key: cord-0730324-47r4lrqk
authors: Wojcieszyńska, Danuta; Guzik, Henryk; Guzik, Urszula
title: Non-steroidal anti-inflammatory drugs in the era of the Covid-19 pandemic in the context of the human and the environment
date: 2022-04-19
journal: Sci Total Environ
DOI: 10.1016/j.scitotenv.2022.155317
sha: a24d1a6273269858f8ad023360c534ebc0df1ad5
doc_id: 730324
cord_uid: 47r4lrqk

From 2019, life in the world has mainly been determined by successive waves of the COVID-19 epidemic. During this time, the virus structure, action, short- and long-term effects of the infection were discovered, and treatments were developed. This epidemic undoubtedly affected people's lives, but increasing attention is also being paid to the effects of the epidemic on the environment. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, a global scoping review of peer-reviewed information has been conducted on the use of over-the-counter non-steroidal anti-inflammatory drugs in the treatment of symptoms of SARS-CoV-2 infections and their positive and negative effects on the human body, the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on aquatic organisms, and their adverse effects on non-target organisms. The literature from 1998 to 2021 was analysed using the Scopus®, Web of Science™ (WoS) and Google Scholar databases. As non-steroidal anti-inflammatory drugs place a heavy burden on the environment, all reports of the presence of these drugs in the environment during the pandemic period have been thoroughly analysed. Of the 70 peer-reviewed records within the scope, only 14% (n = 10) focussed on the analysis of non-steroidal anti-inflammatory drugs concentrations in wastewater and surface waters during the pandemic period. The percentage of these works indicates that it is still an open topic, and this issue should be supplemented with further reports in which the results obtained during the pandemic, which has been going on for several years, will be published. The authors hope this review will inspire scientists to investigate the problem of non-steroidal anti-inflammatory drugs in the environment to protect them for the next generation.

In December 2019, the first cases of the disease caused by severed acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared in Wuhan, China. In the first months of 2020, over 200 people had already been affected by this disease in countries around the world. Initially, the pandemic hit the United States, Spain and Italy the most (Yunus et al. 2020 ). However, the pandemic effects were reflected not only in the economy and social relationships but also in the environment. The latter is widely commented on in the scientific literature, both in the positive aspect (reduction of greenhouse gas emissions, suspended particulate matter) and in the negative aspect (pollution of wastewater with anti-inflammatory and anti-viral drugs, personal protective equipment, etc.) (Rupani et al. 2020 , Shakil et al. 2020 , Usman et al. 2020 , Yunus et al. 2020 . For example, in China, carbon dioxide emissions decreased by 25% during the lockdown, which is about 1 million tonnes of carbon dioxide less than the same period in the previous year. Simultaneously, hospitals generated 240 tonnes of medical waste per day in this city compared to the 50 tonnes per day in the pre-COVID-19 period (Shakil et al. 2020) . In COVID-19 therapy, apart from dedicated antiviral drugs, auxiliary drugs, including NSAIDs, have been used. The latter are widely used in outpatient treatment. The results of clinical trials indicate that the use of NSAIDs in therapies is relatively safe, and that is how they function in the social consciousness. However, many reports in the literature indicate that exposure to these drugs by non-target organisms can lead to a wide range of side effects, ranging from behavioural changes through damage to internal organs and characterized NSAIDs as one of the most frequently used drug groups in the home treatment of Covid-19 and the risks of using them during an epidemic, both for humans and the environment. Considering this, the article characterized NSAIDs as one of the most commonly used drug groups in the home treatment of Covid-19 and the risks associated with their use during an epidemic, both for humans and the environment, based on a literature review data analysis conducted following the PRISMA guidelines. This analysis should identify the main causes of the release of NSAIDs into the environment. In addition, it should allow the verification of the thesis whether the COVID-19 epidemic has had a significant impact on increasing environmental concentrations of NSAIDs and, therefore, whether the risk of exposure to non-target organisms to these drugs has increased. The review, pointing to the risks associated with the increased use of NSAIDs during epidemics, will change the scientific community's position on the need to monitor these pharmaceuticals in the outflow of sewage treatment plants. The emphasis on the problem by opinion-forming circles may, as a result, contribute to legal changes related to the monitoring of NSAIDs and the establishment of limit values for concentrations of these drugs in the outflows of sewage treatment plants by legislative bodies around the world. In addition, increased public awareness will contribute to the responsible use and disposal of NSAIDs.

According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Metaanalyses) guidelines (Moher et al. 2009 ), the following databases were searched, the throat, fever, dry cough, headache, general weakness, hypogeusia and hyposmia, muscle pain, shortness of breath, diarrhoea, or acute respiratory distress syndrome and multiorgan failure.

The variety of symptoms result from the attachment of the SARS-CoV-2 virus to the angiotensin-converting enzyme 2 (ACE2) receptor, which is present on the surface of cells in various organs, including the lungs, heart, kidneys, intestines, and arteries (Babaei et al. 2020 , Pujari et al. 2020 ).

In the course of the disease requiring hospitalization, the most commonly used groups of drugs are anti-viral drugs to treat inflammatory diseases, immunomodulating agents, and angiotensin-converting enzyme inhibitors. Most of the targeted anti-viral therapies were aimed to reduce the essential virus proteins (3CLpro and Plpro) responsible for its replication and packaging. Hence, previously approved drugs for treating SARS and MERS virus infections -disulfiram, lopinavir, ritonavir -were widely used. However, patients are most often treated symptomatically using primary nonsteroidal anti-inflammatory and antitussive drugs during home treatment. This type of treatment affects the majority, i.e. nearly 80% of patients with COVID-19, and is most often out of control (Boregowda et al. 2020 , Lam et al. 2020 , Pujari et al. 2020 ).

The recent months have been full of reports related to the use of NSAIDs in COVID therapy.

These reports contain radically different information (De Girolamo et al. 2020 , Giollo et al. 2021 , Javid et al. 2020 , Lund et al. 2020 , Paprocki 2020 . Moreover, many authors indicate that the therapeutic effect of NSAIDs in SARS-CoV-2 infection is not only related to their associated with NSAIDs in COVID therapy. Many authors emphasize that this risk should be analysed from two different perspectives. The first, with the risk of long-term use of NSAIDs by patients before infection with SARS-CoV-2, and the second, with the risk of using In turn, Giollo et al. (2021) suggest that people taking long-term NSAIDs in the case of infection with coronavirus should not be treated with these drugs. Moreover, a higher level of ACE2 secretion was observed after the use of ibuprofen, resulting in a more severe course of COVID-19. A report prepared in France based only on four patients showed a worsening of the symptoms in COVID-19 after ibuprofen usage (Kawthalkar 2020). However, no unequivocal reports link the increase in COVID-19 mortality or the severity of COVID-19 after ibuprofen use during therapy (Lund et al. 2020 , Paprocki 2020 . It only indicates that diabetics with higher ACE2 levels are more likely to develop acute disease (Paprocki 2020 , Pergolizzi et al. 2020 . Zolk et al. (2020) indicate that undoubtedly indirectly, the mechanism of action of NSAIDs may contribute to the complicated course of pneumonia. This is because NSAIDs inhibit significant inflammation symptoms, such as fever and pain, which leads to a delayed diagnosis of pneumonia and a delay in initiating the appropriate therapy. therapy to acute COVID-19 cases. There was no unequivocal evidence linking a cytokine storm to NSAID use. At the same time, this commission, due to inconclusive results, recommends the use of paracetamol under the condition of restrictive dosing (Pergolizzi et al. 2020 ).

So far, the results and conclusions related to the safety of NSAIDs are incredibly different and even mutually exclusive. One of the reasons is the size of the analysed groups. Reports based on the analysis of small, even several-person groups have appeared in prestigious literature.

This precludes a correct statistical analysis. This is all the more surprising that after more than two years of the pandemic, the group of infected people, on the day of writing the article, has reached almost 490 million. This would allow for a broad and comprehensive analysis of the results, but it requires the cooperation of scientific and therapeutic units worldwide.

Nonsteroidal anti-inflammatory drugs (NSAIDs) belong to a broad group of drugs with diverse structural profiles but similar action modes, anti-inflammatory, antipyretic and analgesic properties. They are among the most commonly consumed medications either by prescription or over-the-counter (Osafo et al. 2017) . Today, more than 50 different NSAIDs are available on the global pharmaceutical market, and almost 35 million people use them daily (Fokunang et al. 2018 ). Among the most popular NSAIDs today, apart from acetylsalicylic acid, are ibuprofen, diclofenac, naproxen, ketoprofen, piroxicam, mefenamic acid, celecoxib or rofecoxib (Lonappan et al. 2016 , Osafo et al. 2017 . Although not directly classified as NSAIDs in pharmacology textbooks, paracetamol without an anti-inflammatory component is also discussed along with these drugs (Jóźwiak-Bębenista and Nowak 2014).

NSAIDs are non-selective inhibitors of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Both isoforms are responsible for converting arachidonic acid into prostaglandins, prostacyclins and thromboxanes (Fokunang et al. 2018 , Lucas et al. 2019 .

NSAIDs inhibit COX enzymes by blocking the entrance of arachidonic acid to a hydrophobic channel, leading to the enzyme's active site (Bjarnason et al. 2018) . COX-1 is expressed constitutively in most mammalian cells. Prostaglandins produced by this isoform play a role in gastro and renal protection, macrophage differentiation, platelet aggregation and mucus production. It was confirmed that COX-1 has a limited role in the inflammatory process.

However, its non-selective inhibition by NSAIDs during treatment may have adverse effects (Osafo et al. 2017) . COX-2 is an inducible enzyme expressed during tissue injury and is active in various tissues such as the vascular endothelium and rheumatoid synovial endothelial cells mediating inflammation, pain and fever. An increase in COX-2 levels results in enhanced synthesis of pro-inflammatory prostaglandins in the arachidonic acid pathway ( Figure 2 ). The degree of influence of NSAIDs on COX became the basis for the classification of these drugs into non-target NSAIDs, including diclofenac, ketoprofen, aspirin, naproxen, flunixin, ibuprofen, flurbiprofen, indomethacin and meglumine, COX-2 preferential inhibitors including meloxicam, etodolac, nimesulide, carprofen, and highly selective COX-2 inhibitors including celecoxib, robenacoxib, rofecoxib, lumiracoxib and etoricoxib (Lucas et al. 2019; Rigas et al. 2020 ). The differences in the selectivity of COXs result from differences in the structure of the hydrophobic channel of enzymes. Conventional

NSAIDs have access to both types of channels and bind to the enzyme via their carboxyl or enolic groups. The COX-1 channel is smaller and does not allow access to COX-2 inhibitors.

In turn, the substrate specificity of COX-2 is enhanced by the presence of a polar binding site for the aryl sulfonamide and sulfone groups of COX-2 selective inhibitors (Bjarnason et al. It is also known that NSAIDs usage, probably except for naproxen, is connected with an increased cardiovascular risk (Li et al. 2020) . It is hypothesized that differential inhibition of COX isoenzymes influences the cardiovascular safety of NSAIDs. COX-1 produces thromboxane A2, which causes platelet aggregation, vasoconstriction and intensify vascular and cardiac remodelling (Li et al. 2020 ). However, most typical NSAIDS do not inhibit COX-1 sufficient to inhibit platelet activation. Only naproxen has a sufficiently long half-life for effective platelet COX-1 inhibition and platelet aggregation prevention. More COX-2 is selectivity correlated with a higher cardiovascular risk because COX-2 produces antiinflammatory prostacyclin, a cardioprotective molecule in the circulatory system (Angiolillo Moreover, the mixture of these pharmaceuticals induced oxidative stress at environmentally relevant concentrations (Stancova et al. 2017) . The cell response to the formation of free J o u r n a l P r e -p r o o f Journal Pre-proof radicals is the induction of antioxidant enzymes and changes in the transcription of genes associated with the detoxifying pathway. These processes are associated with the high energy expenditure of the organism, which in turn is reflected in changes in many physiological processes, including reproduction. In addition, oxidative stress can also lead to DNA damage and changes at the cellular level. Moreover, NSAIDs can cause teratogenic effects (Świacka et al. 2020) .

As a result of the literature analysis, a surprisingly small number of literature reports related to the study of chronic toxicity, which in the case of NSAIDs is crucial due to the low concentrations found in the environment of these relatively resistant structures degradation, were found. Therefore, non-target organisms are exposed to these drugs in the long term, often over generations, which may eventually lead to the degeneration of the population. It is all the more surprising that most of the literature reports concern acute toxicity to non-target organisms that do not occur in the environment. In conclusion, although NSAIDs function as entirely safe in public awareness, the above review clearly indicated that they negatively influence biocenoses at environmental concentrations.

Research into water pollution with pharmaceuticals has been ongoing since the 1990s when Ternes published his famous work on water pollution with prescriptions (Ternes 1998) .

Particular attention is given to monitoring the drugs most commonly used in the population, such as hormones, antibiotics, antihypertensive drugs, and over-the-counter NSAIDs (Godoy et al. 2015 , Kraemer et al. 2019 .

Despite the great interest of the world of science in this problem, there is still no legal regulation mandating systematic testing of the aquatic environment's condition in terms of drug content. The emergence of the SARS-CoV-2 pandemic made it even more difficult to conduct systematic research due to the introduction of a complete lockdown in many J o u r n a l P r e -p r o o f Journal Pre-proof countries. The obtained and published results of NSAID concentrations in the environment are often not representative, because they come from research centres using various methodologies, often not validated, and analyses are conducted inconsistently, at irregular intervals, and samples are collected from unrepresentative areas. On the other hand, there are more and more alarming reports that the raging epidemic substantially impacts the environment. Large amounts of drugs, including antibiotics, anti-viral and anti-inflammatory drugs, and personal protective equipment, are sent to sewage and landfills (Usman et al. 2020 ). During the pandemic, there has been an increase in the consumption of disposable plastic equipment, used both by healthcare professionals and the rest of the population, such as personal protective devices, gloves and masks for medical workers, disposable plastic items for life support tools, respirators, and common plastic items containing medical needles (Rume and Islam 2020, Rupani, et al. 2020) . It is estimated that during the first lockdown, Wuhan in China produced 190 million tonnes of medical waste per day, more than during normal time. The use of a huge amount of disinfectants has led to the killing of non-target beneficial species, which can cause an ecological imbalance (Rume and Islam 2020) . On the other hand, a reduction in environmental pollution has been observed, which is associated with reduced vehicle traffic and the exclusion of many industries from operating for a month or longer due to the pandemic (Rupani et al. 2020 , Shakil et al. 2020 ). Among other things, it has been shown to improve the quality of surface waters in terms of suspended particulate matter (SPM) in Lake Vembanad, India. Based on the established turbidity algorithm from the Landsat-8 OLI images estimated that the concentration of SPM during the blockage period decreased on average by 16% compared to with pre-closing period. Compared to the previous year, a 34% decrease in SPM was observed in April 2020 (Yunus et al. 2020 ). However, we cannot ignore the overwhelming impact of the pandemic on water pollution from treatment and disinfection agents. In the absence of targeted therapy, various substances have been used J o u r n a l P r e -p r o o f Journal Pre-proof in the treatment of Covid-19 throughout the year. In the initial period of the pandemic, known anti-viral, anti-malarial and anti-inflammatory drugs were introduced into treatment. Also, in reports from China and India, recommendations for the use of traditional medicinal plants to treat COVID-19 can be found. However, the most commonly used drugs were chloroquine and hydroxychloroquine, lopinavir, remdesivir, favipiravir and azithromycin. Despite divergent data, NSAIDs have also been widely used in the treatment of especially in patients treated at home. With over-the-counter availability, they are often used without medical supervision to treat the basic symptoms of Covid, and NSAIDs can be found in the sewage treatment plant along with domestic and hospital sewage (Barcelo 2020). After reaching the sewage plant, these drugs undergo a partial biological or chemical transformation, often into intermediates with a higher toxicity than the parent drug (Marchlewicz et al. 2017, Wojcieszyńska and . Increasing contamination with these drugs and their degradation products was already observed in the period before the pandemic in the waters of all continents (Godoy et al. 2015 , Lacina et al. 2012 , Lonappan et al. 2016 , Madikizela and Chimuka 2017 , Shanmugam et al. 2014 , Ternes 1998 In India, a country particularly hit by the coronavirus pandemic, a large share of NSAIDs has been observed in both rivers and sewage treatment plant inflows. Particularly high concentrations of ketoprofen (2747.29 µg/l), aspirin (125-2213.36 µg/l) and naproxen (3-2132.48 µg/l) were observed in the inflow to the treatment plant (Praveenkumarreddy et al. 2021, Thalla and Vannarath 2020) . On the other hand, in the Gurupura River in south-west India, the following concentrations were found, naproxen 8.8 µg/l, ketoprofen 1.5 µg/l, diclofenac 1.6 µg/l, ibuprofen 0.17 µg/l and aspirin 0.02 µg/l (Praveenkumarreddy et al. 2021 ). Studies of Praveenkumarreddy et al. (2021) on the ecotoxicological risk of NSAIDs in this river have shown, among other things, a medium risk related to the appearance of ibuprofen and naproxen concerning the Hydra attenuata polyp. In addition, ibuprofen was also toxic to Vibrio fischeri, Daphnia magna and algae (Praveenkumarreddy et al. 2021) . In contrast, diclofenac has shown an average ecological risk to Ceriodaphnia dubia. In turn, Thalla and Vannarath (2020) results were compared to those between March 2019 and January 2020. The authors found a decrease in paracetamol concentration in the wastewater, probably due to the changing lifestyle, limiting social contacts, and thus the spread of diseases such as colds and flu, in the According to the PRISMA guidelines, an analysis of the literature indicated that only a tiny percentage of the available literature actually relates to studies of NSAID concentrations in the environment during the pandemic period. Most of the literature that appeared in this period publishes data from before the pandemic period. These modest data probably result from the introduced lockdowns in virtually all regions of the world, which significantly hindered the implementation of projects and sampling for analysis. In addition, they may indicate that the problem of increased NSAID consumption during a pandemic was not identified. This is supported by reports mainly on the increase amount of personal protective equipment, antibiotics or antiviral drugs in the environment. Without constant and regular monitoring of NSAIDs, this approach can lead to uncontrolled growth in these drugs' surface waters, especially given that the pandemic is becoming endemic. The review indicates a need for more extensive research by the scientific community in monitoring and studying the fate of NSAIDs in the environment.

The literature analysis indicated that the frequent use of NSAIDs as drugs supporting COVID-19 therapy and slight changes in the structure of these drugs during changes in the body is the reason for the appearance of NSAIDs in the environment in an unchanged or only slightly altered form. NSAIDs are observed in rivers and aquifers and in the inflows and outflows of wastewater treatment plants worldwide. A literature review also indicated a high ecotoxicological risk of NSAIDs to aquatic organisms. Data analysis from two years of the 

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