key: cord-0901968-lvhzl9xg authors: Colalto, Cristiano title: Volatile molecules for COVID‐19: A possible pharmacological strategy? date: 2020-07-19 journal: Drug Dev Res DOI: 10.1002/ddr.21716 sha: 29785fc9f4b21fa41130200cd6290bb28f5479cd doc_id: 901968 cord_uid: lvhzl9xg COVID‐19 is a novel coronavirus disease with a higher incidence of bilateral pneumonia and pleural effusion. The high pulmonary tropism and contagiousness of the virus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have stimulated new approaches to combat its widespread diffusion. In developing new pharmacological strategies, the chemical characteristic of volatility can add therapeutic value to the hypothetical drug candidate. Volatile molecules are characterized by a high vapor pressure and are consequently easily exhaled by the lungs after ingestion. This feature could be exploited from a pharmacological point of view, reaching the site of action in an uncommon way but allowing for drug delivery. In this way, a hypothetical molecule for COVID‐19 should have a balance between its lung exhalation characteristics and both antiviral and anti‐inflammatory pharmacological action. Here, the feasibility, advantages, and disadvantages of a therapy based on oral administration of possible volatile drugs for COVID‐19 will be discussed. Both aerosolized antiviral therapy and oral intake of volatile molecules are briefly reviewed, and an evaluation of 1,8‐cineole is provided in view of a possible clinical use and also for asymptomatic COVID‐19. Since December 2019, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been causing a pandemic pneumonia named COVID-19. Infection started in Wuhan, the largest city of Hubei Chinese province, and rapidly spread throughout the world. SARS-CoV-2 is a coronavirus belonging to the β-coronavirus cluster, which includes MERS-CoV, the causative agent of Middle East respiratory syndrome (MERS) (Rabaan, Al-Ahmed, Haque, et al., 2020) . The mortality rate of COVID-19 has been reported to range from 3.4% (WHO) up to 14% (Wu, Hao, Lau, Wong, et al., 2020) depending on different authors and modalities of data collection. The unstoppable COVID-19 has forced countries to develop new strategies to ensure both constant monitoring of the epidemic and an active response in terms of reorganization of intensive care (Remuzzi & Remuzzi, 2020) and to discover possible experimental drug therapies (Dong, Hu, & Gao, 2020) . In this way, many authors are sharing clinical experience using different pharmacological approaches in COVID-19 patients (Caputo, Lentini, & Habtemariam, 2020) . A brief summary of some pharmacological therapies currently under investigation is reported in Table 1 . Scientists and pharmaceutical companies are starting to develop several types of vaccines (Gao, Bao, Mao, et al., 2020) . However, it seems that more time is required for the results to establish a reasonable level of safety. Effectiveness of vaccines is another important aspect because of the high amount of variability, linked to the mutation rate of the novel virus, which could make a previously helpful vaccine or new antiviral molecule ineffective. Government regulatory T A B L E 1 COVID-19 pharmacological therapies registered on clinicaltrial.gov (accessed at April 8, 2020) agencies are called upon to guarantee an accurate and careful evaluation process to satisfy all the necessary safety, quality, and efficacy requirements, avoiding any shortcuts in assessment (Jiang, 2020) . In the absence of a known efficient pharmacological therapy and because of the lack of time due to this public health emergency, it is reasonable to explore any possible strategy of pharmacological intervention (Ebrahimi, 2020; Phadke & Saunik, 2020; Rothlin, Vetulli, Duarte, & Pelorosso, 2020) . Screening existing drugs or molecules with known pharmacological and safety profiles is a consolidated approach. This has already happened with the choice of tocilizumab, approved for rheumatoid arthritis, to block the massive release of cytokine IL6, induced by the coronavirus at the cellular level, and thus prevent its lethal effects (Wu, Wang, Kuo, et al., 2020) . In China, more than 80 clinical trials are testing both the newest molecules and the oldest remedies, even those from Traditional Chinese Herbal Medicine (Maxmen, 2020) , as reported in Table 1 . The situation that is developing is one in which there are many studies with therapeutic possibilities but limited time. Here, an approach is discussed considering the possibility of slowing the engraftment of the virus at the level of the pulmonary alveoli through a pharmacological strategy with nonspecific mechanisms of action or toward specific molecular targets. Pathophysiology of COVID-19 pneumonia involves an immune response that could result in pulmonary damage reducing lung capacity with functional impairment (Li, Fan, Lai, et al., 2020) . The spread of the virus occurs due to close contact with an infected person, exposed to respiratory droplets resulting from coughing, sneezing, or aerosols. The virus penetrates the human body through the lungs by inhalation (Shereen, Khan, Kazmi, Bashir, & Siddique, 2020) . Pathogenetic mechanism of SARS-Cov-2 involves binding with the ACE-2 receptor for cells attachment and penetration (Renu, Prasanna, & Abilash, 2020) . Lungs are an internal organ with a high total capacity of 6 L, an average surface area of approximately 50 m 2 , and peculiar pharmacokinetics involving the absorption, metabolism, and elimination of substances in its lumen. The importance of this organ as a site of action for targeted drug therapies is clear, especially in asymptomatic people to reduce the viral load even before the onset of pathogenesis and symptoms, the Achille's heel of COVID-19 pandemic (Arons, Hatfield, Reddy, et al., 2020; Gandhi, Yokoe, & Havlir, 2020; McHugh, 2020) . Considering what above, here data from inhaled antiviral aerosol studies are reviewed and the potential use of volatile molecules orally ingested, easily eliminated and exhaled by the lungs, are argued. This last pharmacological strategy has never considered before in clinical treatment and could be analyzed with some limitations in this time of emergency. Inhalation is the preferred route of administration for many drugs that • pressurized metered inhalers • expansion chambers • nebulizers • gas Some data have suggested the use of aerosolization in antiviral therapy or symptomatic treatment, and this is confirmed by some trials recently registered for COVID-19 treatment (Table 1) It has been argued that aerosol delivery of antiviral drugs or vaccines may lead to some advantages in safety and efficacy in treating influenza (Morgan, Hemmink, Porter, et al., 2016; Strong, Ito, Murray, & Rapeport, 2018; Wong, Christopher, Viswnaan, Schnell, et al., 2010) . For antiviral drugs, the main advantage of the inhalation route is the lack of first pass metabolism, which leads to increased bioavailability. For example, the old drug ribavirin (RBV) has been proposed for aerosol therapy in critical care situations, but it lacks of strong recommendation and is restricted to high-risk patients (Diot & Plantier, 2016; Velkov, Rahim, Zhou, Chan, et al., 2015) . A recent comparative retrospective cohort analysis has found no significant differences in clinical outcome between oral and inhaled RBV therapy but higher costs for aerosol therapy emerged as a problem (Trang, Whalen, Hilts-Horeczko, Doernberg, et al., 2018) . The inhaled RBV therapy combined with intravenous immunoglobulin is applied in bone marrow transplant patients in cases of viral pneumonia because of its poor systemic absorption, protecting against haemolytic anemia frequently noted after oral administration (Velkov et al., 2015) . One of the most well-known antiviral drugs, zanamivir (Relenza®, GlaxoSmithKline), has showed low oral bioavailability: to solve it, a new inhaled formulation has been approved with a 15% of the inhaled dose reaching the lower respiratory tract (Peng, Milleri, & Stein, 2000) . A comparative clinical study has underlined the greater effect of aerosol compared to oral oseltamivir in reducing symptoms of influenza A or B (Kawai, Ikematsu, Iwaki, Maeda, et al., 2008) . IFN-γ is not an antiviral drug but useful in the treatment of some respiratory diseases due to its immunomodulatory pharmacological activity. Recently, a novel nebulized formulation of interferon gamma (IFN-γ) has been tested using special vibrating mesh-type nebulizers. This experiment was conducted following the regulatory standard requirements of methodologies for the assessment of pulmonary drug delivery. The increase bioavailability through special nebulization system has improved the delivery of this large molecule achieving optimal bioavailability in the lower respiratory tract, while maintaining its pharmacological activity (Hilberg et al., 2012; Moon, Smyth, Watts, & Williams 3rd., 2019) . Aerosolized IFN-γ has been tested in clinical trials showing great tolerability with some improvement in the reduction of cavity lesion size and bacterial loads (Condos, Hull, Schluger, Rom, & Smaldone, 2004; Condos, Rom, & Schluger, 1997; Moss, Mayer-Hamblett, Wagener, Daines, et al., 2005 ). An important limit to improve aerosol therapy could be represented by the risk of dispersion of the virus into the environment already reported for hypoxemic COVID-19 patients requiring oxygen therapy (Ari, 2020; Li, Fink, & Ehrmann, 2020) . The authors reviewed the available data on the use of the high-flow nasal cannula for oxygen administration. Analysis of the generation and dispersion of bio-aerosols showed a risk similar to standard oxygen masks and therefore of aerosol treatment. Aerosol generators posed a potential risk of intrahospital contamination and may carry bacteria and increase the risk of bacterial lung infection in patients with viral pneumonia (Ari, 2020; Pitchford, Corey, Highsmith, et al., 1987; Wexler et al., 1991) . Lungs are the organ most affected by COVID-19 pandemic. Assuming a strategy based on seeking localized pharmacological action, could the lung elimination process be considered from a "drug delivery" point of view rather than a "drug elimination" one? The ability of a drug to cross cell membranes depends on its partition coefficient depending on its chemical-physical characteristics; hydrophilic groups refer to those that are capable of forming hydrogen bonds with water, such as the carboxylic, alcoholic, amino, aldehyde and ketone groups and electrically charged groups. The partition coefficient of a drug (i.e., its ability to cross cell membranes) can vary due to metabolization processes. Generally, metabolic transformations lead to multiple hydrophilic compounds with partition coefficients lower than those of the original drugs. Furthermore, it is important to remember that many drugs are organic molecules that contain acidic or basic residues, that is, groups which, depending on the pH of the solution in which they are found, can be electrically neutral or charged. For these drugs, the partition coefficient is also dependent on the pH of the environment and the pKA of the reactive groups. The diffusion of drugs follows Fick's law, so a drug with an adequate partition coefficient can diffuse through cell membranes (Krämer, Lombardi, Primorac, Thomae, & Wunderli-Allenspach, 2009 ). The laws governing the diffusion between two compartments sepa- Knowledge of this physiological mechanism could be useful in the review of possible molecules with low pharmacodynamic specificity toward the virus but with a high tropism for pulmonary elimination. The site of action in this case becomes the first element of pharmacological advantage over the aetiopathological agent. Pulmonary elimination is inversely proportional to the blood solubility of a molecule. Other chemical characteristics, such as vapor pressure and molecular dimension, increase lung clearance via exhalation: higher lipophilic properties, higher vapor pressure, and lower molecular weight contribute to easier elimination through exhalation. The main classes of volatile organic compounds exhalated by the lungs can be summarized as saturated (ethane, pentane and aldehydes) and unsaturated hydrocarbons (isoprene), and oxygen-(acetone), sulfur-(ethyl mercaptan and dimethyl sulphide) and nitrogen-(dimethylamine, ammonia) containing compounds (Dent, Sutedja, & Zimmerman, 2013) . The pharmacokinetic pathway of lung elimination is known, for example, for chloral hydrate a highly lipophilic and small molecule used as sedative. This drug is now used only in a few cases due to its narrow therapeutic index, but it had been preferred in the pediatric population for its easy oral administration and short half-life ( The chemical-physical properties of eucalyptol (1,8-cineole) allow significant concentrations to be achieved in the lungs through pulmonary exhalation. In addition, taking note of its characterized kinetics of pulmonary elimination and according to Fick's law, the time of persistence should also be sufficient for eucalyptol to perform a considerable pharmacological action. Furthermore, due to the negligible side effects, the risk/benefit ratio suggests that its pharmacological effects are worth testing. Eucalyptol ( Figure 1 ) is a natural saturated bicyclic monoterpenoid that is extracted from various species of Eucalyptus (e.g., Eucalyptus globulus Labill., Eucalyptus polybractea R.T. Baker and Eucalyptus smithii R.T. Baker, Fam. Myrtaceae). The essential oil of eucalyptus contains not less than 70% of eucalyptol as reported in Ph. Eur. 10th ed. Pure eucalyptol is a clear liquid at room temperature, and the melting point is 1.5 C with a flash point of 49 C (Prasanthi & Lakshmi, 2012) . Eucalyptus essential oil appears in almost all European national pharmacopeias and is traditionally used as a mucolytic, as an antiseptic and to treat asthma, fever, flu, bronchitis and whooping cough. EMA indicates its traditional use of this essential oil as a treatment for the cough associated with a cold. In Germany, 1,8-cineole is a licensed medicinal product formulated in gut soluble capsules containing 100 mg/capsule and is indicated for acute and chronic bronchitis, sinusitis, and respiratory infections. In vitro studies have underlined the pharmacology of eucalyptol as a bronchodilator, in enhancing the activity of mucociliary cells with a corresponding effect on clearance and in decreasing mucus production (Galan, Ezeudu, Garcia, Geronimo, et al., 2020) . In vitro investigation has shown up to a 92% inhibition of the release of proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1b) by lipopolysaccharide (LPS)-stimulated monocytes treated with 1.5 μg/ml of eucalyptol (Juergens, Dethlefsen, Steinkamp, Gillissen, et al., 2003) . Another study reported eucalyptol extract significantly to inhibit the nuclear factor (NF)-κB p65 gene promoter in LPS-stimulated human cell lines resulting in a decrease in inflammation compared to that of the control (Greiner, Müller, Zeuner, Hauser, et al., 2013) . Another in vitro study has showed an antiviral response stimulation of 1,8-cineole in human stem cells both by increasing activity of antiviral transcription factor interferon regulatory factor 3 and by reducing proinflammatory NF-κB activity (Müller et al., 2016 ). An interesting experiment was conducted analyzing human blood of asthmatic patients and healthy subjects, both pretreated with 200 mg eucalyptol thrice daily for 3 days, ex vivo. Up to 40.1% inhibition of LTB4 and PGE2 from monocytes from asthmatic patients (n = 10) and up to 57.9% inhibition of those from healthy subjects (n = 12) have been reported ex vivo (Juergens, Stöber, Schmidt- Kleuver, et al., 1999) . A placebo-controlled clinical trial analyzing 242 patients with acute bronchitis has measured the effect of 200 mg eucalyptol thrice daily for 10 day on the "Bronchitis-Sum-Score" bronchitis endpoint on day fourth and 10th. The group treated with eucalyptol showed a significant reduction in the score compared to that of the placebo group (3.55 vs. 2.91) on day 4, but no significant differences were reported on day 10 (Fischer & Dethlefsen, 2013a , 2013b . A double-blind placebo-controlled trial has considered glucocorticosteroid reduction endpoints for 32 asthmatic patients given 200 mg of eucalyptol, or placebo, thrice daily for 12 weeks. The results demonstrated a significant reduction of glucocorticosteroid medication in the treatment group, even when the use of salbutamol was doubled in this group, compared to the baseline condition, but the score of dyspnea was significantly greater in the placebo arm (Juergens et al., 2003) . Assumption of same dosage of eucalyptol for 6 months has been tested as an adjunctive therapy in a more recent multicenter placebo- pnea, and quality of life, improved without reaching significance (Worth, Schacher, & Dethlefsen, 2009 ). Data from a COPD experimental animal model exposed to cigarette smoke have highlighted normal lung parenchyma and significantly less leukocyte infiltration by 40-50% in mice treated with 3 and 10 mg/kg eucalyptol compared to placebo. In the same study, the eucalyptol group showed a significant 60% reduction in myeloperoxidase activity and 50 and 40% decreases in IL-1β and interleukin-6 (IL-6) expression, respectively; TNF-α levels were reduced by 80% in the higher dosage group. In addition to the anti-inflammatory effect, a predictable disinfectant effect in reducing bacterial colonies was also measured in this experimental COPD model of mice treated with 260 mg of eucalyptol per day (Yu, Sun, Su, He, et al., 2019) . In vitro antiviral activity of nebulized eucalyptol essential oil has been explored by Usachev, Pyankov, Usacheva, and Agranovski ( assay (Astani, Reichling, & Schnitzler, 2010) . A similar in vitro investigation confirmed the antiviral activity against the infectious bronchitis virus (IBV) with an antiviral IC 50 equal to about a sixth of the maximum nonlethal dose (Yang et al., 2010) . and IFN-γ) expression in lung have been reported (Lay et al., 2017) . A small number of both in vivo and in vitro pharmacokinetic studies have considered oral administration. In a rabbit model given 200 mg/kg of eucalyptol, a peak plasma concentration was reached after 1 hr (Bhowal & Gopal, 2015) . The oxidative metabolic pathway of eucalyptol produces 2-hydroxy-1,8-cineole and 3-hydroxy-1,8-cineole, conjugated to glucuronide products. It has been reported that chronic administration of 800 mg/day does not imply accumulation (Juergens et al., 2003) . By extrapolation from data on other monoterpenes with similar chemical structures, it could be supposed that lung elimination of the unchanged form of eucalyptol could range from 1 to 10% in the expired air (Kohlert, van Rensen, März, Schindler, et al., 2000) . However, in an interesting and unconventional way, an association with a macrolide such as clarithromycin or with pharma- The novel SARS-CoV-2 infection is straining global health systems. The massive spread of the virus is requiring new response paradigms from the scientific community. The first step of the pharmacological strategy was to consider molecules already on the market for a reasoned use in the treatment of viral pneumonia COVID-19 (Li & De Clercq, 2020) . As a consequence, most of the antiviral drugs currently registered in clinical trials are medicines with other indications, but which can potentially benefit patients affected by COVID-19 (Caputo et al., 2020) . Based on clinical experience from SARS and MERS, and considering the characteristic of this single-stranded RNA beta-coronavirus, a number of antiviral nucleoside analogue drugs, such as favipiravir, which selectively inhibits viral RNA-dependent RNA polymerase, or ritonavir, a protease inhibitor used against the hepatitis C virus, are currently in trials (Gul, Htun, Shaukat, Imran, & Khan, 2020) . Remdesevir has just received a recommendation from the EMA's human medicines committee (CHMP) for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen. Other specific antiviral drugs are being analyzed in order to find a specific pharmacological response to this pandemic (Li & De Clercq, 2020) . Alongside this approach, some nonspecific pharmacological strategies with secondary mechanisms of action against the virus have been considered, such as the immune modulator chloroquine (Touret & de Lamballerie, 2020) . This strategy has shown promising in vivo and in vitro data and some clinical evidence, the latest reported by Gao, Tian, and Yang (2020) describing the superiority of chloroquine over the control group in a Chinese clinical trial. However, now a series of tests is not confirming these preliminary data (Molina, Delaugerre, Le Goff, et al., 2020) and clinical trials with this drug have been temporarily stopped and resumed (WHO, 2020a (WHO, , 2020b Lungs are the target organ of COVID-19 disease and the virus load in the pulmonary airways promotes person-to-person contagion. Here, the possibility of a nonspecific pharmacological effect focused on the pulmonary site of action has been discussed, with the aim of finding new therapeutic approaches (Geller, Varbanov, & Duval, 2012) . In addition to pharmaceutical aerosols targeting drugs to the lower respiratory tract, here the possibility of exploiting the pulmonary elimination mechanism to concentrate orally administrated molecules with (Usachev et al., 2013) , confirming the antiviral properties already described (Astani et al., 2010; Yang et al., 2010) . Furthermore, its anti-inflammatory effect in the lung has been well characterized, and specific clinical trials of its traditional use by oral intake have highlighted its efficacy and safety in asthmatic patients. The pharmacological characteristics of this monoterpene could make it a candidate to test for the treatment of COVID-19, and its use as a prophylactic or when the viral load is particularly low is also hypothesized. The easy oral administration and the pulmonary elimination of this substance which can exert its loco potential virucidal effect already highlighted in vitro and in vivo, makes this molecule an interesting candidate for a clinical trial (Sharifi-Rad, Salehi, Schnitzler, et al., 2017) . The pharmacological action seems not to be specific toward a viral molecular target, but through a direct virucidal nonspecific mechanism of action. This also makes it a candidate as a direct antiviral for SARS-Cov-2 in which research is utterly delineating specific molecular targets for drug development. It could be asserted that possible pharmacological strategy could be given by a nonspecific but localized therapy in the lungs, contrary to the current research approach that is looking for specificity and a systemic response (McHugh, 2020) . Another point of view is to consider the volatile molecule particularly useful as antiviral prophylaxis, where the viral load is particularly low. This last is the case of asymptomatic virus transmitters which represents a major obstacle to the containment strategy (Gao, Xu, Sun, et al., 2020; Park, Cornforth, Dushoff, & Weitz, 2020; Rothe, Schunk, Sothmann, et al., 2020; Zhou, Li, Chen, et al., 2020) , as demonstrated by the case-study of COVID-19 epidemic in the municipality of Vo', Italy (Lavezzo et al., 2020) . It has been reported that asymptomatic persons play a crucial role in the transmission and diffusion of SARS-Cov-2 (Gandhi et al., 2020). Some authors have explored the possibility of therapy for asymptomatic COVID-19 infection patients and hydroxychloroquine is proposed as prophylaxis (D'Cruz, 2020; Lother, Abassi, Agostinis, et al., 2020) . The treatment in asymptomatic cases leaves numerous new openings on possible preventive drug therapy effective in deactivating the virus and stopping the contagion by transmitters that show no symptoms. Measuring prophylactic antiviral capacity in this case would open new ways of taking the drug by limiting it to an occasional and noncontinuous frequency depending on the results of the possible virucidal ability of the drug, given the long latency of SARS-Cov-2 (Lauer, Grantz, Bi, et al., 2020; Liu, Magal, Seydi, & Webb, 2020) . The latency of SARS-Cov-2 virus allows an initial therapeutic window in which the low viral load may not require drugs with full systemic but partial antiviral action specific for the respiratory tract. The importance of identifying molecules with oral absorption but pulmonary elimination would allow easier administration and greater compliance than inhaled drug (Fabbri, Piattella, Caramori, & Ciaccia, 1996; Kallstrom, 2004; Shahiwala, 2011) . Therefore, specific studies are required to measure the pharmacokinetic of this approach. A further advantage is given by the great flexibility of 1,8-cineole, which can be proposed as virucidal both by inhalation or spray for the upper respiratory tract in order to avoid the spread of the virus, and orally for the lower respiratory tract in order to avoid the beginning of the pathogenesis of COVID. In fact, an aspect of transmission by asymptomatic person is the high viral load shedding in the upper respiratory tract and nasal cavity that spreads through the respiratory droplets (Wölfel, Corman, Guggemos, et al., 2020) . Another point to consider is the great availability of different monoterpenes with similar characteristics that can be taken into consideration in a more detailed scientific analysis and for subsequent use in therapy. The use of these molecules as a starting point for the synthesis of new compounds could be advantageous; however, 1,8cineole is supported by EMA monograph which makes it a candidate ready for use if it proves to be effective. The use of naturally derived substances in this particular emergency situation is also reflected in recent clinical trials that focus on a possible role of traditional Chinese medicine (TCM) in support of standard therapy. Some Chinese guidelines have described the use of traditional herbal medicine for prophylactic purposes (Jin, Cai, Cheng, Cheng, et al., 2020) . Furthermore, the recent precious gift made by the People's Republic of China to Italy as emergency support contained TCM products (Ansa, 2020). A possible antiviral strategy can focus specifically on the respiratory tract, sacrificing the molecule for a chemical characteristic of volatility instead of a specific antiviral molecular activity, however, with virucidal activity even if nonspecific. Volatile molecule can be exhaled by the lungs promoting a local pharmacological action. Searching for possible antiviral molecules has highlighted possible candidates among monoterpene molecules with virucidal action. Aiming to search for molecules with nonspecific action allows to bypass possible changes of viral molecular targets that may develop in the future (Dawood, 2020) . In light of the above, it is clear that trials on small volatile molecules with antiviral characteristics could lead to positive results. These can be expected both from a prophylaxis and in slowing down and/or inhibiting the progression of the disease (against the virus) from the initial stages to the more severe phases in association with other therapies (Table 3) . This perspective is reinforced by the negligible side effects and, therefore, the positive risk/benefit ratio. A suggested approach could be to start with the already characterized volatile compounds from the points of view of safety and known effectiveness against viruses, for example, 1,8-cineole. In conclusion, a deeper clinical investigation could be reasonable but also greater pharmacological research aimed at identifying nontoxic formulation with volatile and nonspecific antiviral characteristics. The author wishes to thank Dr. E. Aiello for valuable suggestions and language input in preparation of the manuscript. 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International Journal of Infectious Diseases How to cite this article: Colalto C. Volatile molecules for COVID-19: A possible pharmacological strategy? The author declares no conflicts of interest. https://orcid.org/0000-0001-7386-2486