Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19)

FAISAL ALOTAIBI

doi:10.2478/acph-2022-0014

ALOTAIBI, FAISAL

2022-06-01 00:00:00

Acta Pharm. 72 (2022) 171–197 Review https://doi.org/10.2478/acph-2022-0014 Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19) FAISAL ALOTAIBI The epidemic of COVID-19 spread quickly through China and engulfed all of the countries across the globe. Several Department of Pharmacy Practice advances have been made in understanding the novel coro - College of Pharmacy navirus’s pathophysiology and in the development of newer Shaqra University, KSA diagnostics with pinpoint accuracy. Several newer thera- peutic methods have either been accepted or are awaiting acceptance. In many countries, vaccination programs have been rolled out. Despite all these eo ff rts, coronavirus still exists, though with lesser propensity. Multiple new forms of the novel coronavirus unexpectedly appeared in various areas of the world, undermining previously existing diag - nosis and care protocols. This article highlights our under- standing of the novel coronavirus’s symptoms in brief, pathogenesis, diagnostics, and therapeutic strategies to contain COVID-19. The clinical findings, including sero - logical, radiological, and other advanced diagnostic strate- gies, contributed much to control the disease. To date, sup- portive interventions have been used in tandem with potent antiviral therapies such as remdesivir, lopinavir/ ritonavir, or corticosteroids with a level of trust in the care of COVID-19 patients. However, in several areas of the world, vaccination initiatives took place; the vaccines’ safety and ec ffi acy to control the outbreak is yet to be identie fi d. This review concludes that improvement in therapies and diagnostics for COVID-19 must continually be explored as new variants constantly emerge. Keywords: coronavirus disease 2019, COVID-19, SARS- Accepted March 31, 2021 Published online April 1, 2021 -CoV-2, pathogenesis, remdesivir; treatment options INTRODUCTION More than a year ago, a new form of beta coronavirus appeared in Wuhan Area, China, and spread like a bush fire around the globe (1). None of the country on earth was spared from the devastation of the disease. The human sue ff rings are unaccountable due to the complete breakdown of the economy and healthcare system. * Correspondence; e-mail: f.alshaibani@su.edu.sa; f.alotaibi@hotmail.com F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. The strain was a die ff rent form of the coronavirus, and the people did have little to no understanding of the virus. Everything about the virus was unknown to health care work- ers: the sign and symptoms of the novel coronavirus disease, the mode of transmission, the pathogenesis (2). In the beginning, the whole world lacked adequate facilities to diag- nose this unique virus, and for the countries, there was no other option but to cut off the human to human contact and proximity. A complete lockout has been placed into ee ff ct in nearly every area of the world. One year has passed on, the virus still exists, the shock and despair might have diminished, but the virus’s after-ee ff cts are seen everywhere. As of the th 24 of March 2021, more than 123 million people got infected, and almost 3 million people lost their lives (3). Coronaviruses (CoVs) are made up of single-stranded RNA and belong to the Corona- viridae group, which infect a number of hosts and cause pathological changes from the common cold to severe/fatal respiratory diseases (4). Up until early January 2021, neither active immunity in the form of vaccines nor potent antiviral medications were available for the treatment of human coronavirus infections. The health care agencies were not hav- ing any other options but to follow WHO guidelines; the social distancing and quarantin- ing of patients suspected or confirmed for COVID-19. Remdesivir, lopinavir/ritonavir alone or in conjunction with interferon-β, convalescent plasma, and monoclonal antibodies (mAbs) are the main therapeutic choices used to treat COVID-19 patients (5). At the beginning of 2021, except in the USA, the novel coronavirus’s transmission started declining; the reasons were not clear; the scientist speculated about herd immu- nity. For almost one year, the world put its entire eo ff rt to develop strategies to contain the virus. Most diagnostic techniques have been developed and introduced to the diagnosis of novel coronavirus. Many countries rolled out their vaccines; some were well evaluated and followed the clinical trial guidelines, data of some vaccines were never published. Despite the discrepancies in their results, those vaccines were employed for human use. Now we have advanced to our approaches in diagnosing and treating this novel coro - navirus with a high degree of certainty. Multiple new forms of the novel coronavirus un- expectedly appeared in various areas of the world, undermining previously existing diag- nosis and care protocols. These newer variants, the new UK coronavirus type B117 and the South African form (501Y.V2), presented a larger threat to the structures currently in place to manage the virus (6). Will the war footing works across the globe prove futile if these novel mutated strains evade all the recently designed strategies? The question remains unanswered. This article highlights our latest understanding of the novel coronavirus’s symptoms in brief, pathogenesis, diagnostics, and therapeutic strategies to contain COVID-19. These facts and g fi ures may generate some novel ideas which will play a role in getting rid of this deadly coronavirus disease. SYMPTOMS The warning sign of COVID-19 infection generally appears after an average of 5.2 days of infections (5). In the case of a deathly outcome, the documented duration between the beginning of COVID-19 symptoms and death is 6 and 41 days, with an average value of 14 days (7). This period is based on the patient’s age and immunity level. Fever, cough, and 172 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. Fig. 1. The virus appears to start with fever accompanied by dry cough and then leads to breathing dic ffi ulties after a week and some patients need hospital admission. weakness or myalgia are the most frequent indications at the start of COVID-19 (Fig. 1), although other symptoms include sputum development, fever, blood-stained bronchial mucus, diarrhea, trouble breathing and loss of smell and taste (8–11). Novel SARS-CoV-2 virus and older beta coronaviruses worsen ee ff cts such as head - ache, dry cough, and shortness of breath. However, novel SARS-CoV-2 displayed some exclusive clinical features that comprise infecting the lower respiratory tract soon after the upper respiratory tract symptoms like runny nose, sneezing, and sore throat appear (12). Few patients ae ff cted by SARS-CoV-2 had digestive issues such as diarrhoea, however, a small percentage of patients reported similar GI discomfort. PATHOGENESIS AND DIAGNOSIS: CLINICAL MANIFESTATION A signic fi ant number of documented clinical and literature reports offered ample knowledge regarding the pathogenesis process of novel SARS-CoV-2 infection. The virus reaches to lungs, infecting all around the respiratory tract, primarily the mucous mem- brane of the larynx and nasal cavity. The virus then reaches the supply of peripheral blood from the lungs and then targets the targeting organs expressing ACE2, such as the lungs, the heart, the gastrointestinal tract, the renal system, etc. (13, 14). According to new studies, three elements are involved in the entry of novel SARS-CoV-2: the ACE2 receptor, the neu- ropilin-1 (NRP1) receptor, and the transmembrane protease serine 2 (TMPRSS2) receptor (15). NRP1 and TMPRSS2 serve as co-receptors to allow SARS-CoV-2 to enter the cells and to cause the viral infection. The olfactory epithelium of humans who died from COVID-19 infection has indicated that the novel coronavirus targets more neuropilin-1(NRP1)-pro- ducing cells in the nasal cavity. This may be the basis to assume that the loss of smell is 173 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. due to the excessive viral entry and infectivity of the olfactory epithelial cells. SARS-CoV-2 was detected in stool most likely that it travels from the lungs through the bloodstream and then from the bloodstream to the gastrointestinal tract (16). In SARS-CoV-2-infected patients, numerous biochemical changes have been observed. Many biomarkers have been discovered to be a signic fi ant parameter for verifying infec - tion with SARS-CoV-2, and those biomarkers suggest the magnitude of the disease. Table I highlights alterations of some biomarkers. COVID-19 infection is investigated using a range of approaches, including molecular, serological, radiological, and microbiological processes. In molecular diagnosis, detection of the virus is done by viral nucleic acid or RNA sequence amplic fi ation utilizing the re - verse transcriptase-polymerase chain reaction (RT-PCR) technique (30). When using sero- logical diagnosis, a laboratory can screen for antibodies in patients that have novel coro- navirus disease, whereas point-of-care or radiology-based diagnoses rely on the existence of clinical changes in patients that may have or are believed to have novel coronavirus disease (31, 32). Microbiological methods, especially the diagnosis via viral culture, rely on SARS-CoV-2 separation on cell lines enhancing virus growth and replication (33). Fig. 2. highlights the SARS-CoV-2 RT-PCR testing procedure: (A) Collection of sample and deposition of viral particles in transport medium. (B) Detergent/chaotropic reagents or heating is used to inac - tivate the virus. (C) Separation or extraction of RNA is done. In (D) and (E) steps show transfer to PCR-plate in which cDNA synthesis by RT and detection by qPCR happen. The (F) and (G) routes are the direct approaches in which samples are deposited in the transport medium, viral particles are attenuated either through heating or by direct lysis in the detergent-holding buffer. The attenuated samples are then used for the downstream RT-PCR diagnostic reaction. On this theory of molecular detection (reproduced with permission from reference (41)), numerous POC kits and devices operate. 174 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. tt ff fl fi Table I. Main biochemical changes seen in extreme COVID-19 patients Biomarker(s) Status Remarks Ref. Lymphocyte Decreased Virus directly infect lymphocytes, principally T cells 17–19 Elevated An early indicator of COVID-19, suggesting extreme respiratory illness and Neutrophils 20, 9 levels worse results, is blood neutrophils Blood platelet Decreased The immune system, which induces thrombocytopenia, kills platelets. 21 A higher level of cytokines such as IL-6, IL-2, IL-7, TNF-α, interferon-γ was Cytokine Increased 22 found in moderate to severe COVID-19 patients C-reactive protein (CRP) Increased CRP is a good diagnostic tool for detecting COVID 19 in a very early stage 23 An increased risk of ARDS, ICU entry, and mortality, is linked with D-dimer Increased 24 increased D-dimer levels The severity and mortality of COVI-19 are related to an increased level of Coagulation factors Increased 25 coagulation parameters Specically, hypocalcemia, hypokalemia, hyponatremia, etc ., have been Electrolyte balance Decreased 26 observed with severe illness Liver enzymes (aspartate transferase AST, There has been no direct association. This can be aributed to secondary alanine transferase ALT, alkaline phosphatase Elevated liver damage caused by systemic inammation, hepatotoxic medicinal 27 ALP, gamma glutamyltransferase GGT, etc.) administration, etc. The alteration of creatine kinase in COVID-19 may be as a result of kidney dysfunction and cardiac injury, or a direct eect of the SARS-CoV-2, which Creatine kinase (CK) Increased 28 can also infect cells of the muscle tissue due to the expression of the ACE2 receptor Cardiac troponin Increased Indicating cardiac injury 29 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. Fig. 3. Various steps of the ELISA technique (reproduced with permission from ref. 46). Molecular tests (RT-PCR) The swabs are placed through nasal and or oral routes into the upper airways for the collection of samples. For mechanically ventilated patients, samples are collected through expectorated phlegm and bronchoalveolar lavage from the lower airways. In order to detect the pathogen’s genetic content, the sample was amplie fi d in the 4 °C annealing stage using a reverse transcription process. To allow the formation of a double-stranded DNA molecule, Table II. Different target genes to diagnose the COVID-19 worldwide Country/ Target gene/s Country/organization Target gene/s organization CDC USA Three targets in the N gene NIH, Thailand N gene China ORF1ab and N gene Hong Kong ORF1b-nsp14 and N gene Germany RdRP, E and N gene NIID, Japan Spike protein France Two regions of the RdRP gene PHA, Canada RdRp, E and Any3 gene CDC – Centers for Disease Control and Prevention, NIH – National Institute of Health, NIID – National Institute of Infectious Diseases, PHA – Pulmonary Hypertension Association 176 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. a reverse transcription method or a real-time RT-PCR technique can be used from a single- -stranded viral RNA molecule (34, 35). Finally, replication of genetic information is used to identify the SARS-CoV-2 genetic code. For the molecular level identic fi ation of the COVID-19 pathogen, various countries have introduced die ff rent target genes (Table II) (36, 37). The sensitivity of these measures is moderate; for example, 53.3 percent of COVID-19 documented patients had positive oropharyngeal swab test, whereas 71 percent of patients had positive sputum test (38, 39). After 2–8 days of viral infection, the outcomes of RT-PCR generally show positivity (40). Serology based diagnosis When molecular techniques deliver an unsatisfactory result, serological tests come into place by detecting antibodies in the patient’s blood (42). At the beginning of a novel coronavirus outbreak, serological techniques were considered a supplementary diagnostic method (43). There are several serological measures widely used in laboratories around the world to diagnose novel coronavirus infections (44). The enzyme-linked immunosorbent assay (ELISA) is widely used to identify a variety of viruses, such as novel coronaviruses (45). The various phases of the novel SARS-CoV-2 ELISA experiment are represented in Fig. 3 (46). The degree of sensitivity of this examina- tion to IgG or IgM in COVID-19 positive patients is almost 84.3 percent (47). Fig. 4. Steps in lateral o fl w immunoassay (LFIA)-based COVID-19 diagnosis (reproduced with per - mission from ref. 50). 177 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. For the identic fi ation of novel coronavirus, a tweaked form of luminescent ELISA is used in the chemiluminescent immunoassay (CLIA). Chemiluminescent immunoassay is used to determine the quantity of antibodies such as IgG, IgM, and IgA (48). Patient sam - ples may be mixed with virus-specic fi proteins using this process. The development of the antigen-antibody complex is then observed by the attachment of another secondary anti - body, which undergoes a particular chemical reaction to create illumination. The sum of light released is then measured for the calculation of the number of antibodies found in the COVID-19 sample (44). The degree of sensitivity of CLIA is almost 97.8 % in the COVID-19 positive patients (47). In Point of Care (POC) immunodiagnostics, rapid diagnostic tests (RDTs) are gaining popularity due to their compact, simple, and portable nature (44, 49). RDTs utilize the late - ral o fl w immunoassay (LFIA) technique which uses colour lines to assess if samples of saliva, nasal swabs, and/or blood for viruses are positive or negative (Fig. 4) (50). Two distinct lines are present in a lateral flow immunoassay where a membrane con - taining gold-nanoparticle-labeled antibodies (Au-Ab) and trap antibodies are present (44). As the sample of the patient is placed on the membrane, it moves across the membrane by capillary motion. The viral antigens bind and shape a complex with Au-Ab. This complex then moves forward and is caught by the capture antibodies in the second line, resulting in the formation of coloured lines on the surface, verifying the tests (44, 50). Diagnosis based on radiology Chest X-ray. – Chest x-rays normally do not display noticeable alterations in the early stages of the illness. When the infection develops, bilateral multifocal alveolar opacities are discovered, and pleural effusion is often seen in the latter stages (51). Computed tomography. – High-resolution computed tomography (HRCT) is particu- larly sensitive and, also in the early stages of the illness, is the preferable technique for COVID-19 pneumonia diagnosis. The most prominent attributes are multifocal bilateral ‘ground-glass’ areas consistent with convergence and patchy peripheral distribution, with the lower lobes becoming more involved. In certain patients, a ‘reverse halo sign’ is also seen, which is known as a focal region of patchy opacities surrounded by a consolidation peripheral ring. Other observations include pleural effusion, calcic fi ation, cavitation, and lymphadenopathy (52). a) b) c) Fig. 5. a) The COVID-19 infected chest, b) pneumonia infected chest, c) normal chest (reproduced with permission from ref. 51). 178 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. Fig. 6. The inter-lobular septal thickening, multiple ground-glass opacities, and an insane pattern in the two lung lobes (reproduced with permission from ref. 52), comparisons were illustrated in the HRCT scan. Diagnosis through histopathological changes Usually, microscopic findings have low sensitivity and are associated with indivi - duals who are less symptomatic or not symptomatic (44). The post mortem findings of an elderly COVID-19 patient revealed a variety of lung complications, including inflamma - tion in the lungs, pneumocyte hyperplasia, ground-glass opacities in chest x-rays, and lymphocytic focal inflammation, among others (53). These features were close to those identie fi d with previously reported SARS and MERS infections (54, 55). Lung consolida - tion, pleurisy, pericarditis, and pulmonary edema in the ae ff cted lung are some of the most noticeable macro-findings (44). In comparison to normal healthy lungs, COVID-19 patients’ lungs had an elevated weight (56). Newer techniques CRISPR in the diagnosis of SARS-CoV-2. – The coronavirus preventive antiviral CRISPR, which is a Cas 13-based process, was created as a therapeutic tool, but drug authorities around the world are yet to sanction human clinical trials. The CRISPR-based DETECTR assay oe ff rs positive and negative COVID-19 outcomes with 95 and 100 percent accurate predictions, respectively (57). Algorithm-based coronavirus detection. – An algorithmic technique that focuses on ran- dom access instead of batch-wise testing for easy diagnosis of the disease is Hologic Pan- ther Fusion (PF) screening (58, 59). Some Iranian experts are recommending one of the techniques to diagnose and provide appropriate care for children sue ff ring from C OVID-19 (44, 60). Following the analysis of patient symptoms, their response to treatments, and surveillance data obtained from their country, this technique was devised and in use in many countries (44). When comparing PF assay with Laboratory Developed Test (LTD), PF was 98.3 % in agreement with LTD (61). 179 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. LAMP-based detection of SARS-CoV-2. – The technique utilizes the spectrophotometric method to detect the virus. This technique was found to be equally sensitive to the existing RT-qPCR molecular screenings for viral identic fi ation (62). Jinzhao Song recommended that the LAMP technique could be improved by combining two stages of amplic fi ation in a single tube utilizing recombinase polymerase amplic fi ation (RPA) (63). He further recom- mended using the LAMP to build a POC testing system for user-friendly diagnosis. On combining with paper-based technology, these devices had remarkable features in their ability to be tagged with an advanced cellphone on which quarantined and self-isolated individuals can obtain highly responsive, accurate, and rapid results on their own (64). The findings of paper-based tests may be uploaded to the cloud internet and made accessible to physicians for immediate updates about an individual’s health condition, as well as forwarded to the government (65). As a result, rushing to the hospital for a checkup is reduced, and the risks of spreading the virus are signic fi antly decreased (66). When com - bined with surveillance data, tests that measure the potential of antibody responses to novel coronavirus infection are critical for the production of vaccines and contribute to the estimation of the number of patients that should be screened for a suspected infection (67). The existing scenario necessitates the implementation of lessons gained through the previ- ous coronavirus outbreak in order to address the latest COVID-19 pandemic with a more systematic approach (44, 68). THERAPEUTIC STRATEGIES When the COVID-19 pandemic ramic fi ations become evident, pharmaceutical compa - nies immediately seek to either develop new drugs or repurpose medications to manage this menace. A host of ee ff ctive drug development projects is ongoing in Europe, America, China, and other parts of the world. Pharmaceutical firms such as GlaxoSmithKline, Pfizer, Sano, fi Moderna, AstraZeneca, and Gilead Sciences are designing the majority of treatment options, keeping in mind the various aspects of the disease. The Gilead remde- sivir clinical trial, which was performed in partnership with the Chinese Authority, pro- duced mixed results; however, another clinical trial data showed the drug’s potential to decrease hospitalization stay and mortality of the COVID-19 patients (69). The following strategies have been developed so far to contain COVID-19 infection: (i) virus-neutralizing agents, (ii) ACE2-receptor blockers, (iii) TMPRSS2 inhibitor, (iv) NRP-1 inhibitor, (v) cytokines release inhibitors, (vi) protease inhibitors, (vii) RNA-dependent RNA polymerase inhibitor, (viii) use of antibiotics, (ix) use of antimalarial drugs, ( x) miscel- laneous agents. The strategies that successfully g fi ht the virus are shown in Fig. 7. A brief overview of the widely discussed drugs has been separately outlined and all the available drugs and therapeutics that can be used in the die ff rent conditions and stages of novel SARS-CoV-2 infection have been listed in Table III. Mild symptomatic COVID-19 patients, suspected or confirmed cases (with light fever, fatigue without dyspnoea), should be excluded in quarantine and palliative care is recom - mended (71). Fever is usually treated with paracetamol or anti-inflammatory non-steroidal medicines, and no additional medication is recommended at this stage (71). In addition, the use of conventional Chinese medicine to control patient conditions is also encouraged 180 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. Fig. 7. The figure highlights different strategies to contain the SARS-COV-2 infection (reproduce with permission from ref. 70). by Chinese health professionals and doctors (72). However, the use of hydroxychloroquine (HCQ) was endorsed by European guidelines in patients with documented COVID-19 (73). In the other severe cases such as COVID-19 pneumonia, COVID-19 ARDS, and septic shock the health caregivers are advised to follow the treatment strategies recommended by the WHO (71). Therapeutics in use/consideration RNA-dependent, RNA polymerase inhibitor: Remdesivir. – Remdesivir, produced by G ilead Sciences, a US-based corporation, has traditionally been used to eradicate the Ebola virus (103). The drug is widely being used in the USA and globally against COVID-19 infection (104). The latest study of hospitalized patients specic fi ally shows a dramatically decreased mortality risk (from 11 to 7.1 %) with the usage of remdesivir (105). Protease inhibitors: Lopinavir/ritonavir. – Many clinical trial reports concluded that the treatment with Lopinavir/ritonavir were inconsistent for severely ill COVID-19 patient (78). In addition, a team of Chinese scientists (ChiCTR2000029308) undertook an open-label randomized control study of serious COVID-19 patients seeking treatment with lopinavir/ ritonavir and compared the results with standard care. Their results revealed that there was no therapeutic benet fi from lopinavir/ritonavir. In the less severe cases of COVID-19, the possibility of benec fi ial ee ff cts lopinavir/ritonavir is yet to be ascertained (78). 181 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. fi ff ffi ffi ffi ffi Table III. COVID-19 therapies possibly in use in various parts of the world Drug Clinical trial/status Trial registration No. Safety parameter Dose in clinical trial/s Ref. Antimalarial Drugs Evaluation of the eectiveness and Cardiac arrhythmias (e.g., QT 500-mg dose peroral, protection of chloroquine in hospita- prolongation), retinal damage, Chloroquine ChiCTR2000029542 twice a day, for not 74, 75 lized patients with COVID-19 infections/ not safe for people with G6PD more than 10 days phase-4 deciency and diabetes 200 mg peroral thrice The purpose of the trial is to determine a day for 10 days; ChiCTR2000029559 Hydroxy- the ecacy and protection of hydroxy - Same as chloroquine generally in combina- 76, 77 chloroquine chloroquine in the therapy of COVID-19 NCT04261517 tion with azithromy- pneumonia/phase-3 cin Protease Inhibitors A controlled, open-label trial to Lopinavir: 400 mg Cardiac arrhythmias (e.g., QT determine the ecacy and protection of peroral twice a day; Lopinavir/ prolongation), Not safe for lopinavir/ritonavir in patients with ChiCTR2000029539 ritonavir: 100 mg 78, 79 ritonavir patients with hepatic disease moderate COVID-19 pneumonia/ peroral twice a day for or hepatitis phase-0 (completed) 14 days RNA-Dependent RNA Polymerase Inhibitors 1600 mg per os twice Ecacy and protection of favipiravir for one day, followed by Cardiac arrhythmias (e.g., QT novel coronavirus-infected pneumonia: 600 mg per os twice prolongation) Favipiravir multicenter, randomized, open-label, ChiCTR2000030254 80–82 per day until the optimistic, parallel-controlled clinical Hyperuricemia and diarrhoea cessation of the trial/phase-0 (completed) illness 200 mg dose i.v. once a Research to assess the protection and day for 1 day followed antiviral ecacy of remdesivir Remdesivir NCT04292899 Hepatotoxicity by 100-mg dose i.v. 83–85 TM (GS-5734 ) in participants with severe once a day for the next COVID-19/phase-3 4–9 days F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. fi fi ff ff ffi ffi Drug Clinical trial/status Trial registration No. Safety parameter Dose in clinical trial/s Ref. Antibiotics Eciency and protection of azithromy - 500 mg peroral for the cin relative to base therapeutic dosage Cardiac arrhythmias (e.g., QT rst day accompanied Azithromycin of hydroxychloroquine in mild to severe NCT04359316 86, 87 prolongation) by 250 mg daily for COVID-19: A randomized, regulated, the upcoming 4 days double-blind, clinical trial/phase-4 Cytokine Release Inhibitors Multicenter, randomized clinical study –1 GI perforation, hepatotoxicity; 4–8 mg kg intrave- of the eectiveness and protection of nous diluted in not safe for patients with Tocilizumab tocilizumab in the management of new ChiCTR2000029765 88, 89 normal saline (single thrombocytopenia and coronavirus pneumonia (COVID-19)/ dose) neutropenia phase-4 Research to assess the eectiveness and Minimal or no toxicity was Leronlimab 700 mg Leronlimab protection of leronlimab in patients with NCT04347239 90 observed per os weekly more severe or critical COVID-19/phase-2 Analysis of the performance and The toxicity and safety prole Single or multiple Sarilumab protection of sarilumab in hospital pa- NCT04315298 of the drug is yet to come 91, 92 intravenous doses tients with novel COVID-19/phase-2 online Passive Immunity Convalescent plasma (400 mL) from the COVID-19 Convalescent plasma trial in COVID-19 Some sporadic anaphylactic recovered patient can convalescent NCT04356534 93, 94 patients/phase-0 (completed) shock were observed be delivered as 200 plasma mL at 2 hours interval on 2 successive days Corticosteroids Methylprednisolone Eciency and protection of corticoste - –1 Methyl- Reactivation of hepatitis B virus, 1 mg kg per day roids (methylprednisolone) in NCT04273321 95 prednisolone herpes virus, tuberculosis intra- v enously for 7 COVID-19/ phase-0 (completed) days F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. ff ff ff ff fi ffi Drug Clinical trial/status Trial registration No. Safety parameter Dose in clinical trial/s Ref. 16 mg intravenous for In COVID-19 dexamethasone linked the first 5 days was Reactivation of hepatitis B virus, Dexamethasone ARDS: Multicenter, randomized clinical NCT04395105 accompanied with 8 96 herpes virus, tuberculosis study/phase-3 mg intravenous over the next 5 days ACE-2 Receptor Antagonist Clinical research of arbidol hydrochlo- Two tablets peroral ride tablets for the prevention of Arbidol NCT04260594 No seriously side-eects three times a day for 97, 98 pneumonia induced by COVID-19/ 10–14 days phase-4 Neuropilin-1 (NRP-1) Receptor Antagonist Computer-based recognition and EG00229-like conrmation of interactions between Not applicable Data not available Data not available 99 compounds neuropilin receptor 1 and SARS-CoV-2 Spike protein Miscellaneous Agents A randomized anticoagulation study Every 12 hours, –1 Enoxaparin (enoxaparin) COVID-19 approach/ NCT04359277 Usual side-eect but rare 1 mg kg subcutane- 100 phase-3 ously Eciency and protection of thalido - Other less threatening 100 mg per os every Thalidomide mide in adjuvant therapy of mild NCT04273529 side-eects are: constipation, 101 night for 14 days COVID-19 pneumonia/phase-2 dizziness and malaise Fingolimod for the care of COVID-19/ 0.5 mg per os every day Fingolimod NCT04280588 Usual side-eects 102 Phase-2 for 3 days in a row F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. TMPRSS2 blocker: Camostat mesylate. – Camostat mesylate is a powerful protease in- hibitor. Previously, the medication was used for a number of therapeutic purposes, includ- ing u fl and pancreatic inflammatory disorders. The drug also causes the breakdown of the TMPRSS2 co-receptor and therefore, blocks the virus entry into host cells. The serine pro- tease TMPRSS2 interacts with the novel coronavirus spike (S) enzyme to cause the virus to reach the host cell (106). There are no clinical trial reports for this intriguing medication against novel coronavirus infection. ACE2-Inhibitor: Arbidol (umifenovir). – It is suspected that arbidol (umifenovir) prevents endocytosis of SARS-CoV-2 inside the host cell. Arbidol is reportedly involved in multiple clinical trials against COVID-19 for this cause (107). Along with the NIH, the Chinese clinical research organisations are both running ec ffi acy studies on arbidol, either alone or in con - junction with the protease inhibitor favipiravir (NCT04260594, ChiCTR2000030254). Human recombinant soluble ACE2: APN01. – Parenteral administration of human recom- binant soluble ACE2 binds with the SARS-CoV-2 spike protein, results in suppression of cellular endocytosis (108). This will, in fact, cause a marked decline in damage to lung cells. A human recombinant ACE2 (APN01) was engineered and shown to contribute to a substantial reduction in AN-II-mediated lung injury and IL-6 levels based on these posi- tive results. The evidence was adequate to justify a clinical trial with RhACE2. Apeiron Biologics is also sponsoring clinical research on the ee ff ctiveness and protection of APN01, currently in phase II (NCT04335136). Adjuvant therapy Anticoagulant therapy. – Endothelial disturbance during the novel coronavirus infec- tion induces thromboembolism, which is a rare and lethal complication in critically ill patients. Multiple reports showed that anticoagulants perform well in reducing serious complications in critically ill COVID-19 patients (25, 109). Vitamin C supplementation. – In 2019, Fowler et al. focused on the usage of vitamin C vs. placebo in ARDS septic patients, and they found that any ina fl mmatory markers or organ failure score did not boost the vitamin C infusion (110). Many current clinical studies con- firm the ee ff cts of vitamin C in the treatment of COVID-19 (NCT04682574, NCT04335084). Anecdotal treatment Hydroxychloroquine. – Antimalarial medication hydroxychloroquine has demonstrated substantial ee ff ctiveness, including HIV-1, Type A, and Type B inu fl enza ec ffi acy. Its anti - viral ee ff ct on SARS-CoV-2 is based on the ee ff ctive blockage of viral penetration by ob - structing the glycosylation of the ACE-2 receptor (111). It has also been shown that alka- linization of the organelle prevents the development of mature endosomes that shield the virus from immune cells and replication (112). Even though many clinical trials were con- ducted, the findings were not promising. So far the drug is no more in clinical use. Ivermectin. – Antiviral behavior was also demonstrated by this wide spectrum anti- parasitic agent. It was speculated that the antiviral activity of ivermectin against COVID-19 was achieved from importin-a/b12 obstruction (113). The drug displayed ee ff ctiveness in 185 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. an improvement in dyspnea and oxygen saturation and a reduction in time of recovery was observed (NCT04668469). Teicoplanin. – This glycopeptide antibiotic has demonstrated antiviral properties against Ebola, MERS, SARS, and HIV-1. Teicoplanin is known to interact with endosome development by alkalization. S-protein breaking by cathepsin in the late endosome is blocked, which in turn inhibits viral RNA from being released out of the cells (114). Baron et al. demonstrated that the cathepsin L sequence is also found in the S-protein of novel SARS-CoV-2 and, therefore, causes the virus to enter the cells. It was also reported that in the event of early detection of novel coronavirus disease 19, teicoplanin is probably a good choice of treatment (115). Humanized monoclonal antibodies: Tocilizumab, bevacizumab, sarilumab. – Monoclonal anti- bodies (mAbs) normally modify the host organism’s immune system response, i.e. a drop in plasma IL-6 levels, which is frequently higher in severe cases of SARS-CoV-2 patients (116). Table III presents the status of tocilizumab, bevacizumab, and sarilumab. However, to de- crease the cytokine storm, health care providers around the world often use these drugs. Interferon-α. – Interferon-alpha (INF-α) has been proven to be ee ff ctive in containing SARS-CoV-1, it is predicted that INF-α may control the SARS-CoV-2 also, as both the strains are structurally similar. A clinical trial (ChiCTR2000029387) was performed to af- firm the ee ff ctiveness of INF-alpha against SARS-CoV-2, together with ribavirin, and the findings were disappointing (117). Zongji Hospital has funded a clinical trial registered with the NIH to determine the ec ffi acy of INF-5-0072β (NCT04293887) and is currently in early phase I (118). Corticosteroids. – The use of corticosteroid treatment to recover and/or shorten the duration of hospitalisation for COVID-19 patients has traditionally been problematic owing to lack of clinical evidence (119). However, some trials have suggested its ee ff ctive - ness, which has prompted NIH to establish recommendations for the use and dosing of dexamethasone in COVID-19 patients. However, these recommendations suggested start- ing steroids in COVID-19 patients with extra oxygen and artic fi ial ventilation in the novel coronavirus (120). Passive immunity/convalescent plasma. – Recently, a randomized clinical trial was per - formed to determine the ee ff cts of convalescent plasma in severely ill COVID-19 patients and findings indicated little or no benet fi s. In addition, the length of the illness did not seem to be reduced by its addition to the normal treatment of COVID-19 (121). There are, however, dangers involved with the administration of immunoglobulins, which is why it can only be used with serious or life-threatening COVID-19, according to the FDA Advi- sory Board (122). Vaccines: The most sought after therapeutic What makes the novel coronavirus so infectious? The answer is simple; this is a new virus, and there is no protection mechanism in our bodies against that virus. Taking precau- tionary steps and the usage of vaccination are the two most successful methods of alleviat- ing the spread of a pandemic. More notably, the vaccine should be needed to eradicate the high spread capability of COVID-19, which, if not managed, would continue to drive the current pandemic. The most commonly selected target for the development of the COVID-19 186 F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022) 171–197. fi fi tt Table IV. Vaccines in use or under consideration Nature of vaccine Target of vaccine Principal developer of vaccine Country Clinical trial status Ref. Phase 2/3 DNA vaccine (INO-4800) Spike (S) protein Inovio Pharmaceuticals USA 123 NCT04642638 Phase 2/3 Non-replicating virus (AZD1222) Spike (S) protein University of Oxford UK NCT04324606 124 NCT04400838 Sinovac Research and China and Phase 3 Whole inactivated virus vaccine Entire virus 125 Development Co. Ltd. Brazil NCT04456595 Phase 3 mRNA vaccine Spike (S) protein Moderna, USA USA 126 NCT04470427 Recombinant vaccine (adenovirus Phase 3 127, Spike (S) protein CanSino Biologics China type-5 vector) NCT04526990 128 Serum Institute of India in Pre-clinical/animal Aenuated live vaccine Entire virus India and USA 129 collaboration with Codagenix studies Nucleoside-modied messenger Spike glycoprotein Phase 2/3 RNA Pzer & BioNTech SE USA 130 (S) NCT04368728 BNT162b1&b2 Phase 1/2 Whole-virion inactivated Spike (S) protein Bharat Biotech India India 131 SARS-CoV-2 vaccine BBV152 NCT04471519 Heterologous recombinant Gamaleya Research Institute Phase 3 adenovirus (rAd) vaccine Spike (S) protein Russia 132 Russia NCT04656613 Gam-COVID-Vac (Sputnik V) F. Alotaibi: Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19), Acta Pharm. 72 (2022 171–197. vaccine is the spike (S) protein embedded in the SARS-CoV-2 envelope. Die ff rent platforms are actively focusing on the creation of COVID-19 vaccines. Globally, signic fi ant COVID-19 vaccines in clinical use or die ff rent stages of the clinical trial are listed in Table IV. There are some side-ee ff cts reported since the vaccination program started. The resear- chers are in the opinion that these are minor hiccups. The benet fi s of taking vaccines outweigh the devastation of the ongoing pandemic. Moreover, the side-ee ff cts of these vaccines were not properly documented; therefore, the author did not incorporate the sporadic reports. The author r fi mly believes that the vaccines will contribute much to the prevention of the disease. WHAT FUTURE HOLDS? As of February 2021, treatment for COVID-19 depends on the case’s severity. In milder conditions, it is enough to rest at home and take medication to relieve fever. The most severe cases require hospital admission, with therapeutic management that might consist of oxygen supplementation, assisted ventilation, and a complete course of therapeutics. Battling SARS-CoV-2 and the infection it causes is of top importance in health research and therapeutic development. A growing number of research organizations are battling to minimize the ee ff cts of the disease and to avoid further spreading of COVID-19 infection. Several organizations, including all big and small pharmaceutical industries, are working on die ff rent classes of vaccines. Reports of many vaccines have been published in the most reputed journals and are accessible to everyone. Some undesirable ee ff cts, not reported in the published data, were observed in many countries during the vaccination programs. The propensity and infectivity of COVID-19 have been lessened in many parts of the world; however, the USA is still facing the heat and peak of the infection. Getting life back to normal is still a distant dream. EXECUTIVE SUMMARY The epidemic of COVID-19 spread quickly through China and engulfed all of the countries across the globe. Several advances have been made in understanding the novel coronavirus’s physicochemical properties, the discovery of antiviral drugs and vaccines. This article highlights our understanding of the novel coronavirus’s symptoms in brief, pathogenesis, diagnostics, and therapeutic strategies to contain COVID-19. SARS-COV-2 emerged from bats and is likely to enter some unknown intermediate hosts; binding to high- -affinity ACE2 receptors inevitably infects humans. The clinical findings including serolo - gical, radiological, and other advanced diagnostic strategies contributed much to control the disease. 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Acta Pharmaceutica de Gruyter

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Publisher: de Gruyter
ISSN: 1846-9558
eISSN: 1846-9558
DOI: 10.2478/acph-2022-0014
Publisher site: See Article on Publisher Site

Abstract

Journal

Acta Pharmaceutica – de Gruyter

Published: Jun 1, 2022

Keywords: coronavirus disease 2019; COVID-19; SARS--CoV-2; pathogenesis; remdesivir; treatment options

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Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19)

Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19)

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Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19)

Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19)

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Journal

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