key: cord-1048083-mxfljy2o
authors: Kuroda, Keisuke; Li, Cong; Dhangar, Kiran; Kumar, Manish
title: Predicted occurrence, ecotoxicological risk and environmentally acquired resistance of antiviral drugs associated with COVID-19 in environmental waters
date: 2021-02-15
journal: Sci Total Environ
DOI: 10.1016/j.scitotenv.2021.145740
sha: f6b227393573ceef7c579c5b55c2fab40c58a92c
doc_id: 1048083
cord_uid: mxfljy2o

Antiviral drugs have been used to treat the ever-growing number of coronavirus disease 2019 (COVID-19) patients. Consequently, unprecedented amounts of such drug residues discharging into ambient waters raise concerns on the potential ecotoxicological effects to aquatic lives, as well as development of antiviral drug-resistance in wildlife. Here, we estimated the occurrence, fate and ecotoxicological risk of 11 therapeutic agents suggested as drugs for COVID-19 treatment and their 13 metabolites in wastewater and environmental waters, based on drug consumption, physical-chemical property using quantitative structure-activity relationship (QSAR), and ecotoxicological and pharmacological data for the drugs. Our results suggest that the removal efficiencies at conventional wastewater treatment plants will remain low (< 20%) for half of the substances, and consequently, high drug residues (e.g. 7402 ng/L ribavirin, 4231 ng/L favipiravir, 730 ng/L lopinavir, 319 ng/L remdesivir; each combined for both unchanged forms and metabolites; and when each drug is administered to 100 patients out of 100,000 populations on a day) can be present in secondary effluents and persist in the environmental waters. Ecotoxicological risk in receiving river waters can be high (risk quotient > 1) by a use of favipiravir, lopinavir, umifenovir and ritonavir, and medium (risk quotient > 0.1) by a use of chloroquine, hydroxychloroquine, remdesivir, and ribavirin, while the risk will remain small (risk quotient < 0.1) for dexamethasone and oseltamivir. The potential of wild animals acquiring antiviral drug resistance is estimated to be small. Our prediction suggests a pressing need for proper usage and waste management of antiviral drugs as well as for improving removal efficiencies of drug residues in wastewater.

After human consumption, pharmaceuticals are excreted from human body and discharged into wastewater as unchanged drugs or metabolites, which are often only partly removed in conventional wastewater treatment plants (WWTPs) (Joss et al., 2005; Nannou et al., 2020) . These residues present in receiving environmental waters have posed ecotoxicological concerns (Al Aukidy et al., 2012; Fick et al., 2010; Godoy and Kummrow, 2017; Santos et al., 2010) . In particular, during pandemic events, high amount of antiviral drugs and their metabolites released into environmental waters are likely to pose a high risk to aquatic ecosystems (Jain et al., 2013; Nannou et al., 2020) . In addition, such high amount of antiviral drugs in environmental waters may lead to the development of antiviral drug-resistant viral strains inside the body of specific wild animals, which are natural reservoirs of viruses (Kumar et al., 2020a) . That is, when animal reservoirs continuously ingest environmental waters containing elevated levels of antiviral drugs and their metabolites, the viruses inside their bodies may develop resistance through rapid mutations (Jain et al., 2013; Nannou et al., 2020; Singer et al., 2007) . We define this type of antiviral drug resistance as environmentally acquired antiviral drug resistance (EDR). EDR has been concerned for influenza A virus during past outbreaks (Fick et al., 2007; Ghosh et al., 2010; Singer et al., 2007) . SARS-CoV-2 might similarly develop EDR inside animal hosts such as bats , owing to expected mass use of antiviral drugs during the current waves of COVID-19 (Kumar et al., 2020a; Kumar et al., 2020b; Race et al., 2020; Sims and Kasprzyk-Hordern, 2020) . To date, however, there has been no quantitative evaluation of EDR of SARS-CoV-2.

The occurrence, fate and ecotoxicity of a diverse range of pharmaceuticals, including antiviral drugs, in WWTPs and in environmental waters during past outbreaks as well as normal times have been summarized (Aymerich et al., 2016; Jain et al., 2013; Kasprzyk-Hordern et al., 2009; Nannou et al., 2020; Ncube et al., 2018; Tran et al., 2018) . However, those past studies hardly include most of the therapeutic agents which have been considered for COVID-19 treatment, except for oseltamivir (anti-influenza drug) (Azuma et al., 2012; Fick et al., 2007; Ghosh et al., 2010; Prasse et al., 2010;  J o u r n a l P r e -p r o o f Singer et al., 2007) and lopinavir/ritonavir (anti-HIV drugs) (Abafe et al., 2018; Wood et al., 2015) .

The potential occurrence and fate in aquatic environments, the general physical-chemical properties, and ecotoxicological risks of various COVID-19-associated drugs are largely unknown. For screening environmental fate and toxicity of pharmaceuticals, quantitative structure-activity relationship (QSAR) models have been applied to diverse pharmaceuticals (Escher et al., 2011; Kar et al., 2020; Sanderson et al., 2004) .

The objective of the study is to provide a model-based evaluation on the occurrence, fate and ecotoxicological effects of a suite of therapeutic agents associated with COVID-19 treatment and their metabolites in wastewater and environmental waters during pandemic events. Predicted environmental concentrations (PECs) were calculated with assumed patient numbers treated with these drugs (100 patients out of 100k populations are on the course of treatment every day), taking into account drug consumption patterns, excretion from human body, and elimination at WWTPs. QSAR models were used to predict elimination at WWTPs and chronic toxicity to aquatic lives for the substances for which measurement-based data were not available. Furthermore, potential of EDR by animal reservoirs was assessed by in vitro pharmacological data of the drugs against SARS-CoV-2. To our knowledge, this is the first study to estimate ecotoxicological impacts of mass use of multi-antiviral drugs associated with COVID-19 on ambient waters and suggest necessary global precautionary measures.

We evaluated 11 representative potential therapeutic drugs for COVID-19 treatment (chloroquine, dexamethaxone, favipiravir, hydroxychloroquine, lopinavir, oseltamivir, remdesivir, ribavirin, ritonavir, teicoplanin and umifenovir) and their 13 major metabolites (Table 1) , which were selected from literature Yousefi et al.) . The drugs" original purposes are shown in Table 1 , and their CAS number and simplified molecular-input line-entry system (SMILES) in Table S1 in the Supplemental Information (hereafter, SI). J o u r n a l P r e -p r o o f

The concentrations of the target substances in raw wastewater, secondary effluent, and river waters were predicted by the following Eqs. (1)-(3), which are adapted from past modelling studies on antivirals and/or down-the-drain chemicals (Singer et al 2007 , Ghosh et al 2010 and Keller et al 2014 :

where PEC raw is a predicted concentration in raw wastewater; N t is a number of patients on the course of treatment with a drug per 100,000 population in a day (assumed as 100); D d is an average daily drug dose expected for COVID-19 treatment; f is a fraction of excreted substances (to urine and faeces) to drug dose; Wc is water consumption per person per day of 200 L, which has been used by European Medicine Agency (EMA) for environmental risk assessment of pharmaceuticals (EMA, 2018); 10 6 is a conversion factor from mg of substances to ng; PEC se is a predicted concentration in secondary effluent; R is the removal efficiency in conventional WWTPs (mentioned below); and PEC riv is a predicted concentration in rivers.

The average daily drug dose D d ranged from 6 mg/day for dexamethasone to 2473 mg/day for ribavirin.

The details of drug dose can be found in Table S1 . The fraction of excretion (f), identified based on literature and database search, varied largely, ranging from 0.8% to 83% for unchanged drugs and from 1.5% to 80% for metabolites (Table 1) . We assumed dilution of secondary effluent by ten times in the receiving rivers, which represents a minimum dilution in many countries (Keller et al., 2014) and also used for environmental risk assessment by EMA (2018). To give a conservative estimation, no in-stream degradation was assumed.

J o u r n a l P r e -p r o o f

Removal efficiency in conventional WWTPs (employing activated sludge process as secondary treatment) were obtained as "total removal at STPs" predicted by STPWIN program in EPI Suite TM (EPA, 2013) . LogK ow was searched for experimentally derived octanol-water distribution coefficient (K ow ), but it was available only for chloroquine, dexamethasone, ribavirin and teicoplanin (Table 1) .

For the other drugs and metabolites, LogK ow was estimated by Kowwin v.1.68 in EPI Suite TM .

Considering its importance in determining environmental fate, LogK ow was also calculated by SPARC program (Hilal et al., 2003) for comparison. Kowwin modelling is based on a database of substances with known K ow , whereas SPARC program calculates strictly from molecular structure (Hilal et al., 

Journal Pre-proof a Average daily dose (mg) was calculated as the total amount of a drug for expected use for COVID-19 treatment, divided by expected treatment duration (see Table S1 ).

b Excretion (%) is the amount, expressed as a fraction of dose, of a parent drug (unchanged drug) or its metabolites which are eliminated from human body via urine and feces. The excretion data were obtained from literature and drug database search.

c Ducharme and Farinotti (1996) . J o u r n a l P r e -p r o o f

Chronic toxicity of the target substances was evaluated, either using experimentally derived ecotoxicity (when available) or otherwise using predicted ecotoxicity by ECOSAR, a computerized structure activity relationship for aquatic toxicity (EPA, 2017). Experimentally derived ecotoxicity data was searched by US EPA Ecotox knowledgebase (https://cfpub.epa.gov/ecotox/) and Google Scholar, and was obtained for only chloroquine (Zurita et al., 2005) and dexamethasone (DellaGreca et al., 2004) . As ecotoxicity of chloroquine was obtained for only acute toxicity, the median effective concentration (EC 50 ; hereafter denoted as eEC 50 to differentiate from viral inhibitory concentration)

was converted to chronic toxicity by acute-to-chronic ratio of 10 (Mayo-Bean et al., 2017). For the remaining substances, chronic ecotoxicity was predicted by ECOSAR, and the smallest values of chronic ecotoxicity for three model organisms (daphnia, algae and fish) was taken for a conservative estimate. For each substance, the predicted no-effect concentration (PNEC) was estimated as the chronic toxicity value divided by UF, a standard uncertainty factor, as shown in Eq. (4); the UF value of 1000 was conventionally adopted to consider the intra-and interspecies variability in the sensitivity (Hernando et al., 2006) :

In addition, the mode of action in aquatic organisms was predicted by VEGA (2019) for each substance.

Risk quotient (RQ) was calculated for each substance as the ratio between PEC riv and PNEC, as shown in Eq. (5):

The risk is classified into three levels: RQ 0.01-0.1, low risk; RQ 0.1-1, medium risk; and RQ >1, high risk (Hernando et al., 2006) .

The drug concentration which inhibits in vitro viral growth by 50% (the half maximal inhibitory concentration; IC 50 ) is a measure of susceptibility of viruses to antiviral agents (Pillay and Zambon, 1998) , and it can also be expressed as half maximal effective concentration (EC 50 ); here, we denote J o u r n a l P r e -p r o o f IC 50 and EC 50 of antiviral agents as vIC 50 and vEC 50 to differentiate from ecotoxicological median effective concentration eEC 50 .

The likelihood of developing antiviral resistance by a virus is the largest when the drug concentrations are close to vIC 50 (Pillay and Zambon, 1998) . Thus, we evaluated the potential of EDR by animal reservoirs exposed to environmental waters, by defining EDR potential (EDRP) as the minimum values between the ratio of PEC riv to vIC 50 values of an antiviral drug and its reciprocal (Eq. (6)):

By definition, EDRP of 1 is the maximal value. The vIC 50 and vEC 50 values of the target pharmaceuticals determined in vitro against SARS-CoV-2 were summarized from literature ( J o u r n a l P r e -p r o o f (Holwerda et al., 2020) 1.13 (Wang et al., 2020a) 1.31 (Ohashi et al., 2020) 5.47 (Yao et al., 2020) 2.71-7.36 7.28, 12.0 (Jeon et al., 2020) 9.27 (Xiong et al., 2020) 

The predicted physical-chemical properties of the target substances are summarized in Tables 1.

Approximately half of the parent drugs (6/11, 54%) and the metabolites (6/12, 50%) were found to be hydrophilic (LogK ow < 3). These hydrophilic substances mostly have low molecular weight (mw < 400), but a few substances had high molecular weight (e.g., remdesivir, mw 602.6; teicoplanin, mw 1709.4; umifenovir M10, mw 556.5; and umifenovir M20, mw 669.5) but low LogK ow values (1.74, −1.10, 2.91 and 0.76, respectively). The predicted removal in conventional WWTPs were low for the half of the substances (removal efficiency < 20% for 12 substances), whereas high removal efficiency (> 80%) was predicted for only six substances (chloroquine, lopinavir, ritonavir, umifenovir, and two metabolites). The predicted high removal rates would be largely associated with adsorptive behavior of the substances; predicted LogK ow values and predicted removal efficiencies were expressed in a sigmoid-like growth curve (Fig. 1 ). In addition, biodegradability at WWTPs predicted by STPWIN ("Biodegradation in STP") were only less than 0.77%. "Primary biodegradation", which indicates the time required for the transformation of a substance to an initial metabolite (EPA, 2013), were "days to weeks" and "weeks to months" for most of the target substances. 

and −192% to −58%, respectively (Abafe et al., 2018) ); however, this results could be treated with care because the wastewater samples were taken by grab sampling. Favipiravir was predicted to be persistent during activated sludge process (2% removal); this is in accordance with its persistence against biodegradation in a batch-scale experiment (Azuma et al., 2017) . Note that, favipiravir can be easily degraded by sunlight in the latter study, indicating a rapid decrease in environmental waters.

The large concentrations in secondary effluents were predicted for TCONH 2 (5339 ng/L), the major active metabolite of ribavirin, followed by T705M1 (4168 ng/L; the major inactive metabolite of favipiravir) and ribavirin (2063 ng/L), as shown in Table 3 . On the contrary, low PECs in secondary effluents are predicted for dexamethasone (2.9 ng/L), ritonavir (26 ng/L) and remdesivir (54 ng/L), because of low dose (dexamethasone), high removal at activated sludge process (ritonavir) and high rate of transformation to metabolites (remdesivir, with 265 ng/L of active metabolite, GS-451524). For all substances, concentrations in the river waters are lower by a factor of 10 because of assumed dilution.

As for oseltamivir, the PEC in secondary effluents in this study (118 ng/L and 589 ng/L) was similar with the maximum concentrations in treated wastewater (293 ng/L to 672 ng/L) determined during pandemic events in Japan (Azuma et al., 2017; Azuma et al., 2012; Ghosh et al., 2010) , but lower than the predicted concentrations of oseltamivir carboxylate in UK and US rivers of 31.8 g/L during the peak of influenza outbreaks (Singer et al., 2007) . Favipiravir has been rarely detected in wastewater effluents after activated sludge process and in river waters in Japan during the past influenza season, presumably because of low usage of favipiravir to influenza patients in Japan and low excretion unchanged (0.8%) (Azuma et al., 2017) . Lopinavir was abundant in wastewater South Africa (1200-2500 in influents, 130-3800 ng/L in effluents) (Abafe et al., 2018; Wood et al., 2015) . Concentrations of ribavirin were below limit of quantification in raw wastewater and treated wastewater in Germany and

China (Peng et al., 2014; Prasse et al., 2010) . Ritonavir has been determined in wastewater in South Africa (mean 1600-3200 ng/L) (Abafe et al., 2018) and treated hospital effluent in Switzerland (max J o u r n a l P r e -p r o o f 108 ng/L) (Kovalova et al., 2012) , and surface water from France (max. 12±5 ng/L) (Aminot et al., 2015) . The predictions of lopinavir and ritonavir are several times lower than the abovementioned high concentrations of lopinavir and ritonavir in wastewater in South Africa, probably owing to the daily usage for HIV treatment in South Africa (Abafe et al., 2018) . The occurrence of the other substances has not been determined in environmental waters.

Clearly, the PECs of the target substances greatly depend on N t , the number of treated patients per 100k population in a day. Since expected treatment duration is 5-10 days for most therapeutics in this study, the assumed N t value of 100 would imply that there are additional 10-20 patients treated by a drug per 100k population each day. As of February 2021, multiple countries have reported more than 10 new daily confirmed cases per 100k population; for example, Gibraltar (364), Belgium (143) (27), and Russia (20) (7-day moving average; WHO, 2020). These numbers would have been much larger at regional/county level; in the US, 7-day moving average of daily new cases per 100k population have been up to more than 500 in 88 counties (1.63 million population in total), and up to more than 1000 in 34 counties (0.74 million population in total) as of Feb 1, 2020 (USAFacts). Considering these numbers and the ratio of severely or critically ill patients of COVID-19 (19%) (Wu and McGoogan, 2020) , the predicted number of patients given in this study can be a likely scenario in many parts of the world, and the number can be even larger in areas with high infection rates. J o u r n a l P r e -p r o o f

For all the antiviral drugs in this study, the risk of EDRP against SARS-CoV-2 appears to be insignificant, because there are at least three orders of margins between PEC and vLC 50 /vEC 50 for all substances (Tables 3). In river waters, largest EDRP was found for hydroxychloroquine (0.00032), followed by GS-451524 (the major active metabolite of remdesivir; 0.00012), and chloroquine (0.000097). The small EDRP in the present study would be primarily due to the large vLC 50 /vEC 50 values of the therapeutic drugs in this study against SARS-CoV-2 (0.72 to >100 M; 242 to > 31200 g/L). While in the case of influenza, vLC 50 of oseltamivir carboxylate, the active form of oseltamivir, are much smaller (e.g., 0.28-0.81 nM; 80-230 ng/L) (Gubareva et al., 2001; Monto et al., 2006) . Hence, environmental concentrations of oseltamivir carboxylate can be comparable to vLC 50 during influenza outbreak, suggesting a significant risk of EDR in the body of water fowls (the natural reservoir of influenza virus) in wastewater-impacted water bodies (Azuma et al., 2012; Fick et al., 2007; Ghosh et al., 2010; Jain et al., 2013; Nannou et al., 2020; Singer et al., 2007) .

Regardless of the small EDRP as above, we must note that numerous populations of wild or domestic animals potentially possess SARS-CoV-2; coronaviruses are known to circulate in mammals, and various animals can be direct or intermediate host for SARS-CoV-2. In the case of SARS-CoV-2, bats have been suggested as animal reservoirs as they carry a coronavirus named RaTG13, which is genetically 96.2% identical to SARS-CoV-2 . Pangolins also have coronaviruses similar to SARS-CoV-2 (Lam et al., 2020) , but they are unlikely the reservoir and they likely acquired these coronaviruses after spillover from the natural hosts . Besides bats and pangolins, some of domestic or cultured animals such as cats, ferrets and minks are susceptible to SARS-CoV-2, and infections between individuals have been observed for cats and minks (Oreshkova et al., 2020; Shi et al., 2020) . In the past coronavirus-outbreaks, palm civets were found to be the intermediate host animals for SARS-CoV, and dromedary camels for MERS-CoV .

Journal Pre-proof Therefore, regardless of the small EDRP as above, it is recommended that residues of antiviral drugs in wastewater must be reduced. In domestic/cultured settings, wastewater-impacted waters should not be fed to animals which are susceptible to SARS-CoV-2. Similarly to antiviral drugs, excessive usage of therapeutic or non-therapeutic antimicrobials has been a matter of concern over disruption of natural biological systems as well as development of antimicrobial resistance in the aquatic systems (Usman et al., 2020) .

We acknowledge following uncertainties in our predictions. First, usage of each drug would differ depending on regulatory status, drug characteristics (e.g., dosage form, utility, adverse reactions) and

patients" health conditions. There are also cases where practitioners and general public are using more than one drug for their own precautions from COVID-19, perhaps owing to a lack of reliable guidelines on specific drug usage for COVID-19. Such practice would result in even higher amount of drugs and their metabolites releasing into the environment, further exacerbating the ecotoxicological concerns.

Second, the QSAR models used in this study are supposed to be only for screening analysis of chemicals (EPA, 2013) . Therefore, further studies are required for precise evaluations of chemical properties, environmental behaviour and ecotoxicity of the substances. Third, the prediction we provided is for a given snapshot concentrations of drug residues, which needs to be substantiated through time-course analysis of drug concentrations in ambient waters during pandemic events, as was done for oseltamivir during influenza outbreak (Singer et al., 2007) . In terms of spatial distribution of drug residues in environmental waters, specific facilities (i.e. hospitals or quarantined hotels and residences) can be important point sources, to which a large proportion of symptomatic patients are often transferred. The impact of such specific medical facilities on environmental pharmaceutical discharge can often be significant in relatively small suburban catchments (Kuroda et al., 2016) .

In the fight against COVID-19, medication is obviously essential in saving human lives and speeding up the recovery. Meanwhile, the potential negative environmental impact of increased drug usage should not be overlooked. Our study suggests the following:

1. Conventional WWTPs are not capable of efficiently eliminating (removal efficiency < 20%) dexamethasone, favipiravir, hydroxychloroquine, oseltamivir, remdesivir, ribavirin and their metabolites from raw wastewater. Therefore, effluents from conventional WWTPs may contain high concentrations of these drugs and their metabolites (up to 7402 ng/L, combined for ribavirin and its metabolite TCONH 2 ), potentially posing high risk to aquatic lives.

2. High risk quotients in effluent-receiving rivers are predicted for T705M1, a metabolite of favipiravir (RQ 5.2), metabolites of lopinavir (0.78-3.9), umifenovir (1.7) and lopinavir (1.5). Use of chloroquine, hydroxychloroquine, remdesivir, ribavirin and ritonavir also imply medium ecotoxicological risk (RQ > 0.1) by the parent compounds or their metabolites in rivers.

3. EDR is less concerning for SARS-CoV-2, because PECs of the antiviral drugs in rivers are more than a thousand times smaller than reported vEC 50 /vLC 50 values of antiviral drugs against SARS-CoV-2. Nevertheless, efforts to reduce environmental discharge of antiviral drugs and their metabolites are important in terms of EDR prevention, as there are numerous populations of SARS-CoV-2-susceptible animals.

In order to address these issues, proper usage and management of antiviral drugs, and proper management of unused pharmaceuticals must be shared and implemented. Direct disposal of drugs into wastewater must be avoided, and using wastewater-impacted waters for animal feeding must be refrained. In the long term, upgrading WWTPs with advanced treatments, such as ozonation, must be facilitated to efficiently remove diverse pharmaceuticals, including several antiviral drugs. On-site treatment of hospital effluents will be also effective in reducing environmental discharge of pharmaceuticals. Proper collection and treatment of wastewater in developing communities are also a

LC-MS/MS determination of antiretroviral drugs in influents and effluents from wastewater treatment plants in

Dissipation and removal of oseltamivir (Tamiflu) in different aquatic environments

Monitoring release of pharmaceutical compounds: Occurrence and environmental risk assessment of two WWTP effluents and their receiving bodies in the Po Valley

Development and application of a multi-residue method for the determination of 53 pharmaceuticals in water, sediment, and suspended solids using liquid chromatography-tandem mass spectrometry

Hope of a covid-19 vaccine is good news, but comes with many uncertainties. The BMJopinion

Attenuation of pharmaceuticals and their transformation products in a wastewater treatment plant and its receiving river ecosystem

Fate of new three anti-influenza drugs and one prodrug in the water environment

Synchronous Dynamics of Observed and Predicted Values of Anti-influenza drugs in Environmental Waters during a Seasonal Influenza Outbreak

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Toxicity of prednisolone, dexamethasone and their photochemical derivatives on aquatic organisms

Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans

Dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19

Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements

Electronic Medicines Compendium: Tamiflu (oseltamivir phosphate) 30 mg Hard Capsules Monograph

Environmental toxicology and risk assessment of pharmaceuticals from hospital wastewater

EMA) Guideline on the environmental risk assessment of medicinal products for human use

Antiviral Oseltamivir Is not Removed or Degraded in Normal Sewage Water Treatment: Implications for Development of Resistance by Influenza A Virus

Predicted critical environmental concentrations for 500 pharmaceuticals

Oseltamivir Carboxylate, the Active Metabolite of Oseltamivir Phosphate (Tamiflu), Detected in Sewage Discharge and River Water in Japan

What do we know about the ecotoxicology of pharmaceutical and personal care product mixtures? A critical review

Timing of antiviral treatment initiation is critical to reduce SARS-CoV-2 viral load

Comparison of the Activities of Zanamivir, Oseltamivir, and RWJ-270201 against Clinical Isolates of Influenza Virus and Neuraminidase Inhibitor-Resistant Variants

Clinical Pharmacokinetics of the Prodrug Oseltamivir and its Active Metabolite Ro 64-0802

Product Monograph: Kaletra (lopinavir/ritonavir) for oral use

Environmental risk assessment of pharmaceutical residues in wastewater effluents, surface waters and sediments

PREDICTION OF CHEMICAL REACTIVITY PARAMETERS AND PHYSICAL PROPERTIES OF ORGANIC COMPOUNDS FROM MOLECULAR STRUCTURE USING SPARC

Identification of five antiviral compounds from the Pandemic Response Box targeting SARS-CoV-2

Characteristics of SARS-CoV-2 and COVID-19

Occurrence and Removal of Antiviral Drugs in Environment: A Review

Japan Approves Remdesivir For Use On Severe COVID-19 Patients

Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs

Removal of pharmaceuticals and fragrances in biological wastewater treatment

Ecotoxicological assessment of pharmaceuticals and personal care products using predictive toxicology approaches

The removal of pharmaceuticals, personal care products, endocrine disruptors and illicit drugs during wastewater treatment and its impact on the quality of receiving waters

Worldwide estimation of river concentrations of any chemical originating from sewage-treatment plants using dilution factors

Hospital Wastewater Treatment by Membrane Bioreactor: Performance and Efficiency for Organic Micropollutant Elimination

Potential Emergence of Antiviral-Resistant Pandemic Viruses via Environmental Drug Exposure of Animal Reservoirs

A chronicle of SARS-CoV-2: Seasonality, environmental fate, transport, inactivation, and antiviral drug resistance

Hospital-Use Pharmaceuticals in Swiss Waters Modeled at High Spatial Resolution

Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins

Absorption, Metabolism, and Excretion of [14C]Viramidine in Humans

Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Pharmacokinetic properties and bioequivalence of two formulations of arbidol: An open-label, single-dose, randomized-sequence, two-period crossover study in healthy chinese male volunteers

Evaluation of 19 antiviral drugs against SARS-CoV-2 Infection

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

Methodology Document for the Ecological Structure-Activity Relationship Model (ECOSAR) Class Program, 2017. Ministry of Health

Detection of Influenza Viruses Resistant to Neuraminidase Inhibitors in Global Surveillance during the First 3 Years of Their Use

Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity

Environmental fate and ecotoxicological effects of antiretrovirals: A current global status and future perspectives

Multidrug treatment with nelfinavir and cepharanthine against

SARS-CoV-2 infection in farmed minks, the Netherlands

Profile and behavior of antiviral drugs in aquatic environments of the Pearl River Delta

Antiviral drug resistance

Antiviral Drugs in Wastewater and Surface Waters: A New Pharmaceutical Class of Environmental Relevance?

Current emerging SARS-CoV-2 pandemic: Potential direct/indirect negative impacts of virus persistence and related therapeutic drugs on the aquatic compartments

Ranking and prioritization of environmental risks of pharmaceuticals in surface waters

Ecotoxicological aspects related to the presence of pharmaceuticals in the aquatic environment

Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2

Future perspectives of wastewater-based epidemiology: Monitoring infectious disease spread and resistance to the community level

Potential Risks Associated with the Proposed Widespread Use of Tamiflu

Ostavimir is ineffective against COVID-19: in silico assessment, in vitro and retrospective study

Disposal practices for unused medications around the world

Occurrence and fate of emerging contaminants in municipal wastewater treatment plants from different geographical regions-a review

US EPA Estimation Programs Interface Suite™ for Microsoft® Windows, 4.11. United States Environmental Protection Agency

ECOSAR) Version 2.0. United States Environmental Protection Agency

Environmental side effects of the injudicious use of antimicrobials in the era of COVID-19

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Laboratory of Environmental Chemistry and Toxicology

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro

Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo

The occurrence of anti-retroviral compounds used for HIV treatment in South African surface water

An Update on Current Therapeutic Drugs Treating COVID-19

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Several FDA-approved drugs effectively inhibit SARS-CoV-2 infection in vitro

Nelfinavir inhibits replication of severe acute respiratory syndrome coronavirus 2 in vitro

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

A global treatments for coronaviruses including COVID-19

Teicoplanin potently blocks the cell entry of 2019-nCoV

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Ecotoxicological evaluation of the antimalarial drug chloroquine

This study was financially supported by Kurita Water and Environment Foundation (KWEF) research grant (No. 19B078).