Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19.

Background: An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Method: Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results: In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. Conclusions: These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. Clinical Trials Registration. ClinicalTrials.gov NCT04535167.

Contents and quality of travel tips on malaria in English and Spanish travel blogs.

BACKGROUND: Europe has about 10,000 imported cases of malaria each year, or around 80 cases per 100,000 trips to endemic areas. Non-use of chemoprophylaxis in travellers remains the main reason for this. The proliferation of online travel blogs as a source of advice (sometimes the only one used) for preparing a trip to an endemic area may play a role in the decision to use chemoprophylaxis. The aim of this study was to analyse the information offered on malaria in the main travel blogs in English and Spanish. METHODS: Five hundred travel blogs in English and 100 in Spanish, considered highly relevant were analysed. The relevance were according to different metrics: (1) Alexa Rank; (2) social networks (RRSS) measuring the total followers of Facebook, Twitter, Instagram and YouTube; (3) number of monthly visits using the SEMrush tool; (4) domain authority; and (5) number of backlinks or incoming links using the SEMrush tool. RESULTS: Of the included travel blogs, 57% of those in English and 64% of those in Spanish offered information on malaria, and 79 and 75%, respectively, featured a discussion on malaria written as a blog post or in forum comments. Information on chemoprophylaxis was available in 56.1% of English-language blogs and 10.7% of Spanish-speaking blogs, while its side effects were discussed in 38.6 and 68.8%, respectively (p < 0.001). Content analysis revealed that the information was usually insufficient, incomplete or, more seriously, inaccurate. In many cases, this could discourage users from taking appropriate preventive measures. CONCLUSIONS: Travel blogs in English and Spanish provide low-quality information on malaria. The so-called "travel influencers" must communicate reliable, verified and quality information on malaria on their channels in a way that could contribute to reducing the burden of the disease in travellers.

Compassionate Use of Tocilizumab in Severe SARS-CoV2 Pneumonia. When late administration is too late.

IntroductionTocilizumab is an interleukin 6 receptor antagonist which has been used for the treatment of severe SARS-CoV-2 pneumonia (SSP), aiming to ameliorate the cytokine release syndrome (CRS) -induced acute respiratory distress syndrome (ARDS). However, there is no data about the best moment for its administration along the course of the disease. MethodsWe provided tocilizumab on a compassionate-use basis to patients with SSP hospitalized (excluding intensive care and intubated cases) who required oxygen support to have a saturation >93%. Primary endpoint was intubation or death after 24 hours of its administration. Patients received at least one dose of 400 mg intravenous tocilizumab during March 8-2020, through April 20-2020. FindingsA total of 207 patients were studied and 186 analysed. The mean age was 65 years and 68% were male. A co-existing condition was present in 68 % of cases. At baseline, 114 (61%) required oxygen support with FiO2 >0.5 % and 72 (39%) [≤]0.5%. Early administration of tocilizumab, when the need of oxygen support was still below FiO2 [≤]0.5%, was significantly more effective than given it in advanced stages (FiO2 >0.5 %), achieving lower rates of intubation or death (13% vs 37% repectively, p<0{middle dot}001). InterpretationThe benefit of tocilizumab in severe SARS-Cov-2 pneumonia is only expected when it is administrated before the need of high oxygen support. FundingNone.

COVID-19 Outcomes in 4712 consecutively confirmed SARS-CoV2 cases in the city of Madrid.

There is limited information describing features and outcomes of patients requiring hospitalization for COVID19 disease and still no treatments have clearly demonstrated efficacy. Demographics and clinical variables on admission, as well as laboratory markers and therapeutic interventions were extracted from electronic Clinical Records (eCR) in 4712 SARS-CoV2 infected patients attending 4 public Hospitals in Madrid. Patients were stratified according to age and stage of severity. Using multivariate logistic regression analysis, cut-off points that best discriminated mortality were obtained for each of the studied variables. Principal components analysis and a neural network (NN) algorithm were applied. A high mortality incidence associated to age >70, comorbidities (hypertension, neurological disorders and diabetes), altered vitals such as fever, heart rhythm disturbances or elevated systolic blood pressure, and alterations in several laboratory tests. Remarkably, analysis of therapeutic options either taken individually or in combination drew a universal relationship between the use of Cyclosporine A and better outcomes as also a benefit of tocilizumab and/or corticosteroids in critically ill patients. We present a large Spanish population-based study addressing factors influencing survival in current SARS CoV2 pandemic, with particular emphasis on the effectivity of treatments. In addition, we have generated an NN capable of identifying severity predictors of SARS CoV2. A rapid extraction and management of data protocol from eCR and artificial intelligence in-house implementations allowed us to perform almost real time monitoring of the outbreak evolution.