1. Introduction
The vast majority of countries around the world are going through the second wave of COVID-19 pandemic, which constitutes an imminent threat to society, both in terms of human lives’ loss and devastating economic consequences. Up to December 17th, more than 74,635,000 people have contracted the disease and deaths exceed 1,657,000 (Worldometer, 2020). Since the beginning of the outbreak, the main features of SARS-CoV-2, the clinical characteristics of the disease and the role of many pharmacological treatments have been extensively studied. For instance, nowadays it is well known that the COVID-19 is a complex disease with several clinical phases of progression, affecting many organs apart from the respiratory tract. Specifically, its progression seems to follow four main stages (Cordon-Cardo et al., 2020). The first one is the phase during which the SARS-CoV-2 binds to epithelial cells and starts its replication. This stage occurs in the initial 1-2 days. The main proteins involved in the cell entry of SARS-CoV-2 are ACE2 receptor and TMPRSS2 (Fehr and Perlman, 2015; Hoffmann et al., 2020) and the soluble form of ACE2 receptor could be the target of potential therapeutic strategies (Scialo et al., 2020). Many patients can be asymptomatic at this stage and the innate immune response is commonly limited. In the second stage, the virus migrates down the respiratory tract, leading to the occurrence of many symptoms, such as fever, cough, shortness of breath, fatigue, muscle pain, headache, loss of taste or smell, sore throat, nausea or vomiting, and diarrhoea (Liu et al., 2020b). In this stage the innate immune response is triggered and an increase in the level of CXCL10 or other innate response cytokine (the so-called ”cytokine storm”) is observed as well (Wang et al., 2011; Qian et al., 2013). The third stage, which commonly occur within 1–2 weeks after symptom onset, is represented by the multi-system inflammation. Given the seriousness of symptoms (dyspnoea and hypoxia, ground glass infiltrate and progression to acute respiratory distress syndrome - ARDS), and possible cardiac, kidney, and liver damage), patients frequently require hospitalization (Guo et al., 2020a). This is also the phase in which abnormal coagulation biomarkers can be detected (such as, elevated D-dimer), representing sub-clinical progression toward stage 4. Lastly, a generalized hyper-inflammatory state is common in the stage (Del Valle et al., 2020; Leppkes et al., 2020). Lastly, a number of patients may reach the most critical and lethal stage (the last one), which is characterized by endothelial damage, thrombosis, and multi-organ dysfunction. The elevated levels of von Willebrand factor and endothelialitis together with hyperinflammation and hypercoagulability lead to microthrombi formation and systemic microvascular dysfunction (Nadkarni et al., 2020). On the other hand, the combinations of the severe respiratory failure and multi-organ failure, acute neurological disease, venous and arterial thromboembolic events, contribute to the increase in mortality for patients at this stage. In figure 1 the main COVID-19 symptoms by organs and tissues are shown. The clinical features of COVID-19 and the inter-patients variability in its progression demonstrate the complexity of this disease but also the difficulties faced today in the proper choice of pharmacological treatments and patients’ management. Several clinical trials and observational studies have been recently carried out worldwide. In the first wave of COVID-19 pandemic, many drugs have been used in the different phases of the disease. In fact, last May, we reported an overview of the benefit/risk profile of pharmacological treatments used in patients suffering from COVID-19 (Scavone et al., 2020). Considering new evidence recently acquired on the effect of different pharmacological treatments in patients with COVID-19, in this paper we aim to provide an up-to-date overview of medicines, including antivirals, antinflammatory and immune-modulating drugs, anticoagulants and other therapies which have been used around the world to treat COVID-19 and the related evidence in terms of efficacy and safety profile from interventional and observational clinical studies. Lastly, an update of vaccines under advanced clinical development is provided as well.