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HIGH DOSE IV COBALAMIN FOR THE TREATMENT OF SEPSIS

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Carmen Wheatley
added 2 research items
THIS IS A DRAFT CLINICAL TRIAL PROTOCOL[WORK IN PROGRESS ]BUT APPLICABLE NOW, FOR ARDS IN COVID.19, ON ACCOUNT OF THE EXCEPTIONAL PHARMACOLOGICAL CLINICAL SAFETY PROFILE OF HIGH DOSE IV COBALAMIN, ALREADY USED IN THE CLINIC IN DIVERSE EXTREME SCENARIOS -CN, H2S, N2O POISONING, REFRACTORY VASOPLEGIC SYNDROME IN CARDIAC AND LIVER SURGERY. FROM THE RESEARCH DONE BY MYSELF AND COLLABORATORS AT THE WILLIAM HARVEY INSTITUTE IN LONDON, THIS TREATMENT SHOULD ALSO BE APPLICABLE FOR SIRS/ SEPSIS/ SEPTIC SHOCK. THUS FOR ARDS.
CORONA VIRUS/Covid/19 ADULT RESPIRATORY DISTRESS SYNDROME ************************************************* HIGH DOSE IV METHYLCOBALAMIN IS A SAFE & COST EFFECTIVE RESCUE TREATMENT for ARDS.
Carmen Wheatley
added 3 research items
Background. NOS/ NO inhibitors are potential therapeutics for sepsis, yet they increase clinical mortality. However, there has been no in vivo investigation of the (in vitro) NO scavenger, cobalamin's (Cbl) endogenous eects on NOS/ NO/inammatory mediators during the immune response to sepsis. Methods. We used quantitative polymerase chain reaction (qPCR), ELISA, Western blot, and NOS Griess assays, in a CBL/ mouse, acute endotoxaemia model. Results. During the immune response, pro-inammatory phase, parenteral hydroxocobalamin (HOCbl) treatment partially inhibits hepatic, but not lung, iNOS mRNA and promotes lung eNOS mRNA, but attenuates the LPS hepatic rise in eNOS mRNA, whilst paradoxically promoting high iNOS/eNOS protein translation, but relatively moderate NO production. HOCbl/NOS/ NO regulation is reciprocally associated with lower h expression of TNF-, IL-, COX-, and lower circulating TNF-, but not IL-. In resolution, h aer LPS, HOCbl completely abrogates a major late mediator of sepsis mortality, high mobility group box (HMGB) mRNA, inhibits iNOS mRNA, and attenuates LPS-induced hepatic inhibition of eNOS mRNA, whilst showing increased, but still moderate, NOS activity, relative to LPS only. experiments (LPS+D-Galactosamine) HOCbl aorded signicant, dose-dependent protection in mice Conclusions. HOCbl produces a complex, time-and organ-dependent, selective regulation of NOS/ NO during endotoxaemia, corollary regulation of downstream inammatory mediators, and increased survival. is merits clinical evaluation.
Background. NOS/ NO inhibitors are potential therapeutics for sepsis, yet they increase clinical mortality. However, there has been no in vivo investigation of the (in vitro) NO scavenger, cobalamin's (Cbl) endogenous eects on NOS/ NO/inammatory mediators during the immune response to sepsis. Methods. We used quantitative polymerase chain reaction (qPCR), ELISA, Western blot, and NOS Griess assays, in a CBL/ mouse, acute endotoxaemia model. Results. During the immune response, pro-inammatory phase, parenteral hydroxocobalamin (HOCbl) treatment partially inhibits hepatic, but not lung, iNOS mRNA and promotes lung eNOS mRNA, but attenuates the LPS hepatic rise in eNOS mRNA, whilst paradoxically promoting high iNOS/eNOS protein translation, but relatively moderate NO production. HOCbl/NOS/ NO regulation is reciprocally associated with lower h expression of TNF-, IL-, COX-, and lower circulating TNF-, but not IL-. In resolution, h aer LPS, HOCbl completely abrogates a major late mediator of sepsis mortality, high mobility group box (HMGB) mRNA, inhibits iNOS mRNA, and attenuates LPS-induced hepatic inhibition of eNOS mRNA, whilst showing increased, but still moderate, NOS activity, relative to LPS only. experiments (LPS+D-Galactosamine) HOCbl aorded signicant, dose-dependent protection in mice Conclusions. HOCbl produces a complex, time-and organ-dependent, selective regulation of NOS/ NO during endotoxaemia, corollary regulation of downstream inammatory mediators, and increased survival. is merits clinical evaluation.
Background. NOS/•NO inhibitors are potential therapeutics for sepsis, yet they increase clinical mortality. However, there has been no in vivo investigation of the (in vitro) •NO scavenger, cobalamin's (Cbl) endogenous effects on NOS/•NO/inflammatory mediators during the immune response to sepsis. Methods. We used quantitative polymerase chain reaction (qPCR), ELISA, Western blot, and NOS Griess assays, in a C57BL/6 mouse, acute endotoxaemia model. Results. During the immune response, pro-inflammatory phase, parenteral hydroxocobalamin (HOCbl) treatment partially inhibits hepatic, but not lung, iNOS mRNA and promotes lung eNOS mRNA, but attenuates the LPS hepatic rise in eNOS mRNA, whilst paradoxically promoting high iNOS/eNOS protein translation, but relatively moderate •NO production. HOCbl/NOS/•NO regulation is reciprocally associated with lower 4 h expression of TNF-α, IL-1β, COX-2, and lower circulating TNF-α, but not IL-6. In resolution, 24 h after LPS, HOCbl completely abrogates a major late mediator of sepsis mortality, high mobility group box 1 (HMGB1) mRNA, inhibits iNOS mRNA, and attenuates LPS-induced hepatic inhibition of eNOS mRNA, whilst showing increased, but still moderate, NOS activity, relative to LPS only. experiments (LPS+D-Galactosamine) HOCbl afforded significant, dose-dependent protection in mice Conclusions. HOCbl produces a complex, time- and organ-dependent, selective regulation of NOS/•NO during endotoxaemia, corollary regulation of downstream inflammatory mediators, and increased survival. This merits clinical evaluation.
Carmen Wheatley
added 3 research items
Cobalamin carrier proteins,the Transcobalamins (TCS), are elevated during trauma, infections and chronic inflammatory conditions. This remains un-explained. It is proposed that such TC elevations signal a need for cobalamin central to the resolution of inflammation. Thus Cobalamin may regulate the transcription factor, NFkappaB, activation or suppression of which determines the inflammatory response and its resolution. Such regulation may involve at least 5 separate mechanisms: (i) hormone-like regulation of TNFalpha, through reduction of excess NO by cobalamin, as well as through the selective inhibition, in tandem with glutathione, of inducible nitric oxide synthase; (ii) quenching of nitric oxide radicals and reactive oxygen species, enhanced by cobalamin's glutathione sparing effect; (iii) the promotion of acetylcholine synthesis, central to the neuro-immune cholinergic anti-inflammatory pathway; (iv) the promotion of oxidative phosphorylation; (v) and a bacteriostatic role of the TCS released by neutrophil secondary granules during phagocytosis, which also appears to modulate the inflammatory response. TC elevations are dependent on NFkappaB activation, through crosstalk between NFkappaB and Sp1, another member of the helix-loop-helix protein family, which directly mediates transcription of the TCII gene. Sp1 also has binding sites on the TNFalpha and EGF gene promoters. NFkappaB may thus ensure sufficient cobalamin to determine its own eventual suppression. Cobalamin's established regulation of EGF may additionally preserve normal function of macrophages and the coagulation cascade in wound healing. By regulating NFkappaB, Cobalamin may also be the as yet unidentified mediator needed to potentiate the anti-inflammatory action of eicosanoids derived from omega-3 essential fatty acids. Moreover, animal and human clinical data suggests that high dose cobalamin may prove a promising approach to SIRS/sepsis/septic and traumatic shock.