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preclinical trials in sepsis

Jorge Zorzopulos, Steven M Opal, Andrés Hernando-Insúa, Juan M Rodriguez, Fernanda Elías, Juan Fló, Ricardo A López, Norma A Chasseing, Victoria A Lux-Lantos, Maria F Coronel, Raul Franco, Alejandro D Montaner, David L Horn
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions...
March 26, 2017: World Journal of Stem Cells
Kendra M Hodgkinson, Jeffrey Kiernan, Andrew W Shih, Ziad Solh, William P Sheffield, Nicolas Pineault
The principal theme of the symposium was centered on how the world of regenerative medicine intersects with that of transfusion medicine, with a particular focus on hematopoietic stem cells (HSCs) and stem cell therapies. The symposium highlighted several exciting developments and identified areas where additional research is needed. A revised map of human hematopoietic hierarchy was presented based on the functional and phenotypic analysis of thousands of single stem and progenitor cells from adult bone marrow and fetal liver...
March 22, 2017: Transfusion Medicine Reviews
Alpha A Fowler Iii, Christin Kim, Lawrence Lepler, Rajiv Malhotra, Orlando Debesa, Ramesh Natarajan, Bernard J Fisher, Aamer Syed, Christine DeWilde, Anna Priday, Vigneshwar Kasirajan
We report a case of virus-induced acute respiratory distress syndrome (ARDS) treated with parenteral vitamin C in a patient testing positive for enterovirus/rhinovirus on viral screening. This report outlines the first use of high dose intravenous vitamin C as an interventional therapy for ARDS, resulting from enterovirus/rhinovirus respiratory infection. From very significant preclinical research performed at Virginia Commonwealth University with vitamin C and with the very positive results of a previously performed phase I safety trial infusing high dose vitamin C intravenously into patients with severe sepsis, we reasoned that infusing identical dosing to a patient with ARDS from viral infection would be therapeutic...
February 4, 2017: World Journal of Critical Care Medicine
Christian L Johnson, Yorick Soeder, Marc H Dahlke
Despite extensive research on candidate pharmacological treatments and a significant and increasing prevalence, sepsis syndrome, and acute respiratory distress syndrome (ARDS) remain areas of unmet clinical need. Preclinical studies examining mesenchymal stromal cell (MSCs) based-therapies have provided compelling evidence of potential benefit; however, the precise mechanism by which MSCs exert a therapeutic influence, and whether MSC application is efficacious in humans, remains unknown. Detailed evaluation of the limited number of human trials so far completed is further hampered as a result of variations in trial design and biomarker selection...
April 2017: Stem Cells Translational Medicine
Kevin M Gallagher, Stephen O'neill, Ewen M Harrison, James A Ross, Stephen J Wigmore, Jeremy Hughes
Despite significant need and historical trials, there are no effective drugs in use for the prevention or treatment of acute kidney injury (AKI). There are several promising agents in early clinical development for AKI and two trials have recently been terminated. There are also exciting new findings in pre-clinical AKI research. There is a need to take stock of current progress in the field to guide future drug development for AKI. Areas covered: The main clinical trial registries, PubMed and pharmaceutical company website searches were used to extract the most recent clinical trials for sterile, transplant and sepsis-associated AKI...
February 2017: Expert Opinion on Investigational Drugs
Michael A Matthay, Shibani Pati, Jae-Woo Lee
Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients...
February 2017: Stem Cells
Manoj M Lalu, Katrina J Sullivan, Shirley Hj Mei, David Moher, Alexander Straus, Dean A Fergusson, Duncan J Stewart, Mazen Jazi, Malcolm MacLeod, Brent Winston, John Marshall, Brian Hutton, Keith R Walley, Lauralyn McIntyre
Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0...
November 17, 2016: ELife
Nicholas M Donin, Sandra Duarte, Andrew T Lenis, Randy Caliliw, Cristobal Torres, Anthony Smithson, Dalit Strauss-Ayali, Yael Agmon-Gerstein, Nadav Malchi, Jonathan Said, Steven S Raman, Stuart Holden, Allan Pantuck, Arie S Belldegrun, Karim Chamie
OBJECTIVE: To evaluate the safety and feasibility of single and serial instillations of MitoGel into the upper urinary tract using a preclinical swine animal model. MitoGel is a novel sustained release formulation of mitomycin C (MMC) based on RTGel, a proprietary thermosensitive hydrogel technology. MitoGel is liquid at cold temperatures and solidifies to gel state at body temperature. It is intended as a treatment for upper tract urothelial carcinoma, given its ability to provide sustained release of MMC in the upper urinary tract...
January 2017: Urology
Yaoming Wang, Zhen Zhao, Sanket V Rege, Min Wang, Gabriel Si, Yi Zhou, Su Wang, John H Griffin, Steven A Goldman, Berislav V Zlokovic
Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation...
September 2016: Nature Medicine
Ankit Madan, Benjamin S Jones, Rodolfo Bordoni, Mansoor N Saleh, Mary S Jerome, Deborah K Miley, Bradford E Jackson, Francisco Robert
PURPOSE: Given the success of cabazitaxel in patients with prostate cancer who progressed after receiving prior chemotherapy, its preclinical efficacy in various cell lines and possible ability to cross blood-brain barrier, cabazitaxel was hypothesized to increase objective response rate (ORR) in second-line setting in non-small cell lung cancer (NSCLC). METHODS: This was a phase II 2-stage trial in 28 patients using two different treatment schedules (A: 20 mg/m(2) every 3 weeks intravenously and B: 8...
September 2016: Cancer Chemotherapy and Pharmacology
C Tkaczyk, M M Hamilton, A Sadowska, Y Shi, C S Chang, P Chowdhury, R Buonapane, X Xiao, P Warrener, J Mediavilla, B Kreiswirth, J Suzich, C K Stover, B R Sellman
UNLABELLED: Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis of S...
2016: MBio
Paolo Manzoni
To discuss the potential clinical benefits of lactoferrin in preterm and term infants, as well as in young children and to review information on the burden of neonatal sepsis. Current evidence on the mechanisms that explain the role of human milk in the neonatal and infant anti-infective responses will be briefly reviewed and preclinical research data on the potential mechanisms of action by which lactoferrin may impact infant gut health, gut immune development and functions, including the lactoferrin effects on the neonatal microbiome, will be examined...
June 2016: Journal of Pediatrics
Jlenia Brunetti, Chiara Falciani, Giulia Roscia, Simona Pollini, Stefano Bindi, Silvia Scali, Unai Cossio Arrieta, Vanessa Gómez-Vallejo, Leila Quercini, Elisa Ibba, Marco Prato, Gian Maria Rossolini, Jordi Llop, Luisa Bracci, Alessandro Pini
A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60-80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically...
2016: Scientific Reports
Francisco Espinoza, Felipe Aliaga, Patricia Luz Crawford
Development of innovative therapies in intensive care medicine is particularly important since diseases as sepsis, acute respiratory distress syndrome (ARDS) and acute renal injury (AKI) have an elevated morbidity and mortality in spite of current gold-standard approaches. Mesenchymal stem cells (MSC) may have a promising role due to their properties in immunomodulation, tissue reparation and microbial clearance. Preclinical data and results of a systematic review of PubMed, PMC and have been included to review the role of MSC therapy in sepsis, ARDS and AKI...
February 2016: Revista Médica de Chile
Philippe Saas, Etienne Daguindau, Sylvain Perruche
The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases...
June 2016: Stem Cells
Matthew J Maiden, Marianne J Chapman, David J Torpy, Timothy R Kuchel, Iain J Clarke, Coralie H Nash, Jonathan D Fraser, Guy L Ludbrook
OBJECTIVES: Triiodothyronine concentration in plasma decreases during septic shock and may contribute to multiple organ dysfunction. We sought to determine the safety and efficacy of administering triiodothyronine, with and without hydrocortisone, in a model of septic shock. DESIGN: Randomized blinded placebo-controlled trial. SETTING: Preclinical research laboratory. SUBJECTS: Thirty-two sheep rendered septic with IV Escherichia coli and receiving protocol-guided sedation, ventilation, IV fluids, and norepinephrine infusion...
June 2016: Critical Care Medicine
Anna L Peters, Maike E van Hezel, Bart Cortjens, Anita M Tuip-de Boer, Robin van Bruggen, Dirk de Korte, René E Jonkers, Peter I Bonta, Sacha S Zeerleder, Rene Lutter, Nicole P Juffermans, Alexander P J Vlaar
OBJECTIVE: Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. Preclinical studies have shown that aged RBCs can induce transfusion-related acute lung injury in the presence of a "first hit" (e.g., sepsis). Clinical studies, however, show conflicting results on this matter. We tested whether maximally stored RBCs are able to induce lung injury in the presence of a "first hit" in humans (Dutch Trial Register: NTR4455). DESIGN: Open-label, randomized controlled trial...
June 2016: Critical Care Medicine
Tushar A Chopra, Charles H Brooks, Mark D Okusa
Acute kidney injury (AKI) is a condition associated with significant morbidity and mortality. The incidence of AKI is increasing due to predisposing factors (sepsis, nephrotoxins, and hypotension). This review will focus on the risk stratification of patients vulnerable to developing AKI in whom the timing of the insult is known (e.g., cardiac surgery, contrast exposure) as well as the clinical context in which the risk intensifies. The review will also focus on preventive measures and different pharmacological agents for preventing AKI...
2016: Contributions to Nephrology
Xue Li, Xiaogang Wang, Christopher D Thompson, Saeyoung Park, Wan Beom Park, Jean C Lee
UNLABELLED: Treatment of Staphylococcus aureus infections has become increasingly difficult because of the emergence of multidrug-resistant isolates. Development of a vaccine to prevent staphylococcal infections remains a priority. To determine whether clumping factor A (ClfA) is a good target protein for inclusion in a multivalent vaccine, we evaluated its efficacy in a variety of relevant staphylococcal infection models, challenging with different S. aureus strains. ClfA adsorbed to Alhydrogel and mixed with Sigma Adjuvant System was more immunogenic and stimulated a more robust Th17 response than ClfA administered with alum alone...
February 2, 2016: MBio
Dale M Needham, Elizabeth Colantuoni, Victor D Dinglas, Catherine L Hough, Amy W Wozniak, James C Jackson, Peter E Morris, Pedro A Mendez-Tellez, E Wesley Ely, Ramona O Hopkins
BACKGROUND: Delirium is common in mechanically ventilated patients and is associated with cognitive impairment lasting at least 1 year after hospital discharge. Preclinical and observational studies suggest that the use of statins might reduce delirium in intensive care. We assessed whether the pleiotropic effects of statins can reduce delirium in intensive care and decrease subsequent cognitive impairment in a randomised controlled trial. METHODS: We did this ancillary study within the SAILS trial, a randomised controlled trial assessing mortality and ventilator-free days for rosuvastatin versus placebo for patients with sepsis-associated acute respiratory distress syndrome...
March 2016: Lancet Respiratory Medicine
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