Chrono-pharmaceutical approaches to optimize dosing regimens based on the circadian clock machinery

Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The “circadian clock” is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables ‘chrono-pharmaceutical’ applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.

Physiological Changes in Chicken Embryos Inoculated with Drugs and Viruses Highlight the Need for More Standardisation of This Animal Model

Several works have been developed using the Gallus gallus embryo as an experimental model to study the toxicity of drugs and infections. Studies that seek to standardise the evaluated parameters are needed to better understand and identify the viability of chicken embryos (CE) as an experimental model. Therefore, we sought to verify whether macroscopic, histopathological, blood count, metabolites and/or enzymes changes and oxidative stress in CE of different ages are peculiar to the model. To achieve this goal, in ovo assays were performed injecting a virus (Gammacoronavirus) and two drugs (filgrastim and dexamethasone) that cause known changes in adult chickens and other animals. Embryo response to virus and drug challenges may not occur as expected for adult chickens and even different species. While macroscopic and microscopic damage was visible in the case of viral infections, the white blood cell count and inflammation biomarkers did not change. Filgrastim (FG) testing did not result in the expected effects for CE. On the other hand, with dexamethasone (DX), changes in blood parameters and biomarkers were inherent to the model and depended on the stage of CE development. Our work reinforces the importance of standardization and correct use of the model so that the results of infection, toxicity and pharmacokinetics are recorded.

STUDY OF HEPATOPROTECTIVE ACTIVITY OF STINGLESS BEE PROPOLIS AGAINTS TOXICITY OF DRUGS

Objective: The aim of this study is to determine the effect of stingless bee propolis supplementation as a hepatoprotector on the prevention of DILI and the effect of healing and restoring nutrition for DILI patients due to drug induction. Methods: The literature review starts from problem identification, library data collection, reading, taking notes, analyzing, and processing the data obtained and then compiling it into a systematic review Results: The results of a literature study conducted show that propolis has a good hepatoprotective ability against drugs that cause DILI cases such as the anti-tuberculosis, antibiotic and antipyretic groups as indicated by the SGPT, SGOT, BT, GSH, and SOD values that are close to normal values. In addition, propolis supplementation can accelerate the healing and restoration of the nutritional status of DILI patients. All active compounds contained in propolis such as phytochemicals and lipopolysaccharides work to protect the liver from the toxic effects of DILI through antioxidant mechanisms. Conclusion: Overall, the data from this literature study show that the hepatoprotective activity of propolis has the potential to complement drug therapy to reduce hepatotoxic effects and can conclusively beneficial to accelerate the restoration of nutritional status for DILI patients.

Physiological Changes in Chicken Embryos Inoculated With Drugs and Viruses Highlight the Need for More Standardisation of This Animal Model

Background: Several works have been developed using the Gallus gallus embryo as an experimental model to study the toxicity of drugs and infections. Studies that seek to standardise the evaluated parameters are needed to better understand and identify the viability of chicken embryos (CE) as an experimental model. Therefore, we sought to verify whether macroscopic, histopathological, blood count, metabolites and/or enzymes changes and oxidative stress in CE of different ages are peculiar to the model. To achieve this goal, in ovo assays were performed injecting a virus (Gammacoronavirus) and two drugs (filgrastim and dexamethasone) that cause known changes in adult chickens and other animals. Results: Embryo response to virus and drug challenges may not occur as expected for adult chickens and even different species. While macroscopic and microscopic damage was visible in the case of viral infections, the white blood cell count and inflammation biomarkers did not change. Filgrastim (FG) testing did not result in the expected effects for CE. On the other hand, with dexamethasone (DX), changes in blood parameters and biomarkers were inherent to the model and depended on the stage of CE development.Conclusions: Our work reinforces the importance of standardization and correct use of the model so that the results of infection, toxicity and pharmacokinetics are recorded.

A Novel System for Evaluating the Inhibition Effect of Drugs on Cytochrome P450 Enzymes in vitro Based on Human-Induced Hepatocytes (hiHeps)

Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes in vitro. Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 in vitro based on hiHeps. Curcumin can inhibit many CYP enzymes in vitro, and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC50 values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system in vitro. Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS–SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated in vitro. The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes in vitro, which has broad application prospects in drug research.

Comparative analysis of the effects of opioids in angiogenesis

Background Angiogenesis, the formation of blood vessel from pre-existing ones, plays an important role in many pathophysiological diseases, such as cancer. Opioids are often used in clinic for the management of chronic pain in cancer patients at terminal phases. Here, we investigated and compared the effects and mechanisms of four opioids on angiogenesis. Methods We performed angiogenesis assays on human umbilical vein endothelial cells (HUVEC) that represent an in vitro model to assess the toxicity of drugs to endothelium. Results Morphine and oxycodone at 0.1 μM to 100 μM dose-dependently increased endothelial cell tube formation and proliferation. We observed the same in endothelial cells exposed to fentanyl at 0.1 μM to 10 μM but there was a gradual loss of stimulation by fentanyl at 100 μM and 1000 μM. Morphine and fentanyl reduced endothelial cell apoptosis-induced by serum withdrawal whereas oxycodone did not display anti-apoptotic effect, via decreasing Bax level. Oxycodone at the same concentrations was less potent than morphine and fentanyl. Different from other three opioids, codeine at all tested concentrations did not affect endothelial cell tube formation, proliferation and survival. Mechanism studies demonstrated that opioids acted on endothelial cells via μ-opioid receptor-independent pathway. Although we observed the increased phosphorylation of mitogen-activated protein kinase (MAPK) in cells exposed to morphine, fentanyl and oxycodone, the rescue studies demonstrated that the stimulatory effects of morphine but not fentanyl nor oxycodone were reversed by a specific MAPK inhibitor. Conclusion Our work demonstrates the differential effects and mechanisms of opioids on angiogenesis.

A Review: In – Silico Approaches in Predictive Toxicology

This article deals with the in – silico techniques for predicting the toxicity of chemical compounds. Toxicology is the branch of biology that deals with the study of adverse effect of chemical substances on the living organisms and the practice of treating and preventing such adverse effects. Predicting toxicity of a new drug to be produced is the first aim of preclinical trials. It is achieved by in-silico methods. There are several in - silico technique softwares which are used for the prediction of ADME and hence toxicity of drugs. In – silico methods involves the use of various softwares to calculate and then predict the toxicity of a compound by first determining its structural and pharmacokinetic and pharmacodynamic properties and then it correlates this information with already existing drugs and molecules and thus gives us conclusion. The article focuses on QSAR and its techniques, HQSAR, several other methods like structural alerts and rule-based models, chemical category and read across model, dose and time response model, virtual ligand screening, docking, 3D pharmacophore mapping, simulation approaches, PKPD models and several other approaches like bioinformatics. After reviewing and studying various in silico techniques the conclusion comes out to be that, in-silico methods of predictive toxicology are more better than in-vitro and in-vivo methods since they are much more safe (as animals are not harmed), economic, fast and accurate w.r.to, results/output in predicting toxicity of compounds by computational methods and hence are widely used in the production of new drug for accessing its toxicity

Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment

The study describes the current state of knowledge on nanotechnology and its utilization in medicine. The focus in this manuscript was on the properties, usage safety, and potentially valuable applications of chitosan-based nanomaterials. Chitosan nanoparticles have high importance in nanomedicine, biomedical engineering, discovery and development of new drugs. The manuscript reviewed the new studies regarding the use of chitosan-based nanoparticles for creating new release systems with improved bioavailability, increased specificity and sensitivity, and reduced pharmacological toxicity of drugs. Nowadays, effective cancer treatment is a global problem, and recent advances in nanomedicine are of great importance. Special attention was put on the application of chitosan nanoparticles in developing new system for anticancer drug delivery. Pre-clinical and clinical studies support the use of chitosan-based nanoparticles in nanomedicine. This manuscript overviews the last progresses regarding the utilization, stability, and bioavailability of drug nanoencapsulation with chitosan and their safety.

Contribution of Gut Microbiome to Human Health and the Metabolism or Toxicity of Drugs and Natural Products

Trillions of microorganisms with a complex and diverse community are in the human gastrointestinal tract. Gut microbial genomes have much more genes than human genome, thus having a variety of enzymes for many metabolic activities; therefore, gut microbiota is recognized as an “organ” that has essential functions to human health. There are interactions between host and gut microbiome, and there are correlations between gut microbiome in the healthy state and in certain disease states, such as cancer, liver diseases, diabetes, and obesity. Gut microbiota can produce metabolites from nutrients of dietary sources and from drug metabolisms; these metabolites, for example, short-chain fatty acids (SCFAs), have substantial effects on human health. Drug-microbiome interactions play a crucial role in therapeutic efficiency. Some drugs are able to change compositions of gut microbiota, which can lead to either enhance or reduce therapeutic efficiency. This chapter provides an overview of roles of gut microbiota in human health and diseases and recent research studies on the metabolism or toxicity of drugs and natural products. Since gut bacteria considerably contribute to drug metabolism, research on the influence of gut microbiome on drug candidates (or natural products) should be part of the drug development processes.

Nano- and Micro-Porous Chitosan Membranes for Human Epidermal Stratification and Differentiation

The creation of partial or complete human epidermis represents a critical aspect and the major challenge of skin tissue engineering. This work was aimed at investigating the effect of nano- and micro-structured CHT membranes on human keratinocyte stratification and differentiation. To this end, nanoporous and microporous membranes of chitosan (CHT) were prepared by phase inversion technique tailoring the operational parameters in order to obtain nano- and micro-structured flat membranes with specific surface properties. Microporous structures with different mean pore diameters were created by adding and dissolving, in the polymeric solution, polyethylene glycol (PEG Mw 10,000 Da) as porogen, with a different CHT/PEG ratio. The developed membranes were characterized and assessed for epidermal construction by culturing human keratinocytes on them for up to 21 days. The overall results demonstrated that the membrane surface properties strongly affect the stratification and terminal differentiation of human keratinocytes. In particular, human keratinocytes adhered on nanoporous CHT membranes, developing the structure of the corneum epidermal top layer, characterized by low thickness and low cell proliferation. On the microporous CHT membrane, keratinocytes formed an epidermal basal lamina, with high proliferating cells that stratified and differentiated over time, migrating along the z axis and forming a multilayered epidermis. This strategy represents an attractive tissue engineering approach for the creation of specific human epidermal strata for testing the effects and toxicity of drugs, cosmetics and pollutants.