**2.2 Lopinavir/ritonavir**

The combination of lopinavir/ritonavir was considered as an option for the treatment of Covid-19 during initial pandemic days. Lopinavir is an HIV-1 protease inhibitor, which is combined with ritonavir to increase its half-life through cytochrome p-450 inhibition. Both anti-HIV drugs interact with residues at the active site of SARS-CoV 3C-like protease, suggesting the mechanism of action in COVID-19 [14]. Its role was first evaluated in the treatment of SARS where patients treated with lopinavir/ritonavir for 14 days combined with ribavirin for 21 days. They had a milder disease in form of less diarrhea, fever, lymphadenopathy, the incidence of nosocomial infections, viral loads, demonstration of virus in the fecal sample by reverse transcription-polymerase chain reaction (RT-PCR), and 21 days adverse outcomes [15]. The combination was tested for MERS-CoV. It was postulated that the lopinavir/ritonavir combination may inhibit the 3C-like protease of MERS-CoV and may affect apoptosis in human cells. Results revealed that treatment with lopinavir/ritonavir led to clinical, radiological, and pathological improvement. Those animals treated with this combination had the lowest mean viral load detected by RT-PCR in lung and other extrapulmonary tissue [16]. There was only a single case report of a man being treated and recovered with a combination of lopinavir/ ritonavir, ribavirin, and interferon-α for the MERS [17]. Based on this data, an

*Pharmacotherapy for COVID-19: A Ray of Hope DOI: http://dx.doi.org/10.5772/intechopen.97012*

urgent RCT was done to study the efficacy of lopinavir/ritonavir in the Wuhan province of China [18]. The analysis revealed no significant difference in terms of time for clinical improvement and mortality at 28 days. The median time for clinical improvement was just one day shorter in the lopinavir-ritonavir group compared to the standard care group. In July 2020, WHO discontinued the lopinavir/ritonavir arm of the solidarity trial due to a lack of any mortality benefit [19]. It causes QTc prolongation, just like HCQ [20].

#### **2.3 Azithromycin**

Azithromycin is a broad-spectrum antibiotic belonging to the macrolide group, having anti-inflammatory properties also. It is commonly used for treating atypical respiratory pathogens. Azithromycin's anti-viral efficacy against some RNA viruses has also been described. Its efficacy has been demonstrated in-vitro against Zika virus and rhinovirus, as well as SARS-CoV-2 [21, 22]. As described, azithromycin also has immunomodulatory effects and can decrease acute exacerbations of chronic airway disease. Owing to its wide availability, excellent safety profile, and easy availability, azithromycin is one of the commonest drugs being used in the COVID-19 pandemic also. The Lancet reported the result of the COALITION II trial, [23] which was an open-label randomized trial evaluating azithromycin in addition to the standard of care (including HCQ ), against the standard of care alone in severe COVID-19 patients. Azithromycin demonstrated no benefit in clinical outcome including clinical status or mortality, as compared to the standard of care alone (OR 1·36 [95% CI 0·94–1·97], p = 0·11). There was no increase in adverse events with azithromycin. In a study published in NEJM, HCQ alone or in combination with azithromycin had no demonstrable improvement in clinical status at 15 days compared with standard care in mild to moderate COVID-19 admissions [24].

#### **2.4 Ivermectin**

Ivermectin is a commonly used drug for various parasitic infestations including head lice, scabies, strongyloidiasis, ascariasis, and lymphatic filariasis. It is a macrocyclic lactone, which is derived from streptomyces avermitilis [25]. Its mechanism of activity against SARS-CoV-2 is believed to be via viral IMPα/ β1 (Importin) mediated nuclear import inhibition. This leads to a decrease in the multiplication of the virus and hence the viral load [26, 27]. Ivermectin and doxycycline combination also inhibit viral entry and increases viral load clearance by the targeting of multiple viral proteins [28]. A recent study from India demonstrated that 2-dose ivermectin prophylaxis (300 micrograms/kg) within a gap of 3 days led to a 73% reduction in the number of COVID-19 infections among healthcare workers [29]. In studies conducted in Bangladesh also, the ivermectin-doxycycline combination was demonstrated to be highly effective in virological clearance in mild to moderate COVID-19 patients [30, 31]. National Institute of Health (NIH) stated in January 2021 that there was insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19 [32].

#### **2.5 Melatonin**

Melatonin is a hormone, which is synthesized from tryptophan in the pineal gland of the body and also by mostly all the organs of the body, as its production is associated with mitochondria. Higher levels of melatonin have positive roles in health and aging. Melatonin promises to be a great adjunctive drug for viral infections owing to its anti-inflammatory, anti-apoptotic, immunomodulatory, and antioxidant activities [33]. Sirtuin-1 (SIRT1) is the proposed mediator of melatonin's anti-inflammatory action. This is via inhibition of high mobility group boxechromosomal protein-1 (HMGB-1), leading to down-regulation of the polarization of macrophages towards pro-inflammatory type [34]. It inhibits the over-activity of the innate immune system. Hence, theoretically, the cytokine storm induced by COVID-19 can be suppressed by melatonin. But the use of melatonin in COVID-19 is still very sparse, with only a few studies evaluating the same, hence further research is warranted [35]. Owing to melatonin's anti-inflammatory, anti-oxidant, and anti-viral actions, its role in critical illness caused due to COVID has been studied. Melatonin has easy availability, is not expensive, and has an excellent safety profile [36]. A trial (EudraCT: 2020–001808-42) is ongoing for the identification of the doses of melatonin that may prove effective in this disease. It is a phase II, single-center, double-blind, RCT to address the efficacy and safety of intravenous melatonin in COVID-19 ICU patients [37].
