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preclinical trials in sepsis

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https://www.readbyqxmd.com/read/27888550/mesenchymal-stem-stromal-cells-biology-and-preclinical-evidence-for-therapeutic-potential-for-organ-dysfunction-following-trauma-or-sepsis
#1
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 anti-microbial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients...
November 26, 2016: Stem Cells
https://www.readbyqxmd.com/read/27870924/evaluating-mesenchymal-stem-cell-therapy-for-sepsis-with-preclinical-meta-analyses-prior-to-initiating-a-first-in-human-trial
#2
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 (odds ratio 0...
November 17, 2016: ELife
https://www.readbyqxmd.com/read/27720772/sustained-release-formulation-of-mitomycin-c-to-the-upper-urinary-tract-using-a-thermosensitive-polymer-a-preclinical-study
#3
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 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 UTUC given its ability to provide sustained release of MMC in the upper urinary tract...
October 5, 2016: Urology
https://www.readbyqxmd.com/read/27548576/3k3a-activated-protein-c-stimulates-postischemic-neuronal-repair-by-human-neural-stem-cells-in-mice
#4
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
https://www.readbyqxmd.com/read/27417317/phase-ii-study-of-a-novel-taxane-cabazitaxel-xrp-6258-in-previously-treated-advanced-non-small-cell-lung-cancer-nsclc-patients
#5
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
https://www.readbyqxmd.com/read/27353753/targeting-alpha-toxin-and-clfa-with-a-multimechanistic-monoclonal-antibody-based-approach-for-prophylaxis-of-serious-staphylococcus%C3%A2-aureus-disease
#6
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
https://www.readbyqxmd.com/read/27234411/clinical-benefits-of-lactoferrin-for-infants-and-children
#7
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
https://www.readbyqxmd.com/read/27169671/in-vitro-and-in-vivo-efficacy-toxicity-bio-distribution-and-resistance-selection-of-a-novel-antibacterial-drug-candidate
#8
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
https://www.readbyqxmd.com/read/27092677/-overview-and-perspectives-of-mesenchymal-stem-cell-therapy-in-intensive-care-medicine
#9
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 ClinicalTrials.gov have been included to review the role of MSC therapy in sepsis, ARDS and AKI...
February 2016: Revista Médica de Chile
https://www.readbyqxmd.com/read/27018198/concise-review-apoptotic-cell-based-therapies-rationale-preclinical-results-and-future-clinical-developments
#10
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
https://www.readbyqxmd.com/read/26963323/triiodothyronine-administration-in-a-model-of-septic-shock-a-randomized-blinded-placebo-controlled-trial
#11
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
https://www.readbyqxmd.com/read/26937863/transfusion-of-35-day-stored-rbcs-in-the-presence-of-endotoxemia-does-not-result-in-lung-injury-in-humans
#12
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
https://www.readbyqxmd.com/read/26881939/acute-kidney-injury-prevention
#13
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
https://www.readbyqxmd.com/read/26838725/preclinical-efficacy-of-clumping-factor-a-in-prevention-of-staphylococcus-aureus-infection
#14
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...
2016: MBio
https://www.readbyqxmd.com/read/26832963/rosuvastatin-versus-placebo-for-delirium-in-intensive-care-and-subsequent-cognitive-impairment-in-patients-with-sepsis-associated-acute-respiratory-distress-syndrome-an-ancillary-study-to-a-randomised-controlled-trial
#15
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
https://www.readbyqxmd.com/read/26670422/efficacy-and-safety-of-anticoagulant-therapy-in-three-specific-populations-with-sepsis-a-meta-analysis-of-randomized-controlled-trials
#16
Y Umemura, K Yamakawa, H Ogura, H Yuhara, S Fujimi
UNLABELLED: ESSENTIALS: Most anticoagulant therapy has failed to demonstrate a survival benefit in the overall sepsis population. We conducted separate meta-analyses of anticoagulant therapy in three different populations. Survival benefit was observed only in the septic disseminated intravascular coagulation (DIC) population. Further randomized controlled trials should focus on specific populations with septic DIC. SUMMARY: HASH(0x54ec768) BACKGROUND: Although many preclinical trials have indicated the effectiveness and safety of anticoagulant therapy as an adjuvant therapy against sepsis, there is little evidence to support its effectiveness to reduce mortality in the overall population with sepsis in clinical situations...
March 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/26509673/ticagrelor-does-not-inhibit-adenosine-transport-at-relevant-concentrations-a-randomized-cross-over-study-in-healthy-subjects-in-vivo
#17
RANDOMIZED CONTROLLED TRIAL
T N A van den Berg, S El Messaoudi, G A Rongen, P H H van den Broek, A Bilos, A R T Donders, M E Gomes, N P Riksen
BACKGROUND AND PURPOSE: In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo. EXPERIMENTAL APPROACH: In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively...
2015: PloS One
https://www.readbyqxmd.com/read/26502877/inflammatory-mediators-in-intra-abdominal-sepsis-or-injury-a-scoping-review
#18
REVIEW
Zhengwen Xiao, Crystal Wilson, Helen Lee Robertson, Derek J Roberts, Chad G Ball, Craig N Jenne, Andrew W Kirkpatrick
INTRODUCTION: Inflammatory and protein mediators (cytokine, chemokine, acute phase proteins) play an important, but still not completely understood, role in the morbidity and mortality of intra-abdominal sepsis/injury. We therefore systematically reviewed preclinical and clinical studies of mediators in intra-abdominal sepsis/injury in order to evaluate their ability to: (1) function as diagnostic/prognostic biomarkers; (2) serve as therapeutic targets; and (3) illuminate the pathogenesis mechanisms of sepsis or injury-related organ dysfunction...
October 27, 2015: Critical Care: the Official Journal of the Critical Care Forum
https://www.readbyqxmd.com/read/26446942/a-phase-ii-trial-of-azd6244-selumetinib-arry-142886-an-oral-mek1-2-inhibitor-in-relapsed-refractory-multiple-myeloma
#19
Beata Holkova, Adriana Zingone, Maciej Kmieciak, Prithviraj Bose, Ashraf Z Badros, Peter M Voorhees, Rachid Baz, Neha Korde, Hui-Yi Lin, Jin-Qiu Chen, Michelle Herrmann, Liqiang Xi, Mark Raffeld, Xiuhua Zhao, Wen Wan, Mary Beth Tombes, Ellen Shrader, Caryn Weir-Wiggins, Heidi Sankala, Kevin T Hogan, Austin Doyle, Christina M Annunziata, Martha Wellons, John D Roberts, Daniel Sullivan, Ola Landgren, Steven Grant
PURPOSE: AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma. EXPERIMENTAL DESIGN: AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles. RESULTS: Thirty-six patients received therapy...
March 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26274493/embracing-failure-what-the-phase-iii-progesterone-studies-can-teach-about-tbi-clinical-trials
#20
REVIEW
Donald G Stein
BACKGROUND: Despite positive preclinical studies and two positive Phase II clinical trials, two large Phase III clinical trials of progesterone treatment of acute traumatic brain injury (TBI) recently ended with negative results, so a 100% failure rate continues to plague the field of TBI trials. METHODS: This paper reviews and analyses the trial structures and outcomes and discusses the implications of these failures for future drug and clinical trial development...
2015: Brain Injury: [BI]
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