Pubblicato in: Medicina e Biologia

Coronavirus e Tocilizumab. Cosa riportano le riviste scientifiche.

Giuseppe Sandro Mela.

2020-03-24.

Cigni Neri 001

I media fanno un gran parlare della pandemia da coronavirus e taluni articoli riportano come scientificamente provato l’effetto terapeutico di taluni farmaci, sulla base di dichiarazioni personali.

Si reputa utile riportare dei brevi abstract delle pubblicazioni su riviste internazionali circa l’uso del Tocilizumab in corso di infezione da Covid-19.

Dovrebbero essere facilmente comprensibili anche da parte di non addetti ai lavori.

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Nature. Coronavirus puts drug repurposing on the fast track

Existing antivirals and knowledge gained from the SARS and MERS outbreaks gain traction as the fastest route to fight the current coronavirus epidemic.

China’s biotech companies have been gearing up to repurpose existing drugs, approved in the West for other viruses, as treatments for the coronavirus outbreak originating in Wuhan.

Last month, Hangzhou-based Ascletis Pharma applied to the Chinese authorities to test two HIV protease inhibitors (ritonavir and ASC09) in clinical trials to treat COVID-19, the illness caused by the new coronavirus (Table 1). And Suzhou-based BrightGene Bio-Medical Technology announced in early February that it would begin to manufacture Gilead Sciences’ remdesivir (GS-5734), a broad-spectrum investigational antiviral, as a treatment for coronavirus infection. Remdesivir, originally developed to treat Ebola virus and then dropped, will also be tested by Gilead in partnership with Chinese health authorities in randomized, controlled trials. “The general genomic layout and the general replication kinetics and the biology of the MERS, SARS and [SARS-CoV-2] viruses are very similar, so testing drugs which target relatively generic parts of these coronaviruses is a logical step,” says Vincent Munster, chief, Viral Ecology Unit, US National Institute of Health. Testing therapies approved for other indications also makes sense, as these drugs are already mass produced and available on a large scale.

From the start of the COVID-19 outbreak, medical practitioners have followed China’s guidelines set up in January and treated hospitalized patients with α-interferon combined with the repurposed drug Kaletra, an approved cocktail of the HIV protease inhibitors ritonavir and lopinavir. The World Health Organization has noted that this combination could provide some clinical benefit. ….

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New England Medical Journal. History in a Crisis — Lessons for Covid-19

Writing in the heady days of new antibiotics and immunizations, esteemed microbiologists Macfarlane Burnet and David White predicted in 1972 that “the most likely forecast about the future of infectious diseases is that it will be very dull.”1 They acknowledged that there was always a risk of “some wholly unexpected emergence of a new and dangerous infectious disease, but nothing of the sort has marked the last fifty years.” Epidemics, it seemed, were of interest only to historians.

Times have changed. From herpes and legionnaires’ disease in the 1970s, to AIDS, Ebola, the severe acute respiratory syndrome (SARS), and now Covid-19, contagious diseases continue to threaten and disrupt human populations. Historians, who never lost interest in epidemics, have much to offer.

When asked to explain past events, historians are quick to assert the importance of context. If you want to understand how or why something happened, you must attend to local circumstances. But there is something about epidemics that has elicited an opposite reaction from historians: a desire to identify universal truths about how societies respond to contagious disease. ….

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Centre Evidence Based Medicine. COVID-19 Registered Trials – and analysis

COVID-19 trials registered up to 8 March 2020—an analysis of 382 studies

Download COVID-19 registered trials—an analysis (1).

On 31 December 2019, China reported cases of pneumonia from a previously unknown coronavirus, 2019-nCoV, also called SARS-CoV-2.  The disease it causes has been called COVID-19. The latest figures (17 March 2020) suggest that about 180,00 people have been infected worldwide, with about 7200 deaths. The World Health Organization (WHO) designated COVID-19 a “public health emergency of international concern” on 30 January and declared it a pandemic on 11 March.

COVID-19 should have come as no surprise. Gralinski and Baric, in a review in 2015 wrote: “The existence of novel bat SARS-like coronaviruses that also use bat, civet and human angiotensin 1 converting enzyme 2 (ACE2) receptors for entry, such as SARS-CoV [now SARS-CoV-1], strongly suggests an opportunity for further zoonotic disease outbreaks in human and animal populations.” Yet attempts to develop effective treatments against two other coronavirus diseases, SARS and MERS, have so far failed.

The coronaviruses are single-stranded RNA viruses that encode for four enzymes essential to the viral life cycle. They enter mammalian cells through an interaction of a viral spike glycoprotein and a receptor—ACE2 for SARS-CoV-1 and SARS-CoV-2 and dipetidylpeptidase 4 for MERS.

While the outbreak of COVID-19 was intensifying and spreading globally, 382 trials were registered between 23 January and 8 March (379 registered in China) on the WHO’s International Clinical Trials Registry Platform (ICTRP), some of which might affect morbidity and mortality and help us understand the disease.

We downloaded the listings of these 382 registered trials and classified them to aid interpretation of the type of interventions being proposed. The numbers of new trials that have been added to the list since the middle of  January are shown in Figure 1. ….

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British Medical Journal. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists

Scientists and senior doctors have backed claims by France’s health minister that people showing symptoms of covid-19 should use paracetamol (acetaminophen) rather than ibuprofen, a drug they said might exacerbate the condition.

The minister, Oliver Veran, tweeted on Saturday 14 March that people with suspected covid-19 should avoid anti-inflammatory drugs. “Taking anti-inflammatory drugs (ibuprofen, cortisone . . .) could be an aggravating factor for the infection. If you have a fever, take paracetamol,” he said.

His comments seem to have stemmed in part from remarks attributed to an infectious diseases doctor in south west France. She was reported to have cited four cases of young patients with covid-19 and no underlying health problems who went on to develop serious symptoms after using non-steroidal anti-inflammatory drugs (NSAIDs) in the early stage of their symptoms. The hospital posted a comment saying that public discussion of individual cases was inappropriate.

But Jean-Louis Montastruc, a professor of medical and clinical pharmacology at the Central University Hospital in Toulouse, said that such deleterious effects from NSAIDS would not be a surprise given that since 2019, on the advice of the National Agency for the Safety of Medicines and Health Products, French health workers have been told not to treat fever or infections with ibuprofen.

Experts in the UK backed this sentiment. Paul Little, a professor of primary care research at the University of Southampton, said that there was good evidence “that prolonged illness or the complications of respiratory infections may be more common when NSAIDs are used—both respiratory or septic complications and cardiovascular complications.”

He added, “The finding in two randomised trials that advice to use ibuprofen results in more severe illness or complications helps confirm that the association seen in observational studies is indeed likely to be causal. Advice to use paracetamol is also less likely to result in complications.” ….

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Guide to Pharmacology. Coronavirus Information.

Given the novelty of SARS-CoV-2 infection (COVID-19), and the lack of proven therapies, a wide variety of strategies are being employed to combat this worldwide epidemic. Many of these emerging strategies rely on repurposing existing drugs, and others are completely new, but all rely on existing scientific evidence of mechanistic approaches that are effective against either similar viral infections or the serious symptoms that are caused by COVID-19.

– The effects of existing antiviral medications are being evaluated

– The inflammatory aspects of the disease are being targeted using existing medications including glucocorticoids, COX inhibitors, immunosuppressants and immunomodulators

– Strategies to block engagement of the virus with its host receptor (ACE2), or inhibition of spike protein activation are being explored

– Novel inhibitors of the main CoV protease are being developed

– Mucolytic drugs and drugs to counter pulmonary edema are in clinical trials

All of these tactics are intended to mitigate against COVID-19 and provide a window during which vaccine development can progress (with the caveat that the search for vaccines to prevent infection by existing circulating coronaviruses has been notoriously unsuccessful). The tables provide information gathered from various sources, and aim to cover as many of the pharmacological strategies being considered as we could find. Our ligands (therapeutics) table excludes traditional natural product-based medicines, blood-derived products (e.g. serum from recovered patients and stem cells), investigational vaccines, antibacterials for secondary infections and supportive treatments (oxygen therapy). ….

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The Lancet. Reducing mortality from 2019-nCoV: host-directed therapies should be an option

The number of confirmed cases of the 2019 novel coronavirus (2019-nCoV) reported to WHO continues to rise worldwide.

As with two other WHO Blueprint priority coronaviruses, SARS-CoV and MERS-CoV,

2019-nCoV is lethal. As of Feb 3, 2020, 2019-nCoV has caused 362 deaths out of 17 391 confirmed cases reported to WHO.

No specific anti-viral treatment exists. The mainstay of clinical management is largely symptomatic treatment, with organ support in intensive care for seriously ill patients. The unprecedented flurry of activity by WHO and other global public health bodies has mainly focused on preventing transmission, infection control measures, and screening of travellers. The development of vaccines has received immediate funding; however, as with SARS-CoV and MERS-CoV, support for developing treatments for 2019-nCoV that reduce mortality has not been forthcoming. There is an urgent need for focusing funding and scientific investments into advancing novel therapeutic interventions for coronavirus infections.

All three coronaviruses induce excessive and aberrant non-effective host immune responses that are associated with severe lung pathology, leading to death.

Similar to patients with SARS-CoV and MERS-CoV, some patients with 2019-nCoV develop acute respiratory distress syndrome (ARDS) with characteristic pulmonary ground glass changes on imaging. In most moribund patients, 2019-nCoV infection is also associated with a cytokine storm, which is characterised by increased plasma concentrations of interleukins 2, 7, and 10, granulocyte-colony stimulating factor, interferon-γ-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and tumour necrosis factor α.

In those who survive intensive care, these aberrant and excessive immune responses lead to long-term lung damage and fibrosis, causing functional disability and reduced quality of life. ….

Specific drugs to treat 2019-nCoV will take several years to develop and evaluate. In the meantime, a range of existing host-directed therapies that have proven to be safe could potentially be repurposed to treat 2019-nCoV infection. Several marketed drugs with excellent safety profiles such as metformin, glitazones, fibrates, sartans, and atorvastin, as well as nutrient supplements and biologics could reduce immunopathology, boost immune responses, and prevent or curb ARDS.

Zinc and other metal-containing formulations appear to have anti-viral activity, are safe, cheap, and readily available. These formulations could be used as adjuncts to monotherapy or as combinational therapies with cyclosporine, lopinavir–ritonavir, interferon beta‑1b, ribavirin, remdesivir, monoclonal antibodies, and anti-viral peptides targeting 2019-nCoV.

Tocilizumab, a monoclonal antibody that targets the interleukin 6 receptor, has a good safety profile. Monoclonal and polyclonal antibodies to 2019-nCoV could be developed for post-exposure prophylaxis. ….

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The Lancet. COVID-19: consider cytokine storm syndromes and immunosuppression

As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality.

Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality.

Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections and occurs in 3·7–4·3% of sepsis cases.

Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients.

A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α.

Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p<0·001) and IL-6 (p<0·0001), suggesting that mortality might be due to virally driven hyperinflammation. ….

A multicentre, randomised controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome), has been approved in patients with COVID-19 pneumonia and elevated IL-6 in China (ChiCTR2000029765). ….

All patients with severe COVID-19 should be screened for hyperinflammation using laboratory trends (eg, increasing ferritin, decreasing platelet counts, or erythrocyte sedimentation rate) and the HScore to identify the subgroup of patients for whom immunosuppression could improve mortality. Therapeutic options include steroids, intravenous immunoglobulin, selective cytokine blockade (eg, anakinra or tocilizumab) and JAK inhibition. ….

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Chinese Clinical Trial Registry. A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19). 

The patients who were diagnosed with the common type of NCP (including severe risk factors) and severe cases of new coronavirus pneumonia; 2. Aged 18 to 85 years; 3. IL-6 elevated (using Elisa method, using the same company kit); 4. Patients or authorized family members volunteered to participate in this study and signed informed consent. Definition of Novel Coronavirus Pneumonia (NCP) clinical cases: 1. Regular patients with NCP (including severe risk factors): patients with dual pulmonary lesions based on common NCP clinical symptoms accompanied by fever or no fever; 2. Critical NCP patient: Refer to the “New Coronavirus Pneumonia Diagnosis and Treatment Plan (Fifth Edition)” formulated by the National Health Commission.  ….

To evaluate the efficacy and safety of tocilizumab in treating regular patients with NCP (including severe risk factors) and critical NCP patients.

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Roche. Farmaci e dispositivi medici, risorse economiche e umane per combattere la pandemia da coronavirus.

…. l’azienda ha deciso di rispondere innanzitutto al bisogno più urgente indotto dalla pandemia: la necessità di disporre di farmaci utili a contrastare l’aggravamento delle condizioni di salute dei pazienti positivi al virus SARS-CoV-2. Il gruppo si impegna a fornire gratuitamente per il periodo dell’emergenza, tocilizumab (RoActemra) a tutte le Regioni che ne facciano richiesta, fatte salve le scorte necessarie a consentire la continuità terapeutica ai pazienti affetti da patologie per cui il prodotto è autorizzato. Il farmaco, attualmente impiegato per il trattamento dell’artrite reumatoide, non è indicato per il trattamento della polmonite da Covid-19, ma la comunità scientifica sta dimostrando interesse al suo utilizzo dopo l’inserimento nelle linee guida cinesi. Oltre alla donazione del farmaco, l’Azienda ha dato la propria disponibilità ad AIFA per avviare uno studio clinico sull’efficacia e sicurezza di tocilizumab anche in questi pazienti. ….