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12 pages, 1126 KiB

Open AccessArticle

Population-Based Registry Analysis of Antidiabetics Dispensations: Trend Use in Spain between 2015 and 2018 with Reference to Driving

by Eduardo Gutiérrez-Abejón, Paloma Criado-Espegel, Francisco Herrera-Gómez and F. Javier Álvarez

Pharmaceuticals 2020, 13(8), 165; https://doi.org/10.3390/ph13080165 - 25 Jul 2020

Cited by 4 | Viewed by 2178

Abstract

Insulins and some oral antidiabetics are considered to be driving-impairing medicines (DIM) and they belong to the Driving under the Influence of Drugs, alcohol, and medicines (DRUID) category I (minor influence on fitness to drive). The trend of antidiabetics use in Castilla y [...] Read more.

Insulins and some oral antidiabetics are considered to be driving-impairing medicines (DIM) and they belong to the Driving under the Influence of Drugs, alcohol, and medicines (DRUID) category I (minor influence on fitness to drive). The trend of antidiabetics use in Castilla y León from 2015 to 2018 is presented through a population-based registry study. Treatment duration with these medicines and the concomitant use of other DIMs were observed. An adjustment method was used with information from the drivers’ license census. For all calculations, age and gender were taken into account. 3.98% of the general population used at least one antidiabetic, as well as 2.92% of drivers. The consumption of antidiabetics in men was higher than in women (4.35% vs. 3.61%, p = 0.001), and the use increases with age, especially from 35–39 years to 75–79 years in men and 85–89 years in women. Antidiabetics were consumed chronically, specifically 100% in the case of insulins and 95% in the case of oral antidiabetics. In addition to antidiabetics, 2.5 ± 1.86 DIMs were consumed, mainly anxiolytics (25.53%), opioids (23.03%), other analgesics and antipiretics (19.13%), and antidepressants (17.73%). Collaboration between pharmacists and physicians is a priority to clearly transmitting risks to patients. It is necessary that the health authorities include information on DIMs, such as the DRUID classification, in the prescription and dispensing software. Full article

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14 pages, 1840 KiB

Open AccessArticle

Trends in Antidepressants Use in Spain between 2015 and 2018: Analyses from a Population-Based Registry Study with Reference to Driving

by Eduardo Gutiérrez-Abejón, Francisco Herrera-Gómez, Paloma Criado-Espegel and F. Javier Álvarez

Pharmaceuticals 2020, 13(4), 61; https://doi.org/10.3390/ph13040061 - 3 Apr 2020

Cited by 10 | Viewed by 3984

Abstract

Antidepressants are considered driving-impairing medicines (DIM). This is a population-based registry study that shows the trend in the use of antidepressants in Castile and León, Spain, from 2015 to 2018. Data on antidepressant dispensations at pharmacies and the adjusted use of these medicines [...] Read more.

Antidepressants are considered driving-impairing medicines (DIM). This is a population-based registry study that shows the trend in the use of antidepressants in Castile and León, Spain, from 2015 to 2018. Data on antidepressant dispensations at pharmacies and the adjusted use of these medicines by the driver population are presented. For the purposes of analysis, population distribution by age and gender has been taken into account, as well as the three Driving Under the Influence of Drugs, alcohol, and medicines (DRUID) categories. Antidepressants were used by 8.56% of the general population and 5.66% of drivers. Antidepressants were used more commonly by females than by males (12.12% vs. 4.87%, χ² = 1325.124, p = 0.001), and users increased as the age increased, even if women who drive used less antidepressants after turning 60 years of age. Chronic use of antidepressants was relevant (8.28%) in the same way as daily use (3.15%). Most of the consumption included SSRIs (4.99%), which are also known as “other antidepressants” (3.71%). Regardless of antidepressants consumed, users took 2.75 ± 1.19 DIMs, which are mainly anxiolytics (58.80%) and opioids (26.43%). Lastly, regarding consumption of antidepressants according to the DRUID classification, category I predominated over categories II and III. Our findings should serve as a starting point for health and traffic authorities to raise awareness of the risk for traffic accidents, especially involving SSRIs. Full article

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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 8 | Viewed by 3968

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

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16 pages, 2706 KiB

Open AccessArticle

ASA Suppresses PGE₂ in Plasma and Melanocytic Nevi of Human Subjects at Increased Risk for Melanoma

by Amir Varedi, Hafeez Rahman, Dileep Kumar, Jonathan L. Catrow, James E. Cox, Tong Liu, Scott R. Florell, Kenneth M. Boucher, Nwanneka Okwundu, William J. Burnett, Matthew W. VanBrocklin and Douglas Grossman

Pharmaceuticals 2020, 13(1), 7; https://doi.org/10.3390/ph13010007 - 2 Jan 2020

Cited by 7 | Viewed by 3966

Abstract

Potential anti-inflammatory and anticarcinogenic effects of aspirin (ASA) may be suitable for melanoma chemoprevention, but defining biomarkers in relevant target tissues is prerequisite to performing randomized controlled chemoprevention trials. We conducted open-label studies with ASA in 53 human subjects with melanocytic nevi at [...] Read more.

Potential anti-inflammatory and anticarcinogenic effects of aspirin (ASA) may be suitable for melanoma chemoprevention, but defining biomarkers in relevant target tissues is prerequisite to performing randomized controlled chemoprevention trials. We conducted open-label studies with ASA in 53 human subjects with melanocytic nevi at increased risk for melanoma. In a pilot study, 12 subjects received a single dose (325 mg) of ASA; metabolites salicylate, salicylurate, and gentisic acid were detected in plasma after 4–8 h, and prostaglandin E2 (PGE₂) was suppressed in both plasma and nevi for up to 24 h. Subsequently, 41 subjects received either 325 or 81 mg ASA (nonrandomized) daily for one week. ASA metabolites were consistently detected in plasma and nevi, and PGE₂ levels were significantly reduced in both plasma and nevi. Subchronic ASA dosing did not affect 5” adenosine monophosphate-activated protein kinase (AMPK) activation in nevi or leukocyte subsets in peripheral blood, although metabolomic and cytokine profiling of plasma revealed significant decreases in various (non-ASA-derived) metabolites and inflammatory cytokines. In summary, short courses of daily ASA reduce plasma and nevus PGE₂ and some metabolites and cytokines in plasma of human subjects at increased risk for melanoma. PGE₂ may be a useful biomarker in blood and nevi for prospective melanoma chemoprevention studies with ASA. Full article

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11 pages, 9689 KiB

Open AccessArticle

APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade

by Debolina Ganguly, Chun Cai, Michelle M. Sims, Chuan He Yang, Matthew Thomas, Jinjun Cheng, Ali G. Saad and Lawrence M. Pfeffer

Pharmaceuticals 2019, 12(1), 45; https://doi.org/10.3390/ph12010045 - 26 Mar 2019

Cited by 18 | Viewed by 4661

Abstract

Glioblastoma (GBM) is the most common and deadliest primary adult brain tumor. Invasion, resistance to therapy, and tumor recurrence in GBM can be attributed in part to brain tumor-initiating cells (BTICs). BTICs isolated from various patient-derived xenografts showed high expression of the poorly [...] Read more.

Glioblastoma (GBM) is the most common and deadliest primary adult brain tumor. Invasion, resistance to therapy, and tumor recurrence in GBM can be attributed in part to brain tumor-initiating cells (BTICs). BTICs isolated from various patient-derived xenografts showed high expression of the poorly characterized Apelin early ligand A (APELA) gene. Although originally considered to be a non-coding gene, the APELA gene encodes a protein that binds to the Apelin receptor and promotes the growth of human embryonic stem cells and the formation of the embryonic vasculature. We found that both APELA mRNA and protein are expressed at high levels in a subset of brain tumor patients, and that APELA is also expressed in putative stem cell niche in GBM tumor tissue. Analysis of APELA and the Apelin receptor gene expression in brain tumor datasets showed that high APELA expression was associated with poor patient survival in both glioma and glioblastoma, and APELA expression correlated with glioma grade. In contrast, gene expression of the Apelin receptor or Apelin was not found to be associated with patient survival, or glioma grade. Consequently, APELA may play an important role in glioblastoma tumorigenesis and may be a future therapeutic target. Full article

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14 pages, 3249 KiB

Open AccessArticle

Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative

by Isadora T. S. Bastos, Pedro de Sena M. Pinheiro, Fanny N. Costa, Miguel D. Rocha, Carlos Mauricio R. Sant’Anna, Delson Braz, Everton T. Souza, Marco A. Martins, Eliezer J. Barreiro, Fabio F. Ferreira, Regina C. Barroso and Carlos A. M. Fraga

Pharmaceuticals 2018, 11(4), 119; https://doi.org/10.3390/ph11040119 - 1 Nov 2018

Cited by 8 | Viewed by 4151

Abstract

Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able [...] Read more.

Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A_2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use. In this paper, we describe the design concept of LASSBio-1835, a novel structural analogue of LASSBio-1359, planned by exploiting ring bioisosterism. Using X-ray powder diffraction, calorimetric techniques, and molecular modeling, we clearly indicate the presence of a preferred synperiplanar conformation at the amide function, which is fixed by an intramolecular 1,5-N∙∙∙S σ-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 (4) as a PDE4 inhibitor and as an A_2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH. Full article

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14 pages, 719 KiB

Open AccessArticle

Creatinine-Based Renal Function Estimates and Dosage of Postoperative Pain Management for Elderly Acute Hip Fracture Patients

by Morten Baltzer Houlind, Kristian Kjær Petersen, Henrik Palm, Lillian Mørch Jørgensen, Mia Aakjær, Lona Louring Christrup, Janne Petersen, Ove Andersen and Charlotte Treldal

Pharmaceuticals 2018, 11(3), 88; https://doi.org/10.3390/ph11030088 - 18 Sep 2018

Cited by 8 | Viewed by 5815

Abstract

Many analgesics and their metabolites are renally excreted. The widely used Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) equations are not developed for use in the elderly, while the recent Berlin Initiative Study (BIS), Full Age Spectrum (FAS), and Lund-Malmö [...] Read more.

Many analgesics and their metabolites are renally excreted. The widely used Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) equations are not developed for use in the elderly, while the recent Berlin Initiative Study (BIS), Full Age Spectrum (FAS), and Lund-Malmö revised (LMR) equations are. This observational study investigated differences between creatinine-based eGFR equations and how the choice of equation influences dosage of analgesics in elderly (≥70 years) patients admitted with acute hip fracture. eGFR was calculated by the CKD-EPI, BIS, Cockcroft-Gault (CG), FAS, LMR, and Modification of Diet in Renal Disease (MDRD) equations. Standard daily dose for postoperative pain medications ibuprofen, morphine and gabapentin was simulated for each equation according to dosage recommendations in Renbase^®. For 118 patients, mean eGFR from the CKD-EPI, BIS, CG, FAS, LMR, and MDRD equations was 67.3 mL/min/1.73 m², 59.1 mL/min/1.73 m², 56.9 mL/min/1.73 m², 60.3 mL/min/1.73 m², 58.9 mL/min/1.73 m², and 79.1 mL/min/1.73 m², respectively (p < 0.0001). Mean difference to CKD-EPI was −10.4 mL/min/1.73 m² to 11.8 mL/min/1.73 m². Choice of eGFR equation significantly influenced the recommended dose (p < 0.0001). Shifting to BIS, FAS, or LMR equations led to a lower recommended dose in 20% to 31% of patients. Choice of eGFR equation significantly influenced dosing of ibuprofen, morphine, and gabapentin. Full article

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23 pages, 1081 KiB

Open AccessArticle

A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages

by Aymeric Ousset, Rosanna Chirico, Florent Robin, Martin Alexander Schubert, Pascal Somville and Kalliopi Dodou

Pharmaceuticals 2018, 11(3), 81; https://doi.org/10.3390/ph11030081 - 27 Aug 2018

Cited by 2 | Viewed by 5434

Abstract

This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in [...] Read more.

This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug–polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1–50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases. Full article

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13 pages, 4747 KiB

Open AccessArticle

Diagnostic Accuracy of Protein Glycation Sites in Long-Term Controlled Patients with Type 2 Diabetes Mellitus and Their Prognostic Potential for Early Diagnosis

by Sandro Spiller, Yichao Li, Matthias Blüher, Lonnie Welch and Ralf Hoffmann

Pharmaceuticals 2018, 11(2), 38; https://doi.org/10.3390/ph11020038 - 30 Apr 2018

Cited by 14 | Viewed by 5314

Abstract

Current screening tests for type 2 diabetes mellitus (T2DM) identify less than 50% of undiagnosed T2DM patients and provide no information about how the disease will develop in prediabetic patients. Here, twenty-nine protein glycation sites were quantified after tryptic digestion of plasma samples [...] Read more.

Current screening tests for type 2 diabetes mellitus (T2DM) identify less than 50% of undiagnosed T2DM patients and provide no information about how the disease will develop in prediabetic patients. Here, twenty-nine protein glycation sites were quantified after tryptic digestion of plasma samples at the peptide level using tandem mass spectrometry and isotope-labelled peptides as internal standard. The glycation degrees were determined in three groups, i.e., 48 patients with a duration of T2DM exceeding ten years, 48 non-diabetic individuals matched for gender, BMI, and age, and 20 prediabetic men. In long-term controlled diabetic patients, 27 glycated peptides were detected at significantly higher levels, providing moderate diagnostic accuracies (ACCs) from 61 to 79%, allowing a subgrouping of patients in three distinct clusters. Moreover, a feature set of one glycated peptides and six established clinical parameters provided an ACC of 95%. The same number of clusters was identified in prediabetic males (ACC of 95%) using a set of eight glycation sites (mostly from serum albumin). All patients present in one cluster showed progression of prediabetic state or advanced towards diabetes in the following five years. Overall, the studied glycation sites appear to be promising biomarkers for subgrouping prediabetic patients to estimate their risk for the development of T2DM. Full article

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24 pages, 15492 KiB

Open AccessArticle

A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors

by Alexander Schnitzler, Andreas Gratz, Andre Bollacke, Michael Weyrich, Uwe Kuckländer, Bernhard Wünsch, Claudia Götz, Karsten Niefind and Joachim Jose

Pharmaceuticals 2018, 11(1), 23; https://doi.org/10.3390/ph11010023 - 17 Feb 2018

Cited by 7 | Viewed by 5682

Abstract

Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol [...] Read more.

Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC₅₀ values of 7 nM (4a) and 5 nM (5) and an apparent K_i value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected π-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency. Full article

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11 pages, 1417 KiB

Open AccessArticle

Self-Assembled Supramolecular Nanoparticles Improve the Cytotoxic Efficacy of CK2 Inhibitor THN7

by Abdelhamid Nacereddine, Andre Bollacke, Eszter Róka, Christelle Marminon, Zouhair Bouaziz, Ferenc Fenyvesi, Ildikó Katalin Bácskay, Joachim Jose, Florent Perret and Marc Le Borgne

Pharmaceuticals 2018, 11(1), 10; https://doi.org/10.3390/ph11010010 - 26 Jan 2018

Cited by 7 | Viewed by 4685

Abstract

Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been [...] Read more.

Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been revealed to have high potency against human cancer cell lines such as MCF-7 breast carcinoma and A-427 lung carcinoma. 4-Methoxy-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (THN7), identified as a potent inhibitor of CK2 (IC₅₀ = 71 nM), was selected for an encapsulation study in order to evaluate its antiproliferative activity as THN7-loaded cyclodextrin nanoparticles. Four α-cyclodextrins (α-CDs) were selected to encapsulate THN7 and all experiments indicated that the nanoencapsulation of this CK2 inhibitor in α-CDs was successful. No additional surface-active agent was used during the nanoformulation process. Nanoparticles formed between THN7 and α-C₆H₁₃ amphiphilic derivative gave the best results in terms of encapsulation rate (% of associated drug = 35%), with a stability constant (K₁₁) of 298 mol·L⁻¹ and a size of 132 nm. Hemolytic activity of the four α-CDs was determined before the in cellulo evaluation and the α-C₆H₁₃ derivative gave the lowest value of hemolytic potency (HC₅₀ = 1.93 mol·L⁻¹). Only the THN7-loaded cyclodextrin nanoparticles showing less toxicity on human erythrocytes (α-C₆H₁₃, α-C₈H₁₇ and α-C₄H₉) were tested against A-427 cells. All drug-loaded nanoparticles caused more cytotoxicity against A-427 cells than THN7 alone. Based on these results, the use of amphiphilic CD nanoparticles could be considered as a drug delivery system for indeno[1,2-b]indoles, allowing an optimized bioavailability and offering perspectives for the in vivo development of CK2 inhibitors. Full article

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3233 KiB

Open AccessFeature PaperArticle

Synthesis of Nitric Oxide Donors Derived from Piloty’s Acid and Study of Their Effects on Dopamine Secretion from PC12 Cells

by Daniele Sanna, Gaia Rocchitta, Maria Serra, Marcello Abbondio, Pier Andrea Serra, Rossana Migheli, Lidia De Luca, Eugenio Garribba and Andrea Porcheddu

Pharmaceuticals 2017, 10(3), 74; https://doi.org/10.3390/ph10030074 - 5 Sep 2017

Cited by 7 | Viewed by 6892

Abstract

This study investigated the mechanisms and kinetics of nitric oxide (NO) generation by derivatives of Piloty’s acid (NO-donors) under physiological conditions. In order to qualitatively and quantitatively measure NO release, electron paramagnetic resonance (EPR) was carried out with NO spin trapping. In addition, [...] Read more.

This study investigated the mechanisms and kinetics of nitric oxide (NO) generation by derivatives of Piloty’s acid (NO-donors) under physiological conditions. In order to qualitatively and quantitatively measure NO release, electron paramagnetic resonance (EPR) was carried out with NO spin trapping. In addition, voltammetric techniques, including cyclic voltammetry and constant potential amperometry, were used to confirm NO release from Piloty’s acid and its derivatives. The resulting data showed that Piloty’s acid derivatives are able to release NO under physiological conditions. In particular, electron-withdrawing substituents favoured NO generation, while electron-donor groups reduced NO generation. In vitro microdialysis, performed on PC12 cell cultures, was used to evaluate the dynamical secretion of dopamine induced by the Piloty’s acid derivatives. Although all the studied molecules were able to induce DA secretion from PC12, only those with a slow release of NO have not determined an autoxidation of DA itself. These results confirm that the time-course of NO-donors decomposition and the amount of NO released play a key role in dopamine secretion and auto-oxidation. This information could drive the synthesis or the selection of compounds to use as potential drugs for the therapy of Parkinson’s disease (PD). Full article

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Open AccessArticle

Individual and Combined Effects of Engineered Peptides and Antibiotics on Pseudomonas aeruginosa Biofilms

by Biswajit Mishra and Guangshun Wang

Pharmaceuticals 2017, 10(3), 58; https://doi.org/10.3390/ph10030058 - 25 Jun 2017

Cited by 55 | Viewed by 8473

Abstract

Pseudomonas aeruginosa is involved in a variety of difficult-to-treat infections frequently due to biofilm formation. To identify useful antibiofilm strategies, this article evaluated efficacy of two newly engineered cationic antimicrobial peptides (17BIPHE2 and DASamP2), traditional antibiotics, and their combinations against biofilms at different [...] Read more.

Pseudomonas aeruginosa is involved in a variety of difficult-to-treat infections frequently due to biofilm formation. To identify useful antibiofilm strategies, this article evaluated efficacy of two newly engineered cationic antimicrobial peptides (17BIPHE2 and DASamP2), traditional antibiotics, and their combinations against biofilms at different stages. 17BIPHE2 is designed based on the 3D structure of human cathelicidin LL-37 and DASamP2 is derived from database screening. While both peptides show effects on bacterial adhesion, biofilm formation, and preformed biofilms, select antibiotics only inhibit biofilm formation, probably due to direct bacterial killing. In addition, the time dependence of biofilm formation and treatment in a static in vitro biofilm model was also studied. The initial bacterial inoculum determines the peptide concentration needed to inhibit biofilm growth. When the bacterial growth time is less than 8 h, the biomass in the wells can be dispersed by either antibiotics alone or peptides alone. However, nearly complete biofilm disruption can be achieved when both the peptide and antibiotics are applied. Our results emphasize the importance of antibiofilm peptides, early treatment using monotherapy, and the combination therapy for already formed biofilms of P. aeruginosa. Full article

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Open AccessArticle

Barriers to the Access of Bevacizumab in Patients with Solid Tumors and the Potential Impact of Biosimilars: A Physician Survey

by Bradley J. Monk, Philip E. Lammers, Thomas Cartwright and Ira Jacobs

Pharmaceuticals 2017, 10(1), 19; https://doi.org/10.3390/ph10010019 - 28 Jan 2017

Cited by 43 | Viewed by 7188

Abstract

Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of [...] Read more.

Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non–small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, ~50% of physicians reported they “definitely” or “probably” would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM. Full article

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Open AccessFeature PaperCommunication

3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

by Polya G. Roydeva, Anna-Madeleine Beckmann, Marit Stirnberg, Jožko Cesar, Danijel Kikelj, Janez Ilaš and Michael Gütschow

Pharmaceuticals 2016, 9(1), 2; https://doi.org/10.3390/ph9010002 - 13 Jan 2016

Cited by 7 | Viewed by 5919

Abstract

The liver enzyme matriptase-2 is a multi-domain, transmembrane serine protease with an extracellular, C-terminal catalytic domain. Synthetic low-molecular weight inhibitors of matriptase-2 have potential as therapeutics to treat iron overload syndromes, in particular in patients with β-thalassemia. A sub-library of 64 compounds was [...] Read more.

The liver enzyme matriptase-2 is a multi-domain, transmembrane serine protease with an extracellular, C-terminal catalytic domain. Synthetic low-molecular weight inhibitors of matriptase-2 have potential as therapeutics to treat iron overload syndromes, in particular in patients with β-thalassemia. A sub-library of 64 compounds was screened for matriptase-2 inhibition and several active compounds were identified. (S)-Ethyl 2-(benzyl(3-((4-carbamidoylphenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-oxoacetate ((S)-12) showed an IC₅₀ value of less than 10 µM. Structure-activity relationships were discussed and proposals to design new matriptase-2 inhibitors were made. Full article

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Review

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41 pages, 3530 KiB

Open AccessFeature PaperReview

Current Trends in the Pharmacotherapy of Cataracts

by Segewkal H. Heruye, Leonce N. Maffofou Nkenyi, Neetu U. Singh, Dariush Yalzadeh, Kalu K. Ngele, Ya-Fatou Njie-Mbye, Sunny E. Ohia and Catherine A. Opere

Pharmaceuticals 2020, 13(1), 15; https://doi.org/10.3390/ph13010015 - 16 Jan 2020

Cited by 39 | Viewed by 18288 | Correction

Abstract

Cataracts, one of the leading causes of preventable blindness worldwide, refers to lens degradation that is characterized by clouding, with consequent blurry vision. As life expectancies improve, the number of people affected with cataracts is predicted to increase worldwide, especially in low-income nations [...] Read more.

Cataracts, one of the leading causes of preventable blindness worldwide, refers to lens degradation that is characterized by clouding, with consequent blurry vision. As life expectancies improve, the number of people affected with cataracts is predicted to increase worldwide, especially in low-income nations with limited access to surgery. Although cataract surgery is considered safe, it is associated with some complications such as retinal detachment, warranting a search for cheap, pharmacological alternatives to the management of this ocular disease. The lens is richly endowed with a complex system of non-enzymatic and enzymatic antioxidants which scavenge reactive oxygen species to preserve lens proteins. Depletion and/or failure in this primary antioxidant defense system contributes to the damage observed in lenticular molecules and their repair mechanisms, ultimately causing cataracts. Several attempts have been made to counteract experimentally induced cataract using in vitro, ex vivo, and in vivo techniques. The majority of the anti-cataract compounds tested, including plant extracts and naturally-occurring compounds, lies in their antioxidant and/or free radical scavenging and/or anti-inflammatory propensity. In addition to providing an overview of the pathophysiology of cataracts, this review focuses on the role of various categories of natural and synthetic compounds on experimentally-induced cataracts. Full article

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28 pages, 2175 KiB

Open AccessReview

Bioinspired Designs, Molecular Premise and Tools for Evaluating the Ecological Importance of Antimicrobial Peptides

by Elvis Legala Ongey, Stephan Pflugmacher and Peter Neubauer

Pharmaceuticals 2018, 11(3), 68; https://doi.org/10.3390/ph11030068 - 10 Jul 2018

Cited by 24 | Viewed by 7703

Abstract

This review article provides an overview of recent developments in antimicrobial peptides (AMPs), summarizing structural diversity, potential new applications, activity targets and microbial killing responses in general. The use of artificial and natural AMPs as templates for rational design of peptidomimetics are also [...] Read more.

This review article provides an overview of recent developments in antimicrobial peptides (AMPs), summarizing structural diversity, potential new applications, activity targets and microbial killing responses in general. The use of artificial and natural AMPs as templates for rational design of peptidomimetics are also discussed and some strategies are put forward to curtail cytotoxic effects against eukaryotic cells. Considering the heat-resistant nature, chemical and proteolytic stability of AMPs, we attempt to summarize their molecular targets, examine how these macromolecules may contribute to potential environmental risks vis-à-vis the activities of the peptides. We further point out the evolutional characteristics of the macromolecules and indicate how they can be useful in designing target-specific peptides. Methods are suggested that may help to assess toxic mechanisms of AMPs and possible solutions are discussed to promote the development and application of AMPs in medicine. Even if there is wide exposure to the environment like in the hospital settings, AMPs may instead contribute to prevent healthcare-associated infections so long as ecotoxicological aspects are considered. Full article

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1258 KiB

Open AccessReview

Essential Oils and Antifungal Activity

by Filomena Nazzaro, Florinda Fratianni, Raffaele Coppola and Vincenzo De Feo

Pharmaceuticals 2017, 10(4), 86; https://doi.org/10.3390/ph10040086 - 2 Nov 2017

Cited by 502 | Viewed by 30366

Abstract

Since ancient times, folk medicine and agro-food science have benefitted from the use of plant derivatives, such as essential oils, to combat different diseases, as well as to preserve food. In Nature, essential oils play a fundamental role in protecting the plant from [...] Read more.

Since ancient times, folk medicine and agro-food science have benefitted from the use of plant derivatives, such as essential oils, to combat different diseases, as well as to preserve food. In Nature, essential oils play a fundamental role in protecting the plant from biotic and abiotic attacks to which it may be subjected. Many researchers have analyzed in detail the modes of action of essential oils and most of their components. The purpose of this brief review is to describe the properties of essential oils, principally as antifungal agents, and their role in blocking cell communication mechanisms, fungal biofilm formation, and mycotoxin production. Full article

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381 KiB

Open AccessReview

Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance

by Felix Schmidt and Thomas Efferth

Pharmaceuticals 2016, 9(2), 33; https://doi.org/10.3390/ph9020033 - 16 Jun 2016

Cited by 91 | Viewed by 11433

Abstract

Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed [...] Read more.

Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients. Full article

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1076 KiB

Open AccessReview

How Efficient Is My (Medicinal) Chemistry?

by Jean Jacques Vanden Eynde

Pharmaceuticals 2016, 9(2), 26; https://doi.org/10.3390/ph9020026 - 16 May 2016

Cited by 12 | Viewed by 10201

Abstract

“Greening” a chemical transformation is not about only changing the nature of a solvent or decreasing the reaction temperature. There are metrics enabling a critical quantification of the efficiency of an experimental protocol. Some of them are applied to different sequences for the [...] Read more.

“Greening” a chemical transformation is not about only changing the nature of a solvent or decreasing the reaction temperature. There are metrics enabling a critical quantification of the efficiency of an experimental protocol. Some of them are applied to different sequences for the preparation of paracetamol in order to understand their performance parameters and elucidate pathways for improvement. Full article

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1063 KiB

Open AccessFeature PaperReview

Hormesis: Decoding Two Sides of the Same Coin

by Dipita Bhakta-Guha and Thomas Efferth

Pharmaceuticals 2015, 8(4), 865-883; https://doi.org/10.3390/ph8040865 - 16 Dec 2015

Cited by 57 | Viewed by 13767

Abstract

In the paradigm of drug administration, determining the correct dosage of a therapeutic is often a challenge. Several drugs have been noted to demonstrate contradictory effects per se at high and low doses. This duality in function of a drug at different concentrations [...] Read more.

In the paradigm of drug administration, determining the correct dosage of a therapeutic is often a challenge. Several drugs have been noted to demonstrate contradictory effects per se at high and low doses. This duality in function of a drug at different concentrations is known as hormesis. Therefore, it becomes necessary to study these biphasic functions in order to understand the mechanistic basis of their effects. In this article, we focus on different molecules and pathways associated with diseases that possess a duality in their function and thus prove to be the seat of hormesis. In particular, we have highlighted the pathways and factors involved in the progression of cancer and how the biphasic behavior of the molecules involved can alter the manifestations of cancer. Because of the pragmatic role that it exhibits, the imminent need is to draw attention to the concept of hormesis. Herein, we also discuss different stressors that trigger hormesis and how stress-mediated responses increase the overall adaptive response of an individual to stress stimulus. We talk about common pathways through which cancer progresses (such as nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1), sirtuin-forkhead box O (SIRT-FOXO) and others), analyzing how diverse molecules associated with these pathways conform to hormesis. Full article

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1113 KiB

Open AccessReview

Antimicrobial Peptides in 2014

by Guangshun Wang, Biswajit Mishra, Kyle Lau, Tamara Lushnikova, Radha Golla and Xiuqing Wang

Pharmaceuticals 2015, 8(1), 123-150; https://doi.org/10.3390/ph8010123 - 23 Mar 2015

Cited by 168 | Viewed by 25097

Abstract

This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. [...] Read more.

This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms. Full article

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3317 KiB

Open AccessMeeting Report

31ièmes Journées Franco-Belges de Pharmacochimie: Meeting Report

by Raphaël Frédérick, Lionel Pochet, Pascal De Tullio and François Dufrasne

Pharmaceuticals 2017, 10(4), 94; https://doi.org/10.3390/ph10040094 - 4 Dec 2017

Cited by 1 | Viewed by 4237

Abstract

The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented [...] Read more.

The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report. Full article

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6249 KiB

Open AccessMeeting Report

“The 24th Conference” of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A)

by Jean-Jacques Hélesbeux and Olivier Duval

Pharmaceuticals 2017, 10(1), 17; https://doi.org/10.3390/ph10010017 - 28 Jan 2017

Viewed by 5854

Abstract

The GP2A European Conference is a two-day meeting focused on medicinal chemistry and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, MS studies, in vitro in vivo assays, and structure activity [...] Read more.

The GP2A European Conference is a two-day meeting focused on medicinal chemistry and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, MS studies, in vitro in vivo assays, and structure activity relationships. Abstracts of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collated in this report. Full article

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5531 KiB

Open AccessMeeting Report

30ièmes Journées Franco-Belges de Pharmacochimie

by Samia Aci-Sèche, Frédéric Buron, Karen Plé, Laurent Robin, Franck Suzenet and Sylvain Routier

Pharmaceuticals 2016, 9(4), 73; https://doi.org/10.3390/ph9040073 - 18 Nov 2016

Viewed by 5409

Abstract

The “Journées Franco-Belges de Pharmacochimie” is a recognized annual meeting in organic and medicinal chemistry known for the quality of scientific exchange and conviviality. Young researchers were encouraged to present their work and share ideas with senior scientists. Abstracts of plenary lectures, oral [...] Read more.

The “Journées Franco-Belges de Pharmacochimie” is a recognized annual meeting in organic and medicinal chemistry known for the quality of scientific exchange and conviviality. Young researchers were encouraged to present their work and share ideas with senior scientists. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report. Full article

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7560 KiB

Open AccessMeeting Report

1st Joint European Conference on Therapeutic Targets and Medicinal Chemistry (TTMC 2015)

by Marc Le Borgne, Samer Haidar, Olivier Duval, Bernhard Wünsch and Joachim Jose

Pharmaceuticals 2016, 9(1), 1; https://doi.org/10.3390/ph9010001 - 26 Dec 2015

Viewed by 9618

Abstract

The European Conference on Therapeutic Targets and Medicinal Chemistry is a new two-day meeting on drug discovery that is focused on therapeutic targets and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic [...] Read more.

The European Conference on Therapeutic Targets and Medicinal Chemistry is a new two-day meeting on drug discovery that is focused on therapeutic targets and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, NMR studies, fragment screening, in vitro assays, in vivo assays, structure activity relationships, autodisplay. Abstracts of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collected in this report. Full article

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726 KiB

Open AccessMeeting Report

29ièmes Journées Franco-Belges de Pharmacochimie: Meeting Report

by The Members of the Organizing Committee

Pharmaceuticals 2015, 8(4), 758-777; https://doi.org/10.3390/ph8040758 - 17 Nov 2015

Viewed by 6020

Abstract

The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented [...] Read more.

The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report. Full article

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

610 KiB

Open AccessConcept Paper

Opioid Facilitation of β-Adrenergic Blockade: A New Pharmacological Condition?

by Joseph Vamecq, Karine Mention-Mulliez, Francis Leclerc and Dries Dobbelaere

Pharmaceuticals 2015, 8(4), 664-674; https://doi.org/10.3390/ph8040664 - 25 Sep 2015

Cited by 1 | Viewed by 6562

Abstract

Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through β-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature [...] Read more.

Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through β-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature evidence exists for a cross-talk between β-adrenergic receptors (protein targets of propranolol) and δ-opioid receptor. In this literature context, it is hypothesized here that anti-diarrheic racecadotril (a pro-drug of thiorphan, an inhibitor of enkephalinases), which, in the cited observation, was co-administered with propranolol, might have facilitated the β-blocker-driven inhibition of glycolysis and resulting lactate production. The opioid-facilitated β-adrenergic blockade would be essentially additivity or even synergism putatively existing between antagonism of β-adrenergic receptors and agonism of δ-opioid receptor in lowering cellular cAMP and dependent functions. Full article

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