Reinforcing the supply chain of umifenovir and other antiviral drugs with retrosynthetic software.
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ABSTRACT:
SUBMITTER: Lin Y
PROVIDER: S-EPMC8677791 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Free radical reactions play an important role in biological functions of living systems. The balance between oxidants and antioxidants is necessary for the normal homeostasis of cells and organisms. Experimental works demonstrate the role of oxidative stress that is caused by influenza virus as well as the toxic effects of some antiviral drugs. Therefore, antiviral drugs should be characterized by its pro- and antioxidant activity, because it can affect its therapeutic efficiency. The aim of the study was to quantify the antioxidant capacity and propose the mechanism of the antioxidant effect of the antiviral drug Umifenovir (Arbidol®). The kinetic chemiluminescence with the 2,2'-azobis (2-amidinopropane) dihydrochloride + luminol system was used to quantify the antioxidant capacity of Umifenovir relative to the standard compound Trolox. With computer simulation, the reaction scheme and rate constants were proposed. The antioxidant capacity of 0.9 ?M Umifenovir (maximum concentration of Umifenovir in blood after oral administration of 200 mg) was as high as 1.65 ± 0.18 ?M of Trolox. Thus, the total antioxidant capacity of Umifenovir is comparable to the antioxidant capacity of Trolox. Unlike Trolox, Umifenovir reacts with free radicals in two stages. For Trolox, the free radical scavenging rate constant was k = 2000 nM-1 min.-1, for Umifenovir k1 = 300 nM-1min.-1, k2 = 4 nM-1min.-1. Slower kinetics of Umifenovir provides the prolonged antioxidant effect when compared to Trolox. This phenomenon can make a serious contribution to the compensation of oxidative stress that is caused by a viral disease and the therapeutic effect of the drug.
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Project description:We present the open-source AiZynthFinder software that can be readily used in retrosynthetic planning. The algorithm is based on a Monte Carlo tree search that recursively breaks down a molecule to purchasable precursors. The tree search is guided by an artificial neural network policy that suggests possible precursors by utilizing a library of known reaction templates. The software is fast and can typically find a solution in less than 10 s and perform a complete search in less than 1 min. Moreover, the development of the code was guided by a range of software engineering principles such as automatic testing, system design and continuous integration leading to robust software with high maintainability. Finally, the software is well documented to make it suitable for beginners. The software is available at http://www.github.com/MolecularAI/aizynthfinder .
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Project description:Pallet is a very important innovation in logistics industry. Pallets are so widely used that we can find them in nearly every logistical operation scenario. In order to manage pallets efficiently, researchers have developed several pallet management strategies (PMS). The most common and widely accepted PMS includes extensive management of pallets (EMP), transfer of pallet's ownership (TPO), and pallet rent (PR). This paper addresses mainly on how to help pallet managers choose a certain kind of PMS from the perspective of supply chain cost. Firstly, cost models of three kinds of PMS are presented. Secondly, all parameters involved in the models are valued based on data that is collected from industry survey. The results show that the cost of PR is constantly lower than EMP, and also lower than TPO when the operation period is no more than 37 months. Finally, the effect of several important parameters on the cost is studied by sensitivity analysis. The selection strategies of PMS are proposed based on the results.
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Project description:The COVID-19 crisis has notably impacted global supply chains as it has disrupted manufacturing operations. To recover from the aforementioned disruptions, supply chain digitalization [SCD] is increasingly being acknowledged to help the recovery process. Based on this, scholars have called for additional research on how SCD can enhance supply chain visibility [SCV] and boost supply chain performance [SCP] in turbulent environments. Based on 399 valid responses collected through cross-sectional method from Turkish manufacturing firms and using a non-probabilistic sampling method [i.e., purposive sampling], this research explores the effect of SCD on SCP. The mediating role of SCV and the moderating role of supply chain survivability [SCS] on the SCD-SCP relationship were also explored. The findings showed that SCD has a positive effect on SCP. SCD has a positive effect on SCV. SCV has a positive effect on SCP. The link between SCD and SCP is mediated by SCP. The results also revealed that SCS moderated the SCD-SCV link such that SCD has a stronger, positive relationship with SCV when SCS is high than when it's low. SCS moderates the SCD-SCP link, such that at low levels of SCS, the positive effect of SCD on SCP is weakened. The indirect positive effect of SCD on SCP via SCV is strongest when supply chain survivability is high. The findings suggest that SCD can improve cost-effectiveness, promote communication and information efficiency, and enhance supply chain resilience to improve performance after disruptions. This study provides insightful new implications for both supply chain literature and practitioners.
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Project description:This study assessed the veterinary drug supply chain in Uganda, the constraints faced by the actors, and how the challenges influence the use of antimicrobial (AMs) by livestock farmers. We carried out stakeholder consultation workshops, key informant interviews and a knowledge, practices, and awareness survey with actors of the veterinary drug supply chain. We also profiled drugs stored in 23 urban and peri-urban drug shops in Lira and Mukono districts to record the commonly sold drugs. The veterinary drug supply chain is made of several actors including wholesalers, retailers, Animal Health Service Providers (AHSP) and farmers. Nearly ninety per cent of drug retailers and veterinary practitioners did not receive specialized training in veterinary medicine, and most of veterinary practitioners have been in the drug business market for more than 10 years. Antibiotics and anti-helminthics were the most stocked drugs by retailers, with antibiotics ranking highest in terms of contribution to annual financial profits, accounting for 33%. The choice of a drug by veterinary practitioners was mainly informed by past success with efficacy of the drug, and financial capacity of the client (the farmer) to meet the treatment cost. Many veterinary practitioners were not conversant with veterinary drug policies of the country, with Mukono having a higher number (72%) compared to Lira (37%). Veterinary practitioners from Lira district compared to Mukono and those mainly serving small scale farmers relative to large scale smallholders were more knowledgeable about antibiotics and AMR. Several supply chain constraints were identified as potential drivers of misuse of antibiotics that could contribute to AMR. These included low level of education of supply chain actors, particularly drug retailers, poor handling of drugs at purchase and administration practices, low enforcement of policies and regulations, and lack of awareness of stakeholders about policies that regulate drug use. Thus, future interventions to reduce misuse of AM drugs in livestock production systems in Uganda such as capacity building, should also target veterinary input suppliers, and deliberately involve a strong policy advocacy component.
| S-EPMC8455991 | biostudies-literature
Project description:Arthropod-borne flaviviruses are human pathogens of global medical importance, against which no effective small molecule-based antiviral therapy has currently been reported. Arbidol (umifenovir) is a broad-spectrum antiviral compound approved in Russia and China for prophylaxis and treatment of influenza. This compound shows activities against numerous DNA and RNA viruses. The mode of action is based predominantly on impairment of critical steps in virus-cell interactions. Here we demonstrate that arbidol possesses micromolar-level anti-viral effects (EC50 values ranging from 10.57 ± 0.74 to 19.16 ± 0.29 µM) in Vero cells infected with Zika virus, West Nile virus, and tick-borne encephalitis virus, three medically important representatives of the arthropod-borne flaviviruses. Interestingly, no antiviral effects of arbidol are observed in virus infected porcine stable kidney cells (PS), human neuroblastoma cells (UKF-NB-4), and human hepatoma cells (Huh-7 cells) indicating that the antiviral effect of arbidol is strongly cell-type dependent. Arbidol shows increasing cytotoxicity when tested in various cell lines, in the order: Huh-7 < HBCA < PS < UKF-NB-4 < Vero with CC50 values ranging from 18.69 ± 0.1 to 89.72 ± 0.19 µM. Antiviral activities and acceptable cytotoxicity profiles suggest that arbidol could be a promising candidate for further investigation as a potential therapeutic agent in selective treatment of flaviviral infections.
| S-EPMC5923478 | biostudies-literature
Project description:The neglected zoonotic cestode Taenia solium is endemic in many low- and middle-income countries, including Zambia. The parasite infects humans and pigs, inflicting high socioeconomic and disease burdens in endemic areas. Health education is regarded as an important component in T. solium control and previous studies indicate that 'The Vicious Worm' may be an effective T. solium health education tool for Tanzanian medical and agricultural professionals and Zambian primary school students. This study aimed to assess the effects of health education using 'The Vicious Worm' among Zambian pork supply chain workers, because the pork supply chain greatly influences food safety and security in Zambia. Half-day educational workshops using 'The Vicious Worm' and subsequent follow-up sessions were organized in the Lusaka and Katete districts of Zambia in March and April 2019. Questionnaires were administered before, after, and three weeks after the use of 'The Vicious Worm' to assess the program's impact on knowledge uptake and short-term retention. Focus group discussions were conducted to assess the program's user experience and the participants' beliefs, attitudes, and insights. In total, 47 pork supply chain workers participated: 25 from Lusaka and 22 from Katete. Overall, knowledge about T. solium was significantly higher (p<0.001) both immediately after, and three weeks after the use of 'The Vicious Worm' compared to baseline knowledge. Focus group discussions indicated incipient attitudinal and behavioral change, as well as a positive reception of the software; with participants describing the software as simple, educative, and useful to share knowledge. The study results indicate that workshops using 'The Vicious Worm' may be effective for short-term T. solium health education among key pork supply chain workers. Follow-up studies are required to assess long-term effects, transfer of knowledge and behavioral change. However, educational interventions with 'The Vicious Worm' could be considered for integrated T. solium control programs in sub-Saharan Africa, especially if the educational content is further simplified and clarified.
| S-EPMC7595624 | biostudies-literature
Project description:In this paper, we study the topological properties of the global supply chain network in terms of its degree distribution, clustering coefficient, degree-degree correlation, bow-tie structure, and community structure to test the efficient supply chain propositions proposed by E. J.S. Hearnshaw et al. The global supply chain data in the year 2017 are constructed by collecting various company data from the web site of Standard & Poor's Capital IQ platform. The in- and out-degree distributions are characterized by a power law of the form of γin = 2.42 and γout = 2.11. The clustering coefficient decays [Formula: see text] with an exponent βk = 0.46. The nodal degree-degree correlations 〈knn(k)〉 indicates the absence of assortativity. The bow-tie structure of giant weakly connected component (GWCC) reveals that the OUT component is the largest and consists 41.1% of all firms. The giant strong connected component (GSCC) is comprised of 16.4% of all firms. We observe that upstream or downstream firms are located a few steps away from the GSCC. Furthermore, we uncover the community structures of the network and characterize them according to their location and industry classification. We observe that the largest community consists of the consumer discretionary sector based mainly in the United States (US). These firms belong to the OUT component in the bow-tie structure of the global supply chain network. Finally, we confirm the validity of Hearnshaw et al.'s efficient supply chain propositions, namely Proposition S1 (short path length), Proposition S2 (power-law degree distribution), Proposition S3 (high clustering coefficient), Proposition S4 ("fit-gets-richer" growth mechanism), Proposition S5 (truncation of power-law degree distribution), and Proposition S7 (community structure with overlapping boundaries) regarding the global supply chain network. While the original propositions S1 just mentioned a short path length, we found the short path from the GSCC to IN and OUT by analyzing the bow-tie structure. Therefore, the short path length in the bow-tie structure is a conceptual addition to the original propositions of Hearnshaw.
| S-EPMC7529254 | biostudies-literature
Project description:http://www.sanger.ac.uk/resources/downloads/bacteria/streptococcus-suis.htmlThese data are part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2014-04-28 | E-ERAD-241 | biostudies-arrayexpress
Project description:An indole derivative umifenovir (Arbidol) is one of the most widely used antiviral drugs for the prevention and treatment of COVID-19 and some other viral infections. The purpose of the present study was to shed light on the transformation processes of umifenovir in municipal wastewater, including disinfection with active chlorine, as well as to assess the levels of the antiviral drug and its metabolites entering and accumulating in natural reservoirs under conditions of the SARS-CoV-2 pandemic. The combination of high-performance liquid chromatography with electrospray ionization high-resolution mass-spectrometry and inductively coupled plasma mass spectrometry was used for tentative identification and quantification of umifenovir and its transformation products in model reaction mixtures and real samples of wastewater, river water, biological sludge and bottom sediments taken at the wastewater treatment plant in Arkhangelsk, a large cultural and industrial center at the Russian North. Laboratory experiments allowed identifying fifteen bromine-containing transformation products, forming at the initial stages of the chlorination and fourteen classic volatile and semi volatile disinfection by-products with bromoform as the dominant one. Chlorinated derivatives are only the minor disinfection by-products forming by substitution of alkylamine group in the aromatic ring. The schemes of umifenovir transformation in reactions with dissolved oxygen and sodium hypochlorite are proposed. Two established primary transformation products formed by oxidation of the thioether group to sulfoxide and elimination of thiophenol were detected in noticeable concentrations in the wastewater together with their precursor. The level of umifenovir reached 1.3 mg kg-1 in the sludge and municipal wastewater treat contained 1 μg L-1 of that drug, while its removal during biological wastewater treatment was about 40%. Pronounced accumulation of umifenovir and its transformation products in biological sludge and bottom sediments of natural reservoirs may be a source of the future secondary pollution of the environment.
| S-EPMC8451976 | biostudies-literature