The Oral Hydroalcoholic Extract of Licorice for Management of Mild to Moderate Coronavirus Disease-19 Patients: A Double-Blind Randomized Clinical Trial
Abstract
Background: Licorice is proposed as a treatment option for coronavirus disease-19 (COVID-19) by inhibiting the virus binding, penetration and replication; it also modulates various cellular signaling pathways. In this double-blind randomized-controlled trial, efficacy of Licorice hydroalcoholic extract oral formulation has been evaluated in patients with mild–moderate COVID-19in an outpatient clinic. Methods: A total of 40 mild to moderate outpatient Covid-19cases were randomly assigned into either Licorice or placebo groups (n=20 in each). Patients in Licorice group were given 700 mg capsules of hydroalcoholic extract of Licorice, trice a day for 2 weeks, while controls were given placebo capsules that were filled with Avicel (microcrystalline cellulose). Blood samples were collected from all participants before starting the medication and on days three, seven, and 14 for laboratory parameters including quantitative C-reactive protein (CRP), WBCs, lymphocytes, and neutrophils counts. The clinical symptoms were also recorded. Results: Our results showed that Licorice extract significantly decreased the frequency of cough on day seven (P=0.004) and the frequency of dyspnea on day three (P=0.02). No significant differences were found in the frequency of nausea, diarrhea, body pain, sore throat, runny nose, dizziness, lethargy, and loss of taste or smell between the two groups. Patients in Licorice group showed significantly higher oxygen saturations on days three, seven, and 14. Other laboratory parameters did not show any changes between the two groups. Conclusion: licorice extract improved some clinical symptoms such as cough and dyspnea while only increased the oxygen saturation. Further studies with larger sample sizes at different stages of Covid-19are suggested.
1. van Gelderen CE, Bijlsma JA, van Dokkum W, Savelkoul TJ. Glycyrrhizic acid: the assessment of a no effect level. Hum Exp Toxicol. 2000;19(8):434-9.
2. Guo YR, Cao QD, Hong ZS,et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 2020;7(1):11.
3. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (New York, NY). 2020;367(6483):1260-3.
4. Pfortmueller CA, Spinetti T, Urman RD, Luedi MM, Schefold JC. COVID-19 associated acute respiratory distress syndrome (CARDS): Current knowledge on pathophysiology and ICU treatment- A narrative review. Best Pract Res Clin Anaesthesiol. 2021;35(3):351-68.
5. Krynytska I, Marushchak M, Birchenko I, Dovgalyuk A, Tokarskyy O. COVID-19-associated acute respiratory distress syndrome versus classical acute respiratory distress syndrome (a narrative review). Iran J Microbiol. 2021;13(6):737-747.
6. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020;215:108427-.
7. Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92(4):418-23.
8. Jia HP, Look DC, Shi L, et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol. 2005;79(23):14614-21.
9. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
10. Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30-e1.
11. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial. Crit Care Med. 2016;44(2):275-81.
12. Amawi H, Abu Deiab GI, A Aljabali AA, Dua K, Tambuwala MM. COVID-19 pandemic: an overview of epidemiology, pathogenesis, diagnostics and potential vaccines and therapeutics. Ther Deliv. 2020;11(4):245-268.
13. Khan M, Adil SF, Alkhathlan HZ, et al. COVID-19: A Global Challenge with Old History, Epidemiology and Progress So Far. Molecules. 2020;26(1):39.
14. Uddin M, Mustafa F, Rizvi TA, et al. SARS-CoV-2/COVID-19: Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions. Viruses. 2020;12(5):526.
15. El-Saber Batiha G, Magdy Beshbishy A, El-Mleeh A, Abdel-Daim MM, Prasad Devkota H. Traditional Uses, Bioactive Chemical Constituents, and Pharmacological and Toxicological Activities of Glycyrrhiza glabra L. (Fabaceae). Biomolecules. 2020;10(3):352.
16. Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res. 2008;22(6):709-24.
17. Xiang C, Qiao X, Ye M, Guo DA. Classification and distribution analysis of components in Glycyrrhiza using licorice compounds database. Yao Xue Xue Bao. 2012;47(8):1023-30. Chinese.
18. Mamedov NA, Egamberdieva D. Phytochemical Constituents and Pharmacological Effects of Licorice: A Review. In: Ozturk M, Hakeem KR, editors. Plant and Human Health, Volume 3: Pharmacology and Therapeutic Uses. Cham: Springer International Publishing; 2019. p. 1-21.
19. Cheng M, Zhang J, Yang L, et al. Recent advances in chemical analysis of licorice (Gan-Cao). Fitoterapia. 2021;149:104803.
20. Fiore C, Eisenhut M, Krausse R, et al. Antiviral effects of Glycyrrhiza species. Phytother Res. 2008;22(2):141-8.
21. Gupta VK, Fatima A, Faridi U, et al. Antimicrobial potential of Glycyrrhiza glabra roots. J Ethnopharmacol. 2008;116(2):377-80.
22. Matsui S, Matsumoto H, Sonoda Y, et al. Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line. Int Immunopharmacol. 2004;4(13):1633-44.
23. Yang R, Wang L-q, Liu Y. Antitumor Activities of Widely-used Chinese Herb-Licorice. Chinese Herbal Medicines. 2014;6(4):274-81.
24. Lateef M, Iqbal L, Fatima N, et al. Evaluation of antioxidant and urease inhibition activities of roots of Glycyrrhiza glabra. Pakistan Journal of Pharmaceutical Sciences. 2012;25(1):99-102.
25. Wan XY, Luo M, Li XD, He P. Hepatoprotective and anti-hepatocarcinogenic effects of glycyrrhizin and matrine. Chem Biol Interact. 2009;181(1):15-9.
26. Ojha S, Golechha M, Kumari S, Bhatia J, Arya DS. Glycyrrhiza glabra protects from myocardial ischemia-reperfusion injury by improving hemodynamic, biochemical, histopathological and ventricular function. Exp Toxicol Pathol. 2013;65(1-2):219-27.
27. Dhingra D, Sharma A. Antidepressant-like activity of Glycyrrhiza glabra L. in mouse models of immobility tests. Prog Neuropsychopharmacol Biol Psychiatry.2006;30(3):449-54.
28. Dhingra D, Parle M, Kulkarni SK. Memory enhancing activity of Glycyrrhiza glabra in mice. J Ethnopharmacol. 2004;91(2-3):361-5.
29. Kalaiarasi P, Pugalendi KV. Antihyperglycemic effect of 18 beta-glycyrrhetinic acid, aglycone of glycyrrhizin, on streptozotocin-diabetic rats. Eur J Pharmacol. 2009;606(1-3):269-73.
30. Shin YW, Bae EA, Lee B, et al. In vitro and in vivo antiallergic effects of Glycyrrhiza glabra and its components. Planta Medica. 2007;73(3):257-61.
31. Yang R, Yuan BC, Ma YS, Zhou S, Liu Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharm Biol. 2017;55(1):5-18.
32. Wang L, Yang R, Yuan B, Liu Y, Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm Sin B. 2015;5(4):310-5.
33. Diomede L, Beeg M, Gamba A, Fumagalli O, Gobbi M, Salmona M. Can Antiviral Activity of Licorice Help Fight COVID-19Infection? Biomolecules. 2021;11(6).
34. Wang L, Yang R, Yuan B, Liu Y, Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm Sin B. 2015;5(4):310-5.
35. Wahab S, Annadurai S, Abullais SS, Das G, et al. Glycyrrhiza glabra (Licorice): A comprehensive review on its phytochemistry, biological activities, clinical evidence and toxicology. Plants (Basel). 2021;10(12):2751.
36. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361(9374):2045-6.
37. World Health O. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 2020. Geneva: World Health Organization, 2020. Report No.: Contract No.: WHO/nCoV/Clinical/2020.3.
38. Blair JE, Gotimukul A, Wang F, et al. Mild to moderate COVID-19illness in adult outpatients: Characteristics, symptoms, and outcomes in the first 4 weeks of illness. Medicine. 2021;100(24):e26371.
39. Tan R, Xiang X, Chen W, et al. Efficacy of diammonium glycyrrhizinate combined with vitamin C for treating hospitalized COVID-19 patients: a retrospective, observational study. QJM. 2022;115(2):77-83.
40. Nicola M, O'Neill N, Sohrabi C, Khan M, Agha M, Agha R. Evidence based management guideline for the COVID-19pandemic - Review article. International Journal of Surgery. 2020;77:206-16.
41. Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res. 2016;25(3):1057-73.
42. Cao JF, Gong Y, Wu M, et al. Exploring the mechanism of action of licorice in the treatment of COVID-19through bioinformatics analysis and molecular dynamics simulation. Front Pharmacol. 2022;13:1003310.
43. Michaelis M, Geiler J, Naczk P, et al. Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PloS One. 2011;6(5):e19705.
44. Bhattacharjee S, Bhattacharjee A, Majumder S, Majumdar SB, Majumdar S. Glycyrrhizic acid suppresses Cox-2-mediated anti-inflammatory responses during Leishmania donovani infection. J Antimicrob Chemother. 2012;67(8):1905-14.
45. Gao L, Tang H, He H, et al. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats. Front Pharmacol. 2015;6:215.
46. Li J, Xu D, Wang L, Zhang M. Glycyrrhizic acid inhibits SARS-CoV-2 Infection by blocking spike protein-mediated cell attachment. Molecules. 2021;26(20):6090.
47. Zhang Qh, Huang Hz, Qiu M, et al. Traditional Uses, pharmacological effects, and molecular mechanisms of licorice in potential therapy of COVID-19. Front Pharmacol. 2021;12:719758.
48. van de Sand L, Bormann M. Glycyrrhizin effectively inhibits SARS-CoV-2 Replication by inhibiting the viral main protease. Viruses. 2021;13(4):609.
49. Dastagir G, Rizvi MA. Review - Glycyrrhiza glabra L. (Liquorice). Pak J Pharm Sci. 2016;29(5):1727-1733.
50. Ding H, Deng W, Ding L, Ye X, Yin S, Huang W. Glycyrrhetinic acid and its derivatives as potential alternative medicine to relieve symptoms in nonhospitalized COVID-19 patients. J Med Virol. 2020;92(10):2200-4.
51. LU H, HUO N, WANG G, LI H, NIE L, XU X. Clinical observation of therapeutic effect of compound glycyrrhizin on SARS. China Pharmacy. 2001.
52. Adamyan TI, Gevorkyan ES, Minasyan SM, Oganesyan KR, Kirakosyan KA. Effect of licorice root on peripheral blood indexes upon vibration exposure. Bull Exp Biol Med. 2005;140(2):197-200.
2. Guo YR, Cao QD, Hong ZS,et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 2020;7(1):11.
3. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (New York, NY). 2020;367(6483):1260-3.
4. Pfortmueller CA, Spinetti T, Urman RD, Luedi MM, Schefold JC. COVID-19 associated acute respiratory distress syndrome (CARDS): Current knowledge on pathophysiology and ICU treatment- A narrative review. Best Pract Res Clin Anaesthesiol. 2021;35(3):351-68.
5. Krynytska I, Marushchak M, Birchenko I, Dovgalyuk A, Tokarskyy O. COVID-19-associated acute respiratory distress syndrome versus classical acute respiratory distress syndrome (a narrative review). Iran J Microbiol. 2021;13(6):737-747.
6. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020;215:108427-.
7. Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92(4):418-23.
8. Jia HP, Look DC, Shi L, et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol. 2005;79(23):14614-21.
9. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
10. Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30-e1.
11. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial. Crit Care Med. 2016;44(2):275-81.
12. Amawi H, Abu Deiab GI, A Aljabali AA, Dua K, Tambuwala MM. COVID-19 pandemic: an overview of epidemiology, pathogenesis, diagnostics and potential vaccines and therapeutics. Ther Deliv. 2020;11(4):245-268.
13. Khan M, Adil SF, Alkhathlan HZ, et al. COVID-19: A Global Challenge with Old History, Epidemiology and Progress So Far. Molecules. 2020;26(1):39.
14. Uddin M, Mustafa F, Rizvi TA, et al. SARS-CoV-2/COVID-19: Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions. Viruses. 2020;12(5):526.
15. El-Saber Batiha G, Magdy Beshbishy A, El-Mleeh A, Abdel-Daim MM, Prasad Devkota H. Traditional Uses, Bioactive Chemical Constituents, and Pharmacological and Toxicological Activities of Glycyrrhiza glabra L. (Fabaceae). Biomolecules. 2020;10(3):352.
16. Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res. 2008;22(6):709-24.
17. Xiang C, Qiao X, Ye M, Guo DA. Classification and distribution analysis of components in Glycyrrhiza using licorice compounds database. Yao Xue Xue Bao. 2012;47(8):1023-30. Chinese.
18. Mamedov NA, Egamberdieva D. Phytochemical Constituents and Pharmacological Effects of Licorice: A Review. In: Ozturk M, Hakeem KR, editors. Plant and Human Health, Volume 3: Pharmacology and Therapeutic Uses. Cham: Springer International Publishing; 2019. p. 1-21.
19. Cheng M, Zhang J, Yang L, et al. Recent advances in chemical analysis of licorice (Gan-Cao). Fitoterapia. 2021;149:104803.
20. Fiore C, Eisenhut M, Krausse R, et al. Antiviral effects of Glycyrrhiza species. Phytother Res. 2008;22(2):141-8.
21. Gupta VK, Fatima A, Faridi U, et al. Antimicrobial potential of Glycyrrhiza glabra roots. J Ethnopharmacol. 2008;116(2):377-80.
22. Matsui S, Matsumoto H, Sonoda Y, et al. Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line. Int Immunopharmacol. 2004;4(13):1633-44.
23. Yang R, Wang L-q, Liu Y. Antitumor Activities of Widely-used Chinese Herb-Licorice. Chinese Herbal Medicines. 2014;6(4):274-81.
24. Lateef M, Iqbal L, Fatima N, et al. Evaluation of antioxidant and urease inhibition activities of roots of Glycyrrhiza glabra. Pakistan Journal of Pharmaceutical Sciences. 2012;25(1):99-102.
25. Wan XY, Luo M, Li XD, He P. Hepatoprotective and anti-hepatocarcinogenic effects of glycyrrhizin and matrine. Chem Biol Interact. 2009;181(1):15-9.
26. Ojha S, Golechha M, Kumari S, Bhatia J, Arya DS. Glycyrrhiza glabra protects from myocardial ischemia-reperfusion injury by improving hemodynamic, biochemical, histopathological and ventricular function. Exp Toxicol Pathol. 2013;65(1-2):219-27.
27. Dhingra D, Sharma A. Antidepressant-like activity of Glycyrrhiza glabra L. in mouse models of immobility tests. Prog Neuropsychopharmacol Biol Psychiatry.2006;30(3):449-54.
28. Dhingra D, Parle M, Kulkarni SK. Memory enhancing activity of Glycyrrhiza glabra in mice. J Ethnopharmacol. 2004;91(2-3):361-5.
29. Kalaiarasi P, Pugalendi KV. Antihyperglycemic effect of 18 beta-glycyrrhetinic acid, aglycone of glycyrrhizin, on streptozotocin-diabetic rats. Eur J Pharmacol. 2009;606(1-3):269-73.
30. Shin YW, Bae EA, Lee B, et al. In vitro and in vivo antiallergic effects of Glycyrrhiza glabra and its components. Planta Medica. 2007;73(3):257-61.
31. Yang R, Yuan BC, Ma YS, Zhou S, Liu Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharm Biol. 2017;55(1):5-18.
32. Wang L, Yang R, Yuan B, Liu Y, Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm Sin B. 2015;5(4):310-5.
33. Diomede L, Beeg M, Gamba A, Fumagalli O, Gobbi M, Salmona M. Can Antiviral Activity of Licorice Help Fight COVID-19Infection? Biomolecules. 2021;11(6).
34. Wang L, Yang R, Yuan B, Liu Y, Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm Sin B. 2015;5(4):310-5.
35. Wahab S, Annadurai S, Abullais SS, Das G, et al. Glycyrrhiza glabra (Licorice): A comprehensive review on its phytochemistry, biological activities, clinical evidence and toxicology. Plants (Basel). 2021;10(12):2751.
36. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361(9374):2045-6.
37. World Health O. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 2020. Geneva: World Health Organization, 2020. Report No.: Contract No.: WHO/nCoV/Clinical/2020.3.
38. Blair JE, Gotimukul A, Wang F, et al. Mild to moderate COVID-19illness in adult outpatients: Characteristics, symptoms, and outcomes in the first 4 weeks of illness. Medicine. 2021;100(24):e26371.
39. Tan R, Xiang X, Chen W, et al. Efficacy of diammonium glycyrrhizinate combined with vitamin C for treating hospitalized COVID-19 patients: a retrospective, observational study. QJM. 2022;115(2):77-83.
40. Nicola M, O'Neill N, Sohrabi C, Khan M, Agha M, Agha R. Evidence based management guideline for the COVID-19pandemic - Review article. International Journal of Surgery. 2020;77:206-16.
41. Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res. 2016;25(3):1057-73.
42. Cao JF, Gong Y, Wu M, et al. Exploring the mechanism of action of licorice in the treatment of COVID-19through bioinformatics analysis and molecular dynamics simulation. Front Pharmacol. 2022;13:1003310.
43. Michaelis M, Geiler J, Naczk P, et al. Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PloS One. 2011;6(5):e19705.
44. Bhattacharjee S, Bhattacharjee A, Majumder S, Majumdar SB, Majumdar S. Glycyrrhizic acid suppresses Cox-2-mediated anti-inflammatory responses during Leishmania donovani infection. J Antimicrob Chemother. 2012;67(8):1905-14.
45. Gao L, Tang H, He H, et al. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats. Front Pharmacol. 2015;6:215.
46. Li J, Xu D, Wang L, Zhang M. Glycyrrhizic acid inhibits SARS-CoV-2 Infection by blocking spike protein-mediated cell attachment. Molecules. 2021;26(20):6090.
47. Zhang Qh, Huang Hz, Qiu M, et al. Traditional Uses, pharmacological effects, and molecular mechanisms of licorice in potential therapy of COVID-19. Front Pharmacol. 2021;12:719758.
48. van de Sand L, Bormann M. Glycyrrhizin effectively inhibits SARS-CoV-2 Replication by inhibiting the viral main protease. Viruses. 2021;13(4):609.
49. Dastagir G, Rizvi MA. Review - Glycyrrhiza glabra L. (Liquorice). Pak J Pharm Sci. 2016;29(5):1727-1733.
50. Ding H, Deng W, Ding L, Ye X, Yin S, Huang W. Glycyrrhetinic acid and its derivatives as potential alternative medicine to relieve symptoms in nonhospitalized COVID-19 patients. J Med Virol. 2020;92(10):2200-4.
51. LU H, HUO N, WANG G, LI H, NIE L, XU X. Clinical observation of therapeutic effect of compound glycyrrhizin on SARS. China Pharmacy. 2001.
52. Adamyan TI, Gevorkyan ES, Minasyan SM, Oganesyan KR, Kirakosyan KA. Effect of licorice root on peripheral blood indexes upon vibration exposure. Bull Exp Biol Med. 2005;140(2):197-200.
| Files | ||
| Issue | Vol 11, No 3 (Summer 2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v11i3.15996 | |
| Keywords | ||
| Licorice; Covid-19; Clinical Trial | ||
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How to Cite
1.
Jeddi A, Mohammadpour AH, Iranshahy M, Moradi A, Zarei B. The Oral Hydroalcoholic Extract of Licorice for Management of Mild to Moderate Coronavirus Disease-19 Patients: A Double-Blind Randomized Clinical Trial. J Pharm Care. 2023;11(3):135-144.
