1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. 2Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Currently, the world is challenged by the coronavirus disease 2019 (COVID-19) pandemic. Epidemiologists and researchers worldwide are invariably trying to understand and combat this precarious new disease. Scrutinizing available drug options and developing potential new drugs are urgent needs to subdue this pandemic. Several intervention strategies are being considered and handled worldwide with limited success, and many drug candidates are yet in the trial phase. Despite these limitations, the development of COVID-19 treatment strategies has been accelerated to improve the clinical outcome of patients with COVID-19, and some countries have efficiently kept it under control. Recently, the use of natural and traditional medicine has also set the trend in coronavirus treatment. This review aimed to discuss the prevailing COVID-19 treatment strategies available globally by examining their efficacy, potential mechanisms, limitations, and challenges in predicting a future potential treatment candidate and bridging them with the effective traditional Chinese medicine (TCM). The findings might enrich the knowledge on traditional alternative medication and its complementary role with Western medicine in managing the COVID-19 epidemic.
Peng Yu,Tao Hongxun,Satyanarayanan Senthil Kumaran, et al. A Comprehensive Summary of the Knowledge on COVID-19 Treatment[J]. Aging and disease,
2021, 12(1): 155-191.
1. The total number of peripheral blood leukocytes was normal or decreased; 2. Decreased lymphocyte count; 3. Increased CRP and erythrocyte sedimentation rate [44].
Complication
1. Acute kidney injury (AKI) is a significant characteristic of SARS patients [38].
1. Acute kidney injury (AKI) is a significant characteristic of MERS patients; 2. Vasopressor therapy was much more common in MERS, (81%)[31].
1. Age 2. Underlying condition 3. Male 4. LDH level 5. Neutrophil count 6. CD4 7. CD8 [38]
1. Age 2. Underlying condition 3. Male [45]
1. Age 2. Underlying condition 3. Male 4. Lymphocyte count 5. Lactic acid 6. IL-6 and CRP [18]
Clinical management
-Continuous nasal cannula oxygen is given early (the oxygen concentration is generally 1~3 L/min); -Given oseltamivir within 48 hours of onset can help reduce the symptoms. -Fever>38.5, or obvious body aches, can use antipyretic analgesics; Those with high fever should be given physical cooling measures; Salicylic acid antipyretic analgesics are forbidden for children. -Cough and expectorants can be given antitussive and expectorant drugs; -With damage to organs such as heart, liver, kidney, etc. should be treated accordingly. -With diarrhea should be paid attention to rehydration and correct water and electrolyte imbalances; -Use of glucocorticoids, the recommended adult dose is equivalent to 80-320 mg/d of methylprednisolone, reduced or stopped when the clinical manifestations have been improved or the chest radiograph shown the absorbed shadows in lung; -Antiviral therapy has not yet found specific drugs; Possible to try protease inhibitors such as lopinavir and ritonavir; -When the diagnosis is unclear, new quinolones or β-lactams combined with macrolides can be used for trial treatment; -The pathogens of secondary infections include gram-negative bacilli, drug-resistant gram-positive cocci, fungi, and Mycobacterium tuberculosis, and appropriate antibacterial drugs should be selected accordingly; -Chinese medicine as an alternative strategy. [46, 47]
For patients with pneumonia or comorbidities: -With signs of severe respiratory distress, shock or hypoxemia, oxygen therapy should be started immediately. -It is recommended that fluid management in patients is necessary, while provided that there is no sign of shock. -Empirical antibacterial treatment (including antibiotics and antiviral drugs) should be initiated for hospitalized patients with suspected MERS pneumonia; If sepsis is suspected, it should be started within one hour; -Antipyretic/analgesic is recommended to control fever and pain. -Corticosteroids are generally not recommended; however, stress doses can be given when needed. -Patients who are about to develop or have developed respiratory failure should be admitted to the ICU ward. For patients without pneumonia or comorbidities: -Supportive treatment is recommended, including the use of antipyretics and analgesics (such as acetaminophen, ibuprofen) to relieve pain and fever; -Patients should stay hydrated, but should not consume too much fluid, as this may worsen oxygenation [48].
-General treatment: strengthen supportive treatment, ensure adequate energy intake; pay attention to water and electrolyte balance, maintain internal environment stability; give effective oxygen therapy measures in time, including nasal cannula, mask oxygen and nasal high flow oxygen therapy; avoid blind or inappropriate use of antibacterial drugs, especially the combined use of broad-spectrum antibacterial drugs. -Antiviral treatment: drugs with potential antiviral effects (such as α-interferon, ribavirin, chloroquine, and arbidol) should be used early, and recommended to be applied to patients with severe high-risk factors and severely ill tendencies. -Immunotherapy: convalescent plasma from recovered patients, intravenous injection of COVID-19 human immunoglobulin, tocilizumab; -Glucocorticoid treatment can be applied for patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive activation of the body's inflammatory response for a short period of time (equivalent to methylprednisolone 0.5~1mg/kg/day, 3 to 5 days); -For severe and critical cases: On the basis of the above treatment, actively prevent and treat complications, treat basic diseases, prevent secondary infections, and provide organ function support in time; -Chinese medicine as an alternative strategy [49].
Table 1 Pathogenetic, epidemiological and clinical characteristics of SARS-CoV-2, SARS-CoV and MERS-CoV.
Treatment
Drug
Drug target
Dosage
Source
Arbidol + Bromhexine
Arbidol
Membrane fusion inhibitor
PO
NCT04273763 (CN)
Bromhexine
Expectorant
PO
Arbidol + IFN-β1α
Arbidol
Membrane fusion inhibitor
PO, 200 mg, tid, 14 d
NCT04254874 (CN)
IFN-β1α
Immunomodulator
INH, 14 d
Chloroquine + Ivermectin
Chloroquine
Membrane fusion inhibitor and immunomodulator
PO
NCT04382846 (EG)
Ivermectin
Importin (IMP) α/β receptor
PO
Chloroquine + Ivermectin + Vitamin D
Chloroquine
Membrane fusion inhibitor and immunomodulator
PO, 500 mg, 4 d, 30 d
NCT04399746 (MX)
Ivermectin
IMP α/β receptor
PO, 6 mg, qd, Day 1, 7 and 8
Vitamin D
Vitamins
PO, 400 UI, bid
Chloroquine + Losartan
Chloroquine
Membrane fusion inhibitor and immunomodulator
PO, 450 mg, bid
NCT04428268 (MX)
Losartan
Angiotensin II receptor (type AT1) antagonis
PO, 25 mg, bid
Chloroquine + Zinc
Chloroquine
Membrane fusion inhibitor and immunomodulator
PO
NCT04447534 (EG)
Zinc
PO
Hydroxychloroquine + Azithromycin
Hydroxychloroquine
--/ Receptor binding and membrane fusion inhibitor
Table 2 Combined use of different treatments in COVID19.
Figure 1. The development of COVID19. Viral infection: TMPRSS2 cleaves the S protein of SARS-CoV-2; The RBD on the S1 subunit binds to ACE2 on the cell surface. Following entry into the cell, viral RNA is released and combined with RdRp to synthesize a full-length negative-strand RNA as an RNA replication template. After translation, structural proteins are localized to the inner membrane of Golgi for assembly. Cytokine storm syndrome: The immune system is over-activated, followed by the overproduction of multiple inflammatory factors. Multiple immune cells are recruited. As a result, healthy cells are damaged by overactive immune response. Acute respiratory distress syndrome: In the exudative phase, macrophages are activated and release pro-inflammatory mediators, which leads to the aggregation of neutrophils and monocytes. Activated neutrophils induce further damage. The injury leads to loss of barrier function and fluid accumulation in the interstitium and alveoli. In the proliferative period, the tissue homeostasis is recovered.
Clinical stage
Syndrome
Symptom
Formula
Ref.
Observation period
Fatigue with gastrointestinal discomfort
Huoxiang Zhengqi (HXZQ) capsule (pill, liquid or oral solution)
Aversion to cold with fever or no fever, muscle aches or headaches, dry throat with cough, tiredness and fatigue, stuffy feeling in chest and stomach, or vomiting, loose stools, light or red tongue, white and greasy fur, tight, wiry or moisten pulse i
Low or no fever, slight aversion to cold, fatigue, heavy head and body feeling, muscular soreness, dry cough with less sputum, sore throat, dry mouth without desire of drinking, or accompanied by stuffy feeling in chest and stomach, no sweat or sweating is not smooth, with a disgusted and dull expression, laxness or loose stools, reddish tongue with thick and greasy or light yellow fur, rolling, rapid or moisten pulse
Low to medium fever, which is obvious in the afternoon, slight aversion to cold, dry cough with less sputum, dry and sore throat, light tongue with yellow greasy fur, rolling and rapid pulse
Hidden low fever, dry cough with less sputum, tiredness and fatigue, stuffy feeling in chest and stomach, or vomiting, and loose stools, pale or light red tongue with white or greasy fur, moisten pulse
Toxic damp accumulated in interior, involving lung and spleen
Low fever, which is obvious in the afternoon, dry cough with less sputum, dry and sore throat, stuffy feeling in chest and stomach, vomiting and anorexia, laxness and fatigue, pale tongue with greasy fur, rolling and rapid pulse
Mental depression, fatigue, weakness, anorexia, loose stools, borborygmus, abdominal fullness, chest tightness and shortness of breath, pale tongue with greasy fur, soft and moisten pulse
Fever or high fever, cough, yellow or thick phlegm, fatigue, headache, muscular stiffness, dry and bitter mouth, anxiety, red urinary and constipation, red tongue with yellow or greasy fur, rolling and rapid pulse
Chest tightness, shortness of breath, coughing and panting, extreme fatigue, asthmatic, cough with less sputum or hemoptysis or yellow sputum, thirsty and irritable, high fever does not retreat, bloating and constipation, dark red tongue with yellow greasy fur, slippery or heavy pulse
Fever, cough, thick yellow phlegm, chest tightness, wheezing, thirst, stinking tone, bloating and constipation, dark red tongue with thick and yellow fur, slippery or tight pulse
Hidden fever, disturbed hidrosis, panting, dry coughing or bucking, or with sore throat, stuffy feeling in chest and stomach, dry mouth, bitter or sticky in the mouth, sticky stools, dark red tongue with yellow and greasy fur, slippery pulse
Hot and thirsty, panting, dizzy delirium, blurred vision with macula, hematemesis and epistaxis, convulsions in the limbs, crimson tongue with little or no fur, deep, thin and rapid pulse, or floating and rapid pulse
Dyspnea, asthmatic, or assisted ventilation needed, with dizziness and irritability, sweating, cold limbs, dark purple tongue with thick, greasy or dry fur, large floating and weak pulse
Radix Ginseng 15g, Radix Aconiti Lateralis Preparata 10g (decocted first), Fructus Corni 15g; with Suhexiang pill or Angong Niuhuang pill; high fever plus Zixue powder; severe breathing plus Semen Lepidii and Herba Ephedrae
Radix Ginseng 15g, Radix Aconiti Lateralis Preparata 10g (decocted first), Fructus Corni 15g; with Suhexiang pill or Angong Niuhuang pill
[102]
High fever and irritability, cough and shortness of breath, the nose wings incite, phlegm in the throat, holding breath in embarrassment, intermittent voice, spots of rash, or even dizzy coma, sweating, cold limbs, dark purple lips, dark red tongue with yellow and greasy fur, deep, thin and delicate pulse
Shortness of breath, fatigue, coughing, less phlegm, low or no fever, thirst, anorexia, dry and dark tongue with dry and white fur, thin and weak pulse
Table 3 Prescription for COVID-19 recommended by Chinese medicine.
Treatment
Administration and Dosage
Outcome Measures
Source
Lianhua Qingwen
PO, 4 capsules, tid, 7 d
Virological clearance
NCT04433013 (SG)
Xiyanping injection
IV, 10-20 mL, qd, Combination medication, 14 d
Clinical recovery time
NCT04275388 (CN) NCT04295551 (CN)
Huaier keli
PO, 20 g, 14 d
Mortality
NCT04291053 (CN)
T89 (Danshen Diwan)
PO, 30 pills, bid
Improve oxygen saturation
NCT04285190 (CN)
Fuzheng Huayu Tablet
PO, 1.6 g, tid
Evaluation of Pulmonary fibrosis Improvement.
NCT04279197 (CN)
Conventional medicines (Oxygen therapy, alfa interferon via aerosol inhalation, and lopinavir/ritonavir) and Traditional Chinese Medicines (TCMs) granules
PO, 20 g, bid, 14 d
The incidence rate of ARDS development
NCT04251871 (CN)
Chinese Herbal Medicine
PO
Patient reported main complaint
NCT04380870 (US)
Reginmune
PO, 1000 mg, tid, 10 d
Time to clinical improvement
NCT04494204 (IN)
Licorice extract
PO, 250 mg standardized extract, 10 d
Increased number of recovery from COVID19
NCT04487964 (EG)
Iota-Carrageenan
ISIN, 4 times, 21 d
Change in SARS-CoV-2 antibody titers
NCT04521322 (AR)
çaí palm berry extract
PO, 520 mg, tid, 30 d
7-point ordinal symptom scale
NCT04404218 (CA)
P2Et (Caesalpinia spinosa extract)
PO, 250 mg, bid, 14 d
Proportion of patients who reduce the time in the hospital
NCT04410510 (CO)
Nigella sativa
PO, 500 mg, Black seed oil
Proportion of patients who are clinically recovered
NCT04401202 (SA)
Nigella Sativa / Black Cumin
PO, 80 mg/kg/d, 14 d
Time needed to turn positive COVID-19 PCR to negative
NCT04472585 (PK) NCT04347382
Natural Honey
PO, 30 mL, bid, 14 d
Time needed to turn positive COVID-19 PCR to negative
NCT04323345 (EG) NCT04347382 (PK)
Antioxidation Therapy
Two proprietary formulations composed of reduced glutathione, N-acetylcysteine, supero×ide dismutase, and bovine lactoferrin and immunoglobulins. PO, 28 d
Time to clinical improvement
NCT04466657 (NG)
Aromatherapy
INH, 15 min
Change from baseline in state anxiety on the State portion of the State Trait Anxiety Scale (STAI-S) at 15 minutes
NCT04495842 (US)
Ayurveda
PO
Time to achieve afebrile
NCT04395976 (GB) NCT04345549 (GB) NCT04351542
Ayurvedic Kadha
PO, 30 d
Prevention
NCT04387643 (IN)
Natural Honey
PO, 1 g/kg/d, 14 d
Rate of recovery
NCT04323345 (EG) NCT04347382 (PK)
QuadraMune(TM)
PO, 2 pills, 84 d
Prevention
NCT04421391 (US)
Resveratrol
PO, 15 d
Length of stay in hospital
NCT04400890 (US)
Tetrandrine
PO, 60 mg, qd, 7 d
Survival rate
NCT04308317 (CN)
Quercetin
PO, 500 mg, 90 d
Prevalence of COVID-19
NCT04377789 (TR)
Silymarin
PO, 140 mg, tid, 7-28 d
Time to clinical improvement
NCT04394208 (EG)
Escin
PO, 40 mg, tid, 12 d
Mortality
NCT04322344 (IT)
Pyronaridine-Artesunate
PO, Pyronaridine 180mg/ Artesunate 60mg, 7 d
Virological clearance
NCT04475107 (KR)
Artemisinin / Artesunate
PO, 100 mg, 5 d
Length of stay in hospital
NCT04387240 (SA)
ArtemiC
PO
Time to clinical improvement
NCT04382040 (IL)
Fisetin
PO, 20 mg/kg/d
Serious adverse events and change in oxygenation status
NCT04476953 (US)
LEAF-4L6715
IV, initial dose of 5 mg, 2.5 mg, qd
Improve oxygenation status
NCT04378920 (FR)
LEAF-4L7520
IV, 0.25 mg/kg per 3h
Improve oxygenation status
NCT04378920 (FR)
Manremyc
PO, 1×10^5 heat-inactivated Mycobacterium s. 14 d
Documented cumulative incidence of SARS-CoV-2 infection
Bacterial strains in Omni-Biotic® 10 AAD are Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Enterococcus faecium W54, Lactobacillus acidophilus W37, Lactobacillus acidophilus W55, Lactobacillus paracasei W20, Lactobacillus plantarum W1, Lactobacillus plantarum W62, Lactobacillus rhamnosus W71 and Lactobacillus salivarius W24 which are embedded in a matri× containing maize starch, maltode×trin, inulin, potassium chloride, hydrolysed rice protein, magnesium sulphate, fructooligosaccharide (FOS), enzymes (amylases), vanilla flavour and manganese sulphate, 30 d
Delta of time of disappearance of acute diarrhea
NCT04420676 (AT)
MRx-4DP0004
Lyophilised formulation of a proprietary strain of bacteria: 4 × 10^9 to 4 ×10^10 colony forming units, PO, 14 d
Change in mean clinical status score in each treatment arm
NCT04363372 (GB)
Probiotic
PO, 1×10^9 cfu of the probiotic, 30 d
Cases with discharge to ICU
NCT04390477 (ES) NCT04517422
bacTRL-Spike
Single dose of bacTRL-Spike, equivalent to 1-3 billion colony forming units (cfu) of Bifidiobacterium longum; PO
Genetically modified probiotic bacteria colonize the gut, bind directly to intestinal epithelial cells and constitutively replicate, secrete and deliver plasmid DNA molecules encoding antigenic transgenes and neutralizing nanobodies.
NCT04334980 (US, CA)
Previfenon®
PO, 250 mg, tid
Improve symptoms
NCT04446065 (AU)
Table 4 Commercial Chinese medicine preparations and herb supplement in treatment of COVID19.
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2021,
Vol. 12
