Antisense agents against antibiotic-resistant bacteria

The dramatically increasing levels of antibiotic resistance are being seen worldwide, and is a significant threat to public health. Antibiotic and drug resistance is seen in various bacterial species. Antibiotic resistance is associated with increased morbidity and mortality and increased treatment costs. Antisense-relevant technologies include the utilization of oligonucleotide molecules to interfere with gene expression, as a new technique for the treatment of antibiotic-resistant bacteria has been proposed antisense agents or nucleic acids analogs with antibacterial properties, which are commonly very short and their size almost 10-20 bases and can be hinted to peptide nucleic acids (PNAs), phosphorodiamidate morpholino oligomers (PPMOs) and locked nucleic acids (LNAs). This review highlights that PNAs, PPMOs, and LNAs target the genes that cause destroy the gene and inhibit the growth of bacteria. These results open a new perspective for therapeutic intervention. In future studies, it is necessary to examine different aspects of antisense agents, for example, safety, toxicity, and pharmacokinetic properties of antisense agents to be employed in clinical treatment.

Dosing Therapeutic Radiopharmaceuticals in Obese Patients

The prevalence of obesity has increased dramatically in the Western population. Obesity is known to influence not only the proportion of adipose tissue but also physiological processes that could alter drug pharmacokinetics. Yet, there are no specific dosing recommendations for radiopharmaceuticals in this patient population. This could potentially lead to underdosing and thus suboptimal treatment in obese patients, while it could also lead to drug toxicity due to high levels of radioactivity. In this review, relevant literature is summarized on radiopharmaceutical dosing and pharmacokinetic properties, and we aimed to translate these data into practical guidelines for dosing of radiopharmaceuticals in obese patients. For radium-223, dosing in obese patients is well established. Furthermore, for samarium-153-ethylenediaminetetramethylene (EDTMP), dose-escalation studies show that the maximum tolerated dose will probably not be reached in obese patients when dosing on MBq/kg. On the other hand, there is insufficient evidence to support dose recommendations in obese patients for rhenium-168-hydroxyethylidene diphosphonate (HEDP), sodium iodide-131, iodide 131-metaiodobenzylguanidine (MIBG), lutetium-177-dotatate, and lutetium-177-prostate-specific membrane antigen (PSMA). From a pharmacokinetic perspective, fixed dosing may be appropriate for these drugs. More research into obese patient populations is needed, especially in the light of increasing prevalence of obesity worldwide.

Recent development of imidazole derivatives as potential anticancer agents

Cancer, one of the key health problems globally, is a group of related diseases that share a number of characteristics primarily the uncontrolled growth and invasive to surrounding tissues. Chemotherapy is one of the ways for the treatment of cancer which uses one or more anticancer agents as per chemotherapy regimen. Limitations of most anticancer drugs due to a variety of reasons such as serious side effects, drug resistance, lack of sensitivity and efficacy etc. generate the necessity towards the designing of novel anticancer lead molecules. In this regard, the synthesis of biologically active heterocyclic molecules is an appealing research area. Among heterocyclic compounds, nitrogen containing heterocyclic molecules has fascinated tremendous consideration due to broad range of pharmaceutical activity. Imidazoles, extensively present in natural products as well as synthetic molecules, have two nitrogen atoms, and are five membered heterocyclic rings. Because of their countless physiological and pharmacological characteristics, medicinal chemists are enthused to design and synthesize new imidazole derivatives with improved pharmacodynamic and pharmacokinetic properties. The aim of this present chapter is to discuss the synthesis, chemistry, pharmacological activity, and scope of imidazole-based molecules in anticancer drug development. Finally, we have discussed the current challenges and future perspectives of imidazole-based derivatives in anticancer drug development.

JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model

Background: Alzheimer’s disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROLTM, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. Objective: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. Methods: For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. Results: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. Conclusion: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.

Disrupting GPCR Complexes with Smart Drug-like Peptides

G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehensive overview of GPCR complexes, with an emphasis on current studies using GPCR-disrupting peptides mimicking TM domains involved in multimerization, and we also highlight recent strategies used to achieve drug-like versions of such TM peptide candidates for therapeutic application.

Antimicrobial Stewardship Program: Reducing Antibiotic’s Spectrum of Activity Is not the Solution to Limit the Emergence of Multidrug-Resistant Bacteria

Overconsumption of antibiotics in hospitals has led to policy implementation, including the control of antibiotic prescriptions. The impact of these policies on the evolution of antimicrobial resistance remains uncertain. In this work, we review the possible limits of such policies and focus on the need for a more efficient approach. Establishing a causal relationship between the introduction of new antibiotics and the emergence of new resistance mechanisms is difficult. Several studies have demonstrated that many resistance mechanisms existed before the discovery of antibiotics. Overconsumption of antibiotics has worsened the phenomenon of resistance. Antibiotics are responsible for intestinal dysbiosis, which is suspected of being the source of bacterial resistance. The complexity of the intestinal microbiota composition, the impact of the pharmacokinetic properties of antibiotics, and the multiplicity of other factors involved in the acquisition and emergence of multidrug-resistant organisms, lead us to think that de-escalation, in the absence of studies proving its effectiveness, is not the solution to limiting the spread of multidrug-resistant organisms. More studies are needed to clarify the ecological risk caused by different antibiotic classes. In the meantime, we need to concentrate our efforts on limiting antibiotic prescriptions to patients who really need it, and work on reducing the duration of these treatments.

A Review of Pharmacology, Toxicity and Pharmacokinetics of 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside

Polygonum multiflorum Thunb. (He-shou-wu in Chinese), a Chinese botanical drug with a long history, is widely used to treat a variety of chronic diseases in clinic, and has been given the reputation of “rejuvenating and prolonging life” in many places. 2,3,4′,5-tetrahydroxystilbene-2-O-β-D-glucoside (TSG, C20H22O9) is the main and unique active ingredient isolated from Polygonum multiflorum Thunb., which has extensive pharmacological activities. Modern pharmacological studies have confirmed that TSG exhibits significant activities in treating various diseases, including inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, hepatic steatosis, osteoporosis, depression and diabetic nephropathy. Therefore, this review comprehensively summarizes the pharmacological and pharmacokinetic properties of TSG up to 2021 by searching the databases of Web of Science, PubMed, ScienceDirect and CNKI. According to the data, TSG shows remarkable anti-inflammation, antioxidation, neuroprotection, cardiovascular protection, hepatoprotection, anti-osteoporosis, enhancement of memory and anti-aging activities through regulating multiple molecular mechanisms, such as NF-κB, AMPK, PI3K-AKT, JNK, ROS-NO, Bcl-2/Bax/Caspase-3, ERK1/2, TGF-β/Smad, Nrf2, eNOS/NO and SIRT1. In addition, the toxicity and pharmacokinetics of TSG are also discussed in this review, which provided direction and basis for the further development and clinical application of TSG.

Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands

Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug sensing fluorescent reporters ('iDrugSnFRs') for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by > 30 fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

Radical Scavenging Activity and Pharmacokinetic Properties of Coumarin–Hydroxybenzohydrazide Hybrids

Free radicals often interact with vital proteins, violating their structure and inhibiting their activity. In previous studies, synthesis, characterisation, and the antioxidative properties of the five different coumarin derivatives have been investigated. In the tests of potential toxicity, all compounds exhibited low toxicity with significant antioxidative potential at the same time. In this paper, the radical scavenging activity of the abovementioned coumarin derivatives towards ten different radical species was investigated. It was found that all investigated compounds show good radical scavenging ability, with results that are in correlation with the results published in the previous study. Three additional mechanisms of radical scavenging activity were investigated. It was found that all three mechanisms are thermodynamically plausible and in competition. Interestingly, it was found that products of the Double Hydrogen Atom Transfer (DHAT) mechanism, a biradical species in triplet spin state, are in some cases more stable than singlet spin state analogues. This unexpected trend can be explained by spin delocalisation over the hydrazide bridge and phenolic part of the molecule with a low probability of spin pairing. Besides radical-scavenging activity, the pharmacokinetic and drug-likeness of the coumarin hybrids were investigated. It was found that they exhibit good membrane and skin permeability and potential interactions with P-450 enzymes. Furthermore, it was found that investigated compounds satisfy all criteria of the drug-likeness tests, suggesting they possess a good preference for being used as potential drugs.

Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?

Cancer has become a global health problem, accounting for one out of six deaths. Despite the recent advances in cancer therapy, there is still an ever-growing need for readily accessible new therapies. The process of drug discovery and development is arduous and takes many years, and while it is ongoing, the time for the current lead compounds to reach clinical trial phase is very long. Drug repurposing has recently gained significant attention as it expedites the process of discovering new entities for anticancer therapy. One such potential candidate is the antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo. In this review, major molecular and cellular mechanisms underlying the anticancer effect of artemisinin and its derivatives are summarised. Furthermore, major mechanisms of action and some key signaling pathways of this group of compounds have been reviewed to explore potential targets that contribute to the proliferation and metastasis of tumor cells. Despite its established profile in malaria treatment, pharmacokinetic properties, anticancer potency, and current formulations that hinder the clinical translation of artemisinin as an anticancer agent, have been discussed. Finally, potential solutions or new strategies are identified to overcome the bottlenecks in repurposing artemisinin-type compounds as anticancer drugs.