Future Pharmacol., Volume 2, Issue 1 (March 2022) – 7 articles

During the SARS-CoV-2 pandemic, hydroxychloroquine (HCQ), was among the first drugs to be tested due to demonstrated in vitro antiviral activity against SARS-CoV-2. Pharmacokinetic variability was expected due to the frequent comorbidities and pathophysiological modifications observed in severe COVID-19 patients hospitalized in intensive care units (ICUs). The aim of this study was to describe HCQ plasmatic concentrations in ICUs and assess variability factors. A multicentric retrospective study was carried in four ICUs in Marseille from March to April 2020. There were two dosing regimens: 400 mg after a 400 mg loading dose (DR1); and 600 mg without a loading dose (DR2). HCQ concentrations were determined every 2 or 3 days. The impacts of demo-graphic, biological, and clinical covariates were investigated. The median HCQ concentration was: 0.096 mg/L on day (D) 2, 0.129 mg/L on D3 to D5, 0.140 mg/L on D6 to D10 for DR1 versus 0.116 mg/L, 0.261 mg/L, and 0.30 mg/L, respectively, for DR2. At D2, 53.9% and 46.2% of patients with DR1 and DR2, respectively, presented HCQP concentrations <0.1µg/mL and 48.2% versus 10.7% at D3 to D5. Time post-initiation, dosing regimen, nasogastric administration, and weight showed significant association with HCQ variability. The high proportion of suboptimal HCQ concentrations can be explained by a lack of optimized dosing regimen and numerous pathophysiological changes in the COVID-19/ICU population. Full article

Bergenin (BER), a key constituent of Bergenia crassifolia (Saxifragaceae), has gained extensive attention, owing to its array of pharmacological actions, including anti-infective, anti-cancer, anti-diabetic, neuroprotective, hepatoprotective, anti-urolithiatic, anti-hyperuricemic, and anti-bradykinin properties. Despite ever-intensifying support for its therapeutic features, the poor solubility, lower oral bioavailability, shorter half-life, and more intestinal pH degradation (pH 6.8 or above) of BER have puzzled researchers. To circumvent these pharmaceutical challenges, and to improve its therapeutic efficacy, newer approaches have been adopted by research scientists. Thus, a discussion of the existing literature may provide complete information about the advances in delivery strategies for enhancing its utility. This paper summarizes up-to-date works on the design and development of novel delivery carriers of this bioactive compound, such as phospholipid complexes, extended-release core tablets, prodrugs, herbal gels, polyherbal ointments, nanoparticles, and poly (lactic acid) polymers, with the objective of harnessing its full potential. This review also provides a deep insight into its bioactivities, along with mechanisms. Additionally, the physicochemical attributes, chemistry, and pharmacokinetics of BER are discussed herein. Hence, the comprehensive information documented in this review may introduce new avenues for research advancements of BER. Full article

Patients in the intensive care unit often lose a considerable fraction of their gut microbiome due to exposure to broad-spectrum antibiotics and other reasons. Dysbiosis often results in prolonged diarrhea and increase occurrence of multi-drug resistant pathogens in the colon with clinical consequences not yet well understood. Restoring the microbiome by fecal microbial transplantation (FMT) is a plausible therapeutic possibility, so far only documented in case reports and case series using very heterogeneous methodologies. Before FMT with critically ill patients can be tested in randomized controlled trials, there is a burning need to describe a standardized operating procedure (SOP) of the whole process, respecting the specifics of the critically ill population, such as the risk of the disrupted intestinal barrier and time-critical nature of the procedure. We describe the SOP that has been developed for experimental use in critically ill patients by a multidisciplinary team of intensivists, gastroenterologists, and microbiologists based on feedback from regulatory authority (State Institute for Drug Control of the Czech Republic). The hallmarks of these SOPs are multi-donor freshly frozen transplants guaranteed for 2 months consisting of seven aliquots from seven unrelated healthy donors and administered by a rectal tube. In this paper we discuss the rationale for this SOP and the process of its development in detail and release the full proposed SOP is in the form of an online appendix. Full article

The objectives of this study were to investigate whether elicitors induce the production of taxoids in Taxus globosa by testing the hypothesis that the cells induce a greater accumulation of taxoids depending on the type and concentration of the elicitor treatment tested. Cell cultures were initiated from Taxus globosa friable calli for producing taxoids using the Gamborg medium supplemented with different initial combinations of growth regulators as follows: naphthaleneacetic acid, benzylaminopurine, picloram, and polyvinylpyrrolidone. The cell suspension cultures were then used for evaluating taxoid production through different elicitor treatments, such as methyl jasmonate, ethanol, buthionine sulphoximine, and hydrogen peroxide. The cell suspension cultures showing the best growth characteristics were found in the medium supplemented with 10.74 µM of naphthaleneacetic acid and 3.33 µM of picloram. The highest biomass for the cell cultures was obtained in the EtOH-2 treatment (0.12 ± 0.005 mg·g⁻¹ of dry weight) after 8 days, while the biomass in the control treatment at that time was 0.095 ± 0.2 mg·g⁻¹ of dry weight. The exogenous application of a combination of elicitors buthionine and hydrogen peroxide in the cell suspension cultures significantly increased the concentration of the 10-deacetylbaccatin (1662 µg·g⁻¹ of dry weight), cephalomannine (334.32 µg·g⁻¹ of dry weight), and the production of taxol (157.0 µg·g⁻¹ of dry weight). Full article

The availability of systematic drug response registries for hundreds cell lines, coupled with the comprehensive profiling of their genomes/transcriptomes enabled the development of computational methods that investigate the molecular basis of drug responsiveness. Herein, we propose an automated, multi-omics systems pharmacology method that identifies genomic markers of anti-cancer drug response. Given a cancer type and a therapeutic compound, the method builds two cell line groups on the antipodes of the drug response spectrum, based on the outer quartiles of the maximum micromolar screening concentration. The method intersects cell lines that share common features in their mutation status, gene expression levels or copy number variants, and a pool of drug response biomarkers (core genes) is built, using genes with mutually exclusive alterations in the two cell line groups. The relevance with the drug target pathways is then quantified, using the combined interaction score of the core genes and an accessory protein network having strong, physical/functional interactions. We demonstrate the applicability and effectiveness of our methodology in three use cases that end up in known drug-gene interactions. The method steps into explainable bioinformatics approaches for novel anticancer drug-gene interactions, offering high accuracy and increased interpretability of the analysis results. Availability: https://github.com/PGxAUTH/PGxGDSC. Full article

The chemical composition of the Cynophalla flexuosa hydroethanolic extract (CFHEE) was identified and its antioxidant, antifungal and antipleomorphic activities against C. albicans and C. tropicalis strains were evaluated. Phytochemical prospecting evidenced polyphenolic and triterpenoid compounds while UPLC-MS analysis revealed the presence of Isopropyl/n-propyl-GLS; Methylpropyl-GLS/butyl-GLS; Methylbutyl-GLS; Quercetin O-di-hexoside; Quercetin-pentosyl-hexoside; Rutin; Quercetin O-glucoside; Kaempferol O-rhamnosyl-hexoside; Kaempferol O-pentosyl-hexoside and Lariciresinol hexoside. The CFHEE inhibited the effect of the DPPH^● free radical, both when evaluated individually and in combination with the antifungal fluconazole. When associated with 256 μg/mL fluconazole, the extract, at concentrations from 128 μg/mL, reduced the effect of the DPPH^● free radical with values ranging from 37.7% to 95.8%. The extract’s antifungal effect was considered clinically irrelevant and its combination with the antifungal triggered an antagonistic effect against the two strains, thus indicating the popular use of bravo beans in the form of teas or infusions should not be combined with the intake of the drug Fluconazole as this may lead to a reduction of its clinical effect. The extract, however, inhibited morphological changes (pleomorphism) in Candida species, preventing the development of hyphae. The CFHEE possesses an antioxidant effect and a potential pharmacological activity for the inhibition of one of the Candida spp. virulence factors. Full article

Glycyrrhizic acid (GA) is the main active component of the licorice root, which has been known in traditional medicine since the ancient times. It is a molecule composed of a hydrophilic part, two glucuronic acid molecules, and a hydrophobic part, glycyrrhetinic acid. GA, when subjected to acid hydrolysis, releases 18β- and 18α-glycyrrhetinic acids. Glycyrrhetinic acid is most responsible for the pharmacological activities of licorice. GA has been reported to have multiple therapeutic properties: anti-viral, anti-inflammatory, antitumor, antimicrobial and hepatoprotective. Different approaches have revealed similar anti-inflammatory mechanisms of action of GA, such as the inhibition of translocation of nuclear factor-κB (NF-κB) and suppression of Tumour Necrosis Factor alpha (TNF-α) and interleukins. In this sense, several in vitro and in vivo studies have described the use of GA in the prevention and treatment of several complications, especially microbial/viral infection, and as a novel chemo-preventive agent for liver injury. Recent studies postulated that GA nanoparticles (GANPs) can be a promising strategy for the treatment of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infections. This mini-review summarizes the pharmacological activities of GA and its beneficial effects against various health problems and provides perspectives on the development of versatile nanoplatforms to overcome some limiting physicochemical properties and for enhancing the therapeutic benefits of GA. Full article