Treatment of patients with Covid‑19 with a high dose of ulinastatin

Huang,Hai; Hu,Ping-Fang; Sun,Liang-Liang; Guo,Yi-Bin; Wang,Qiong; Liu,Zhi-Min; Yin,Ji-Zhong; Shi,Pei-Mei; Yuan,Zong-Li; Xie,Wei-Fen

doi:10.3892/etm.2021.11044

Treatment of patients with Covid‑19 with a high dose of ulinastatin

Authors:
- Hai Huang
- Ping-Fang Hu
- Liang-Liang Sun
- Yi-Bin Guo
- Qiong Wang
- Zhi-Min Liu
- Ji-Zhong Yin
- Pei-Mei Shi
- Zong-Li Yuan
- Wei-Fen Xie
View Affiliations

Affiliations: Department of Pulmonary and Critical Care Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China, Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China, Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China, Department of Health Statistics, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: December 7, 2021 https://doi.org/10.3892/etm.2021.11044
Article Number: 121
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Currently, there are no specific therapeutic agents available for the treatment of coronavirus disease 2019 (Covid‑19). The present study aimed to assess the efficacy of high‑dose ulinastatin for the treatment of patients with Covid‑19. A total of 12 patients hospitalized with confirmed severe acute respiratory syndrome coronavirus 2 infection were treated with a high dose of ulinastatin alongside standard care. Changes in clinical manifestations, laboratory examinations and chest images were retrospectively analyzed. A total of 10 patients with severe Covid‑19 and two patients with moderate Covid‑19 received ulinastatin treatment. The average age of the patients was 68.0±11.9 years (age range, 48‑87 years). In total, nine of the 12 patients (75.0%) had one or more comorbidities. The most common symptoms on admission were fever (8/12, 66.7%), cough (5/12, 41.7%) and dyspnea (5/12, 41.7%). The percentage of lymphocytes was decreased in 41.7% of patients (5/12) and 58.3% of patients (7/12) had elevated hypersensitive C‑reactive protein (CRP) levels (mean, 49.70±77.70 mg/l). The white blood cell levels and the percentage of lymphocytes returned to normal in all of the patients, and CRP was significantly decreased and returned to normal in 83.3% of patients (10/12; mean, 6.87±6.63 mg/l) on day 7 after ulinastatin treatment. Clinical symptoms were relieved synchronously. The peripheral oxygen saturation improved and 66.7% of the patients (8/12) did not require further oxygen therapy 7 days after ulinastatin treatment. No patients required intensive care unit admission or mechanical ventilation. All patients revealed different degrees of absorption of pulmonary lesions after treatment. Compared with the standard care group, ulinastatin treatment significantly prevented illness deterioration. In conclusion, these preliminary data revealed that high‑dose ulinastatin treatment was safe and exhibited a potential beneficial effect for patients with Covid‑19.

View Figures

View References

1	Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, et al: Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 382:1708–1720. 2020.PubMed/NCBI View Article : Google Scholar
2	Cucinotta D and Vanelli M: WHO declares COVID-19 a pandemic. Acta Biomed. 91:157–160. 2020.PubMed/NCBI View Article : Google Scholar
3	Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, et al: Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med. 8:475–481. 2020.PubMed/NCBI View Article : Google Scholar
4	Zhou YW, Xie Y, Tang LS, Pu D, Zhu YJ, Liu JY and Ma XL: Therapeutic targets and interventional strategies in COVID-19: Mechanisms and clinical studies. Signal Transduct Target Ther. 6(317)2021.PubMed/NCBI View Article : Google Scholar
5	Calina D, Docea AO, Petrakis D, Egorov AM, Ishmukhametov AA, Gabibov AG, Shtilman MI, Kostoff R, Carvalho F, Vinceti M, et al: Towards effective COVID-19 vaccines: Updates, perspectives and challenges (Review). Int J Mol Med. 46:3–16. 2020.PubMed/NCBI View Article : Google Scholar
6	Nitulescu GM, Paunescu H, Moschos SA, Petrakis D, Nitulescu G, Ion GND, Spandidos DA, Nikolouzakis TK, Drakoulis N and Tsatsakis A: Comprehensive analysis of drugs to treat SARS-CoV-2 infection: Mechanistic insights into current COVID-19 therapies (Review). Int J Mol Med. 46:467–488. 2020.PubMed/NCBI View Article : Google Scholar
7	Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, et al: Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 130:2620–2629. 2020.PubMed/NCBI View Article : Google Scholar
8	Cao X: COVID-19: Immunopathology and its implications for therapy. Nat Rev Immunol. 20:269–270. 2020.PubMed/NCBI View Article : Google Scholar
9	Mehta P, Mcauley DF, Brown M, Sanchez E, Tattersall RS and Manson JJ: HLH Across Speciality Collaboration, UK. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 395:1033–1034. 2020.PubMed/NCBI View Article : Google Scholar
10	Yamamoto M, Matsuyama S, Li X, Takeda M, Kawaguchi Y, Inoue JI and Matsuda Z: Identification of nafamostat as a potent inhibitor of Middle East respiratory syndrome coronavirus S protein-mediated membrane fusion using the split-protein-based cell-cell fusion assay. Antimicro Agents Chemother. 60:6532–6539. 2016.PubMed/NCBI View Article : Google Scholar
11	Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al: SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 181:271–280.e8. 2020.PubMed/NCBI View Article : Google Scholar
12	Scudellari M: How the coronavirus infects cells-and why delta is so dangerous. Nature. 595:640–644. 2021.PubMed/NCBI View Article : Google Scholar
13	Lagoo JY, D'souza MC, Kartha A and Kutappa AM: Role of ulinastatin, a trypsin inhibitor, in severe acute pancreatitis in critical care setting: A retrospective analysis. J Crit Care. 45:27–32. 2018.PubMed/NCBI View Article : Google Scholar
14	Karnad DR, Bhadade R, Verma PK, Moulick ND, Daga MK, Chafekar ND and Iyer S: Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: A multicenter randomized controlled study. Intensive Care Med. 40:830–838. 2014.PubMed/NCBI View Article : Google Scholar
15	Ji M, Chen T, Wang B, Chen M, Ding Q, Chen L, Fang Y, Yu X, Chen Y, Wang X, et al: Effects of ulinastatin combined with mechanical ventilation on oxygen metabolism, inflammation and stress response and antioxidant capacity of ARDS. Exp Ther Med. 15:4665–4670. 2018.PubMed/NCBI View Article : Google Scholar
16	Zhang X, Zhu Z, Jiao W, Liu W, Liu F and Zhu X: Ulinastatin treatment for acute respiratory distress syndrome in China: A meta-analysis of randomized controlled trials. BMC Pulm Med. 19(196)2019.PubMed/NCBI View Article : Google Scholar
17	National Health Commission of China. Guideline for diagnosis and treatment for novel coronavirus pneumonia (seventh edition). http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml. Accessed March 4, 2020.
18	Sanders JM, Monogue ML, Jodlowski TZ and Cutrell JB: Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA. 323:1824–1836. 2020.PubMed/NCBI View Article : Google Scholar
19	Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W and Xiao G: Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30:269–271. 2020.PubMed/NCBI View Article : Google Scholar
20	Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilkerson S, Tural A, et al: First case of 2019 novel coronavirus in the United States. N Engl J Med. 382:929–936. 2020.PubMed/NCBI View Article : Google Scholar
21	Lescure FX, Bouadma L, Nguyen D, Parisey M, Wicky PH, Behillil S, Gaymard A, Bouscambert-Duchamp M, Donati F, Le Hingrat Q, et al: Clinical and virological data of the first cases of COVID-19 in Europe: A case series. Lancet Infect Dis. 20:697–706. 2020.PubMed/NCBI View Article : Google Scholar
22	Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, Feldt T, Green G, Green ML, Lescure FX, et al: Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 382:2327–2336. 2020.PubMed/NCBI View Article : Google Scholar
23	Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, et al: A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 382:1787–1799. 2020.PubMed/NCBI View Article : Google Scholar
24	Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 395:1054–1062. 2020.PubMed/NCBI View Article : Google Scholar
25	Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, Liu XQ, Chen RC, Tang CL, Wang T, et al: Comorbidity and its impact on 1590 patients with Covid-19 in China: A nationwide analysis. Eur Respir J. 55(2000547)2020.PubMed/NCBI View Article : Google Scholar
26	Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, Cereda D, Coluccello A, Foti G, Fumagalli R, et al: Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the lombardy region, Italy. JAMA. 323:1574–1581. 2020.PubMed/NCBI View Article : Google Scholar
27	Chen Q, Hu C, Liu Y, Liu Y, Wang W, Zheng H, Rong L, Jia J, Sun S, Yu C and Liu YM: Safety and tolerability of high-dose ulinastatin after 2-h intravenous infusion in adult healthy Chinese volunteers: A randomized, double-blind, placebo-controlled, ascending-dose study. PLoS One. 12(e0177425)2017.PubMed/NCBI View Article : Google Scholar
28	World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 13, 2020.
29	Linder A and Russell JA: An exciting candidate therapy for sepsis: Ulinastatin, a urinary protease inhibitor. Intensive Care Med. 40:1164–1167. 2014.PubMed/NCBI View Article : Google Scholar
30	Kanai T, Ishiwata T, Kobayashi T, Sato H, Takizawa M, Kawamura Y, Tsujimoto H, Nakatani K, Ishibashi N, Nishiyama M, et al: Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: A retrospective study. Circulation. 124:2822–2828. 2011.PubMed/NCBI View Article : Google Scholar
31	Wagner C, Griesel M, Mikolajewska A, Mueller A, Nothacker M, Kley K, Metzendorf MI, Fischer AL, Kopp M, Stegemann M, et al: Systemic corticosteroids for the treatment of COVID-19. Cochrane Database Syst Rev. 8(CD014963)2021.PubMed/NCBI View Article : Google Scholar