Frontiers in Pharmacology

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ISSN / EISSN : 1663-9812 / 1663-9812
Current Publisher: Frontiers Media SA (10.3389)
Total articles ≅ 9,816
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Bingqing Yang, Dan Fang, Qingyan Lv, Zhiqiang Wang,
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.673239

Abstract:
The emergence and rapid spread of antibiotic resistance in pathogenic bacteria constitute a global threat for public health. Despite ongoing efforts to confront this crisis, the pace of finding new potent antimicrobials is far slower than the evolution of drug resistance. The abuse of broad-spectrum antibiotics not only accelerates the formation of resistance but also imposes a burden on the intestinal microbiota, which acts a critical role in human homeostasis. As such, innovative therapeutic strategies with precision are pressingly warranted and highly anticipated. Recently, target therapies have achieved some breakthroughs by the aid of modern technology. In this review, we provide an insightful illustration of current and future medical targeted strategies, including narrow-spectrum agents, engineered probiotics, nanotechnology, phage therapy, and CRISPR-Cas9 technology. We discuss the recent advances and potential hurdles of these strategies. Meanwhile, the possibilities to mitigate the spread of resistance in these approaches are also mentioned. Altogether, a better understanding of the advantages, disadvantages, and mechanisms of action of these targeted therapies will be conducive to broadening our horizons and optimizing the existing antibacterial approaches.
Lei Kuang, Yu Zhu, Yue Wu, Kunlun Tian, Xiaoyong Peng, Mingying Xue, Xinming Xiang, Billy Lau, Fei Chuen Tzang, , et al.
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.652716

Abstract:
Background: Hypotensive resuscitation is widely applied for trauma and war injury to reduce bleeding during damage-control resuscitation, but the treatment time window is limited in order to avoid hypoxia-associated organ injury. Whether a novel hemoglobin-based oxygen carrier (HBOC), YQ23 in this study, could protect organ function, and extend the Golden Hour for treatment is unclear. Method: Uncontrolled hemorrhagic shock rats and miniature pigs were infused with 0.5, 2, and 5% YQ23 before bleeding was controlled, while Lactate Ringer’s solution (LR) and fresh whole blood plus LR (WB + LR) were set as controls. During hypotensive resuscitation the mean blood pressure was maintained at 50–60 mmHg for 60 min. Hemodynamics, oxygen delivery and utilization, blood loss, fluid demand, organ function, animal survival as well as side effects were observed. Besides, in order to observe whether YQ23 could extend the Golden Hour, the hypotensive resuscitation duration was extended to 180 min and animal survival was observed. Results: Compared with LR, infusion of YQ23 in the 60 min pre-hospital hypotensive resuscitation significantly reduced blood loss and the fluid demand in both rats and pigs. Besides, YQ23 could effectively stabilize hemodynamics, and increase tissue oxygen consumption, increase the cardiac output, reduce liver and kidney injury, which helped to reduce the early death and improve animal survival. In addition, the hypotensive resuscitation duration could be extended to 180 min using YQ23. Side effects such as vasoconstriction and renal injury were not observed. The beneficial effects of 5% YQ23 are equivalent to similar volume of WB + LR. Conclusion: HBOC, such as YQ23, played vital roles in damage-control resuscitation for emergency care and benefited the uncontrolled hemorrhagic shock in the pre-hospital treatment by increasing oxygen delivery, reducing organ injury. Besides, HBOC could benefit the injured and trauma patients by extending the Golden Hour.
Peter M. Andrew,
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.674325

Abstract:
Acute intoxication with organophosphates (OPs) can cause a potentially fatal cholinergic crisis characterized by peripheral parasympathomimetic symptoms and seizures that rapidly progress to status epilepticus (SE). While current therapeutic countermeasures for acute OP intoxication significantly improve the chances of survival when administered promptly, they are insufficient for protecting individuals from chronic neurologic outcomes such as cognitive deficits, affective disorders, and acquired epilepsy. Neuroinflammation is posited to contribute to the pathogenesis of these long-term neurologic sequelae. In this review, we summarize what is currently known regarding the progression of neuroinflammatory responses after acute OP intoxication, drawing parallels to other models of SE. We also discuss studies in which neuroinflammation was targeted following OP-induced SE, and explain possible reasons why such therapeutic interventions have inconsistently and only partially improved long-term outcomes. Finally, we suggest future directions for the development of therapeutic strategies that target neuroinflammation to mitigate the neurologic sequelae of acute OP intoxication.
, Dario Tuccinardi, Silvia Pieralice, Sara Giannone, Myriam Carpenito, Lavinia Monte, Mikiko Watanabe, Ilaria Cavallari, Ernesto Maddaloni, Gian Paolo Ussia, et al.
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.670155

Abstract:
In type 2 diabetes, anti-thrombotic management is challenging, and current anti-platelet agents have demonstrated reduced efficacy. Old and new anti-diabetic drugs exhibited—besides lowering blood glucose levels—direct and indirect effects on platelet function and on thrombotic milieu, eventually conditioning cardiovascular outcomes. The present review summarizes existing evidence on the effects of glucose-lowering agents on platelet properties, addressing pre-clinical and clinical research, as well as drug–drug interactions with anti-platelet agents. We aimed at expanding clinicians’ understanding by highlighting new opportunities for an optimal management of patients with diabetes and cardiovascular disease. We suggest how an improvement of the thrombotic risk in this large population of patients may be achieved by a careful and tailored combination of anti-diabetic and anti-platelet therapies.
, Yvonne Denier, Isabelle Huys, Steven Simoens
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.631527

Abstract:
Background: Decision-makers have implemented a variety of value assessment frameworks (VAFs) for orphan drugs in European jurisdictions, which has contributed to variations in access for rare disease patients. This review provides an overview of the strengths and limitations of VAFs for the reimbursement of orphan drugs in Europe, and may serve as a guide for decision-makers. Methods: A narrative literature review was conducted using the databases Pubmed, Scopus and Web of Science. Only publications in English were included. Publications known to the authors were added, as well as conference or research papers, or information published on the website of reimbursement and health technology assessment (HTA) agencies. Additionally, publications were included through snowballing or focused searches. Results: Although a VAF that applies a standard economic evaluation treats both orphan drugs and non-orphan drugs equally, its focus on cost-effectiveness discards the impact of disease rarity on data uncertainty, which influences an accurate estimation of an orphan drug’s health benefit in terms of quality-adjusted life-years (QALYs). A VAF that weighs QALYs or applies a variable incremental cost-effectiveness (ICER) threshold, allows the inclusion of value factors beyond the QALY, although their methodologies are flawed. Multi-criteria decision analysis (MCDA) incorporates a flexible set of value factors and involves multiple stakeholders’ perspectives. Nevertheless, its successful implementation relies on decision-makers’ openness toward transparency and a pragmatic approach, while allowing the flexibility for continuous improvement. Conclusion: The frameworks listed above each have multiple strengths and weaknesses. We advocate that decision-makers apply the concept of accountability for reasonableness (A4R) to justify their choice for a specific VAF for orphan drugs and to strive for maximum transparency concerning the decision-making process. Also, in order to manage uncertainty and feasibility of funding, decision-makers may consider using managed-entry agreements rather than implementing a separate VAF for orphan drugs.
Fei Xiao, Wen-Ping Xu, Han-Qing Yao, Jia-Ming Fan, Xin-Zhong Chen
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.608198

Abstract:
Purpose: Prophylactic infusion of a vasopressor is preferred as a rational choice in clinical practice in Cesarean delivery. Metaraminol is one of most common vasopressors used in obstetric clinical practice. However, the dose-response of metaraminol has not been fully determined and the optimal infusion dose is unknown. Therefore, this study aimed to determine the median effective dose (ED50) and 90% effective dose (ED90) of weight-based fixed-rate metaraminol infusions for preventing spinal-anesthesia-induced hypotension in patients having combined spinal-epidural anesthesia for elective Caesarean delivery. Methods: One hundred and seventeen patients with singleton pregnancies were enrolled and randomly allocated into one of five groups in this study. Patients received prophylactic metaraminol infusion at a fixed rate of 0, 0.25, 1.0, 1.75 or 2.5 μg/kg/min in each group immediately after induction with intrathecal 10 mg of hyperbaric bupivacaine mixed with 5 μg of sufentanil. An effective prophylactic dose was defined as no occurrence of hypotension during the period of spinal introduction and neonatal delivery. Values for ED50 and ED90 of prophylactic infusion of metaraminol were calculated using probit regression. Characteristics of spinal anesthesia and side effects were recorded. Results: The ED50 and ED90 values of weight-based fixed rate of metaraminol infusion were 0.64 (95% CI, 0.04–1.00) μg/kg/min and 2.00 (95% CI, 1.58–2.95) μg/kg/min respectively. The incidence of hypotension decreased with an increased infusion rate of metaraminol in the five groups (test for trend, p < 0.001). The incidence of hypotension was similar between group 0 and 0.25, but significant higher than other groups; the incidence of hypotension was also similar between group 1.0 and 1.75, but higher than group 2.5. The incidence of reactive hypertension was significantly higher in group 2.5 compared to the other groups. Physician interventions were more frequent in group 0, 0.25 and 2.5 than in group 1.0 and 1.75 (adjusted p < 0.001). No difference was found in neonatal outcomes, including Apgar score and pH value of the umbilical artery. Conclusion: In summary, we have compared four different prophylactic weight-based infusion doses of metaraminol for preventing post-spinal hypotension in Cesarean delivery. The ED50 and ED90 values of metaraminol infusion for preventing spinal anesthesia-induced hypotension were 0.64 μg/kg/min and 2.00 μg/kg/min, respectively. This finding may be helpful for guiding clinical practice and further research.
Shana M. Busch, Zareeb Lorenzana, Amy L. Ryan
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.645858

Abstract:
The extracellular matrix (ECM) is not simply a quiescent scaffold. This three-dimensional network of extracellular macromolecules provides structural, mechanical, and biochemical support for the cells of the lung. Throughout life, the ECM forms a critical component of the pulmonary stem cell niche. Basal cells (BCs), the primary stem cells of the airways capable of differentiating to all luminal cell types, reside in close proximity to the basolateral ECM. Studying BC-ECM interactions is important for the development of therapies for chronic lung diseases in which ECM alterations are accompanied by an apparent loss of the lung’s regenerative capacity. The complexity and importance of the native ECM in the regulation of BCs is highlighted as we have yet to create an in vitro culture model that is capable of supporting the long-term expansion of multipotent BCs. The interactions between the pulmonary ECM and BCs are, therefore, a vital component for understanding the mechanisms regulating BC stemness during health and disease. If we are able to replicate these interactions in airway models, we could significantly improve our ability to maintain basal cell stemness ex vivo for use in in vitro models and with prospects for cellular therapies. Furthermore, successful, and sustained airway regeneration in an aged or diseased lung by small molecules, novel compounds or via cellular therapy will rely upon both manipulation of the airway stem cells and their immediate niche within the lung. This review will focus on the current understanding of how the pulmonary ECM regulates the basal stem cell function, how this relationship changes in chronic disease, and how replicating native conditions poses challenges for ex vivo cell culture.
Rachana Singh, Pradhyumna Kumar Singh, Rajnish Kumar, Tanvir Kabir, Mohammad Amjad Kamal, Abdur Rauf, Ghadeer M. Albadrani, Amany A. Sayed, Shaker A. Mousa, Mohamed M. Abdel-Daim, et al.
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.652335

Abstract:
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has a disastrous effect on mankind due to the contagious and rapid nature of its spread. Although vaccines for SARS-CoV-2 have been successfully developed, the proven, effective, and specific therapeutic molecules are yet to be identified for the treatment. The repurposing of existing drugs and recognition of new medicines are continuously in progress. Efforts are being made to single out plant-based novel therapeutic compounds. As a result, some of these biomolecules are in their testing phase. During these efforts, the whole-genome sequencing of SARS-CoV-2 has given the direction to explore the omics systems and approaches to overcome this unprecedented health challenge globally. Genome, proteome, and metagenome sequence analyses have helped identify virus nature, thereby assisting in understanding the molecular mechanism, structural understanding, and disease propagation. The multi-omics approaches offer various tools and strategies for identifying potential therapeutic biomolecules for COVID-19 and exploring the plants producing biomolecules that can be used as biopharmaceutical products. This review explores the available multi-omics approaches and their scope to investigate the therapeutic promises of plant-based biomolecules in treating SARS-CoV-2 infection.
Jazlyn P. Borges, Katrina Mekhail, Gregory D. Fairn, Costin N. Antonescu,
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.642820

Abstract:
Chronic pain has been widely recognized as a major public health problem that impacts multiple aspects of patient quality of life. Unfortunately, chronic pain is often resistant to conventional analgesics, which are further limited by their various side effects. New therapeutic strategies and targets are needed to better serve the millions of people suffering from this devastating disease. To this end, recent clinical and preclinical studies have implicated the epidermal growth factor receptor signaling pathway in chronic pain states. EGFR is one of four members of the ErbB family of receptor tyrosine kinases that have key roles in development and the progression of many cancers. EGFR functions by activating many intracellular signaling pathways following binding of various ligands to the receptor. Several of these signaling pathways, such as phosphatidylinositol 3-kinase, are known mediators of pain. EGFR inhibitors are known for their use as cancer therapeutics but given recent evidence in pilot clinical and preclinical investigations, may have clinical use for treating chronic pain. Here, we review the clinical and preclinical evidence implicating EGFR in pathological pain states and provide an overview of EGFR signaling highlighting how EGFR and its ligands drive pain hypersensitivity and interact with important pain pathways such as the opioid system.
Zhen-Hua Wang, Xiao-Gang Bao, Jun-Jie Hu, Si-Bo Shen, Guo-Hua Xu, Ye-Lin Wu
Frontiers in Pharmacology, Volume 12; doi:10.3389/fphar.2021.671563

Abstract:
Lack of vascularization is directly associated with refractory wound healing in diabetes mellitus (DM). Enrichment of endothelial precursor cells (EPCs) is a promising but challenging approach for the treatment of diabetic wounds. Herein, we investigate the action of nicotinamide riboside (NR) on EPC function for improved healing of diabetic wounds. Db/db mice that were treated with NR-supplemented food (400 mg/kg/d) for 12 weeks exhibited higher wound healing rates and angiogenesis than untreated db/db mice. In agreement with this phenotype, NR supplementation significantly increased the number of blood EPCs and bone marrow (BM)-derived EPCs of db/db mice, as well as the tube formation and adhesion functions of BM-EPCs. Furthermore, NR-supplemented BM-EPCs showed higher expression of sirtuin 1 (Sirt1), phosphorylated adenosine monophosphate–activated protein kinase (p-AMPK), and lower expression of acetylated peroxisome proliferator–activated receptor γ coactivator (PGC-1α) than BM-EPCs isolated from untreated db/db mice. Knockdown of Sirt1 in BM-EPCs significantly abolished the tube formation and adhesion function of NR as well as the expression of p-AMPK and deacetylated PGC-1a. Inhibition of AMPK abolished the NR-regulated EPC function but had no effect on Sirt1 expression, demonstrating that NR enhances EPC function through the Sirt1-AMPK pathway. Overall, this study demonstrates that the oral uptake of NR enhances the EPC function to promote diabetic wound healing, indicating that NR supplementation might be a promising strategy to prevent the progression of diabetic complications.
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