Dried blood spot (DBS) sample analysis for drug and metabolomic profiling in oncology clinical trials: Cost-effective decentralized sampling modality for precision Oncology

The COVID19 pandemic accelerated opportunities for innovation within the decentralization process of clinical trials with opportunities for implementation of patient-centric workflows for efficiency and cost-reduction. Decentralized sample collection, particularly whole blood using dried blood spots (DBS) provides the ideal mechanism for patient driven sample collection with ease of access to sample generation, drug level assessments and metabolomic prMegofiling, providing longitudinal real-time measure of drug specific pharmacodynamic readout for safety and efficacy. In this study, we report the development of a protocol for the capture and comprehensive profiling of metabolomics using dried blood spots from a cohort of 49 healthy volunteer donors. Using liquid chromatography combined with mass spectrometric (UPLC-MS/MS) methods an untargeted metabolomic approach resulted in the identification of >800 biochemicals of which a significant subset was found to be presented in corresponding matched plasma (from whole blood) samples. The biochemicals identified from the DBS samples included metabolites that were part of the lipid, amino acid, nucleotide, peptide, cofactors, carbohydrate and energy super pathways. A significant number of metabolites identified in the DBS samples were xenobiotics including those representing the biotransformation products of drugs. The overall metabolite profiles were analyzed for precision and accuracy of measure, variability in performance and dynamic range to establish benchmarks for evaluation. An additional cohort with a longitudinal sampling as part of the protocol provided the reproducibility of the analytic method for inter-day variability of metabolite performance over time. Although metabolomic profiles varied between individuals from a population perspective, there was minimal variation observed within individuals when samples were profiled longitudinally over several weeks. Thus, the protocols for DBS collection and the corresponding capture of a large set of metabolites with reproducible performance provides an opportunity for its implementation in oncological clinical trials as part of a de-centralized clinical trial solution.

Environmental concerns and bioaccumulation of psychiatric drugs in water bodies - Conventional versus biocatalytic systems of mitigation.

The COVID-19 pandemic has brought increments in market sales and prescription of medicines commonly used to treat mental health disorders, such as depression, anxiety, stress, and related problems. The increasing use of these drugs, named psychiatric drugs, has led to their persistence in aquatic systems (bioaccumulation), since they are recalcitrant to conventional physical and chemical treatments typically used in wastewater treatment plants. An emerging environmental concern caused by the bioaccumulation of psychiatric drugs has been attributed to the potential ecological and toxicological risk that these medicines might have over human health, animals, and plants. Thus, by the application of biocatalysis-assisted techniques, it is possible to efficiently remove psychiatric drugs from water. Biocatalysis, is a widely employed and highly efficient process implemented in the biotransformation of a wide range of contaminants, since it has important differences in terms of catalytic behavior, compared to common treatment techniques, including photodegradation, Fenton, and thermal treatments, among others. Moreover, it is noticed the importance to monitor transformation products of degradation and biodegradation, since according to the applied removal technique, different toxic transformation products have been reported to appear after the application of physical and chemical procedures. In addition, this work deals with the discussion of differences existing between high- and low-income countries, according to their environmental regulations regarding waste management policies, especially waste of the drug industry.

The Potential Impact of Ayurvedic Traditional Bhasma on SARS-CoV-2-Induced Pathogenesis

The mass casualties caused by the delta variant and the wave of the newer "Omicron" variant of SARS-COV-2 in India have brought about great concern among healthcare officials. The government and healthcare agencies are seeking effective strategies to counter the pandemic. The application of nanotechnology and repurposing of drugs are reported as promising approaches in the management of COVID-19 disease. It has also immensely boomed the search for productive, re-liable, cost-effective, and bio-assimilable alternative solutions. Since ancient times, the traditional-ly employed Ayurvedic bhasmas have been used for diverse infectious diseases, which are now employed as nanomedicine that could be applied for managing COVID-19-related health anomalies. Like currently engineered metal nanoparticles (NPs), the bhasma nanoparticles (BNPs) are also packed with unique physicochemical properties, including multi-elemental nanocrystalline compo-sition, size, shape, dissolution, surface charge, hydrophobicity, and multi-pathway regulatory as well as modulatory effects. Because of these conformational and configurational-based physico-chemical advantages, Bhasma NPs may have promising potential to manage the COVID-19 pandemic and reduce the incidence of pneumonia-like common lung infections in children as well as age-related inflammatory diseases via immunomodulatory, anti-inflammatory, antiviral, and adju-vant-related properties.Copyright © 2023 Bentham Science Publishers.

Socio-Economic Stability and Sustainable Development in the Post-COVID Era: Lessons for the Business and Economic Leaders

This paper focuses on social and economic stability, as well as sustainable development, in the post-COVID era in light of the recent theoretical approaches and leadership practices. As governments worldwide resorted to repeated national- and regional-specific impositions of social and economic isolation in an (often failed) attempt to contain the spread of the coronavirus, their economies have been plunged into recessions, which have been deeper than those associated with the global financial crisis in the past. Successful business and economic leaders need to be aware of the dominant trends unfolding as the COVID-19 pandemic is gradually coming to its end and the New Globalization (a new era of international economy and international relations after COVID-19) is materializing. With global living, international travel, and trade interconnected, businesses need to plan for handling the future outbreaks and their economic, as well as social, consequences. The aim of this paper is to draw the lessons for business and economic leaders in the post-COVID era with a focus on the new trends and challenges for the sustainable development and the Sustainable Development Goals (SDGs). The paper also presents an empirical model that assesses the novel ways of doing business and innovating using the sustainable economic practices after the COVID-19 pandemic. The model employs our own data collected from 450 managers and owners of small and medium enterprises (SMEs) in the Czech Republic and Russia. Our results show that innovation and digitalization (e.g., smart metering or the Internet of Things (IoT)) are becoming the main drivers of the sustainable economic transformation of small and medium enterprises in the post-pandemic period. These results might be useful for both academic researchers and business practitioners searching for new pathways for innovating their sustainable business practices and recreating their customer base in the post-COVID era. © 2023 by the authors.

Biotransformation of hydroxychloroquine to evaluate the cytotoxicity of its metabolites and mimic mammalian metabolism.

Hydroxychloroquine (HCQ) displays attractive anti-inflammatory and antiviral effects. Because of that, such a drug made part of some clinical trials for combating Sars-CoV-2 during the COVID-19 pandemic. The present study aimed to conduct the biotransformation of HCQ by filamentous fungi reported as microbial models of mammalian drug metabolism to evaluate its cytotoxic after metabolization. Cunninghamella echinulata var. elegans ATCC 8688a could efficiently biotransform HCQ into one main metabolite identified as the new 4-(1,2,3,4-tetrahydroquinolin-4-ylamino)pentan-1-ol (HCQ-M). The microbial transformation occurred through N-dealkylation, 7-chloro-elimination, and reduction of the two conjugated double-bond from the quinoline system of HCQ. The cytotoxic profiles of HCQ and its metabolite were evaluated using CCD-1059Sk cells (human fibroblasts) through sulforhodamine B, trypan blue, and Live/Dead assays. Both HCQ and HCQ-M displayed cytotoxic activities in human fibroblasts, but HCQ-M was significantly more toxic than HCQ. The reported findings should be considered for further clinical studies of HCQ and will be important for guidance in achieving new derivatives from it.

Bioconvertible IVC filters: safety, efficacy, and bioconversion times in a real-world cohort

Purpose: To examine the outcomes of patients with venous thromboembolism (VTE) who underwent placement of a bioabsorbable inferior vena cava filter (IVCF) for temporary pulmonary embolism (PE) protection Materials and Methods: From 10/1/2020 to 11/31/2021, 17 patients (mean age 71, range 45-92, 58% female) underwent placement of a bioabsorbable IVCF (Sentry, Boston Scientific) at a single academic center. Thirteen of the 17 filters (76.4%) were placed in the inpatient setting, and the remainder were placed outpatient. VTE risk factors included malignancy (70.6%), immobility (5.9%), COVID-19 (5.9%), and unprovoked (7.6%). Prior to IVCF, 11 patients presented with deep venous thrombosis (DVT) alone, two had PE alone, and four were diagnosed both DVT and PE. The contraindication to anticoagulation (AC) was active bleeding in 47.1% of the cohort, upcoming surgery in 41.2%, worsening of DVT on AC in 5.9%. and brain tumor in 5.9%. The pre-implantation infrarenal IVC diameter ranged from 1.6 to 2.6 cm. Technical success (TS), adverse events (AEs), and follow-up IVCF characteristics were recorded. Results: TS was 100%. No AEs occurred during placement. Mean follow-up period was 4.9 months (range 0-12.9). No new PEs were diagnosed after IVCF placement, and no patients required replacement of IVCF. Nine of the 17 patients had follow-up CTs after filter placement, two had follow up radiographs in which the filter state could be assessed, and the remaining six had no imaging evaluating the filter after placement. Asymptomatic IVCF associated non-occlusive thrombosis was seen in 3 patients. The longest amount of time after placement that a Sentry filter was observed to still be in the filter state was 3.9 months, and the shortest time in which imaging showed a filter bio-converted to the open state was 3.1 months. Three patients underwent serial imaging which incidentally demonstrated the timeframe in which the IVCF converted from a filter-state to an open-state. In one patient this conversion occurred between 2.1 and 3.1 months, in another between 1.7 and 3.3 months, and in the last patient between 3.9 and 4.4 months. Conclusion: In VTE patients with either a temporary contraindication to anticoagulation or a transitory high-PE-risk period, bioconvertible IVC filters are a safe and effective option for short-term protection against pulmonary embolism.

Distribution, Biotransformation, Pharmacological Effects, Metabolic Mechanism and Safety Evaluation of Platycodin D: A Comprehensive Review.

Platycodonis Radix (Jiegeng), the dried root of Platycodon grandiflorum, is a traditional herb used as both medicine and food. Its clinical application for the treatment of cough, phlegm, sore throat, pulmonary and respiratory diseases has been thousands of years in China. Platycodin D is the main active ingredient in Platycodonis Radix, which belongs to the family of pentacyclic triterpenoid saponins because it contains an oleanolane type aglycone linked with double sugar chains. Modern pharmacology has demonstrated that Platycodin D displays various biological activities, such as analgesics, expectoration and cough suppression, promoting weight loss, anti-tumor and immune regulation, suggesting that Platycodin D has the potential to be a drug candidate and an interesting target as a natural product for clinical research. In this review, the distribution and biotransformation, pharmacological effects, metabolic mechanism and safety evaluation of Platycodin D are summarized to lay the foundation for further studies.

Glycosylation of Methylflavonoids in the Cultures of Entomopathogenic Filamentous Fungi as a Tool for Obtaining New Biologically Active Compounds

Flavonoid compounds are secondary plant metabolites with numerous biological activities;they naturally occur mainly in the form of glycosides. The glucosyl moiety attached to the flavonoid core makes them more stable and water-soluble. The methyl derivatives of flavonoids also show increased stability and intestinal absorption. Our study showed that such flavonoids can be obtained by combined chemical and biotechnological methods with entomopathogenic filamentous fungi as glycosylation biocatalysts. In the current paper, two flavonoids, i.e., 2′-hydroxy-4-methylchalcone and 4′-methylflavone, have been synthesized and biotransformed in the cultures of two strains of entomopathogenic filamentous fungi Isaria fumosorosea KCH J2 and Beauveria bassiana KCH J1.5. Biotransformation of 2′-hydroxy-4-methylchalcone resulted in the formation of two dihydrochalcone glucopyranoside derivatives in the culture of I. fumosorosea KCH J2 and chalcone glucopyranoside derivative in the case of B. bassiana KCH J1.5. 4′-Methylflavone was transformed in the culture of I. fumosorosea KCH J2 into four products, i.e., 4′-hydroxymethylflavone, flavone 4′-methylene-O-β-d-(4″-O-methyl)-glucopyranoside, flavone 4′-carboxylic acid, and 4′-methylflavone 3-O-β-d-(4″-O-methyl)-glucopyranoside. 4′-Methylflavone was not efficiently biotransformed in the culture of B. bassiana KCH J1.5. The computer-aided simulations based on the chemical structures of the obtained compounds showed their improved physicochemical properties and antimicrobial, anticarcinogenic, hepatoprotective, and cardioprotective potential.

A Novel Formononetin Derivative Promotes Anti-ischemic Effects on Acute Ischemic Injury in Mice.

Natural flavonoids, formononetin and ononin, possess antioxidant, antibacterial, anti-inflammatory and neuroprotective effects. Many complications caused by SARS-CoV-2 make patients difficult to recover. Flavonoids, especially formononetin and ononin, have the potential to treat SARS-CoV-2 and improve myocardial injury. However, their poor water solubility, poor oral absorption, high toxicity, and high-cost purification limit industrial practical application. Succinylation modification provides a solution for the above problems. Formononetin-7-O-ß-(6″-O-succinyl)-D-glucoside (FMP), a new compound, was succinyl glycosylated from formononetin by the organic solvent tolerant bacteria Bacillus amyloliquefaciens FJ18 in a 10.0% DMSO (v/v) system. The water solubility of the new compound was improved by over 106 times compared with formononetin, which perfectly promoted the application of formononetin and ononin. The conversion rate of formononetin (0.5 g/L) was almost 94.2% at 24 h, while the yield of formononetin-7-O-ß-(6″-O-succinyl)-D-glucoside could achieve 97.2%. In the isoproterenol (ISO)-induced acute ischemia mice model, the myocardial injury was significantly improved with a high dose (40 mg/kg) of formononetin-7-O-ß-(6″-O-succinyl)-D-glucoside. The lactate dehydrogenase level was decreased, and the catalase and superoxide dismutase levels were increased after formononetin-7-O-ß-(6″-O-succinyl)-D-glucoside treatment. Thus, formononetin-7-O-ß-(6″-O-succinyl)-D-glucoside has high water solubility, low toxicity, and shows significant antimyocardial ischemia effects.

Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Simple and Rapid Method for Wogonin Preparation and Its Biotransformation.

Wogonin is one of the most active flavonoids from Scutellaria baicalensis Georgi (baikal skullcap), widely used in traditional Chinese medicine. It exhibits a broad spectrum of health-promoting and therapeutic activities. Together with baicalein, it is considered to be the one of main active ingredients of Chinese medicines for the management of COVID-19. However, therapeutic use of wogonin may be limited due to low market availability connected with its low content in baikal skullcap and lack of efficient preparative methods for obtaining this compound. Although the amount of wogonin in skullcap root often does not exceed 0.5%, this material is rich in wogonin glucuronide, which may be used as a substrate for wogonin production. In the present study, a rapid, simple, cheap and effective method of wogonin and baicalein preparation, which provides gram quantities of both flavonoids, is proposed. The obtained wogonin was used as a substrate for biotransformation. Thirty-six microorganisms were tested in screening studies. The most efficient were used in enlarged scale transformations to determine metabolism of this xenobiotic. The major phase I metabolism product was 4'-hydroxywogonin-a rare flavonoid which exhibits anticancer activity-whereas phase II metabolism products were glucosides of wogonin. The present studies complement and extend the knowledge on the effect of substitution of A- and B-ring on the regioselective glycosylation of flavonoids catalyzed by microorganisms.

Endophytes: the novel sources for plant terpenoid biosynthesis.

Terpenoids are natural compounds predominantly present in plants. They have many pharmaceutical and/or nutritional functions, and have been widely applied in medical, food, and cosmetics industries. Recently, terpenoids have been used in the clinical treatment of COVID-19 due to the good antiviral activities. The increasing demand for terpenoids in international markets poses a serious threat to many plant species. For environmentally sustainable development, microbial cell factories have been utilized as the promising platform to produce terpenoids. Nevertheless, the bioproduction of most terpenoids cannot meet commercial requirements due to the low cost-benefit ratio until now. The biosynthetic potential of endophytes has gained attention in recent decades owing to the continual discovery of endophytes capable of synthesizing plant bioactive compounds. Accordingly, endophytes could be alternative sources of terpenoid-producing strains or terpenoid synthetic genes. In this review, we summarized the research progress describing the main and supporting roles of endophytes in terpenoid biosynthesis and biotransformation, and discussed the current problems and challenges which may prevent the further exploitation. This review will improve our understanding of endophyte resources for terpenoid production in industry in the future. The four main research interests on endophytes for terpenoid production. A: Isolation of terpenoid-producing endophytes; B: The heterologous expression of endophyte-derived terpenoid synthetic genes; C: Endophytes promoting their hosts' terpenoid production. The blue dashed arrows indicate signal transduction; D: Biotransformation of terpenoids by endophytes or their enzymes. Key points• The mechanisms employed by endophytes in terpenoid synthesis in vivo and in vitro.• Endophytes have the commercial potentials in terpenoid bioproduction and biotransformation.• Synthetic biology and multiomics will improve terpenoid bioproduction in engineered cell factories.

Biological removal of benzalkonium chlorides from wastewater by immobilized cells of Pseudomonas sp. BIOMIG1 in an up-flow packed bed reactor.

Quaternary ammonium compounds (QACs) are active ingredients of many disinfectants used against SARS-CoV-2 to control the transmission of the virus through human-contact surfaces. As a result, QAC consumption has increased more than twice during the pandemic. Consequently, the concentration of QACs in wastewater and receiving environments may increase. Due to their antimicrobial activity, high levels of QACs in wastewater may cause malfunctioning of biological treatment systems resulting in inadequate treatment of wastewater. In this study, a biocatalyst was produced by entrapping Pseudomonas sp. BIOMIG1 capable of degrading QACs in calcium alginate. Bioactive 3-mm alginate beads degraded benzalkonium chlorides (BACs), a group of QACs, with a rate of 0.47 µM-BACs/h in shake flasks. A bench-scale continuous up-flow reactor packed with BIOMIG1-beads was operated over one and a half months with either synthetic wastewater or secondary effluent containing 2-20 µM BACs at an empty bed contact time (EBCT) ranging between 0.6 and 4.7 h. Almost complete BAC removal was achieved from synthetic and real wastewater at and above 1.2 h EBCT without aeration and effluent recirculation. The microbial community in beads dominantly composed of BIOMIG1 with trace number of Achromobacter spp. after the operation of the reactor with the real wastewater, suggesting that BIOMIG1 over-competed native wastewater bacteria during the operation. This reactor system offers a low cost and robust treatment of QACs in wastewater. It can be integrated to conventional treatment systems for efficient removal of QACs from the wastewater, especially during the pandemic period.

Improvement of caffeic acid biotransformation into para-hydroxybenzoic acid by Candida albicans CI-24 via gamma irradiation and model-based optimization.

Para-hydroxybenzoic acid (PHBA) has great potential in biological applications due to its putative antiviral activity against SARS-CoV-2 and its antimicrobial activity in the face of the radically increasing number of multidrug-resistant pathogens. This is in addition to its antimutagenic, anti-inflammatory, antioxidant, hypoglycemic, antiestrogenic, and antiplatelet aggregating activities. In this study, an approximate sixfold increase in the production of PHBA was achieved via biotransformation of caffeic acid by Candida albicans. The improvement was performed in two steps: first, through mutation by gamma irradiation (5 KGy dose), resulting in the recovery of a mutant (CI-24), which produced approximately triple the amount of PHBA produced by the wild-type isolate. Then, biotransformation by this mutant was further optimized via response surface methodology model-based optimization. The maximum PHBA production (7.47 mg/mL) was obtained in a fermentation medium composed of 1% w/v yeast extract as a nitrogen source, with an initial pH of 6.6, incubated at 28 °C at an agitation rate of 250 rpm. To further enhance the performance and economics of the process, cells of the CI-24 mutant were immobilized in calcium alginate beads and could retain an equivalent biotransformation capacity after three successive biotransformation cycles.