The COVID-19 Pandemic - A Global Public Health Crisis: A Brief Overview Regarding Pharmacological Interventions

WHO reported that viral diseases remain as an international public health concern. Quite a lot of viral outbreaks such as the SARS coronavirus from 2002 to 2003, H1N1 influenza in 2009, and the MERS syndrome coronavirus in 2012, in the last two decades. The recent outburst of COVID-19 disease has to turn out a global public health catastrophe that has a profound consequence on every aspect of human life. Currently, national governments, international health agencies, UN different bodies are working relentlessly to find the best way to save and mitigate our world from the shattering effects of COVID-19. Simultaneously, all related scientists around the planet determinedly made enormous efforts to find the COVID-19 transmission process, clinicopathological issues, diagnostics tools, and prevention policy planning and pharmacological intervention approaches. There are many problems that are not resolved regarding COVID-19, like the virus-host relations and the development and progression of the pandemic, with precise reference to the times when the current pandemic will reach its ultimate level to produce maximum damage. At this moment in time, yet we do not possess and definite and specific treatment options to fight with the COVID-19 viral infectious diseases. Currently, the majority of the scientist is involved in finding a way through drug repurposing. Up to the present time lot of medicines were identified that possess definite antiviral effects against COVID-19 but need to go a long way with well-designed study to obtain the best possible answer. After that, to this point, supportive and preventive remain as the best weapon.


Introduction
Microbial diseases (bacteria, viruses, parasites, and fungus) have instigated disaster throughout human history [1]. Emerging and re-emerging microbial diseases along with multiple drug-resistant (MDR), pandrug-resistant (PDR), extensively drug-resistant (XDR) are now taking place at skyrocket high-speed [2][3][4]. The World Health Organization (WHO) reported that our planet has feast your eyes on the escalation of quite a lot of infectious disease eruptions and epidemics began by more than twenty infectious agents over the last ten years [5]. These epidemics were often of novel viral origin such as a novel influenza A virus (H1N1) and Middle East respiratory syndrome (MERS) [6][7][8][9][10].
The evolution of coronavirus-associated diseases, Severe Acute Respiratory Syndrome (SARS and MERS) for the last twenty years, imposed comprehensive international challenges regarding the management of these viral diseases and ensured a threat to public health all over the globe [11,12]. The SARS-CoV-2 is the causative virus agent for coronavirus disease , the latest version of the β-coronavirus family, single-stranded RNA, the enveloped virus that is 50-200 nm in diameter [13][14][15][16], after that, the WHO confirmed COVID-19, a public health emergency of global distress on January-30-2020 and a pandemic on March-11-2020 [17][18][19]. The mortality total and daily new death profile of selected countries are depicted in  The World Health Organization promoted these strategies to prevent COVID-19 transmission [20]: 1) Clean your hands frequently with soap and water, or an alcohol-based hand sanitizer; 2) Conserve a safe space from any person who is coughing or sneezing; 3) Avoid touching your own eyes, nose or mouth; 4) Shield your nose and mouth with your bent elbow or tissue while you are coughing or sneezing; 5) Stay home; 6) If you develop a fever, cough and difficulty breathing, urgently seek medical care; 7) Comply and conform the directions of your local health authority; 8) Avoid unnecessary visits to clinics and hospitals facilities that will reduce the possibility of acquiring COVID-19 infection; additionally, permits healthcare systems to function more efficiently, consequently protecting you and others.

COVID-19 and Intensive Care Unit
Coronaviruses are an outsized family of viruses that are recognized to driving force sickness extending from the common cold to more ascetic illnesses such as MERS, SARS, and the current global pandemic of COVID-19 [21,22]. There is no explicit pharmacological intervention, curative treatment, and vaccine caused by the novel coronavirus [21,23]. Nevertheless, many of the pathological issues of COVID-19 currently managed with available clinical options, and consequently, current treatment planning principally founded on the individual patients' clinical context [24][25][26]. Additionally, COVID-19 patients frequently need supportive medical care, including the Intensive Care Unit with ventilator, and dialysis as these found highly effective in saving lives [27][28][29]. were cured, released from the hospital and reached home [32].
One the US reported that out of twenty-four definite COVID-19 patients admitted in ICU service, 58% had diabetes mellitus. Among these patients, 50% of cases passed away from day-1 to day-8. Remaining 50% patients survived, 21% were cured, released and go home, 17% were released from the ICU care, but the improvement was not enough, thereby, need to stay in the hospital, and 12% patients were not improved and needed continuing to receive mechanical ventilation in the ICU. The study concluded that the full picture requiring the ICU service was a hypoxemic respiratory failure [33].
A prospective study was conducted in hospitals allied with Columbia University, New York, USA, between March/2020 to April/2020. In this time frame, 1150 cases of laboratory-confirmed COVID-19 were admitted, and among them, 22% were in severe condition. The median age of these COVID-19 patients was 62 years (IQR 51-72); additionally, 67% and 33% were men and women, respectively. Moreover, 82% of admitted patients had at least one comorbidity, such as hypertension (63%), diabetes (36%), and obesity (46% per decile increase), respectively [34].
The Scottish Government has proclaimed till June/2020 that a total of 220,198 Scottish population have been examined for COVID-19. Among these, 202,121 and 18,077 were confirmed negative and positive, respectively [35]. In Scotland, those patients admitted ICUs 38% of COVID-19 do not recover and expire [36]. Among Scottish patients required ICUs, they need about 80%, almost 80%, and nearly 30% required advanced respiratory support, cardiovascular support, and dialysis, respectively [36].

Currently Utilized Medication for COVID-19: Clinically Approved for Other Indication
Currently, there are no specific and approved medicines for the treatment of COVID-19 infections. A recent systematic review and meta-analysis reported that studies, although HCQ + azithromycin (Azi) appears safe and effective. Nevertheless, more multi research studies with large data sizes are obligatory for an ultimate inference. Additionally, this review reported that HCQ has better shreds of evidence and promising efficacy and safety profile to avert radiological progression (deterioration) of COVID-19 cases when compared with control or conventional treatment group [44]. The French group of researchers reported that HCQ + Azi combination when applied to COVID-19 patients, it was successfully eradicated 100% virological load when compared with the HCQ alone (57.1%) and the control (12.5%) group [45]. The same research group in their second study with a higher number sample size revealed that HCQ + Azi combination reduces 83% and 93% of the virological load of COVID-19 cases on day-seven and day-eight, respectively. It was reported that 81.25% were cured and released from the hospital [46]. The identical research cluster in their third study with an additional number sample than the second study reported that HCQ + Azi combination diminishes 91.7% of the virological load among COVID-19 patients by day-ten and the unfortunate clinical consequence was observed in only 4.3% patients, and 0.47% patients passed away [47].
Another French group of researchers 48 working separately revealed quite the reverse findings and were unsuccessful in imitating the earlier results [45][46][47]. The case selection of this study was much different [48]. These COVID-19 patients belong to the severe category with multiple substantial comorbidities like carcinoma, HIV, and over-weight [48]. It was reported that HCQ + Azi combination causes mild adverse drug reactions (ADRs) that include nausea, vomiting, diarrhea, and blurring of vision [46]. Another study reported that only one of their study participants developed electrocardiographic changes of QT prolongation [48].
Another study showed that 11% of research participants of COVID-19 cases with these combination antimicrobials developed substantial QTc prolongation. Additionally, those cases develop of acute renal failure was an imperative forecaster of extreme QTc prolongation [49]. concluded that pharmacological intervention with HCQ, Azi, alone, or HCQ + Azi (combination) was not correlated with statistically significantly in lowering mortality, among COVID-19 hospitalized patients [50].
As there are no definite or specific treatment options, by this means, the global pandemic COVID-19 initiated available medicine repurposing is viewed as the instantaneous choice [51].

Computational Drug Repurposing and Repositioning
Computational drug repurposing (as well recognized as drug repositioning) intentions at identifying new clinical indication for by now available and clinically utilized for indication, exclusively when the thorough 3D structures of significant viral proteins are invented within five days [52][53][54]. Drug repurposing has developed as a dynamic division of medicine invention for novel clinical indication [52].
Accordingly, there has been a blast in drug repurposing experiments to invent innovative medicines as aspirants and research studies regarding circumstantial findings. One second-generation cephalosporin -Cefuroxime has been spotted with quite a lot of anecdotal benefits in the treatment of COVID-19 [51]. In that way, one scoping review reported that cefuroxime reveals promising efficacy in opposing three significant COVID-19 proteins necessary for replication in drug repurposing experimentations. In this manner, cefuroxime possibly possesses auspicious multi-target pharmacodynamics that can help us to combat the current pandemic [51]. Additionally, cefuroxime was approved by the US FDA in 1998. Subsequently, it has a long history for clinical use and post-market-surveillance that raises it as a reliable alternative for additional research studies in the global battle against COVID-19 -the current highest threat of human existence [51,55].
Ivermectin was FDA-approved for parasitic infections in 1996 for the treatment of strongyloidiasis and onchocerciasis [61]. However, ivermectin is an antiparasitic medicine but possesses a broad-spectrum antiviral activity in experimental studies outside of a living organism, including the COVID-19 virus [59]. It has around 5000 times the potential to reduce viral load at 48 hours in cell-line culture [59]. Another study reported similarly that ivermectin possesses broad-spectrum antiviral efficacy to inhibit viral replication and transcription of numerous animal and human viruses, which include both RNA and DNA viruses. The broadspectrum antiviral property of ivermectin depends on through the inhibition of importin α/β-mediated nuclear transport of viral proteins. The identical pharmacodynamics of ivermectin was observed with COVID-19. This study finally concluded that the beneficial clinical potential and ADRs of ivermectin yet not adequately assessed in prescribing COVID-19 patients [60].

Convalescent Plasma Therapy
Passive immunization (PI) and antibody therapy had been over a hundred years back. After that, convalescent plasma therapy is a long-standing therapeutic resource with new evidence for the discouragement and treatment of hypoimmunoglobulinemias, carcinoma, and human infectious diseases such as measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia [62][63][64].
The availability and easy accessibility of antimicrobials had put down, and PI therapy issues went exile and considered as out-of-date treatment options for especially infectious diseases [63]. The advent of multi-drug resistant (MDR) pathogenic microbial contagious diseases, and laterally with the initiation of novel monoclonal antibody synthesis methods has to reawaken, and PI technique has been returned in clinical medicine PI [63].
Convalescent plasma had been prescribed as the last remedy among gravely sick SARS patients who were continued to worsen despite having methylprednisolone. Additionally, multiple research reported that convalescent plasma reduces hospital stay and death rates than those who did not have [65][66][67][68]. WHO in 2014 recommended prescribing and utilizing convalescent plasma as an empirical therapeutic option during the Ebola epidemic in Western Africa [69,70]. A similar treatment code of practice had been developed to use convalescent plasma as a last resort for therapeutic intervention among severely sick MERS patients' management program in 2015 [71,72].
The mortality risk of COVID-19 infection, pneumonia, and acute respiratory distress syndrome (ARDS) among critically ill patients over 65 years old remains extremely high, around 12%. It was observed these patients passed away by one to two weeks after admitted in ICU [73,74]. Multiple studies have been reported that human convalescent plasma of COVID-19 patients appeared to be a safe and possesses high prospect and possibilities for beneficial effects among the current global epidemic patients and asymptomatic cases with exposure to COVID-19 sick individual [21,[75][76][77]. Multiple recent research studies reported that convalescent plasma therapy was well tolerated among COVID-19 patients and improved the clinical consequences through reducing viral load and deactivating coronavirus virulence potential [78][79][80][81].
Nonetheless, it is judgmentally imperative to conduct well-designed controlled clinical studies to establish efficacy, the optimum number of convalescent plasma transfusion, and to ascertain the appropriate time of administration. Thereby determine the clinical benefit of convalescent plasma therapy, and it can be generalized to notify the rationality of convalescent plasma therapy has been developed based on scientifically proven evidence [75,78].

Role of Clinical Available Antiviral Medication in COVID-19
The US FDA issued a EUA for the broad-spectrum antiviral agent remdesivir for severe laboratory polymerase chain reaction (PCR) positive cases or suspected COVID-19 hospital admitted to both adults and pediatric patients [82,83]. Remdesivir is a nucleotide analog RNA polymerase inhibitor. The clinical trial was conducted in the Democratic Republic of Congo regarding remdesivir efficacy on Ebola virus infections revealed insubstantial clinical advantageous potential [84].
Multiple studies showed that remdesivir exhibits potential pharmacodynamics to inhibit replication and transcription of other human coronaviruses such as SARS-CoV in 2003 and MERS-CoV in 2012 [85][86][87].
Additionally, remdesivir antiviral pharmacodynamic was evidenced in animal models that have been confirmed for SARS-CoV and MERS-CoV [85]. It has been reported that Remdesivir is one of the top computational drug repurposing, and repositioning agents possess promising pharmacodynamics to combat COVID-19 [88,89].
Multiple studies reported that Remdesivir is one of the top computational drug repurposing, and repositioning agents possess promising pharmacodynamics to combat COVID-19 [88][89][90]. On the contrary, some studies indicated that remdesivir was not correlated with statistically significant clinical benefits among severe COVID-19 patients [91,92]. One systematic review comprising of twenty original studies regarding lopinavir-ritonavir antiviral efficacy against COVID-19. Among these studies, twenty, one, and one research studies were conducted in China, South Korea, and Singapore, respectively. The current systematic review revealed that there were no sharply identified antiviral pieces of evidence found with this combination (lopinavir-ritonavir) in improving COVID-19 patients or not. The present state of affairs of the global pandemic of COVID-19 is a severe 'red flag" for universal health-related organizations, including WHO [93].
This study finally concluded that the current global pandemic -COVID-19 and yet to come epidemics, healthrelated organizations including WHO should trail more pre-emptive activities and well-designed strategy for clinical trials to obtain high-quality clinical results that can face imminent epidemics [93].

Systemic Corticosteroids
WHO, in general, does not recommend corticosteroids are for the treatment of COVID-19 pneumonia [94]. Additionally, it was reported that the use of systemic glucocorticoids in the treatment of acute respiratory distress syndrome (ARDS) secondary to viral pneumonia is debatable [95]. The reason for nonrecommendation glucocorticoids; as the administration of these steroids lengthen and protract viral clearance and increased risk of secondary infection [96]. Even though there are not much data available regarding the use of glucocorticoids among COVID-19 pneumonia [96], nevertheless, mostly, no single exclusive evidence subsists to anticipate that patients with COVID-19 infection can improve with glucocorticoids.
Moreover, researchers have intense apprehension of worsening and further aggravation of the disease process [97]. Furthermore, earlier studies regarding SARS and MERS revealed that no correlation of glucocorticoids with deterring mortality. Nonetheless, steroids' administration correlated with deferred viral clearance from the pulmonary tree and blood and elevated possibilities of complications, including hyperglycemia, psychosis, and avascular necrosis [98,99]. Additionally, one systematic review and metaanalysis comprising of ten research studies in 2029 among 6548 influenza caused pneumonia patients. This study found that glucocorticoids were correlated with an increased risk of mortality (Risk Ratio = 1.75; 95% CI COVID-19 has elicited a vast number of deaths and remarkable economic destruction give rise to international threat not only for healthcare but also in every aspect of life. Henceforth, the current pandemic of COVID-19 identified the pressing necessity of therapeutic options with specific antiviral pharmacodynamic against SARS-CoV-2. The globe needs to wait and look forward to new scientific development to fightback with COVID-19. In the meantime, preventive measures are considered as the best possible way. Finally, COVID-19 teaches us the healthcare system almost all countries need to total overhaul based on primary health care policy planning to fight against any future or health crisis [101][102][103][104][105][106][107].

Conclusion
The COVID-19 pandemic has currently gone into a catastrophic new chapter. The earlier epidemic of SARS and MERS was much slower to spread around the globe than COVID-19. Increased globalization, international traveling, and virus adaptability in almost all countries equally often reported as the primary reasons for rapid spread. Another reason frequently appeared globally risk assessment regarding COVID-19 virulence capacity the globe fails to appraise in time. To date, there is no single specific therapeutic option for battling against this virus.

Authors' Contributions
MH 0000-0002-6124-7993 Conceptualization, Investigation, Formal Analysis, Writing -Original Draft Preparation and Writing -Review and Editing. All authors declare that they contributed to critical review of intellectual content and approval of the final version to be published.

Financial Support
None.