علی اصغر همتی

Covid-19 is the name of the disease caused by the new SARS-Cov-2 virus. Thus far, numerous non-specific therapies have been employed for this viral infection, however, the majority of these medications have proven to be ineffective and have been correlated with a multitude of adverse effects for patients. Therefore, the use of medicinal plants has received a lot of attention. The current study aims to investigate the effects of the supplemental drug Curcumex on the healing process in outpatients with COVID-19.

The present study, which is a double-blind randomized controlled clinical trial, was conducted on outpatients with covid-19 which has the code of ethics number IR.MAZUMS.REC.1400.593 from Mazandaran University of Medical Sciences. The inclusion criteria for this study include patients who had a ground glass appearance in the CT scan of the chest, the presence of clinical symptoms such as dry cough, shortness of breath, fever, weakness, diarrhea, headache, runny nose, or having a history of contact with a corona patient or recent travel to High-risk areas and people who had a positive PCR result in the nasopharyngeal swab were defined. Curcumex is a new herbal medicine that contains a combination of black pepper, turmeric, and ginger. Black pepper is hot in nature and has astringent, anti-bloating, and digestive properties. Antioxidant and anti-inflammatory effects have been reported for this plant, which can be useful in COVID-19 disease. The sample size was equal to 60 people who were divided into 2 intervention and control groups of 30 people. Both groups received routine medications prescribed for outpatients. In addition to these treatments, one group received curcumex (containing 170 mg of ginger, 4 mg of black pepper, and 340 mg of turmeric) daily, and the control group received a placebo.

The results of the current study indicated that the average duration of all clinical symptoms measured in this study was significantly less in the intervention group than in the control group (shortness of breath: 2.13 days vs. 3.66 days; cough: 4 days vs. 7.6 days; Gastrointestinal symptoms: 0.73 days vs. 2.21 days and myalgia: 4.1 days vs. 9.2 days). Also, these results show that the average body temperature before the start of the intervention in the intervention group was 38.32 degrees Celsius and 38.17 degrees Celsius in the control group. This rate 5 day after the start of the study in the intervention group was significantly lower than the control group (37.46 degrees Celsius vs. 37.92). The average oxygen saturation before the intervention was 94.76% in the intervention group and 95.63% in the control group. This amount 5 day after the start of the study in the intervention group was significantly higher than the control group (97.16% vs. 96.1%) (Table 2). to the control group. The results of this study showed that the average number of lymphocytes after the intervention in the intervention group increased significantly compared to the control group (1544.46 in the intervention group and 1132.58 in the control group).

This study showed that daily consumption of Curcumex drug as a supplement along with other routine treatments of COVID-19 disease has a positive effect on the recovery process of the disease shortens the course of clinical symptoms, reduces inflammatory markers by a quarter, and corrects lymphopenia. The duration of clinical symptoms, including shortness of breath, cough, myalgia, and gastrointestinal symptoms in patients with COVID-19 who have been treated with Curcomex has significantly decreased. Furthermore, these results indicated that the recovery of fever and hypoxemia (decreased hemoglobin oxygen saturation) in the intervention group was faster than the placebo group and was significantly less than the group of patients who received a placebo.

The coronavirus disease 2019 (COVID-19) outbreak was initially announced in Wuhan, China in late December 2019, which is caused by SARS-CoV-2, and rapidly spread worldwide (1). The severity of the disease varied from asymptomatic to the need for a ventilator (3, 4). Generally, there are no beneficial antiviral drugs for COVID-19. The used medications are commonly prescribed to relieve the complications of COVID-19, such as fever, inflammation, chest pain, cough, and respiratory distress (5-7). The immune system involvement and an increase in the release of inflammatory cytokines can be observed in COVID-19 patients. On the other hand, herbal drugs with anti-inflammatory and immunomodulatory properties can be preventive and even treat COVID-19 (8). The effectiveness of natural and herbal medicines for the prevention and treatment of COVID-19 have been reported (9-11). Among herbal medicines, the grape seed extract (GSE) has valuable medicinal properties due to having proanthocyanidins, flavonoids and polyphenols compounds. GSE as a natural bioactive compound possesses several pharmacological benefits, including cardioprotective, neuroprotective, antioxidant, hepatoprotective, antidiabetic, anti-inflammatory, anticarcinogenic, antiaging, anti-cholesterol, anti-platelet and antimicrobial properties (14, 15).  Grape seed extract also exerts antiviral effects in the management of patients with human enteric virus, hepatitis A virus (HAV) (18) hepatitis C virus (HCV) (19), human immunodeficiency virus 1 (HIV) (20), and human norovirus surrogates, such as murine norovirus (MNV-19) (21) and feline calicivirus (FCV) strain F9. But its effects on COVID-19 remain unclear. The purpose of this study was to evaluate the effects of GSE on the treatment of hospitalized patients with COVID-19.

The current double-blind, parallel, randomized clinical trial was performed in 2021 on Ayatollah Taleghani Hospital, Abadan, Iran. The supplemental Figure 1 presents the study flowchart. COVID-19 cases (N=80) were randomly assigned to the GSE and placebo groups via block randomization using block randomization (block sizes of 4 and 8, respectively).The GSE group was given one capsule of GSE (with 200 mg of GSE) every 12 hours, plus national standard treatment for COVID-19. The placebo group was treated with placebo capsules. The COVID-19 clinical symptoms, respiratory rate, O2 saturation (SaO2), and blood pressure were evaluated at baseline and on day 14. Complete blood count, hematocrit level, white blood cell count, hemoglobin level, alkaline phosphatase, blood urea  nitrogen, erythrocyte sedimentation rate, serum alanine aminotransferase, aspartate aminotransferase, international normalized ratio, serum creatinine, partial thromboplastin time, and prothrombin time were evaluated at baseline and after the treatment. Comparison of the primary outcome of this study (hospital stay difference) was done between the two groups by independent t-test and Cox proportional hazards regression analysis. ANOVA test was also used to evaluate secondary outcomes. To control for the baseline measurements, ANCOVA test was performed.

The patients’ baseline information in the placebo and GSE groups is shown in Table 1. Moreover, an intention-to-treat analysis was our primary analysis on all patients with random assignment. Based on t-test, the hospital stay was half a day longer in the placebo group than the GSE group; however, this difference was not significant (mean difference=0.5; 95% CI: -1.09-2.09; P=0.53). The secondary outcomes were compared using t-test (Table 2). Based on the results of this table, no significant difference was found between the secondary outcomes, except for the red blood cells (RBC) and hemoglobin level. After adjusting for the baseline values of RBC and hemoglobin based on the analysis of covariance (ANCOVA), no significant difference was detected between the two groups in these two variables (mean difference for RBC= -0.11; 95% CI: -0.32, 0.08; P=0.26; mean difference for Hb= -1.78, 95% CI: -3.64, -0.08, P=0.06). After expanding the data to the sample size using an expansion module in STATA (version 12), a 17% difference in the mean duration of hospitalization became significant between the GSE and placebo groups (HR=0.85; 95% CI: 0.93-0.33; P=0.001). After controlling for age, sex, and blood pressure, this relationship remained significant.

The results indicated that GSE did not affect the clinical signs or biochemical markers of 80 patients evaluated in this study. However, the power analysis showed that the difference in hospital stay would be significant if the study was performed on a larger sample size (about 1,273 cases) in each group. Due to similarities between HCV, HIV and SARS-CoV-2, medicines that are used for the treatment of HIV and HCV have been also suggested for COVID-19. One of the similarities between HIV and COVID-19 is that both viruses can increase the generation of proinflammatory cytokines. They increase the formation of cytokines involved in secondary complications associated with the viral load of SARS-CoV-2 (29). Since no specific accepted antiviral medicine is available to treat COVID-19, antiviral agents for HIV and HCV infections have been suggested for treatment (29, 30). Evidence suggests that GSE has antiviral effects against human enteric virus, hepatitis A virus (18), HCV(19) , HIV-1 (20), and human norovirus surrogates, including the MNV-19 and FCV (21) .It is known that GSE contains a high level of proanthocyanidins, can suppress HCV replication (34). Zannella et al 2021, indicated that Vitis vinefra leaf extract showed the inhibitory effect on SARS-CoV-2 replication in the early stages of infection. They suggested that directly blocking the proteins enriched on the viral surface may be involved mechanism (22). According findings of Hajibeygi et al in 2022, diet Iranian traditional including Ficus carica; Vitis vinifera; Cicer arietinum; Descurainiasophia seeds, Safflower, Ziziphus jujuba, chicken soup; barley soup, rose water, and saffron and cinnamon spices decrease the inflammatory markers and CPR level in COVID-10 patients (23). So, recent studies indicated the efficacy of different parts of Vitis vinifera in decreasing symptoms of COVID-19, but more researches with a larger sample size was suggested.GSE did not have significant effects on the biochemical markers and signs of COVID-19. However, the current study is the first randomized controlled trial, in which the GSE effects were observed in COVID-19 patients. This clinical trial had some limitations. Such as it was conducted in the main referral hospital for COVID-19 patients with low population, severity of disease was not considered and total extract of Grape seed was used. Finally, it is suggested to conduct a similar survey as a multi-center trial on a large population in the future.

Traditional medicine reported the appropriate analgesic and anti-inflammatory effects of Malva sylvestris, The anti-inflammatory effect, which was proved by literature, made it likely that the plant would be effective in pain modulation. Therefore, the effect of its hydro-alcoholic extract on the analgesic effect of morphine was assessed for reducing morphine dosage.

Pain intensity was assessed using Tail Flick test at spot heat of 55°C and cut off time of 10 seconds on adult male rats. An appropriate dose of morphine to cause analgesia was determined intraperitoneally using dose-response method. The analgesic effect of different doses 100,200,400 and 600 mg/kg of Malva sylvestris extract and the effect of the doses on the analgesic property of an appropriate dose of morphine (2.5mg/kg) were examined.

The best analgesic effect with the ability to increase the threshold for occurrence of tail painful reflex was related to dose 400 mg/kg of the extract, which its highest analgesic effect was observed in minute 45. Administration of the most effective dose of the extract with morphine significantly (pvalue<0.05) increased morphine’s analgesic effect. Naloxone administration, 15 minutes before administration of this dose, could significantly (pvalue<0.05) decrease its analgesic effect.

Hydroalcoholic extract of Malva sylvestris (HEMS) is capable of increasing morphine’s analgesic effect. Some of this effect is through its effect on opioid receptors, which are inhibited by Naloxone as an antagonist of morphine that is probably one of its analgesic mechanisms.