Regulatory and clinical development to support the approval of advanced therapies medicinal products in Japan.

INTRODUCTION: A new category of products, i.e. regenerative medicine products (RPs), has been defined for advanced therapies medicinal products in Japan, as well as a legislative and regulatory framework to promote their clinical development. AREAS COVERED: This review analyses the most relevant features of the regulatory strategies and clinical development that led RPs to their approval in Japan. EXPERT OPINION: As of 31st September 2021, a total of 14 RPs were approved for 16 indications. From a regulatory standpoint, the available designations allow attractive benefit packages that promote the development of innovative products in Japan and is one of the key points to consider when the global regulatory strategy for the product is being developed. RPs regulations in Japan allow adaptive licensing and constitute shortcut through the clinical development to the approval. RPs have been mainly approved so far based on small studies with inconclusive and limited evidence of efficacy and safety, prioritizing the unmet medical needs of the target diseases, and therefore, the early access for patients. This review also compares the regulatory and clinical development for the current approved RPs in Japan with the development trends in the European Union and United States of America.

Beta Blockers as Salvage Treatment in Refractory Septic Shock Complicated With Dynamic Left Ventricular Outflow Tract Obstruction: A Rare Case Presentation.

Hypotension is the main finding in patients admitted to an intensive care unit (ICU) with the diagnosis of septic shock and it is related to worse outcomes. In these patients, several underlying causes of hypotension may co-exist, including vasoplegia, hypovolemia, drug-mediated venodilation, or myocardial dysfunction. Nowadays, echocardiography has been positioned as an essential tool in any ICU set to assess fluid status, ventricular ejection fraction, or any other myocardial complications. The high sympathetic tone in severely ill patients, in addition to high doses of adrenergic drugs often needed, may provoke a hypercontractile cardiac state. In the basis of our experience, we present a case of a patient with refractory septic shock and severe hemodynamic collapse, refractory to vasopressors with concomitant respiratory deterioration due to dynamic left ventricular outflow tract obstruction (LVOTO). Transesophageal echocardiography (TOE) was used to assess hemodynamic status and to guide treatment. A critical response to intravenous ß-blockers was seen, with a dramatic decrease in vasopressor dosage and respiratory support.

Low-density lipoprotein cholesterol levels are associated with poor clinical outcomes in COVID-19

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the sole causative agent of coronavirus infectious disease-19 (COVID-19). MethodsWe performed a retrospective single-center study of consecutively admitted patients between March 1st and May 15th, 2020, with a definitive diagnosis of SARS-CoV-2 infection. The primary end-point was to evaluate the association of lipid markers with 30-days all-cause mortality in COVID-19. ResultsA total of 654 patients were enrolled, with an estimated 30-day mortality of 22.8% (149 patients). Non-survivors had lower total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) levels during the entire course of the disease with complete resolution among survivors. Both showed a significant inverse correlation with inflammatory markers and a positive correlation with lymphocyte count. In a multivariate analysis, LDL-c [≤] 69 mg/dl (hazard ratio [HR] 1.94; 95% confidence interval [CI] 1.14-3.31), C-reactive protein > 88 mg/dl (HR 2.44; 95% CI, 1.41-4.23) and lymphopenia < 1,000 (HR 2.68; 95% CI, 1.91-3.78) at admission were independently associated with 30-day mortality. This association was maintained 7 days after admission. ConclusionHypolipidemia in SARS-CoV-2 infection may be secondary to an immune-inflammatory response, with complete recovery in survivors. Low LDL-c serum levels are independently associated with higher 30-day mortality in COVID-19 patients.

Corticosteroid pulses for hospitalized patients with COVID-19. Effects on mortality and in-hospital stay.

Background: COVID-19 has high mortality in hospitalized patients, and we need effective treatments. Our objective was to assess corticosteroid pulses influence on 60-days mortality in hospitalized patients with severe COVID-19, intensive care admission, and hospital stay. Methods: We designed a multicenter retrospective cohort study in three teaching hospitals of Castilla y Leon, Spain (865.096 people). We selected patients with confirmed COVID-19 and lung involvement with a pO2/FiO2 < 300, excluding those exposed to immunosuppressors before or during hospitalization, patients terminally ill at admission, or died the first 24 hours. We performed a propensity score matching (PSM) adjusting covariates that modify the probability of being treated. Then we used a Cox regression model in the PSM group to consider factors affecting mortality. Findings: From 2933 patients, 257 fulfilled the inclusion and exclusion criteria. One hundred and twenty-four patients were on corticosteroid pulses, and 133 were not. 30{middle dot}3% (37/122) of patients died in the corticosteroid pulses group and 42{middle dot}9% (57/133) in the non-exposed cohort. These differences (12{middle dot}6% CI95% [8{middle dot}54-16{middle dot}65]) were statically significant (log-rank 4{middle dot}72, p=0{middle dot}03). We performed PSM using the exact method. Mortality differences remained in the PSM group (log-rank 5{middle dot}31, p=0{middle dot}021) and were still significant after a Cox regression model (HR for corticosteroid pulses 0{middle dot}561, p= 0{middle dot}039). There were no significant differences in intensive care admission rate (p=0{middle dot}173). The hospital stay was longer in the corticosteroid group (p<0,001). Interpretation: This study provides evidence about treatment with corticosteroid pulses in severe COVID-19 that might significantly reduce mortality. Strict inclusion and exclusion criteria with that selection process set a reliable frame to compare mortality in both exposed and non-exposed groups. Funding: There was no funding provided.