key: cord-0923101-yi1idn61 authors: Panda, Ashok Kumar; Kar, Sarbeswar; Rai, Amit Kumar; Rao, B.C.S.; Srikanth, N. title: AYUSH- 64: A Potential Therapeutic Agent in COVID-19 date: 2022-01-04 journal: J Ayurveda Integr Med DOI: 10.1016/j.jaim.2021.100538 sha: 2048389877bb33f6a90263b5ba9d7eb341a9fa4c doc_id: 923101 cord_uid: yi1idn61 Corona Virus disease (COVID-19) has become a global pandemic resulting in large scale morbidity and mortality worldwide. The causative agent SARS-CoV-2 is easily subject to repeated mutation with swift spread of infection. The management of COVID-19 has been a big challenge on account of non-availability of specific therapeutic agents. The complex and multifactorial pathophysiology of COVID-19 requires therapeutic agents with anti-viral properties against SARS-CoV-2 as well as immunomodulatory properties that have a broad-spectrum effectiveness covering the disease in totality. AYUSH-64, a poly-herbal formulation developed by CCRAS, Ministry of AYUSH, Govt. of India through extensive pharmacological, toxicological and clinical studies has proven efficacy in infective febrile conditions such as malaria, micro filaremia, chikungunya and influenza with no safety issues observed in published clinical studies. Based on the empirical evidence, it has been repurposed as an adjuvant to standard care or standalone therapy for asymptomatic and mild to moderate cases of COVID- 19 by the Ministry of AYUSH at a time when India is experiencing wave after wave of COVID-19 variants causing mass distress to the healthcare delivery systems. AYUSH- 64 has four ingredients having immune-modulator, anti-inflammatory, antipyretic, antioxidant and anti-viral activities. These effects could arrest the extreme inflammatory responses in COVID-19 that causes progression to significant morbidity. Several clinical studies on AYUSH-64 in asymptomatic and mild to moderate cases of COVID-19 have been undertaken at reputed medical institutions across the country. The evidence generated through these studies is promising. AYUSH-64 has also been incorporated in the National COVID management protocol based on Ayurveda and Yoga by Government of India for asymptomatic and mild cases of COVID-19. Further, on the basis of tangible evidence generated through robust clinical and experimental studies on AYUSH-64, the Ministry of AYUSH has launched nation-wide campaign for mass distribution of AYUSH-64 to asymptomatic, mild to moderate COVID-19 patients in home isolation to reduce the burden on the hospital-based health care delivery system. This review will highlight about the specifications of AYUSH-64, its probable mechanism of action, its repurposing for COVID-19, various clinical and experimental studies undertaken during the COVID-19 pandemic and the initiatives taken to translate the outcomes of these studies on AYUSH-64. Several clinical studies on AYUSH-64 in asymptomatic and mild to moderate cases of have been undertaken at reputed medical institutions across the country. The evidence generated through these studies is promising. AYUSH-64 has also been incorporated in the National COVID management protocol based on Ayurveda and Yoga by Government of India for asymptomatic and mild cases of COVID-19. Further, on the basis of tangible evidence generated through robust clinical and experimental studies on AYUSH-64, the Ministry of Ayush has launched nation-wide campaign for mass distribution of AYUSH-64 to asymptomatic, mild to moderate COVID-19 patients in home isolation to reduce the burden on the hospital-based health care delivery system. This review will highlight about the specifications of AYUSH-64, its probable mechanism of action, its repurposing for COVID-19, various clinical and experimental studies undertaken during the COVID-19 pandemic and the initiatives taken to translate the outcomes of these studies on AYUSH-64. Historically, outbreak of infectious diseases offers some model of the course of diseases and treatment such as Spanish flu, Bird flu etc. which unfold over the time. Some diseases have predictable seasonal peak with high transmission as some pathogen may spread rapidly in dynamics of humidity, social mixing pattern leaving predictable pattern for each variant. The 'wave' of COVID-19 and its implications is the prominent topic of debate in current times. An epidemic wave/phase is defined as natural pattern of peaks and valleys which indicate the number of sick people and deaths in time frame and then decline. 1 The first wave peaked in India in September 2020 and second wave started from 1 st week of March 2021. The second wave of COVID-19 tragedy and its impact on health care systems of our nation has been devastating and unprecedented. 2 There could be several factors responsible for the increased number of cases in the second wave. It is observed that the mutant strain of SARS-CoV-2 has higher transmission capability along with lesser incubation period. There has been a widespread disregard to the 'COVID Appropriate Behavior' by the general public, resulting in more severe illness, reduction in neutralizing antibodies and reduced effectiveness of vaccination. clinical recovery compared to standard of care alone without progression of the disease to severe or critical stage. [19] [20] [21] [22] The mean time to negative RT-PCR assay for COVID -19 was also better in the AYUSH-64 add-on group. 19, 21 . Also, there was improvement in Quality of life (QoL) parameters. 19 AYUSH-64 was found to be well tolerated and safe. Based on the leads generated through experimental and clinical studies, AYUSH-64 has been incorporated in the National COVID management protocol based on Ayurveda and Yoga for asymptomatic and mild cases of COVID-J o u r n a l P r e -p r o o f 19. 3 AYUSH-64 is further included in the "Guidelines for Ayurveda Practitioners for COVID-19 Patients in Home Isolation" issued by the Ministry of AYUSH during the second outbreak of COVID-19 in the country. 23 The Ministry of AYUSH has also launched nation-wide campaign for mass distribution of AYUSH-64 to asymptomatic, mild to moderate COVID-19 patients in home isolation to reduce the burden on the hospital-based health care delivery system. 24 The objective of this review is to scientifically explain the general therapeutic approach of AYUSH-64 to intervene in disease progression during various clinical and pathogenic stages of COVID-19. SARS-CoV-2 virus spreads through respiratory droplets of infected individuals. The average incubation period ranges from 1 to 14 days and mean is (5 to 6 days). 25 The headache (34%), dyspnea (50%), sore throat (14%), rhinorrhea (7%), anosmia (Loss of smell) and ageusia (Loss of taste) (< 7%), diarrhea (20%), vomiting (14%) and weakness (70%) in the hospitalized patients 28-30 along with a significant increase of Creactive protein (>20mg/dl). The CRP concentration is more in severe (>40mg/dl) and critical cases (>100mg/dl) compared to mild cases (< 18mg/dl). 31 The raised absolute lymphocyte count (<100cells/µl) is also found in severe patients. 32 The increased respiratory rate >30/min and SpO2 <90% are the indicators of severe COVID-19. Some patients proceed to critical stage as observed by systemic inflammation due to cytokine storm and widespread platelet aggregation leading to multi-organ failure as the end stage of COVID-19. An infected person initially moves through stages of replication over first few days followed by a stage of adaptive immunity over the next few days. In the replication stage, the virus replicates leading to flu-like illness characterized by mild symptoms due to direct cytopathic effect (structural changes in host cells) of the virus. In the stage of adaptive immunity, virus levels decline as immune system takes over, but in inflammatory phase, there is possibility of cytokine storm leading to tissue destruction and clinical deterioration. 33 To develop effective therapeutics and preventive measures against COVID-19, an accurate and precise understanding of its pathogenesis at the molecular level is needed. Based on the most recently published literature, the overall COVID-19 pathogenesis process can be summarized as three clinically distinct and potentially overlapping phases. As shown in Figure 1 , its pathological progression can be classified in chronological order as viral replication or early infection, pulmonary, proinflammatory, and prothrombotic phases. 34 J o u r n a l P r e -p r o o f The chemical constituents and therapeutic indications of the four ingredients of AYUSH-64 are given in Table 1 J o u r n a l P r e -p r o o f The majority of COVID-19 patients have subnormal or reduced leucocyte count, Karst may reduce the inflammatory process. 49 The ingredients of AYUSH-64 have the potential to control the initial symptoms of Epidemiology of COVID-19 Differences between First wave and Second wave of COVID-19 in India National Clinical Management Protocol based on Ayurveda and Yoga for management of Covid-19 A double-blind clinical trial with Ayush-64 an Ayurvedic drug in P. vivax Malaria Role of AYUSH-64 in malaria epidemic Ayush-64" (A Coded Antimalarial Medicine) in Cases of Malaria Effect of Ayush-64 and SaptaparnaghanaVati on Microfilaraemia Central Council for Research in Ayurvedic Sciences, Department of Ayush, Ministry of Health & Family Welfare, Government of India AYUSH 64, a polyherbal Ayurvedic formulation in influenza like illness: results of a pilot study Ayush-64 A New Ayurvedic Anti-Malarial Compound. Central Council for Research in Ayurveda and Siddha, Ministry of Health & Family Welfare Pharmacological Investigations of certain Medicinal Plants and Compound Formulations used in Ayurveda and Siddha. Central Council for Research in Ayurveda and Siddha, Ministry of Health & Family Welfare, Govt Effect of total alkaloids from Alstonia scholaris on airway inflammation in rats Anti-inflammation action of xanthones from Swertia chirayita by regulating COX-2/NF-κB/MAPKs/Akt signaling pathways in RAW 264.7 macrophage cells In vivo nut Caesalpinia bonducella seeds Studies on antiinflammatory, antipyretic and analgesic properties of Caesalpinia bonducella F. seed oil in experimental animal models Immunomodulatory activity of biopolymeric fraction RLJ-NE-205 from Picrorhiza kurroa Anti-inflammatory Effect of Picrorhiza kurroa in Experimental Models of Inflammation In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease Infectious Disease Epidemic: Where We Are, What Can Be Done and Hope For Association of SARS-CoV-2 Genomic Load with Outcomes in Patients with COVID-19 Review of the clinical characteristics of coronavirus disease 2019 (COVID-19) Clinical Characteristics and Differential Clinical Diagnosis of Novel Coronavirus Disease COVID-19) SARS-CoV-2 and COVID-19: From the Bench to the Bedside Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19 Absolute lymphocyte count is a prognostic marker in Covid-19: A retrospective cohort review Immune response in COVID-19: What do we currently know? Characteristics of asymptomatic COVID-19 infection and progression: A multicenter, retrospective study Antiviral activity of traditional medicinal plants from Ayurveda against SARS-CoV-2 infection Add-on Ayurveda Treatment for Early Stage COVID-19: A Single Center Retrospective Cohort Study From Gujarat The interplay between central metabolism and innate immune responses ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation Corona Virus: An Immunological Perspective Review Analgesic and anti-inflammatory activities of ethanoic root extract of Swertia chirata (Gentianaceae) Total alkaloids from Alstonia scholaris inhibit influenza a virus replication and lung immunopathology by regulating the innate immune response Antiviral Cystine Knot α-Amylase Inhibitors from Alstoniascholaris Review of Antiviral Activities Present in some Indian Medicinal Plants -Can they be used against SARS-CoV-2? Inhibitory potential of Picrorhizakurroa royle ex. benth extracts on phenylhydrazine induced reticulocytosis in rats A Picrorhiza kurroa derivative, picroliv, attenuates the development of dextran-sulfate-sodium-induced colitis in mice Pharmacological Perspectives of Ayurvedic herbs viz. Alstonia scholaris L., Picrorhiza kurroa, Swertia chirata and Caesalpinia crista against COVID-19: A Mini-Review. Mini-Reviews in Organic Chemistry Eric Wei Chiang entitled Caesalpinia Crista: A costal woody Climber with promising therapeutic values Ayush-64 A New Ayurvedic Anti-Malarial Compound. Central Council for Research in Ayurveda and Siddha, Ministry of Health & Family Welfare Pharmacological Investigations of certain Medicinal Plants and Compound Formulations used in Ayurveda and Siddha. Central Council for Research in Ayurveda and Siddha, Ministry of Health & Family Welfare, Govt Effect of total alkaloids from Alstonia scholaris on airway inflammation in rats Antiinflammation action of xanthones from Swertia chirayita by regulating COX-2/NF-κB/MAPKs/Akt signaling pathways in RAW 264.7 macrophage cells In vivo immunomodulatory activities of the aqueous extract of bonduc nut Caesalpinia bonducella seeds Studies on anti-inflammatory, antipyretic and analgesic properties of Caesalpinia bonducella F. seed oil in experimental animal models Immunomodulatory activity of biopolymeric fraction RLJ-NE-205 from Picrorhiza kurroa Anti-inflammatory Effect of Picrorhiza kurroa in Experimental Models of Inflammation In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease Coadministration of AYUSH 64 as an adjunct to Standard of Care in mild and moderate COVID-19: A randomised, controlled, multicentric clinical trial AYUSH-64 as an add-on to standard care in asymptomatic and mild cases of COVID-19: A randomized controlled trial AYUSH-64 as an adjunct to Standard Care in mild to moderate COVID-19: An openlabel randomized controlled trial in Chandigarh Efficacy and Safety of Ayurveda Intervention (AYUSH 64) as add-on therapy for patients with COVID-19 infections -An open labelled, Parallel Group, Randomized controlled clinical trial Ayush Ministry launches nationwide distribution campaign of AYUSH 64 & Kabasura Kudineer. 7 th The Natural History, Pathobiology, and Clinical Manifestations of SARS-CoV-2 Infections Infectious Disease Epidemic: Where We Are, What Can Be Done and Hope For Association of SARS-CoV-2 Genomic Load with Outcomes in Patients with COVID-19 Review of the clinical characteristics of coronavirus disease 2019 (COVID-19) Clinical Characteristics and Differential Clinical Diagnosis of Novel Coronavirus Disease COVID-19). 2020;55-70 SARS-CoV-2 and COVID-19: From the Bench to the Bedside Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19 Absolute lymphocyte count is a prognostic marker in Covid-19: A retrospective cohort review Immune response in COVID-19: What do we currently know? Characteristics of asymptomatic COVID-19 infection and progression: A multicenter, retrospective study Add-on Ayurveda Treatment for Early Stage COVID-19: A Single Center Retrospective Cohort Study From Gujarat The interplay between central metabolism and innate immune responses ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation Corona Virus: An Immunological Perspective Review Analgesic and antiinflammatory activities of ethanoic root extract of Swertia chirata (Gentianaceae) Total alkaloids from Alstonia scholaris inhibit influenza a virus J o u r n a l P r e -p r o o f replication and lung immunopathology by regulating the innate immune response Antiviral Cystine Knot α-Amylase Inhibitors from Alstoniascholaris Review of Antiviral Activities Present in some Indian Medicinal Plants -Can they be used against SARS-CoV-2? Inhibitory potential of Picrorhizakurroa royle ex A Picrorhiza kurroa derivative, picroliv, attenuates the development of dextran-sulfate-sodium-induced colitis in mice Pharmacological Perspectives of Ayurvedic herbs viz. Alstonia scholaris L., Picrorhiza kurroa, Swertia chirata and Caesalpinia crista against COVID-19: A Mini-Review. Mini-Reviews in Organic Chemistry Eric Wei Chiang entitled Caesalpinia Crista: A costal woody Climber with promising therapeutic values SARS-CoV-2 binds platelet ACE2 to enhance J o u r n a l P r e -p r o o f thrombosis in COVID-19 Immunosuppressive effect of Swertia chirata Buch Ham. on Swiss albino mice