Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?

Despite the need for novel, effective therapeutics for the COVID-19 pandemic, no curative regimen is yet available, therefore patients are forced to rely on supportive and nonspecific therapies. Some SARS-CoV-2 proteins, like the 3 C-like protease (3CLpro) or the major protease (Mpro), have been identified as promising targets for antiviral drugs. The Mpro has major a role in protein processing as well as pathogenesis of the virus, and could be a useful therapeutic target. The antiviral drug nirmatrelvir can keep SARS-CoV-2 from replicating through inhibiting Mpro. Nirmatrelvir was combined with another HIV protease inhibitor, ritonavir, to create Paxlovid (Nirmatrelvir/Ritonavir). The metabolizing enzyme cytochrome P450 3 A is inhibited by ritonavir to lengthen the half-life of nirmatrelvir, so rintonavir acts as a pharmacological enhancer. Nirmatrelvir exhibits potent antiviral activity against current coronavirus variants, despite significant alterations in the SARS-CoV-2 viral genome. Nevertheless, there are still several unanswered questions. This review summarizes the current literature on nirmatrelvir and ritonavir efficacy in treating SARS-CoV-2 infection, and also their safety and possible side effects.

Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?

Despite the need for novel, effective therapeutics for the COVID-19 pandemic, no curative regimen is yet available, therefore patients are forced to rely on supportive and nonspecific therapies. Some SARS-CoV-2 proteins, like the 3C-like protease (3CLpro) or the major protease (Mpro), have been identified as promising targets for antiviral drugs. The Mpro has major a role in protein processing as well as pathogenesis of the virus, and could be a useful therapeutic target. The antiviral drug nirmatrelvir can keep SARS-CoV-2 from replicating through inhibiting Mpro. Nirmatrelvir was combined with another HIV protease inhibitor, ritonavir, to create Paxlovid (Nirmatrelvir/Ritonavir). The metabolizing enzyme cytochrome P450 3 A is inhibited by ritonavir to lengthen the half-life of nirmatrelvir, so rintonavir acts as a pharmacological enhancer. Nirmatrelvir exhibits potent antiviral activity against current coronavirus variants, despite significant alterations in the SARS-CoV-2 viral genome. Nevertheless, there are still several unanswered questions. This review summarizes the current literature on nirmatrelvir and ritonavir efficacy in treating SARS-CoV-2 infection, and also their safety and possible side effects. Graphical

Does prior immunization with measles, mumps, and rubella vaccines contribute to the antibody response to COVID-19 antigens?

BACKGROUND: Incidence and severity of SARS-CoV2 infection are significantly lower in children and teenagers proposing that certain vaccines, routinely administered to neonates and children may provide cross-protection against this emerging infection. OBJECTIVE: To assess the cross-protection induced by prior measles, mumps and rubella (MMR) vaccinations against COVID-19. METHODS: The antibody responses to MMR and tetanus vaccines were determined in 53 patients affected with SARS-CoV2 infection and 52 age-matched healthy subjects. Serum levels of antibodies specific for NP and RBD of SARS-CoV2 were also determined in both groups of subjects with ELISA. RESULTS: Our results revealed significant differences in anti-NP (P<0.0001) and anti-RBD (P<0.0001) IgG levels between patients and healthy controls. While the levels of rubella- and mumps specific IgG were not different in the two groups of subjects, measles-specific IgG was significantly higher in patients (P<0.01). The serum titer of anti-tetanus antibody, however, was significantly lower in patients compared to healthy individuals (P<0.01). CONCLUSION: Our findings suggest that measles vaccination triggers those B cells cross-reactive with SARS-CoV2 antigens leading to the production of increased levels of measles-specific antibody.

Comprehensive overview of COVID-19-related respiratory failure: focus on cellular interactions.

The pandemic outbreak of coronavirus disease 2019 (COVID-19) has created health challenges in all parts of the world. Understanding the entry mechanism of this virus into host cells is essential for effective treatment of COVID-19 disease. This virus can bind to various cell surface molecules or receptors, such as angiotensin-converting enzyme 2 (ACE2), to gain cell entry. Respiratory failure and pulmonary edema are the most important causes of mortality from COVID-19 infections. Cytokines, especially proinflammatory cytokines, are the main mediators of these complications. For normal respiratory function, a healthy air-blood barrier and sufficient blood flow to the lungs are required. In this review, we first discuss airway epithelial cells, airway stem cells, and the expression of COVID-19 receptors in the airway epithelium. Then, we discuss the suggested molecular mechanisms of endothelial dysfunction and blood vessel damage in COVID-19. Coagulopathy can be caused by platelet activation leading to clots, which restrict blood flow to the lungs and lead to respiratory failure. Finally, we present an overview of the effects of immune and non-immune cells and cytokines in COVID-19-related respiratory failure.

National Research Institute of Tuberculosis and Lung Disease (NRITLD) Protocol for the Treatment of Patients with COVID-19.

More than a year after the onset of the coronavirus disease pandemic in 2019, the disease remains a major global health issue. During this time, health organizations worldwide have tried to provide integrated treatment guidelines to control coronavirus disease 2019 (COVID-19) at different levels. However, due to the novel nature of the disease and the emergence of new variants, medical teams' updating medical information and drug prescribing guidelines should be given special attention. This version is an updated instruction of the National Research Institute of Tuberculosis and Lung Disease (NRITLD) in collaboration with a group of specialists from Masih Daneshvari Hospital in Tehran, Iran, which is provided to update the information of caring clinicians for the treatment and care of COVID-19 hospitalized patients.

Mini review ATF4 and GRP78 as novel molecular targets in ER-Stress modulation for critical COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in more than 4.4 million deaths worldwide as of August 24, 2021. Viral infections such as SARS-CoV2 are associated with endoplasmic reticulum (ER) stress and also increased the level of reactive oxygen species. Activating transcription factor 4 (ATF4) is preferentially translated under integrated stress conditions and controls the genes involved in protein homeostasis, amino acid transport and metabolism, and also protection from oxidative stress. The GRP78, regulated either directly or indirectly by ATF4, is an essential chaperone in the ER and overexpressed and appears on the surface of almost all cells during stress and function as a SARS-CoV2 receptor. In this mini-review article, we briefly discuss the effects of SARS-CoV2 infection on the ER stress, and then the stress modulator functions of ATF4 and GRP78 as novel therapeutic targets were highlighted. Finally, the effects of GRP78 inhibitory components as potential factors for targeted therapies for COVID-19 critical cases were discussed.

Favipiravir Effects on the Control of Clinical Symptoms of Hospitalized COVID-19 Cases: An Experience with Iranian Formulated Dosage Form.

Coronavirus disease -19 (COVID-19) pandemic, caused by SARS-CoV-2, has gradually spread worldwide, becoming a major public health event. This situation requires designing a novel antiviral agent against the SARS-CoV-2; however, this is time-consuming and the use of repurposed medicines may be promising. One such medicine is favipiravir, primarily introduced as an anti-influenza agent in east world. The aim of this study was to evaluate the efficacy and safety of favipiravir in comparison with lopinavir-ritonavir in SARS-CoV-2 infection. In this randomized clinical trial, 62 patients were recruited. These patients had bilateral pulmonary infiltration with peripheral oxygen saturation lower than 93%. The median time from symptoms onset to intervention initiation was seven days. Favipiravir was not available in the Iranian pharmaceutical market, and it was decided to formulate it at the research laboratory of School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. The patients received favipiravir tablet at a dose of 1600 mg orally twice a day for day one and then 600 mg orally twice a day for days 2 to 6. In the second group, the patients received lopinavir-ritonavir combination tablet at a dose of 200/50 mg twice a day for seven days. Fever, cough, and dyspnea were improved significantly in favipiravir group in comparison with lopinavir-ritonavir group on days four and five. Mortality rate and ICU stay in both groups were similar, and there was no significant difference in this regard (P = 0.463 and P = 0.286, respectively). Chest X-ray improvement also was not significantly different between the two groups. Adverse drug reactions occurred in both groups, and impaired liver enzymes were the most frequent adverse effect. In conclusion, early administration of oral favipiravir may reduce the duration of clinical signs and symptoms in patients with COVID-19 and hospitalization period. The mortality rate also should be investigated in future clinical trials.

RdRp inhibitors and COVID-19: Is molnupiravir a good option?

Rapid changes in the viral genome allow viruses to evade threats posed by the host immune response or antiviral drugs, and can lead to viral persistence in the host cells. RNA-dependent RNA polymerase (RdRp) is an essential enzyme in RNA viruses, which is involved in RNA synthesis through the formation of phosphodiester bonds. Therefore, in RNA viral infections such as SARS-CoV-2, RdRp could be a crucial therapeutic target. The present review discusses the promising application of RdRp inhibitors, previously approved or currently being tested in human clinical trials, in the treatment of RNA virus infections. Nucleoside inhibitors (NIs) bind to the active site of RdRp, while nonnucleoside inhibitors (NNIs) bind to allosteric sites. Given the absence of highly effective drugs for the treatment of COVID-19, the discovery of an efficient treatment for this pandemic is an urgent concern for researchers around the world. We review the evidence for molnupiravir (MK-4482, EIDD-2801), an antiviral drug originally designed for Alphavirus infections, as a potential preventive and therapeutic agent for the management of COVID-19. At the beginning of this pandemic, molnupiravir was in preclinical development for seasonal influenza. When COVID-19 spread dramatically, the timeline for development was accelerated to focus on the treatment of this pandemic. Real time consultation with regulators took place to expedite this program. We summarize the therapeutic potential of RdRp inhibitors, and highlight molnupiravir as a new small molecule drug for COVID-19 treatment.

The nano-based theranostics for respiratory complications of COVID-19.

High morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made coronavirus disease 2019 (COVID-19) the leading challenge for health experts all over the world. Currently, there is no specific treatment for COVID-19; however, thanks to worldwide intense attempts, novel vaccines such as mRNA-1273 (Moderna TX, Inc.) and BNT162b2 (Biontech/Pfizer) were developed very fast and FDA approved them for emergency use. Nanomedicine-based drug delivery can be an advanced therapeutic strategy to deal with clinical complications of COVID-19. Given the fact that SARS-CoV-2 typically affects the respiratory tract, application of inhalable nanoparticles (NPs) for targeted drug delivery to the alveolar space appears to be an effective and promising therapeutic strategy. Loading the medicinal components into NPs enhances the stability, bioavailability, solubility and sustained release of them. This approach can circumvent major challenges in efficient drug delivery such as solubility and any adverse impact of medicinal components due to off-targeted delivery and resulting systemic complications. Inhalable NPs could be delivered through nasal sprays, inhalers, and nebulizers. NPs also could interfere in virus attachment to host cells and prevent infection. Moreover, nanomedicine-based technologies can facilitate accurate and rapid detection of virus compared to the conventional methods. In this review, the nano-based theranostics modalities for the management of respiratory complications of COVID-19 were discussed.

The story of critical care in Asia: a narrative review.

BACKGROUND: Asia has more critically ill people than any other part of our planet. The aim of this article is to review the development of critical care as a specialty, critical care societies and education and research, the epidemiology of critical illness as well as epidemics and pandemics, accessibility and cost and quality of critical care, culture and end-of-life care, and future directions for critical care in Asia. MAIN BODY: Although the first Asian intensive care units (ICUs) surfaced in the 1960s and the 1970s and specialisation started in the 1990s, multiple challenges still exist, including the lack of intensivists, critical care nurses, and respiratory therapists in many countries. This is aggravated by the brain drain of skilled ICU staff to high-income countries. Critical care societies have been integral to the development of the discipline and have increasingly contributed to critical care education, although critical care research is only just starting to take off through collaboration across groups. Sepsis, increasingly aggravated by multidrug resistance, contributes to a significant burden of critical illness, while epidemics and pandemics continue to haunt the continent intermittently. In particular, the coronavirus disease 2019 (COVID-19) has highlighted the central role of critical care in pandemic response. Accessibility to critical care is affected by lack of ICU beds and high costs, and quality of critical care is affected by limited capability for investigations and treatment in low- and middle-income countries. Meanwhile, there are clear cultural differences across countries, with considerable variations in end-of-life care. Demand for critical care will rise across the continent due to ageing populations and rising comorbidity burdens. Even as countries respond by increasing critical care capacity, the critical care community must continue to focus on training for ICU healthcare workers, processes anchored on evidence-based medicine, technology guided by feasibility and impact, research applicable to Asian and local settings, and rallying of governments for support for the specialty. CONCLUSIONS: Critical care in Asia has progressed through the years, but multiple challenges remain. These challenges should be addressed through a collaborative approach across disciplines, ICUs, hospitals, societies, governments, and countries.

IgM-enriched immunoglobulin in COVID-19: Case series of 15 severely ill SARS-CoV-2-infected patients.

The healthcare system in Iran, like most around the world, is managing thousands of patients hospitalised with COVID-19. In Iran, in-hospital mortality is in the region of 25%, rising to 50-60% in patients admitted to intensive care. Hyperinflammation, characterised by cytokine storm, appears to be a hallmark of severe COVID-19 and to date only the anti-inflammatory drug dexamethasone has been shown to reduce mortality in those hospitalised with the disease. There is a sound scientific rationale behind the use of IgM-enriched immunoglobulin in the management of patients with severe COVID-19. It has been used successfully in the management of hyperinflammation in patients with sepsis and has led to improved radiographic scores in patients with severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Recently the successful treatment of a patient with COVID-19 with IgM-enriched immunoglobulin was reported. Here we report the outcome of a further 15 patients hospitalised with COVID-19 treated with IgM-enriched immunoglobulin. Improvements in computed tomography (CT) score were observed in nine patients, indicating that further clinical studies into the use of IgM-enriched immunoglobulin in the treatment of severe COVID-19 are warranted.

Recent advances and challenges of RT-PCR tests for the diagnosis of COVID-19.

Since the outbreak of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the control of virus spread has remained challenging given the pitfalls of the current diagnostic tests. Nevertheless, RNA amplification techniques have been the gold standard among other diagnostic methods for monitoring clinical samples for the presence of the virus. In the current paper, we review the shortcomings and strengths of RT-PCR (real-time polymerase chain reaction) techniques for diagnosis of coronavirus disease (COVID)-19. We address the repercussions of false-negative and false-positive rates encountered in the test, summarize approaches to improve the overall sensitivity of this method. We discuss the barriers to the widespread use of the RT-PCR test, and some technical advances, such as RT-LAMP (reverse-transcriptase-loop mediated isothermal amplification). We also address how other molecular techniques, such as immunodiagnostic tests can be used to avoid incorrect interpretation of RT-PCR tests.

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients. METHODS: A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases). FINDINGS: There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24-48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48-96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2-7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5-19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery. INTERPRETATION: We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

Neurological Manifestations of COVID-19: A Case Report.

A novel coronavirus disease (COVID-19) was reported in Wuhan, China in December 2019 and spread rapidly around the world, causing high rates of mortality and morbidity. This disease is known for its respiratory manifestations. Also, there have been several reports of neurological involvement in patients with COVID-19. In this study, we present a 55-year-old Iranian male patient, who was referred from another medical center with a decreased level of consciousness. Upon admission, only respiratory signs of COVID-19 were observed, but later, some neurological manifestations were also observed, such as an alteration in mental status, disorientation, stupor, and finally coma. In radiological studies, a hemorrhagic encephalopathy pattern was detected. Despite improved oxygenation and alleviation of respiratory symptoms with antiviral and anti-inflammatory therapies, cerebral injuries progressed, and the patient died due to severe brain damage.

Therapeutic modalities and novel approaches in regenerative medicine for COVID-19.

The recent coronavirus disease 2019 outbreak around the world has had an enormous impact on the global health burden, threatening the lives of many individuals, and has had severe socio-economic consequences. Many pharmaceutical and biotechnology companies have commenced intensive research on different therapeutic strategies, from repurposed antiviral drugs to vaccines and monoclonal antibodies to prevent the spread of the disease and treat infected patients. Among the various strategies, advanced therapeutic approaches including cell- and gene-editing-based therapeutics are also being investigated, and initial results in in-vitro and early phase I studies have been promising. However, further assessments are required. This article reviews the underlying mechanisms for the pathogenesis of severe acute respiratory syndrome coronavirus-2, and discusses available therapeutic candidates and advanced modalities that are being evaluated in in-vitro/in-vivo models and are of note in clinical trials.

Challenges of Iranian Clinicians in Dealing with COVID-19: Taking Advantages of The Experiences in Wenzhou.

The novel coronavirus has been spreading since December 2019. It was initially reported in Wuhan, Hubei province of China. Coronavirus disease 2019 (COVID-19) has currently become a pandemic affecting over seven million people worldwide, and the number is still rising. Wenzhou, as the first hit city out of Hubei Province, achieved a remarkable success in effectively containing the disease. A great record was also observed in Wenzhou for the clinical management of COVID-19 patients, leading to one of the lowest death rates in China. Researchers and clinical specialists proposed and formulated combined approaches such as computerized tomography (CT)- scans and molecular assays, as well as using both allopathic and traditional medications to mitigate its effects. Iranian and Chinese specialists and scientists had a communication in clinical, molecular and pharmaceutical aspects of COVID-19. A proper guideline was prepared according to the experiences of Chinese clinicians in managing the full spectrum of COVID-19 patients, from relatively mild to highly complex cases. The purpose of this guideline is to serve a reference in the hospital for specialists so that they may better diagnose cases and provide effective therapies and proposed antiviral and anti-inflammatory drugs for patients.

Promising effects of tocilizumab in COVID-19: A non-controlled, prospective clinical trial.

BACKGROUND: The clinical presentation of SARS-CoV-2 infection ranges from mild symptoms to severe complications, including acute respiratory distress syndrome. In this syndrome, inflammatory cytokines are released after activation of the inflammatory cascade, with the predominant role of interleukin (IL)-6. The aim of this study was to evaluate the effects of tocilizumab, as an IL-6 antagonist, in patients with severe or critical SARS-CoV-2 infection. METHODS: In this prospective clinical trial, 76 patients with severe or critical SARS-CoV-2 infection were evaluated for eligibility, and ultimately, 42 patients were included. Tocilizumab was administered at a dose of 400 mg as a single dose via intravenous infusion. Primary outcomes included changes in oxygenation support, need for invasive mechanical ventilation, and death. Secondary outcomes included radiological changes in the lungs, IL-6 plasma levels, C-reactive protein levels, and adverse drug reactions. The data were analyzed using SPSS software. RESULTS: Of the 42 included patients, 20 (48%) patients presented the severe infection stage and 22 (52%) were in the critical stage. The median age of patients was 56 years, and the median IL-6 level was 28.55 pg/mL. After tocilizumab administration, only 6 patients (14%) required invasive ventilation. Additionally, 35 patients (83.33%) showed clinical improvement. By day 28, a total of 7 patients died (6 patients in the critical stage and 1 patient in the severe stage). Neurological adverse effects were observed in 3 patients. CONCLUSIONS: Based on the current results, tocilizumab may be a promising agent for patients with severe or critical SARS-CoV-2 infection, if promptly initiated during the severe stage.