Pharmaceuticals

15 pages, 4425 KiB

Open AccessArticle

Discovery of Substituted (2-Aminooxazol-4-yl)Isoxazole-3-carboxylic Acids as Inhibitors of Bacterial Serine Acetyltransferase in the Quest for Novel Potential Antibacterial Adjuvants

by Joana Magalhães, Nina Franko, Samanta Raboni, Giannamaria Annunziato, Päivi Tammela, Agostino Bruno, Stefano Bettati, Stefano Armao, Costanza Spadini, Clotilde Silvia Cabassi, Andrea Mozzarelli, Marco Pieroni, Barbara Campanini and Gabriele Costantino

Pharmaceuticals 2021, 14(2), 174; https://doi.org/10.3390/ph14020174 - 23 Feb 2021

Cited by 7 | Viewed by 2857

Abstract

Many bacteria and actinomycetales use L-cysteine biosynthesis to increase their tolerance to antibacterial treatment and establish a long-lasting infection. In turn, this might lead to the onset of antimicrobial resistance that currently represents one of the most menacing threats to public health worldwide. [...] Read more.

Many bacteria and actinomycetales use L-cysteine biosynthesis to increase their tolerance to antibacterial treatment and establish a long-lasting infection. In turn, this might lead to the onset of antimicrobial resistance that currently represents one of the most menacing threats to public health worldwide. The biosynthetic machinery required to synthesise L-cysteine is absent in mammals; therefore, its exploitation as a drug target is particularly promising. In this article, we report a series of inhibitors of Salmonella thyphimurium serine acetyltransferase (SAT), the enzyme that catalyzes the rate-limiting step of L-cysteine biosynthesis. The development of such inhibitors started with the virtual screening of an in-house library of compounds that led to the selection of seven structurally unrelated hit derivatives. A set of molecules structurally related to hit compound 5, coming either from the original library or from medicinal chemistry efforts, were tested to determine a preliminary structure–activity relationship and, especially, to improve the inhibitory potency of the derivatives, that was indeed ameliorated by several folds compared to hit compound 5 Despite these progresses, at this stage, the most promising compound failed to interfere with bacterial growth when tested on a Gram-negative model organism, anticipating the need for further research efforts. Full article

(This article belongs to the Special Issue Small Molecules as Antimicrobials)

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16 pages, 2360 KiB

Open AccessArticle

Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd₂Spm) in Mice

by Martin Vojtek, Salomé Gonçalves-Monteiro, Edgar Pinto, Sára Kalivodová, Agostinho Almeida, Maria P. M. Marques, Ana L. M. Batista de Carvalho, Clara B. Martins, Helder Mota-Filipe, Isabel M. P. L. V. O. Ferreira and Carmen Diniz

Pharmaceuticals 2021, 14(2), 173; https://doi.org/10.3390/ph14020173 - 23 Feb 2021

Cited by 14 | Viewed by 3681

Abstract

Palladium-based compounds are regarded as potential analogs to platinum anticancer drugs with improved properties. The present study assessed the pharmacokinetics and biodistribution of a dinuclear palladium(II)-spermine chelate (Pd₂Spm), which has previously been shown to possess promising in vitro activity against several [...] Read more.

Palladium-based compounds are regarded as potential analogs to platinum anticancer drugs with improved properties. The present study assessed the pharmacokinetics and biodistribution of a dinuclear palladium(II)-spermine chelate (Pd₂Spm), which has previously been shown to possess promising in vitro activity against several therapy-resistant cancers. Using inductively coupled plasma-mass spectrometry, the kinetic profiles of palladium/platinum in serum, serum ultrafiltrate and tissues (kidney, liver, brain, heart, lungs, ovaries, adipose tissue and mammary glands) were studied in healthy female Balb/c mice after a single intraperitoneal bolus injection of Pd₂Spm (3 mg/kg bw) or cisplatin (3.5 mg/kg bw) between 0.5 and 48 h post-injection. Palladium in serum exhibited biphasic kinetics with a terminal half-life of 20.7 h, while the free palladium in serum ultrafiltrate showed a higher terminal half-life than platinum (35.5 versus 31.5 h). Palladium was distributed throughout most of the tissues except for the brain, with the highest values in the kidney, followed by the liver, lungs, ovaries, adipose tissue and mammary glands. The in vitro cellular accumulation was also evaluated in breast cancer cells, evidencing a passive diffusion as a mechanism of Pd₂Spm’s cellular entry. This study reports, for the first time, the favorable pharmacokinetics and biodistribution of Pd₂Spm, which may become a promising pharmacological agent for cancer treatment. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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12 pages, 2587 KiB

Open AccessArticle

Up-Regulated Vitamin D Receptor by Pelargonium sidoides Extract EPs^® 7630 Contributes to Rhinovirus Defense in Bronchial Epithelial Cells

by Michael Roth, Qingzhu Sun and Michael Tamm

Pharmaceuticals 2021, 14(2), 172; https://doi.org/10.3390/ph14020172 - 22 Feb 2021

Cited by 13 | Viewed by 3296

Abstract

EPs^®7630, extracted from Pelargonium sidoides, reduces the severity of viral upper respiratory tract infections. Vitamin D also improves anti-viral host defense through similar signaling pathways. This study assessed if EPs^®7630 modifies vitamin D receptor (VDR) expression and function [...] Read more.

EPs^®7630, extracted from Pelargonium sidoides, reduces the severity of viral upper respiratory tract infections. Vitamin D also improves anti-viral host defense through similar signaling pathways. This study assessed if EPs^®7630 modifies vitamin D receptor (VDR) expression and function by human bronchial epithelial cells. Bronchial epithelial cells were incubated with EPs^®7630 over 48 h before calcitriol stimulation and/or infection with Rhinovirus (RV)-16. Protein expression was determined by Western-blotting. Intracellular signaling of mitogen activated protein kinases (MAPK) was studied by chemical inhibitors. The anti-viral effect was assessed by immunofluorescence for RV-16 protein. EPs^®7630 upregulated VDR expression through Erk1/2 MAPK and thereby increased the cell’s sensitivity to calcitriol. Compared ton untreated cells, the shift of the VDR into the nucleus at 5.3 times lower calcitriol concentration. EPs^®7630 increased Erk1/2 MAPK signaling, but reduced p38 phosphorylation, and had no effect on Jun N-terminal kinase (JNK). EPs^®7630 improved the anti-viral effect of vitamin D on RV-16 infection by 2.1 folds compared to vitamin D alone or to untreated cells. Furthermore, EPs^®7630 improved the differentiation of epithelial cells by upregulating E-cadherin expression through Erk1/2. In conclusion, EPs^®7630 increased host defense against Rhinovirus infection by upregulating the VDR and the differentiation of epithelial cells. Full article

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

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13 pages, 949 KiB

Open AccessArticle

Cannabis-Based Oral Formulations for Medical Purposes: Preparation, Quality and Stability

by Francesca Baratta, Marco Simiele, Irene Pignata, Lorenzo Ravetto Enri, Antonio D’Avolio, Riccardo Torta, Anna De Luca, Massimo Collino and Paola Brusa

Pharmaceuticals 2021, 14(2), 171; https://doi.org/10.3390/ph14020171 - 22 Feb 2021

Cited by 13 | Viewed by 5772

Abstract

Current legislation in Italy provides that medical Cannabis may be administered orally or by inhalation. One of the fundamental criteria for the administration of oral formulations is that they deliver a known consistent quantity of the active ingredients to ensure uniform therapies leading [...] Read more.

Current legislation in Italy provides that medical Cannabis may be administered orally or by inhalation. One of the fundamental criteria for the administration of oral formulations is that they deliver a known consistent quantity of the active ingredients to ensure uniform therapies leading to the optimisation of the risks/benefits. In 2018, our group developed an improved Cannabis oil extraction technique. The objective of the present work was to carry out a stability study for the oil extracts obtained by this method. Furthermore, in order to facilitate the consumption of the prescribed medical Cannabis therapy by patients, a standard procedure was defined for the preparation of a single-dose preparation for oral use (hard capsules) containing the oil extract; thereafter, the quality and stability were evaluated. The hard capsules loaded with the oil extract were analysed and found to be uniform in content. The encapsulation process did not alter the quantity of the active molecule present in the oil. The stability tests yielded excellent results. Since the capsule dosage form is easily transported and administered, has pleasant organoleptic properties and is stable at room temperature for extended periods of time, this would facilitate the adherence to therapy by patients in treatment. Full article

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

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15 pages, 1773 KiB

Open AccessCommunication

PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance

by Julita Pietrzak, Karolina Gronkowska and Agnieszka Robaszkiewicz

Pharmaceuticals 2021, 14(2), 170; https://doi.org/10.3390/ph14020170 - 22 Feb 2021

Cited by 3 | Viewed by 3088

Abstract

Secondary infections cause sepsis that lead to patient disability or death. Contact of macrophages with bacterial components (such as lipopolysaccharide—LPS) activates the intracellular signaling pathway downstream of Toll-like receptors (TLR), which initiate an immune proinflammatory response. However, the expression of nuclear factor-kappa B [...] Read more.

Secondary infections cause sepsis that lead to patient disability or death. Contact of macrophages with bacterial components (such as lipopolysaccharide—LPS) activates the intracellular signaling pathway downstream of Toll-like receptors (TLR), which initiate an immune proinflammatory response. However, the expression of nuclear factor-kappa B (NF-κB)-dependent proinflammatory cytokines significantly decreases after single high or multiple LPS stimulations. Knowing that poly(ADP-ribose) polymerase-1 (PARP1) serves as a cofactor of NF-κB, we aimed to verify a hypothesis of the possible contribution of PARP1 to the development of LPS-induced tolerance in human macrophages. Using TNF-α mRNA expression as a readout, we demonstrate that PARP1 interaction with the TNF-α promoter, controls macrophage immunoparalysis. We confirm that PARP1 is extruded from the gene promoter, whereas cell pretreatment with Olaparib maintains macrophage responsiveness to another LPS treatment. Furthermore, cell pretreatment with proteasome inhibitor MG132 completely abrogates the effect of Olaparib, suggesting that PARP1 acts with NF-κB in the same regulatory pathway, which controls pro-inflammatory cytokine transcription. Mechanistically, PARP1 trapping allows for the re-rebinding of p65 to the TNF-α promoter in LPS-stimulated cells. In conclusion, PARP traps prevent PARP1 extrusion from the TNF-α promoter upon macrophage stimulation, thereby maintaining chromatin responsiveness of TLR activation, allowing for the re-binding of p65 and TNF-α transcription. Full article

(This article belongs to the Special Issue Epigenetic Drugs)

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54 pages, 14187 KiB

Open AccessArticle

Synthesis and Biological Evaluation of 1-(Diarylmethyl)-1H-1,2,4-triazoles and 1-(Diarylmethyl)-1H-imidazoles as a Novel Class of Anti-Mitotic Agent for Activity in Breast Cancer

by Gloria Ana, Patrick M. Kelly, Azizah M. Malebari, Sara Noorani, Seema M. Nathwani, Brendan Twamley, Darren Fayne, Niamh M. O’Boyle, Daniela M. Zisterer, Elisangela Flavia Pimentel, Denise Coutinho Endringer and Mary J. Meegan

Pharmaceuticals 2021, 14(2), 169; https://doi.org/10.3390/ph14020169 - 22 Feb 2021

Cited by 6 | Viewed by 5063

Abstract

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a [...] Read more.

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC₅₀ value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G₂/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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12 pages, 766 KiB

Open AccessReview

Non-Coding RNAs: The “Dark Side Matter” of the CLL Universe

by Marcello Francesco Lingua, Giovanna Carrà, Beatrice Maffeo and Alessandro Morotti

Pharmaceuticals 2021, 14(2), 168; https://doi.org/10.3390/ph14020168 - 21 Feb 2021

Cited by 5 | Viewed by 2177

Abstract

For many years in the field of onco-hematology much attention has been given to mutations in protein-coding genes or to genetic alterations, including large chromosomal losses or rearrangements. Despite this, biological and clinical needs in this sector remain unmet. Therefore, it is not [...] Read more.

For many years in the field of onco-hematology much attention has been given to mutations in protein-coding genes or to genetic alterations, including large chromosomal losses or rearrangements. Despite this, biological and clinical needs in this sector remain unmet. Therefore, it is not surprising that recent studies have shifted from coded to non-coded matter. The discovery of non-coding RNAs (ncRNAs) has influenced several aspects related to the treatment of cancer. In particular, in chronic lymphocytic leukemia (CLL) the knowledge of ncRNAs and their contextualization have led to the identification of new biomarkers used to follow the course of the disease, to the anticipation of mechanisms that support resistance and relapse, and to the selection of novel targeted treatment regimens. In this review, we will summarize the main ncRNAs discovered in CLL and the molecular mechanisms by which they are affected and how they influence the development and the progression of the disease. Full article

(This article belongs to the Special Issue Non-coding RNA in Hematological Cancers)

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40 pages, 8763 KiB

Open AccessReview

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics

by Mária Bodnár Mikulová and Peter Mikuš

Pharmaceuticals 2021, 14(2), 167; https://doi.org/10.3390/ph14020167 - 21 Feb 2021

Cited by 15 | Viewed by 3339

Abstract

Radiolabeled biomolecules targeted at tumor-specific enzymes, receptors, and transporters in cancer cells represent an intensively investigated and promising class of molecular tools for the cancer diagnosis and therapy. High specificity of such biomolecules is a prerequisite for the treatment with a lower burden [...] Read more.

Radiolabeled biomolecules targeted at tumor-specific enzymes, receptors, and transporters in cancer cells represent an intensively investigated and promising class of molecular tools for the cancer diagnosis and therapy. High specificity of such biomolecules is a prerequisite for the treatment with a lower burden to normal cells and for the effective and targeted imaging and diagnosis. Undoubtedly, early detection is a key factor in efficient dealing with many severe tumor types. This review provides an overview and critical evaluation of novel approaches in the designing of target-specific probes labeled with metal radionuclides for the diagnosis of most common death-causing cancers, published mainly within the last three years. Advances are discussed such traditional peptide radiolabeling approaches, and click and nanoparticle chemistry. The progress of radiolabeled peptide based ligands as potential radiopharmaceuticals is illustrated via novel structure and application studies, showing how the molecular modifications reflect their binding selectivity to significant onco-receptors, toxicity, and, by that, practical utilization. The most impressive outputs in categories of newly developed structures, as well as imaging and diagnosis approaches, and the most intensively studied oncological diseases in this context, are emphasized in order to show future perspectives of radiometal labeled amino acid-based compounds in nuclear medicine. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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17 pages, 3684 KiB

Open AccessArticle

Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer’s Mice

by Henning Johannes Drews, Roman Klein, Ali Lourhmati, Marine Buadze, Elke Schaeffeler, Thomas Lang, Torgom Seferyan, Leah R. Hanson, William H. Frey II, Tom C.G.M. de Vries, Inge A.E.W. Thijssen-van Loosdregt, Christoph H. Gleiter, Matthias Schwab and Lusine Danielyan

Pharmaceuticals 2021, 14(2), 166; https://doi.org/10.3390/ph14020166 - 20 Feb 2021

Cited by 21 | Viewed by 4039

Abstract

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also [...] Read more.

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment. Full article

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

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11 pages, 796 KiB

Open AccessArticle

Α Multicenter Retrospective Study Evaluating Brivaracetam in the Treatment of Epilepsies in Clinical Practice

by Maria Stefanatou, Eirini Vasileiadou Kapetanou, Vasilios K. Kimiskidis, Vasileios Papaliagkas, Panagiotis Polychronopoulos, Sofia Markoula, Kleoniki Charisiou, Dimitrios Kazis, Anastasia Verentzioti, Panayiotis Patrikelis, Athanasia Alexoudi and Stylianos Gatzonis

Pharmaceuticals 2021, 14(2), 165; https://doi.org/10.3390/ph14020165 - 19 Feb 2021

Cited by 4 | Viewed by 3152

Abstract

Brivaracetam (BRV) is the latest approved antiepileptic drug. The aim of the study was to evaluate the efficacy and tolerability of BRV in everyday clinical practice. In this retrospective, observational, multicenter study, data from epilepsy patients receiving BRV from January 2018 to July [...] Read more.

Brivaracetam (BRV) is the latest approved antiepileptic drug. The aim of the study was to evaluate the efficacy and tolerability of BRV in everyday clinical practice. In this retrospective, observational, multicenter study, data from epilepsy patients receiving BRV from January 2018 to July 2019 were analyzed. Patients with age ≥16 suffering from any type of epilepsy and having at least one follow up encounter after dose titration were included. 156 consecutive patients were included in the study. The mean age was 40 (16–84 years) and the mean duration of epilepsy was 21 years. Of the 156 patients, 81% were diagnosed with focal-onset seizures, 16% with generalized seizures, while 3% suffered from unclassified seizures. Nine patients received BRV as monotherapy as a switching therapy. At the first follow up visit, seizure cessation was achieved in 56 (36%) patients and the rate of ≥50% responders was 36%. Twenty four patients (15%) remained unchanged; six patients (4%) were recorded with increased seizure frequency, while the remaining 9% had a response of less than 50%. Twenty-six patients (17%) showed clinically significant adverse events, but none were life threatening. Brivaracetam seems to be an effective, easy to use and safe antiepileptic drug in the clinical setting. Full article

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

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18 pages, 2859 KiB

Open AccessArticle

In Vitro Characterization of Inhalable Cationic Hybrid Nanoparticles as Potential Vaccine Carriers

by Iman M. Alfagih, Kan Kaneko, Nitesh K. Kunda, Fars Alanazi, Sarah R. Dennison, Hesham M. Tawfeek and Imran Y. Saleem

Pharmaceuticals 2021, 14(2), 164; https://doi.org/10.3390/ph14020164 - 18 Feb 2021

Cited by 12 | Viewed by 3416

Abstract

In this study, PGA-co-PDL nanoparticles (NPs) encapsulating model antigen, bovine serum albumin (BSA), were prepared via double emulsion solvent evaporation. In addition, chitosan hydrochloride (CHL) was incorporated into the external phase of the emulsion solvent method, which resulted in surface adsorption onto the [...] Read more.

In this study, PGA-co-PDL nanoparticles (NPs) encapsulating model antigen, bovine serum albumin (BSA), were prepared via double emulsion solvent evaporation. In addition, chitosan hydrochloride (CHL) was incorporated into the external phase of the emulsion solvent method, which resulted in surface adsorption onto the NPs to form hybrid cationic CHL NPs. The BSA encapsulated CHL NPs were encompassed into nanocomposite microcarriers (NCMPs) composed of l-leucine to produce CHL NPs/NCMPs via spray drying. The CHL NPs/NCMPs were investigated for in vitro aerosolization, release study, cell viability and uptake, and stability of protein structure. Hybrid cationic CHL NPs (CHL: 10 mg/mL) of particle size (480.2 ± 32.2 nm), charge (+14.2 ± 0.72 mV), and BSA loading (7.28 ± 1.3 µg/mg) were produced. The adsorption pattern was determined to follow the Freundlich model. Aerosolization of CHL NPs/NCMPs indicated fine particle fraction (FPF: 46.79 ± 11.21%) and mass median aerodynamic diameter (MMAD: 1.49 ± 0.29 µm). The BSA α-helical structure was maintained, after release from the CHL NPs/NCMPs, as indicated by circular dichroism. Furthermore, dendritic cells (DCs) and A549 cells showed good viability (≥70% at 2.5 mg/mL after 4–24 h exposure, respectively). Confocal microscopy and flow cytometry data showed hybrid cationic CHL NPs were successfully taken up by DCs within 1 h of incubation. The upregulation of CD40, CD86, and MHC-II cell surface markers indicated that the DCs were successfully activated by the hybrid cationic CHL NPs. These results suggest that the CHL NPs/NCMPs technology platform could potentially be used for the delivery of proteins to the lungs for immunostimulatory applications such as vaccines. Full article

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

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10 pages, 1632 KiB

Open AccessArticle

Development and Validation of an LC-MS/MS Method for Quantification of the Novel Antibacterial Candidate DA-7010 in Plasma and Application to a Preclinical Pharmacokinetic Study

by Mi Hye Kwon, Dae Young Lee and Hee Eun Kang

Pharmaceuticals 2021, 14(2), 163; https://doi.org/10.3390/ph14020163 - 18 Feb 2021

Cited by 2 | Viewed by 2625

Abstract

DA-7010 is a new candidate for an antibacterial agent that targets Gram-negative pathogens by acting as a leucyl-tRNA synthetase inhibitor. In this study, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine DA-7010 levels in the plasma [...] Read more.

DA-7010 is a new candidate for an antibacterial agent that targets Gram-negative pathogens by acting as a leucyl-tRNA synthetase inhibitor. In this study, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine DA-7010 levels in the plasma from mice, rats, and dogs. Plasma samples were mixed with methanol for protein precipitation. Chromatographic separation was carried out using a reversed-phase C₁₈ column (Agilent Poroshell 120, 50 × 3.0 mm, 2.7 μm). An isocratic elution of the mobile phase consisting of 5 mM formic acid in water and acetonitrile at a ratio of 84:16 (v/v) was applied at a flow rate of 0.3 mL/min. The total chromatographic run time was 3.5 min. Multiple reaction monitoring (MRM) mode was used for mass spectrometric detection using an Agilent 6460 triple quadrupole coupled with an electrospray ionization (ESI) source operated in positive-ion mode. The MRM transitions analyzed were m/z 220.1→162.1 for DA-7010 and m/z 206.1→170.1 for the internal standard (structural analogue of DA-7010). Calibration curves were constructed in the range of 10–10,000 ng/mL. The intra- and interday precision and accuracy were within 11.3%, excluding those for the lower limit of quantification (LLOQ) samples, which were within 17.1%. The developed LC-MS/MS method was successfully validated and applied in preclinical pharmacokinetic studies of DA-7010 in mice, rats, and dogs following single oral administrations. The oral absorption of DA-7010 was rapid, and the systemic exposure was approximately four times higher in the dogs than in the mice or rats. Full article

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

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13 pages, 1929 KiB

Open AccessArticle

Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data

by Félicien Le Louedec, Fanny Gallais, Fabienne Thomas, Mélanie White-Koning, Ben Allal, Caroline Protin, Loïc Ysebaert, Étienne Chatelut and Florent Puisset

Pharmaceuticals 2021, 14(2), 162; https://doi.org/10.3390/ph14020162 - 18 Feb 2021

Cited by 5 | Viewed by 3735

Abstract

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUC_IBRU) instead of trough concentration (C_min,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy [...] Read more.

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUC_IBRU) instead of trough concentration (C_min,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUC_IBRU associated with Bayesian estimation. The actual AUC_IBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUC_IBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUC_IBRU and C_min,ss was poor (r² = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUC_IBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately. Full article

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

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16 pages, 1833 KiB

Open AccessReview

Bacteriophages as Therapeutic and Diagnostic Vehicles in Cancer

by Valentina Foglizzo and Serena Marchiò

Pharmaceuticals 2021, 14(2), 161; https://doi.org/10.3390/ph14020161 - 17 Feb 2021

Cited by 35 | Viewed by 6985

Abstract

Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors this process, which has opened up new roads in drug and gene delivery studies. By displaying antibodies, peptides, or proteins on [...] Read more.

Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors this process, which has opened up new roads in drug and gene delivery studies. By displaying antibodies, peptides, or proteins on the surface of different bacteriophages through the phage display technique, it is now possible to unravel specific molecular determinants of both cancer cells and tumor-associated microenvironmental molecules. Downstream applications are manifold, with peptides being employed most of the times to functionalize drug carriers and improve their therapeutic index. Bacteriophages themselves were proven, in this scenario, to be good carriers for imaging molecules and therapeutics as well. Moreover, manipulation of their genetic material to stably vehiculate suicide genes within cancer cells substantially changed perspectives in gene therapy. In this review, we provide examples of how amenable phages can be used as anticancer agents, especially because their systemic administration is possible. We also provide some insights into how their immunogenic profile can be modulated and exploited in immuno-oncology for vaccine production. Full article

(This article belongs to the Special Issue Bacteriophages as Therapeutic Delivery Vehicles)

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17 pages, 2631 KiB

Open AccessArticle

Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment

by Anne-Laure Larroque-Lombard, Etienne Chatelut, Jean-Pierre Delord, Diane-Charlotte Imbs, Philippe Rochaix, Bertrand Jean-Claude and Ben Allal

Pharmaceuticals 2021, 14(2), 160; https://doi.org/10.3390/ph14020160 - 16 Feb 2021

Cited by 3 | Viewed by 3799

Abstract

The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH [...] Read more.

The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model. Its target modulation was studied by western blotting and immunohistochemistry. AL530 released PD98059+CBL-A at mild acidic pH and in vitro was fivefold more potent than CBL and three-to-fivefold more potent than CBL+PD98059. In vivo it released high levels of PD98059 in tumors with a tumor/plasma ratio of five. It induced γ-H2AX phosphorylation and blocked pErk1,2, indirectly indicating its ability to damage DNA and modulate MEK. It induced significant tumor delay and less toxicity at unachievable doses for CBL and CBL+PD98059. We demonstrated the feasibility of a pH-labile combi-molecule capable of delivering high MEK inhibitor concentration in tumors, damaging DNA therein, and inducing tumor growth delay. Full article

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

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9 pages, 585 KiB

Open AccessCase Report

Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature

by Ottavia Bernocchi, Marianna Sirico, Silvia Paola Corona, Carla Strina, Manuela Milani, Maria Rosa Cappelletti, Giuseppina Ferrero, Nicoletta Ziglioli, Valeria Cervoni, Andrea Macchiavelli, Giandomenico Roviello and Daniele Generali

Pharmaceuticals 2021, 14(2), 159; https://doi.org/10.3390/ph14020159 - 16 Feb 2021

Cited by 6 | Viewed by 3503

Abstract

Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting [...] Read more.

Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse. Discussion: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors. Conclusions: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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13 pages, 1210 KiB

Open AccessArticle

Preparation and Bioevaluation of Novel ^99mTc-Labeled Complexes with a 2-Nitroimidazole HYNIC Derivative for Imaging Tumor Hypoxia

by Qing Ruan, Qianqian Gan, Xuran Zhang, Si’an Fang and Junbo Zhang

Pharmaceuticals 2021, 14(2), 158; https://doi.org/10.3390/ph14020158 - 15 Feb 2021

Cited by 6 | Viewed by 3114

Abstract

To develop novel ^99mTc-labeled single-photon emission computed tomography (SPECT) radiotracers for imaging hypoxia, a novel HYNICNM ligand (6-hydrazinonicotinamide (HYNIC) 2-nitroimidazole derivative) was designed and synthesized. It was radiolabeled with technetium-99m using tricine/trisodium triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS), tricine/sodium triphenylphosphine-3-monosulfonate (TPPMS) and tricine as co-ligands to [...] Read more.

To develop novel ^99mTc-labeled single-photon emission computed tomography (SPECT) radiotracers for imaging hypoxia, a novel HYNICNM ligand (6-hydrazinonicotinamide (HYNIC) 2-nitroimidazole derivative) was designed and synthesized. It was radiolabeled with technetium-99m using tricine/trisodium triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS), tricine/sodium triphenylphosphine-3-monosulfonate (TPPMS) and tricine as co-ligands to obtain [^99mTc]Tc-tricine-TPPTS-HYNICNM, [^99mTc]Tc-tricine-TPPMS-HYNICNM, and [^99mTc]Tc-(tricine)₂-HYNICNM, respectively. The three technetium-99m complexes were radiolabeled in one step with a high yield (95%) and had good stability in saline and mouse serum. In vitro cellular uptake results showed that these complexes exhibited good hypoxic selectivity. The partition coefficient indicated that they were good hydrophilic complexes, and [^99mTc]Tc-tricine-TPPTS-HYNICNM displayed the highest hydrophilicity (−3.02 ± 0.08). The biodistribution in mice bearing S180 tumors showed that [^99mTc]Tc-tricine-TPPTS-HYNICNM exhibited higher tumor uptake (1.05 ± 0.27% IA/g); more rapid clearance from the liver, blood, muscle, and other non-target organs; and a higher tumor/non-target ratio, especially for the tumor/liver ratio (1.95), than [^99mTc]Tc-tricine-TPPMS-HYNICNM and [^99mTc]Tc-(tricine)₂-HYNICNM. The results of single-photon emission computed tomography (SPECT) imaging studies of [^99mTc]Tc-tricine-TPPTS-HYNICNM were in accordance with the biodistribution results, which suggested that [^99mTc]Tc-tricine-TPPTS-HYNICNM is a promising agent for imaging tumor hypoxia. Full article

(This article belongs to the Special Issue Forward Thinking towards Theranostic (Radio)ligands Targeting the Tumor Microenvironment (TME))

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28 pages, 6335 KiB

Open AccessReview

Status and Challenges of Plant-Anticancer Compounds in Cancer Treatment

by Paula Garcia-Oliveira, Paz Otero, Antia Gonzalez Pereira, Franklin Chamorro, Maria Carpena, Javier Echave, Maria Fraga-Corral, Jesus Simal-Gandara and Miguel Angel Prieto

Pharmaceuticals 2021, 14(2), 157; https://doi.org/10.3390/ph14020157 - 14 Feb 2021

Cited by 132 | Viewed by 12304

Abstract

Nowadays, cancer is one of the deadliest diseases in the world, which has been estimated to cause 9.9 million deaths in 2020. Conventional treatments for cancer commonly involve mono-chemotherapy or a combination of radiotherapy and mono-chemotherapy. However, the negative side effects of these [...] Read more.

Nowadays, cancer is one of the deadliest diseases in the world, which has been estimated to cause 9.9 million deaths in 2020. Conventional treatments for cancer commonly involve mono-chemotherapy or a combination of radiotherapy and mono-chemotherapy. However, the negative side effects of these approaches have been extensively reported and have prompted the search of new therapeutic drugs. In this context, scientific community started to look for innovative sources of anticancer compounds in natural sources, including traditional plants. Currently, numerous studies have evaluated the anticancer properties of natural compounds derived from plants, both in vitro and in vivo. In pre-clinical stages, some promising compounds could be mentioned, such as the sulforaphane or different phenolic compounds. On the other hand, some phytochemicals obtained positive results in clinical stages and were further approved for cancer treatment, such as vinca alkaloids or the paclitaxel. Nevertheless, these compounds are not exempt of limitations, such as low solubility, restricted effect on their own, negative side-effects, etc. This review aims to compile the information about the current phytochemicals used for cancer treatment and also promising candidates, main action mechanisms and also reported limitations. In this sense, some strategies to face the limitations have been considered, such as nano-based formulations to improve solubility or chemical modification to reduce toxicity. In conclusion, although more research is still necessary to develop more efficient and safe phytochemical drugs, more of these compounds might be used in future cancer therapies. Full article

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

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8 pages, 1294 KiB

Open AccessArticle

Quetiapine-Induced Place Preference in Mice: Possible Dopaminergic Pathway

by Yusuf S. Althobaiti

Pharmaceuticals 2021, 14(2), 156; https://doi.org/10.3390/ph14020156 - 14 Feb 2021

Cited by 4 | Viewed by 2718

Abstract

Quetiapine, an atypical antipsychotic, is effective in the management of schizophrenia, depression, and anxiety. Although quetiapine overdosage and misuse have been reported, its abuse potential has not been investigated in animals. In this study, the abuse potential of quetiapine was assessed based on [...] Read more.

Quetiapine, an atypical antipsychotic, is effective in the management of schizophrenia, depression, and anxiety. Although quetiapine overdosage and misuse have been reported, its abuse potential has not been investigated in animals. In this study, the abuse potential of quetiapine was assessed based on the conditioned place preference (CPP) paradigm of drug addiction in a mouse model. First, mice received intraperitoneal injections of quetiapine (40, 80, or 120 mg/kg) every other day during the conditioning phase. In the second experiment, mice were pretreated with 0.03 mg/kg SKF-35866, a D1 receptor antagonist, before receiving saline or quetiapine (120 mg/kg) during the conditioning phase. No significant changes in time spent in the quetiapine-paired chamber were observed compared with time spent in the saline-paired chamber in mice treated with 40 or 80 mg/kg. In contrast, the preference to the quetiapine-paired chamber was significantly increased in mice treated with 120 mg/kg quetiapine, and this effect was blocked by SKF-35866 pretreatment. These results demonstrated, for the first time, the abuse potential of quetiapine in an animal model of drug addiction. Interestingly, this CPP-inducing effect was likely mediated by activating D1 receptors. Full article

(This article belongs to the Section Medicinal Chemistry)

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18 pages, 3040 KiB

Open AccessArticle

Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents

by Matteo Mori, Giovanni Stelitano, Laurent R. Chiarelli, Giulia Cazzaniga, Arianna Gelain, Daniela Barlocco, Elena Pini, Fiorella Meneghetti and Stefania Villa

Pharmaceuticals 2021, 14(2), 155; https://doi.org/10.3390/ph14020155 - 13 Feb 2021

Cited by 24 | Viewed by 3939

Abstract

Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An [...] Read more.

Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of I and II, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (IV–IX), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (IV), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound IV offers promising prospects for future studies on the development of novel agents against mycobacterial infections. Full article

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

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12 pages, 304 KiB

Open AccessReview

The Treatment of Lung Involvement in Systemic Sclerosis

by Barbara Ruaro, Marco Confalonieri, Marco Matucci-Cerinic, Francesco Salton, Paola Confalonieri, Mario Santagiuliana, Gloria Maria Citton, Elisa Baratella and Cosimo Bruni

Pharmaceuticals 2021, 14(2), 154; https://doi.org/10.3390/ph14020154 - 13 Feb 2021

Cited by 17 | Viewed by 3308

Abstract

Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous [...] Read more.

Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous SSc or anti-topoisomerase 1 antibodies are most commonly affected. Currently, early ILD diagnosis can be made, and it is pivotal to improve the prognosis. The diagnostic mainstay test for SSc-ILD is high-resolution computed tomography for the morphology and pulmonary function tests for the functional aspects. Treatment planning and intensity are guided by the disease severity and risk of progression. Traditionally, therapy has depended on combinations of immunosuppressants, particularly cyclophosphamide and mycophenolate mofetil, which can be supplemented by targeted biological and antifibrotic therapies. Benefits have been observed in trials on hematopoietic autologous stem cell transplantation for patients with progressive SSc, whilst lung transplantation is reserved for refractory SSc-ILD cases. Herein, recent advances in SSc-ILD treatment will be explored. Full article

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

17 pages, 3619 KiB

Open AccessArticle

Pharyngeal Pumping and Tissue-Specific Transgenic P-Glycoprotein Expression Influence Macrocyclic Lactone Susceptibility in Caenorhabditis elegans

by Alexander P. Gerhard, Jürgen Krücken, Cedric Neveu, Claude L. Charvet, Abdallah Harmache and Georg von Samson-Himmelstjerna

Pharmaceuticals 2021, 14(2), 153; https://doi.org/10.3390/ph14020153 - 13 Feb 2021

Cited by 13 | Viewed by 3424

Abstract

Macrocyclic lactones (MLs) are widely used drugs to treat and prevent parasitic nematode infections. In many nematode species including a major pathogen of foals, Parascaris univalens, resistance against MLs is widespread, but the underlying resistance mechanisms and ML penetration routes into nematodes [...] Read more.

Macrocyclic lactones (MLs) are widely used drugs to treat and prevent parasitic nematode infections. In many nematode species including a major pathogen of foals, Parascaris univalens, resistance against MLs is widespread, but the underlying resistance mechanisms and ML penetration routes into nematodes remain unknown. Here, we examined how the P-glycoprotein efflux pumps, candidate genes for ML resistance, can modulate drug susceptibility and investigated the role of active drug ingestion for ML susceptibility in the model nematode Caenorhabditis elegans. Wildtype or transgenic worms, modified to overexpress P. univalens PGP-9 (Pun-PGP-9) at the intestine or epidermis, were incubated with ivermectin or moxidectin in the presence (bacteria or serotonin) or absence (no specific stimulus) of pharyngeal pumping (PP). Active drug ingestion by PP was identified as an important factor for ivermectin susceptibility, while moxidectin susceptibility was only moderately affected. Intestinal Pun-PGP-9 expression elicited a protective effect against ivermectin and moxidectin only in the presence of PP stimulation. Conversely, epidermal Pun-PGP-9 expression protected against moxidectin regardless of PP and against ivermectin only in the absence of active drug ingestion. Our results demonstrate the role of active drug ingestion by nematodes for susceptibility and provide functional evidence for the contribution of P-glycoproteins to ML resistance in a tissue-specific manner. Full article

(This article belongs to the Special Issue Antiparasitics)

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14 pages, 824 KiB

Open AccessReview

Therapeutic Applications of Type 2 Diabetes Mellitus Drug Metformin in Patients with Osteoarthritis

by Parkyong Song, Ji Sun Hwang, Hyean Cheal Park, Keun Ki Kim, Hong-Joo Son, Yu-Jin Kim and Kwang Min Lee

Pharmaceuticals 2021, 14(2), 152; https://doi.org/10.3390/ph14020152 - 13 Feb 2021

Cited by 13 | Viewed by 3550

Abstract

Type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) are common chronic diseases that frequently co-exist. The link between OA and T2DM is attributed to common risk factors, including age and obesity. Several reports suggest that hyperglycemia and accumulated advanced glycosylation end-products might regulate [...] Read more.

Type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) are common chronic diseases that frequently co-exist. The link between OA and T2DM is attributed to common risk factors, including age and obesity. Several reports suggest that hyperglycemia and accumulated advanced glycosylation end-products might regulate cartilage homeostasis and contribute to the development and progression of OA. Metformin is used widely as the first-line treatment for T2DM. The drug acts by regulating glucose levels and improving insulin sensitivity. The anti-diabetic effects of metformin are mediated mainly via activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is an energy sensing enzyme activated directly by an increase in the AMP/ATP ratio under conditions of metabolic stress. Dysregulation of AMPK is strongly associated with development of T2DM and metabolic syndrome. In this review, we discuss common risk factors, the association between OA and T2DM, and the role of AMPK. We also address the adaptive use of metformin, a known AMPK activator, as a new drug for treatment of patients with OA and T2DM. Full article

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

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18 pages, 982 KiB

Open AccessReview

Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

by Anica Högner and Peter Thuss-Patience

Pharmaceuticals 2021, 14(2), 151; https://doi.org/10.3390/ph14020151 - 12 Feb 2021

Cited by 18 | Viewed by 5025

Abstract

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit [...] Read more.

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitor Therapy)

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13 pages, 379 KiB

Open AccessArticle

Assessment of Novel Inhaler Technique Reminder Labels in Image Format on the Correct Demonstration of Inhaler Technique Skills in Asthma: A Single-Blinded Randomized Controlled Trial

by Iman Basheti, Bassam Mahboub, Laila Salameh, Mena Al-Ani, Ammar Abdulrahman Jairoun, Basema Saddik and Eman Abu-Gharbieh

Pharmaceuticals 2021, 14(2), 150; https://doi.org/10.3390/ph14020150 - 12 Feb 2021

Cited by 4 | Viewed by 2202

Abstract

Background: Prevalence of asthma in the United Arab Emirates (UAE) is high, and training patients on correct inhaler technique is vital. Objectives: To assess the effectiveness of inhaler technique labels incorporating the individual technique steps in image format on the retention of correct [...] Read more.

Background: Prevalence of asthma in the United Arab Emirates (UAE) is high, and training patients on correct inhaler technique is vital. Objectives: To assess the effectiveness of inhaler technique labels incorporating the individual technique steps in image format on the retention of correct inhaler technique for patients with asthma living in the UAE and following inhaler training; secondly to investigate the effect of inhaler technique education using self-check pictorial labels on patients’ overall asthma control. Methods: This single-blinded randomized controlled study was conducted in 2019 and followed consecutive recruitment of asthma patients visiting respiratory clinics at Rashid Hospital in Dubai. Patients were using a controller inhaler (Turbuhaler (TH), Accuhaler (ACC), or pressurized metered-dose inhaler (pMDI)). Following recruitment, patients were randomized into active group receiving educational intervention plus the inhaler label, and control group receiving educational intervention without the label. Patients were assessed at baseline and at one-month on their inhaler technique and asthma control. Results: Participants (n = 245; 93 = TH, 70 = ACC, 82 = pMDI) showed a significant difference between the groups at one-month for inhaler technique scores for TH (active 5.29 ± 1.86 vs. control = 24.4 ± 21.28), ACC (active = 3.99 ± 1.43 vs. control = 25.45 ± 22.57), and pMDI (active = 4.59 ± 0.10 vs. control = 120.55 ± 17.2), p < 0.001 for all. Asthma control for active group indicated significant improvements compared to control for TH and pMDI (p < 0.001 for both), but not ACC group (p = 0.087). Conclusions: Retention of correct inhaler technique and improved asthma control can be enhanced by using a specialized inhaler technique label in image format. Full article

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23 pages, 3860 KiB

Open AccessReview

The Role of miRNA-7 in the Biology of Cancer and Modulation of Drug Resistance

by Ewa Gajda, Małgorzata Grzanka, Marlena Godlewska and Damian Gawel

Pharmaceuticals 2021, 14(2), 149; https://doi.org/10.3390/ph14020149 - 12 Feb 2021

Cited by 15 | Viewed by 3259

Abstract

MicroRNAs (miRNAs, miRs) are small non-coding RNA (ncRNA) molecules capable of regulating post-transcriptional gene expression. Imbalances in the miRNA network have been associated with the development of many pathological conditions and diseases, including cancer. Recently, miRNAs have also been linked to the phenomenon [...] Read more.

MicroRNAs (miRNAs, miRs) are small non-coding RNA (ncRNA) molecules capable of regulating post-transcriptional gene expression. Imbalances in the miRNA network have been associated with the development of many pathological conditions and diseases, including cancer. Recently, miRNAs have also been linked to the phenomenon of multidrug resistance (MDR). MiR-7 is one of the extensively studied miRNAs and its role in cancer progression and MDR modulation has been highlighted. MiR-7 is engaged in multiple cellular pathways and acts as a tumor suppressor in the majority of human neoplasia. Its depletion limits the effectiveness of anti-cancer therapies, while its restoration sensitizes cells to the administered drugs. Therefore, miR-7 might be considered as a potential adjuvant agent, which can increase the efficiency of standard chemotherapeutics. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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46 pages, 6710 KiB

Open AccessReview

Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence

by Gustavo R. Villas-Boas, Stefânia N. Lavorato, Marina M. Paes, Pablinny M. G. de Carvalho, Vanessa C. Rescia, Mila S. Cunha, Manoel F. de Magalhães-Filho, Luis F. Ponsoni, Adryano Augustto Valladao de Carvalho, Roseli B. de Lacerda, Lais da S. Leite, Matheus da S. Tavares-Henriques, Luiz A. F. Lopes, Luiz G. R. Oliveira, Saulo E. Silva-Filho, Ana P. S. da Silveira, Roberto K. N. Cuman, Francielli M. de S. Silva-Comar, Jurandir F. Comar, Luana do A. Brasileiro, Jussileide N. dos Santos, William R. de Freitas, Katyuscya V. Leão, Jonatas G. da Silva, Raphael C. Klein, Mary H. F. Klein, Bruno H. da S. Ramos, Cristiane K. C. Fernandes, Dayane G. de L. Ribas and Silvia A. Oesterreich Show full author list Hide full author list

Pharmaceuticals 2021, 14(2), 148; https://doi.org/10.3390/ph14020148 - 12 Feb 2021

Cited by 20 | Viewed by 6433

Abstract

Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such [...] Read more.

Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the “serotonergic receptosome” in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors. Full article

(This article belongs to the Special Issue Molecular Pharmacology of 5-HT Receptors)

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17 pages, 1448 KiB

Open AccessArticle

Application of RP-18 TLC Retention Data to the Prediction of the Transdermal Absorption of Drugs

by Anna W. Sobańska, Jeremy Robertson and Elżbieta Brzezińska

Pharmaceuticals 2021, 14(2), 147; https://doi.org/10.3390/ph14020147 - 12 Feb 2021

Cited by 13 | Viewed by 2499

Abstract

Several chromatographic parameters (R_M⁰ and S obtained from RP-18 TLC with methanol—pH 7.4 phosphate buffer mobile phases by extrapolation to zero concentration of methanol; R_f and R_M obtained from RP-18 TLC with acetonitrile—pH 7.4 phosphate buffer 70:30 v [...] Read more.

Several chromatographic parameters (R_M⁰ and S obtained from RP-18 TLC with methanol—pH 7.4 phosphate buffer mobile phases by extrapolation to zero concentration of methanol; R_f and R_M obtained from RP-18 TLC with acetonitrile—pH 7.4 phosphate buffer 70:30 v/v as a mobile phase) and calculated molecular descriptors (molecular weight—M_W; molar volume—V_M; polar surface area—PSA; total count of nitrogen and oxygen atoms—(N+O); H-bond donor count—HD; H-bond acceptor count—HA; distribution coefficient—log D; total energy—E_T; binding energy—E_b; hydration energy—E_h; energy of the highest occupied molecular orbital—E_HOMO; energy of the lowest unoccupied orbital—E_LUMO; electronic energy—E_e; surface area—S_a; octanol-water partition coefficient—log P; dipole moment—DM; refractivity—R, polarizability—α) and their combinations (R_f/PSA, R_M/M_W, R_M/V_M) were tested in order to generate useful models of solutes’ skin permeability coefficient log K_p. It was established that neither R_M⁰ nor S obtained in the conditions used in this study is a good predictor of the skin permeability coefficient. The chromatographic parameters R_f and R_f/PSA were also unsuitable for this purpose. A simple and potentially useful, purely computational model based on (N+O), log D and HD as independent variables and accounting for ca. 83% of total variability was obtained. The evaluation of parameters derived from R_M (R_M, R_M/M_W, R_M/V_M) as independent variables in log K_p models proved that R_M/V_M is the most suitable descriptor belonging to this group. In a search for a reliable log K_p model based on this descriptor two possibilities were considered: a relatively simple model based on 5 independent variables: (N+O), log D, R_M/V_M, E_T and E_h and a more complex one, involving also E_b, M_W and PSA. Full article

(This article belongs to the Special Issue Selected Papers from the 6th International Electronic Conference on Medicinal Chemistry (ECMC2020))

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26 pages, 7174 KiB

Open AccessArticle

Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis

by Summya Rashid, Adil Farooq Wali, Shahzada Mudasir Rashid, Rana M. Alsaffar, Ajaz Ahmad, Basit L. Jan, Bilal Ahmad Paray, Saeed M. A. Alqahtani, Azher Arafah and Muneeb U. Rehman

Pharmaceuticals 2021, 14(2), 146; https://doi.org/10.3390/ph14020146 - 11 Feb 2021

Cited by 23 | Viewed by 3234

Abstract

Epilepsy is an intricate neurological disease where the neurons are severely affected, leading to the mortality of millions worldwide. Status epilepticus (SE), induced by lithium chloride (LiCl) and pilocarpine, is the most accepted model for epilepsy. The current work aims to unravel the [...] Read more.

Epilepsy is an intricate neurological disease where the neurons are severely affected, leading to the mortality of millions worldwide. Status epilepticus (SE), induced by lithium chloride (LiCl) and pilocarpine, is the most accepted model for epilepsy. The current work aims to unravel the mechanisms underlying the anti-epileptic efficacy of zingerone (an active ingredient of ginger), which has beneficial pharmacological activities on seizure-induced behavioral, histological, neurochemical, and molecular patterns in mice. Zingerone restored cognitive function by diminishing seizure activity, escape latency, and subsequent hippocampal damage manifested in histology. Seizures are associated with local inflammation, redox imbalance, and neural loss, confirmed by the present study of SE, and was attenuated by zingerone treatment. Nuclear factor-kappa B and its downstream signaling molecules (TNF-α, IL-1β, IL-6, NO, MPO) were activated in the LiCl-and-pilocarpine-induced group leading to inflammatory signaling, which was substantially ameliorated by zingerone treatment. The intrinsic apoptotic process was triggered subsequent to SE, as demonstrated by augmentation of cleaved caspase-3, downregulation of Bcl-2. However, zingerone treatment downregulated caspase-3 and upregulated Bcl-2, increasing cell survival and decreasing hippocampal neural death, deciphering involvement of apoptosis in SE. Therefore, zingerone plays an essential role in neuroprotection, probably by precluding oxidative stress, inflammation, and obstructing the mitochondrial pathway of apoptosis. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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14 pages, 1726 KiB

Open AccessFeature PaperEditor’s ChoiceReview

2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

by Othman Al Musaimi, Danah Al Shaer, Fernando Albericio and Beatriz G. de la Torre

Pharmaceuticals 2021, 14(2), 145; https://doi.org/10.3390/ph14020145 - 11 Feb 2021

Cited by 56 | Viewed by 5717

Abstract

2020 has been an extremely difficult and challenging year as a result of the coronavirus disease 2019 (COVID-19) pandemic and one in which most efforts have been channeled into tackling the global health crisis. The US Food and Drug Administration (FDA) has approved [...] Read more.

2020 has been an extremely difficult and challenging year as a result of the coronavirus disease 2019 (COVID-19) pandemic and one in which most efforts have been channeled into tackling the global health crisis. The US Food and Drug Administration (FDA) has approved 53 new drug entities, six of which fall in the peptides and oligonucleotides (TIDES) category. The number of authorizations for these kinds of drugs has been similar to that of previous years, thereby reflecting the consolidation of the TIDES market. Here, the TIDES approved in 2020 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects. Full article

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

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Pharmaceuticals, Volume 14, Issue 2 (February 2021) – 100 articles

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