Delivery strategies of amphotericin B for invasive fungal infections

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.     

Emerging role of natural products in cancer immunotherapy

Cancer immunotherapy has become a new generation of anti-tumor treatment, but its indications still focus on several types of tumors that are sensitive to the immune system. Therefore, effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy. Natural products are reported to have this effect on cancer immunotherapy, including cancer vaccines, immune-check points inhibitors, and adoptive immune-cells therapy. And the mechanism of that is mainly attributed to the remodeling of the tumor-immunosuppressive microenvironment, which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy. Therefore, this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism. And we found that saponins, polysaccharides, and flavonoids are mainly three categories of natural products, which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment. Besides, this review also collected the studies about nano-technology used to improve the disadvantages of natural products. All of these studies showed the great potential of natural products in cancer immunotherapy.     

Adipokines as targets in musculoskeletal immune and inflammatory diseases

Adipokines are the principal mediators in adipose signaling. Nevertheless, besides their role in energy storage, these molecules can be produced by other cells, such as immune cells or chondrocytes. Given their pleiotropic effects, research over the past few years has also focused on musculoskeletal diseases, showing that these adipokines might have relevant roles in worsening the disease or improving the treatment response. In this review, we summarize recent advances in our understanding of adipokines and their role in the most prevalent musculoskeletal immune and inflammatory disorders.     

Importance of advanced analytical techniques and methods for food quality control and pollution analysis for more sustainable future in the least developed countries

Chemistry education plays a central role in solving the world's pressing societal issues by equipping and inspiring chemists. However, chemistry education and research in the least developed countries (LDCs) is challenging due to a lack of physical infrastructure and human resources. Among a range of issues and challenges, food and herbal adulteration, microplastics pollution, and chemical hazards are more common in the LDCs, and these issues would impede the achievement of the United Nations sustainable development goals (SDGs). These societal issues are frequently highlighted in the academia and social media of the LDCs, and we believe that at least some aspects of these issues could be solved by advancement in chemistry education and research. However, the current chemistry education and research efforts are inadequate to address these societal issues in these countries. In this article, we have summarized the present scenario and offered examples where developments in chemistry education, particularly advancement in analytical techniques and methods, will provide technological solutions to these issues. Our analysis revealed that sophisticated analytical laboratories are unavailable or unaffordable in the LDCs. The governments of these countries are facing extreme challenges in their pursuit of sustainable development primarily due to a lack of financial resources and shortage of skilled personnel. Revised chemistry curricula and sophisticated analytical testing facilities are urgently required in higher education institutions (HEIs) in the LDCs in helping society achieve the SDGs. A concerted effort between policymakers, chemical societies, funding agencies, chemists, and industries is required to advance chemistry education.     

The Impact of Patient Access to Their Electronic Health Record on Medication Management Safety: A Narrative Review

IntroductionAs the American’s Federal Health Insurance Portability and Accountability Act (HIPAA) stated that patients should be allowed to review their medical records, and as information technology is ever more widely used by healthcare professionals and patients, providing patients with online access to their own medical records through a patient portal is becoming increasingly popular. Previous research has been done regarding the impact on the quality and safety of patients’ care, rather than explicitly on medication safety, when providing those patients with access to their electronic health records (EHRs).AimThis narrative review aims to summarise the results from previous studies on the impact on medication management safety concepts of adult patients accessing information contained in their own EHRs.ResultA total of 24 studies were included in this review. The most two commonly studied measures of safety in medication management were: (a) medication adherence and (b) patient-reported experience. Other measures, such as: discrepancies, medication errors, appropriateness and Adverse Drug Events (ADEs) were the least studied.ConclusionThe results suggest that providing patients with access to their EHRs can improve medication management safety. Patients pointed out improvements to the safety of their medications and perceived stronger medication control. The data from these studies lay the foundation for future research.     

Claims-based pharmacy markers for comprehensive medication management program case identification: Validation against concurrent and prospective healthcare costs and utilization

BackgroundThree claims-based pharmacy markers (complex, costly and risky medications) were developed to help automatically identify patients for comprehensive medication management.ObjectiveTo evaluate the association between newly-developed markers and healthcare outcomes.MethodsThis was a two-year retrospective cohort study using PharMetrics Plus patient-level administrative claims in 2014 and 2015. We included all claims from 1,541,873 individuals with: (1) 24-month medical and pharmacy enrollment in 2014 and 2015, (2) aged between 18 and 63 in 2014, and (3) known gender. Independent/control variables came from 2014 while outcomes came from 2014 (concurrent analysis) and 2015 (prospective analysis). Three pharmacy markers, separately or together, were added to four base models to predict concurrent and prospective healthcare costs (total, medical, and pharmacy) and utilization (having any hospitalization, having any emergency department visit, and having any readmission). We applied linear regression for costs while logistic regression for utilization. Measures of model performances and coefficients were derived from a 5-fold cross-validation repeated 20 times.ResultsIndividuals with 1+ complex, risky or costly medication markers had higher comorbidity, healthcare costs and utilization than their counterparts. Nine binary risky category markers performed the best among the three types of risky medication markers; the Medication Complexity Score and three-level complex category both outperformed a simpler complex medication indicator. Adding three novel pharmacy markers separately or together into the base models provided the greatest improvement in explaining pharmacy costs, compared with medical (non-medication) costs. These pharmacy markers also added value in explaining healthcare utilization among the simple base models.ConclusionsThree claims-based pharmacy indicators had positive associations with healthcare outcomes and added value in predicting them. This initial study suggested that these novel markers can be used by pharmacy case management programs to help identify potential high-risk patients most likely to benefit from clinical pharmacist review and other interventions.     

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.     

The role of extracellular ATP in homeostatic immune cell migration

Antigen stimulation induces adenosine triphosphate (ATP) release from naïve lymphocytes in lymphoid tissues. However, previous studies indicated that the non-lytic release of ATP also occurs in most tissues and cell types under physiological conditions. Here, we show that extracellular ATP (eATP) is indeed constitutively produced by naïve T cells in response to lymphoid chemokines in uninflamed lymph nodes and is involved in the regulation of immune cell migration. In this review, we briefly summarize the homeostatic role of extracellular ATP in immune cell migration in vivo.     

Aristolochic acids exposure was not the main cause of liver tumorigenesis in adulthood

Aristolochic acids (AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I (AAI) reacts with DNA to form covalent aristolactam (AL)–DNA adducts, leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in mainland China. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI–DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA–DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.     

Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.     

Applying artificial intelligence for cancer immunotherapy

Artificial intelligence (AI) is a general term that refers to the use of a machine to imitate intelligent behavior for performing complex tasks with minimal human intervention, such as machine learning; this technology is revolutionizing and reshaping medicine. AI has considerable potential to perfect health-care systems in areas such as diagnostics, risk analysis, health information administration, lifestyle supervision, and virtual health assistance. In terms of immunotherapy, AI has been applied to the prediction of immunotherapy responses based on immune signatures, medical imaging and histological analysis. These features could also be highly useful in the management of cancer immunotherapy given their ever-increasing performance in improving diagnostic accuracy, optimizing treatment planning, predicting outcomes of care and reducing human resource costs. In this review, we present the details of AI and the current progression and state of the art in employing AI for cancer immunotherapy. Furthermore, we discuss the challenges, opportunities and corresponding strategies in applying the technology for widespread clinical deployment. Finally, we summarize the impact of AI on cancer immunotherapy and provide our perspectives about underlying applications of AI in the future.     

Continuous Twin Screw Wet Granulation and Drying—Control Strategy for Drug Product Manufacturing

The use of continuous manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density, and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This article focuses on development of appropriate control strategies for continuous wet granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The article also discusses the use of process analytical technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique, thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process such as wet granulation compared with direct compression process.     

Photoswitchable allosteric modulators for metabotropic glutamate receptors

Metabotropic glutamate receptors (mGlu) are a family of class C G protein-coupled receptors (GPCRs) with important biological functions and widespread expression. The mechanisms of mGlu activation and the development of allosteric modulators for these dimeric proteins have attracted singular attention including the use of light regulated ligands. Photopharmacology involves the integration of a photoactive moiety into the ligand structure that following specific illumination undergoes a structural rearrangement and changes its biological activity. The use of light-regulated allosteric ligands offers the opportunity to manipulate mGlu signalling with spatiotemporal precision, unattainable with classical pharmacological approaches. In this review, we will discuss some of the innovations that have been made in the allosteric photopharmacology of mGlu receptors to date. We discuss the prospects of these molecular tools in the control of mGluRs and the new perspectives in understanding mGlu mechanisms, pharmacology and (patho)physiology that can ultimately result in innovative drug discovery concepts.     

Three-dimensional perspective on ryanodine receptor mutations causing skeletal and cardiac muscle-related diseases

Mutations in RyR alter the cell's Ca²⁺ homeostasis and can cause serious health problems for which few effective therapies are available. Until recently, there was little structural context for the hundreds of mutations linked to muscular disorders reported for this large channel. Growing knowledge of the three-dimensional structure of RyR starts to illustrate the fine control of Ca²⁺ release. Current efforts directed towards understanding how disease mutations impinge in such processes will be crucial for future design of novel therapies. In this review article we discuss the up-to-date information about mutations according to their role in the 3D structure, and classified them to provide context from a structural perspective.     

A narrative review of approved and emerging anti-obesity medications

BackgroundRecently, many drugs have been approved for halting overweight and obesity—few types of research shifted to using Anti-obesity medications (AOM) solely for well-being and shape-keeping.ObjectiveThis narrative review's objective was to explore the use of AOM in relation to their medical indications, efficacy, and cardiovascular safety.Methods and materialsWe have conducted a narrative review of the literature on approved/non-approved AOM used for obesity and overweight. We have shed light on the emerging trials of therapies and evolving remedies.ResultsRecently, there has been an enormous change in the use of AOM with high consumption that deserves extensive surveillance for the long-term consequences and impact on social, mental, and physical health. Nearly six AOMs and combined therapy are approved by the Food and Drug Administration. The recent guidelines for obesity management have shifted the focus from weight loss to goals that the patient considers essential and toward targeting the root cause of obesity.ConclusionThe use of AOM increased enormously despite its sometimes-dubious safety and ineffectiveness. The public and medical professionals should be vigilant to the real-world benefits of anti-obesity drugs and their achieved effectiveness with an improved safety profile.     

Antioxidant and fibroblast-activating activities of the by-product of skate chondroitin extractive production

Owing to the increasing popularity of chondroitin sulfate (CS) for joint pain treatment, the CS-production industry has been producing an increasing amount of waste, which includes type II collagen, non-collagenous proteins, and residual CS. To effectively utilize these resources, we intended to develop new products from the by-product of skate chondroitin sulfate production (BP-sCS). In this study, we examined the antioxidant and fibroblast-activating properties of BP-sCS, intending to apply it for a wound-healing promoter. BP-sCS exhibited ABTS and DPPH radical scavenging activities, protected L929 fibroblasts from H₂O₂- or AAPH-induced oxidative stress, and scavenged intracellular reactive oxygen species. Moreover, BP-sCS promoted L929 fibroblast proliferation/metabolism and stimulated collagen deposition into the extracellular matrix. In addition, BP-sCS counteracted AAPH-induced oxidative stress damage that inhibited fibroblast migration. These effect were attributed to the cooperation among the molecules of BP-sCS, namely, type II collagen peptides, non-collagenous peptides, and CS polysaccharides. Our findings indicate that BP-sCS has the potential as a novel wound-healing promoter. This study is the first step toward the realization of a sustainable CS-production industry by waste utilization in healthcare products.     

An overview of structure-based activity outcomes of pyran derivatives against Alzheimer’s disease

Pyran is a heterocyclic group containing oxygen that possesses a variety of pharmacological effects. Pyran is also one of the most prevalent structural subunits in natural products, such as xanthones, coumarins, flavonoids, benzopyrans, etc. Additionally demonstrating the neuroprotective properties of pyrans is the fact that this heterocycle has recently attracted the attention of scientists worldwide. Alzheimer's Disease (AD) treatment and diagnosis are two of the most critical research objectives worldwide. Increased amounts of extracellular senile plaques, intracellular neurofibrillary tangles, and a progressive shutdown of cholinergic basal forebrain neuron transmission are often related with cognitive impairment. This review highlights the various pyran scaffolds of natural and synthetic origin that are effective in the treatment of AD. For better understanding synthetic compounds are categorized as different types of pyran derivatives like chromene, flavone, xanthone, xanthene, etc. The discussion encompasses both the structure–activity correlations of these compounds as well as their activity against AD. Because of the intriguing actions that were uncovered by these pyran-based scaffolds, there is no question that they are at the forefront of the search for potential medication candidates that could treat Alzheimer's disease.     

Multidisciplinary DEprescribing review for Frail oldER adults in long-term care (DEFERAL): Implementation strategy design using behaviour science tools and stakeholder engagement

IntroductionDeprescribing is a strategy for reducing the use of potentially inappropriate medications for older adults. Limited evidence exists on the development of strategies to support healthcare professionals (HCPs) deprescribing for frail older adults in long-term care (LTC).ObjectiveTo design an implementation strategy, informed by theory, behavioural science and consensus from HCPs, which facilitates deprescribing in LTC.MethodsThis study was consisted of 3 phases. First, factors influencing deprescribing in LTC were mapped to behaviour change techniques (BCTs) using the Behaviour Change Wheel and two published BCT taxonomies. Second, a Delphi survey of purposively sampled HCPs (general practitioners, pharmacists, nurses, geriatricians and psychiatrists) was conducted to select feasible BCTs to support deprescribing. The Delphi consisted of two rounds. Using Delphi results and literature on BCTs used in effective deprescribing interventions, BCTs which could form an implementation strategy were shortlisted by the research team based on acceptability, practicability and effectiveness. Finally, a roundtable discussion was held with a purposeful, convenience sample of LTC general practitioners, pharmacists and nurses to prioritise factors influencing deprescribing and tailor the proposed strategies for LTC.ResultsFactors influencing deprescribing in LTC were mapped to 34 BCTs. The Delphi survey was completed by 16 participants. Participants reached consensus that 26 BCTs were feasible. Following the research team assessment, 21 BCTs were included in the roundtable. The roundtable discussion identified lack of resources as the primary barrier to address. The agreed implementation strategy incorporated 11 BCTs and consisted of an education-enhanced 3-monthly multidisciplinary team deprescribing review, led by a nurse, conducted at the LTC site.ConclusionThe deprescribing strategy incorporates HCPs’ experiential understanding of the nuances of LTC and thus addresses systemic barriers to deprescribing in this context. The strategy designed addresses five determinants of behaviour to best support HCPs engaging with deprescribing.     

The role of nuclear factors as “Find-Me”/alarmin signals and immunostimulation in defective efferocytosis and related disorders

Efferocytosis as an apoptotic cell (AC) clearance mechanism facilitates the removal of dangerous and damaged cells, an important process in regulating normal homeostasis. Failure to correctly execute apoptosis and efferocytosis is associated with atherosclerosis, as well as chronic inflammatory and autoimmune disorders such as systemic lupus erythematosus (SLE). Effective and timely efferocytosis involves various molecules that act as “Find-Me” signals or as alarmins to quickly allow identification by phagocytic cells. In recent years, most of these molecules have been investigated, but less attention has been paid to the nuclear molecules associated with efferocytosis of ACs and necrotic cells (NCs). These molecules have several functions including acting as alarmin signals for faster recognition of ACs, facilitating the cleanup of ACs and for maintaining self-tolerance. The same group of molecules is also implicated in several inflammatory and autoimmune diseases. Previous studies have shown that these molecules also serve as targets for pharmacological agents such as necrostatins, recombinant Fcnb, anti-histone, neutralizing antibodies, calbiochem, aminophylline, activated protein C, CD24IgG recombinant fission protein, and recombinant thrombomodulin. Thus, greater understanding of these molecules/pathways will enable developments in the treatment and/or prevention of various disorders, especially autoimmune diseases. Here, we review current knowledge about the mechanisms by which nucleic acids, histones, nucleosomes and monosodium urate microcrystals (MSU) can act as alarmins/“Find-Me” signals, how they might be stimulated in defective efferocytosis and their function and importance as biomarkers for prognosis and treatment of atherosclerosis, inflammatory disorders and autoimmune diseases.