Cobinamide to Supplement Nitroprusside in Acute Heart Failure from Krystal Plonski on Vimeo .
The cobalamin precursor cobinamide detoxifies nitroprusside-generated cyanide .
K. Broderick, et al., Department of Medicine, University of California, San Diego
A main therapy for acute heart failure is nitroprusside, a drug used for hypertension and acute heart failure, works through the mechanism of releasing nitric oxide (NO) to cause vasodilation. The downside of this therapeutic includes the fact that for every NO released, 5 molecules of cyanide are also released. The pharmacological agent, sodium thiosulfate, is a way to remove the cyanide molecule, but has a high toxicity issue, with many side effects associated such as nausea, vomiting, and diarrhea. An alternative treatment to sodium thiosulfate would be cobinamide, a precursor form of Vitamin B12, which has a higher binding affinity for cyanide molecules than hydroxycobalamine, and drastically reduced unpleasant side effects from pharmaceutical supplementation.
This study looked at various aspects of Nitroprusside action with addition of cobinamide through measuring free NO concentration, nitrate/nitrite production, ATP levels, D. melanogaster heart rate, Mouse blood pressure, and Mouse serum and urinary thiocyanate concentrations. The researchers concluded, across all experiments, that at cobinamide concentrations up to 5 times (250μM) to Nitroprusside (50μM) that there was no significant decrease in NO production, increase in hypertension, or reduction of metabolic respiration. They also concluded that at this same concentration, detoxification effects of cyanide were upheld, without interfering with other important metabolic processes. However, concentrations of cobinamide that were 6 times (300 μM) that of Nitroprusside (50μM), induced cobinamide to acquire a shape that bound up NO, reducing the therapetutic effects of Nitroprusside as a vasodilator for acute heart failure.
A major limitation of the study includes rat, fly, and cellular models compared to an in vivo trial. In addition, overestimation of calculations for NO’s affinity for cobinamide were for cobinamide (II), a +2 valency state, only after reduced by another NO molecule, which then turns into nitrite and nitrate. Another limitation was the amount of Nitroprusside administered to the mice, which was about 5μg/g, which is much more than what is administered to humans (Nitroprusside therapeutic range ~ 5μg/kg/min). Also, route of administration is different for mice as intraperitoneal, compared to humans as an intravenous drip.
Cobinamide to Supplement Nitroprusside in Acute Heart Failure from Krystal Plonski on Vimeo .
The cobalamin precursor cobinamide detoxifies nitroprusside-generated cyanide .
K. Broderick, et al., Department of Medicine, University of California, San Diego
A main therapy for acute heart failure is nitroprusside, a drug used for hypertension and acute heart failure, works through the mechanism of releasing nitric oxide (NO) to cause vasodilation. The downside of this therapeutic includes the fact that for every NO released, 5 molecules of cyanide are also released. The pharmacological agent, sodium thiosulfate, is a way to remove the cyanide molecule, but has a high toxicity issue, with many side effects associated such as nausea, vomiting, and diarrhea. An alternative treatment to sodium thiosulfate would be cobinamide, a precursor form of Vitamin B12, which has a higher binding affinity for cyanide molecules than hydroxycobalamine, and drastically reduced unpleasant side effects from pharmaceutical supplementation.
This study looked at various aspects of Nitroprusside action with addition of cobinamide through measuring free NO concentration, nitrate/nitrite production, ATP levels, D. melanogaster heart rate, Mouse blood pressure, and Mouse serum and urinary thiocyanate concentrations. The researchers concluded, across all experiments, that at cobinamide concentrations up to 5 times (250μM) to Nitroprusside (50μM) that there was no significant decrease in NO production, increase in hypertension, or reduction of metabolic respiration. They also concluded that at this same concentration, detoxification effects of cyanide were upheld, without interfering with other important metabolic processes. However, concentrations of cobinamide that were 6 times (300 μM) that of Nitroprusside (50μM), induced cobinamide to acquire a shape that bound up NO, reducing the therapetutic effects of Nitroprusside as a vasodilator for acute heart failure.
A major limitation of the study includes rat, fly, and cellular models compared to an in vivo trial. In addition, overestimation of calculations for NO’s affinity for cobinamide were for cobinamide (II), a +2 valency state, only after reduced by another NO molecule, which then turns into nitrite and nitrate. Another limitation was the amount of Nitroprusside administered to the mice, which was about 5μg/g, which is much more than what is administered to humans (Nitroprusside therapeutic range ~ 5μg/kg/min). Also, route of administration is different for mice as intraperitoneal, compared to humans as an intravenous drip.