Some antiviral drugs like acyclovir, didanosine, and tenofovir can be excreted as largely unchanged parent compound Al-Rajab et al. Presence of organic and inorganic constituents in wastewater may react with the parent compound and give rise to additional molecules, which may be persistent or difficult to remove from wastewater. Formation of such additional molecules after the excretion of parent compounds and metabolites into the water bodies is a serious environmental concern.
Figure 2 outlines the proposed alternatives through which antiviral drugs can enter into the environment via different sources and ultimately reach drinking water sources. Unused drugs are disposed off into the sewage system, drains, and sometimes to trash. There are three main sources for antiviral drugs to reach potable water sources through various pathways:. Some of the antiviral drugs are reported to be persistent and recalcitrant Goncalves et al. The behavior of the majority of the antiviral compounds metabolites or active form present in STPs has been scarcely documented.
When these drugs pass through the STPs, they are found to be highly bioactive, and may have serious health impact on non-target organisms Ghosh Straub concluded on the basis of standard chronic toxicity tests that oseltamivir poses no significant risk to WWTPs or to surface water environment and found that it was persistent.
To date, no information is available on the fate and impact of antiretroviral drugs in the environment and WWTPs Germer and Sinar Singer et al. The properties of relenza are as follows: a readily soluble in water, b chemically stable in water having a half-life greater than 1 year, c not readily volatile, d not likely to sorb on soil or sediment, e lipophobic not likely to decompose to fats , and f not readily mineralized.
These lipophobic compounds are unlikely to adsorb on the sludge matrix if treated through activated sludge. Moreover, this mechanism limits the potential losses in the aqueous phase in the final effluent. Non-volatile organic compounds in sewage sludge are regarded as a potential risk to human health or the environment when sludge is used in agricultural soils Langenkamp et al.
Tenofovir, a nucleotide reverse transcriptase inhibitor, has been found to be largely and rapidly excreted unchanged in the urine. Al-Rajab et al. Research has also shown that oseltamivir is not degraded or removed during conventional wastewater treatment Fick et al. It has been reported to be persistent in surface waters for a longer period of time.
Its half-life in surface water has been reported to be 53 days Accinelli et al. The pharmaceutical concentrations in WWTP in Switzerland receiving pharmaceutical formulation facilities discharge have been reported to range from less than 0. Research has suggested that discharge from production units in Europe may result in increased antiviral drug concentrations in river water Phillips et al.
Recently, it has been found that the administration of the antiviral drug oseltamivir phosphate during a pandemic has posed a risk to drinking water safety and ecological health Ghosh et al.
An active moiety of oseltamivir, used for treatment and prevention of pandemic influenza, has been found to be resistant to biological treatment and UV radiation treatment, and the active substance has been released in wastewater leaving the treatment plant. The UV spectra of OC has absorbance in — nm range, and radiation with wavelengths less than nm do not contain enough energy to break the bonds within the molecules Fick et al.
Ritonavir has gained substantial attention for bioaccumulation potential in the environment. Zanamivir is the second most prescribed drug in Japan used in the treatment of influenza A and influenza B viruses. It was also reported in high concentration Kummerer suggested possible measures to reduce the load of pharmaceuticals in the environment.
It included treatment of pharmaceuticals before their discharge into the environment using advanced oxidation processes AOPs or adsorption. The pharmaceutical industries should also publish data about the impacts of active pharmaceutical ingredients on the environmental components. Strict legislative measures are needed for the proper disposal of expired medications. Such unused drugs should not be disposed off down the drain but instead returned to pharmacy for which take-back system ought to be established.
Table 1 depicts the physicochemical properties of some antiviral drugs, their structure, and molecular weight. Molecular weight of antiviral drugs would be useful while selecting membrane-based treatment processes ranging from ultrafiltration to reverse osmosis, which depend on molecular weight cut-off.
The carbonyl oxygen of ketone group capable of hydrogen bonding with water makes antiviral drugs highly soluble in water. Unsaturated cyclic rings are prominent in antiviral drugs. Presence of aromatic rings makes the compound toxic and resistant to conventional degradation methods. Solubility of the antiviral drug will determine the amount of drug remaining as suspended solid and the part which will go in dissolved solids.
The soluble part will contribute to total organic carbon of waste streams. Acid dissociation constant, p K a, is a very useful parameter for understanding the behavior of antiviral drug molecules in water.
For strong acids, the value of p K a is less than 2; for weak acids, p K a is between 2 and 7; for weak bases, p K a lies between 7 and 10, while for strong bases, the value of p K a is greater than The wastewater from pharmaceutical industries has a wide range of pH, i. With the help of p K a values, appropriate selection of ion exchange adsorbents can be made.
For example, for abacavir, having a p K a value of Ionic species of drug molecules differ in chemical, physical, and biological properties, which can be used to predict the ionic form of the molecule that is present in aqueous solution. T m , melting point, is an important physical property of the antiviral drugs, which determines the limiting temperature of the treatment process. Information about physicochemical properties of antiviral drugs is a useful tool to select appropriate treatment technology.
UV spectrophotometer and high performance liquid chromatography HPLC are the two most common techniques for the detection of antiviral drugs. Majority of the methods are based on the detection of antiviral drugs in biological samples like plasma, urine, and serum Palacios et al.
Jung et al. Even though these methods are used for the analysis of antiviral drugs in biological samples, e. For example, HPLC-UV is not suitable for the analysis of antiviral drugs in aqueous matrices considering the low concentrations nanograms per liter range of these drugs typically observed in the environment.
A solid-phase extraction followed by HPLC method was used to quantify five human immunodeficiency virus protease inhibitors PIs , namely, indinavir, amprenavir, saquinavir, ritonavir, and nelfinavir, and the non-nucleoside reverse transcriptase inhibitor, efavirenz in plasma Marzolini et al.
Antiviral drugs are not efficiently retained on common solid-phase extraction sorbent materials due to their high polarity, and the use of large sample volumes is necessary to achieve sufficient sensitivity.
The same is true for reversed phase HPLC columns, which have limitations with respect to chromatographic resolution. In recent years, hydrophilic interaction liquid chromatography has been successfully employed for the analysis of polar substances in biological matrices.
Contrary to reversed-phase liquid chromatography, polar compounds, viz. Survey of the literature reveals that limited methods are available for determination of antiviral drugs in aqueous solutions like reversed phase HPLC, HPLC—tandem mass spectrometry, and UV—spectrophotometric methods Basavaiah and Anil Kumar ; Djurdjevic et al.
The concentration of antiviral drugs in the wastewater discharge from production units may range in milligrams per liter Mascolo et al. Presently available methods suffer with detection limits confined to low concentrations only, tedious experimental conditions, low sensitivity, and sometimes complex procedures for the preparation of samples or standard solutions.
Considering limited methods for detection of antiviral drugs in aqueous solution, there is an urgent need to develop other reliable detection methods. However, the analysis of antiviral drugs in aqueous medium is a challenging task due to their different structure and wide range of p K a values.
A change in a viral genome after prolonged exposure makes the virus resistant towards that particular drug which is referred to as antiviral drug resistance. The incomplete removal of antiviral drugs from effluent of STPs results in their increased concentration in receiving waters, which may lead to the development of microbial or viral resistance with adverse health effects on humans and harmful effects on environment Kummerer Presence of a wide range of pharmaceuticals in water bodies may pose significant danger to aquatic life and wild birds Bound and Voulvoulis ; Jarhult ; Singer et al.
Examples include development of oseltamivir-resistant virus in animals like wild fowl and dabbling ducks, in which their bowel contains replicating virus as well as oseltamivir Singer et al. These antiviral drugs have been found even in drinking water Ghosh ; Ghosh et al. If wastewater containing resistant bacteria and antibiotics are used for irrigation, and sewage sludge as a fertilizer, the resistant bacteria can enter the food chain also Kummerer Same behavior is expected for viruses and antiviral drugs.
Table 2 shows a list of some FDA-approved antiviral drugs, class, their mechanism of action, and the most frequent adverse events. As far as unmetabolized part is concerned, indinavir, a PI, has been reported to be associated with certain side effects such as urinary complications, nephrolithiasis and crystalluria, renal atrophy, tubulointerstitial nephritis, and hypertension De Araujo and Seguro Prolonged exposure of tenofovir has also been reported to lead to reduced bone mineral density Fontana All other drugs used for treatment of other viral infections such as herpes simplex virus HSV , varicella zoster virus VZV , cytomegalovirus CMV , hepatitis B virus HBV , human papillomavirus, chronic viral hepatitis, and others fall under the category of general antiviral drugs.
General antiviral drugs non-antiretroviral include nucleoside analogs, nucleotide analogs, antisense drugs, and all other antiviral drugs.
Acyclovir, famciclovir, ganciclovir, etc. Nucleoside analogs and other antiviral drugs are associated with kidney failure, neuropsychiatric side effects, encephalopathy, delirium, tremors, etc. These drugs in certain combinations when released into aqueous bodies after partial metabolism can show potential adverse effects to contact organisms and may have fatal consequences.
Gradual release and prolonged exposure of antiviral drugs and combination with other drugs through various channels can affect the human body to a severe extent. Among pharmaceuticals, antibiotic and antiviral drugs are of emerging concern due to their growing role in antibiotic and antiviral drugs resistance among pathogenic bacteria and influenza viruses, respectively. These compounds may also upset sensitive ecosystems, as they are highly bioactive.
Antiviral drugs may have both qualitative and quantitative effects upon the resident microbial population of sediments Kummerer These drugs vary widely in their molecular weight and chemical structure, and therefore, there is a possibility that they would show different nature to wastewater treatment in terms of recalcitrance and environmental behavior.
Release of antiviral drugs like OC to the environment or water bodies may pose risks, which include drinking water safety, ecological health risk, the development of antiviral resistance, destabilization of microbial biofilms or flock or sensitive microbial community, and affecting the performance and function of STPs Ghosh This may often lead to generation of metabolites or degradation-by-products, which may be more harmful than their parent compound and more difficult to remove from wastewater.
OC and peramivir inhibited biofilm formation on microbial community like Pseudomonas aeruginosa , a typical bacterium found in soil, water, and skin flora Soong et al. This may lead to hindrance in biological treatment of wastewater. Large amount of bioactive pharmaceuticals during an influenza pandemic poses significant ecotoxicological challenge and stops the growth of microbial consortia due to antiviral contamination of receiving water bodies, thereby causing concern for freshwater and marine organisms Singer et al.
Acute aquatic ecotoxicity data of famciclovir has been briefly cited in literature Cunningham et al. Ritonavir has also been reported to exhibit a high ecotoxicity potential Escher et al. Zidovudine, an antiretroviral drug, has carcinogenic potential and has been classified in Group 2B which constitutes possible human cancerogens Bottoni et al. Populations exposed to abacavir may have adverse drug reactions and hypersensitivity Bonnefoi et al.
Furthermore, drug residues at high concentrations can have toxic effects on aquatic organisms, e. Atazanavir, adefovir, acyclovir, valacyclovir, tenofovir, and other antiviral drugs have very limited experimental fate or toxicity data available.
One such study about the presence of carboxy-acyclovir, a metabolite of acyclovir, in drinking water reported to be of major concern was because of the neuropsychiatric side effects in patients. Penciclovir PCV , another antiviral drug used in treating herpes infections, and its transformation product TP formed after biological treatment are likely to be of ecotoxicological relevance.
Oseltamivir was found to induce a significant ecotoxicological risk in waterways and reported to be recalcitrant in sewage effluent Goncalves et al. OC was found not to be completely removed by conventional wastewater treatment processes Fick et al. Reynolds developed a mathematical model to predict the effects of antibiotics and antiviral drugs on wastewater treatment ecosystems. It was observed that during mild pandemic, a slight increase in use of antiviral drugs has negligible effect on microbial community.
While large increase in antiviral drugs during severe outbreak of influenza has completely inhibited the growth of microorganisms. At present, potential health risks associated with antiviral drugs other than oseltamivir and its metabolite OC are far less reported in literature. Therefore, occurrence and inhibitory effects of other antiviral drugs on microbial community in the environment needs further attention.
Increased use of antiviral medications for the treatment of influenza can potentially affect the ecosystem and WWTP operations, but to what degree and extent are currently unidentified and need to be further explored.
As far as removal of antiviral drugs from wastewater is concerned, majority of the studies are reported on removal of oseltamivir. The reported literature contains only removal of some antiviral drugs through biological treatment or a combination of biological treatment with some other process. Biodegradation effectiveness of three drugs acyclovir, naproxen, and nalidixic acid from pharmaceutical industrial wastewaters was investigated using Zahn—Wellens test Mascolo et al.
Organic parent compounds and metabolites were reported to be recalcitrant to biodegradation. Out of the three main compounds which were detected in the acyclovir wastewater samples, one compound was reported to be quite persistent and accumulated during biodegradation Mascolo et al. Mascolo et al. These drugs were found to be non-biodegradable, toxic, and inhibitory to activated sludge bacteria and potentially referred as refractory in the environment.
All anti-HIV drugs have been reported to be potential environmental pollutants. Long half-life of nevirapine and also photostability makes it toxic to larger organisms like rat. Nevirapine has been reported to persist for years in the environment due to its bioactive nature.
This is reported as relatively persistent in soils but biodegraded by aerobic microorganisms. All three antibiotics have been significantly removed, but oseltamivir was found to be most persistent among four reported active substances Accinelli et al. Fick et al. On the other hand, the combination of biological and indirect photolysis treatment resulted in decomposition of OC.
Goncalves et al. The conventional treatment of antiviral drugs may result in intermediates which are poorly biodegradable. The presence of antiviral drugs in a WWTP inhibits the growth of microorganisms and thus affecting the removal of the remaining organic matter content Dantas et al.
Longer retention time, usually in days to oxidize antiviral drug, is one of the drawbacks in biological oxidation systems. However, this process requires high temperature incinerators, and moreover, there is a risk of diffusion of gases in the environment in case of any mishap. Table 3 gives an overview of the recent work undertaken for the removal of antiviral drugs from wastewater. From the data of Table 3 , several observations can be made as follows:.
As far as treatment efficiency is concerned, biological treatment is capable of removing some antiviral drugs but not necessarily accompanied by total mineralization. In several cases, degradation by-products and transformation products are found to be more persistent or recalcitrant than the original compound, thus implying that post-treatment is required.
However, majority of the ozonation experiments are conducted on acyclovir and oseltamivir only. These advanced treatment processes can be employed for removal of other antiviral drugs also. Majority of the work has been carried out on removal of antiviral drugs on laboratory scale using biological treatment. Therefore, further studies are required to be made in terms of the design strategies to scale up the treatment process. Highly bioactive in nature, partially resistant towards biological degradation, and often ending up in generation of recalcitrant or persistent by-products are some of the characteristics of these emerging contaminants.
As conventional wastewater and other wastewater treatment processes are unable to act as a reliable barrier towards some of recalcitrant antiviral drugs, it is necessary to work upon some of the additional advanced treatment technologies. It has been assumed that antiviral drugs would behave in the same way as that of antibiotics.
Hence, the removal processes which have been employed for antibiotics can be effectively used for antiviral drugs also. Various techniques are available in literature for the removal of antibiotics from wastewater Adams et al. It includes adsorption, oxidation using chlorination, H 2 O 2 -UV, ozonation, anaerobic biological processes, and membrane separation techniques. Electrochemical methods can also be considered as viable options for treatment of polar antiviral compounds.
Removal or degradation rates depend on the treatment used and duration, concentration, and physical properties of the antiviral drugs in the influent. Kummerer proposed and investigated some risk management strategies to eliminate or remove pharmaceuticals from effluent of STPs or wastewater.
Considering the research work done so far on removal of antiviral drugs, it is desirable to study the other well-established methods of removal of pharmaceuticals from wastewater. Based on a literature review and an overview of occurrence, ecotoxic effects, and detection methods of antiviral drugs in aquatic bodies and environment, this paper proposes a few recommendations in research of antiviral drugs in wastewater by highlighting the potential harmful effects of antiviral drugs on organisms.
To date, limited number of studies has indicated occurrence of antiviral drugs in the low nanograms per liter or milligrams per liter range in STPs or effluents from pharmaceutical industries.
Antiviral drugs have also been found to develop resistance in dabbling ducks. It is recommended to identify potential hazards associated with antiviral drugs when encountered with other animals through waste streams. Limited literature data is available on toxicological effects of antiviral drugs on aquatic organisms. Therefore, more studies are needed to investigate the toxic nature and degradation mechanisms of these antiviral drugs and their metabolites in the environment.
Biodegradation of antiviral drugs is a cost effective method, but degradation products are found to be more persistent than parent compounds. More work is needed to establish the degradation of antiviral drugs from wastewaters. Results show that there is a pronounced lack of data in removal of antiviral drugs; majority of the work has been carried out only on removal of oseltamivir.
There are many other antiviral drugs like abacavir, indinavir, ritonavir, and emtricitabine and certain combination of antiviral agents, HAART having the potential to contaminate water bodies, which are found in significant quantities in water bodies and STPs. The removal method of such antiviral drugs is not well established. Adsorption is one of the most efficient methods for the removal of contaminants from wastewater producing high quality treated effluent.
This process may provide a remarkable alternative in a sense that it does not require any additional pre-treatment step for the treatment of wastewater containing antiviral drugs. Adsorption has been found to be a better option compared to other techniques in terms of ease of operation, flexibility, initial cost and design, and inertness to toxic pollutants. Adsorption also does not generate any harmful by-product Ahmaruzzaman AOPs are efficient methods for the treatment of pharmaceutical wastewaters containing recalcitrant and toxic compounds.
AOPs work in two steps: 1 the formation of strong oxidants and 2 the reaction of these oxidants with organic contaminants in water. AOPs include heterogeneous processes, e. Membrane separation processes, viz. Low pressure membrane filtration, such as microfiltration MF and ultrafiltration UF , can be feasible options for addressing the present removal needs.
Antiviral drugs can be recovered and commercially utilized without any chemical modification using suitable membranes. The resulting water would be relatively clean and can often be directly reused with no further treatment Strathmann Electrochemical methods like electrocoagulation, electrooxidation, electroreduction, and electroflotation offer various advantages over other treatment methods.
High efficiency, ease of operation, and compact facilities are some of the key features of these methods.
As some of the drugs are charged molecules carrying negative, positive, or zwitterions in their ionic forms, these methods can potentially be used to effectively remove antiviral drugs from wastewater. Combining two or more processes can be advantageous leading to improved treatment efficiencies. For instance, adsorption may be employed to remove recalcitrant compounds to a great extent followed by biological treatment.
It would minimize the possibility of formation of transformation products. Therefore, it is recommended that the removal processes or treatment methods should be done or tried on other antiviral drugs also. In addition, the lack of appropriate detection methods of antiviral drugs and their metabolites in aqueous solution is also a problem.
A problem arises, however, when unused medications are disposed off as such in trash or untreated in drains. Antiviral Off-Target Toxicity Testing ReachBio works with clients during preclinical development of antiviral agents to help them predict and rank the potential of their drug candidates to induce myelosuppression anemia, neutropenia, thrombocytopenia.
References: 1. Sommadossi et. Dornsife et. Drapeau et. As these data became available, it was determined that the EUA was no longer justified and it was revoked. Protease inhibitors. Convalescent plasma. Insufficient data are available to recommend convalescent plasma for treatment of COVID infections. It is theorized that plasma from recovered patients may contain antibodies that will suppress viral replication or modify the immune response.
Thousands of patients have received convalescent plasma through expanded access treatment trials. At this time, clear evidence of benefit is not available, and uncommon severe adverse reactions have been reported, including death. Variability in SARS-CoV-2 antibody concentrations in convalescent plasma likely have an impact on the efficacy of plasma products. Currently, standards for screening donor plasma for neutralizing antibody concentrations have not been established.
Potential therapies that are not recommended at this time include baloxavir, nitazoxanide, estrogen products, interferons, ribavirin, niclosamide, famotidine and ivermectin.
A future column will address the status of dexamethasone and other immune modulators, mesenchymal stem cells and immune-based therapy for management of patients with COVID infections. Advertising Disclaimer ». Sign In or Create an Account. Search Close. Create Account. Advanced Search.
Skip Nav Destination Share. Cody Meissner, M. Article type: News. Hydroxychloroquine On March 28, an EUA was issued for oral chloroquine phosphate and hydroxychloroquine sulfate for treatment of COVID infections in hospitalized adolescents and adults.
Convalescent plasma Insufficient data are available to recommend convalescent plasma for treatment of COVID infections.
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