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High-molecular-weight linear polymers (HMWLPs) have earned the name "drag-reducing polymers" because of their ability to reduce drag in turbulent flows. Recently, these polymers have become popular in bioengineering applications. This study investigated whether the addition of HMWLP in a venoarterial extracorporeal circulation (ECC) model could improve microvascular perfusion and oxygenation. Golden Syrian hamsters were instrumented with a dorsal skinfold window chamber and subjected to ECC using a circuit comprised of a peristaltic pump and a bubble trap. The circuit was primed with lactated Ringer solution (LR) containing either 5 ppm of polyethylene glycol (PEG) with a low molecular weight of 500 kDa (PEG500k) or 5 ppm of PEG with a high molecular weight of 3,500 kDa (PEG3500k). After 90 min of ECC at 15% of the animal's cardiac output, the results showed that the addition of PEG3500k to LR improved microvascular blood flow in arterioles and venules acutely (2 h after ECC), whereas functional capillary density showed improvement up to 24 h after ECC. Similarly, PEG3500k improved venular hemoglobin O2 saturation on the following day after ECC. The serum and various excised organs all displayed reduced inflammation with the addition of PEG3500k, and several of these organs also had a reduction in markers of damage with the HMWLPs compared to LR alone. These promising results suggest that the addition of small amounts of PEG3500k can help mitigate the loss of microcirculatory function and reduce the inflammatory response from ECC procedures. [ABSTRACT FROM AUTHOR]

In drug development a frequently used phrase is "data‐driven". Just as high‐test gas fuels a car, so drug development "runs on" high‐quality data; hence, good data management practices, which involve case report form design, data entry, data capture, data validation, medical coding, database closure, and database locking, are critically important. This review covers the essentials of clinical data management (CDM) for the United States. It is intended to demystify CDM, which means nothing more esoteric than the collection, organization, maintenance, and analysis of data for clinical trials. The review is written with those who are new to drug development in mind and assumes only a passing familiarity with the terms and concepts that are introduced. However, its relevance may also extend to experienced professionals that feel the need to brush up on the basics. For added color and context, the review includes real‐world examples with RRx‐001, a new molecular entity in phase III and with fast‐track status in head and neck cancer, and AdAPT‐001, an oncolytic adenovirus armed with a transforming growth factor‐beta (TGF‐β) trap in a phase I/II clinical trial with which the authors, as employees of the biopharmaceutical company, EpicentRx, are closely involved. An alphabetized glossary of key terms and acronyms used throughout this review is also included for easy reference. [ABSTRACT FROM AUTHOR]

Summary: The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS‐oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half‐life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once‐daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601. [ABSTRACT FROM AUTHOR]

Their widespread presence throughout the vasculature, coupled with their reactivity, and thereby to their potential to release reactive oxidative species, or to utilize their anti-oxidative capacities, has promoted much discussion of the role(s) of red blood cells (RBCs) in the progression of health or, alternatively, a wide range of disease states. Moreover, these role(s) have been linked to the development of adhesiveness and, in fact, thereby to the essential pathway to their eventual clearance, e.g., by macrophages in the spleen. These disparate roles coupled with the mechanisms involved are reviewed and given. Following an analysis, novel perspectives are provided; these perspectives can lead to novel assays for identifying the potential for RBC adhesiveness as suggested herein. We describe this paradigm, that involves RBC adhesiveness, hemolysis, and ghost formation, with examples including, inter alia, the progression of atherosclerosis and the suppression of tumor growth along with other disease states. [ABSTRACT FROM AUTHOR]

RRx-001 is a shape shifting small molecule with Fast Track designation for the prevention/amelioration of chemoradiation-induced severe oral mucositis (SOM) in newly diagnosed Head and Neck cancer. It has been intentionally developed or "engineered" as a chimeric single molecular entity that targets multiple redox-based mechanisms. Like an antibody drug conjugate (ADC), RRx-001 contains, at one end a "targeting" moiety, which binds to the NLRP3 inflammasome and inhibits it as well as Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of Nrf2, and, at the other end, a conformationally constrained, dinitro containing 4 membered ring, which fragments under conditions of hypoxia and reduction to release therapeutically active metabolites i.e., the payload. This "payload", which is delivered specifically to hypoperfused and inflamed areas, includes nitric oxide, nitric oxide related species and carbon-centered radicals. As observed with ADCs, RRx-001 contains a backbone amide "linker" attached to a binding site, which correlates with the Fab region of an antibody, and to the dinitroazetidine payload, which is microenvironmentally activated. However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo prooxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues. [ABSTRACT FROM AUTHOR]

Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology. [ABSTRACT FROM AUTHOR]

Background: Bromonitrozidine (RRx-001) is a minimally toxic, NLRP3 inhibitor that has been observed, in experimental systems, to also downregulate CD47, repolarize tumor associated macrophages (TAMs) and normalize aberrant tumor perfusion. This phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced cancer and no standard options. Methods: This single arm, single site, open-label pilot study (NCT02518958) called PRIMETIME was designed to evaluate the safety profile of RRx-001 and nivolumab in patients with advanced malignancies and no other standard therapeutic options. A 3 + 3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. The RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, twelve patients received treatment for only 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 16 weeks of the first dose of RRx-001 and nivolumab were characterized according to CTCAE v4.03. Results: Twelve patients received ≥1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no DLTs. The main adverse event related to RRx-001 was infusion reaction (33.3%). The main adverse event related to the combination was pseudoprogression manifested by larger tumors in patients that were symptomatically improved (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). The objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of ≥SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: The combination of RRx-001 and nivolumab was safe and well-tolerated with preliminary evidence of anti-cancer activity. Further clinical trials with RRx-001 and nivolumab are warranted. Clinical trial registration: ClinicalTrials.gov identifier, NCT02518958. [ABSTRACT FROM AUTHOR]

Background : Previous studies have found that increasing plasma viscosity as whole blood viscosity decrease has beneficial effects in microvascular hemodynamics. As the heart couples with systemic vascular network, changes in plasma and blood viscosity during hemodilution determine vascular pressure drop and flow rate, which influence cardiac function. This study aimed to investigate how changes in plasma viscosity affect on cardiac function during acute isovolemic hemodilution. Materials and Methods: Plasma viscosity was modulated by hemodilution of 40% of blood volume with three different plasma expanders (PEs). Dextran 2000 kDa (Dx2M, 6.3 cP) and dextran 70 kDa (Dx70, 3.0 cP) were used as high and moderate viscogenic PEs, respectively. Polyethylene glycol conjugated with human serum albumin (PEG-HSA, 2.2 cP) was used as low viscogenic PE. The cardiac function was assessed using a miniaturized pressure-volume conductance catheter. Results: After hemodilution, pressure dropped to 84%, 79%, and 78% of baseline for Dx2M, Dx70 and PEG-HSA, respectively. Cardiac output markedly increased for Dx2M and PEG-HSA. Dx2M significantly produced higher stroke work relative to baseline and compared to Dx70. Conclusion: Acute hemodilution with PEG-HSA without increasing plasma viscosity provided beneficial effects on cardiac function compared to Dx70, and similar to those measured with Dx2M. Potentially negative effects of increasing peripheral vascular resistance due to the increase in plasma viscosity were prevented.