Pharmaceuticals

15 pages, 1882 KiB

Open AccessArticle

4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases

by Pasquale Linciano, Eleonora Gianquinto, Martina Montanari, Lorenzo Maso, Pierangelo Bellio, Esmeralda Cebrián-Sastre, Giuseppe Celenza, Jesús Blázquez, Laura Cendron, Francesca Spyrakis and Donatella Tondi

Pharmaceuticals 2020, 13(3), 52; https://doi.org/10.3390/ph13030052 - 24 Mar 2020

Cited by 15 | Viewed by 4851

Abstract

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available β-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of β [...] Read more.

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available β-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of β-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine β−Lactamase (SBLs) KPC-2 and class B1 metallo β−Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent in silico analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems. Full article

(This article belongs to the Section Medicinal Chemistry)

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9 pages, 259 KiB

Open AccessCommentary

Emetine, Ipecac, Ipecac Alkaloids and Analogues as Potential Antiviral Agents for Coronaviruses

by Martin D. Bleasel and Gregory M. Peterson

Pharmaceuticals 2020, 13(3), 51; https://doi.org/10.3390/ph13030051 - 21 Mar 2020

Cited by 61 | Viewed by 11602

Abstract

The COVID-19 coronavirus is currently spreading around the globe with limited treatment options available. This article presents the rationale for potentially using old drugs (emetine, other ipecac alkaloids or analogues) that have been used to treat amoebiasis in the treatment of COVID-19. Emetine [...] Read more.

The COVID-19 coronavirus is currently spreading around the globe with limited treatment options available. This article presents the rationale for potentially using old drugs (emetine, other ipecac alkaloids or analogues) that have been used to treat amoebiasis in the treatment of COVID-19. Emetine had amongst the lowest reported half-maximal effective concentration (EC₅₀) from over 290 agents screened for the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses. While EC₅₀ concentrations of emetine are achievable in the blood, studies show that concentrations of emetine can be almost 300 times higher in the lungs. Furthermore, based on the relative EC₅₀s of emetine towards the coronaviruses compared with Entamoeba histolytica, emetine could be much more effective as an anti-coronavirus agent than it is against amoebiasis. This paper also discusses the known side effects of emetine and related compounds, how those side effects can be managed, and the optimal method of administration for the potential treatment of COVID-19. Given the serious and immediate threat that the COVID-19 coronavirus poses, our long history with emetine and the likely ability of emetine to reach therapeutic concentrations within the lungs, ipecac, emetine, and other analogues should be considered as potential treatment options, especially if in vitro studies confirm viral sensitivity. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

20 pages, 1322 KiB

Open AccessArticle

Unveiling Pharmacological Responses and Potential Targets Insights of Identified Bioactive Constituents of Cuscuta reflexa Roxb. Leaves through In Vivo and In Silico Approaches

by Md. Adnan, Md. Nazim Uddin Chy, A.T.M. Mostafa Kamal, Md. Riad Chowdhury, Md. Shariful Islam, Md. Amzad Hossain, Abu Montakim Tareq, Md. Imam Hossain Bhuiyan, Md Nasim Uddin, Afroza Tahamina, Md Obyedul Kalam Azad, Young Seok Lim and Dong Ha Cho

Pharmaceuticals 2020, 13(3), 50; https://doi.org/10.3390/ph13030050 - 20 Mar 2020

Cited by 18 | Viewed by 7389

Abstract

Cuscuta reflexa Roxb. is traditionally used by the indigenous communities of Bangladesh to treat different diseases, such as pain, edema, tumor, jaundice, and skin infections. This study tested neuro-pharmacological, anti-nociceptive, and antidiarrheal activities by in vivo and in silico experiments for the metabolites [...] Read more.

Cuscuta reflexa Roxb. is traditionally used by the indigenous communities of Bangladesh to treat different diseases, such as pain, edema, tumor, jaundice, and skin infections. This study tested neuro-pharmacological, anti-nociceptive, and antidiarrheal activities by in vivo and in silico experiments for the metabolites extracted (methanol) from the leaves of Cuscuta reflexa (MECR). During the anxiolytic evaluation analyzed by elevated plus maze and hole board tests, MECR (200 and 400 mg/kg) exhibited a significant dose-dependent reduction of anxiety-like behavior in mice. Similarly, mice treated with MECR demonstrated a dose-dependent decrease in the time of immobility in both forced swimming and tail suspension tests. In addition, anti-nociceptive activity was assessed by the chemical-induced (acetic acid and formalin) pain models. In both cases, 400 mg/kg was found to be most effective and significantly (p < 0.001) inhibited acetic acid stimulated writhing and formalin-induced licking (pain response) in mice. Furthermore, antidiarrheal efficacy determined by the castor-oil induced diarrheal model manifested an evident inhibition of diarrheal stool frequency. In parallel, previously isolated bioactive compounds were documented based on the biological activities and subjected to in silico studies to correlate with the current pharmacological outcomes. The selected isolated compounds (15) displayed favorable binding affinities to potassium channels, human serotonin receptor, COX-1, COX-2, M3 muscarinic acetylcholine receptor, and 5-HT3 receptor proteins. Additionally, the ADME/T and toxicological properties were justified to unveil their drug-like properties and toxicity level. Overall, Cuscuta reflexa is bioactive and could be a potential source for the development of alternative medicine. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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17 pages, 3729 KiB

Open AccessReview

Regenerative Injections Including 5% Dextrose and Platelet-Rich Plasma for the Treatment of Carpal Tunnel Syndrome: A Systematic Review and Network Meta-Analysis

by Chih-Peng Lin, Ke-Vin Chang, Yi-Kai Huang, Wei-Ting Wu and Levent Özçakar

Pharmaceuticals 2020, 13(3), 49; https://doi.org/10.3390/ph13030049 - 18 Mar 2020

Cited by 43 | Viewed by 5814

Abstract

This network meta-analysis aimed to integrate the available direct and indirect evidence on regenerative injections—including 5% dextrose (D5W) and platelet-rich plasma (PRP)—for the treatment of carpal tunnel syndrome (CTS). Literature reports comparing D5W and PRP injections with non-surgical managements of CTS were systematically [...] Read more.

This network meta-analysis aimed to integrate the available direct and indirect evidence on regenerative injections—including 5% dextrose (D5W) and platelet-rich plasma (PRP)—for the treatment of carpal tunnel syndrome (CTS). Literature reports comparing D5W and PRP injections with non-surgical managements of CTS were systematically reviewed. The main outcome was the standardized mean difference (SMD) of the symptom severity and functional status scales of the Boston Carpal Tunnel Syndrome Questionnaire at three months after injections. Ranking probabilities of the SMD of each treatment were acquired by using simulation. Ten studies with 497 patients and comparing five treatments (D5W, PRP, splinting, corticosteroid, and normal saline) were included. The results of the simulation of rank probabilities showed that D5W injection was likely to be the best treatment, followed by PRP injection, in terms of clinical effectiveness in providing symptom relief. With respect to functional improvement, splinting ranked higher than PRP and D5W injections. Lastly, corticosteroid and saline injections were consistently ranked fourth and fifth in terms of therapeutic effects on symptom severity and functional status. D5W and PRP injections are more effective than splinting and corticosteroid or saline injection for relieving the symptoms of CTS. Compared with splinting, D5W and PRP injections do not provide better functional recovery. More studies investigating the long-term effectiveness of regenerative injections in CTS are needed in the future. Full article

(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)

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18 pages, 5643 KiB

Open AccessArticle

Administration of Bacterial Lipopolysaccharide during Early Postnatal Ontogenesis Induces Transient Impairment of Long-Term Synaptic Plasticity Associated with Behavioral Abnormalities in Young Rats

by Tatyana Y. Postnikova, Alexandra V. Griflyuk, Julia L. Ergina, Olga E. Zubareva and Aleksey V. Zaitsev

Pharmaceuticals 2020, 13(3), 48; https://doi.org/10.3390/ph13030048 - 18 Mar 2020

Cited by 7 | Viewed by 3922

Abstract

Infectious diseases in early postnatal ontogenesis often result in cognitive impairments, particularly learning and memory. The essential foundation of learning and memory is long-term synaptic plasticity, which depends on N-methyl-D-aspartate (NMDA) receptors. In the present study, bacterial infection was modeled by treating rat [...] Read more.

Infectious diseases in early postnatal ontogenesis often result in cognitive impairments, particularly learning and memory. The essential foundation of learning and memory is long-term synaptic plasticity, which depends on N-methyl-D-aspartate (NMDA) receptors. In the present study, bacterial infection was modeled by treating rat pups with bacterial lipopolysaccharide (LPS, 25 µg/kg) three times, during either the first or the third week of life. These time points are critical for the maturation of NMDA receptors. We assessed the effects of LPS treatments on the properties of long-term potentiation (LTP) in the CA1 hippocampus of young (21–23 days) and adolescent (51–55 days) rats. LTP magnitude was found to be significantly reduced in both groups of young rats, which also exhibited investigative and motor behavior disturbances in the open field test. No changes were observed in the main characteristics of synaptic transmission, although the LTP induction mechanism was disturbed. In rats treated with LPS during the third week, the NMDA-dependent form of LTP was completely suppressed, and LTP switched to the Type 1 metabotropic glutamate receptor (mGluR1)-dependent form. These impairments of synaptic plasticity and behavior were temporary. In adolescent rats, no difference was observed in LTP properties between the control and experimental groups. Lastly, the investigative and motor behavior parameters in both groups of adult rats were similar. Full article

(This article belongs to the Special Issue Choices of the Journal)

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16 pages, 5532 KiB

Open AccessArticle

In Vitro Anti-Prostate Cancer Activity of Two Ebselen Analogues

by Katarzyna B. Kaczor-Keller, Anna Pawlik, Jacek Scianowski, Agata Pacuła, Magdalena Obieziurska, Fabio Marcheggiani, Ilenia Cirilli, Luca Tiano and Jedrzej Antosiewicz

Pharmaceuticals 2020, 13(3), 47; https://doi.org/10.3390/ph13030047 - 17 Mar 2020

Cited by 12 | Viewed by 4094

Abstract

Scientific research has been underway for decades in order to develop an effective anticancer drug, and it has become crucial to find a novel and effective chemotherapeutics in the case of prostate cancer treatment. Ebselen derivatives have been shown to possess a variety [...] Read more.

Scientific research has been underway for decades in order to develop an effective anticancer drug, and it has become crucial to find a novel and effective chemotherapeutics in the case of prostate cancer treatment. Ebselen derivatives have been shown to possess a variety of biological activities, including cytostatic and cytotoxic action against tumor cells. In this study, the cytotoxic effect and anticancer mechanism of action of two organoselenium compounds— (N-allyl-1,2-benzisoselenazol-3(2H)-one (N-allyl-BS) and N-(3-methylbutyl)-1,2-benzisoselenazol-3(2H)-one) (N-(3-mb)-BS)—were investigated on two phenotypically different prostate cancer cell lines DU 145 and PC-3. The influence of analyzed compounds on the viability parameter was also assessed on normal prostate cell line PNT1A. The results showed that both organoselenium compounds (OSCs) efficiently inhibited cancer cell proliferation, whereas normal PNT1A cells were less sensitive to the analazyed ebselen analouges. Both OSCs induced G2/M cell cycle arrest and prompted cell death through apoptosis. The detection of cleaved Poly (ADP-ribose) Polymerase (PARP) confirmed this. In addition, N-allyl-BS and N-(3-m)-b-BS increased the level of reactive oxygen species (ROS) formation, however only N-allyl-BS induced DNA damage. Based on our data, we assume that OSCs’ anticancer action can be associated with oxidative stress induction and inactivation of the Akt- dependent signalling pathway. In conclusion, our data demonstrate that ebselen derivatives showed strong cytotoxic efficiency towards prostate cancer cells and may be elucidated as a novel, potent anticancer agent. Full article

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

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17 pages, 1502 KiB

Open AccessArticle

Products Derived from Buchenavia tetraphylla Leaves Have In Vitro Antioxidant Activity and Protect Tenebrio molitor Larvae against Escherichia coli-Induced Injury

by Tiago Fonseca Silva, José Robson Neves Cavalcanti Filho, Mariana Mirelle Lima Barreto Fonsêca, Natalia Medeiros dos Santos, Ana Carolina Barbosa da Silva, Adrielle Zagmignan, Afonso Gomes Abreu, Ana Paula Sant’Anna da Silva, Vera Lúcia de Menezes Lima, Nicácio Henrique da Silva, Lívia Macedo Dutra, Jackson Roberto Guedes da Silva Almeida, Márcia Vanusa da Silva, Maria Tereza dos Santos Correia and Luís Cláudio Nascimento da Silva

Pharmaceuticals 2020, 13(3), 46; https://doi.org/10.3390/ph13030046 - 16 Mar 2020

Cited by 15 | Viewed by 3819

Abstract

The relevance of oxidative stress in the pathogenesis of several diseases (including inflammatory disorders) has traditionally led to the search for new sources of antioxidant compounds. In this work, we report the selection of fractions with high antioxidant action from B. tetraphylla (BT) [...] Read more.

The relevance of oxidative stress in the pathogenesis of several diseases (including inflammatory disorders) has traditionally led to the search for new sources of antioxidant compounds. In this work, we report the selection of fractions with high antioxidant action from B. tetraphylla (BT) leaf extracts. In vitro methods (DPPH and ABTS assays; determination of phenolic and flavonoid contents) were used to select products derived from B. tetraphylla with high antioxidant action. Then, the samples with the highest potentials were evaluated in a model of injury based on the inoculation of a lethal dose of heat-inactivated Escherichia coli in Tenebrio molitor larvae. Due to its higher antioxidant properties, the methanolic extract (BTME) was chosen to be fractionated using Sephadex LH-20 column-based chromatography. Two fractions from BTME (BTFC and BTFD) were the most active fractions. Pre-treatment with these fractions protected larvae of T. molitor from the stress induced by inoculation of heat-inactivated E. coli. Similarly, BTFC and BTFD increased the lifespan of larvae infected with a lethal dose of enteroaggregative E. coli 042. NMR data indicated the presence of aliphatic compounds (terpenes, fatty acids, carbohydrates) and aromatic compounds (phenolic compounds). These findings suggested that products derived from B. tetraphylla leaves are promising candidates for the development of antioxidant and anti-infective agents able to treat oxidative-related dysfunctions. Full article

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

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22 pages, 5295 KiB

Open AccessArticle

Effects of an Adaptogenic Extract on Electrical Activity of the Brain in Elderly Subjects with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled, Two-Armed Cross-Over Study

by Wilfried Dimpfel, Leonie Schombert, Ingrid K. Keplinger-Dimpfel and Alexander Panossian

Pharmaceuticals 2020, 13(3), 45; https://doi.org/10.3390/ph13030045 - 14 Mar 2020

Cited by 7 | Viewed by 6374

Abstract

Background: The current and potential uses of adaptogens are mainly related to treatment of stress-induced fatigue, impaired cognitive function, mental illness, and behavioral- and age-related disorders. However, clinical evidence regarding the efficacy of adaptogens is limited. The primary aim of this study is [...] Read more.

Background: The current and potential uses of adaptogens are mainly related to treatment of stress-induced fatigue, impaired cognitive function, mental illness, and behavioral- and age-related disorders. However, clinical evidence regarding the efficacy of adaptogens is limited. The primary aim of this study is to determine whether a combination of adaptogenic plant extracts from Andrographis paniculata and Withania somnifera (Adaptra^® Forte) could be used as effective and safe treatment for impaired cognitive, memory, or learning ability functions and sleep disorders. Methods: The changes in electroencephalogram (EEG) frequency ranges in 17 different brain regions, psychometric tests of cognitive performance, as well as standard questionnaires of assessment of mood and sleep were measured after single and repeated administration of Adaptra^® or placebo for four weeks and after a two-week treatment-free follow-up period within a randomized, double-blind, placebo-controlled two-armed cross-over study. Results: Adaptra^® Forte significantly improved cognitive performance in the d2-Test for attention and the concentration performance test after four weeks’ treatment, and was positively correlated with increases in δ and θ power in the quantitative EEG compared with placebo during cognitive challenges. Conclusion: The results of this study suggest that Adaptra^® Forte exhibits a calming and anxiolytic effect without sedation, and is associated with overall stress-protective activity. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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16 pages, 3776 KiB

Open AccessArticle

Preparation, Characterization, and Evaluation of Cisplatin-Loaded Polybutylcyanoacrylate Nanoparticles with Improved In Vitro and In Vivo Anticancer Activities

by Mohsen Ghaferi, Samar Amari, Bhalchandra Vivek Mohrir, Aun Raza, Hasan Ebrahimi Shahmabadi and Seyed Ebrahim Alavi

Pharmaceuticals 2020, 13(3), 44; https://doi.org/10.3390/ph13030044 - 11 Mar 2020

Cited by 55 | Viewed by 4251

Abstract

This study aimed to evaluate the therapeutic efficacy of the cisplatin encapsulated into polybutylcyanoacrylate (PBCA) nanoparticles for the treatment of kidney cancer. The nanoformulation was successfully developed using the miniemulsion polymerization method and characterized in terms of size, size distribution, drug loading and [...] Read more.

This study aimed to evaluate the therapeutic efficacy of the cisplatin encapsulated into polybutylcyanoacrylate (PBCA) nanoparticles for the treatment of kidney cancer. The nanoformulation was successfully developed using the miniemulsion polymerization method and characterized in terms of size, size distribution, drug loading and encapsulation efficiencies, drug release behavior, in vitro cytotoxicity effects, in vivo toxicity, and therapeutic effects. Cisplatin-loaded PBCA nanoparticles were confirmed to be in nanoscale with the drug entrapment efficiency of 23% and controlled drug release profile, in which only 9% of the loaded drug was released after 48 h. The nanoparticles caused an increase in the cytotoxicity effects of cisplatin against renal cell adenocarcinoma cells (ACHN) (2.3-fold) and considerably decreased blood urea nitrogen and creatinine concentrations when compared to the standard cisplatin (1.6-fold and 1.5-fold, respectively). The nanoformulation also caused an increase in the therapeutic effects of cisplatin by 1.8-fold, in which a reduction in the mean tumor size was seen (3.5 mm vs. 6.5 mm) when compared to the standard cisplatin receiver rats. Overall, cisplatin-loaded PBCA nanoparticles can be considered as a promising drug candidate for the treatment of kidney cancer due to its potency to reduce the side effects of cisplatin and its toxicity and therapeutic effects on cancer-bearing Wistar rats. Full article

(This article belongs to the Section Biopharmaceuticals)

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19 pages, 5736 KiB

Open AccessArticle

Fatty Acid Amides Synthesized from Andiroba Oil (Carapa guianensis Aublet.) Exhibit Anticonvulsant Action with Modulation on GABA-A Receptor in Mice: A Putative Therapeutic Option

by Fábio Rodrigues de Oliveira, Keuri Eleuterio Rodrigues, Moisés Hamoy, Ícaro Rodrigues Sarquis, Akira Otake Hamoy, Maria Elena Crespo Lopez, Irlon Maciel Ferreira, Barbarella de Matos Macchi and José Luiz Martins do Nascimento

Pharmaceuticals 2020, 13(3), 43; https://doi.org/10.3390/ph13030043 - 10 Mar 2020

Cited by 12 | Viewed by 4219

Abstract

Epilepsy is a chronic neurological disease characterized by excessive neuronal activity leading to seizure; about 30% of affected patients suffer from the refractory and pharmacoresistant form of the disease. The anticonvulsant drugs currently used for seizure control are associated with adverse reactions, making [...] Read more.

Epilepsy is a chronic neurological disease characterized by excessive neuronal activity leading to seizure; about 30% of affected patients suffer from the refractory and pharmacoresistant form of the disease. The anticonvulsant drugs currently used for seizure control are associated with adverse reactions, making it important to search for more effective drugs with fewer adverse reactions. There is increasing evidence that endocannabinoids can pharmacologically modulate action against seizure and antiepileptic disorders. Therefore, the objective of this study is to investigate the anticonvulsant effects of fatty acid amides (FAAs) in a pentylenetetrazole (PTZ)-induced seizure model in mice. FAAs (FAA1 and FAA2) are obtained from Carapa guianensis oil by biocatalysis and are characterized by Fourier Transform Infrared Analysis (FT-IR) and Gas Chromatography-Mass Spectrometry (GC-MS). Only FAA1 is effective in controlling the increased latency time of the first myoclonic jerk and in significantly decreasing the total duration of tonic-clonic seizures relative to the pentylenetetrazol model. Also, electrocortical alterations produced by pentylenetetrazol are reduced when treated by FAA1 that subsequently decreased wave amplitude and energy in Beta rhythm. The anticonvulsant effects of FAA1 are reversed by flumazenil, a benzodiazepine antagonist on Gamma-Aminobutyric Acid-A (GABA-A) receptors, indicating a mode of action via the benzodiazepine site of these receptors. To conclude, the FAA obtained from C. guianensis oil is promising against PTZ-induced seizures. Full article

(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)

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11 pages, 1059 KiB

Open AccessBrief Report

Is There a Role for the Therapeutic Drug Monitoring of Colistin? An Overview

by Maria-Paula Avila, Tatiana Pacheco, Sara Arias, Rosa-Helena Bustos, Julio-Cesar Garcia and Diego Jaimes

Pharmaceuticals 2020, 13(3), 42; https://doi.org/10.3390/ph13030042 - 6 Mar 2020

Cited by 9 | Viewed by 4326

Abstract

Colistin is used as a last-line antibiotic for the treatment of Gram-negative multiresistant bacteria. Due to its high nephrotoxicity, Therapeutic Drug Monitoring (TDM) is recommended for dose adjustment. We aimed to evaluate the available evidence of TDM in patients given colistin to treat [...] Read more.

Colistin is used as a last-line antibiotic for the treatment of Gram-negative multiresistant bacteria. Due to its high nephrotoxicity, Therapeutic Drug Monitoring (TDM) is recommended for dose adjustment. We aimed to evaluate the available evidence of TDM in patients given colistin to treat Gram-negative infections. In this paper, we offer an overview, using an electronic search of the literature (published up to June 2019, without language restrictions) that compares the clinical outcomes and measurements of colistin TDM. Ultimately, the Therapeutic Drug Monitoring (TDM) of colistin in Plasma could prevent nephrotoxicity risk. Full article

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

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19 pages, 2047 KiB

Open AccessArticle

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

by Christian Carpéné, Francisco Les, Josep Mercader, Saioa Gomez-Zorita, Jean-Louis Grolleau, Nathalie Boulet, Jessica Fontaine, Mari Carmen Iglesias-Osma and Maria José Garcia-Barrado

Pharmaceuticals 2020, 13(3), 41; https://doi.org/10.3390/ph13030041 - 5 Mar 2020

Cited by 3 | Viewed by 5129

Abstract

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several [...] Read more.

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity. Full article

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15 pages, 1847 KiB

Open AccessReview

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

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

Pharmaceuticals 2020, 13(3), 40; https://doi.org/10.3390/ph13030040 - 5 Mar 2020

Cited by 57 | Viewed by 9279

Abstract

2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of [...] Read more.

2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of TIDES authorized increased (seven vs. three). Year after year, TIDES are increasingly present in therapy, as imaging agents, theragnostic and constituent moieties of other complex drugs, such as antibody drug conjugates. This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 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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25 pages, 8973 KiB

Open AccessReview

(Radio)Theranostic Patient Management in Oncology Exemplified by Neuroendocrine Neoplasms, Prostate Cancer, and Breast Cancer

by Irina Velikyan

Pharmaceuticals 2020, 13(3), 39; https://doi.org/10.3390/ph13030039 - 5 Mar 2020

Cited by 12 | Viewed by 5749

Abstract

The role of nuclear medicine in the management of oncological patients has expanded during last two decades. The number of radiopharmaceuticals contributing to the realization of theranostics/radiotheranostics in the context of personalized medicine is increasing. This review is focused on the examples of [...] Read more.

The role of nuclear medicine in the management of oncological patients has expanded during last two decades. The number of radiopharmaceuticals contributing to the realization of theranostics/radiotheranostics in the context of personalized medicine is increasing. This review is focused on the examples of targeted (radio)pharmaceuticals for the imaging and therapy of neuroendocrine neoplasms (NENs), prostate cancer, and breast cancer. These examples strongly demonstrate the tendency of nuclear medicine development towards personalized medicine. Full article

(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)

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12 pages, 1023 KiB

Open AccessReview

[⁶⁸Ga]Ga-DOTA-TOC: The First FDA-Approved ⁶⁸Ga-Radiopharmaceutical for PET Imaging

by Ute Hennrich and Martina Benešová

Pharmaceuticals 2020, 13(3), 38; https://doi.org/10.3390/ph13030038 - 3 Mar 2020

Cited by 107 | Viewed by 12188

Abstract

In the United States, [⁶⁸Ga]Ga-DOTA-TOC has been approved by the Food and Drug Administration (FDA) in 2019 as the first ⁶⁸Ga-radiopharmaceutical for imaging of somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors while employing positron emission tomography (PET). In Europe (Austria, [...] Read more.

In the United States, [⁶⁸Ga]Ga-DOTA-TOC has been approved by the Food and Drug Administration (FDA) in 2019 as the first ⁶⁸Ga-radiopharmaceutical for imaging of somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors while employing positron emission tomography (PET). In Europe (Austria, Germany, France), [⁶⁸Ga]Ga-DOTA-TOC was already approved back in 2016. This radiopharmaceutical combines the radionuclide ⁶⁸Ga with the somatostatin analogue DOTA-TOC for specific imaging of tumor cells expressing SSTRs. Such a targeting approach can also be used for therapy planning in the case of both localized as well as disseminated disease and potentially for the evaluation of treatment response. Full article

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

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19 pages, 8764 KiB

Open AccessReview

Synthesis of Imidazole-Based Medicinal Molecules Utilizing the van Leusen Imidazole Synthesis

by Xunan Zheng, Zhengning Ma and Dawei Zhang

Pharmaceuticals 2020, 13(3), 37; https://doi.org/10.3390/ph13030037 - 3 Mar 2020

Cited by 86 | Viewed by 17823

Abstract

Imidazole and its derivatives are one of the most vital and universal heterocycles in medicinal chemistry. Owing to their special structural features, these compounds exhibit a widespread spectrum of significant pharmacological or biological activities, and are widely researched and applied by pharmaceutical companies [...] Read more.

Imidazole and its derivatives are one of the most vital and universal heterocycles in medicinal chemistry. Owing to their special structural features, these compounds exhibit a widespread spectrum of significant pharmacological or biological activities, and are widely researched and applied by pharmaceutical companies for drug discovery. The van Leusen reaction based on tosylmethylisocyanides (TosMICs) is one of the most appropriate strategies to synthetize imidazole-based medicinal molecules, which has been increasingly developed on account of its advantages. In this review, we summarize the recent developments of the chemical synthesis and bioactivity of imidazole-containing medicinal small molecules, utilizing the van Leusen imidazole synthesis from 1977. Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 3502 KiB

Open AccessReview

Bioisosteric Replacement as a Tool in Anti-HIV Drug Design

by Alexej Dick and Simon Cocklin

Pharmaceuticals 2020, 13(3), 36; https://doi.org/10.3390/ph13030036 - 28 Feb 2020

Cited by 40 | Viewed by 12023

Abstract

Bioisosteric replacement is a powerful tool for modulating the drug-like properties, toxicity, and chemical space of experimental therapeutics. In this review, we focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics. Moreover, [...] Read more.

Bioisosteric replacement is a powerful tool for modulating the drug-like properties, toxicity, and chemical space of experimental therapeutics. In this review, we focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics. Moreover, we cover field-based, computational methodologies for bioisosteric replacement, using studies from our group as an example. It is our hope that this review will serve to highlight the utility and potential of bioisosteric replacement in the continuing search for new and improved anti-HIV drugs. Full article

(This article belongs to the Special Issue Recent Effective Application of Bioisosterism)

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22 pages, 2697 KiB

Open AccessArticle

Efficacy of Bacteriophages Against Staphylococcus aureus Isolates from Bovine Mastitis

by Isabel Titze, Tatiana Lehnherr, Hansjörg Lehnherr and Volker Krömker

Pharmaceuticals 2020, 13(3), 35; https://doi.org/10.3390/ph13030035 - 26 Feb 2020

Cited by 31 | Viewed by 5874

Abstract

The lytic efficacy of bacteriophages against Staphylococcus aureus isolates from bovine milk was investigated in vitro, regarding possible applications in the therapy of udder inflammation caused by bacterial infections (mastitis). The host range of sequenced, lytic bacteriophages was determined against a collection of [...] Read more.

The lytic efficacy of bacteriophages against Staphylococcus aureus isolates from bovine milk was investigated in vitro, regarding possible applications in the therapy of udder inflammation caused by bacterial infections (mastitis). The host range of sequenced, lytic bacteriophages was determined against a collection of 92 Staphylococcus (S.) aureus isolates. The isolates originated from quarter foremilk samples of clinical and subclinical mastitis cases. A spot test and a subsequent plaque assay were used to determine the phage host range. According to their host range, propagation and storage properties, three phages, STA1.ST29, EB1.ST11, and EB1.ST27, were selected for preparing a bacteriophage mixture (1:1:1), which was examined for its lytic activity against S. aureus in pasteurized and raw milk. It was found that almost two thirds of the isolates could be lysed by at least one of the tested phages. The bacteriophage mixture was able to reduce the S. aureus germ density in pasteurized milk and its reduction ability was maintained in raw milk, with only a moderate decrease compared to the results in pasteurized milk. The significant reduction ability of the phage mixture in raw milk promotes further in vivo investigation. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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13 pages, 2763 KiB

Open AccessArticle

Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety

by Takuji Shoda, Nobumichi Ohoka, Genichiro Tsuji, Takuma Fujisato, Hideshi Inoue, Yosuke Demizu, Mikihiko Naito and Masaaki Kurihara

Pharmaceuticals 2020, 13(3), 34; https://doi.org/10.3390/ph13030034 - 25 Feb 2020

Cited by 8 | Viewed by 4830

Abstract

Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the [...] Read more.

Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the aryl hydrocarbon receptor (AhR) E3 ligase complex and induce the AhR-dependent degradation of target proteins. However, these chimeras contain a hydrophobic AhR E3 ligand, and thus, degrade target proteins even in cells that do not express AhR. In this study, we synthesized new compounds in which the AhR ligands were replaced with a hydrophobic adamantane moiety to investigate the mechanisms of AhR-independent degradation. Our results showed that the compounds, 2, 3, and 16 induced significant degradation of some target proteins in cells that do not express AhR, similar to the chimeras containing AhR ligands. However, in cells expressing AhR, 2, 3, and 16 did not induce the degradation of other target proteins, in contrast with their response to chimeras containing AhR ligands. Overall, it was suggested that target proteins susceptible to the hydrophobic tagging system are degraded by chimeras containing hydrophobic AhR ligands even without AhR. Full article

(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)

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Pharmaceuticals, Volume 13, Issue 3 (March 2020) – 19 articles

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