Future Pharmacology

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a worldwide non-fermenting Gram-negative bacillus responsible for potentially severe nosocomial infections, especially in critically ill patients. CRAB tends to colonize inert surfaces and epithelia, especially the respiratory tract of mechanically ventilated patients, and may then become responsible for lower respiratory tract infections, probably the more challenging infection due to the site and the multidrug-resistant phenotype which makes it difficult to establish an effective antimicrobial regimen. Despite its diffusion, data regarding the treatment of CRAB are mainly retrospective and usually heterogeneous. Current international consensus guidelines prefer the use of ampicillin/sulbactam, but the strength of recommendation and grade of evidence tend to be weak to moderate. Moreover, no specific recommendation is given for different sites of infections. The recently introduced cefiderocol still received a recommendation against its use due to the results of the first randomized clinical trial, though retrospective and observational experiences showed favourable outcomes in this setting. We reviewed the major antibacterial drugs active against CRAB and discussed their combination in lower respiratory tract infections. Full article

In this study, we retrospectively reviewed the outcomes of patients treated with one or more series of intravitreal methotrexate (MTX) injections as a surgical adjunct for the prevention of recurrent rhegmatogenous retinal detachment (RRD) related to proliferative vitreoretinopathy (PVR). The study subjects were patients with primary or recurrent RRD associated with grade C PVR, who received one or more series of 9 intravitreal MTX injections. Each series consisted of a single intraoperative MTX injection and then 8 weekly postoperative MTX injections as an off-label surgical adjunct for the prevention of PVR. The primary outcome was the retinal reattachment rate. The secondary outcome was the incidence of treatment-limiting side effects. A total of 14 eyes of 14 patients were identified. The median age was 61 years (range: 9–83), and 43% of the patients were female. Most patients (64%) had a prior primary surgical failure. After one MTX series, 10 eyes (72%) were attached, and 8 (57%) were free of PVR at a median follow-up of 11 months (range: 2–14). All failures after a single MTX series were successfully treated with repeat surgery and a second (n = 4) or third (n = 1) MTX series, for the final reattachment and PVR-free rates of 100%. None of the patients experienced treatment-limiting side effects. Therefore, multiple series of MTX injections can be tolerated if indicated in cases of aggressive PVR threatening the retina. Full article

Curcumin is a biopharmaceutical classification system (BCS) class IV substance with many potential therapeutic effects. However, like many other BCS IV active pharmaceutical ingredients, complex formulations are needed to guarantee a sufficiently high bioavailability. A not-so-well-known delivery system is a suspoemulsion (SE). SEs are emulsions with a crystalline API in continuous or dispersed phases. This study aimed to produce curcumin-loaded o/w suspoemulsions with the particle in the oil phase for, e.g., encapsulation or triggered release effects. The particles need to be smaller than the emulsion droplet size to attain high encapsulation efficiencies (EE) in the oil phase. Sonofragmentation and bead milling were tested for their ability to produce these nanocrystals in different dispersion media. It was discovered that production in miglyol was the best fit for the needed application of the crystals in SEs. Around 85% (by volume) of the particles produced with bead milling were smaller than the droplet size of about 5 µm. In contrast, only 23% of the sonofragmentated particles were below the diameter of those droplets. This oily suspension was then used to successfully produce hydrogel-based o/w suspoemulsions. In the second part of this study, we investigated different methods for determining encapsulation efficiency, but none of the methods accurately and satisfactorily resolved the encapsulation efficiency. Finally, the suspoemulsions could not be macroscopically distinguished from one another and were physically stable. In summary, we showed that stable hydrogel-based curcumin-loaded o/w suspoemulsions could be produced. Full article

Fetal arrhythmias complicate 1% of pregnancies. Although most of them have a benign and intermittent course, sustained fetal tachyarrhythmias constitute an emerging situation, which is associated with high fetal morbidity and mortality. However, one of the major milestones in fetal therapy is the pharmacologic management of fetal arrhythmias by crossing the placental barrier. To date, there is no consensus on the first-line antiarrhythmic treatment for fetal tachyarrhythmias. The role of sotalol in therapeutic management, the use of flecainide versus digoxin as first line of treatment, the need for fetal intramuscular treatment administration, or the best treatment in case of fetal hydrops are situations whose application or management are controversial. The current paper is a scoping review of observational and experimental evidence, addressing the types of best management strategies for each type of tachyarrhythmia and the optimal pharmacological dose, considering precautions and safety elements. Finally, we will highlight new therapeutic perspectives and future diagnostic and therapeutic strategies. Full article

To evaluate possible structural changes and thermal stability of the polyurea unloaded and loaded with diclofenac sodium, polyurea networks based on polyetheramine containing polypropylene oxide (PPO) or polyethylene oxide (PEO) and hexamethylene diisocyanate trimer-HDI were synthesized. The formation of the network was controlled by sol-gel reactions, and the obtained materials were then characterized by different techniques (FTIR, XRD, TGA). Moreover, the amount of diclofenac released could be modulated as a function of time, studying the water absorption or swelling capacity, the cytotoxicity of the material and the amount of drug released. A choice was therefore made on the hydrophilicity of PEO- or PPO-based polyetheramine (with similar molecular weight), and the release profile was hereafter correlated with the water absorption by the PEO/PPO polyurea matrix. Links could finally be established between the release of diclofenac and the polyurea matrices properties, such as the nature of polymer (PEO/PPO) and the hydrophilicity (water uptake). Our objective here is to identify challenges and opportunities for the development of innovative functional biomaterials for health applications. Full article

Depression is a neuropsychiatric disorder characterized by altered emotion and cognition. Alpha lipoic acid (ALA) is a potent natural antioxidant and exhibits neuroprotective effects. However, its antidepressant activity and its mechanism of action in rats exposed to chronic unpredictable mild stress (CUMS) need to be evaluated. The rats were divided into six groups. Group, I vehicle control (without stress), II- CUMS, III- fluoxetine (FLX) (50 mg/kg p.o.), IV, V, and VI were treated with ALA (50, 100, 200 mg/kg, p.o.), respectively. All the groups, except I, were subjected to CUMS + treatments from day 1 to day 42. Body weight and behavioral parameters like sucrose preference test (SPT), Morris water maze (MWM), resident intruder test (RIT), and marble-burying test (MBT) were performed on day 0, day 21, and day 42, and forced swim test (FST) on last day 42 and 43 only. The rats were further sacrificed for biochemical and histopathological evaluation. ALA significantly improved behavioral function, increased antioxidant strength, reduced lipid peroxidation, restored monoamines, and protected CA3 neurons. Further, docking studies revealed strong binding of ALA on the 5HT₃ receptor. The study demonstrates that ALA might be exhibiting antidepressant effects in part by restoring monoamines and modulating the 5HT₃ receptor. Full article

The goal in cardiovascular prevention is the reduction of morbidity and mortality through the promotion of healthy lifestyles in the general population. The management of modifiable risk factors with pharmacological and non-pharmacological interventions, based on the individual risk is the first strategy suggested by the current guidelines. Several epidemiological studies have clearly shown the direct correlation between high levels of low-density lipoprotein cholesterol (LDL-C) and incidence of cardiovascular diseases. On the other hand, numerous randomized clinical studies have reported a huge benefit in terms of major cardiovascular events achievable by the reduction of LDL-C, thus supporting the notion that “the lower is better”. Among the lipid-lowering strategies, statins are the drugs of choice in cardiovascular prevention, at both primary and secondary level. To achieve the ambitious targets suggested by the current guidelines, other lipid-lowering therapies are currently available in addition to statins, such as ezetimibe the inhibitors of the PCSK9. Pharmacological research has recently led to the development of a new drug, the bempedoic acid, which further enrich the available therapies. This drug also acts on the biosynthesis of cholesterol but at upstream level than statins. From the biochemical point of view, it has the potential to be considered before the statin with consequent titration of statins to achieve the desirable LDL-C target. In the present review, the biochemical and pharmacological characteristics of bempedoic acid are discussed. An overview of the clinical data that support its use in the management of the cardiovascular patient and its allocation in the lipid-lowering scenario will be also provided. Full article

The enoyl reductase from Mycobacterium tuberculosis (MtInhA) was shown to be a major target for isoniazid, the most prescribed first-line anti-tuberculosis agent. The MtInhA (EC 1.3.1.9) protein catalyzes the hydride transfer from the 4S hydrogen of β-NADH to carbon-3 of long-chain 2-trans-enoyl thioester substrates (enoyl-ACP or enoyl-CoA) to yield NAD⁺ and acyl-ACP or acyl-CoA products. The latter are the long carbon chains of the meromycolate branch of mycolic acids, which are high-molecular-weight α-alkyl, β-hydroxy fatty acids of the mycobacterial cell wall. Here, stopped-flow measurements under single-turnover experimental conditions are presented for the study of the transient of reactants. Single-turnover experiments at various enzyme active sites were carried out. These studies suggested isomerization of the MtInhA:NADH binary complex in pre-incubation and positive cooperativity that depends on the number of enzyme active sites occupied by the 2-trans-dodecenoyl-CoA (DD-CoA) substrate. Stopped-flow results for burst analysis indicate that product release does not contribute to the rate-limiting step of the MtInhA-catalyzed chemical reaction. The bearings that the results presented herein have on function-based anti-tuberculosis drug design are discussed. Full article

Arboviral diseases caused by flaviviruses, such as dengue, are a continuing threat and major concern worldwide, with over three billion people estimated to be living with the risk of dengue virus (DENV) infections. There are thus far no antiviral drugs available for treatment, and limited or no vaccines are available. Curcumin and seven synthetic analogues were evaluated for their antiviral activity against dengue virus serotype 2, yellow fever virus and Zika virus, as well as for their cytotoxicity in Vero cells, both by employing MTT assays. Compounds 6 and 7, which present a thiazolylhydrazone moiety, showed moderate activity against all three flaviviruses, with selectivity index (SI) values up to 4.45. In addition, the envelope protein (E) was predicted as the potential target inhibited by both compounds, supported by molecular docking and dynamics simulation analysis. We hope that this data can contribute to the development of new curcumin antiviral analogues in the near future and can help in the search for new promising compounds as potential therapeutic agents to treat flaviviruses infections. Full article

Diabetes mellitus type-2 (DMT2) molecular pathophysiology is still challenging since the disease represents a complex, multifactorial metabolic disease caused by polygenic defects and environmental factors. In addition, the resulting secondary organ complications can be affected by various environmental and life-style factors over the years. The metabolic imbalance in DMT2 is manifested by the dysfunction of pancreatic β-cells in secreting insulin and the inability of other tissue cells to respond to insulin and utilize blood glucose. However, over recent years, through the advances in genomics and molecular analysis, several genes and microRNAs have been shown to be correlated as potential biomarkers with DMT2 prognosis, diagnosis, and therapy. Furthermore, drug therapy and clinical pharmacology have benefited from pharmacogenomics in a manner where the molecular knowledge can be translated into clinical information aiming to improve precision and personalized medicine therapeutic methodologies in healthcare. In this work, using systems pharmacology and network analysis approaches, we comprehensively assessed the molecular and genomics data associated with DMT2 to: (a) Better understand miRNA, gene, and drug associations; (b) Create connectivity and interaction maps of practical clinical utility; and (c) Facilitate the application of precision medicine therapeutic decisions in group and individual patients. Moreover, in order for the clinical pharmacology guidelines to be implemented in parallel with the generated molecular data, we also carried out an assessment of drug interactions in specific pharmacological classes that affect DMT2 pharmacotherapy outcomes. Overall, the proposed methodology and the results obtained: (a) Enrich our understanding of DMT2 molecular pathophysiology; (b) Unveil important biomarker and drug-gene pharmacogenomics associations; (c) Help the use of personalized therapy options; and (d) Allow precision medicine concepts to be broadly exploited in new therapeutic developments and within the clinical setting. Full article

Age-related macular degeneration (AMD) is a chronic progressive ocular disease and the main cause of severe visual impairment in the elderly. Vitamin D deficiency may be a risk factor for AMD. Additionally, current evidence suggests dietary advice of increasing consumption of polyphenols, which may have antioxidant and anti-inflammatory properties. The aim of this review was to describe the roles of vitamin D levels and polyphenols in the management of AMD. The results of this review showed mixed evidence regarding the protective effect of vitamin D against AMD. Polyphenols (flavonoids group, curcumin and resveratrol) seem to play an important role as angiogenesis inhibitors, but their effect on AMD is still unclear. Vitamin D and polyphenols may both play an important role as nutritional modifiable protective factors that reduce the risk of AMD progression. However, more research is necessary to better understand the roles of vitamin D and polyphenols in different stages of the disease. Full article

The proper drug choice determines the treatment quality for a disease. The pharmacotherapeutic strategy for respiratory diseases often involves the combination of different drugs with different mechanisms of action. Salbutamol is a short-acting β2-agonist (SABA) used as a reliever in the treatment of asthma and is frequently paired with inhaled corticosteroids (ICS). Indeed, drug–drug interactions (DDI) receive special attention as they are some of the most common causes of adverse effects and can lead to increased morbidity and mortality. DDIs can occur in patients undergoing polytherapy at the pharmacokinetic (PK) or pharmacodynamic (PD) level. Given this, the interaction of salbutamol with other drugs has been extensively explored in terms of PD and PK since its introduction into the pharmaceutical market. To date, more than a thousand salbutamol interactions have been reported. Here, we propose to review some interactions of salbutamol with other drugs such as beta-blockers, anticholinergics, other classes of bronchodilators, corticosteroids, and others, and point out significant gaps in the knowledge of DDI. Full article

In the 21st century, plant-derived metal nanoparticles (PDMNPs) have gained considerable interest because of their tremendous and remarkable potential as therapeutic agents as well as development of less expensive, safer, and easier biomedical equipment. PDMNPs are synthesized from metal salts or oxides by using plant extracts because plants have diversified bioactive compounds that can act as reducing and stabilizing agents at the time of nanoparticle synthesis. Besides, PDMNPs take advantages over the nanoparticles synthesized by other methods because of their low cost, environmental friendliness, and sustainability. The present review explains the synthesis of PDMNPs, their characterization techniques, and oxidative stress-mediated pharmacological effects. The mode of actions for antioxidant, antimicrobial, and anticancer properties has also been critically explored. Due to the plethora of data on plant-derived nanoparticles and their pharmacological properties, we have highlighted PDMNPs’ shape, size, metals of use, and experimental findings regarding their antioxidant, anti-microbial, and anticancer properties in a tabulated form for studies conducted in the last five years, from 2018 to 2022. Because of our review study, we, herein, contemplate that the scientific community as a whole will get a greater comprehension of PDMNPs and their numerous therapeutic applications in a single window. Full article

Obeticholic acid (OCA) or 6-alpha-ethyl-chenodeoxycholic acid is a semisynthetic modified bile acid derivative that acts on the farnesoid X receptor (FXR) as an agonist with a higher potency than bile acid. The FXR is a nuclear receptor highly expressed in the liver and small intestine and regulates bile acid, cholesterol, glucose metabolism, inflammation, and apoptosis. The FXR group of bile acid receptors is currently under investigation for their potential role in the treatment of primary biliary cirrhosis (PBC), non-alcoholic steatohepatitis (NASH), and primary sclerosing cholangitis (PSC). Recent clinical studies suggest OCA may work synergistically with lipid modifying medications to further improve long-term outcomes with primary sclerosing cholangitis. Specifically, OCA can improve clinical outcomes in NASH patients with their different histological, metabolic, and biochemical issues as well as improve morbidity and mortality in patients suffering from PBC, PSC, or liver disease. This improvement is noted in both improved histological examination and reduced need for transplantation. In this review, we examine the pharmacology of OCA towards the treatment of PBC refractory and steatohepatitis (NASH). In addition, we examine future directions and applications of OCA for PBC, PSC, NASH, and NAFLD. Full article

Some pharmaceutical excipients are able to modify intestinal permeability, thus influencing drug absorption and bioavailability. The effect of four polyols (mannitol, maltitol, sorbitol and xylitol) on the permeability of seven active pharmaceutical ingredients (API), representing different BCS classes (furosemide, amiloride, atenolol, ranitidine, nadolol, L-thyroxine and acyclovir), was investigated using the Caco-2 cell permeability model. Analytical methods for the sensitive polyol and API quantification were developed using Ultra High Performance Liquid Chromatography coupled to triple-quadrupole Mass Spectrometry (UHPLC-QqQ). Apparent permeability coefficients (P_app) were calculated from the measured concentrations in the apical and basolateral compartments. The cell monolayer remained intact throughout the experiment in all trials, neither significant Lucifer Yellow (LY) passage, nor modification of the electrical resistance was detected, demonstrating that no active principle or excipient (or combinations thereof) modulated the paracellular transport. The P_app values for apical to basolateral and basolateral to apical directions of drug + excipient combinations were compared with the Papp values for the drug substance alone. Our results show that mannitol, maltitol, sorbitol and xylitol did not modify the permeability of furosemide, amiloride, atenolol, ranitidine, nadolol, acyclovir and L-thyroxine APIs. Moreover, the presence of polyols did not alter the efflux of the active principle (basolateral to apical). Full article

The field of 3D cell culture and its applications is rooted in the understanding of cell biology, tissue engineering, tissue morphology, disease mechanisms, and drug action. For many years, traditional 2D cell culture systems have been widely used but have proven to be limited in their ability to accurately replicate the complex microenvironment of tissues. This often results in issues with cell proliferation, aggregation, and differentiation. 3D cell culture systems have emerged as a solution to this problem and have demonstrated a more accurate simulation of in vivo physiology. This has had a major impact on drug discovery and includes the use of spheroids, organoids, scaffolds, hydrogels, and organs. This review has addressed fundamental questions and exploited utility in 3D in vitro mode of cell culture in view of therapeutics. Full article

Senescence-resumed proliferation (SRP) is proposed to be a mechanism associated with the escape of p21-mediated senescence and the activation of Wnt/β-catenin pathways that enhance malignancy. The keloid genomic landscape shows heavy intersections between TP53 and TGF-β signaling. The machinery to maintain cellular integrity through senescence, apoptosis, and autophagy is co-regulated with stemness, hedgehog, and immunomodulation. Our study demonstrated the presence of SRP and how, on the transcriptome level, TP53 and Wnt/β-catenin pathways are regulated to deliver the same cellular fate. Our study proves that SRP co-regulated with senescence-associated reprogramming (Wnt/β-catenin pathways) and TP53-p21 dysregulations originate from a common etiology and present a novel therapeutic target opportunity. Full article

Antimicrobial resistance has brought great burden to global public health. Alternative strategies are needed to reduce the development of drug resistance. Herein, we have developed an effective synergistic antibacterial strategy combining low–temperature photothermal therapy (LT–PTT) with antibiotic therapy, improving the bactericidal efficiency to avoid antimicrobial resistance. Copper sulfide templated with bovine serum albumin (CuS–BSA) nanoparticles were selected as the photothermal agent, and co–loaded into the hydrogel (Gel) with mupirocin. The Gel could slow down the release rate of CuS–BSA and mupirocin, thereby prolonging the effective drug reaction time. More importantly, when applying near–infrared laser irradiation, the antibacterial activity of the platform could be enhanced greatly by LT–PTT effect of CuS–BSA nanoparticles. In vitro and in vivo results both confirmed that the antibacterial efficacy of the synergistic therapeutic strategy was improved greatly with complete bacterial removal. Overall, this platform has posed a potential strategy to reduce the development of drug resistance and improve patient compliance. Full article

The occurrence of severe bleeding syndrome because of the PML-RARα fusion protein is a life-threatening event in APL. This protein destabilizes homeostasis, maturation, remodeling, and tissue regeneration in addition to hampering the maintenance and differentiation of hematopoietic cells into different lineages, fixing cells in the promyelocyte stage. APL is a classic example of how effective targeted therapy is and, therefore, how important the use of such therapy is to the overall survival of patients, which in this case is represented by the use of ATRA/ATO. Despite that, about 10% of cases of APL patients demonstrate resistance to treatment. Facing this scenario, we point out promising target therapies such as those recommended by the NCCN and Leukemia Net. Since this is such a heterogeneous molecular disease, it is of great importance to understand how important combined chemotherapy, target therapy, immune-based therapy, and combined therapies are in the survival of these APL patients. Full article