{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:06:32Z","timestamp":1790208392924,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T00:00:00Z","timestamp":1576108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The pivotal role of hepatic stellate cells (HSCs) in orchestrating the bidirectional process of progression and regression of liver fibrosis makes them an ideal target for exploring new antifibrotic therapies. Essential phospholipids (EPLs), with their polyenylphosphatidylcholine (PPC) fraction, either alone or combined with other hepatoprotective substances such as silymarin, are recommended in hepatic impairment, but a scientific rationale for their use is still lacking. Herein, we compared the ability of EPLs to restore quiescent-like features in HSCs with that of dilinoleoylphosphatidylcholine (DLPC), PPC fraction\u2019s main component. Specifically, we screened at the cellular level the antifibrotic effects of PPC formulations in the presence and absence of silymarin, by using LX-2 cells (pro-fibrogenic HSCs) and by assessing the main biochemical hallmarks of the activated and deactivated states of this cell line. We also proved the formulations\u2019 direct effect on the motional order of cell membranes of adherent cells. LX-2 cells, examined for lipid droplets as a quiescence marker, showed that PPCs led to a more prominent deactivation than DLPC. This result was confirmed by a reduction of collagen and \u03b1-SMA expression, and by a profound alteration in the cell membrane fluidity. PPC\u2013silymarin formulations deactivated HSCs with a significant synergistic effect. The remarkable bioactivity of PPCs in deactivating fibrogenic HSCs paves the way for the rational design of new therapeutics aimed at managing hepatic fibrosis.<\/jats:p>","DOI":"10.3390\/pharmaceutics11120676","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T11:06:41Z","timestamp":1576148801000},"page":"676","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Synergy of Phospholipid\u2014Drug Formulations Significantly Deactivates Profibrogenic Human Hepatic Stellate Cells"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3161-8746","authenticated-orcid":false,"given":"Gina","family":"Valentino","sequence":"first","affiliation":[{"name":"Institute of Pharmacy, Friedrich Schiller University Jena, Otto Schott Strasse 41, 07745 Jena, Germany"},{"name":"Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Zivko","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Friedrich Schiller University Jena, Otto Schott Strasse 41, 07745 Jena, Germany"},{"name":"Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Friedrich Schiller University Jena, Otto Schott Strasse 41, 07745 Jena, Germany"},{"name":"Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorine","family":"Br\u00fclisauer","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Friedrich Schiller University Jena, Otto Schott Strasse 41, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9664-0149","authenticated-orcid":false,"given":"Paola","family":"Luciani","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Friedrich Schiller University Jena, Otto Schott Strasse 41, 07745 Jena, Germany"},{"name":"Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0168-8278(02)00429-4","article-title":"Liver fibrosis\u2014From bench to bedside","volume":"38","author":"Friedman","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri3623","article-title":"Liver fibrosis and repair: Immune regulation of wound healing in a solid organ","volume":"14","author":"Pellicoro","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/liv.13682","article-title":"Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening","volume":"38","author":"Marcellin","year":"2018","journal-title":"Liver Int."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Byass, P. (2014). The global burden of liver disease: A challenge for methods and for public health. BMC Med., 12.","DOI":"10.1186\/s12916-014-0159-5"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.jhep.2017.07.027","article-title":"Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD","volume":"67","author":"Nasr","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mam.2018.09.002","article-title":"Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues","volume":"65","author":"Parola","year":"2019","journal-title":"Mol. Asp. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/hep.29085","article-title":"Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis","volume":"65","author":"Dulai","year":"2017","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s00535-017-1415-1","article-title":"Current and future pharmacological therapies for NAFLD\/NASH","volume":"53","author":"Sumida","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1136\/gutjnl-2014-306842","article-title":"Pathobiology of liver fibrosis: A translational success story","volume":"64","author":"Lee","year":"2015","journal-title":"Gut"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.jhep.2017.06.001","article-title":"Hepatic stellate cell activation and pro-fibrogenic signals","volume":"67","author":"Gandhi","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1152\/physrev.00013.2007","article-title":"Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver","volume":"88","author":"Friedman","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/cphy.c120035","article-title":"Hepatic Stellate Cells and Liver Fibrosis","volume":"Volume 3","author":"Puche","year":"2013","journal-title":"Comprehensive Physiology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13069-015-0031-z","article-title":"In vitro reversion of activated primary human hepatic stellate cells","volume":"8","author":"Najimi","year":"2015","journal-title":"Fibrogenes. Tissue Repair"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1016\/j.jhep.2015.02.039","article-title":"Hepatic fibrosis: Concept to treatment","volume":"62","author":"Trautwein","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1136\/gut.2004.042127","article-title":"Human hepatic stellate cell lines, LX-1 and LX-2: New tools for analysis of hepatic fibrosis","volume":"54","author":"Xu","year":"2005","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.stemcr.2018.05.017","article-title":"TGF-\u03b21 Negatively Regulates the Number and Function of Hematopoietic Stem Cells","volume":"11","author":"Wang","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lotersztajn, S., and Mallat, A. (2015). Chapter 11\u2014Hepatic Stellate Cells as Target for Reversal of Fibrosis\/Cirrhosis, Elsevier Inc.","DOI":"10.1016\/B978-0-12-800134-9.00011-7"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1055\/s-2001-17558","article-title":"Hepatic stellate cells as a target for the treatment of liver fibrosis","volume":"21","author":"Bataller","year":"2001","journal-title":"Semin. Liver Dis."},{"key":"ref_21","first-page":"105","article-title":"Essential phospholipids in fatty liver: A scientific update","volume":"9","author":"Gundermann","year":"2016","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Varganova, D.L., Pavlov, C.S., Casazza, G., Nikolova, D., and Gluud, C. (2019). Essential phospholipids for people with non-alcoholic fatty liver disease (Protocol). Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD013301"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1002\/ejlt.201400219","article-title":"The use of natural and synthetic phospholipids as pharmaceutical excipients","volume":"116","author":"Wendel","year":"2014","journal-title":"Eur. J. Lipid Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Federico, A., Dallio, M., Loguercio, C., Federico, A., Dallio, M., and Loguercio, C. (2017). Silymarin\/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules, 22.","DOI":"10.3390\/molecules22020191"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.jhep.2009.02.023","article-title":"Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells","volume":"50","author":"Trappoliere","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_26","first-page":"e40285","article-title":"Comparison of the In Vitro Antifibrogenic Effects of Silymarin, Silybin A and 18\u03b1-Glycyrrhizin on Activated Hepatic Stellate Cells","volume":"12","author":"Hosseini","year":"2016","journal-title":"Jundishapur J. Nat. Pharm. Prod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s11894-004-0027-0","article-title":"New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments","volume":"6","author":"Lieber","year":"2004","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S0016-5085(94)95023-7","article-title":"Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon","volume":"106","author":"Lieber","year":"1994","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/S0168-8278(96)80147-4","article-title":"Polyenylphosphatidylcholine attenuates non-alcoholic hepatic fibrosis and accelerates its regression","volume":"24","author":"Ma","year":"1996","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/S0168-8278(97)80361-3","article-title":"Polyenylphosphatidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis","volume":"27","author":"Aleynik","year":"1997","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.nut.2004.11.019","article-title":"Dietary phosphatidylcholine alleviates fatty liver induced by orotic acid","volume":"21","author":"Buang","year":"2005","journal-title":"Nutrition"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/hep.1840150303","article-title":"Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes","volume":"15","author":"Li","year":"1992","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S0022-2143(99)90064-1","article-title":"Dilinoleoylphosphatidylcholine decreases hepatic stellate cell activation","volume":"133","author":"Poniachik","year":"1999","journal-title":"J. Lab. Clin. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bbrc.2006.08.174","article-title":"DLPC and SAMe prevent a 1(I) collagen mRNA up-regulation in human hepatic stellate cells, whether caused by leptin or menadione","volume":"350","author":"Cao","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s00011-011-0309-6","article-title":"Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor \u03b21 are the therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation","volume":"60","author":"Ikeda","year":"2011","journal-title":"Inflamm. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1016\/j.bbamem.2017.04.013","article-title":"Membrane Lipid Replacement for chronic illnesses, aging and cancer using oral glycerolphospholipid formulations with fructooligosaccharides to restore phospholipid function in cellular membranes, organelles, cells and tissues","volume":"1859","author":"Nicolson","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1111\/j.1530-0277.1994.tb00915.x","article-title":"Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine","volume":"18","author":"Lieber","year":"1994","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.colsurfb.2018.02.023","article-title":"Study on the in situ aggregation of liposomes with negatively charged phospholipids for use as injectable depot formulation","volume":"168","author":"Rahnfeld","year":"2018","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1056\/NEJM199104043241401","article-title":"Transforming Growth Factors \u03b21 and \u03b1 in Chronic Liver Disease","volume":"324","author":"Castilla","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s40139-015-0089-8","article-title":"TGF-\u03b2 in Hepatic Stellate Cell Activation and Liver Fibrogenesis: Updated","volume":"3","author":"Dewidar","year":"2015","journal-title":"Curr. Pathobiol. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41420-018-0095-9","article-title":"Kindlin-2 regulates hepatic stellate cells activation and liver fibrogenesis","volume":"4","author":"Yu","year":"2018","journal-title":"Cell Death Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"784","DOI":"10.3748\/wjg.v9.i4.784","article-title":"Effect of transforming growth factor beta and bone morphogenetic proteins on rat hepatic stellate cell proliferation and trans-differentiation","volume":"9","author":"Shen","year":"2003","journal-title":"World J. Gastroenterol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/jcp.22063","article-title":"Downregulation of hepatic stellate cell activation by retinol and palmitate mediated by adipose differentiation-related protein (ADRP)","volume":"223","author":"Lee","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s00418-002-0462-7","article-title":"Deformation of lipid droplets in fixed samples","volume":"118","author":"Fukumoto","year":"2002","journal-title":"Histochem. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1002\/hep.1840080416","article-title":"The effect of retinol on ito cell proliferation in vitro","volume":"8","author":"Davis","year":"1988","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0168-8278(92)90160-Q","article-title":"Phenotypical modulation of liver fat-storing cells by retinoids: Influence on unstimulated and growth factor-induced cell proliferation","volume":"14","author":"Pinzani","year":"1992","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3389\/fonc.2018.00357","article-title":"Transforming growth factor-\u03b2-induced cell plasticity in liver fibrosis and hepatocarcinogenesis","volume":"8","author":"Fabregat","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.lfs.2017.03.012","article-title":"Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling","volume":"176","author":"Duan","year":"2017","journal-title":"Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Anfuso, B., Giraudi, P.J., Tiribelli, C., and Rosso, N. (2019). Silybin modulates collagen turnover in an in vitro model of NASH. Molecules, 24.","DOI":"10.3390\/molecules24071280"},{"key":"ref_50","first-page":"1","article-title":"In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A","volume":"8","author":"Hong","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1016\/S0022-2275(20)38430-3","article-title":"Effects of dietary retinoid and triglyceride on the lipid composition of rat liver stellate cells and stellate cell lipid droplets","volume":"29","author":"Moriwaki","year":"1988","journal-title":"J. Lipid Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.bbalip.2008.11.001","article-title":"Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage","volume":"1791","author":"Blaner","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.mehy.2013.04.045","article-title":"The role of retinoic acid receptors in activated hepatic stellate cells","volume":"81","author":"Mezaki","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1152\/ajpgi.00251.2017","article-title":"Hepatic stellate cells retain retinoid-laden lipid droplets after cellular transdifferentiation into activated myofibroblasts","volume":"315","author":"Jophlin","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.dld.2004.11.009","article-title":"Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation","volume":"37","author":"Carpino","year":"2005","journal-title":"Dig. Liver Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1053\/j.gastro.2012.06.036","article-title":"Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice","volume":"143","author":"Hsu","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1210\/en.2007-1713","article-title":"Minireview: Lipid Droplets in Lipogenesis and Lipolysis","volume":"149","author":"Ducharme","year":"2008","journal-title":"Endocrinology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9448","DOI":"10.1073\/pnas.1201840109","article-title":"Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis","volume":"109","author":"Kisseleva","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1016\/j.bbamem.2016.07.013","article-title":"Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study","volume":"1858","author":"Robalo","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0248-4900(02)00011-4","article-title":"Treatment of the rat hepatic stellate cell line, PAV-1, by retinol and palmitic acid leads to a convenient model to study retinoids metabolism","volume":"94","author":"Sauvant","year":"2002","journal-title":"Biol. Cell"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/12\/676\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:41:46Z","timestamp":1760190106000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/12\/676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,12]]},"references-count":60,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["pharmaceutics11120676"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11120676","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,12]]}}}