPS receptor (NPSR1). The NPS–NPSR1 system is also significantly [...] Read more.

Neuropeptide S (NPS) is an endogenous peptide that regulates various physiological functions, such as immune functions, anxiety-like behaviors, learning and memory, the sleep–wake rhythm, ingestion, energy balance, and drug addiction. These processes include the NPS receptor (NPSR1). The NPS–NPSR1 system is also significantly associated with the onset of disease, as well as these physiologic functions. For example, NPS is involved in bronchial asthma, anxiety and awakening disorders, and rheumatoid arthritis. In this review, among the various functions, we focus on the role of NPS in anesthesia-induced loss of consciousness; analgesia, mainly by anesthesia; and sleep–wakefulness. Progress in the field regarding the functions of endogenous peptides in the brain, including NPS, suggests that these three domains share common mechanisms. Further NPS research will help to elucidate in detail how these three domains interact with each other in their functions, and may contribute to improving the quality of medical care. Full article

(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)

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18 pages, 15325 KiB

Open AccessArticle

Rational Design of Novel Inhibitors of α-Glucosidase: An Application of Quantitative Structure Activity Relationship and Structure-Based Virtual Screening

by Sobia Ahsan Halim, Sumaira Jabeen, Ajmal Khan and Ahmed Al-Harrasi

Pharmaceuticals 2021, 14(5), 482; https://doi.org/10.3390/ph14050482 - 19 May 2021

Cited by 27 | Viewed by 3891

Abstract

α-Glucosidase is considered a prime drug target for Diabetes Mellitus and its inhibitors are used to delay carbohydrate digestion for the treatment of diabetes mellitus. With the aim to design α-glucosidase inhibitors with novel chemical scaffolds, three folds ligand and structure based virtual [...] Read more.

α-Glucosidase is considered a prime drug target for Diabetes Mellitus and its inhibitors are used to delay carbohydrate digestion for the treatment of diabetes mellitus. With the aim to design α-glucosidase inhibitors with novel chemical scaffolds, three folds ligand and structure based virtual screening was applied. Initially linear quantitative structure activity relationship (QSAR) model was developed by a molecular operating environment (MOE) using a training set of thirty-two known inhibitors, which showed good correlation coefficient (r² = 0.88), low root mean square error (RMSE = 0.23), and cross-validated correlation coefficient r² (q² = 0.71 and RMSE = 0.31). The model was validated by predicting the biological activities of the test set which depicted r² value of 0.82, indicating the robustness of the model. For virtual screening, compounds were retrieved from zinc is not commercial (ZINC) database and screened by molecular docking. The best docked compounds were chosen to assess their pharmacokinetic behavior. Later, the α-glucosidase inhibitory potential of the selected compounds was predicted by their mode of binding interactions. The predicted pharmacokinetic profile, docking scores and protein-ligand interactions revealed that eight compounds preferentially target the catalytic site of α-glucosidase thus exhibit potential α-glucosidase inhibition in silico. The α-glucosidase inhibitory activities of those Hits were predicted by QSAR model, which reflect good inhibitory activities of these compounds. These results serve as a guidelines for the rational drug design and development of potential novel anti-diabetic agents. Full article

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

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14 pages, 1189 KiB

Open AccessReview

Possible Antidepressant Effects of Memantine—Systematic Review with a Case Study

by Marek Krzystanek, Stanisław Surma, Artur Pałasz, Monika Romańczyk and Krzysztof Krysta

Pharmaceuticals 2021, 14(5), 481; https://doi.org/10.3390/ph14050481 - 18 May 2021

Cited by 12 | Viewed by 6995

Abstract

The treatment of bipolar depression is hampered by the inadequate efficacy of antidepressants, moderate effect of mood stabilizers, and the side effects of some second-generation antipsychotics. There is limited evidence to date regarding the antidepressant effects of memantine in bipolar depression. The aim [...] Read more.

The treatment of bipolar depression is hampered by the inadequate efficacy of antidepressants, moderate effect of mood stabilizers, and the side effects of some second-generation antipsychotics. There is limited evidence to date regarding the antidepressant effects of memantine in bipolar depression. The aim of the article was to provide a short review of preclinical and clinical studies on the antidepressant effect of memantine, and to present the case of a bipolar depression patient successfully treated with memantine. The described patient with bipolar disorder was unsuccessfully treated with two mood stabilizers. The addition of memantine at a dose of 20 mg/d to the treatment with lamotrigine and valproic acid resulted in a reduction in the severity of depression measured on the HDRS-17 scale by 35%, and by 47.1% after 7 weeks. The discussion presents experimental evidence for the antidepressant effect of memantine, as well as data from clinical trials in recurrent and bipolar depression. The presented case is the second report in the medical literature showing the antidepressant effect of memantine as an add-on treatment for bipolar depression. The described case and literature analysis indicate that memantine may be an effective and safe method of augmentation of mood stabilizing therapy in bipolar depression. Full article

(This article belongs to the Special Issue Psychopharmacology of Affective Disorders)

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10 pages, 451 KiB

Open AccessArticle

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

by Martin Kallab, Kornelia Schuetzenberger, Nikolaus Hommer, Bhavapriya Jasmin Schäfer, Doreen Schmidl, Helga Bergmeister, Markus Zeitlinger, Aimin Tan, Phatsawee Jansook, Thorsteinn Loftsson, Einar Stefansson and Gerhard Garhöfer

Pharmaceuticals 2021, 14(5), 480; https://doi.org/10.3390/ph14050480 - 18 May 2021

Cited by 9 | Viewed by 4425

Abstract

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a [...] Read more.

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (C_max), time of maximal drug concentration (T_max), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the C_max of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a C_max of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while C_max was below 2 ng/g for candesartan. For multiple dosing, the observed C_mean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (C_max 5.64 ± 4.08 ng/mL) and candesartan (C_max 4.32 ± 1.04 ng/mL) were reached 0.5 h (T_max) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model. Full article

(This article belongs to the Special Issue Advances in Ocular Pharmacology)

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11 pages, 2079 KiB

Open AccessArticle

Development and In Vitro Evaluation of Controlled Release Viagra^® Containing Poloxamer-188 Using Gastroplus^™ PBPK Modeling Software for In Vivo Predictions and Pharmacokinetic Assessments

by Mosab Arafat, Muhammad Sarfraz and Salahdein AbuRuz

Pharmaceuticals 2021, 14(5), 479; https://doi.org/10.3390/ph14050479 - 18 May 2021

Cited by 23 | Viewed by 4817

Abstract

Sildenafil is the active substance in Viagra^® tablets, which is approved by the FDA to treat sexual dysfunction in men. Poor solubility and short half-life, however, can limit the span of its effectiveness. Therefore, this study focused on an oral controlled release [...] Read more.

Sildenafil is the active substance in Viagra^® tablets, which is approved by the FDA to treat sexual dysfunction in men. Poor solubility and short half-life, however, can limit the span of its effectiveness. Therefore, this study focused on an oral controlled release matrix system with the aim to improve solubility, control the drug release, and sustain the duration of drug activity. The controlled release matrices were prepared with poloxamer-188, hydroxypropyl methylcellulose, and magnesium stearate. Various formulations of different ratios were developed, evaluated in vitro, and assessed in silico. Poloxamer-188 appeared to have a remarkable influence on the release profile of sildenafil citrate. In general, the rate of drug release decreased as the amount of polymer was gradually increased in the matrix system, achieving a maximum release period over 12 h. The in silico assessment by using the GastroPlus™ PBPK modeling software predicted a significant variation in C_max, t_max, t_1/2, and AUC_0-t among the formulations. In conclusion, the combination of polymers in matrix systems can have substantial impact on controlling and modifying the drug release pattern. Full article

(This article belongs to the Special Issue The Prediction of Pharmacokinetics/Pharmacodynamics Using In-Silico Modeling)

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22 pages, 4218 KiB

Open AccessArticle

MH-76, a Novel Non-Quinazoline α₁-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats

by Monika Kubacka, Szczepan Mogilski, Monika Zadrożna, Barbara Nowak, Małgorzata Szafarz, Bartosz Pomierny, Henryk Marona, Anna Waszkielewicz, Wojciech Jawień, Jacek Sapa, Marek Bednarski, Joanna Knutelska and Magdalena Kotańska

Pharmaceuticals 2021, 14(5), 477; https://doi.org/10.3390/ph14050477 - 18 May 2021

Cited by 6 | Viewed by 3653

Abstract

Background: Quinazoline α₁-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first [...] Read more.

Background: Quinazoline α₁-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α₁-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α₁-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α₁-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 3747 KiB

Open AccessArticle

Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle for Myopathy but Does Not Cause Cachexia

by Dean G. Campelj, Cara A. Timpani, Tabitha Cree, Aaron C. Petersen, Alan Hayes, Craig A. Goodman and Emma Rybalka

Pharmaceuticals 2021, 14(5), 478; https://doi.org/10.3390/ph14050478 - 17 May 2021

Cited by 8 | Viewed by 4279

Abstract

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective [...] Read more.

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15 day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-B subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU. Full article

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

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14 pages, 5373 KiB

Open AccessReview

Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

by Alberto Bongiovanni, Brigida Anna Maiorano, Irene Azzali, Chiara Liverani, Martine Bocchini, Valentina Fausti, Giandomenico Di Menna, Ilaria Grassi, Maddalena Sansovini, Nada Riva and Toni Ibrahim

Pharmaceuticals 2021, 14(5), 476; https://doi.org/10.3390/ph14050476 - 17 May 2021

Cited by 19 | Viewed by 3465

Abstract

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III [...] Read more.

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6–15%, I² = 67%, p < 0.1) and 42% (95% CI: 28–56%, I² = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6–5.4; I² = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8–21.1; I² = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens. Full article

(This article belongs to the Special Issue Neuroendocrine Neoplasms and Endocrine Glands Tumors: Pharmacological and Clinical Aspects)

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18 pages, 4693 KiB

Open AccessArticle

Valproic Acid Suppresses Autoimmune Recurrence and Allograft Rejection in Islet Transplantation through Induction of the Differentiation of Regulatory T Cells and Can Be Used in Cell Therapy for Type 1 Diabetes

by Jeng-Rong Lin, Shing-Hwa Huang, Chih-Hsiung Wu, Yuan-Wu Chen, Zhi-Jie Hong, Chia-Pi Cheng, Huey-Kang Sytwu and Gu-Jiun Lin

Pharmaceuticals 2021, 14(5), 475; https://doi.org/10.3390/ph14050475 - 17 May 2021

Cited by 6 | Viewed by 4987

Abstract

Type 1 diabetes mellitus (T1D) results from the destruction of insulin-producing β cells in the islet of the pancreas by lymphocytes. Non-obese diabetic (NOD) mouse is an animal model frequently used for this disease. It has been considered that T1D is a T [...] Read more.

Type 1 diabetes mellitus (T1D) results from the destruction of insulin-producing β cells in the islet of the pancreas by lymphocytes. Non-obese diabetic (NOD) mouse is an animal model frequently used for this disease. It has been considered that T1D is a T cell-mediated autoimmune disease. Both CD4+ and CD8+ T cells are highly responsible for the destruction of β cells within the pancreatic islets of Langerhans. Previous studies have revealed that regulatory T (Treg) cells play a critical role in the homeostasis of the immune system as well as immune tolerance to autoantigens, thereby preventing autoimmunity. Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Previous reports have demonstrated that VPA treatment decreases the incidence and severity of collagen-induced arthritis and experimental autoimmune neuritis by increasing the population of Treg cells in these mouse disease models. Given the effect of VPA in the induction of Treg cells’ population, we evaluated the therapeutic potential and the protective mechanism of VPA treatment in the suppression of graft autoimmune rejection and immune recurrence in syngeneic or allogenic islet transplantation mouse models. In our study, we found that the treatment of VPA increased the expression of forkhead box P3 (FOXP3), which is a critical transcription factor that controls Treg cells’ development and function. Our data revealed that 400 mg/kg VPA treatment in recipients effectively prolonged the survival of syngeneic and allogenic islet grafts. The percentage of Treg cells in splenocytes increased in VPA-treated recipients. We also proved that adoptive transfer of VPA-induced Tregs to the transplanted recipients effectively prolonged the survival of islet grafts. The results of this study provide evidence of the therapeutic potential and the underlying mechanism of VPA treatment in syngeneic islet transplantation for T1D. It also provides experimental evidence for cell therapy by adoptive transferring of in vitro VPA-induced Tregs for the suppression of autoimmune recurrence. Full article

(This article belongs to the Section Biopharmaceuticals)

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13 pages, 2946 KiB

Open AccessArticle

Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice

by Satoshi Mizutani, Junko Nishio, Kanoh Kondo, Kaori Motomura, Zento Yamada, Shotaro Masuoka, Soichi Yamada, Sei Muraoka, Naoto Ishii, Yoshikazu Kuboi, Sho Sendo, Tetuo Mikami, Toshio Imai and Toshihiro Nanki

Pharmaceuticals 2021, 14(5), 474; https://doi.org/10.3390/ph14050474 - 17 May 2021

Cited by 10 | Viewed by 3904

Abstract

CX3C Motif Chemokine Ligand 1 (CX3CL1; fractalkine) has been implicated in the pathogenesis of rheumatoid arthritis (RA) and its inhibition was found to attenuate arthritis in mice as well as in a clinical trial. Therefore, we investigated the effects of an anti-CX3CL1 monoclonal [...] Read more.

CX3C Motif Chemokine Ligand 1 (CX3CL1; fractalkine) has been implicated in the pathogenesis of rheumatoid arthritis (RA) and its inhibition was found to attenuate arthritis in mice as well as in a clinical trial. Therefore, we investigated the effects of an anti-CX3CL1 monoclonal antibody (mAb) on immune-mediated interstitial lung disease (ILD) in SKG mice, which exhibit similar pathological and clinical features to human RA-ILD. CX3CL1 and CX3C chemokine receptor 1 (CX3CR1), the receptor for CX3CL1, were both expressed in the fibroblastic foci of lung tissue and the number of bronchoalveolar fluid (BALF) cells was elevated in ILD in SKG mice. No significant changes were observed in lung fibrosis or the number of BALF cells by the treatment with anti-CX3CL1 mAb. However, significantly greater reductions were observed in the number of M1 macrophages than in M2 macrophages in the BALF of treated mice. Furthermore, CX3CR1 expression levels were significantly higher in M1 macrophages than in M2 macrophages. These results suggest the stronger inhibitory effects of the anti-CX3CL1 mAb treatment against the alveolar infiltration of M1 macrophages than M2 macrophages in ILD in SKG mice. Thus, the CX3CL1-CX3CR1 axis may be involved in the infiltration of inflammatory M1 macrophages in RA-ILD. Full article

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

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14 pages, 2779 KiB

Open AccessArticle

DNA Aptamers against Vaccinia-Related Kinase (VRK) 1 Block Proliferation in MCF7 Breast Cancer Cells

by Rebeca Carrión-Marchante, Valerio Frezza, Ana Salgado-Figueroa, M. Isabel Pérez-Morgado, M. Elena Martín and Víctor M. González

Pharmaceuticals 2021, 14(5), 473; https://doi.org/10.3390/ph14050473 - 17 May 2021

Cited by 9 | Viewed by 3350

Abstract

Vaccinia-related kinase (VRK) 1 is a serin/threonine kinase that plays an important role in DNA damage response (DDR), phosphorylating some proteins involved in this process such as 53BP1, NBS1 or H2AX, and in the cell cycle progression. In addition, VRK1 is overexpressed in [...] Read more.

Vaccinia-related kinase (VRK) 1 is a serin/threonine kinase that plays an important role in DNA damage response (DDR), phosphorylating some proteins involved in this process such as 53BP1, NBS1 or H2AX, and in the cell cycle progression. In addition, VRK1 is overexpressed in many cancer types and its correlation with poor prognosis has been determined, showing VRK1 as a new therapeutic target in oncology. Using in vitro selection, high-affinity DNA aptamers to VRK1 were selected from a library of ssDNA. Selection was monitored using the enzyme-linked oligonucleotide assay (ELONA), and the selected aptamer population was cloned and sequenced. Three aptamers were selected and characterized. These aptamers recognized the protein kinase VRK1 with an affinity in the nanomolar range and showed a high sensibility. Moreover, the treatment of the MCF7 breast cell line with these aptamers resulted in a decrease in cyclin D1 levels, and an inhibition of cell cycle progression by G1 phase arrest, which induced apoptosis in cells. These results suggest that these aptamers are specific inhibitors of VRK1 that might be developed as potential drugs for the treatment of cancer. Full article

(This article belongs to the Special Issue Potential of the Aptamers to Fill Therapeutic and Diagnostic Gaps)

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21 pages, 4624 KiB

Open AccessReview

Descriptors of Cytochrome Inhibitors and Useful Machine Learning Based Methods for the Design of Safer Drugs

by Tyler C. Beck, Kyle R. Beck, Jordan Morningstar, Menny M. Benjamin and Russell A. Norris

Pharmaceuticals 2021, 14(5), 472; https://doi.org/10.3390/ph14050472 - 17 May 2021

Cited by 32 | Viewed by 5430

Abstract

Roughly 2.8% of annual hospitalizations are a result of adverse drug interactions in the United States, representing more than 245,000 hospitalizations. Drug–drug interactions commonly arise from major cytochrome P450 (CYP) inhibition. Various approaches are routinely employed in order to reduce the incidence of [...] Read more.

Roughly 2.8% of annual hospitalizations are a result of adverse drug interactions in the United States, representing more than 245,000 hospitalizations. Drug–drug interactions commonly arise from major cytochrome P450 (CYP) inhibition. Various approaches are routinely employed in order to reduce the incidence of adverse interactions, such as altering drug dosing schemes and/or minimizing the number of drugs prescribed; however, often, a reduction in the number of medications cannot be achieved without impacting therapeutic outcomes. Nearly 80% of drugs fail in development due to pharmacokinetic issues, outlining the importance of examining cytochrome interactions during preclinical drug design. In this review, we examined the physiochemical and structural properties of small molecule inhibitors of CYPs 3A4, 2D6, 2C19, 2C9, and 1A2. Although CYP inhibitors tend to have distinct physiochemical properties and structural features, these descriptors alone are insufficient to predict major cytochrome inhibition probability and affinity. Machine learning based in silico approaches may be employed as a more robust and accurate way of predicting CYP inhibition. These various approaches are highlighted in the review. Full article

(This article belongs to the Special Issue The Prediction of Pharmacokinetics/Pharmacodynamics Using In-Silico Modeling)

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36 pages, 3594 KiB

Open AccessReview

Physicochemical Features and Peculiarities of Interaction of AMP with the Membrane

by Malak Pirtskhalava, Boris Vishnepolsky, Maya Grigolava and Grigol Managadze

Pharmaceuticals 2021, 14(5), 471; https://doi.org/10.3390/ph14050471 - 17 May 2021

Cited by 55 | Viewed by 5480

Abstract

Antimicrobial peptides (AMPs) are anti-infectives that have the potential to be used as a novel and untapped class of biotherapeutics. Modes of action of antimicrobial peptides include interaction with the cell envelope (cell wall, outer- and inner-membrane). A comprehensive understanding of the peculiarities [...] Read more.

Antimicrobial peptides (AMPs) are anti-infectives that have the potential to be used as a novel and untapped class of biotherapeutics. Modes of action of antimicrobial peptides include interaction with the cell envelope (cell wall, outer- and inner-membrane). A comprehensive understanding of the peculiarities of interaction of antimicrobial peptides with the cell envelope is necessary to perform a rational design of new biotherapeutics, against which working out resistance is hard for microbes. In order to enable de novo design with low cost and high throughput, in silico predictive models have to be invoked. To develop an efficient predictive model, a comprehensive understanding of the sequence-to-function relationship is required. This knowledge will allow us to encode amino acid sequences expressively and to adequately choose the accurate AMP classifier. A shared protective layer of microbial cells is the inner, plasmatic membrane. The interaction of AMP with a biological membrane (native and/or artificial) has been comprehensively studied. We provide a review of mechanisms and results of interactions of AMP with the cell membrane, relying on the survey of physicochemical, aggregative, and structural features of AMPs. The potency and mechanism of AMP action are presented in terms of amino acid compositions and distributions of the polar and apolar residues along the chain, that is, in terms of the physicochemical features of peptides such as hydrophobicity, hydrophilicity, and amphiphilicity. The survey of current data highlights topics that should be taken into account to come up with a comprehensive explanation of the mechanisms of action of AMP and to uncover the physicochemical faces of peptides, essential to perform their function. Many different approaches have been used to classify AMPs, including machine learning. The survey of knowledge on sequences, structures, and modes of actions of AMP allows concluding that only possessing comprehensive information on physicochemical features of AMPs enables us to develop accurate classifiers and create effective methods of prediction. Consequently, this knowledge is necessary for the development of design tools for peptide-based antibiotics. Full article

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25 pages, 2156 KiB

Open AccessReview

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

by Nirmala Tilija Pun and Chul-Ho Jeong

Pharmaceuticals 2021, 14(5), 470; https://doi.org/10.3390/ph14050470 - 16 May 2021

Cited by 41 | Viewed by 7212

Abstract

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., [...] Read more.

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations. Full article

(This article belongs to the Special Issue Statins Use and Cancer)

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14 pages, 3133 KiB

Open AccessArticle

The Embryonic Chick Femur Organotypic Model as a Tool to Analyze the Angiotensin II Axis on Bone Tissue

by Thais Francini Garbieri, Victor Martin, Carlos Ferreira Santos, Pedro de Sousa Gomes and Maria Helena Fernandes

Pharmaceuticals 2021, 14(5), 469; https://doi.org/10.3390/ph14050469 - 16 May 2021

Cited by 5 | Viewed by 2777

Abstract

Activation of renin–angiotensin system (RAS) plays a role in bone deterioration associated with bone metabolic disorders, via increased Angiotensin II (AngII) targeting Angiotensin II type 1 receptor/Angiotensin II type 2 receptor (AT1R/AT2R). Despite the wide data availability, the RAS role remains controversial. This [...] Read more.

Activation of renin–angiotensin system (RAS) plays a role in bone deterioration associated with bone metabolic disorders, via increased Angiotensin II (AngII) targeting Angiotensin II type 1 receptor/Angiotensin II type 2 receptor (AT1R/AT2R). Despite the wide data availability, the RAS role remains controversial. This study analyzes the feasibility of using the embryonic chick femur organotypic model to address AngII/AT1R/AT2R axis in bone, which is an application not yet considered. Embryonic day-11 femurs were cultured ex vivo for 11 days in three settings: basal conditions, exposure to AngII, and modulation of AngII effects by prior receptor blockade, i.e., AT1R, AT2R, and AT1R + AT2R. Tissue response was evaluated by combining µCT and histological analysis. Basal-cultured femurs expressed components of RAS, namely ACE, AT1R, AT2R, and MasR (qPCR analysis). Bone formation occurred in the diaphyseal region in all conditions. In basal-cultured femurs, AT1R blocking increased Bone Surface/Bone Volume (BS/BV), whereas Bone Volume/Tissue Volume (BV/TV) decreased with AT2R or AT1R + AT2R blockade. Exposure to AngII greatly decreased BV/TV compared to basal conditions. Receptor blockade prior to AngII addition prevented this effect, i.e., AT1R blockade induced BV/TV, whereas blocking AT2R caused lower BV/TV increase but greater BS/BV; AT1R + AT2R blockade also improved BV/TV. Concluding, the embryonic chick femur model was sensitive to three relevant RAS research setups, proving its usefulness to address AngII/AT1R/AT2R axis in bone both in basal and activated conditions. Full article

(This article belongs to the Special Issue Cell-Based Therapies for Bone and Cartilage Regeneration)

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23 pages, 10136 KiB

Open AccessArticle

Synthesis, Physicochemical Characteristics and Plausible Mechanism of Action of an Immunosuppressive Isoxazolo[5,4-e]-1,2,4-Triazepine Derivative (RM33)

by Marcin Mączyński, Andrzej Regiec, Aleksandra Sochacka-Ćwikła, Iwona Kochanowska, Maja Kocięba, Ewa Zaczyńska, Jolanta Artym, Wojciech Kałas and Michał Zimecki

Pharmaceuticals 2021, 14(5), 468; https://doi.org/10.3390/ph14050468 - 15 May 2021

Cited by 6 | Viewed by 2827

Abstract

Previous studies demonstrated strong anti-inflammatory properties of isoxazolo[5,4-e]-1,2,4-triazepine (RM33) in vivo. The aim of this investigation was to describe synthesis, determine physicochemical characteristics, evaluate biological activities in murine and human in vitro models, as well as to propose mechanism of action of the [...] Read more.

Previous studies demonstrated strong anti-inflammatory properties of isoxazolo[5,4-e]-1,2,4-triazepine (RM33) in vivo. The aim of this investigation was to describe synthesis, determine physicochemical characteristics, evaluate biological activities in murine and human in vitro models, as well as to propose mechanism of action of the compound. The compound was devoid of cell toxicity up to 100 μg/mL against a reference A549 cell line. Likewise, RM33 did not induce apoptosis in these cells. The compound stimulated concanavalin A (ConA)-induced splenocyte proliferation but did not change the secondary humoral immune response in vitro to sheep erythrocytes. Nevertheless, a low suppressive effect was registered on lipopolysaccharide (LPS)-induced splenocyte proliferation and a stronger one on tumor necrosis factor alpha (TNFα) production by rat peritoneal cells. The analysis of signaling pathways elicited by RM33 in nonstimulated resident cells and cell lines revealed changes associated with cell activation. Most importantly, we demonstrated that RM33 enhanced production of cyclooxygenase 2 in LPS-stimulated splenocytes. Based on the previous and herein presented results, we conclude that RM33 is an efficient, nontoxic immune suppressor with prevailing anti-inflammatory action. Additionally, structural studies were carried out with the use of appropriate spectral techniques in order to unequivocally confirm the structure of the RM33 molecule. Unambiguous assignment of NMR chemical shifts of carbon atoms of RM33 was conducted thanks to full detailed analysis of ¹H, ¹³C NMR spectra and their two-dimensional (2D) variants. Comparison between theoretically predicted chemical shifts and experimental ones was also carried out. Additionally, N-deuterated isotopologue of RM33 was synthesized to eliminate potentially disturbing frequencies (such as NH, NH₂ deformation vibrations) in the carbonyl region of the IR (infrared) spectrum to confirm the presence of the carbonyl group. Full article

(This article belongs to the Section Medicinal Chemistry)

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25 pages, 6082 KiB

Open AccessArticle

A Newfangled Collagenase Inhibitor Topical Formulation Based on Ethosomes with Sambucus nigra L. Extract

by Ana Henriques Mota, Inês Prazeres, Henrique Mestre, Andreia Bento-Silva, Maria João Rodrigues, Noélia Duarte, Ana Teresa Serra, Maria Rosário Bronze, Patrícia Rijo, Maria Manuela Gaspar, Ana Silveira Viana, Lia Ascensão, Pedro Pinto, Pradeep Kumar, António José Almeida and Catarina Pinto Reis

Pharmaceuticals 2021, 14(5), 467; https://doi.org/10.3390/ph14050467 - 15 May 2021

Cited by 11 | Viewed by 4013

Abstract

Sambucus nigra L. (S. nigra) is a shrub widespread in Europe and western Asia, traditionally used in medicine, that has become popular in recent years as a potential source of a wide range of interesting bioactive compounds. The aim of the [...] Read more.

Sambucus nigra L. (S. nigra) is a shrub widespread in Europe and western Asia, traditionally used in medicine, that has become popular in recent years as a potential source of a wide range of interesting bioactive compounds. The aim of the present work was to develop a topical S. nigra extract formulation based on ethosomes and thus to support its health claims with scientific evidence. S. nigra extract was prepared by an ultrasound-assisted method and then included in ethosomes. The ethosomes were analyzed in terms of their size, stability over time, morphology, entrapment capacity (EC), extract release profile, stability over time and several biological activities. The prepared ethosomes were indicated to be well defined, presenting sizes around 600 nm. The extract entrapment capacity in ethosomes was 73.9 ± 24.8%, with an interesting slow extract release profile over 24 h. The extract-loaded ethosomes presented collagenase inhibition activity and a very good skin compatibility after human application. This study demonstrates the potential use of S. nigra extract incorporated in ethosomes as a potential cosmeceutical ingredient and on further studies should be performed to better understand the impact of S. nigra compounds on skin care over the time. 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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14 pages, 1146 KiB

Open AccessArticle

Development and Validation of an RP-HPLC-PDA Method for Determination of Paracetamol, Caffeine and Tramadol Hydrochloride in Pharmaceutical Formulations

by Fernando J. Pereira, Aida Rodríguez-Cordero, Roberto López, Luis C. Robles and A. Javier Aller

Pharmaceuticals 2021, 14(5), 466; https://doi.org/10.3390/ph14050466 - 15 May 2021

Cited by 31 | Viewed by 6924

Abstract

Paracetamol (acetaminophen) (PAR), caffeine (CAF) and tramadol hydrochloride (TRA) are important drugs widely used for many clinical purposes. Determination of their contents is of the paramount interest. In this respect, a quick, simple and sensitive isocratic RP-HPLC method with photodiode array detection was [...] Read more.

Paracetamol (acetaminophen) (PAR), caffeine (CAF) and tramadol hydrochloride (TRA) are important drugs widely used for many clinical purposes. Determination of their contents is of the paramount interest. In this respect, a quick, simple and sensitive isocratic RP-HPLC method with photodiode array detection was developed for the determination of paracetamol, caffeine and tramadol in pharmaceutical formulations. An improved sensitive procedure was also evolved for tramadol using a fluorescence detector system. A C₁₈ column and a mobile phase constituted by methanol/phosphate were used. LODs were found to be 0.2 μg/mL, 0.1 μg/mL and 0.3 μg/mL for paracetamol, caffeine and tramadol hydrochloride, respectively, using photodiode-array detection. Alternatively, LOD for tramadol decreased to 0.1 μg/mL with the fluorescence detector. Other notable analytical figures of merit include the linear concentration ranges, 0.8–270 μg/mL, 0.4–250 μg/mL and 1.0–300 (0.2–40) μg/mL, for the same ordered analytes (including the fluorescence detector). The proposed method was successfully applied for the quantitative determination of the three drugs in tablet dosage forms. Full article

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

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17 pages, 6251 KiB

Open AccessArticle

Evaluation of the Wound Healing Potential of Some Natural Polymers on Three Experimental Models

by Calin Vasile Andritoiu, Corina Elena Andriescu, Maricel Danu, Cristina Lungu, Bianca Ivanescu, Cornel Havarneanu and Marcel Popa

Pharmaceuticals 2021, 14(5), 465; https://doi.org/10.3390/ph14050465 - 14 May 2021

Cited by 4 | Viewed by 3445

Abstract

The aim of this paper was the preparation and investigation of the wound healing properties of four topical formulations based on natural polymers such as collagen, chitosan, lyophilized egg white, and a mixture of them. The therapeutic assessment of these four ointments was [...] Read more.

The aim of this paper was the preparation and investigation of the wound healing properties of four topical formulations based on natural polymers such as collagen, chitosan, lyophilized egg white, and a mixture of them. The therapeutic assessment of these four ointments was carried out in vivo on the incision, excision, and thermal burn wounds induced on Wistar rats. The treatment was applied topically on wounds once a day, for 21 days. The experimental results were analyzed from a clinical and histopathological point of view. The rheological characterization of the topical formulations was also performed in order to verify their spreadability and structural stability. All ointments had a positive effect on wound contraction and re-epithelization processes, but the one based on total polymers had a significant healing potential on the designed cutaneous lesions due to its synergistic effects. Full article

(This article belongs to the Special Issue Formulations for Wound Healing)

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16 pages, 487 KiB

Open AccessFeature PaperArticle

Adequacy of Anesthesia Guidance for Colonoscopy Procedures

by Michał Jan Stasiowski, Małgorzata Starzewska, Ewa Niewiadomska, Seweryn Król, Kaja Marczak, Jakub Żak, Aleksandra Pluta, Jerzy Eszyk, Beniamin Oskar Grabarek, Izabela Szumera, Michał Nycz, Anna Missir, Lech Krawczyk and Przemysław Jałowiecki

Pharmaceuticals 2021, 14(5), 464; https://doi.org/10.3390/ph14050464 - 14 May 2021

Cited by 9 | Viewed by 3315

Abstract

In patients undergoing colonoscopy procedures (CPs), inadequate dosing of hypnotic drugs (HD) and opioid analgesics (OA) during intravenous sedoanalgesia (ISA) may lead to intraprocedural awareness with recall (IAwR), intraprocedural (IPP) and postprocedural pain (PPP), as well as postoperative nausea and vomiting (PONV). The [...] Read more.

In patients undergoing colonoscopy procedures (CPs), inadequate dosing of hypnotic drugs (HD) and opioid analgesics (OA) during intravenous sedoanalgesia (ISA) may lead to intraprocedural awareness with recall (IAwR), intraprocedural (IPP) and postprocedural pain (PPP), as well as postoperative nausea and vomiting (PONV). The aim of this study was to evaluate whether the titration of HD and OA based on the observance of changing values of state entropy (SE) and surgical pleth index (SPI) (adequacy of anesthesia—AoA), state entropy alone, or standard practice may reduce the number of adverse events. One hundred and fifty-eight patients were included in the final analysis. The rate of IAwR and IPP was statistically more frequent in patients from the C group in comparison with the AoA and SE groups (p < 0.01 and p < 0.05, respectively). In turn, the rate of PPP, PONV, and patients’ and operators’ satisfaction with ISA between groups was not statistically significant (p > 0.05). Changes in hemodynamic parameters, demand for HD, and OA were statistically significant, but of no clinical value. In patients undergoing CPs under ISA using propofol and FNT, as compared to standard practice, intraprocedural SE monitoring reduced the rate of IAwR and IPP, with no influence on the rate of PPP, PONV, or patients’ and endoscopists’ satisfaction. AoA guidance on propofol and FNT titration, as compared to SE monitoring only, did not reduce the occurrence of the aforementioned studied parameters, imposing an unnecessary extra cost. Full article

(This article belongs to the Section Pharmacology)

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9 pages, 1306 KiB

Open AccessArticle

Potential Role of Methotrexate Polyglutamates in Therapeutic Drug Monitoring for Pediatric Inflammatory Bowel Disease

by Ryan Morrow, Ryan Funk, Mara Becker, Ashley Sherman, Leon Van Haandel, Taina Hudson, Rebecca Casini and Valentina Shakhnovich

Pharmaceuticals 2021, 14(5), 463; https://doi.org/10.3390/ph14050463 - 14 May 2021

Cited by 5 | Viewed by 2641

Abstract

Inside cells, the immunomodulator methotrexate (MTX) undergoes the addition of glutamates to form methotrexate polyglutamates (MTX-Glu)—promising biomarkers of systemic exposure and treatment response to MTX in rheumatology. MTX-Glu are underexplored in Inflammatory Bowel Disease (IBD), with no data in pediatrics. In this cross-sectional [...] Read more.

Inside cells, the immunomodulator methotrexate (MTX) undergoes the addition of glutamates to form methotrexate polyglutamates (MTX-Glu)—promising biomarkers of systemic exposure and treatment response to MTX in rheumatology. MTX-Glu are underexplored in Inflammatory Bowel Disease (IBD), with no data in pediatrics. In this cross-sectional secondary analysis, we assessed the relationships between MTX-Glu and MTX dose and treatment response in pediatric IBD. Twenty-one children with IBD, receiving maintenance therapy with infliximab (IFX) and MTX, had MTX-Glu_1–6 concentrations and IFX troughs/antibodies measured and disease activity assessed for comparison in remission vs. active IBD using non-parametric tests, with associations explored using Spearman’s correlation (ρ) and regression analyses; SASv9.4 (α = 0.05). Total and long-chain MTX-Glu correlated with MTX dose (ρ = 0.51 and 0.56, respectively; p ≤ 0.02). In children with Crohn’s disease (n = 19), short-chain MTX-Glu_1–2 were 2.5-fold higher in remission vs. active disease, approaching statistical significance (p = 0.066), with no statistical differences in IFX trough (p = 0.549) between groups. Our study highlights a potential role for long-chain MTX-Glu in the therapeutic drug monitoring of MTX in IBD. It is the first study in pediatric IBD and, although statistical significance was not reached, our findings also suggest that higher short-chain MTX-Glu levels may be associated with IBD treatment response to MTX in children. Full article

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

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13 pages, 1572 KiB

Open AccessArticle

Analysis of Cannabinoids Concentration in Cannabis Oil Galenic Preparations: Harmonization between Three Laboratories in Northern Italy

by Alice Palermiti, Alessia Cafaro, Sebastiano Barco, Paolo Bucchioni, Paolo Franceschini, Jessica Cusato, Amedeo De Nicolò, Alessandra Manca, Elisa Delia De Vivo, Eleonora Russo, Francesco Cecchi, Federica Pigliasco, Flavia Lillo, Gino Tripodi, Antonio D’Avolio and Giuliana Cangemi

Pharmaceuticals 2021, 14(5), 462; https://doi.org/10.3390/ph14050462 - 14 May 2021

Cited by 12 | Viewed by 3443

Abstract

Medical cannabis is increasingly being used in the treatment and support of several diseases and syndromes. The quantitative determination of active ingredients (delta-9 tetrahydrocannabinol, THC, and cannabidiol, CBD) in galenic oily preparations is prescribed by law for each produced batch. The aim of [...] Read more.

Medical cannabis is increasingly being used in the treatment and support of several diseases and syndromes. The quantitative determination of active ingredients (delta-9 tetrahydrocannabinol, THC, and cannabidiol, CBD) in galenic oily preparations is prescribed by law for each produced batch. The aim of this work is to describe the organization of the titration activity centralized at three regional reference laboratories in Northern Italy. Pre-analytical, analytical, and post-analytical phases have been defined in order to guarantee high quality standards. A cross-validation between laboratories allowed for the definition of the procedures that guarantee the interchangeability between reference laboratories. The risk management protocol adopted can be useful for others who need to undertake this activity. Full article

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

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45 pages, 2549 KiB

Open AccessReview

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

by Klaudia T. Angula, Lesetja J. Legoabe and Richard M. Beteck

Pharmaceuticals 2021, 14(5), 461; https://doi.org/10.3390/ph14050461 - 13 May 2021

Cited by 32 | Viewed by 6108

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration [...] Read more.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern; herein, we have compiled drug-drug interaction reports, as well as efficacy reports for drug combinations studies involving antitubercular agents in clinical development. Full article

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

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Pharmaceuticals, Volume 14, Issue 5 (May 2021) – 106 articles

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