Received: 18 August 2020 Revised: 14 December 2020 Accepted: 14 December 2020

DOI: 10.1002/ptr.7004

RESEARCH ARTICLE

Oral nano-curcumin formulation efficacy in management of

mild to moderate hospitalized coronavirus disease-19 patients:
An open label nonrandomized clinical trial

Niloofar Saber-Moghaddam1 | Soofia Salari1 | Sepideh Hejazi2 | Mahnaz Amini3 |

Zhila Taherzadeh4 | Saeed Eslami5 | Seyed Mahdi Rezayat6 |
Mahmoud Reza Jaafari7,8 | Sepideh Elyasi1

1
Department of Clinical Pharmacy, School of
Pharmacy, Mashhad University of Medical Curcumin is proposed as a potential treatment option for coronavirus disease-19
Sciences, Mashhad, Iran
(COVID-19) by inhibiting the virus entrance, encapsulation and replication, and mod-
2
Rheumatic Diseases Research Center, School
of Medicine, Mashhad University of Medical ulating various cellular signaling pathways. In this open-label nonrandomized clinical
Sciences, Mashhad, Iran trial, efficacy of nano-curcumin oral formulation has been evaluated in hospitalized
3
Department of Internal Medicine, Mashhad
patients with mild–moderate COVID-19. Forty-one patients who fulfilled the inclu-
University of Medical Sciences, Mashhad, Iran
4
Targeted Drug Delivery Research Center,
sion criteria were allocated to nano-curcumin (n = 21) group (Sinacurcumin soft gel,
School of Pharmacy, Mashhad University of contains 40 mg curcuminoids as nanomicelles, two capsules twice a day) or control
Medical Sciences, Mashhad, Iran
5
(n = 20) group, for 2 weeks. Patients' symptoms and laboratory data were assessed at
Department of Medical Informatics, Faculty
of Medicine, Mashhad University of Medical baseline and during follow-up period. Most of symptoms including fever and chills,
Sciences, Mashhad, Iran tachypnea, myalgia, and cough resolved significantly faster in curcumin group. More-
6
Department of Pharmacology, School of
over, SaO2 was significantly higher in treatment group after 2, 4, 7, and 14 days of
Medicine, Tehran University of Medical
Sciences, Tehran, Iran follow-up and lymphocyte count after 7 and 14 days. Duration of supplemental O2
7
Nanotechnology Research Center, use and hospitalization was also meaningfully shorter in treatment group. It is also
Pharmaceutical Technology Institute, Mashhad
University of Medical Sciences, Mashhad, Iran noteworthy to mention that no patient in treatment group experienced deterioration
8
Department of Pharmaceutical of infection during follow-up period, but it occurred in 40% of control group. Oral
Nanotechnology, School of Pharmacy,
curcumin nano-formulation can significantly improve recovery time in hospitalized
Mashhad University of Medical Sciences,
Mashhad, Iran COVID-19 patients. Further randomized placebo controlled trials with larger sample
size are recommended.
Correspondence
Sepideh Elyasi, Department of Clinical
Pharmacy, School of Pharmacy, Mashhad KEYWORDS
University of Medical Sciences, Mashhad, Iran. antiinflammatory, clinical response, COVID-19, curcumin
Email: elyasis@mums.ac.ir

Funding information
Research Council of Mashhad University of
Medical Sciences

1 | I N T RO DU CT I O N cause of COVID-19 mortality, mostly due to cytokine storm syndrome

Coronavirus disease 2019 (COVID-19)-induced pneumonia became
an international concern, which led to the first pandemic of the cen-
tury in March 2020 (Wang, Horby, Hayden, & Gao, 2020). Respiratory
failure from acute respiratory distress syndrome (ARDS) is the leading
(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

Phytotherapy Research. 2021;1–8. wileyonlinelibrary.com/journal/ptr © 2021 John Wiley & Sons, Ltd. 1
2 SABER-MOGHADDAM ET AL.
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. More-
over, 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 car-
diac 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 proper-
ties of this phytochemical on the lung tissue make it a promising can-
didate 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 cur-
cumin 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 bio-
availability is not sufficient for oral administration. It is mentioned that
manipulation and encapsulation of curcumin into micelles, liposomes,
phospholipid complexes, exosomes, or polymeric nanocarrier formula-
tion 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 clin-
ical trial from April to July 2020 at COVID-19 wards of Imam Reza
and Quaem Hospitals affiliated to Mashhad University of Medical Sci-
ences, 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 sam-
ples, (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 pas-
sed from their onset of symptoms, be pregnant or breastfeeding,
smoking more than five cigarettes a day, had history of hypersensitiv-
ity 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 dis-
ease, active malignancy, autoimmune disease, immune system impair-
ment 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 Sci-
ences approved the study protocol (Code: IR.MUMS.REC.1399.054),
and it was registered at the Iranian Registry of Clinical Trials
SABER-MOGHADDAM ET AL.
(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. Actu-
ally, 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 recom-
mendations were presented to all participants. Furthermore, they
asked not to receive any other medications for COVID-19 manage-
ment 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 pharma-
cist considering the various signs and symptoms of COVID-19 infec-
tion (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 there-
after, until complete resolution. Besides, laboratory data (C-reactive
protein or CRP serum level and lymphocytes count) and atrial O2 satu-
ration (SaO2) were recorded after 2, 4, and 6 days and also at dis-
charge 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 deterio-
ration 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 supple-
mental 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 compli-
ance to treatment and adverse drug reactions (ADRs). They were pro-
posed to be adherent to their treatment if they consumed more than
80% of their administered medicine/placebo (Ho, Bryson, &
3
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 occur-
rence 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 moder-
ate 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 num-
ber 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 nor-
mally distributed variables between two groups. Fisher's exact test
was used to compare proportions between the groups; p < .05 was
considered as significant.
3 | RE SU LT S
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 com-
pleted the trial (Figure 1).
The average age of patients who completed the study was 55.9
± 15.16 years, and 65.9% of them were male. Other baseline charac-
teristics of patients are summarized in Table 1. There were no signifi-
cant 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. How-
ever, it was less than two times the upper limit of normal, except in
one patient in treatment group.
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 per-
formed in 80.49% of patients in treatment and control groups, which
4 SABER-MOGHADDAM ET AL.

FIGURE 1 Flow diagram of the study design

TABLE 1 Patients' characteristics

Nano-curcumin Control p-value
Gender (male/female ratio) 5/16 9/11 .197a
Age (year) 53.48 ± 12.21 58.45 ± 17.71 .305b
Duration of symptoms' occurrence (day) 3.57 ± 1.55 2.9 ± 0.51 .427b

Body temperature ( C) 37.37 ± 0.67 37.26 ± 0.69 .603b
Cough (%) 90.5 80 .41a
Headache (%) 38.1 50 .536a
Chills (%) 62.9 80 .288a
Myalgia (%) 95.2 75 .254a
Weakness (%) 23.8 40 .326a
GI symptoms (%) 14.3 30 .277a
Dyspnea (%) 100 100 1a
Olfactory and taste disturbances (%) 61.9 35 .121a
Serum level of CRP (mg/L) 91.2 ± 53.95 81.8 ± 77.97 .693b
Serum ALT level (IU/L) 52.35 ± 18.84 51.85 ± 17.94 .932b
Serum AST level (IU/L) 48.35 ± 22.19 47.68 ± 21.96 .926b
Serum creatinine level (mg/dl) 0.98 ± 0.17 0.88 ± 0.1 .243b
Lymphocytes count (%) 12.29 ± 7.98 8.87 ± 5.4 .147b
Atrial O2 saturation (%) 68.28 ± 24.17 65.45 ± 25.1 .74b
a
Fisher's exact test.
b
Independent sample t test.

was positive in 93.94% of them. There was no significant difference
regarding PCR and lung CT results between two groups (Table 2).
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).
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
SABER-MOGHADDAM ET AL. 5

T A B L E 2 Comparison of lung CT and RT-PCR findings between earlier. There were no significant difference between treatment and
treatment and control group control groups regarding these factors (p > .05) (Table 4).
Treatment Control p-value a

Lung CT
Consistent with 100 90 .332
4 | DI SCU SSION
COVID-19 (%)
Inconsistent with 0 5 COVID-19 outbreak is an ongoing pandemic occurred by severe
COVID-19 (%) acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with
Not performed (%) 0 5 considerable mortality worldwide. At this time, there are no effective
RT-PCR therapeutic strategies for management of COVID-19 infection

Positive (%) 76.19 75 .996 (Rodriguez-Morales et al., 2020). There is increasing evidence on the
antiviral potential of some herbal compounds (Praditya et al., 2019).
Negative (%) 4.76 5
So, indication of phytochemicals has attracted attention because of
Not performed (%) 19.05 20
their proven efficacy and safety in light of the ethnomedicinal reports.
a
Fisher's exact test. Curcumin, the bioactive ingredient of turmeric (Abdollahi, Momtazi,
Johnston, & Sahebkar, 2018; Mollazadeh et al., 2019), is a good exam-
ple of phytochemicals with multimechanistic mode of action. Over
T A B L E 3 Comparison of prescribed anti-COVID-19 regimens
300 clinical trials have shown the beneficial protective effects of cur-
between treatment and control group
cumin against different diseases and consist of inflammatory, neuro-
Anti-COVID-19 regimen Treatment Control p-valuea logical, cardiovascular, pulmonary, metabolic and liver diseases, and
HCQ (%) 76.19 80 1a also cancers (Jäger et al., 2014). Curcumin has shown antiviral activi-
Azithromycin (%) 52.38 55 1a ties against several different viruses and could be a therapeutic option
a
Broad-spectrum antibiotics (%) 61.9 80 .306 for the management of COVID-19 infection. Previous reports have
Protease inhibitors (%) 28.57 40 .52a shown that curcumin has both direct and indirect antiviral activity
Corticosteroid (%) 57.14 45 .538 a against the HIV by inhibiting virus replication or via blocking inflam-
matory pathways operating in the acquired immunodeficiency syn-
Abbreviation: HCQ, hydroxycholorquine.
a
Fisher's exact test.
drome (Prasad & Tyagi, 2015). It has also efficacy against
chikungunya and Zika virus (Mounce, Cesaro, Carrau, Vallet, &
Vignuzzi, 2017).
[p = .009]). Lymphocyte count was also significantly higher after To the best of our knowledge, this is the first clinical trial which
1 week and at discharge in treatment group (p < .05). Moreover, SaO2 evaluated curcumin efficacy and safety in COVID-19 infection. As
was significantly higher in curcumin group at 2, 4, 7 and 14 days mentioned above, in this open-label nonrandomized study, most
(p < .05), and length of supplemental oxygen use and hospitalization symptoms resolved significantly faster than control group, importantly
were meaningfully shorter for curcumin group (p < .001). However, fever and tachypnea. Moreover, SaO2 was significantly higher after
CRP serum level did not differ meaningfully between two groups after 2, 4, 7, and 14 days of follow-up in treatment group and length of
2, 4, and 7 days and also at discharge time (Table 4). need to supplemental O2, and hospitalization was meaningfully
Considering the patients' final outcome, there was a significant shorter in treatment group. It is also noteworthy to mention that no
difference between two groups (p = .003). In treatment group, about patient in treatment group experienced deterioration of infection dur-
half of patients (47.62%) experienced complete recovery and no one ing follow-up period, but it occurred in 40% of control group. No
experienced deterioration. But in control group, 40% of patients expe- patients died in control and treatment group in this study. In a meta-
rienced deterioration during these 2 weeks follow-up period and just analysis including a total of 58 studies with 122,191 patients, rate of
15% of patients had complete recovery (Table 5). 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%
3.3 | Safety of treatment 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
Three patients in treatment group and six patients in control group expe- mortality among COVID-19-infected patients and older age
rienced GI symptoms including diarrhea and abdominal pain during the (>65 years vs. <65 years) (RR 3.59, 95% CI [1.87–6.90], p < .001), ICU
study period, which was not significantly different. These symptoms may admitted patients (RR 3.72, 95% CI [2.70–5.13], p < .001), cardiovas-
be caused by COVID-19 infection itself or even might be the adverse cular disease (RR 2.51, 95% CI [1.20–5.26], p < .05), and cancer
reaction of other medications like hydroxychloroquine or antibiotics. (RR 2.31, 95% CI [1.80–2.97], p < .001). Furthermore, significant asso-
Moreover, we assessed the AST, ALT, and creatinine serum levels ciation for high risk of mortality was also found for COPD, chronic
at the end of the 2 weeks follow-up or at discharge, each happened renal disease, chronic liver disease, chronic lung disease, and chronic
6 SABER-MOGHADDAM ET AL.

T A B L E 4 Comparison of symptoms
Resolution time Nano-curcumin Control p-value
resolution time and laboratory findings
Fever (day) 0.62 ± 0.74 1.15 ± 1.35 .047*a changes between treatment and control
Cough (day) 1.62 ± 0.8 3.89 ± 1.54 .002*a group
Headache (day) 1.19 ± 1.12 1.33 ± 0.71 .678a
Tachypnea (day) 1.14 ± 0.85 1.85 ± 1.39 .031*a
Chills (day) 1.14 ± 1.31 2.55 ± 1.57 .004*a
Myalgia (day) 1.9 ± 0.83 3.44 ± 1.33 .009*a
Olfactory and taste disturbances (day) 1.62 ± 1.07 1.44 ± 1.59 .769a
Serum level CRP, second day (mg/L) 50.68 ± 32.15 39.52 ± 34.2 .463a
Serum level CRP, fourth day (mg/L) 42.38 ± 36.71 80.79 ± 78.36 .17a
Serum level CRP, 1 week (mg/L) 28.66 ± 36.67 34.17 ± 38.46 .797a
Serum level CRP, discharge/2 weekb (mg/L) 21.29 ± 21.75 21.43 ± 33.68 .993a
b
Serum level of ALT, discharge/2 week (IU/L) 53.13 ± 20.62 55.35 ± 17.41 .757a
Serum level of AST, discharge/2 weekb (IU/L) 49.33 ± 19.41 47.68 ± 21.96 .336a
b
Serum level of creatinine, discharge/2 week (mg/dl) 0.94 ± 0.13 0.91 ± 0.1 .449a
Lymphocyte count, second day (%) 13.62 ± 11.72 13.36 ± 6.64 .947a
Lymphocyte count, fourth day (%) 13.58 ± 7.6 11.56 ± 5.67 .412a
Lymphocyte count, 1 week (%) 16.12 ± 8.47 11.84 ± 5.14 .05*a
b
Lymphocyte count, discharge time/2 week (%) 18.76 ± 6.75 11.99 ± 6.01 .048*a
SaO2, second day (%) 82.12 ± 20.66 58.35 ± 31.46 .023*a
SaO2, fourth day (%) 89.11 ± 6.75 57.48 ± 33.77 .006*a
SaO2, 1 week day (%) 93.94 ± 3.56 69.65 ± 29.6 .022*a
b
SaO2, discharge time day/2 week (%) 94.33 ± 4.01 74.28 ± 22.1 .001*a
Length of need for supplemental O2 (day) 2.1 ± 0.77 3.85 ± 1.39 <.001*a
Hospitalization duration (day) 5.05 ± 1.36 9.15 ± 4.28 <.001*a
a
Independent sample t test.
b
Whichever shorter, without supplemental O2.
*The significance level: p < .05.

T A B L E 5 Comparison of final outcome between treatment and It should be also mentioned that rise of ALT/AST serum level was
control groups found in near 50% of patients in both groups. Mostly, 7.14–64.15% of
Outcome Treatment Control p valuea patients with COVID-19 had increased AST, ALT, gamma-
*a glutamyltransferase (GGT), and bilirubin levels (Kumar et al., 2020).
Complete recovery (%) 47.62 15 0.003
Furthermore, the relative risk of these abnormalities was higher in the
Partial recovery (%) 52.38 45
patients with severe COVID-19 when compared to nonsevere dis-
Deterioration (%) 0 40
ease. In Kumar et al. (2020), meta-analysis which included 128 studies
Death (%) 0 0
on COVID-19 patients, rise of ALT (23.28% [19.92–27.01]), and AST
a
Fisher's exact test. (23.41% [18.84–28.70]) reported in about quarter of patients
*The significance level: p < .05.
(Kulkarni et al., 2020). It seems that as we selected hospitalized
patients, the rate of elevated liver chemistries was somewhat higher
than reported values.
kidney disease (Noor & Islam, 2020). So, as we excluded elderly, ICU Despite the lack of clinical studies in this field, some researchers
admitted patients and also the subjects with various abovementioned proposed curcumin as a possible effective measure for COVID-19
underlying diseases the rate of mortality was zero in our limited management. Zahedipour et al. defined that curcumin could interact
sample size. with various molecular targets like DNA polymerase, thioredoxin
Moreover, adverse reactions particularly GI symptoms did not reductase, focal adhesion kinase (FAK), protein kinase (PK), tubulin,
have higher prevalence in treatment group. Besides, hepatic and renal and lipoxygenase (LOX) and trigger cellular signaling pathways such as
functions of patients were not significantly different between two apoptosis and inflammation. Moreover, curcumin modulates inter-
groups at the end of the study. So, it seems that nano-curcumin with cellular signaling cascades which are crucial for effective virus replica-
daily dose of 160 mg was had good safety in study population. tion such as attenuation of NF-κB and PI3K/Akt signaling. It also
SABER-MOGHADDAM ET AL.
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. Cur-
cumin 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 infec-
tion 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 mecha-
nisms, considering blood coagulation inhibitory properties of curcumin
(by inhibiting platelet aggregation, cyclooxygenase pathway, and
blocking of calcium signaling), as the SARS-CoV-2 coronavirus infec-
tion can be associated with a disseminated intravascular
coagulopathy, curcumin can be an effective agent against this patho-
logical condition.
Moreover, Airton Castro Rocha and Renato de Assis (2020)
suggested that considering the controversy as to whether drugs act-
ing in the angiotensin converting enzyme (ACE) pathway exacerbate
the clinical appearance of patients affected by SARS-CoV-2 and avail-
able 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 cur-
cumin 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 cur-
cumin 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 | C O N CL U S I O N
According to the results of this study, the nano-formulation of cur-
cumin (40 mg/soft gel) with dose of 80 mg twice daily could signifi-
cantly 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.
7
ACKNOWLEDG MENTS
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.
CONFLIC T OF INT ER E ST
Dr. Mahmoud Reza Jaafari, one of the manuscript authors, is the foun-
der of Exir Nano Sina Company which produced the studied medica-
tion. Other authors have nothing to declare.
OR CID
Zhila Taherzadeh https://orcid.org/0000-0001-7185-970X
Sepideh Elyasi https://orcid.org/0000-0001-9857-1175
RE FE RE NCE S
Abdollahi, E., Momtazi, A. A., Johnston, T. P., & Sahebkar, A. (2018). Thera-
peutic effects of curcumin in inflammatory and immune-mediated dis-
eases: A nature-made jack-of-all-trades? Journal of Cellular Physiology,
233(2), 830–848. https://doi.org/10.1002/jcp.25778
Airton Castro Rocha, F. A., & Renato de Assis, M. (2020). Curcumin as a
potential treatment for COVID-19. Phytotherapy Research, 34,
2085–2087. https://doi.org/10.1002/ptr.6745
Akbari, S., Kariznavi, E., Jannati, M., Elyasi, S., & Tayarani-Najaran, Z.
(2020). Curcumin as a preventive or therapeutic measure for chemo-
therapy and radiotherapy induced adverse reaction: A comprehensive
review. Food and Chemical Toxicology, 145, 111699. https://doi.org/
10.1016/j.fct.2020.111699
Avasarala, S., Zhang, F., Liu, G., Wang, R., London, S. D., & London, L.
(2013). Curcumin modulates the inflammatory response and inhibits
subsequent fibrosis in a mouse model of viral-induced acute respira-
tory distress syndrome. PLoS One, 8(2), e57285. https://doi.org/10.
1371/journal.pone.0057285
Avasarala, S., Zhang, F., Liu, G., Wang, R., London, S. D., & London, L.
(2015). Correction: Curcumin modulates the inflammatory response
and inhibits subsequent fibrosis in a mouse model of viral-induced
acute respiratory distress syndrome. PLoS One, 10(8), e0134982.
https://doi.org/10.1371/journal.pone.0057285
Biswas, S. K., McClure, D., Jimenez, L. A., Megson, I. L., & Rahman, I.
(2005). Curcumin induces glutathione biosynthesis and inhibits NF-κB
activation and interleukin-8 release in alveolar epithelial cells: Mecha-
nism of free radical scavenging activity. Antioxidants & Redox Signaling,
7(1–2), 32–41. https://doi.org/10.1089/ars.2005.7.32
Gupta, S. C., Patchva, S., Koh, W., & Aggarwal, B. B. (2012). Discovery of
curcumin, a component of golden spice, and its miraculous biological
activities. Clinical and Experimental Pharmacology and Physiology, 39(3),
283–299. https://doi.org/10.1111/j.1440-1681.2011.05648.x
Hatamipour, M., Sahebkar, A., Alavizadeh, S. H., Dorri, M., & Jaafari, M. R.
(2019). Novel nanomicelle formulation to enhance bioavailability and
stability of curcuminoids. Iranian Journal of Basic Medical Sciences, 22
(3), 282–289. https://doi.org/10.22038/ijbms.2019.32873.7852
Ho, P. M., Bryson, C. L., & Rumsfeld, J. S. (2009). Medication adherence:
Its importance in cardiovascular outcomes. Circulation, 119(23),
3028–3035. https://doi.org/10.1161/circulationaha.108.768986
Jäger, R., Lowery, R. P., Calvanese, A. V., Joy, J. M., Purpura, M., &
Wilson, J. M. (2014). Comparative absorption of curcumin formulations.
Nutrition Journal, 13, 11. https://doi.org/10.1186/1475-2891-13-11
Jain, S. K., Rains, J., Croad, J., Larson, B., & Jones, K. (2009). Curcumin supple-
mentation lowers TNF-α, IL-6, IL-8, and MCP-1 secretion in high glucose-
treated cultured monocytes and blood levels of TNF-α, IL-6, MCP-1, glu-
cose, and glycosylated hemoglobin in diabetic rats. Antioxidants & Redox
Signaling, 11(2), 241–249. https://doi.org/10.1089/ars.2008.2140
8 SABER-MOGHADDAM ET AL.
Kloesch, B., Becker, T., Dietersdorfer, E., Kiener, H., & Steiner, G. (2013).
Anti-inflammatory and apoptotic effects of the polyphenol curcumin
on human fibroblast-like synoviocytes. International Immuno-
pharmacology, 15(2), 400–405. https://doi.org/10.1016/j.intimp.2013.
01.003
Kulkarni, A. V., Kumar, P., Tevethia, H. V., Premkumar, M., Arab, J. P.,
Candia, R., … Reddy, D. N. (2020). Systematic review with meta-analy-
sis: Liver manifestations and outcomes in COVID-19. Alimentary Phar-
macology & Therapeutics, 52(4), 584–599. https://doi.org/10.1111/
apt.15916
Kumar-M, P., Mishra, S., Jha, D. K., Shukla, J., Choudhury, A., Ritin, M., …
Sharma, V. (2020). Coronavirus disease (COVID-19) and the liver: A
comprehensive systematic review and meta-analysis. Hepatology
International, 14, 711–722. https://doi.org/10.1007/s12072-020-
10071-9
Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S.,
Manson, J. J., & Collaboration, H. A. S. (2020). COVID-19: Consider
cytokine storm syndromes and immunosuppression. Lancet, 395
(10229), 1033–1034. https://doi.org/10.1016/S0140-6736(20)
30628-0
Moballegh Naseri, M., Abadi, B., Poormoghadam, D., Zarrabi, A.,
Keyhanvar, P., Khanbabaei, H., … Sethi, G. (2020). Curcumin delivery
mediated by bio-Based nanoparticles. A Review. Molecules, 25(3), 689.
Mollazadeh, H., Cicero, A. F. G., Blesso, C. N., Pirro, M., Majeed, M., &
Sahebkar, A. (2019). Immune modulation by curcumin: The role of
interleukin-10. Critical Reviews in Food Science and Nutrition, 59(1),
89–101. https://doi.org/10.1080/10408398.2017.1358139
Mounce, B. C., Cesaro, T., Carrau, L., Vallet, T., & Vignuzzi, M. (2017). Cur-
cumin inhibits Zika and chikungunya virus infection by inhibiting cell
binding. Antiviral Research, 142, 148–157. https://doi.org/10.1016/j.
antiviral.2017.03.014
Nelson, K. M., Dahlin, J. L., Bisson, J., Graham, J., Pauli, G. F., &
Walters, M. A. (2017). The essential medicinal chemistry of curcumin.
Journal of Medicinal Chemistry, 60(5), 1620–1637.
Noor, F. M., & Islam, M. M. (2020). Prevalence and associated risk factors
of mortality among COVID-19 patients: A meta-analysis. Journal of
Community Health, 45(6), 1270–1282. https://doi.org/10.1007/
s10900-020-00920-x
Praditya, D., Kirchhoff, L., Brüning, J., Rachmawati, H., Steinmann, J., &
Steinmann, E. (2019). Anti-infective properties of the golden spice cur-
cumin. Frontiers in Microbiology, 10, 912.
Prasad, S., & Tyagi, A. K. (2015). Curcumin and its analogues: A potential
natural compound against HIV infection and AIDS. Food & Function, 6,
3412–3419. https://doi.org/10.1039/c5fo00485c
Raflee, P., Nelson, V., Manley, S., Wellner, M., Floer, M., Binion, D., &
Shaker, R. (2009). Effect of curcumin on acidic pH-induced expression
of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): Role of
PKC, MAPKs, and NF-ĸB. American Journal of Physiology-
Gastrointestinal and Liver Physiology, 296, G388–G398. https://doi.
org/10.1152/ajpgi.90428.2008
Richardson, P., Griffin, I., Tucker, C., Smith, D., Oechsle, O., Phelan, A., &
Stebbing, J. (2020). Baricitinib as potential treatment for 2019-nCoV
acute respiratory disease. Lancet, 395(10223), e30. https://doi.org/10.
1016/S0140-6736(20)30304-4
Rodriguez-Morales, A. J., Cardona-Ospina, J. A., Gutiérrez-Ocampo, E.,
Villamizar-Peña, R., Holguin-Rivera, Y., Escalera-Antezana, J. P., …
Sah, R. (2020). Clinical, laboratory and imaging features of COVID-19:
A systematic review and meta-analysis. Travel Medicine and Infectious
Disease, 34, 101623. https://doi.org/10.1016/j.tmaid.2020.101623
Roy, A., Sarkar, B., Celik, C., Ghosh, A., Basu, U., Jana, M., … Ocsoy, I. (2020).
Can concomitant use of zinc and curcumin with other immunity-
boosting nutraceuticals be the arsenal against COVID-19? Phytotherapy
Research, 34, 2425–2428. https://doi.org/10.1002/ptr.6766
Ruan, Q., Yang, K., Wang, W., Jiang, L., & Song, J. (2020). Clinical predic-
tors of mortality due to COVID-19 based on an analysis of data of
150 patients from Wuhan, China. Intensive Care Medicine, 46(5),
846–848. https://doi.org/10.1007/s00134-020-05991-x
Shakoory, B., Carcillo, J. A., Chatham, W. W., Amdur, R. L., Zhao, H.,
Dinarello, C. A., … Opal, S. M. (2016). Interleukin-1 receptor blockade
is associated with reduced mortality in sepsis patients with features of
the macrophage activation syndrome: Re-analysis of a prior Phase III
trial. Critical Care Medicine, 44(2), 275. https://doi.org/10.1097/CCM.
0000000000001402
Song, Y., Ge, W., Cai, H., & Zhang, H. (2013). Curcumin protects mice from
coxsackievirus B3-induced myocarditis by inhibiting the pho-
sphatidylinositol 3 kinase/Akt/nuclear factor-κB pathway. Journal of
Cardiovascular Pharmacology and Therapeutics, 18(6), 560–569.
https://doi.org/10.1177/1074248413503044
Utomo, R. Y., & Meiyanto, E. (2020). Revealing the potency of citrus and
galangal constituents to Halt SARS-CoV-2 infection. Preprints,
2020030214. https://doi.org/10.20944/preprints202003.0214.v1
Wang, C., Horby, P. W., Hayden, F. G., & Gao, G. F. (2020). A novel coro-
navirus outbreak of global health concern. The Lancet, 395(10223),
470–473. https://doi.org/10.1016/S0140-6736(20)30185-9
Whitehead, A. L., Julious, S. A., Cooper, C. L., & Campbell, M. J. (2016).
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 con-
tinuous outcome variable. Statistical Methods in Medical Research, 25
(3), 1057–1073. https://doi.org/10.1177/0962280215588241
Zahedipour, F., Hosseini, S. A., Sathyapalan, T., Majeed, M.,
Jamialahmadi, T., Al-Rasadi, K., … Sahebkar, A. (2020). Potential effects
of curcumin in the treatment of COVID-19 infection. Phytotherapy
Research., 34, 2911–2920. https://doi.org/10.1002/ptr.6738
Zorofchian Moghadamtousi, S., Abdul Kadir, H., Hassandarvish, P.,
Tajik, H., Abubakar, S., & Zandi, K. (2014). A review on antibacterial,
antiviral, and antifungal activity of curcumin. BioMed Research Interna-
tional, 2014, 186864. https://doi.org/10.1155/2014/186864
How to cite this article: Saber-Moghaddam N, Salari S,
Hejazi S, et al. Oral nano-curcumin formulation efficacy in
management of mild to moderate hospitalized coronavirus
disease-19 patients: An open label nonrandomized clinical
trial. Phytotherapy Research. 2021;1–8. https://doi.org/10.
1002/ptr.7004