Oral nano-curcumin formulation efficacy in management of mild to moderate hospitalized coronavirus disease-19 patients: An open label nonrandomized clinical trial

Abstract

Curcumin is proposed as a potential treatment option for coronavirus disease-19 (COVID-19) by inhibiting the virus entrance, encapsulation and replication, and modulating various cellular signaling pathways. In this open-label nonrandomized clinical trial, efficacy of nano-curcumin oral formulation has been evaluated in hospitalized patients with mild–moderate COVID-19. Forty-one patients who fulfilled the inclusion criteria were allocated to nano-curcumin (n = 21) group (Sinacurcumin soft gel, contains 40 mg curcuminoids as nanomicelles, two capsules twice a day) or control (n = 20) group, for 2 weeks. Patients' symptoms and laboratory data were assessed at baseline and during follow-up period. Most of symptoms including fever and chills, tachypnea, myalgia, and cough resolved significantly faster in curcumin group. Moreover, SaO₂ was significantly higher in treatment group after 2, 4, 7, and 14 days of follow-up and lymphocyte count after 7 and 14 days. Duration of supplemental O₂ use and hospitalization was also meaningfully shorter in treatment group. It is also noteworthy to mention that no patient in treatment group experienced deterioration of infection during follow-up period, but it occurred in 40% of control group. Oral curcumin nano-formulation can significantly improve recovery time in hospitalized COVID-19 patients. Further randomized placebo controlled trials with larger sample size are recommended.

1 INTRODUCTION

Coronavirus disease 2019 (COVID-19)-induced pneumonia became an international concern, which led to the first pandemic of the century in March 2020 (Wang, Horby, Hayden, & Gao, 2020). Respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of COVID-19 mortality, mostly due to cytokine storm syndrome (Mehta et al., 2020; Ruan, Yang, Wang, Jiang, & Song, 2020). Actually, high cytokine level including IL-2, IL-7, granulocyte colony–stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)1-α, and tumor necrosis factor (TNF)-α is related to the severity of COVID-19 disease (Mehta et al., 2020; Richardson et al., 2020; Shakoory et al., 2016). Until now, there are no specific approved treatment and vaccine for COVID-19. Supportive care and oxygen therapy remain as the main steps for patients suffering from COVID-19 pneumonia.

Curcumin is a derivative of Curcuma longa (turmeric), a traditional Chinese herb with many therapeutic properties which is used usually as yellow spice. Curcumin and two other carotenoids called demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) beside volatile oils, proteins, carbohydrates, and resins, form majority of turmeric ingredients. There are several evidence supporting its antiinflammatory and antioxidant action in vitro and in vivo. Moreover, it controls cell growth and apoptosis (Gupta, Patchva, Koh, & Aggarwal, 2012). Curcumin can decrease excretion of wide range of cytokines which have critical role in many severe and chronic disease (IL-1, 2, 6, 8, 10, 11, 12, & 17, TNFα, interferon-γ, MCP1, MIP1α, nuclear factor kappa-light-chain enhancer of activated B-cells [NFĸB]) (Biswas, McClure, Jimenez, Megson, & Rahman, 2005; Jain, Rains, Croad, Larson, & Jones, 2009; Kloesch, Becker, Dietersdorfer, Kiener, & Steiner, 2013; Raflee et al., 2009). in vivo study on viral-induced ARDS also showed reduction in IL6, IL10, interferon-γ, and MCP1, leading to suppression of inflammation and fibrosis in a mice model (Avasarala et al., 2015). In another study on an infected mouse with acute viral infection, curcumin administration inhibited the proinflammatory cytokines expression and also local and systemic cardiac damage (Song, Ge, Cai, & Zhang, 2013). Additionally, curcumin showed to have antiviral effects against a variety of viruses such as human immunodeficiency virus (HIV)-1 and 2, herpes simplex virus (HSV), human papillomavirus (HPV), human T-lymphotropic virus-1 (HTLV1), hepatitis B virus (HBV), HCV, and Japanese encephalitis virus (Zorofchian Moghadamtousi et al., 2014).

Considering inflammation due to viral infection as the main cause of COVID-19-induced ARDS, curcumin raises interest as a potential agent for management of COVID-19 lung injury. Overall, the well-known antiinflammatory and immunomodulatory effects of curcumin plus the evidence on the antifibrotic and pulmonoprotective properties of this phytochemical on the lung tissue make it a promising candidate for the treatment of COVID-19. Moreover, it has a good reputation for strong inhibitory effects on NF-κB and several proinflammatory cytokines, and it can be even useful in reversing the fatal cytokine storm that occurs in serious cases of COVID-19 (Zahedipour et al., 2020).

Curcumin use dates back to ancient times, and its safety has been recognized in more than 100 clinical trials. The acceptable daily intake (ADI) value of curcumin has been reported 0–3 mg/kg and up to 12 g/day was tolerable (Nelson et al., 2017). Diarrhea, headache, rash, and stool lightening were the most common reported adverse reactions in patients receiving 0.5–12 g in a dose–response study after 72 hr. In another study, some of the subjects receiving 0.45–3.6 g/day curcumin for 1–4 months just complained of nausea and diarrhea. Rise of serum alkaline phosphatase and lactate dehydrogenase level was also found in some patients (Akbari, Kariznavi, Jannati, Elyasi, & Tayarani-Najaran, 2020).

However, curcurmin has very low solubility in water, and its bioavailability is not sufficient for oral administration. It is mentioned that manipulation and encapsulation of curcumin into micelles, liposomes, phospholipid complexes, exosomes, or polymeric nanocarrier formulation and also utilization of curcumin in combination with cellulosic derivatives, natural antioxidants, and a hydrophilic carrier could improve its bioavailability and half-life (Jäger et al., 2014; Hatamipour, Sahebkar, Alavizadeh, Dorri, & Jaafari, 2019; Moballegh Naseri et al., 2020).

In this nonrandomized open label study, we evaluated efficacy of nano-curcumin oral formulation in the management of mild–moderate hospitalized COVID-19 patients.

2 METHODS

2.1 Study design

This study conducted as a prospective nonrandomized open-label clinical trial from April to July 2020 at COVID-19 wards of Imam Reza and Quaem Hospitals affiliated to Mashhad University of Medical Sciences, Mashhad, Iran.

2.2 Study population

Patients who fulfilled the following inclusion criteria are included to the study: Diagnosis of COVID-19 was based on (a) a positive real-time polymerase chain reaction (RT-PCR) of the respiratory tract samples, (b) clinical signs/symptoms, (c) imaging findings highly suspicious for COVID-19 (e.g., ground-class pattern in chest X ray), age between 18 and 75 years with mild to moderate disease based on national diagnosis and treatment guideline (last available version), who were to be treated in inpatient setting (severe dyspnea, respiratory rate higher than 30/min, atrial O₂ saturation less than 93% in room air) and signed informed consent. Patients were not included if more than 7 days passed from their onset of symptoms, be pregnant or breastfeeding, smoking more than five cigarettes a day, had history of hypersensitivity to turmeric or curcumin formulations or concomitant disease including severe renal failure (eGFR < 30 ml/min), hepatic failure (Child-Pugh Score B or C), heart failure (EF < 40%), chronic lung disease, active malignancy, autoimmune disease, immune system impairment like HIV, gallbladder stone, and active gastrointestinal bleeding. Patients were excluded from study if they were transferred to ICU because of infection exacerbation or intubated or severe drug adverse reactions occurred.

2.3 Ethics

The local Ethics Committee of Mashhad University of Medical Sciences approved the study protocol (Code: IR.MUMS.REC.1399.054), and it was registered at the Iranian Registry of Clinical Trials (IRCT20200408046990N1). All participants were explained and informed for protocol of study and signed written consent forms.

2.4 Study protocol

All included patients were placed in treatment (nano-curcumin) or control group. The herbal medicine used in this trial was Sinacurcumin® soft gel 40 mg, which is a registered product from curcuminoids in Iran (IRC:1228225765) and are industrialized in Nanotechnology Research Center of Mashhad University of Medical Sciences, marketed by Exir Nano Sina Company, Tehran, Iran (Hatamipour et al., 2019). The treatment group received two soft gels after breakfast and two soft gels after dinner daily for 2 weeks. Actually, we included the patients who fulfilled the inclusion criteria in treatment group if they signed the written consent form and accepted to receive curcumin. The patients who refused to receive treatment were included in control group. Patients in both treatment and control groups received standard treatment based on national diagnosis and treatment guideline (last available version). Same nutritional recommendations were presented to all participants. Furthermore, they asked not to receive any other medications for COVID-19 management without consultation. If infection exacerbation occurred, the patients were excluded from the trial, and they were managed based on available guidelines.

2.5 Outcome

Patient's demographic data and past medical and drug history were asked and recorded at the beginning of the study by the pharmacist. Moreover, patients were assessed by the pulmonologist and pharmacist considering the various signs and symptoms of COVID-19 infection (including fever, chills, cough, headache, sore throat, anosmia and taste disturbance, myalgia, weakness, dyspnea, gastrointestinal, and dermatologic disorders) at the beginning of the study and daily thereafter, until complete resolution. Besides, laboratory data (C-reactive protein or CRP serum level and lymphocytes count) and atrial O₂ saturation (SaO₂) were recorded after 2, 4, and 6 days and also at discharge time. Duration of hospitalization and patients' outcome also gathered. Patients considered completely recovered if all symptoms resolved and the assessed laboratory findings (CRP and lymphocyte count) and SaO₂ were normalized. We considered patients in deterioration situation if their symptoms did not resolve or exacerbate in 2 weeks follow-up period, their laboratory findings did not improve, or worsened or the SaO₂ was still low and the patient needed supplemental O₂. These factors were considered as primary outcome of the study. COVID-19 RT-PCR and/or lung CT scan if available was recorded at baseline.

During the study period, patients were also followed for compliance to treatment and adverse drug reactions (ADRs). They were proposed to be adherent to their treatment if they consumed more than 80% of their administered medicine/placebo (Ho, Bryson, & Rumsfeld, 2009). We also evaluated the patients' liver and kidney function at the beginning of the study and at the end of the 2 weeks follow-up or at discharge time, each one happened first. The occurrence of the ADRs considered as secondary outcome.

2.6 Sample size

As to the best of our knowledge, this was the first clinical study on curcumin oral formulation efficacy for management of mild to moderate COVID-19 infection, we proposed it as a pilot study and defined the sample size 30 patients in each group. Based on Whitehead, Julious, Cooper, and Campbell (2016) recommendation, for a main trial designed with 90% power and two-sided 5% significance, pilot trial sample sizes per treatment arm of 75, 25, 15, and 10 are enough for standardized effect sizes that are extra small (≤0.1), small (0.2), medium (0.5), or large (0.8), respectively. So, proposing the curcumin effect medium regarding the proposed mechanism of action, 20 patients in each arm could be acceptable.

2.7 Statistical methods

The analysis was performed by SPSS software, version 19. Results have been reported as mean ± SD for continuous variables and number or percentage for nominal parameters. Kolmogorov–Smirnov test was used to assess the normality of the variables distribution.

Independent sample t test was used respectively to compare normally distributed variables between two groups. Fisher's exact test was used to compare proportions between the groups; p < .05 was considered as significant.

3 RESULTS

3.1 Baseline characteristics

Among 66 evaluated patients according to inclusion criteria, 41 patients were eligible to be enrolled in the study. At the end of the study, 21 patients in treatment and 20 patients in control group completed the trial (Figure 1).

FIGURE 1

Flow diagram of the study design

The average age of patients who completed the study was 55.9 ± 15.16 years, and 65.9% of them were male. Other baseline characteristics of patients are summarized in Table 1. There were no significant differences between nano-curcumin and control groups in these characteristics. 42.86 and 50% of patients in control and treatment group had higher than normal aspartate transaminase (AST)/alanine transaminase (ALT) serum level at the beginning of the study. However, it was less than two times the upper limit of normal, except in one patient in treatment group.

TABLE 1. Patients' characteristics

	Nano-curcumin	Control	p-value
Gender (male/female ratio)	5/16	9/11	.197^a^a Fisher's exact test.
Age (year)	53.48 ± 12.21	58.45 ± 17.71	.305^b^b Independent sample t test.
Duration of symptoms' occurrence (day)	3.57 ± 1.55	2.9 ± 0.51	.427^b^b Independent sample t test.
Body temperature (°C)	37.37 ± 0.67	37.26 ± 0.69	.603^b^b Independent sample t test.
Cough (%)	90.5	80	.41^a^a Fisher's exact test.
Headache (%)	38.1	50	.536^a^a Fisher's exact test.
Chills (%)	62.9	80	.288^a^a Fisher's exact test.
Myalgia (%)	95.2	75	.254^a^a Fisher's exact test.
Weakness (%)	23.8	40	.326^a^a Fisher's exact test.
GI symptoms (%)	14.3	30	.277^a^a Fisher's exact test.
Dyspnea (%)	100	100	1^a^a Fisher's exact test.
Olfactory and taste disturbances (%)	61.9	35	.121^a^a Fisher's exact test.
Serum level of CRP (mg/L)	91.2 ± 53.95	81.8 ± 77.97	.693^b^b Independent sample t test.
Serum ALT level (IU/L)	52.35 ± 18.84	51.85 ± 17.94	.932^b^b Independent sample t test.
Serum AST level (IU/L)	48.35 ± 22.19	47.68 ± 21.96	.926^b^b Independent sample t test.
Serum creatinine level (mg/dl)	0.98 ± 0.17	0.88 ± 0.1	.243^b^b Independent sample t test.
Lymphocytes count (%)	12.29 ± 7.98	8.87 ± 5.4	.147^b^b Independent sample t test.
Atrial O2 saturation (%)	68.28 ± 24.17	65.45 ± 25.1	.74^b^b Independent sample t test.

• ^a Fisher's exact test.
• ^b Independent sample t test.

Lung CT was performed in almost all patients and was in favor of COVID-19 in 97.6% of cases. The PCR test for COVID-19 was performed in 80.49% of patients in treatment and control groups, which was positive in 93.94% of them. There was no significant difference regarding PCR and lung CT results between two groups (Table 2).

TABLE 2. Comparison of lung CT and RT-PCR findings between treatment and control group

	Treatment	Control	p-value^a^a Fisher's exact test.
Lung CT
Consistent with COVID-19 (%)	100	90	.332
Inconsistent with COVID-19 (%)	0	5
Not performed (%)	0	5
RT-PCR
Positive (%)	76.19	75	.996
Negative (%)	4.76	5
Not performed (%)	19.05	20

• ^a Fisher's exact test.

Hydroxychloroquine is the most common prescribed medication to the study population (78%). There was no significant difference between treatment and control group regarding standard treatment (p > .05) (Table 3).

TABLE 3. Comparison of prescribed anti-COVID-19 regimens between treatment and control group

Anti-COVID-19 regimen	Treatment	Control	p-value^a^a Fisher's exact test.
HCQ (%)	76.19	80	1^a^a Fisher's exact test.
Azithromycin (%)	52.38	55	1^a^a Fisher's exact test.
Broad-spectrum antibiotics (%)	61.9	80	.306^a^a Fisher's exact test.
Protease inhibitors (%)	28.57	40	.52^a^a Fisher's exact test.
Corticosteroid (%)	57.14	45	.538^a^a Fisher's exact test.

• Abbreviation: HCQ, hydroxycholorquine.
• ^a Fisher's exact test.

3.2 Efficacy of treatment

Comparing the resolution time for various symptoms related to COVID-19 infection between treatment and placebo group, most of them resolved faster in treatment group (fever [p = .047], cough [p = .002], tachypnea [p = .031], chill [p = .004], and myalgia [p = .009]). Lymphocyte count was also significantly higher after 1 week and at discharge in treatment group (p < .05). Moreover, SaO₂ was significantly higher in curcumin group at 2, 4, 7 and 14 days (p < .05), and length of supplemental oxygen use and hospitalization were meaningfully shorter for curcumin group (p < .001). However, CRP serum level did not differ meaningfully between two groups after 2, 4, and 7 days and also at discharge time (Table 4).

TABLE 4. Comparison of symptoms resolution time and laboratory findings changes between treatment and control group

Resolution time	Nano-curcumin	Control	p-value
Fever (day)	0.62 ± 0.74	1.15 ± 1.35	.047^*^a^a Independent sample t test.
Cough (day)	1.62 ± 0.8	3.89 ± 1.54	.002^*^a^a Independent sample t test.
Headache (day)	1.19 ± 1.12	1.33 ± 0.71	.678^a^a Independent sample t test.
Tachypnea (day)	1.14 ± 0.85	1.85 ± 1.39	.031^*^a^a Independent sample t test.
Chills (day)	1.14 ± 1.31	2.55 ± 1.57	.004^*^a^a Independent sample t test.
Myalgia (day)	1.9 ± 0.83	3.44 ± 1.33	.009^*^a^a Independent sample t test.
Olfactory and taste disturbances (day)	1.62 ± 1.07	1.44 ± 1.59	.769^a^a Independent sample t test.
Serum level CRP, second day (mg/L)	50.68 ± 32.15	39.52 ± 34.2	.463^a^a Independent sample t test.
Serum level CRP, fourth day (mg/L)	42.38 ± 36.71	80.79 ± 78.36	.17^a^a Independent sample t test.
Serum level CRP, 1 week (mg/L)	28.66 ± 36.67	34.17 ± 38.46	.797^a^a Independent sample t test.
Serum level CRP, discharge/2 week^b^b Whichever shorter, without supplemental O2. (mg/L)	21.29 ± 21.75	21.43 ± 33.68	.993^a^a Independent sample t test.
Serum level of ALT, discharge/2 week^b^b Whichever shorter, without supplemental O2. (IU/L)	53.13 ± 20.62	55.35 ± 17.41	.757^a^a Independent sample t test.
Serum level of AST, discharge/2 week^b^b Whichever shorter, without supplemental O2. (IU/L)	49.33 ± 19.41	47.68 ± 21.96	.336^a^a Independent sample t test.
Serum level of creatinine, discharge/2 week^b^b Whichever shorter, without supplemental O2. (mg/dl)	0.94 ± 0.13	0.91 ± 0.1	.449^a^a Independent sample t test.
Lymphocyte count, second day (%)	13.62 ± 11.72	13.36 ± 6.64	.947^a^a Independent sample t test.
Lymphocyte count, fourth day (%)	13.58 ± 7.6	11.56 ± 5.67	.412^a^a Independent sample t test.
Lymphocyte count, 1 week (%)	16.12 ± 8.47	11.84 ± 5.14	.05^*^a^a Independent sample t test.
Lymphocyte count, discharge time/2 week^b^b Whichever shorter, without supplemental O2. (%)	18.76 ± 6.75	11.99 ± 6.01	.048^*^a^a Independent sample t test.
SaO2, second day (%)	82.12 ± 20.66	58.35 ± 31.46	.023^*^a^a Independent sample t test.
SaO2, fourth day (%)	89.11 ± 6.75	57.48 ± 33.77	.006^*^a^a Independent sample t test.
SaO2, 1 week day (%)	93.94 ± 3.56	69.65 ± 29.6	.022^*^a^a Independent sample t test.
SaO2, discharge time day/2 week^b^b Whichever shorter, without supplemental O2. (%)	94.33 ± 4.01	74.28 ± 22.1	.001^*^a^a Independent sample t test.
Length of need for supplemental O2 (day)	2.1 ± 0.77	3.85 ± 1.39	<.001^*^a^a Independent sample t test.
Hospitalization duration (day)	5.05 ± 1.36	9.15 ± 4.28	<.001^*^a^a Independent sample t test.

• ^a Independent sample t test.
• ^b Whichever shorter, without supplemental O₂.
• *The significance level: p < .05.

Considering the patients' final outcome, there was a significant difference between two groups (p = .003). In treatment group, about half of patients (47.62%) experienced complete recovery and no one experienced deterioration. But in control group, 40% of patients experienced deterioration during these 2 weeks follow-up period and just 15% of patients had complete recovery (Table 5).

TABLE 5. Comparison of final outcome between treatment and control groups

Outcome	Treatment	Control	p value^a^a Fisher's exact test.
Complete recovery (%)	47.62	15	0.003^*^a^a Fisher's exact test.
Partial recovery (%)	52.38	45
Deterioration (%)	0	40
Death (%)	0	0

• ^a Fisher's exact test.
• *The significance level: p < .05.

3.3 Safety of treatment

Three patients in treatment group and six patients in control group experienced GI symptoms including diarrhea and abdominal pain during the study period, which was not significantly different. These symptoms may be caused by COVID-19 infection itself or even might be the adverse reaction of other medications like hydroxychloroquine or antibiotics.

Moreover, we assessed the AST, ALT, and creatinine serum levels at the end of the 2 weeks follow-up or at discharge, each happened earlier. There were no significant difference between treatment and control groups regarding these factors (p > .05) (Table 4).

4 DISCUSSION

COVID-19 outbreak is an ongoing pandemic occurred by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with considerable mortality worldwide. At this time, there are no effective therapeutic strategies for management of COVID-19 infection (Rodriguez-Morales et al., 2020). There is increasing evidence on the antiviral potential of some herbal compounds (Praditya et al., 2019). So, indication of phytochemicals has attracted attention because of their proven efficacy and safety in light of the ethnomedicinal reports. Curcumin, the bioactive ingredient of turmeric (Abdollahi, Momtazi, Johnston, & Sahebkar, 2018; Mollazadeh et al., 2019), is a good example of phytochemicals with multimechanistic mode of action. Over 300 clinical trials have shown the beneficial protective effects of curcumin against different diseases and consist of inflammatory, neurological, cardiovascular, pulmonary, metabolic and liver diseases, and also cancers (Jäger et al., 2014). Curcumin has shown antiviral activities against several different viruses and could be a therapeutic option for the management of COVID-19 infection. Previous reports have shown that curcumin has both direct and indirect antiviral activity against the HIV by inhibiting virus replication or via blocking inflammatory pathways operating in the acquired immunodeficiency syndrome (Prasad & Tyagi, 2015). It has also efficacy against chikungunya and Zika virus (Mounce, Cesaro, Carrau, Vallet, & Vignuzzi, 2017).

To the best of our knowledge, this is the first clinical trial which evaluated curcumin efficacy and safety in COVID-19 infection. As mentioned above, in this open-label nonrandomized study, most symptoms resolved significantly faster than control group, importantly fever and tachypnea. Moreover, SaO₂ was significantly higher after 2, 4, 7, and 14 days of follow-up in treatment group and length of need to supplemental O₂, and hospitalization was meaningfully shorter in treatment group. It is also noteworthy to mention that no patient in treatment group experienced deterioration of infection during follow-up period, but it occurred in 40% of control group. No patients died in control and treatment group in this study. In a meta-analysis including a total of 58 studies with 122,191 patients, rate of mortality among the hospitalized COVID-19 patients was 18.88%. Highest mortality was found in Europe (PR 26.85%, 95% CI [19.41–34.29], p < .001) followed by North America (PR 21.47%, 95% CI [16.27–26.68], p < .001) and Asia (PR 14.83%, 95% CI [12.46–17.21], p < .001). A significant association was found between mortality among COVID-19-infected patients and older age (>65 years vs. <65 years) (RR 3.59, 95% CI [1.87–6.90], p < .001), ICU admitted patients (RR 3.72, 95% CI [2.70–5.13], p < .001), cardiovascular disease (RR 2.51, 95% CI [1.20–5.26], p < .05), and cancer (RR 2.31, 95% CI [1.80–2.97], p < .001). Furthermore, significant association for high risk of mortality was also found for COPD, chronic renal disease, chronic liver disease, chronic lung disease, and chronic kidney disease (Noor & Islam, 2020). So, as we excluded elderly, ICU admitted patients and also the subjects with various abovementioned underlying diseases the rate of mortality was zero in our limited sample size.

Moreover, adverse reactions particularly GI symptoms did not have higher prevalence in treatment group. Besides, hepatic and renal functions of patients were not significantly different between two groups at the end of the study. So, it seems that nano-curcumin with daily dose of 160 mg was had good safety in study population.

It should be also mentioned that rise of ALT/AST serum level was found in near 50% of patients in both groups. Mostly, 7.14–64.15% of patients with COVID-19 had increased AST, ALT, gamma-glutamyltransferase (GGT), and bilirubin levels (Kumar et al., 2020). Furthermore, the relative risk of these abnormalities was higher in the patients with severe COVID-19 when compared to nonsevere disease. In Kumar et al. (2020), meta-analysis which included 128 studies on COVID-19 patients, rise of ALT (23.28% [19.92–27.01]), and AST (23.41% [18.84–28.70]) reported in about quarter of patients (Kulkarni et al., 2020). It seems that as we selected hospitalized patients, the rate of elevated liver chemistries was somewhat higher than reported values.

Despite the lack of clinical studies in this field, some researchers proposed curcumin as a possible effective measure for COVID-19 management. Zahedipour et al. defined that curcumin could interact with various molecular targets like DNA polymerase, thioredoxin reductase, focal adhesion kinase (FAK), protein kinase (PK), tubulin, and lipoxygenase (LOX) and trigger cellular signaling pathways such as apoptosis and inflammation. Moreover, curcumin modulates intercellular signaling cascades which are crucial for effective virus replication such as attenuation of NF-κB and PI3K/Akt signaling. It also affects cellular posttranscriptional and posttranslational modifications. So, curcumin may have beneficial effects against COVID-19 infection by interacting with attachment and internalization of SARS-CoV-2 in different organs, like liver, cardiovascular system, and kidney. Curcumin may also suppress pulmonary edema and fibrosis-associated pathways in COVID-19 infection which may be more assessable in severe COVID-19 infection. It produces these effects by reducing the expression of crucial chemokines and cytokines involved in lung infection such as IFNγ, MCP-1, IL-6, and IL-10 (Avasarala et al., 2013; Zahedipour et al., 2020).

Roy et al. (2020) proposed that beside abovementioned mechanisms, considering blood coagulation inhibitory properties of curcumin (by inhibiting platelet aggregation, cyclooxygenase pathway, and blocking of calcium signaling), as the SARS-CoV-2 coronavirus infection can be associated with a disseminated intravascular coagulopathy, curcumin can be an effective agent against this pathological condition.

Moreover, Airton Castro Rocha and Renato de Assis (2020) suggested that considering the controversy as to whether drugs acting in the angiotensin converting enzyme (ACE) pathway exacerbate the clinical appearance of patients affected by SARS-CoV-2 and available data showing that curcumin may either increase or decrease ACE in vivo activity, effect of curcumin on this pathway also could be a probable mechanism for curcumin efficacy in COVID-19.

Recently, a molecular ducking study showed that curcumin owns better binding capability to the ACE2 receptors and may inhibit the entry of COVID-19 virus. ACE2 receptor binds with SARSCoV-2 spike glycoprotein and facilitates membrane fusion and viral infection through endocytosis. So, spike glycoprotein is a potential candidate for drug targeting to inhibit the entry of virus (Utomo & Meiyanto, 2020) that in silico docking studies discovered that curcumin could potentially inhibit ACE2 to suppress COVID19 entry to the cell (Zahedipour et al., 2020).

So, these proposed mechanisms may be applicable to justify our findings. Moreover, as some of these proposed mechanisms of curcumin effectiveness in COVID-19 are related to its anticoagulant and antifibrosis properties, it is recommended to evaluate its efficacy in patients with severe COVID-19 infection who experienced cytokine storm.

The small sample size and open-label and nonrandomized design of this study are other limitations of this study.

5 CONCLUSION

According to the results of this study, the nano-formulation of curcumin (40 mg/soft gel) with dose of 80 mg twice daily could significantly fasten the resolution time of COVID-19-induced symptoms, improve oxygenation, and reduce hospital stay time in comparison with control group, and no significant adverse reaction is reported with nano-curcumin. Double-blind randomized clinical trials with larger sample size particularly on patients with more severe form of infection are recommended.

ACKNOWLEDGMENTS

The authors are thankful for the funding of this study by the Research Council of Mashhad University of Medical Sciences and Exir Nano Sina Company (Tehran, Iran) for providing the Nanocurcumin soft gels.

CONFLICT OF INTEREST

Dr. Mahmoud Reza Jaafari, one of the manuscript authors, is the founder of Exir Nano Sina Company which produced the studied medication. Other authors have nothing to declare.