INTRAVENOUS VITAMIN C SUPPLEMENTATION IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS: SALUTARY IMPACT ON CLINICAL OUTCOMES.

Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (SCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic hematopoietic stem cell transplant (HSCT) were evaluated in a phase I/II trial and clinical outcomes compared with a propensity score - matched historical control. Methods: Patients with advanced hematologic malignancies were enrolled in a phase 2 clinical trial, receiving IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HSCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT. Results: 55 patients received IV vitamin C: these include 10/10 HLA-MRD and MUD (n=48) and 9/10 HLA MUD recipients (n=7). All patients enrolled were deficient in vitamin C at day 0 and had restoration to normal levels for the remainder of the course. Vitamin C recipients had lower non-relapse mortality (11% vs. 25%, p-value = 0.07) and consequently, improved survival compared to historical controls (82% vs 62% p=0.06), with no attributable grade 3 and 4 toxicities to vitamin C. Patients with myeloid malignancies had improved survival (83% vs. 54%, p=0.02) and non-relapse mortality (NRM) (10% vs. 37%, p=0.009), as well as chronic GVHD, with similar relapse rates compared to controls. Conclusions: In patients undergoing allogeneic HSCT the administration of IV vitamin C is safe and reduces non-relapse mortality improving overall survival. Randomized trials are needed to confirm the utility of this easily available and inexpensive therapy.

Intravenous Vitamin C Supplementation in Allogeneic Hematopoietic Cell Transplant Recipients: Salutary Impact on Clinical Outcomes.

Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (HCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic HCT were evaluated in a phase I/II trial. Clinical outcomes were compared with a propensity score - matched historical control. Methods: Patients with advanced hematologic malignancies received IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT. Results: 55 patients received IV vitamin C. All patients were deficient in vitamin C at day 0. Vitamin C recipients had lower non-relapse mortality (NRM) (p = 0.07) and improved survival compared to historical controls (p=0.06), with no attributable grade 3 and 4 toxicities. Vitamin C recipients had similar relapse rate and acute graft versus host disease (GVHD) (p=0.35), but lower severe chronic GVHD (p=0.35). Patients with myeloid malignancies had improved survival (p=0.02) and NRM (p=0.009), as well as chronic GVHD, with similar relapse rates compared to controls. Conclusions: In patients undergoing allogeneic HCT the administration of IV vitamin C is safe and reduces non-relapse mortality and chronic GVHD improving overall survival.

Dietary Bioactive Fatty Acids as Modulators of Immune Function: Implications on Human Health.

Diet is major modifiable risk factor for cardiovascular disease that can influence the immune status of the individual and contribute to persistent low-grade inflammation. In recent years, there has been an increased appreciation of the role of polyunsaturated fatty acids (PUFA) in improving immune function and reduction of systemic inflammation via the modulation of pattern recognition receptors (PRR) on immune cells. Extensive research on the use of bioactive lipids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their metabolites have illustrated the importance of these pro-resolving lipid mediators in modulating signaling through PRRs. While their mechanism of action, bioavailability in the blood, and their efficacy for clinical use forms an active area of research, they are found widely administered as marine animal-based supplements like fish oil and krill oil to promote health. The focus of this review will be to discuss the effect of these bioactive fatty acids and their metabolites on immune cells and the resulting inflammatory response, with a brief discussion about modern methods for their analysis using mass spectrometry-based methods.

Interventional vitamin C: A strategy for attenuation of coagulopathy and inflammation in a swine multiple injuries model.

BACKGROUND: Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage. METHODS: Male Sinclair swine (n = 24; mean body weight, 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiologic monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500 mL of hydroxyethyl starch, and randomized to receive either intravenous normal saline (NS), low-dose VitC (50 mg/kg; LO), or high-dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours postresuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung. RESULTS: Compared with VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue proinflammatory mediators (IL-1ß, IL-8, TNFα), plasminogen activation inhibitor-1 and tissue factor. There were no statistically significant differences between treatment groups on mean arterial pressure or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours. CONCLUSION: Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the proinflammatory/procoagulant response that contributes to multiple organ failure following acute severe multiple injuries. LEVEL OF EVIDENCE: Prospective randomized controlled blinded trial study, Preclinical (animal-based).

Impact of high dose vitamin C on platelet function.

AIM: To examine the effect of high doses of vitamin C (VitC) on ex vivo human platelets (PLTs). METHODS: Platelet concentrates collected for therapeutic or prophylactic transfusions were exposed to: (1) normal saline (control); (2) 0.3 mmol/L VitC (Lo VitC); or (3) 3 mmol/L VitC (Hi VitC, final concentrations) and stored appropriately. The VitC additive was preservative-free buffered ascorbic acid in water, pH 5.5 to 7.0, adjusted with sodium bicarbonate and sodium hydroxide. The doses of VitC used here correspond to plasma VitC levels reported in recently completed clinical trials. Prior to supplementation, a baseline sample was collected for analysis. PLTs were sampled again on days 2, 5 and 8 and assayed for changes in PLT function by: Thromboelastography (TEG), for changes in viscoelastic properties; aggregometry, for PLT aggregation and adenosine triphosphate (ATP) secretion in response to collagen or adenosine diphosphate (ADP); and flow cytometry, for changes in expression of CD-31, CD41a, CD62p and CD63. In addition, PLT intracellular VitC content was measured using a fluorimetric assay for ascorbic acid and PLT poor plasma was used for plasma coagulation tests [prothrombin time (PT), partial thrombplastin time (PTT), functional fibrinogen] and Lipidomics analysis (UPLC ESI-MS/MS). RESULTS: VitC supplementation significantly increased PLTs intracellular ascorbic acid levels from 1.2 mmol/L at baseline to 3.2 mmol/L (Lo VitC) and 15.7 mmol/L (Hi VitC, P < 0.05). VitC supplementation did not significantly change PT and PTT values, or functional fibrinogen levels over the 8 d exposure period (P > 0.05). PLT function assayed by TEG, aggregometry and flow cytometry was not significantly altered by Lo or Hi VitC for up to 5 d. However, PLTs exposed to 3 mmol/L VitC for 8 d demonstrated significantly increased R and K times by TEG and a decrease in the α-angle (P < 0.05). There was also a fall of 20 mm in maximum amplitude associated with the Hi VitC compared to both baseline and day 8 saline controls. Platelet aggregation studies, showed uniform declines in collagen and ADP-induced platelet aggregations over the 8-d study period in all three groups (P > 0.05). Collagen and ADP-induced ATP secretion was also not different between the three groups (P > 0.05). Finally, VitC at the higher dose (3 mmol/L) also induced the release of several eicosanoids including thromboxane B2 and prostaglandin E2, as well as products of arachidonic acid metabolism via the lipoxygenases pathway such as 11-/12-/15-hydroxyicosatetraenoic acid (P < 0.05). CONCLUSION: Alterations in PLT function by exposure to 3 mmol/L VitC for 8 d suggest that caution should be exerted with prolonged use of intravenous high dose VitC.

Vitamin C promotes wound healing through novel pleiotropic mechanisms.

Vitamin C (VitC) or ascorbic acid (AscA), a cofactor for collagen synthesis and a primary antioxidant, is rapidly consumed post-wounding. Parenteral VitC administration suppresses pro-inflammatory responses while promoting anti-inflammatory and pro-resolution effects in human/murine sepsis. We hypothesised that VitC could promote wound healing by altering the inflammatory, proliferative and remodelling phases of wound healing. Mice unable to synthesise VitC (Gulo(-/-) ) were used in this study. VitC was provided in the water (sufficient), withheld from another group (deficient) and supplemented by daily intra-peritoneal infusion (200 mg/kg, deficient + AscA) in a third group. Full thickness excisional wounds (6 mm) were created and tissue collected on days 7 and 14 for histology, quantitative polymerase chain reaction (qPCR) and Western blotting. Human neonatal dermal fibroblasts (HnDFs) were used to assess effects of In conclusion, VitC favorably on proliferation. Histological analysis showed improved wound matrix deposition and organisation in sufficient and deficient +AscA mice. Wounds from VitC sufficient and deficient + AscA mice had reduced expression of pro-inflammatory mediators and higher expression of wound healing mediators. Supplementation of HnDF with AscA induced the expression of self-renewal genes and promoted fibroblast proliferation. VitC favourably impacts the spatiotemporal expression of transcripts associated with early resolution of inflammation and tissue remodelling.

Resolution of sterile inflammation: role for vitamin C.

INTRODUCTION: Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited. METHODS: To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages. RESULTS: VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response to in vitro LPS stimulation. VitC sufficiency and in vivo VitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses. CONCLUSION: VitC sufficiency favorably modulates macrophage function. In vivo or in vitro VitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation.

Utilization Patterns of IV Iron and Erythropoiesis Stimulating Agents in Anemic Chronic Kidney Disease Patients: A Multihospital Study.

Intravenous (IV) iron and Erythropoiesis Stimulating Agents (ESAs) are recommended for anemia management in chronic kidney disease (CKD). This retrospective cohort study analyzed utilization patterns of IV iron and ESA in patients over 18 years of age admitted to University Health System Hospitals with a primary or secondary diagnosis of CKD between January 1, 2006 to December 31, 2008. A clustered binomial logistic regression using the GEE methodology was used to identify predictors of IV iron utilization. Only 8% (n = 6678) of CKD patients on ESA therapy received IV iron supplementation in university hospitals. Those receiving iron used significantly less amounts of ESAs. Patient demographics (age, race, primary payer), patient clinical conditions (admission status, severity of illness, dialysis status), and physician specialty were identified as predictors of IV iron use in CKD patients. Use of IV iron with ESAs was low despite recommendations from consensus guidelines. The low treatment rate of IV iron represents a gap in treatment practices and signals an opportunity for healthcare improvement in CKD anemic patients.

Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.

Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.