Evaluating therapeutic potential of AYUSH-64 constituents against omicron variant of SARS-CoV-2 using ensemble docking and simulations.

The COVID-19 pandemic in the later phase showed the presence of the B.1.1.529 variant of the SARS-CoV-2 designated as Omicron. AYUSH-64 a poly herbal drug developed by Central Council for Research in Ayurvedic Sciences (CCRAS) has been recommended by Ministry of Ayush in asymptomatic, mild to moderate COVID-19 patients. One of the earlier, in-silico study has shown the binding of the constituents of AYUSH-64 to the main protease (Mpro) of the SARS-CoV-2. This study enlisted four phytochemicals of AYUSH-64, which were found to have significant binding with the Mpro. In continuation to the same, the current study proposes to understand the binding of these four phytochemicals to main protease (Mpro) and receptor binding domain (RBD) of spike protein of the Omicron variant. An enhanced molecular docking methodology, namely, ensemble docking has been used to find the most efficiently binding phytochemical. Using molecular dynamics (MD) simulations and clustering approach it was observed that the Mpro and RBD Spike of Omicron variant of SARS-CoV-2 in complex with human ACE2 tends to attain 4 and 8 conformational respectively. Based on the docking studies, the best binding phytochemical of the AYUSH-64, akummicine N-oxide was selected for MD simulations. MD simulations of akummicine N-oxide bound to omicron variant of Mpro and RBD Spike-ACE complex was performed. The conformational, interaction and binding energy analysis suggested that the akummicine N-oxide binds well with Mpro and RBD Spike-ACE2 complex. The interaction between RBD Spike and ACE2 was observed to weaken in the presence of akummicine N-oxide. Hence, it can be inferred that, these phytochemicals from AYUSH-64 formulation may have the potential to act against the Omicron variant of SARS-CoV-2.

Learnings from a veteran oncologist's long-standing efforts in integrative oncology.

Kerala's first medical oncologist, the erstwhile Dr. CP Mathew, has left a rich legacy in cancer patients' case diaries and medical records. These documents contain valuable information about his attempts to integrate Siddha and Ayurveda treatments to manage cancer. A preliminary examination of these documents compiled over more than four decades gives us a glimpse of his contributions relevant to the development of Integrative Oncology in India. Patients who received treatment from Dr. CP Mathew presented with different types of cancer in varying stages of progression. In his clinical practice, he developed treatment approaches that integrated Ayurveda and Siddha with the standard of care for specific types and presentations of cancer. At Cherian Ashram in Kottayam, where he treated cancer patients, a team of medical doctors, including a senior Ayurveda physician and a Naturopathy and Yoga expert, worked together to offer integrative care. Based on his experience, he emphasized that the public should be made aware of the available options for alternative treatments even in advanced stages of cancer. While Ayurveda and Siddha could bolster the patient's immunity and improve clinical outcomes, he pointed out that such interventions could also improve tolerance to chemotherapy and radiation. In the wake of the growing global interest in Integrative Oncology, the work of Dr. CP Mathew preserved in the medical records of his cancer patients deserves to be studied with an open mind.

Randomized, double blind, placebo controlled, clinical trial to study co-administration of Ashwagandha on safety, immunogenicity, and protection with COVID-19 vaccine: A Study Protocol

IntroductionThe government of India has rolled out COVID-19 vaccine program for individuals who are 18 years of age and above and priority is being given to the elderly, and individuals with morbidity. Oxford-AstraZeneca COVID-19 vaccine (COVISHIELD) is most widely used in India. A large number of Indian people have been consuming various traditional medicines in the hope of better protection against COVID-19 infection. Several studies have reported immunological benefits of Ashwagandha and its potential as vaccine adjuvant. We plan to study co-administration of Ashwagandha with COVISHIELD vaccine on safety, immunogenicity and protection. Methods and analysisWe designed a prospective, randomized, double blind, parallel group, placebo controlled, two arm, exploratory study on healthy volunteers receiving the COVISHIELD vaccine. In addition to the two dose schedule of COVISHIELD vaccine as per national guidelines, participants will be administered 8gm Ashwagandha or placebo tablets respectively per day. Primary outcome measure is immunogenicity as measured by SARS-CoV-2 spike (S1) and RBD-specific IgG antibody titres. Secondary outcome measures are safety, protective immune response and quality of life measures. Adverse event following immunization will be monitored at each time throughout the study. Participants will be tracked on a daily basis with a user friendly mobile phone application. Following power calculation 600 participants will be recruited per arm to demonstrate superiority by a margin of 7% with 80% power. Study duration is 28 weeks with interim analysis at the end of 12 weeks. Ethics and disseminationEthical approval was obtained through the Central and institutional Ethics Committees. Participant recruitment is expected to commence by August 2021. Results will be presented in conferences and published in preprint followed by peer-reviewed medical journals. Registration detailsClinical Trial Registry - India (CTRI) Registration Number: CTRI/2021/06/034496. Date of Registration June 30, 2021. Strengths and limitations of this studyO_LINovel study to demonstrate effect of coadministration of immune adjuvant and COVID-19 vaccine on safety and immunogenicity. C_LIO_LIRandomised placebo controlled 28 weeks study with 80 percent power to demonstrate role of putative natural immunomodulator to augment the protection and reduce breakthrough infections C_LIO_LIState of art immune assays to measure specific antibodies to SARS-CoV-2 to demonstrate both persistent and late upsurge in immune response C_LIO_LIDaily tracking of participants using a study specific designed mobile app C_LIO_LIAn interim analysis is planned to provide information on early immune response after first dose of vaccine C_LIO_LIParticipants may be reluctant to donate blood repeatedly for immune assays; compliance with the test drug may be a challenge; asymptomatic infections may be missed; the study is not measuring cellular immune response. C_LI

Coadministration of AYUSH 64 as an adjunct to Standard of Care in mild and moderate COVID-19: A randomised, controlled, multicentric clinical trial

ObjectivesTo compare the co-administration of an Ayurvedic drug AYUSH 64 as an adjunct to standard of care (SOC) and SOC for efficacy and safety in the management of COVID-19. DesignMulticentre, parallel efficacy, randomized, controlled, open label, assessor blind, exploratory trial with a convenience sample. Patients followed to complete 12 weeks of study duration. SettingCOVID-19 dedicated non-intensive care wards at 1 government hospital, 1 medical college teaching hospital and 1 medical university teaching hospital Participants140 consenting, eligible, hospitalized adult patients suffering from mild and moderate symptomatic COVID-19 and confirmed by a diagnostic (SARS-CoV-2) RT-PCR assay on nasal and throat swab were randomized to SOC or SOC plus AYUSH 64. To be withdrawn if disease becomes severe. InterventionsTwo tablets of AYUSH 64, 500 mg each, twice daily after meals, and continued till study completion. SOC (symptomatic and supportive) as per national guidelines of India for mild and moderate disease. Main outcome measuresTime period to clinical recovery (CR) from randomization baseline and proportion with CR within 28 days time frame; CR defined in the protocol Results140 patients randomized (70 in each arm); 138 patients with CR qualified for analysis. Both groups were matched at baseline. The mean time to CR from randomization was significantly superior in AYUSH 64 group (95% CI -3.03 to 0.59 days); a higher proportion (69.7%) in the first week (p=0.046, Chi-square). No significant differences observed for COVID-19 related blood assays (such as D-Dimer). AYUSH 64 arm showed significant (p<0.05) superior persistent improvement in general health, quality of life, fatigue, anxiety, stress, sleep and other psychosocial metrics. 1 patient on SOC required critical care. 48 adverse events (AE) reported in each group. Barring three SAE (in SOC), AE were mild and none were drug related. 22 participants (8 on AYUSH) were withdrawn. No deaths were reported. ConclusionsAYUSH 64 hastened recovery, reduced hospitalization and improved overall health in mild and moderate COVID-19 when co-administered with SOC under medical supervision. It was safe and well tolerated. Further studies are warranted. Trial registrationThe Clinical Trials Registry India Number CTRI/2020/06/025557 FundingCCRAS, Ministry of AYUSH, Government of India

Chyawanprash for the prevention of COVID-19 infection among healthcare workers: A Randomized Controlled Trial

BackgroundCoronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are at high risk of exposure, the standard of care is personal protection from getting infected. Whether Ayurvedic rasayana drug like Chyawanprash can prevent symptomatic infection in frontline health care workers is unknown. ObjectiveTo evaluate the effect of the combination of Chyawanprash and Standard Preventive Regimen compared to the use of Standard Preventive Regimen alone on the proportion of RT-PCR confirmed COVID-19 infections among frontline healthcare workers (HCWs). MethodsAn open-label randomized controlled trial was conducted in the HCWs between 25 to 60 years age currently working in an environment with chance of direct exposure to COVID-19 cases. The interventions to be compared in this trial were Standard Preventive Regimen as per institutional guidelines and based on their roles (Group I) and Ayurvedic Intervention viz., Chyawanprash 12 g twice for 30 days from day of randomization plus Standard Preventive Regimen (Group II). The incidence of RT PCR confirmed COVID-19 cases in both groups, was the primary outcome measure. Evaluation of the safety of the study drug (by any statistically significant change in various biochemical and hematological parameters and occurrence of any adverse drug reactions); incidence of any other infective diseases (bacterial /viral/ fungal / etc.) like upper respiratory tract illness during the study period and any change in the immunoglobulins like IgG, IgM and IgE and inflammatory markers like TNF alpha, IL-6 and IL-10 were the secondary outcome measures. ResultsOut of 193 participants who completed the study, no participant in both groups was COVID-19 positive at the end of one month. In post intervention follow-up, 4 subjects in Group I and 2 subjects in Group II were COVID-19 positive. No adverse drug reaction or any serious adverse event was reported during the study. No clinically significant change in the safety parameters was observed before and after the study. Statistically significant rise in Serum IgG level was seen in Group II but other inflammatory and immune markers did not show statistically significant difference. ConclusionChyawanprash was well tolerated by all the participants in the intervention group but to prove its adaptogenic effect and efficacy as an add-on to the standard care in preventing the occurrence of COVID-19, clinical trial for longer duration with larger sample size is needed. Trial registrationClinical Trials Registry of India vide CTRI/2020/05/025275 dated 20/05/2020 Date of IEC approval19.5.2020