鋅、槲皮素、菠蘿蛋白酶和維生素 C 對 COVID-19 患者影響的評價
抽象的
2019 年冠狀病毒病 (COVID-19) 是一種由新型冠狀病毒引起的傳染病。 COVID-19分為三個階段：分別是早期感染階段、肺部階段和過度炎症階段。 重要的是通過藥物或非藥物治療預防 II 期和 III 期損傷，從而預防肺或其他器官損傷。 這是對 22 名確診感染 SARS-CoV-2 並診斷為 COVID-19 的患者進行的病例係列研究。 本研究中的患者在 SARS-CoV-2 感染期間每天服用槲皮素 800 毫克、菠蘿蛋白酶 165 毫克、醋酸鋅 50 毫克和抗壞血酸 1 克作為補充劑，持續 3 至 5 天。 本研究的目的是評估槲皮素、菠蘿蛋白酶、鋅和抗壞血酸聯合補充劑對 COVID-19 患者的安全性和有效性。 所有納入患者服用槲皮素、菠蘿蛋白酶、鋅和抗壞血酸補充劑前後的 WBC、ANC、ALC、AMC 和 AST 平均水平正常（P 值 > 0.05）。 槲皮素 800 毫克、菠蘿蛋白酶 165 毫克、醋酸鋅 50 毫克和抗壞血酸 1 克每天一次補充劑對感染 SARS-CoV-2 的患者是安全的，並可防止不良預後。 未來需要進行隨機臨床試驗以確保槲皮素、菠蘿蛋白酶、鋅和維生素 c 組合的療效。
介紹
2019 年冠狀病毒病 (COVID-19) 是一種由新型冠狀病毒引起的傳染病。 [ 1 ] 全世界有超過 3000 萬人感染並感染了 COVID-19，其中至少有 100 萬人死於急性呼吸窘迫綜合徵 (ARDS) 和細胞因子風暴等疾病並發症。 [ 2 ]
COVID-19 分為三個階段：第一階段（早期感染階段）； 其中 SARS-CoV-2 開始傳播和增殖並激活先天免疫。 II 期（肺期）； 以肺組織損傷和白細胞募集增加為特徵。 第三階段（過度炎症階段）； 各種器官都可能受到損害，並且免疫反應會極度惡化。 為了治療 COVID-19 患者； 重要的是通過藥物或非藥物治療預防 II 期和 III 期損傷，從而預防肺或其他器官損傷。 [ 3 ]
槲皮素是一種天然類黃酮分子，廣泛分佈於許多水果和蔬菜中，包括紅洋蔥、蔓越莓、羽衣甘藍、西紅柿、匈牙利蠟和豆瓣菜。 [ 4 ] 以往的研究表明，槲皮素通過抑制環氧合酶（COX）和脂氧合酶（LOX）來阻止促炎的前列腺素和白三烯，從而具有抗炎和抗過敏作用，因此； 槲皮素在各種試驗中被用作提取物來治療不同的傳染性和非傳染性疾病。 [ 5 ] 此外，槲皮素顯示可減少慢性炎症的腫瘤壞死因子-α (TNF-α) 的產生。 [ 6 ] 在 ，CD4 比例降低， + :CD8 + 臨床前研究中，特定組織用槲皮素處理後 T 細胞 並抑制巨噬細胞、樹突細胞、肥大細胞和白細胞介素 6 (IL-6) 水平。見圖 1 ）。 [ 7 - 8 ] 此外，槲皮素有望通過作為鋅螯合劑和鋅離子載體而具有抗病毒活性。 [ 9 ] 然而，由於這些研究大多是在體外使用高濃度槲皮素進行的，體內研究不能使用相同的劑量； 它在臨床試驗中顯示出最小的影響。 現有數據表明，槲皮素是一種非常安全的分子，用作營養補充劑，劑量達到每天 1500 毫克。 [ 10 ]
Role of quercetin in inhibiting inflammation by blocking the activity of COX (cyclooxygenase) enzymes and LOX (lipoxygenase) enzyme, in addition to reducing TNF-α (tumor necrosis factor-alpha) and macrophages levels.
菠蘿蛋白酶是一種蛋白質酶，主要存在於菠蘿植物的莖中。 菠蘿蛋白酶通過口服途徑的生物利用度很高，即使每天攝入超過 11 克也是安全的。 [ 11 ] 體外研究表明，菠蘿蛋白酶通過降低緩激肽血清 [ 12 ] 和調節與炎症相關的一些基因的表達來發揮抗炎作用。 [ 13 ] 三個與炎症相關的基因，包括TLR4、TNF-α和IL-8，在菠蘿蛋白酶處理後被發現較少表達（見圖 2 ）。 另一方面，菠蘿蛋白酶處理後 PPARγ 基因表達升高。 [ 14 ] 因此，菠蘿蛋白酶可能具有減輕各種疾病期間炎症的作用，並可與其他鎮痛藥和抗炎藥聯合使用。
由於 COVID-19 期間患者的炎症狀態可能導致嚴重後果甚至死亡，如果不加以充分預防或治療； 重要的是確保為患者提供高質量的護理並提供循證預防和治療。
本研究的目的是評估槲皮素、菠蘿蛋白酶、鋅和抗壞血酸補充劑對 COVID-19 患者的療效。
方法
研究設計和科目
這是 2020 年 6 月至 9 月期間對 22 名確診感染 SARS-CoV-2 並被診斷為 COVID-19 的患者進行的病例係列研究。 研究對象包括在利雅得伊瑪目阿卜杜勒拉赫曼阿爾費薩爾醫院住院的成年人。
補充和測量
本研究中的 COVID-19 患者在 SARS-CoV-2 感染期間每天服用槲皮素 800 毫克、菠蘿蛋白酶 165 毫克、醋酸鋅 50 毫克和抗壞血酸 1 克作為補充劑，持續 3 至 5 天。 對本研究中包括的所有患者進行了多項實驗室檢查。 這些測試包括絕對中性粒細胞計數 (ANC)、絕對淋巴細胞計數 (ALC)、絕對單核細胞計數 (AMC)、血紅蛋白 (Hb)、血小板 (Plts)、鉀 (K)、天冬氨酸轉氨酶 (AST)、氧飽和度百分比 (SaO2 )、D-二聚體和白細胞 (WBC)。 此外，還報告了醫療和用藥史。
終點和統計分析
主要終點是通過評估補充劑前後的實驗室結果來確保槲皮素、菠蘿蛋白酶、鋅和抗壞血酸補充劑的功效。 配對 t 檢驗用於揭示患者在槲皮素、菠蘿蛋白酶、鋅和維生素 C 組合補充劑前後不同實驗室測試之間的差異。
Ethical approval
Institutional review board (IRB) was obtained from the Saudi ministry of health on the 7th of June 2020 with the central IRB log number: 20-95M.
Results
Twenty-two hospitalized patients diagnosed with COVID-19 were enrolled in this study, all of them were taking quercetin, bromelain, zinc and ascorbic acid as supplements. The mean age of patients was 49.27 years, and 59% of them were older than 50 years old. The percentage of male patients was 68.18%. More than 13% of the patients were having chronic diseases. About half of the patients were receiving antibacterial and antiviral medications during hospitalization, and 63.63% of total patients were on anti-coagulants. Days of stay average was 9 days (see table.1).
Patients’ Baseline Characteristics.
The mean D-dimer level at admission was elevated (1.0082 mcg/ml). Mean WBCs levels at admission and at discharge were 7440 and 8550 cells/mm3 respectively (P-value = 0.34). Mean ANC at admission and at discharge were 5570 and 5800 cells/microliter respectively (P-value = 0.86). O2sat% mean was less than 94% at admission, and was more than 94% at discharge (P-value = 0.83). AST mean levels were slightly elevated at admission and at discharge (46 and 44.8 U/L respectively, P-value = 0.9). Mean ALC was 1240 at admission and was 1740 cells/microliter at discharge (P-value = 0.11). Mean platelets count at admission and at discharge were 243830 and 304200 cells/microliter respectively (P-value = 0.45). The mean AMC was 456 at admission and 587 cells/microliters (P-value = 0.09). Regarding hemoglobin mean levels, it was 13.68 at admission and 13.24 g/dl at discharge (P-value = 0.78). Mean potassium concentration at admission and at discharge were 4.53 and 4.38 mmol/l (P-value = 0.45) (see table.2).
Laboratory Tests Pre- and Post-Supplements.
Discussion
Quercetin supplement was and still interested by many researchers globally since various types of studies were focusing on it. Regarding studies about infectious diseases; quercetin was studied with Zika virus[15], Ebola virus[16], murine coronavirus[17], dengue virus[18], SARS-CoV-2[19] and influenza A virus[20], and most of these studies conclude that quercetin may have a substantial role as prophylactic or treatment of different types of viruses. Unlike quercetin, bromelain supplement was not widely studied about its efficacy against infections, however, few types of researches done claimed that bromelain could prevent or eradicate some microorganisms including Escherichia coli[21] and SARS-CoV-2.[22]
In this study, the mean D-dimer level of patients diagnosed with COVID-19 was more than 0.5 mcg/ml; which indicates that their condition was not mild and need hospitalization based on the Chinese study. In addition to quercetin and bromelain supplements, most of the twenty-two patients were on hospital medications which include vitamin C, zinc, enoxaparin, drugs expected to have an anti-SARS-CoV-2 effect (ribavirin, hydroxychloroquine or lopinavir-ritonavir) and antibacterial drugs. As shown in the results, all the patients’ lab tests done at admission and at discharge were not significantly different and the mean days of stay at the hospital was 9 days. These results reveal that quercetin 800 mg once daily with bromelain 165 mg, in addition to zinc acetate 50 mg and vitamin c 1 g supplements are safe with COVID-19 patients who were on multiple therapies including antivirals and antibacterial medications. The efficacy of quercetin, bromelain, zinc and ascorbic acid combination was not clear in this study, because of lacking placebo or comparable group; however, their efficacy in preventing severe consequences of SARS-CoV-2 infections cannot be ruled out based on previous studies (see figure.3). Large comparable studies need to be done about quercetin and bromelain to confirm their efficacy in treating COVID-19 cases.
The expected efficacy of quercetin, bromelain, zinc and ascorbic acid combination in preventing poor prognosis of COVID-19 patients by restraining from pulmonary and hyper-inflammation stages.
Conclusion
Quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg and ascorbic acid 1 g once daily as supplements for 3 to 5 days were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis through restraining from hyper-inflammation and cytokine storm. Randomized clinical trials are needed in the future to ensure the efficacy of quercetin, bromelain, zinc and ascorbic acid combination.
Conflict of interest
The authors have no conflict of interest.
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