Pharmaceuticals

22 pages, 3478 KiB

Open AccessArticle

Native RNA Purification Method for Small RNA Molecules Based on Asymmetrical Flow Field-Flow Fractionation

by Alesia A. Levanova, Mirka Lampi, Kiira Kalke, Veijo Hukkanen, Minna M. Poranen and Katri Eskelin

Pharmaceuticals 2022, 15(2), 261; https://doi.org/10.3390/ph15020261 - 21 Feb 2022

Cited by 7 | Viewed by 3299

Abstract

RNA molecules provide promising new possibilities for the prevention and treatment of viral infections and diseases. The rapid development of RNA biology and medicine requires advanced methods for the purification of RNA molecules, which allow fast and efficient RNA processing, preferably under non-denaturing [...] Read more.

RNA molecules provide promising new possibilities for the prevention and treatment of viral infections and diseases. The rapid development of RNA biology and medicine requires advanced methods for the purification of RNA molecules, which allow fast and efficient RNA processing, preferably under non-denaturing conditions. Asymmetrical flow field-flow fractionation (AF4) enables gentle separation and purification of macromolecules based on their diffusion coefficients. The aim of the study was to develop an AF4 method for efficient purification of enzymatically produced antiviral small interfering (si)RNA molecules and to evaluate the overall potential of AF4 in the separation of short single-stranded (ss) and double-stranded (ds) RNA molecules. We show that AF4 separates monomeric ssRNA from dsRNA molecules of the same size and monomeric ssRNA from multimeric forms of the same ssRNA. The developed AF4 method enabled the separation of enzymatically produced 27-nt siRNAs from partially digested substrate dsRNA, which is potentially toxic for mammalian cells. The recovery of AF4-purified enzymatically produced siRNA molecules was about 70%, which is about 20% higher than obtained using anion-exchange chromatography. The AF4-purified siRNAs were not toxic for mammalian cells and fully retained their biological activity as confirmed by efficient inhibition of herpes simplex virus 1 replication in cell culture. Our work is the first to develop AF4 methods for the separation of short RNA molecules. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery and Development of Biomolecules as Antiviral Drugs)

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21 pages, 9761 KiB

Open AccessArticle

Human Cryptic Host Defence Peptide GVF27 Exhibits Anti-Infective Properties against Biofilm Forming Members of the Burkholderia cepacia Complex

by Andrea Bosso, Rosa Gaglione, Rocco Di Girolamo, Edwin J. A. Veldhuizen, Pilar García-Vello, Salvatore Fusco, Valeria Cafaro, Maria Monticelli, Rosanna Culurciello, Eugenio Notomista, Angela Arciello and Elio Pizzo

Pharmaceuticals 2022, 15(2), 260; https://doi.org/10.3390/ph15020260 - 21 Feb 2022

Cited by 5 | Viewed by 2663

Abstract

Therapeutic solutions to counter Burkholderia cepacia complex (Bcc) bacteria are challenging due to their intrinsically high level of antibiotic resistance. Bcc organisms display a variety of potential virulence factors, have a distinct lipopolysaccharide naturally implicated in antimicrobial resistance. and are able to form [...] Read more.

Therapeutic solutions to counter Burkholderia cepacia complex (Bcc) bacteria are challenging due to their intrinsically high level of antibiotic resistance. Bcc organisms display a variety of potential virulence factors, have a distinct lipopolysaccharide naturally implicated in antimicrobial resistance. and are able to form biofilms, which may further protect them from both host defence peptides (HDPs) and antibiotics. Here, we report the promising anti-biofilm and immunomodulatory activities of human HDP GVF27 on two of the most clinically relevant Bcc members, Burkholderia multivorans and Burkholderia cenocepacia. The effects of synthetic and labelled GVF27 were tested on B. cenocepacia and B. multivorans biofilms, at three different stages of formation, by confocal laser scanning microscopy (CLSM). Assays on bacterial cultures and on human monocytes challenged with B. cenocepacia LPS were also performed. GVF27 exerts, at different stages of formation, anti-biofilm effects towards both Bcc strains, a significant propensity to function in combination with ciprofloxacin, a relevant affinity for LPSs isolated from B. cenocepacia as well as a good propensity to mitigate the release of pro-inflammatory cytokines in human cells pre-treated with the same endotoxin. Overall, all these findings contribute to the elucidation of the main features that a good therapeutic agent directed against these extremely leathery biofilm-forming bacteria should possess. Full article

(This article belongs to the Section Biopharmaceuticals)

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15 pages, 8015 KiB

Open AccessArticle

Synthesis, Characterization and Host-Guest Complexation of Asplatin: Improved In Vitro Cytotoxicity and Biocompatibility as Compared to Cisplatin

by Sherif Ashraf Fahmy, Fortuna Ponte, Giulia Grande, Iten M. Fawzy, Asmaa A. Mandour, Emilia Sicilia and Hassan Mohamed El-Said Azzazy

Pharmaceuticals 2022, 15(2), 259; https://doi.org/10.3390/ph15020259 - 21 Feb 2022

Cited by 15 | Viewed by 2863

Abstract

Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, [...] Read more.

Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, it has been characterized using ¹H NMR, mass spectrometry, elemental analysis, and UHPLC. A host-guest complex of asplatin and p-sulfocalix[4]arene (PSC4) has been developed and characterized using UV, Job’s plot analysis, HPLC, and density functional theory (DFT) calculations. The experimental and computational investigations propose that a 1:1 complex between asplatin and PSC4 is formed. The stability constant of the designed complex has been determined using Job’s plot and UHPLC and computed to be 9.1 × 10⁴ M^–1 and 8.7 × 10⁴ M⁻¹, which corresponds to a free energy of complexation of −6.8 kcal mol^–1, while the calculated value for the inclusion free energy is −13.2 kcal mol⁻¹. Both experimentally and theoretically estimated complexation free energy show that a stable host-guest complex can be formed in solution. The in vitro drug release study displayed the ability of the complex to release its cargo at a cancerous pH (pH of 5.5). Additionally, the asplatin/PSC4 complex is shown to be biocompatible when tested on human skin fibroblast noncancerous cells, demonstrating the highest in vitro cytotoxic activity against (MCF-7), cervical (HeLa), and lung cancer cells (A-549), with IC₅₀ values of 0.75, 2.15, and 3.60 µg/mL, respectively. This is as compared to either cisplatin (IC₅₀ of 5.47, 5.94 and 9.61 µg/mL, respectively) or asplatin (IC₅₀ of 1.54, 5.05 and 3.91 µg/mL, respectively). On the other hand, the free asplatin exhibited higher cytotoxicity on cancerous cells and lower toxicity on noncancerous cells. The outcomes of the present joint theoretical and experimental investigation reinforce the interest in platinum-based anticancer therapeutics when they are protected from undesired interactions and suggest the use of the PSC4 macromolecule as a promising carrier for Pt(IV) anticancer drugs. The formed asplatin/PSC4 inclusion complex may represent an effective chemotherapeutic agent. Full article

(This article belongs to the Section Medicinal Chemistry)

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13 pages, 18165 KiB

Open AccessArticle

Potential Anti-SARS-CoV-2 Activity of Pentosan Polysulfate and Mucopolysaccharide Polysulfate

by Fuming Zhang, Peng He, Andre L. Rodrigues, Walter Jeske, Ritesh Tandon, John T. Bates, Michael A. Bierdeman, Jawed Fareed, Jonathan Dordick and Robert J. Linhardt

Pharmaceuticals 2022, 15(2), 258; https://doi.org/10.3390/ph15020258 - 21 Feb 2022

Cited by 25 | Viewed by 3865

Abstract

With the increased prevalence of new SARS-CoV-2 variants of concern, such as Delta and Omicron, the COVID-19 pandemic has become an ongoing human health disaster, killing millions worldwide. SARS-CoV-2 invades its host through the interaction of its spike (S) protein with a host [...] Read more.

With the increased prevalence of new SARS-CoV-2 variants of concern, such as Delta and Omicron, the COVID-19 pandemic has become an ongoing human health disaster, killing millions worldwide. SARS-CoV-2 invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition, heparan sulfate (HS) on the surface of host cells plays an important role as a co-receptor for this viral pathogen–host cell interaction. Our previous studies demonstrated that many sulfated glycans, such as heparin, fucoidans, and rhamnan sulfate have anti-SARS-CoV-2 activities. In the current study, a small library of sulfated glycans and highly negatively charged compounds, including pentosan polysulfate (PPS), mucopolysaccharide polysulfate (MPS), sulfated lactobionic acid, sulodexide, and defibrotide, was assembled and evaluated for binding to the S-proteins and inhibition of viral infectivity in vitro. These compounds inhibited the interaction of the S-protein receptor-binding domain (RBD) (wild type and different variants) with immobilized heparin, a highly sulfated HS, as determined using surface plasmon resonance (SPR). PPS and MPS showed the strongest inhibition of interaction of heparin and S-protein RBD. The competitive binding studies showed that the IC₅₀ of PPS and MPS against the S-protein RBD binding to immobilized heparin was ~35 nM and ~9 nM, respectively, much lower than the IC₅₀ for soluble heparin (IC₅₀ = 56 nM). Both PPS and MPS showed stronger inhibition than heparin on the S-protein RBD or spike pseudotyped lentiviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, PPS and MPS exhibited strong antiviral activities against pseudotyped viral particles of SARS-CoV-2 containing wild-type or Delta S-proteins. Full article

(This article belongs to the Topic Broad-Spectrum Antiviral Agents)

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15 pages, 1524 KiB

Open AccessArticle

A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity

by Harrison T. Shanley, Aya C. Taki, Joseph J. Byrne, Abdul Jabbar, Tim N. C. Wells, Kirandeep Samby, Peter R. Boag, Nghi Nguyen, Brad E. Sleebs and Robin B. Gasser

Pharmaceuticals 2022, 15(2), 257; https://doi.org/10.3390/ph15020257 - 21 Feb 2022

Cited by 12 | Viewed by 3342

Abstract

Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread [...] Read more.

Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the ‘Pandemic Response Box’ (from Medicines for Malaria Venture, MMV) for activity against H. contortus and its free-living relative, Caenorhabditis elegans—a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of H. contortus and C. elegans. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of H. contortus larvae (IC₅₀ = 3.4 ± 1.1 μM) and young adults of C. elegans (IC₅₀ = 7.1 ± 4.6 μM), and the development of H. contortus larvae (IC₅₀ = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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18 pages, 3975 KiB

Open AccessArticle

Population Pharmacokinetics of Hydroxychloroquine and 3 Metabolites in COVID-19 Patients and Pharmacokinetic/Pharmacodynamic Application

by Jean Claude Alvarez, Benjamin Davido, Pierre Moine, Isabelle Etting, Djillali Annane, Islam Amine Larabi and Nicolas Simon

Pharmaceuticals 2022, 15(2), 256; https://doi.org/10.3390/ph15020256 - 21 Feb 2022

Cited by 3 | Viewed by 2417

Abstract

We develop a population pharmacokinetic model for hydroxychloroquine (HCQ) and three of its metabolites (desethylhydroxychloroquine, Des HCQ; desethylchloroquine, DesCQ; and didesethylchloroquine, didesCQ) in COVID-19 patients in order to determine whether a pharmacokinetic (PK)/pharmacodynamic (PD) relationship was present. The population PK of HCQ was [...] Read more.

We develop a population pharmacokinetic model for hydroxychloroquine (HCQ) and three of its metabolites (desethylhydroxychloroquine, Des HCQ; desethylchloroquine, DesCQ; and didesethylchloroquine, didesCQ) in COVID-19 patients in order to determine whether a pharmacokinetic (PK)/pharmacodynamic (PD) relationship was present. The population PK of HCQ was described using non-linear mixed effects modelling. The duration of hospitalization, the number of deaths, and poor clinical outcomes (death, transfer to ICU, or hospitalization ≥ 10 d) were evaluated as PD parameters. From 100 hospitalized patients (age = 60.7 ± 16 y), 333 BHCQ and M were available for analysis. The data for BHCQ were best described by a four-compartment model with a first-order input (KA) and a first-order output. For M, the better model of the data used one compartment for each metabolite with a first-order input from HCQ and a first-order output. The fraction of HCQ converted to the metabolites was 75%. A significant relationship was observed between the duration of hospitalization and BHCQ at 48 h (r² = 0.12; p = 0.0052) or 72 h (r² = 0.16; p = 0.0012). At 48 h or 72 h, 87% or 91% of patients vs. 63% or 62% had a duration < 25 d with a BHCQ higher or below 200 μg/L, respectively. Clinical outcome was significantly related to BHCQ at 48 h (good outcome 369 +/− 181 μg/L vs. poor 285 +/− 144 μg/L; p = 0.0441) but not at 72 h (407 +/− 207 μg/L vs. 311 +/− 174 μg/L; p = 0.0502). The number of deaths was not significantly different according to the trough concentration (p = 0.972 and 0.836 for 48 h and 72 h, respectively). Full article

(This article belongs to the Section Pharmacology)

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14 pages, 665 KiB

Open AccessReview

Gender and Sex-Related Differences in Normal Tissue Effects Induced by Platinum Compounds

by Loredana G. Marcu

Pharmaceuticals 2022, 15(2), 255; https://doi.org/10.3390/ph15020255 - 20 Feb 2022

Cited by 15 | Viewed by 2911

Abstract

Gender medicine in the field of oncology is an under-researched area, despite the existing evidence towards gender-dependent response to therapy and treatment-induced adverse effects. Oncological treatment aims to fulfil its main goal of achieving high tumour control by also protecting normal tissue from [...] Read more.

Gender medicine in the field of oncology is an under-researched area, despite the existing evidence towards gender-dependent response to therapy and treatment-induced adverse effects. Oncological treatment aims to fulfil its main goal of achieving high tumour control by also protecting normal tissue from acute or chronic damage. Chemotherapy is an important component of cancer treatment, with a large number of drugs being currently in clinical use. Cisplatin is one of the most commonly employed chemotherapeutic agents, used either as a sole drug or in combination with other agents. Cisplatin-induced toxicities are well documented, and they include nephrotoxicity, neurotoxicity, gastrointestinal toxicity, ototoxicity, just to name the most frequent ones. Some of these toxicities have short-term sequelae, while others are irreversible. Furthermore, research showed that there is a strong gender-dependent aspect of side effects caused by the administration of cisplatin. While evidence towards sex differences in animal models is substantial, clinical studies considering sex/gender as a variable factor are limited. This work summarises the current knowledge on sex/gender-related side effects induced by platinum compounds and highlights the gaps in research that require more attention to open new therapeutic possibilities and preventative measures to alleviate normal tissue toxicity and increase patients’ quality of life in both males and females. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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18 pages, 3524 KiB

Open AccessArticle

Ethanolic Fenugreek Extract: Its Molecular Mechanisms against Skin Aging and the Enhanced Functions by Nanoencapsulation

by Waleewan Eaknai, Phichaporn Bunwatcharaphansakun, Chutikorn Phungbun, Angkana Jantimaporn, Sasikan Chaisri, Suwimon Boonrungsiman, Ubonthip Nimmannit and Mattaka Khongkow

Pharmaceuticals 2022, 15(2), 254; https://doi.org/10.3390/ph15020254 - 20 Feb 2022

Cited by 7 | Viewed by 9430

Abstract

Fenugreek, or Trigonella foenum-graecum L. (family Leguminosae) seeds, are typically used as food supplements to increase postnatal lactation. Fenugreek extract displays antioxidative and anti-inflammatory properties, but its mechanisms against skin aging have not been exploited. In this research, we are the first to [...] Read more.

Fenugreek, or Trigonella foenum-graecum L. (family Leguminosae) seeds, are typically used as food supplements to increase postnatal lactation. Fenugreek extract displays antioxidative and anti-inflammatory properties, but its mechanisms against skin aging have not been exploited. In this research, we are the first to define an in vitro collagenase inhibitory activity of fenugreek extract (IC₅₀ = 0.57 ± 0.02 mg/mL), which is 2.6 times more potent than vitamin C (IC₅₀ = 1.46 mg/mL). Nanoencapsulation has been applied to improve the extract stability, and subsequently enhanced its bioactivities. Liponiosome encapsulating fenugreek extract (LNF) was prepared using a high-speed homogenizer, resulting in homogeneous spherical nanoparticles with sizes in the range of 174.7 ± 49.2 nm, 0.26 ± 0.04 in PdI, and 46.6 ± 7.4% of entrapment efficiency. LNF formulation significantly facilitated a sustained release and significantly enhanced skin penetration over the extracts, suggesting a potential use of LNF for transdermal delivery. The formulated LNF was highly stable, not toxic to human fibroblast, and was able to enhance cell viability, collagen production, and inhibit MMP1, MMP9, IL-6, and IL-8 secretions compared to the extract in the co-cultured skin model. Therefore, ethanolic fenugreek extract and its developed LNF display molecular mechanisms against skin aging and could potentially be used as an innovative ingredient for the prevention of skin aging. Full article

(This article belongs to the Special Issue Pharmaceuticals and Cosmeceuticals from Plants: Molecular Pharmacology and Toxicology)

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12 pages, 510 KiB

Open AccessArticle

Effects of Ultramicronized Palmitoylethanolamide (um-PEA) in COVID-19 Early Stages: A Case–Control Study

by Maria Albanese, Giulia Marrone, Agostino Paolino, Manuela Di Lauro, Francesca Di Daniele, Carlo Chiaramonte, Cartesio D’Agostini, Annalisa Romani, Alessandro Cavaliere, Cristina Guerriero, Andrea Magrini, Nicola Biagio Mercuri, Nicola Di Daniele and Annalisa Noce

Pharmaceuticals 2022, 15(2), 253; https://doi.org/10.3390/ph15020253 - 19 Feb 2022

Cited by 12 | Viewed by 4033

Abstract

Ultramicronized palmitoylethanolamide (um-PEA), a compound with antioxidant, anti-inflammatory and neuroprotective properties, appears to be a potential adjuvant treatment for early stages of Coronavirus disease 2019 (COVID-19). In our study, we enrolled 90 patients with confirmed diagnosis of COVID-19 that were randomized into two [...] Read more.

Ultramicronized palmitoylethanolamide (um-PEA), a compound with antioxidant, anti-inflammatory and neuroprotective properties, appears to be a potential adjuvant treatment for early stages of Coronavirus disease 2019 (COVID-19). In our study, we enrolled 90 patients with confirmed diagnosis of COVID-19 that were randomized into two groups, homogeneous for age, gender and BMI. The first group received oral supplementation based on um-PEA at a dose of 1800 mg/day for a total of 28 days; the second group was the control group (R.S. 73.20). At baseline (T0) and after 28 days of um-PEA treatment (T1), we monitored: routine laboratory parameters, inflammatory and oxidative stress (OS) biomarkers, lymphocytes subpopulation and COVID-19 serological response. At T1, the um-PEA-treated group presented a significant reduction in inflammation compared to the control group (CRP p = 0.007; IL-6 p = 0.0001; neutrophils to lymphocytes ratio p = 0.044). At T1, the controls showed a significant increase in OS compared to the treated group (FORT p = 0.05). At T1, the um-PEA group exhibited a significant decrease in D-dimer levels (p = 0.0001) and higher levels of IgG against SARS-CoV-2 (p = 0.0001) compared to the controls. Our data demonstrated, in a randomized clinical trial, the beneficial effects of um-PEA in both asymptomatic and mild-symptomatic patients related to reductions in inflammatory state, OS and coagulative cascade alterations. Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods with Pharmaceutical Interest 2022)

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11 pages, 823 KiB

Open AccessReview

The Potential Application of Extracellular Vesicles from Liquid Biopsies for Determination of Pharmacogene Expression

by Henok D. Habtemariam and Henk-Jan Guchelaar

Pharmaceuticals 2022, 15(2), 252; https://doi.org/10.3390/ph15020252 - 19 Feb 2022

Cited by 2 | Viewed by 2603

Abstract

Pharmacogenomics (PGx) entails the study of heritability of drug response. This may include both variability in genes related to pharmacokinetics (drug absorption, distribution, metabolism and excretion) and pharmacodynamics (e.g., drug receptors or signaling pathways). Individualizing drug therapy taking into account the genetic profile [...] Read more.

Pharmacogenomics (PGx) entails the study of heritability of drug response. This may include both variability in genes related to pharmacokinetics (drug absorption, distribution, metabolism and excretion) and pharmacodynamics (e.g., drug receptors or signaling pathways). Individualizing drug therapy taking into account the genetic profile of the patient has the potential to make drug therapy safer and more effective. Currently, this approach relies on the determination of genetic variants in pharmacogenes by genotyping. However, it is widely acknowledged that large variability in gene expression is attributed to non-structural genetic variants. Therefore, at least from a theoretical viewpoint individualizing drug therapy based upon expression of pharmacogenes rather than on genotype may be advantageous but has been difficult to implement in the clinical setting. Extracellular vesicles (EVs) are lipid encapsulated structures that contain cargo such as lipids, nucleic acids and proteins. Since their cargo is tissue- and cell-specific they can be used to determine the expression of pharmacogenes in the liver. In this review, we describe methods of EV isolation and the potential of EVs isolated from liquid biopsies as a tool to determine the expression of pharmacogenes for use in personalized medicine. Full article

(This article belongs to the Special Issue Clinical Utility of Applying PGx and Deprescribing-Based Decision Support in Polypharmacy: Future Perspectives)

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22 pages, 7256 KiB

Open AccessArticle

Experimental Evidence for Diiodohydroxyquinoline-Induced Neurotoxicity: Characterization of Age and Gender as Predisposing Factors

by Ahmed S. Kamel, Ahmed F. Mohamed, Mostafa A. Rabie, Marwa E. Elsherbiny, Kawkab A. Ahmed, Mahmoud M. Khattab and Noha F. Abdelkader

Pharmaceuticals 2022, 15(2), 251; https://doi.org/10.3390/ph15020251 - 19 Feb 2022

Cited by 5 | Viewed by 2563

Abstract

Though quinoline anti-infective agents-associated neurotoxicity has been reported in the early 1970s, it only recently received regulatory recognition. In 2019, the European Medicines Agency enforced strict use for quinoline antibiotics. Thus, the current study evaluates the relation between subacute exposure to diiodohydroxyquinoline (DHQ), [...] Read more.

Though quinoline anti-infective agents-associated neurotoxicity has been reported in the early 1970s, it only recently received regulatory recognition. In 2019, the European Medicines Agency enforced strict use for quinoline antibiotics. Thus, the current study evaluates the relation between subacute exposure to diiodohydroxyquinoline (DHQ), a commonly misused amebicide, with the development of motor and sensory abnormalities, highlighting age and gender as possible predisposing factors. Eighty rats were randomly assigned to eight groups according to their gender, age, and drug exposure; namely, four control groups received saline (adult male, adult female, young male, and young female), and the other four groups received DHQ. Young and adult rats received DHQ in doses of 176.7 and 247.4 mg/kg/day, respectively. After 4 weeks, rats were tested for sensory abnormality using analgesiometer, hot plate, and hind paw cold allodynia tests, and for motor function using open field and rotarod tests. Herein, the complex behavioral data were analyzed by principal component analysis to reduce the high number of variables to a lower number of representative factors that extracted components related to sensory, motor, and anxiety-like behavior. Behavioral outcomes were reflected in a histopathological examination of the cerebral cortex, striatum, spinal cord, and sciatic nerve, which revealed degenerative changes as well demyelination. Noteworthy, young female rats were more susceptible to DHQ’s toxicity than their counterparts. Taken together, these findings confirm previous safety concerns regarding quinoline-associated neurotoxicity and provide an impetus to review risk/benefit balance for their use. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 2079 KiB

Open AccessArticle

In Vitro–In Silico Modeling of Caffeine and Diclofenac Permeation in Static and Fluidic Systems with a 16HBE Lung Cell Barrier

by Lukas Kovar, Lena Wien, Dominik Selzer, Yvonne Kohl, Robert Bals and Thorsten Lehr

Pharmaceuticals 2022, 15(2), 250; https://doi.org/10.3390/ph15020250 - 18 Feb 2022

Cited by 2 | Viewed by 2136

Abstract

Static in vitro permeation experiments are commonly used to gain insights into the permeation properties of drug substances but exhibit limitations due to missing physiologic cell stimuli. Thus, fluidic systems integrating stimuli, such as physicochemical fluxes, have been developed. However, as fluidic in [...] Read more.

Static in vitro permeation experiments are commonly used to gain insights into the permeation properties of drug substances but exhibit limitations due to missing physiologic cell stimuli. Thus, fluidic systems integrating stimuli, such as physicochemical fluxes, have been developed. However, as fluidic in vitro studies display higher complexity compared to static systems, analysis of experimental readouts is challenging. Here, the integration of in silico tools holds the potential to evaluate fluidic experiments and to investigate specific simulation scenarios. This study aimed to develop in silico models that describe and predict the permeation and disposition of two model substances in a static and fluidic in vitro system. For this, in vitro permeation studies with a 16HBE cellular barrier under both static and fluidic conditions were performed over 72 h. In silico models were implemented and employed to describe and predict concentration–time profiles of caffeine and diclofenac in various experimental setups. For both substances, in silico modeling identified reduced apparent permeabilities in the fluidic compared to the static cellular setting. The developed in vitro–in silico modeling framework can be expanded further, integrating additional cell tissues in the fluidic system, and can be employed in future studies to model pharmacokinetic and pharmacodynamic drug behavior. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 4503 KiB

Open AccessArticle

Utilization of Polymeric Micelles as a Lucrative Platform for Efficient Brain Deposition of Olanzapine as an Antischizophrenic Drug via Intranasal Delivery

by Hadel A. Abo El-Enin, Marwa F. Ahmed, Ibrahim A. Naguib, Shaymaa W. El-Far, Mohammed M. Ghoneim, Izzeddin Alsalahat and Hend Mohamed Abdel-Bar

Pharmaceuticals 2022, 15(2), 249; https://doi.org/10.3390/ph15020249 - 18 Feb 2022

Cited by 10 | Viewed by 2939

Abstract

Schizophrenia is a mental disorder characterized by alterations in cognition, behavior and emotions. Oral olanzapine (OZ) administration is extensively metabolized (~up to 40% of the administrated dose). In addition, OZ is a P-glycoproteins substrate that impairs the blood–brain barrier (BBB) permeability. To direct [...] Read more.

Schizophrenia is a mental disorder characterized by alterations in cognition, behavior and emotions. Oral olanzapine (OZ) administration is extensively metabolized (~up to 40% of the administrated dose). In addition, OZ is a P-glycoproteins substrate that impairs the blood–brain barrier (BBB) permeability. To direct OZ to the brain and to minimize its systemic side effects, the nasal pathway is recommended. OZ-loaded polymeric micelles nano-carriers were developed using suitable biodegradable excipients. The developed micelles were physicochemically investigated to assess their appropriateness for intranasal delivery and the potential of these carriers for OZ brain targeting. The selected formula will be examined in vivo for improving the anti-schizophrenic effects on a schizophrenia rat model. The binary mixture of P123/P407 has a low CMC (0.001326% w/v), which helps in maintaining the formed micelles’ stability upon dilution. The combination effect of P123, P407 and TPGS led to a decrease in micelle size, ranging between 37.5–47.55 nm and an increase in the EE% (ranging between 68.22–86.84%). The selected OZ–PM shows great stability expressed by a suitable negative charge zeta potential value (−15.11 ± 1.35 mV) and scattered non-aggregated spherical particles with a particle size range of 30–40 nm. OZ–PM maintains sustained drug release at the application site with no nasal cytotoxicity. In vivo administration of the selected OZ–PM formula reveals improved CNS targeting and anti-schizophrenia-related deficits after OZ nasal administration. Therefore, OZ–PM provided safe direct nose-to-brain transport of OZ after nasal administration with an efficient anti-schizophrenic effect. Full article

(This article belongs to the Section Pharmaceutical Technology)

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18 pages, 4229 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M₁ Antagonists

by Jonas Kilian, Marius Ozenil, Marlon Millard, Dorka Fürtös, Verena Maisetschläger, Wolfgang Holzer, Wolfgang Wadsak, Marcus Hacker, Thierry Langer and Verena Pichler

Pharmaceuticals 2022, 15(2), 248; https://doi.org/10.3390/ph15020248 - 18 Feb 2022

Cited by 4 | Viewed by 2587

Abstract

Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified [...] Read more.

Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4’-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been evaluated for their physico–chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM₁-hM₅, the most promising compound 2 displayed a high binding affinitiy towards hM₁R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM_2-5R (4–189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM1R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico–chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development. Full article

(This article belongs to the Special Issue Structure and Ligand Based Drug Design)

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26 pages, 3453 KiB

Open AccessArticle

From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin

by Daniëlle Copmans, Sara Kildgaard, Emma Roux, Michèle Partoens, Gert Steurs, Xinhui Wang, Wim M. De Borggraeve, Camila V. Esguerra, Alexander D. Crawford, Thomas O. Larsen and Peter A. M. de Witte

Pharmaceuticals 2022, 15(2), 247; https://doi.org/10.3390/ph15020247 - 18 Feb 2022

Cited by 5 | Viewed by 4010

Abstract

PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its [...] Read more.

PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin’s antiseizure action. Full article

(This article belongs to the Special Issue Chemistry and Biomedical Potential of Marine Natural Products)

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35 pages, 9600 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition

by Mater H. Mahnashi, Fardous F. El-Senduny, Mohammed Abdulrahman Alshahrani and Mahrous A. Abou-Salim

Pharmaceuticals 2022, 15(2), 246; https://doi.org/10.3390/ph15020246 - 18 Feb 2022

Cited by 11 | Viewed by 3176

Abstract

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 [...] Read more.

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds 12a–c and 14a had the best MGI%, among the tested compounds. The target fluorinated compound 12b, as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC₅₀ values of 11.5, 11.6, and 13 µM against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound 12b (IC₅₀ = 0.092 µM) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC₅₀ = 0.049 µM). Furthermore, the ability of compound 12b in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound 12b decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for E-cadherin and N-cadherin showed lower expression of the neuronal N-cadherin and increased expression of epithelial E-cadherin, indicating the ability of 12b to suppress metastasis. Furthermore, 12b-treated HepG2 cells expressed a low level of anti-apoptotic BCL-2 and over-expressed proapoptotic Bax genes, respectively. Using the DAF-FM DA fluorescence probe, compound 12b produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of 12b with sorafenib. Interestingly, the drug-likeness properties of compound 12b met the expectations of Pfizer’s rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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28 pages, 2687 KiB

Open AccessArticle

Development of ¹⁸F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging

by Rocío García-Vázquez, Jesper Tranekjær Jørgensen, Klas Erik Bratteby, Vladimir Shalgunov, Lars Hvass, Matthias M. Herth, Andreas Kjær and Umberto Maria Battisti

Pharmaceuticals 2022, 15(2), 245; https://doi.org/10.3390/ph15020245 - 18 Feb 2022

Cited by 20 | Viewed by 3423

Abstract

Pretargeted PET imaging is an emerging and fast-developing method to monitor immuno-oncology strategies. Currently, tetrazine ligation is considered the most promising bioorthogonal reaction for pretargeting in vivo. Recently, we have developed a method to ¹⁸F-label ultrareactive tetrazines by copper-mediated fluorinations. However, bispyridyl [...] Read more.

Pretargeted PET imaging is an emerging and fast-developing method to monitor immuno-oncology strategies. Currently, tetrazine ligation is considered the most promising bioorthogonal reaction for pretargeting in vivo. Recently, we have developed a method to ¹⁸F-label ultrareactive tetrazines by copper-mediated fluorinations. However, bispyridyl tetrazines—one of the most promising structures for in vivo pretargeted applications—were inaccessible using this strategy. We believed that our successful efforts to ¹⁸F-label H-tetrazines using low basic labeling conditions could also be used to label bispyridyl tetrazines via aliphatic nucleophilic substitution. Here, we report the first direct ¹⁸F-labeling of bispyridyl tetrazines, their optimization for in vivo use, as well as their successful application in pretargeted PET imaging. This strategy resulted in the design of [¹⁸F]45, which could be labeled in a satisfactorily radiochemical yield (RCY = 16%), molar activity (A_m = 57 GBq/µmol), and high radiochemical purity (RCP > 98%). The [¹⁸F]45 displayed a target-to-background ratio comparable to previously successfully applied tracers for pretargeted imaging. This study showed that bispyridyl tetrazines can be developed into pretargeted imaging agents. These structures allow an easy chemical modification of ¹⁸F-labeled tetrazines, paving the road toward highly functionalized pretargeting tools. Moreover, bispyridyl tetrazines led to near-instant drug release of iTCO-tetrazine-based ‘click-to-release’ reactions. Consequently, ¹⁸F-labeled bispyridyl tetrazines bear the possibility to quantify such release in vivo in the future. Full article

(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)

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14 pages, 8462 KiB

Open AccessArticle

Determination of Phloridzin and Other Phenolic Compounds in Apple Tree Leaves, Bark, and Buds Using Liquid Chromatography with Multilayered Column Technology and Evaluation of the Total Antioxidant Activity

by Anežka Adamcová, Aleš Horna and Dalibor Šatínský

Pharmaceuticals 2022, 15(2), 244; https://doi.org/10.3390/ph15020244 - 18 Feb 2022

Cited by 9 | Viewed by 2541

Abstract

Apples are known to be a rich source of phenolic compounds, however detailed studies about their content in the individual parts of apple trees are reported rarely. For this purpose, we tested various stationary phases for the determination of phenolic compounds in leaves, [...] Read more.

Apples are known to be a rich source of phenolic compounds, however detailed studies about their content in the individual parts of apple trees are reported rarely. For this purpose, we tested various stationary phases for the determination of phenolic compounds in leaves, bark, and buds. Phloridzin, phloretin, chlorogenic acid, rutin, and quercitrin were analyzed with high performance liquid chromatography coupled with diode array detection. A YMC Triart C18-ExRS 150 × 4.6 mm, 5 µm particle size analytical column with multilayered particle technology was used. The separation was performed with a mobile phase that consisted of acetonitrile and 0.1% phosphoric acid, according to the gradient program, at a flow rate of 1 mL/min for 12.50 min. The concentration of phenolic compounds from 13 cultivars was in the range of 64.89–106.01 mg/g of dry weight (DW) in leaves, 70.81–113.18 mg/g DW in bark, and 100.68–139.61 mg/g DW in buds. Phloridzin was a major compound. The total antioxidant activity was measured using flow analysis and the correlation with the total amount of phenolic compounds was found. This finding can lead to the re-use of apple tree material to isolate substances that can be utilized in the food, pharmaceutical, or cosmetics industries. Full article

(This article belongs to the Special Issue Perspectives and Challenges in the Synthesis and Analysis of Drugs—49th Conference “Synthesis and Analysis of Drugs” (SAD 2021))

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15 pages, 7024 KiB

Open AccessArticle

Potential Synergistic Antibiotic Combinations against Fluoroquinolone-Resistant Pseudomonas aeruginosa

by Ashish Kothari, Neeraj Jain, Shyam Kishor Kumar, Ankur Kumar, Karanvir Kaushal, Satinder Kaur, Atul Pandey, Amit Gaurav and Balram Ji Omar

Pharmaceuticals 2022, 15(2), 243; https://doi.org/10.3390/ph15020243 - 18 Feb 2022

Cited by 6 | Viewed by 3651

Abstract

The rise in multiple-drug-resistant (MDR) phenotypes in Gram-negative pathogens is a major public health crisis. Pseudomonas aeruginosa is one of the leading causes of nosocomial infections in clinics. Treatment options for P. aeruginosa have become increasingly difficult due tdo its remarkable capacity to [...] Read more.

The rise in multiple-drug-resistant (MDR) phenotypes in Gram-negative pathogens is a major public health crisis. Pseudomonas aeruginosa is one of the leading causes of nosocomial infections in clinics. Treatment options for P. aeruginosa have become increasingly difficult due tdo its remarkable capacity to resist multiple antibiotics. The presence of intrinsic resistance factors and the ability to quickly adapt to antibiotic monotherapy warrant us to look for alternative strategies like combinatorial antibiotic therapy. Here, we report the frequency of P. aeruginosa multidrug-resistant and extensively drug-resistance (XDR) phenotypes in a super-specialty tertiary care hospital in north India. Approximately 60 percent of all isolated P. aeruginosa strains displayed the MDR phenotype. We found highest antibiotic resistance frequency in the emergency department (EMR), as 20 percent of isolates were resistant to 15 antipseudomonal antibiotics. Presence of plasmids with quinolone-resistance determinants were major drivers for resistance against fluoroquinolone. Additionally, we explored the possible combinatorial therapeutic options with four antipseudomonal antibiotics—colistin, ciprofloxacin, tobramycin, and meropenem. We uncovered an association between different antibiotic interactions. Our data show that the combination of colistin and ciprofloxacin could be an effective combinatorial regimen to treat infections caused by MDR and XDR P. aeruginosa. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 1118 KiB

Open AccessArticle

Evaluation of the Potency of Anti-HIV and Anti-HCV Drugs to Inhibit P-Glycoprotein Mediated Efflux of Digoxin in Caco-2 Cell Line and Human Precision-Cut Intestinal Slices

by Martin Huličiak, Ivan Vokřál, Ondřej Holas, Ondřej Martinec, František Štaud and Lukáš Červený

Pharmaceuticals 2022, 15(2), 242; https://doi.org/10.3390/ph15020242 - 18 Feb 2022

Cited by 3 | Viewed by 2760

Abstract

The inhibition of P-glycoprotein (ABCB1) could lead to increased drug plasma concentrations and hence increase drug toxicity. The evaluation of a drug’s ability to inhibit ABCB1 is complicated by the presence of several transport-competent sites within the ABCB1 binding pocket, making it difficult [...] Read more.

The inhibition of P-glycoprotein (ABCB1) could lead to increased drug plasma concentrations and hence increase drug toxicity. The evaluation of a drug’s ability to inhibit ABCB1 is complicated by the presence of several transport-competent sites within the ABCB1 binding pocket, making it difficult to select appropriate substrates. Here, we investigate the capacity of antiretrovirals and direct-acting antivirals to inhibit the ABCB1-mediated intestinal efflux of [³H]-digoxin and compare it with our previous rhodamine123 study. At concentrations of up to 100 µM, asunaprevir, atazanavir, daclatasvir, darunavir, elbasvir, etravirine, grazoprevir, ledipasvir, lopinavir, rilpivirine, ritonavir, saquinavir, and velpatasvir inhibited [³H]-digoxin transport in Caco-2 cells and/or in precision-cut intestinal slices prepared from the human jejunum (hPCIS). However, abacavir, dolutegravir, maraviroc, sofosbuvir, tenofovir disoproxil fumarate, and zidovudine had no inhibitory effect. We thus found that most of the tested antivirals have a high potential to cause drug–drug interactions on intestinal ABCB1. Comparing the Caco-2 and hPCIS experimental models, we conclude that the Caco-2 transport assay is more sensitive, but the results obtained using hPCIS agree better with reported in vivo observations. More inhibitors were identified when using digoxin as the ABCB1 probe substrate than when using rhodamine123. However, both approaches had limitations, indicating that inhibitory potency should be tested with at least these two ABCB1 probes. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 5603 KiB

Open AccessArticle

Tyrphostin AG1024 Suppresses Coronaviral Replication by Downregulating JAK1 via an IR/IGF-1R Independent Proteolysis Mediated by Ndfip1/2_NEDD4-like E3 Ligase Itch

by Cheng-Wei Yang, Yue-Zhi Lee, Hsing-Yu Hsu, Guan-Hao Zhao and Shiow-Ju Lee

Pharmaceuticals 2022, 15(2), 241; https://doi.org/10.3390/ph15020241 - 17 Feb 2022

Cited by 3 | Viewed by 2581

Abstract

JAK1 depletion or downregulation was previously reported to account for coronavirus inhibition. Here, we found that AG1024, an IR (insulin receptor) and IGF-1R (insulin-like growth factor 1 receptor) inhibitor, diminishes JAK1 protein levels and exerts anti-coronaviral activities with EC₅₀ values of 5.2 [...] Read more.

JAK1 depletion or downregulation was previously reported to account for coronavirus inhibition. Here, we found that AG1024, an IR (insulin receptor) and IGF-1R (insulin-like growth factor 1 receptor) inhibitor, diminishes JAK1 protein levels and exerts anti-coronaviral activities with EC₅₀ values of 5.2 ± 0.3 μM against transmissible gastroenteritis coronavirus (TGEV) and 4.3 ± 0.3 μM against human flu coronavirus OC43. However, although the IR and IGF-1R signaling pathways are activated by insulin or IGF-1 in swine testis cells, they are not triggered upon TGEV infection. AG1024, therefore, inhibits coronaviral replication and downregulates JAK1 protein levels independently of IR and IGF-1R. Moreover, JAK1 proteolysis caused by AG1024 was found through activation of upstream Ndfip1/2 and its effector NEDD4-like E3 ligase Itch. In addition, ouabain, which was reported to mediate JAK1 proteolysis causing anti-coronaviral activity by activation of Ndfip1/2 and NEDD4 E3 ligase, additively inhibited anti-coronaviral activity and JAK1 diminishment in combination with AG1024. This study provides novel insights into the pharmacological effects of AG1024 and Itch E3 ligase mediated JAK1 proteolysis and identified Ndfip1/2 as a cognate effector for JAK1 proteolysis via the diversified E3 ligases NEDD4 and NEDD4-like Itch. These findings are expected to provide valued information for the future development of anti-viral agents. Full article

(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)

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15 pages, 4056 KiB

Open AccessReview

Chiral Switch: Between Therapeutical Benefit and Marketing Strategy

by Gabriel Hancu and Adriana Modroiu

Pharmaceuticals 2022, 15(2), 240; https://doi.org/10.3390/ph15020240 - 17 Feb 2022

Cited by 69 | Viewed by 15008

Abstract

Chirality of pharmaceutical substances is an important aspect in drug research because it determines how enantiomers will interact with chiral biological targets. Enantiomers of a chiral drug can have different pharmacokinetic and pharmacological profiles; consequently, using a single pure enantiomer instead of a [...] Read more.

Chirality of pharmaceutical substances is an important aspect in drug research because it determines how enantiomers will interact with chiral biological targets. Enantiomers of a chiral drug can have different pharmacokinetic and pharmacological profiles; consequently, using a single pure enantiomer instead of a racemate can enhance the effectiveness and/or safety of the treatment. The tendencies of modern pharmaceutical industry regarding the current market of chiral drugs are divided between the chiral switch of previously used racemates and the development of new enantiopure drugs. The term chiral switch refers to the replacement on the market of a previously approved racemate with its single enantiomer version. The potential advantages of chiral switch can be related to a higher therapeutic index due to better potency, selectivity and fewer adverse effects, faster onset of action and exposure of the patient to lower drug dosages. However, chiral switch is also a strategy that permits manufacturers to keep market exclusivity for chiral pharmaceuticals that have lost their patent protection, even if the pure enantiomers have not demonstrated higher effectiveness or safety profile compared with the racemates. Full article

(This article belongs to the Special Issue The Story of Successful Drugs and Recent FDA-Approved Molecules)

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17 pages, 674 KiB

Open AccessReview

Black Elder and Its Constituents: Molecular Mechanisms of Action Associated with Female Reproduction

by Adriana Kolesarova, Simona Baldovska, Ladislav Kohut and Alexander V. Sirotkin

Pharmaceuticals 2022, 15(2), 239; https://doi.org/10.3390/ph15020239 - 17 Feb 2022

Cited by 6 | Viewed by 4805

Abstract

The present review summarizes the current knowledge concerning provenance, properties, physiological and therapeutic actions of elderberry and the bioactive molecules present in the plant, with emphasis on their action on female reproduction. Elderberry or black elder (Sambucus nigra L.) attracts attention due [...] Read more.

The present review summarizes the current knowledge concerning provenance, properties, physiological and therapeutic actions of elderberry and the bioactive molecules present in the plant, with emphasis on their action on female reproduction. Elderberry or black elder (Sambucus nigra L.) attracts attention due to its easy cultivation and high availability of bioactive compounds. Most of the available data concerning black elder’s therapeutic action are focused on its effects such as activation of immune processes and anti-inflammatory processes (cytokine production, etc.) and regulation of hormones and their receptors in cancer cells. The effects of elderberry on reproduction have been poorly investigated so far. Nevertheless, conducted studies so far demonstrate the stimulatory influence of black elder extract and its constituents, such as rutin, anthocyanins and agglutinins, on the viability and steroidogenesis of healthy ovarian cells as well as their ability to promote apoptosis and reduce the viability and proliferation of ovarian cancer cells. Furthermore, the action of black elder extract and its constituent biomolecules, such as anthocyanins and lectins, on embryogenesis and the embryonal estradiol-estradiol receptor system have also been reported. The available information, despite limitations, suggest the applicability of black elder constituents for improvement of reproductive processes in animal biotechnology, animal production and assisted reproduction, as well as for prevention and treatment of reproductive disorders (including cancer) in veterinary and human medicine. Full article

(This article belongs to the Section Pharmacology)

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23 pages, 22399 KiB

Open AccessReview

The Evolution of Pharmacological Activities Bouea macrophylla Griffith In Vivo and In Vitro Study: A Review

by Intan Tsamrotul Fu’adah, Sri Adi Sumiwi and Gofarana Wilar

Pharmaceuticals 2022, 15(2), 238; https://doi.org/10.3390/ph15020238 - 16 Feb 2022

Cited by 8 | Viewed by 4896

Abstract

Bouea macrophylla Griffith (B. macrophylla) is one of the many herbal plants found in Asia, and its fruit is plum mango. This plant is rich in secondary metabolites, including flavonoids, tannins, polyphenolic compounds, and many others. Due to its bioactive components, plum [...] Read more.

Bouea macrophylla Griffith (B. macrophylla) is one of the many herbal plants found in Asia, and its fruit is plum mango. This plant is rich in secondary metabolites, including flavonoids, tannins, polyphenolic compounds, and many others. Due to its bioactive components, plum mango has powerful antioxidants that have therapeutic benefits for many common ailments, including cardiovascular disease, diabetes, and cancer. This review describes the evolution of plum mango’s phytochemical properties and pharmacological activities including in vitro and in vivo studies. The pharmacological activities of B. macrophylla Griffith reviewed in this article are antioxidant, anticancer, antihyperglycemic, antimicrobial, and antiphotoaging. Each of these pharmacological activities described and studied the possible cellular and molecular mechanisms of action. Interestingly, plum mango seeds show good pharmacological activity where the seed is the part of the plant that is a waste product. This can be an advantage because of its economic value as a herbal medicine. Overall, the findings described in this review aim to allow this plant to be explored and utilized more widely, especially as a new drug discovery. Full article

(This article belongs to the Topic Animal Model in Biomedical Research)

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13 pages, 582 KiB

Open AccessArticle

Adverse Events during Vitreoretinal Surgery under Adequacy of Anesthesia Guidance—Risk Factor Analysis

by Michał Jan Stasiowski, Aleksandra Pluta, Anita Lyssek-Boroń, Seweryn Król, Lech Krawczyk, Ewa Niewiadomska, Jakub Żak, Magdalena Kawka, Dariusz Dobrowolski, Beniamin Oskar Grabarek, Izabela Szumera, Michael Janusz Koss, Anna Missir, Robert Rejdak and Przemysław Jałowiecki

Pharmaceuticals 2022, 15(2), 237; https://doi.org/10.3390/ph15020237 - 16 Feb 2022

Cited by 4 | Viewed by 2777

Abstract

Vitreoretinal surgeries require the administration of general anesthesia (GA) in selected groups of patients. The administration of intraoperative rescue narcotic analgesia (IRNA) during GA poses the risk of postoperative nausea and vomiting (PONV). The surgical pleth index (SPI), a crucial component of the [...] Read more.

Vitreoretinal surgeries require the administration of general anesthesia (GA) in selected groups of patients. The administration of intraoperative rescue narcotic analgesia (IRNA) during GA poses the risk of postoperative nausea and vomiting (PONV). The surgical pleth index (SPI), a crucial component of the adequacy of anesthesia (AoA) guidance of GA, optimizes the intraoperative titration of IRNA. The current analysis evaluated the risk factors for the occurrence of PONV and the oculo-cardiac reflex (OCR) in patients undergoing pars plana vitrectomy (PPV) under AoA guidance. In total, 175 patients undergoing PPV were randomly allocated to receive either GA with SPI-guided IRNA administration using fentanyl alone or in addition to different preoperative analgesia techniques. Any incidence of PONV or OCR was recorded. Obesity, overweight, smoking status, motion sickness, postoperative intolerable pain perception, female gender, fluid challenge and arterial hypertension did not correlate with an increased incidence of PONV or OCR under AoA guidance. Diabetes mellitus, regardless of insulin dependence, was found to correlate with the increased incidence of PONV. The AoA regimen including SPI guidance of IRNA presumably created similar conditions for individual subjects, so no risk factors of the occurrence of PONV or OCR were found, except for diabetes mellitus. We recommend using AoA guidance for GA administration to reduce OCR and PONV rates. Full article

(This article belongs to the Special Issue Drug Candidates for Anesthesia and Analgesia)

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17 pages, 23130 KiB

Open AccessArticle

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

by Min-Jeong Kim, Sarita Pandit and Jun-Goo Jee

Pharmaceuticals 2022, 15(2), 236; https://doi.org/10.3390/ph15020236 - 16 Feb 2022

Viewed by 2491

Abstract

A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine [...] Read more.

A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine learning (ML) classifiers, and validated by biochemical and biophysical experiments. ML trained by CA I and CA II inhibitor molecular fingerprints predicted candidates from the protein-specific bioactive molecules approved or under clinical trials. For experimental tests, three sulfonamide-containing kinase inhibitors, 5932, 5946, and 6046, were chosen. The enzyme assays with CA I, CA II, CA IX, and CA XII have allowed the quantitative comparison in the molecules’ inhibitory activities. While 6046 inhibited weakly, 5932 and 5946 exhibited potent inhibitions with 100 nM to 1 μM inhibitory constants. The ML screening was extended for finding CAs inhibitors of all known kinase inhibitors. It found XMU-MP-1 as another potent CA inhibitor with an approximate 30 nM inhibitory constant for CA I, CA II, and CA IX. Differential scanning fluorimetry confirmed the direct interaction between CAs and small molecules. Cheminformatics studies, including docking simulation, suggest that each molecule possesses two separate functional moieties: one for interaction with kinases and the other with CAs. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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19 pages, 2733 KiB

Open AccessArticle

Zinc-Substituted Pheophorbide A Is a Safe and Efficient Antivascular Photodynamic Agent

by Milena J. Szafraniec, Monika Toporkiewicz and Andrzej Gamian

Pharmaceuticals 2022, 15(2), 235; https://doi.org/10.3390/ph15020235 - 16 Feb 2022

Cited by 5 | Viewed by 2399

Abstract

The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to [...] Read more.

The present study focuses on the photodynamic activity of zinc-substituted pheophorbide a against human endothelial cells. Previously, zinc pheophorbide a has been shown to be a very potent photosensitizer but also a strong albumin binder. Binding to albumin significantly reduces its availability to cancer cells, which may necessitate the use of relatively high doses. Here we show that zinc pheophorbide a is very effective against vascular endothelial cells, even in its albumin-complexed form. Albumin complexation increases the lysosomal accumulation of the drug, thus enhancing its efficiency. Zinc pheophorbide a at nanomolar concentrations induces endothelial cell death via apoptosis, which in many cases is considered a desirable cell death mode because of its anti-inflammatory effect. Additionally, we demonstrate that in comparison to tumor cells, endothelial cells are much more susceptible to photodynamic treatment with the use of the investigated compound. Our findings demonstrate that zinc pheophorbide a is a very promising photosensitizer for use in vascular-targeted photodynamic therapy against solid tumors, acting as a vascular shutdown inducer. It can also possibly find application in the treatment of a range of vascular disorders. Numerous properties of zinc pheophorbide a are comparable or even more favorable than those of the well-known photosensitizer of a similar structure, palladium bacteriopheophorbide (TOOKAD^®). Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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30 pages, 5567 KiB

Open AccessReview

AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications

by Cyril Fersing, Nicolas Masurier, Léa Rubira, Emmanuel Deshayes and Vincent Lisowski

Pharmaceuticals 2022, 15(2), 234; https://doi.org/10.3390/ph15020234 - 16 Feb 2022

Cited by 9 | Viewed by 3726

Abstract

With the development of ⁶⁸Ga and ¹⁷⁷Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating [...] Read more.

With the development of ⁶⁸Ga and ¹⁷⁷Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., ⁶⁸Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Testing of Next Generation Theranostic Radiopharmaceuticals)

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13 pages, 7747 KiB

Open AccessArticle

Anxiolytic-like Effects of the Positive GABA_B Receptor Modulator GS39783 Correlate with Mice’s Individual Basal Anxiety and Stress Reactivity

by Ahmet Oguzhan Bicakci, Mousumi Sarkar, Yu-Hsin Chang, Evelyn Kahl, Lorenzo Ragazzi, Angel Moldes-Anaya and Markus Fendt

Pharmaceuticals 2022, 15(2), 233; https://doi.org/10.3390/ph15020233 - 16 Feb 2022

Cited by 7 | Viewed by 2832

Abstract

Positive gamma-aminobutyric acid type B (GABA_B) receptor modulators such as GS39783 have showed anxiolytic-like effects in several studies while such effects were absent in other studies. These conflicting findings led us hypothesize that the anxiolytic-like effects of such compounds depend on [...] Read more.

Positive gamma-aminobutyric acid type B (GABA_B) receptor modulators such as GS39783 have showed anxiolytic-like effects in several studies while such effects were absent in other studies. These conflicting findings led us hypothesize that the anxiolytic-like effects of such compounds depend on the individual basal anxiety and/or the anxiogenic properties of the used tests. The present study addresses this hypothesis by testing GS39783 effects on mice’s anxiety-like behavior in a light–dark box. We found that GS39783 had no effects on a whole-group level. However, after grouping the mice for their basal anxiety, GS39783 reduced anxiety-like behavior in the subgroup with highest basal anxiety. Moreover, GS39783 effects correlated with individual basal anxiety. Next, the anxiogenic properties of the light–dark box test were increased by prior stress exposure. Again, GS39783 was not effective on a whole-group level. However, GS39783 had an anxiolytic-like effect in the most stress-responsive subgroup. Moreover, GS39783 effects correlated with individual stress responsiveness. Finally, we show that GS39783 brain levels were within a behaviorally relevant range. Overall, our study demonstrates that GS39783 effects depend on individual basal anxiety and stress responsiveness. This suggests that anxiety tests should generally be designed to capture individual basal anxiety and/or stress responsiveness as well as individual compound effects. Full article

(This article belongs to the Section Pharmacology)

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Open AccessArticle

Xanthine Oxidase Inhibitor, Febuxostat Is Effective against 5-Fluorouracil-Induced Parotid Salivary Gland Injury in Rats Via Inhibition of Oxidative Stress, Inflammation and Targeting TRPC1/CHOP Signalling Pathway

by Walaa Yehia Abdelzaher, Mohamed A. Nassan, Sabreen Mahmoud Ahmed, Nermeen N. Welson, Gaber El-Saber Batiha and Hanaa Mohamed Khalaf

Pharmaceuticals 2022, 15(2), 232; https://doi.org/10.3390/ph15020232 - 16 Feb 2022

Cited by 6 | Viewed by 2467

Abstract

The current research aimed to examine the ameliorative role of febuxostat (FEB), a highly potent xanthine oxidase inhibitor, against 5-fluorouracil (5-FU)-induced parotid salivary gland damage in rats, as FEB is a pleiotropic drug that has multiple pharmacological effects. A total of 32 Wistar [...] Read more.

The current research aimed to examine the ameliorative role of febuxostat (FEB), a highly potent xanthine oxidase inhibitor, against 5-fluorouracil (5-FU)-induced parotid salivary gland damage in rats, as FEB is a pleiotropic drug that has multiple pharmacological effects. A total of 32 Wistar adult male rats were randomly arranged into four groups. Group 1: the control group; given only the vehicle for 14 days, then given a saline i.p. injection from the 10th to the 14th day. Group 2: the FEB group; rats received FEB (10 mg/kg) once daily po for 14 days before receiving a saline i.p. injection from the 10th to the 14th day. Group 3: the 5-FU group; from the 10th to the 14th day, rats received an intraperitoneal injection of 5-FU (35 mg/kg/day). Group 4: the FEB/5-FU group; rats were pre-treated with FEB po for 14 days before receiving 5-FU i.p injections for five consecutive days from the 10th to the 14th day. Parotid gland damage was detected histologically and biochemically by the evaluation of oxidative stress markers (malondialdehyde (MDA) and nitric oxide levels (NOx)), oxidant defences (reduced glutathione (GSH) and superoxide dismutase (SOD)), inflammatory markers (tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β)), and transient receptor potential canonical1 (TRCP1) and C/EBP homologous protein (CHOP). FEB pre-treatment reduced MDA, TNF-, and IL-1 while increasing SOD, GSH, and NOx. FEB also significantly increased TRPC1 and decreased CHOP in parotid gland tissue. In conclusion, FEB pre-treatment reduced 5-FU-induced parotid salivary gland damage not only through its powerful anti-inflammatory and antioxidant effects, but also through its effect on the TRPC1/CHOP signalling pathway. Full article

(This article belongs to the Section Pharmacology)

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Pharmaceuticals, Volume 15, Issue 2 (February 2022) – 153 articles

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