Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. h eeeauersiaoysnrm ooaiu SR-o)aesnl-taddpstv-es RNA positive-sense single-stranded are (SARS-CoV) coronavirus syndrome respiratory acute severe The ACE: 2; effect. Introduction serine Cytopathic Activator protease CPE: Transmembrane and Enzyme; Mitogen-Activated Transducer Converting TMPRSS2: MAPK: Angiotensin Signal dysplasia; STAT: ACE: 3; bronchopulmonary Oxygenation; receptor BPD: Membrane Transcription; NOD-like Extracorporeal of adenosine NLRP3: Cyclic ECMO: A; cAMP: Kinase; Factor; Kinase Protein Stimulating Protein Colony PKA: Granulocyte GCSF: 3’,5’-monophosphate; Factor; NF- HDAC: in- receptor; Growth Toll-like 1; IL: Metalloproteinase; TLR: Endothelial Protein Matrix Interferon; Phospholipid; cular Chemoattractant Oxidized MMP: IFN: OxPL: Monocyte lipopolysaccharide; Injury; Species; LPS: Oxygen Lung MCP-1: Reactive Acute 10; ROS: failure; deacetylase; ALI: Protein Heart histone Interferon-inducible Prematurity; Chronic CHF: of IP-10: Factor; Apnea terleukin; Necrosis AOP: Tumour TNF: phosphodiesterase; Syndrome; PDE: Distress Respiratory Acute ARDS: potential speculation. a this as confirm Abbreviations use to future required aforementioned for are considerations the studies of with glimpse clinical Along a additional well. However, offer evidence caffeine as treatment. and of diseases COVID-19 pentoxifylline shreds virus-related to efficiently both adjuvant significant against profiles, also caffeine are safety COVID-19 caffeine and high There in pentoxifylline and and analgesic. evidences outcomes of oxygenation, effective clinical properties tissue an the better and and proved for that disease, microcirculation beneficial cardiovascular improves be reduces apnea flow, may well-known (TNF- microcirculation, treat this Factor blood are improves to and Necrosis caffeine enhances decades diseases, Tumor Pentoxifylline and for pulmonary suppress pentoxifylline in use to patients. Both cytokines shown clinical inflammatory already in function. have other been respiratory that as improve has molecules and caffeine anti-oxidative infants and and preterm ARDS anti-inflammatory of in (AOP) symptoms pentoxifylline like multi-organ prematurity the Drugs and of of response. (ARDS), improvement immune for syndrome exaggerated shown pathogenesis distress the suppressing by respiratory already COVID-19 storm acute in have cytokine / patients. and of role oxidation, (ALI) COVID-19 role possible inflammation, injury excessive of potential lung the are management acute failures the Having the pneumonia, discusses severe COVID-19. in review like caffeine for features this clinical treatment and clinical symptoms, pentoxifylline specific multiple respiratory like of Despite improving drugs lack and methylxanthine treatment. a antiviral for still modulation, drugs is immune effective there inflammation, identify agents, to different challenge using unprecedented trials an presents pandemic COVID-19 Abstract 2020 22, May (ASTAR) Research 2 1 of Monji Faezeh case storm the the as in caffeine and port Pentoxifylline any COVID-19 of to review adjuvant A an treatment: as methylxanthines of role Potential nttt fMlclradCl ilg IC) gnyfrSine ehooyand Technology Science, for Agency (IMCB), Biology Cell University and Azad Molecular Islamic of Sciences, Institute Medical Tehran Pharmacy, of Faculty 1 ba Siddiquee Abrar , 2 n asa Hashemian Farshad and , 1 κ :NcerFco ap ;VG:Vas- VEGF: B; kappa Factor Nuclear B: 1 α swell as ) Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. rnhdltr ffc i hshdetrs PE niiin n dnsn eetratgns (Sullivan its antagonism disease, receptor respiratory adenosine of and by treatment inhibition, the and (PDE) in caffeine immunomodulation phosphodiesterase of Moreover, via by effects effect the lesions 2018). bronchodilatory established fibrotic III extensively has Murgia treat al. research et and Previous to 2017). (Whitfield Zito demonstrated al. (severe) 2016; et been hepatitis (Wen Bignamini has alcoholic inflammation and of pentoxifylline Harris reducing (Coccheri management 1988; of off-label the effect al. ulcer for the et used leg (Hsu also venous oxygenation is and Pentoxifylline tissue 1985). 2009) treat Aviado and 2017). to and microcirculation approved (Dettelbach al. improves limbs dose- been et the pentoxifylline has a of patients, pentoxifylline disease in ameliorat- these action, arterial activity occlusive of and In chronic mode hemorheological viscosity to aforementioned due produced blood the claudication pentoxifylline intermittent decreasing on by Based of flow Administration manner. dependent blood flexibility. enhance 2009). erythrocyte metabolites al. ing et active (Shaw its the (CHF) and failure including Pentoxifylline heart properties chronic immunomodulatory of have syndrome to the (TNF) derivative xanthine Factor in documented al. produced in Necrosis widely commercially et Tumour the used been of (Batterman and 2009) downregulation been has diseases cardiovascular al. pentoxifylline have et 1990), like Kimura theobromine Newhouse 2005; drug and and al. (Lam et (HAYASHI theophylline, example, cancer diseases For 1959), caffeine, respiratory scopes. like of for medical of treatment different used methylxanthines in widely comprising the occurring benefits been xanthine have therapeutic naturally Methylxanthines proven of with the 2012). derivatives decades, al. for methylated et purposes (Talik are therapeutic rings imidazole that and COVID-19 pyrimidinedione compounds for coupled treatment heterocyclic specific of are can lack Methylxanthines therapies evident but aforementioned an outcomes, still the 2020). is clinical of convalescent there al. improved range as COVID-19, a et also well tackle Although (Huang patients, to as COVID-19 strategy effect. 2020), near-term observed ill a al. the severely be justify et in to limited (Xu 2020) data a Tocilizumab clinical in al. 2020). inadequate only et but al. (Duan benefits et therapy et clinical (Gautret Gautret plasma potential patients 2020; showed COVID-19 al. hydroxychloroquine of et with effects number (Gao azithromycin hydroxychloroquine side and chloroquine, adverse However, 2020) the 2020a). al. to al. due et terminated (Cao data, improvement was aforementioned any remdesivir the website). of to WHO 2020; controversy trial COVID-19 from reported in clinical al. report improvement WHO COVID-19 et recently, clinical (Al-Tawfiq very full 68% However, suggested a showed ribavirin 2020). study been and but remdesivir has al. ), compassionate-use (GS-5734) et a (ChiCTR2000029387 (Grein Remdesivir and patients patients 2020b) 2016). et COVID-19 (Wang al. al. on (T-705) et et evaluated Favipiravir Cao (Zumla been needed. effects have urgently side in ribavirin is reported trunk that and pandemic 2020). 2020b) noted COVID-19 Recalcati body 2020; the been the al. 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More ICU of acute manifestations et consciousness COVID-19 number 2020), (Doyen in and 2020b). the myocarditis complications paresthesia, thrombotic and al. as al. headache, 2020), et time Ruan et as (Ye with 2020; (Wu al. such encephalitis, However, well symptoms including al. as neurological 2020a). 19, et reported few (Huang were al. world, death disorders et the and Wang across failure, 2020a; increase pneumonia, multi-organ severe (ARDS), to al. illness syndrome tract nowet respiratory 2020). the distress self-limiting is of al. includes respiratory disease COVID-19 portion et for acute Zhu This large symptoms 2020; of a range Normile affecting 2020). full and globally, The (Cohen spread al. world SARS-CoV-2 has et as the that December known across (Huang 2) now In population coronavirus China coronavirus novel human 2007). Wuhan, syndrome the by respiratory al. in caused acute et emerged (COVID-19) (severe (Cheng 2019 cases disease individuals coronavirus pneumonia affected as of the known to cluster diseases a respiratory 2019, severe cause that viruses nadto,lpnvrrtnvrteteto OI-9ptet i o show not did patients COVID-19 on treatment lopinavir–ritonavir addition, In α otetteijroseet u oimn activation immune to due effects injurious the treat to 2 (unpublished Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. al(ulvne l 94.Ee ic,mtyxnhnshv enecetyue hrpuial for therapeutically used efficiently been have (which methylxanthines eosinophils since, EG2+ Ever in eventually decrease Ali 1994). were significant methylxanthines 1987; bronchial a the diseases. of (Pauwels al. in showed respiratory lymphocytes properties pigs et CD4+ that anti-inflammatory of (Sullivan guinea reduction studies The asthma), wall and clinical during inflammation 1993). airway rabbits, of decreased to series rats, al. correlates a like et in species Manzini shown have established several 1992; Methylxanthines in 2011). al. (Tilley inflammations et transport mucociliary allergic deacetylase on lower histone effect the its to of of via induction inhibition also via include expression and which activity, gene humans airway(HDAC) mechanisms, proinflammatory in and of additional lung hyperresponsiveness reduction via airway activation, asthmatic effect reducing cell therapies for their immune and used exert prescribed obstruction commonly also airflow drugs Methylxanthines the the of reversing of inflammation. class in one role unique their as a of used are because Methylxanthines and on stimulants asthma. therapies respiratory bronchial the as for focusing known COVID- that by well all hypothesized achieved are in be Methylxanthines be feature potentially conceivably major may features. a could progression inflammation disease be it disease the major to of of Hence, these seemed mitigation amplifying function potential and diseases. immune patients, a repressed lung cases, 19 and induced both inflammation, In mono- CoV storm, cytokine 2016). inflammatory the cytokine the al. underlying the models, et involved decreasing expression Channappanavar disease is Furthermore, 2010; increased SARS by al. In 2016). et accompanied IFN- (Smits the was 2020). of al. (ALI) ablation et Injury or al. (Channappanavar cytes/macrophages Lung et genes Acute (Huang inflammatory in disease pathology of and the disease IL-10 of associated IL-9, IL-8, progression storm IL-7, the IL-4, showed to also patients and contribute COVID-19 (MCP-1), (TNF) from 1 Factor blood protein Necrosis of chemoattractant Tumour analysis monocyte Further (IP-10), 2020). 1 10 al. interleukin well protein et including as COVID- factors, (Chen hypo-albuminemia, inflammatory about cells of publications neutropenia, underlying T levels early primary lymphopenia, high CD8+ very by the in the followed of decrease of system one a One immune is as coro- 2020). suppressed condition al. with this a et studies; associated reported (Mehta of 19 pathology aggravation variety in disease a the storm” from of ”cytokine established mechanism well by now played is role purpose It critical naviruses. therapeutic the for disease. recognizes use arterial research methylxanthines peripheral Existing of with patients potential their in and exploiting pentoxifylline pathogenesis by of to COVID-19 symptoms doses shown respiratory been therapeutic also induced by have COVID-19 increased levels pentoxifylline oxygen treat significantly and Tissue to be potentials. caffeine therapy anti-inflammatory like adjuvant and methylxanthines 2010), 1992). immunomodulatory an used (Lara al. reported as widely et disorder 2008). used that (Bruce anxiety Wit evidence be caffeine to extensive de may to lead with and OTC sensitive may review (Childs more the we caffeine are to fatigue Besides, Herein, of adjuvant disorder during 2017). doses anxiety an wakefulness al. high an As or et caffeine, with headaches. seizure alertness patients of (Lipton treating maintain and mental headache benefits in to restore numerous treat role stimulant to the to its CNS is Despite as analgesics the al. well caffeine of as et of as efficacy 2018) (Bøhn labeling the role al. stroke enhances its et and in it include disease Koert 2002), (AOP) analgesics, (van also heart prematurity al. epilepsy coronary caffeine of during et reduced of control apnea (Okuno to indications humans neural treat related Therapeutic in and was to microcirculation 2012). function, consumption used improved muscle caffeine widely also respiratory moderate sensitivity, is administration and CO2 Caffeine caffeine ventilation, Furthermore, drive. minute respiratory improving 2011). by Tilley infants 1994; preterm al. et α n vrrdcino hs namtr yoie n hmknsmay chemokines and cytokines inflammatory these of overproduction and α/β eetrrsle nicesdsria ftecrnvrshost coronavirus the of survival increased in resulted receptor 3 β (IL-1 β ,interferon ), γ (IFN- γ ,interferon-inducible ), Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. iue2. Figure ARDS: injury; lung Acute ALI: viruses. Interleukin-10. as against IL-10: and ALI syndrome, events and cardiovascular and distress enzymes in cells, respiratory anti-oxidant efficacy pulmonary immune Acute as pen- IL-10, well proinflammatory by macrophages, as prevented anti-inflammatory cytokines, exchange on be gas inflammatory effect potentially stimulatory on can its effect which as COVID-19well inhibitory disorders in organ its resulting multiple invasion via SARS-CoV-2 and toxifylline the sepsis after ALI/ARDS, results like storm cytokine symptoms that postulated We festations. 1. 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Sprague neutrophil The anti-inflammatory in (NF- cytokine-induced tent and B 2003). suppressed kappa proinflammatory pentoxifylline al. factor by that nuclear et driven demonstrated (Tong mainly al. study al. is et another et (Poulakis which lavage Tong sarcoidosis, bronchoalveolar by TNF- in for reported suppressed and indication pentoxifylline also significant Sibille an that was a cate with finding elicited 1990; patients pentoxifylline This (Kelley from that diseases isolated 1999). shown monocytes pulmonary been has blood TNF- inflammatory it of eral of production literature, TNF- the prognosis the as in with such the reduction Consistent cytokines in inflammatory 1990). role release Reynolds important macrophages alveolar an that plays 2020). reported have al. studies et Prior (Huang responses cell IL-1 (Th1) of T-helper-1 amounts activated Pentoxifylline: high an the also towards further of and points levels was IL-9 heightened probably speculation IL-8, with which IL-7, This patients MCP-1, IL-4, COVID-19 patients. IL-2, in to COVID-19 like observed in due cytokines response involved proinflammatory hypoxia, inflammatory (ICUs) be speculate severe units including to we the Accordingly, care likely by inflammation, intensive is 2011). supported Ward the oxidation in and excessive to treated (Sarma SARS-CoV-2 similar infection contribute are distress viral that with factors ALI/ARDS and respiratory infected cytokines of Several acute like cases patients severe mediators by inflammatory severe inflammation. SARS-CoV, COVID-19 caused with OxPLs to severe for Patients was of due have challenge ALI production ALI 2020). and ongoing of induced that al. challenge SARS-CoV an shown et the the was is (Matthay to to cases it it treatment addition due and severe model, In (ARDS) response signaling the disease syndrome immune 2008). (TLR4)/NF-kB a all innate 4 al. activated the In receptor in et Toll-like the in (Imai OxPLs via 2008). of macrophages of resulting result Analysis alveolar al. a pathways formation 2008). in was et massive stress IL-6 al. (Imai of the oxidative et (ALI) overproduction (Imai showed the the injury (OxPL) infections Previously trigger phospholipid lung SARS-CoV oxidized acute can products. of in of production oxidized pathogens died local of lung humans as generation well viral of constant as that ROS the of shown with generation been associated are has general, it in infections, Viral COVID- for agent antioxidant ARDS: and prematurity, anti-inflammatory potential of 19 a Apnea as CD8+ Caffeine diseases. AOP: on and coronary Pentoxifylline dysplasia, effects and Bronchopulmonary asthma, fibrosis positive syndrome. improved BPD: reduced have distress activity, myeloperoxidase, 3, respiratory also antiviral on Acute receptor Caffeine microcirculation, effect NOD-like proinflam- stimulatory as infants. well and inflammasome, NLRP3: as in lymphocytes NLRP-3 ARDS total AOP the function, cells, and inhibit lung T BPD significantly cytotoxic as to cells, inflammation. well potential T mediated the as SARS-CoV-2 has macrophages, on also matory caffeine caffeine of effect addition, anti-inflammatory In proposed We manifestations. κ ) arxmtlortiae2(M-) M- n ylprxds con- myeloperoxidase and MMP-9 (MMP-2), metalloproteinase-2 Matrix B), α nclue el fLS-tmltdavoa arpae n periph- and macrophages alveolar -stimulated LPS of cells cultured in α rdcini oedpnetmne navoa macrophages alveolar in manner dose-dependent a in production 5 β, IFN γ, P1,and IP-10, α that Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. hr sagoigbd fltrtr htrcgie aiu ciiiso etxflieo muecells immune on pentoxifylline of activities various recognizes that literature of body 1). growing (Figure a is There immune-modulatory (Tilley have immunomodulators to as known exploited Pentoxifylline: potentially are be Methylxanthines can therefore 2020). and, IP10, concentration 2011). al. of serum et levels low high reduced (Huang at showed effects COVID-19 be ICU in of can cases severity exchange COVID-19 the severe gas TNF with and and patients GCSF, that ventilation MCP1, reported of also support was capacity care it critical the Moreover, require damage, and 2018). failure this respiratory al. to acute et develop Due (Yang may dysfunction patient endothelium vascular the increasing 2015). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. utemr,ardcini ypoye n D+pstv el nteprpea lo fCOVID-19 of cells. blood T study peripheral on same the caffeine The in caffeine of cells pre-exercise role 2005). T stimulatory with immune positive exercise al. the CD8+ after shows et and and it lymphocytes (Bishop before Therefore, in count cells 2005). reduction cell T a al. T Furthermore, CD4+CD69+ et increase CD8+ of an (Bishop in caused increase only caffeine increase role an ingestion mg/kg caffeine’s an that 6 with of and myeloperoxi- reported line dose of count also bolus In enhancement lymphocyte a the condition. that was total 2020), disease reported neutrophils in study COVID-19 of al. intriguing improve reduction et an a potentially (Liu immunomodulation, As could patients in caffeine 1995). 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Data may be preliminary. yl.Hwvr hr salc feog lncldt n ieteiec nCVD1 ainsaeytto yet are replication patients COVID-19 viral in the evidence of direct antiviral and stages potential data Pentoxifylline: different clinical a at enough as of interfering used lack studied. via a be be patients is can there infected remdesivir However, coronavirus as 2020). cycle. analogs, such the nucleoside al. lopinavir, raised inhibitors et for the (Hoffmann Neuraminidase antibody treatment like intervention inhibitors and also therapeutic protease ribavirin, for and IFN-alpha, protease target including as respiratory targets, serine such possible lower drug the drugs a the antiviral both potential be and Broad-spectrum and provide could infection kidney, 2 can SARS-CoV-2 ACE infect liver, against they the protect can the and Therefore, partly They like least TMPRSS2 organs at exocytosis. 2016). viral could of as SARS-CoV The process well al. against (Graham the as et reticulum host. through endoplasmic lymphocytes, (Tynell their released the T of tract be of including genome will lumen the cells, virions the Subsequently, adopting various into expresses enter TMPRSS2 by on 2010). virus cytoplasm, protease proteins entry Baric the entry, the accessory serine protein and its in Following by and SARS-CoV-2-S assembled 2020). blocked structural reported are al. be all nucleocapsids also et can encoding study (Ou entry endocytosis genes another by Similarly, this the mediated SARS- and mainly 2020). of is receptor, entry cells 2 293/hACE2 al. the ACE that et acid evidence the amino (Hoffmann compelling 76% on inhibitor showed about al. study share depends et et SARS-CoV-2 recent (Shulla also (Li of activation a protein CoV-2 and receptor results, SARS-2-S priming host previous entry and S-protein and the the SARS-CoV Following the 2020). tropism, of as identity. out protein tissue al. 2) carries SARS-S virus, et (ACE TMPRSS2 2011). the (Hoffmann protease 2 of al. serine cells enzyme virulence cellular target angiotensin-converting the the the uses and determining to protein 2003), in entry SARS-S component viral The essential allows an range. ) is (CoV protein coronaviruses S treatment of CoV COVID-19 protein (S) for spike symptoms. 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Data may be preliminary. 9smtm nldn eprtr alr u ohprestvt n xgeae muersos,is response, immune COVID- exaggerated of has spectrum and review anti-inflammatory, broad hypersensitivity like current properties the to therapeutic to The proven Addressing and extensively due attempts with pentoxifylline caffeine patients. failure like and the profile. 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No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. hn .F-. un . o,K-. o .K-. h,H,Yn,J,Xn,F,Lu . i,C C.-Y., C. J.-P., associated Yip, Cai, pneumonia J., D., of cluster J. Liu, familial Ip, F., A W.-M., (2020) Xing, Chan, K.-Y. K.-M., Yuen, J., and V. Yang, K.-M. Poon, H., C. K.-H., Chu, Hui, Chan, H., K.-W., K.-F., Chen, S. K. C.-C., Lo, To, V. H.-W., Cheng, K.-H., Tsoi, Kok, W.-S., R. S., coronavirus L., Qiu, Poon, Yuan, syndrome Peng, H., respiratory F.-W., of acute evidence. J., Trial Zhan, J. severe the A for Wu, J., Chan, of Remdesivir (2020a) He, S., (2020b) evaluation C. X. An Q., Luo, Wang, S. Ge, and COVID-19: Dai, S., Shang, and causing D. X., X. H., Ruan, 2 Zhang, Wu, Q. Li, X., W., Deng, S., P. Y., C., Wang, Hu, Horby, Y. Zhang, Covid-19. X., G., Cao, H., S., Severe Z., F. Liu, Huang, Lu, with Liu, Hayden, J., H., Hospitalized Z., T., J., Wang, Li, Adults Jaki, Xu, Qu, C., H., in C., X., Lopinavir–Ritonavir Chen, Jia, X., Huang, Xia, Gu, Y., J., Dong, L., X., Yuan, F., Zou, Guo, Li, X., C., Zhou, F., M., L., Li, Zhou, Wei, C., Pan, L., Y., K., Dong, F., Zhang, Cai, Y., Li, Cheng, B., X., Wei, K., Song, Xie, Y., L., Wang, T., Liu, Ruan, Bai, L., F., G., patients T., Fan, Gong, Yu, in J., S., caffeine J., Wang, Tu, of Xiang, W., effects N., Liu, Anxiogenic Chen, D., (1992) Wen, J., P. Y., G. Wang, o. B., A. Cao, 867-869. J. cardiovascular (11), M. on 49 coffee Lader, and disorders. and P. tea anxiety of Shine, with Effects N., (2012) Scott, D. M., K. Bruce, of Croft, Effect and (2005) M. J. p. (5-6), Hodgson, a. risk. 93 C., disease o. N. cycling. Ward, j. strenuous K., E. following S. J. Bohn, vivo C. in A. activation Smith, and subset and Effects and A. Bronchodilator counts G. 606-613. The Scanlon, lymphocyte (1984) J., on P. 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A. for global Al-Homoud, this A., tackle J. to Al-Tawfiq, and strategies efficacy additional their develop highlighted also review to and this studied used References from be be gained to can COVID-19. insights yet and the of are COVID-19 considered, patients manifestation in COVID-19 be safety identified in should recently caffeine effects can a and side pentoxifylline pentoxifylline possible Moreover, complications, of thrombotic patients. evidence respiratory COVID-19 of direct of in treatment Although alleviation treatment the adjuvant the an in address as effects also considered beneficial be their can as symptoms well as antiviral, immunomodulatory, antioxidant, o d&Function & Food 8() 230-233. (5), 38 rvlmdcn n netosdisease infectious and medicine Travel 6,575-591. (6), 3 eiti research Pediatric 11 lnclIfciu Diseases Infectious Clinical rvlMdIfc Dis Infect Med Travel 101615-101615. , 1() 583-589. (5), 71 101647. , 3() 748-756. (6), 43 Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. etlah .R n vao .M 18)Ciia hraooyo etxfliewt pca eeec to reference special with (2007) 8-26. pentoxifylline claudication. intermittent of R. (1), of pharmacology 25 shock. Coimbra, treatment Clinical the and (1985) hemorrhagic for effect M. P. hemorrheologic in D. Wolf, its Aviado, activity H., and R. W. factor H. (2), Loomis, Dettelbach, transcription 82 G., modulates J. Research trial. Surgical and Putnam, of (2017) controlled injury T., Journal r. randomized Campos, lung P. a J. De attenuates B. J., Pentoxifylline A. birth: Martins, Pas, at (2005) Te J., and infants Deree, v. E. preterm Lopriore, o. of S., J. R. effort J. Witlox, breathing J. J., 290-296. signaling 2058-2065. J. R. improve ATM (4), Vonderen, Pomerantz, to van an 79 and B., of cells. Caffeine M. S. nondividing utilization A. Hooper, of Skalka, and transduction J., Y., Dekker, 1 Induction type R. (2005) virus Zhao, immunodeficiency E., v. human Argyris, inhibits Caffeine o. E., Marusich, J. R., J. Daniel, L. 13007-13017. (20), T. 79 Benjamin, polyomavirus. remodeling and by tissue J. pathway in You, MMP-9 and J., MMP-2 Dahl, gelatinases of h. Role injury. agents, (2000) and lung V. acute Lagente, Coronavirus-19 r. and following by b. E. inflammation Boichot, o. lung (2). M., J. 34 and Corbel, J. S. IL-6) strategies. Kritas, anti-inflammatory and I., (IL-1 SARS-CoV-2): Frydas, or cytokines R., (COVI-19 Ross, pro-inflammatory C., of Gallenga, Induction A., (2020) Caraffa, G., Ronconi, P., Conti, Science. of (2020) Advancement D. the Normile, and J. Cohen, England. R., London, UK: (2016) Longhi, Sage A. S., Publications A. hu- Bignamini, Ruzzante, reduces and and L., S. persons. 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(1), 143 α e ASlk iu nCiatigr alarm triggers China in virus SARS-like New rdcinb odbodmncts h oeo dnsn eetr.65 receptors. adenosine of role the monocytes: blood cord by production xeietladCiia Psychopharmacology Clinical and Experimental hraooia ducsfrcrncvnu le healing ulcer venous chronic for adjuncts Pharmacological 12 Pediatrics h ora fCiia Pharmacology Clinical of Journal The 1 6,1979-87. (6), 117 mrcnAscainfor Association American . 3() 749-754. (7), 33 6() 13. (1), 16 ora of Journal SAGE . The Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. elpiigicesscoa rqece nscnaypoieaiersossadihbt apoptosis. inhibits during pentoxifylline and of responses Presence proliferative (1999) V. secondary Bal, in and Immunology frequencies M. of clonal J. Journal Durdik, increases S., priming disease, Rath, severe cell in R., with role T Sen, action, A., patients of George, mechanism for M., Inflammasomes: remdesivir Gupta, (2015) M. m. of 677. N. Green, (7), use J. P. 21 G., Compassionate J. therapeutics. Green, Ting, (2020) and and T., B. M. Feldt, J. Callaway, o. A., H., J. Guo, Castagna, E. E., N. Asperges, of J. G., mechanisms F.-X. Diaz, COVID-19. spike: Lescure, D., modular Shin, and the N., L. and Ohmagari, reservoirs, J., Recombination, Grein, (2010) S. factor R. transmission. necrosis double-blind, Baric, cross-species randomized tumor and coronavirus a of L. of levels R. results serum Graham, patients: 2023-2028. decreases hemodialysis (5), Pentoxifylline in 27 (2012) trial. protein clinical C-reactive T. controlled and D. 6 N. interleukin J. alpha, and M. G´omez-Navarro, B. A. Pe˜na-Quintero, P., Medina-P´erez, M., Cueto-Manzano, E., Rojas-Campos, and Gonz´alez-Espinoza, L., adhesion lymphocytes. inhibits T Pentoxifylline human treatment (1998) of a Mart´ınez-Mart´ınez,activation Y´a˜nez-M´o, S´anchez-Madrid, as F. M., azithromycin S., and and J. Garc´ıa-Vicu˜na, Caba˜nas, Hydroxychloroquine C. 105949. Redondo, V., (2020) M., R., trial. L., Giordanengo, a. clinical Baranda, J., a. non-randomized Portales-P´erez, D., Courjon, Gonz´alez-Amaro, o. open-label R., B., an j. Doudier, of I. M., J. results apparent T. Mailhe, shown COVID-19: H. L., of has Dupont, Meddeb, and phosphate P., E. Chloroquine V. Parola, Vieira, studies. Breakthrough: J.-C., clinical (2020) Lagier, in P., t. pneumonia Gautret, B. pentoxifylline associated COVID-19 J. of of X. Administration treatment Yang, in (2001) and efficacy Z. W. Tian, P. J., Finn, hyperresponsiveness. Gao, airway and from D. 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(1), 161 Atherosclerosis 9 (1), 196 The Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. ug . i,M . ak .H,Jog .adK,K .J .o .f 21)Clua nixdn and antioxidant Cellular (2017) f. m. o. J. J. lung. 626-635. S. the (6), K. of 20 Ko, Cytokines levels. and (1990) roasting Y. J. different Kelley, Jeong, with (3), H., extracts L., 4 J. coffee B. Park, of human Yount, effects coronavirus. H., novel anti-inflammatory with M. S., SARS infection Kim, V. to with S., response Carter, differences Jung, host P., Cell important (2013) Sova, and M. S., antivirals J. G. Agnihothram, potential e00165-13. M. Katze, predicts E., and EMC L. S. R. coronavirus dengue. Gralinski, Baric, for D., L., mistaken R. be V. Graham, and Menachery, rash L., a with Josset, present can COVID-19 (2020) Dermatol V. 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(1), 97 α, u o yteat-a nioy nmc.65 mice. in antibody, anti-Fas the by not but nentoa ora fatmcoilagents antimicrobial of journal International nesv aemedicine care Intensive 1-3. , Posted on Authorea 22 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159015270.02586731 — This a preprint and has not been peer reviewed. Data may be preliminary. e,W . e,S . in,R n o,R .J .i .(07 eupsn etxfliefrthe for pentoxifylline Repurposing (2017) t. i. A. J. Y. R. Koh, asthma. and 1245-1269. for (6), R. Caffeine 34 Siang, overview. (2010) an Y., fibrosis: J. S. of C. Lee, treatment Cates, X., W. and (2020b) Wen, E. G. Barley, Xiao, and A., W. Reviews Bara, Zhong, Systematic J., Z., Hu, vitro. E. in Z., Welsh, (2019-nCoV) Shi, coronavirus M., novel Xu, emerged recently J., Research the Liu, Cell inhibit X., 2019 effectively Yang, Disease chloroquine Coronavirus L., and follow-up. 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