{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:41:57Z","timestamp":1789036917917,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:00:00Z","timestamp":1691539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clinic of Social and Family Medicine at the University of Crete"},{"name":"Olvos Science SA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Introduction: The need for effective therapeutic regimens for non-critically ill patients during the COVID-19 pandemic remained largely unmet. Previous work has shown that a combination of three aromatic plants\u2019 essential oils (CAPeo) (Thymbra capitata (L.) Cav., Origanum dictamnus L., Salvia fruticose Mill.) has remarkable in vitro antiviral activity. Given its properties, it was urgent to explore its potential in treating mild COVID-19 patients in primary care settings. Methods: A total of 69 adult patients were included in a clinical proof-of-concept (PoC) intervention study. Family physicians implemented the observational study in two arms (intervention group and control group) during three study periods (IG2020, n=13, IG2021\/22, n=25, and CG2021\/22, n=31). The SARS-CoV-2 infection was confirmed by real-time PCR. The CAPeo mixture was administered daily for 14 days per os in the intervention group, while the control group received usual care. Results: The PoC study found that the number and frequency of general symptoms, including general fatigue, weakness, fever, and myalgia, decreased following CAPeo administration. By Day 7, the average presence (number) of symptoms decreased in comparison with Day 1 in IG (4.7 to 1.4) as well as in CG (4.0 to 3.1), representing a significant decrease in the cumulative presence in IC (\u22123.3 vs. \u22120.9, p &lt; 0.001; \u03b72 = 0.20) on Day 7 and on Day 14 (\u22124.2 vs. \u22122.9, p = 0.027; \u03b72 = 0.08). Discussion\/Conclusions: Our findings suggest that CAPeo possesses potent antiviral activity against SARS-CoV-2 in addition t\u03bf its effect against influenza A and B and human rhinovirus HRV14 strains. The early and effective impact on alleviating key symptoms of COVID-19 may suggest this mixture can act as a complementary natural agent for patients with mild COVID-19.<\/jats:p>","DOI":"10.3390\/diseases11030105","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T10:08:59Z","timestamp":1691575739000},"page":"105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Mixture of Essential Oils from Three Cretan Aromatic Plants Inhibits SARS-CoV-2 Proliferation: A Proof-of-Concept Intervention Study in Ambulatory Patients"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-2839","authenticated-orcid":false,"given":"Christos","family":"Lionis","sequence":"first","affiliation":[{"name":"Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece"},{"name":"Department of Health, Medicine and Care, General Practice, Link\u00f6ping University, SE-581 85 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8838-7470","authenticated-orcid":false,"given":"Elena","family":"Petelos","sequence":"additional","affiliation":[{"name":"Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece"},{"name":"Department of Health Services Research, CAPHRI-Care and Public Health Research Institute, Maastricht University, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3849-3907","authenticated-orcid":false,"given":"Manolis","family":"Linardakis","sequence":"additional","affiliation":[{"name":"Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Diamantakis","sequence":"additional","affiliation":[{"name":"Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanouil","family":"Symvoulakis","sequence":"additional","affiliation":[{"name":"Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5394-8087","authenticated-orcid":false,"given":"Maria-Nefeli","family":"Karkana","sequence":"additional","affiliation":[{"name":"Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilena","family":"Kampa","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stergios A.","family":"Pirintsos","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Sciences and Technology, University of Crete, 71003 Heraklion, Greece"},{"name":"Botanical Garden, University of Crete, 71003 Rethymnon, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Sourvinos","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8370-1835","authenticated-orcid":false,"given":"Elias","family":"Castanas","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,9]]},"reference":[{"key":"ref_1","first-page":"892","article-title":"Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)","volume":"11","year":"2020","journal-title":"Trends Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1126\/science.abe2402","article-title":"Regn-Cov2 Antibodies Prevent and Treat SARS-CoV-2 Infection in Rhesus Macaques and Hamsters","volume":"6520","author":"Baum","year":"2020","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1126\/science.abd0827","article-title":"Studies in Humanized Mice and Convalescent Humans Yield a SARS-CoV-2 Antibody Cocktail","volume":"6506","author":"Hansen","year":"2020","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1056\/NEJMoa2035002","article-title":"Regn-Cov2, a Neutralizing Antibody Cocktail, in Outpatients with COVID-19","volume":"3","author":"Weinreich","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the Bnt162b2 Mrna COVID-19 Vaccine","volume":"27","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0140-6736(20)32661-1","article-title":"Safety and Efficacy of the Chadox1 Ncov-19 Vaccine (Azd1222) against SARS-CoV-2: An Interim Analysis of Four Randomised Controlled Trials in Brazil, South Africa, and the UK","volume":"10269","author":"Voysey","year":"2021","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1038\/s41467-023-40018-1","article-title":"In Vitro and in Vivo Characterization of SARS-CoV-2 Resistance to Ensitrelvir","volume":"1","author":"Kiso","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kundi, M. (2023). Vaccine Effectiveness against Delta and Omicron Variants of SARS-CoV-2. BMJ, 1111.","DOI":"10.1136\/bmj.p1111"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115503","DOI":"10.1016\/j.ejmech.2023.115503","article-title":"Bench-to-Bedside: Innovation of Small Molecule Anti-SARS-CoV-2 Drugs in China","volume":"257","author":"Yang","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bolarin, J.A., Oluwatoyosi, M.A., Orege, J.I., Ayeni, E.A., Ibrahim, Y.A., Adeyemi, S.B., Tiamiyu, B.B., Gbadegesin, L.A., Akinyemi, T.O., and Odoh, C.K. (2021). Therapeutic Drugs for SARS-CoV-2 Treatment: Current State and Perspective. Int. Immunopharmacol., 107228.","DOI":"10.1016\/j.intimp.2020.107228"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wang, M.Y., Zhao, R., Gao, L.J., Gao, X.F., Wang, D.P., and Cao, J.M. (2020). SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development. Front. Cell Infect. Microbiol., 587269.","DOI":"10.3389\/fcimb.2020.587269"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107262","DOI":"10.1016\/j.intimp.2020.107262","article-title":"Convalescent Plasma May Be a Possible Treatment for COVID-19: A Systematic Review","volume":"91","author":"Wang","year":"2021","journal-title":"Int. Immunopharmacol"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Low, Z., Lani, R., Tiong, V., Poh, C., AbuBakar, S., and Hassandarvish, P. (2023). COVID-19 Therapeutic Potential of Natural Products. Int. J. Mol. Sci., 11.","DOI":"10.20944\/preprints202305.0492.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"926507","DOI":"10.3389\/fphar.2022.926507","article-title":"Bioactive Natural Products in COVID-19 Therapy","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Karao\u011flu, \u00d6., Serhatl\u0131, M., Pelvan, E., Karadeniz, B., Demirtas, I., \u00c7ak\u0131rca, G., Sipahix, H., \u00d6zhan, Y., Karap\u0131nar, G., and Charehsaz, M. (2023). Chewable Tablet with Herbal Extracts and Propolis Arrests Wuhan and Omicron Variants of SARS-CoV-2 Virus. J. Funct. Foods, 105544.","DOI":"10.1016\/j.jff.2023.105544"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, Z., and Yang, L. (2021). Chinese Herbal Medicine: Fighting SARS-CoV-2 Infection on All Fronts. J. Ethnopharmacol., 113869.","DOI":"10.1016\/j.jep.2021.113869"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.3389\/fphar.2020.01189","article-title":"Medicinal Plants as Sources of Active Molecules against COVID-19","volume":"11","author":"Benarba","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_18","first-page":"811","article-title":"Lessons for the Global Primary Care Response to COVID-19: A Rapid Review of Evidence from Past Epidemics","volume":"6","author":"Desborough","year":"2021","journal-title":"Fam. Pract."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"522213","DOI":"10.3389\/fphar.2020.522213","article-title":"The Therapeutic Potential of the Essential Oil of Thymbra capitata (L.) Cav., Origanum dictamnus L. and Salvia fruticosa Mill. and a Case of Plant-Based Pharmaceutical Development","volume":"11","author":"Pirintsos","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Anastasaki, M., Bertsias, A., Pirintsos, S.A., Castanas, E., and Lionis, C. (2017). Post-Market Outcome of an Extract of Traditional Cretan Herbs on Upper Respiratory Tract Infections: A Pragmatic, Prospective Observational Study. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-017-1978-7"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jep.2015.01.030","article-title":"Reporting Effectiveness of an Extract of Three Traditional Cretan Herbs on Upper Respiratory Tract Infection: Results from a Double-Blind Randomized Controlled Trial","volume":"163","author":"Duijker","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100288","DOI":"10.1016\/j.hermed.2019.100288","article-title":"Antiviral Effect of an Essential Oil Combination Derived from Three Aromatic Plants (Coridothymus capitatus (L.) Rchb. F., Origanum dictamnus L. And Salvia Fruticosa Mill.) against Viruses Causing Infections of the Upper Respiratory Tract","volume":"17\u201318","author":"Tseliou","year":"2019","journal-title":"J. Herb. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pirintsos, S., Panagiotopoulos, A., Bariotakis, M., Daskalakis, V., Lionis, C., Sourvinos, G., Karakasiliotis, I., Kampa, M., and Castanas, E. (2022). From Traditional Ethnopharmacology to Modern Natural Drug Discovery: A Methodology Discussion and Specific Examples. Molecules, 13.","DOI":"10.3390\/molecules27134060"},{"key":"ref_24","unstructured":"(2022, March 01). National Organization of Public Health. COVID-19, Weekly Surveillance Reports from August 2020 until February 2022, Available online: https:\/\/www.health.nsw.gov.au\/Infectious\/covid-19\/Pages\/weekly-reports-archive.aspx."},{"key":"ref_25","unstructured":"WHO (2022, March 01). Tracking SARS-CoV-2 Variants. Available online: https:\/\/www.who.int\/en\/activities\/tracking-SARS-CoV-2-variants\/."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"133681","DOI":"10.1016\/j.scitotenv.2019.133681","article-title":"From Wild Harvest Towards Precision Agriculture: Use of Ecological Niche Modelling to Direct Potential Cultivation of Wild Medicinal Plants in Crete","volume":"694","author":"Bariotakis","year":"2019","journal-title":"Sci. Total Environ."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"230s","DOI":"10.1093\/ajcn\/81.1.230S","article-title":"Bioavailability and Bioefficacy of Polyphenols in Humans. I. Review of 97 Bioavailability Studies","volume":"81","author":"Manach","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S0753-3322(02)00205-6","article-title":"Absorption and Metabolism of Polyphenols in the Gut and Impact on Health","volume":"6","author":"Scalbert","year":"2002","journal-title":"Biomed. Pharmacother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1038\/s41562-020-00944-2","article-title":"Population-Scale Longitudinal Mapping of COVID-19 Symptoms, Behaviour and Testing","volume":"9","author":"Allen","year":"2020","journal-title":"Nat. Hum. Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/joim.13089","article-title":"Clinical and Epidemiological Characteristics of 1420 European Patients with Mild-to-Moderate Coronavirus Disease 2019","volume":"3","author":"Lechien","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"993","DOI":"10.15585\/mmwr.mm6930e1","article-title":"Symptom Duration and Risk Factors for Delayed Return to Usual Health among Outpatients with COVID-19 in a Multistate Health Care Systems Network\u2014United States, March\u2013June 2020","volume":"30","author":"Tenforde","year":"2020","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100141","DOI":"10.1016\/j.metop.2021.100141","article-title":"Herbal Medicine Use for the Management of COVID-19: A Review Article","volume":"12","author":"Demeke","year":"2021","journal-title":"Metab. Open"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wernhart, S., F\u00f6rster, T.H., and Weihe, E. (2020). Outpatient Management of Oligosymptomatic Patients with Respiratory Infection in the Era of SARS-CoV-2: Experience from Rural German General Practitioners. BMC Infect. Dis., 1.","DOI":"10.1186\/s12879-020-05538-x"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"577","DOI":"10.7326\/M20-0504","article-title":"The Incubation Period of Coronavirus Disease 2019 (COVID-19) from Publicly Reported Confirmed Cases: Estimation and Application","volume":"9","author":"Lauer","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e00798","DOI":"10.1002\/prp2.798","article-title":"P-Cymene Impairs SARS-CoV-2 and Influenza a (H1n1) Viral Replication: In Silico Predicted Interaction with SARS-CoV-2 Nucleocapsid Protein and H1n1 Nucleoprotein","volume":"4","author":"Panagiotopoulos","year":"2021","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_36","first-page":"2001483","article-title":"Duration of Infectiousness and Correlation with Rt-Pcr Cycle Threshold Values in Cases of COVID-19, England, January to May 2020","volume":"32","author":"Singanayagam","year":"2020","journal-title":"Eurosurveillance"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10124","DOI":"10.1038\/s41598-021-89545-1","article-title":"COVID-19\u2019s Natural Course among Ambulatory Monitored Outpatients","volume":"1","author":"Weinbergerova","year":"2021","journal-title":"Sci. Rep."}],"container-title":["Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-9721\/11\/3\/105\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:29:48Z","timestamp":1760128188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-9721\/11\/3\/105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,9]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["diseases11030105"],"URL":"https:\/\/doi.org\/10.3390\/diseases11030105","relation":{},"ISSN":["2079-9721"],"issn-type":[{"value":"2079-9721","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,9]]}}}