Khamira Banafsha for the symptomatic treatment of Covid-19 Disease

Respiratory illness is one of the most important public health problems in many countries worldwide. Even though most of the ailments are treatable with normal care, respiratory-related mortality continues to increase year after year. The global situation is deteriorating as a result of the COVID-19 epidemic. Numerous Unani formulations are beneficial against a variety of respiratory disorders, but they must be clinically researched before they can obtain widespread acceptance in the modern world. At the moment, no antiviral medication is either available for each respiratory disease or is costly and not easy to use in pandemics like COVID-19 on large scale, although Unani medicines may be considered an option. Khamira Banafsha (KB) is a semi-solid blend of three dried flowers, Viola odorata L., Borago officinalis L., and Rosa damascena Mill and the distillate of Rosa damascena , and sugar. The components in this formulation are well-known and frequently utilized in the treatment of respiratory problems.The formulation has been used to treat a wide range of illnesses for decades. This review will discuss the pharmacology, ethnopharmacology, and repurposing of KB as an adjuvant or symptomatic treatment for Covid-19 illness.The chemical composition of the ingredients may be evaluated In-silico to identify their eligibility for Covid-19 disease symptomatic management. Antiviral, Antipyretic, Covid-19, ,


Introduction
In addition to the rhinoviruses and coronaviruses, the common cold is caused by many other viruses and mostly affects the upper respiratory system 1 . It is a prevalent condition worldwide that affects the population of all age groups particularly younger people in adulthood 2 .Acute respiratory infection is the second most commonly recognized disease entity in medical facilities 3 and also the most typical diagnosis in emergency rooms 4 . A quarter of respondents in the United States said they had taken a cough or cold drug followed by a sedating or non-sedating antihistamine in the previous week for the management of respiratory diseases. One of the most common reasons to take vitamins and herbs is to help prevent colds and influenza 5 .In a study conducted by telephone or personal interview to estimate the prevalence of recent OTC medication use in a national sample of 3-year-old preschool-age children. Total 8145 children were interviewed by their mothers about OTC medications given in the last 30 days and the type of medication given. In the last 30 days, 53.7% of all 3-year-olds in the US received OTC medications. Among OTC medication users, acetaminophen (66%) and cough/cold medicine were most commonly reported (66.7 percent ) 6 .
The successful use of herbal drugs, from Unani and Ayurveda to enhance immunity and deal with Coronavirus signs and symptoms, has provided an opportunity to prove its strength and develop an effective and safe remedy for respiratory viral infections. The Unani system of medicine (USM) is holistic and treats the whole body rather than the virus or causative organism. There are several single and compound formulations that Unani physicians are using for centuries to treat respiratory diseases. It is high time that these formulations should be tested clinically for each indication and also for new indications like Coronavirus. The Coronavirus affects the respiratory system, so the drugs used in respiratory diseases may be tried. An important formulation Khamira Banafshais chosen here to discussits possible use in Coronavirus prevention and treatment 7,8,9 .

Methodology
The details of Khamira Banafsha in Unani medical practice have been gleaned from Qarabadeen Ahsani (Urdu), while the information regarding its ingredients was collected from various books including Aljameul Mufradat Al-Adviawal-Aghzia; Khazain-ul-Adviya; Al-Qanunfi'l Tibb; Bustanul Mufradat; Makhzanul Mufradat; Tajul Mufradat and National Formulary of Unani Medicine. We conducted a systematic review of contemporary research on ingredients of the formulation about their pharmacological studies, clinical trials, and ethnopharmacology, using online resources such as PubMed, Scopus, Science Direct, and Google Scholar. Keywords such as Antiviral, Antipyretic, Covid-19, Herbal medicine, Khamira Banafsha, Repurposing, Respiratory diseases, Unani medicine, and ethnopharmacology were used.

Clinical Presentation and Epidemiology
COVID-19 has a wide range of clinical symptoms, from asymptomatic to acute respiratory distress syndrome and multi-organ failure. Fever, cough, sore throat, dyspnea, myalgia or fatigue, sputum production, headache, hemoptysis, and diarrhoea are among the first symptoms of Covid-19. Conjunctivitis has also been described. Only a few patients did not have a fever when the disease was still in its early stages. Nearly 30% of patients developed acute respiratory distress syndrome (ARDS), (12%) developed an acute cardiac injury, 7% developed acute kidney injury (AKI), and 7% developed shock. As a result, they are difficult to distinguish from other respiratory infections. In a small percentage of patients, the condition can develop to pneumonia, respiratory failure, and mortality by the end of the first week 10,11 .
COVID-19 has been confirmed in approximately 3.2 crore people worldwide as of September 2021. Because only a fraction of acute infections is detected and reported, the reported case counts understate the actual burden of COVID-19. After accounting for probable false positives or negatives, seropositivity suggests that the rate of past exposure to SARS-CoV-2, as expressed by seropositivity, surpasses the incidence of reported cases by around 10-fold or more, according to seroprevalence surveys in the United States and Europe 12,13,14 .

Modern Medical interventions
Medications for SARS, MERS, HIV/AIDS, and malaria have been repurposed as successful COVID-19 treatments. Rather than researching novel medicines, medication repurposing can save time and money 15 .It appears that the catalytic sites of 2019-nCoV enzymes that potentially be antiviral targets are substantially conserved, with strong sequence similarity to the SARS and MERS enzymes. Structural analysis of viral enzymes suggests that drug-binding pockets are conserved in 2019-nCoV, SARS, and MERS 16 .Thus, existing MERS and SARS inhibitors were repurposed for 2019-nCoV. Listed below are licensed medications or experimental compounds that have already been evaluated in clinical trials for other diseases 17 .Several approved and investigational nucleoside analogs (favipiravir, ribavirin) may be effective against 2019-nCoV. Adenine or guanine derivatives target the RNA-dependent RNA polymerase and inhibit viral RNA synthesis in RNA viruses, including human coronaviruses. Favipiravir (T-705), a guanine analog licensed for influenza treatment, can efficiently inhibit the RNA-dependent RNA polymerase of RNA viruses such as influenza, Ebola, yellow fever, chikungunya, norovirus, and enterovirus 18 , and recently against 2019-nCoV (EC50 = 61.88 M in Vero E6 cells) 19 .
Remdesivir exhibits broad-spectrum activity against RNA viruses such as MERS and SARS. 2019-nCoV was suppressed by remdesivir (EC50 = 0.77 M in Vero E6 cells) 18 , and in January, 2019-nCoV patient in the US recovered after receiving intravenous remdesivir 19 .An approved immune modulator, chloroquine, shows inhibitory effects against 2019-nCoV (EC50=1.13 μM in Vero E6 cells)and is being evaluated in an open-label trial (ChiCTR2000029609). Nitazoxanide, approved for diarrhea treatment, could also inhibit 2019-nCoV (EC50 = 2.12 μM in Vero E6 cells) 18 . Remdesivir was also discovered to exhibit antiviral activity against other RNA viruses, particularly those belonging to the Coronaviridae family, such as SARS-CoV, MERS-CoV, and COVID-19 20, 21 . Grein et al. published the most comprehensive study to date, reporting on the compassionate use of Remdesivir in 61 patients, 53 of whom had complete followup. There was an improvement in oxygen support in 36 of 53 patients (68%) 22 . Even though there is a general dearth of prospective randomized studies at the moment, Remdesivir continues to demonstrate very encouraging results.
Convalescent plasma therapy with COVID-19 survivor antibodies has been used in many trials, most notably in case-based settings. Shen et al. reported on the use of convalescent plasma in five critically ill patients with ARDS who were ventilated mechanically (age range, 36-65 years) 23 . Additionally, Zhang et al. described significant clinical improvement in four patients treated with convalescent plasma 24 . Ye et al. recently reported on six COVID-19 patients from Wuhan, China, who had a favourable outcome in terms of signs and symptoms improvement 25 . The combination of chloroquine, hydroxychloroquine, and azithromycin has gained considerable popularity and the promise for effective treatment; however, there are some disagreements and divergences between research and results 20,26,27 . Il-6 monoclonal antibodies were launched for the treatment of COVID-19-associated cytokine release syndrome and have been utilized in just a few case series worldwide, with generally favourable results 28,29 . Statins are also regarded safe, and they have significant preventative benefits on the prevalence of atherosclerosis, plaque stabilization, and endothelial dysfunction recovery 30 .

Natural Therapies
Traditional Chinese Medicine (TCM) based treatments improved symptoms and enhanced immunity in COVID-19 patients. Patients respond well to combining TCM and Western medicine methods on COVID-19 31,32 . Approximately 3100 TCM personnel had been deputed to the Hubei district at the time of the epidemic. TCM was formally accepted by Chinese guidelines to treat COVID-19 [33]. The decoction, Chinese patent medicine, acupuncture, and other TCM-specific therapies were all utilised extensively, with the majority of cases being treated based on syndrome differentiation. Specific TCM wards have been developed, as well as a recognized hospital; also, the TCM staff participates in treatment collaboratively 31,34 .
TCM has advocated providing prescriptions that are likely to be successful based on existing treatment outcomes, such as qingfeipaidu decoction (QPD), gancaoganjiang decoction, sheganmahuang decoction, and qingfeitouxiefuzheng recipe. QPD, which is composed of approximately 21 herbs, has been advocated in China as a general prescription for the diagnosis and treatment of COVID-19 34 . Among the 701 confirmed patients treated with QPD, 130 cases were cured and discharged, 51 cases had their clinical symptoms resolved, 268 cases had their symptoms improved, and 212 cases had their symptoms remained stable without aggravation [35]. QPD has a cure rate of more than 90% against COVID-19. The primary location of the pharmacological activity is the lung. Additionally, it has been shown to protect the heart, kidneys, and other organs. Among the identified potential targets, the majority co-expressed ACE-2, the COVID-19 receptor, implying the possibility of improving COVID-19. It prevents the replication of COVID-19 by interfering with various ribosomal proteins 36 . QPD may regulate and alleviate excessive immune response and inflammation by modifying immune and cytokine-related pathways, as demonstrated by functional enrichment analysis 37 . Additionally, molecular docking suggested that the patchouli alcohol, ergosterol, and shionone components of the formula would have a greater anti-COVID-19 effect, leading to the discovery of novel molecule structures for the creation of new medications 38 . The results of molecular docking indicated that the phytocompounds in Arq Ajīb (a multi-ingredient Unani formulation) have a high affinity for and contact with the S glycoprotein and 3CLpro. Quercetin and isorhoifolin were found as interesting candidates from Menthaarvensis for their ability to bind with 3CLpro and spike glycoprotein and thereby impede viral replication and entry into the host 39 .

Unani Medicines
Khamira Banafsha is a compound formulation containing the decoction of three important flowers, i.e., Gul-e-Banafsha (flowers of Viola odorataL.), Gul-e-Gaozaban (flowers of Borago officinalis L.), and Gul-e-Surkh (flowers of Rosa damascena Mill.) [40]. Khamira is a semisolid preparation made up of decoction of plant parts in the base (Qiwam) made of purified sugar. The composition of the KhamiraBanafsha is given in Table-1.    47 .

Important formulations of GB
In Unani Medicine, drugs from the plant, mineral, and animal origin have been used either as a single entity or in a combination of more than one drug in specific proportion mentioned in Unani Pharmacopoeias and National formularies. If more than one drug has been mixed in a specific proportion by a particular method, it is called compound formulation. The following compound formulations contain Banafsha (Viola odorata L.) as an ingredient.

Gul-e Surkh (GS) (Flowers of Rosa damascena Mill.)
It is the flower of Rosa damascena Mill. they are commonly used in USM in various forms. There are several formulations where it is the main ingredient, like Gulqand (a mixture of flowers with sugar), Araq Gulab (a distillate of flowers), Roghan-e Gul (oil obtained from flowers), and also used as an ingredient in several formulations.

Important formulations of GS -Araq Gulab has been used to treat Du'f al-A'da'
Ra'isa (weakness of vital organ) and Khafaqān (palpitation).

Gul-e Gaozaban (Flowers of Borago officinalis L.)
The flowers and leaves of Borago officinalis L.are commonly used in the USM as Gul-e Gaozaban (GG) and Berg-e-Gaozaban (BG), respectively. The GG is the main ingredient in several formulations, while in many a subsidiary ingredient. In Khamira Banafsha, flowers are used. The therapeutic actions, therapeutic uses, and essential formulations used to treat respiratory diseases mentioned in Unani literature are described here.

Important formulations of GG -Ambari has been used to treat Du'f al-A'dā'
Ra'isa (weakness of vital organ), Du'f al-Badan (general weakness).

Discussion
Coronavirus disease is a viral respiratory illness in which the elderly and those with medical conditions such as cardiovascular disease, diabetes, lung disease, and cancer are more likely to become seriously ill. The symptoms of COVID-19 can be classified into three categories: the more frequently such as fever, dry cough, and tiredness; the less common include aches, sore throat, diarrhea, conjunctivitis, headache, loss of taste or scent, and a rash on the skin, as well as discoloration of fingers or toes. The severe symptoms include breathing difficulties or shortness of breath, chest pain or discomfort, and speech or movement loss 56 .
There is no drug available for the prophylaxis and management of active COVID-19 infection, although several antiviral drugs were used during the COVID-19 pandemic. Natural drugs' success in boosting immunity during the pandemic has shown a way to discover a natural way to treat viral infections. The USM is holistic and treats the body as a unit instead of killing the virus or bacteria. The basic concept is to help the body to fight against the antigen and to restore normal homeostasis. The management of respiratory diseases in USM is given in detail, and several single and compound formulations are mentioned in the literature 57 .
In Unani literature, GB is indicated as a Muhallil-  63 antitussive, anti-asthmatic 64 and antibacterial activity 65 .
The Muqawwi (tonic) concept for the body and specific organs is a unique concept of the USM. The use of Muqawwi-i-Ri'a (lungs tonic) along with and Muqawwi-i-Badan (immunity booster) may be adopted as a gold standard for the management of COVID-19 infection. The Khamira Banafsha may be used as prophylactic for strengthening the specific organ as per need and as a therapeutic application as an adjuvant to treatmild and moderate active COVID-19 cases. The use of Muqawwi-i-Dimāgh (brain tonic) and Muqawwi-i-A'sab (nervine tonic) may be the best regime for managing psychological effects in COVID patients after recovery and in the general population.

Conclusion
Khamira Banafshais a unique Unani herbal formulation that is used for respiratory ailments. It has three commonly used components that can be used individually and in formulations that treat respiratory problems. The ingredients also possess general tonic and immune-boosting activities, which may add up to its usefulness in the management of COVID-19 as a prophylactic and therapeutic application. The clinical trial for its efficacy and safety in coronavirus infection may be carried out to validate its actions and uses.