A continuación presento un resumen (muy breve) de un artículo publicado recientemente (fuente más abajo) con multitud de referencias científicas sobre el posible efecto positivo de ingerir ácido ascórbico internamente (y también de forma intravenosa como ascorbato de sodio) cuando se presentan síntomas de la infección por COVID-19.
Puesto que el artículo original (enlace abajo) está en inglés decidí copiar los párrafos más reveladores y además ofrecer un resumen en español con objetivos educativos y de divulgación. No se pretende ofrecer un tratamiento sino compartir información científica que está publicada pero que quizás las personas interesadas (tanto médicos como pacientes) todavía no conozcan.
Artíclo original: https://www.evolutamente.it/covid-19-ards-cell-free-hemoglobin-the-ascorbic-acid-connection/
RESUMEN (super reducido) en español:
La malaria tiene un mecanismo de acción por el cual libera una forma oxidada del grupo hemo (una molécula que se encuentra en la hemoglobina de los glóbulos rojos que contiene hierro). Esta forma oxidada es tóxica para las membranas celulares. El parásito de la malaria puede “secuestrar” esta forma tóxica del grupo hemo y así protegerse cuando infecta los glóbulos rojos. Fármacos como la cloroquina interfieren con esta capacidad del parásito luchando así contra su propagación.
La liberación de este grupo hemo está asociada con inflamación alveolar y coagulación en el síndrome de dificultad respiratoria aguda (ARDS por sus siglas en inglés). La forma libre y tóxica que daña las membranas celulares se refiere a un grupo hemo que ya no está dentro de la hemoglobin y donde su hierro se encuentra en un estado oxidado (óxido férrico) en lugar de un estado reducido (óxido ferroso).
La haptoglobina es una molécula que se encarga de unirse a complejos hemo para mantenerlos en una forma química más estable. Pero esta enzima depende de reductores (antioxidantes) como el ácido ascórbico para convertir el óxido férrico en ferroso y evitar así el daño que conlleva en los tejidos (por medio de hemólisis, vasoconstrición, cascada de inflamacion…etc.).
Nota personal: algunos genotipos presentan una haptoglobina más eficaz a la hora de asociarse a los grupos hemo libres. Quizás por eso italianos y españoles (similares genéticamente) somos más susceptibles.
Más allá de la predisposición genética el suministro de antioxidantes como el ácido ascórbico también determina la capacidad de trabajo de la haptoglobina.
Se sabe, además, que los enfermos en estado crítico presentan niveles en plasma muy bajos de ácido ascórbico. Esto tiene a su vez efecto en otra enzima importante a la hora de reducir el hierro a su forma más estable (óxido ferroso). Se trata de la enzima citocromo b561 (una ferrirreductasa).
La terapia con ácido ascórbico se ha empleado en China no sólo de forma intravenosa (como ascorbato de sodio) sino también de forma oral (como ácido ascórbico) con resultados muy positivos porque permite a estas enzimas reducir la forma tóxica del hierro (óxido férrico) a una que es más estable (ferroso) y así evitar el daño epitelial general y en particular pulmonar.
El ácido ascórbico (sorprendentemente) se absorbe mucho mejor de lo que tradicionalmente se pensaba según estudios muy recientes y no tiene los efectos secundarios de los fármacos antimalaria como lo cloroquina.
Las dosis empleadas se encuentran al final del resumen en inglés. Todas las referencias científicas se hayan al final de esta entrada.
Esperamos que esta información llegue a las personas adecuadas por el beneficio de todos. Un salud-o.
A CONTINUACIÓN LOS PÁRRAFOS MÁS RELEVANTES DEL ARTÍCULO ORIGINAL EN INGLÉS
The Malaria parasite infects hosts by digesting hemoglobin and releasing an oxidized form of heme that is toxic for biological membranes. The malaria parasite can sequester these toxic free hemes to protect themselves. The antimalarial drug chloroquine binds to the toxic free heme, enhancing its toxicity, while interfering with the ability of the parasite to sequester these toxic free heme. Thus the cytotoxic free heme accumulates to lethal levels in erythrocytes (red blood cells) that are infected by malaria parasites [28, 29].
In severe malaria, cell-free hemoglobin (that contains that oxidized form of heme that is toxic), being a POTENT QUENCHER OF NITRIC OXIDE, are often significantly elevated, causing hemolysis (the rupture or destruction of red blood cells). Cell-free hemoglobin increases in proportion to disease severity in malaria and its levels are often correlated to poor clinical outcome [30].
Critically ill COVID-19 patients often develop acute respiratory distress syndrome (ARDS). It has been known for a long time that during critical illness, red blood cells undergo deleterious changes that cause hemolysis. It is only recently that the release of free heme is also associated with alveolar inflammation and coagulation in ARDS [39]. A study by Shaver et al. indicated that the red color observed in the exudates from ARDS patients is not merely a benign sign of edema, but the presence of CFH and hemolysis [41]. Doctors in the USA are now reporting secretions from COVID-19 patients with ARDS that are pink in color [50].
A landmark study published by Shaver et. al in 2016 showed conclusively that elevated cell-free hemoglobin (CFH) in the air space is the essential driver of lung barrier permeability, inflammation and epithelial injury in human and experimental animal models of ARDS.
“Free heme” actually describes heme that is NOT STABILIZED within heme proteins such as hemoglobin or myoglobin. Free heme is in the unstable FERRIC form that can be transferred to a wide range of heme acceptor membrane-based proteins and lipids, such as lipoproteins and albumin [31].
Cell-free hemoglobin in the vasculature leads to vasoconstriction and injury via nitric oxide scavenging and/or oxidative reactions of these free heme [32].
Just like the malaria parasite that can protect itself from the toxic effects of free heme, the human body also has an effective innate defense system that sequesters cytotoxic cell-free hemoglobin. One of them is haptoglobin, an acute-phase protein that binds and removes free hemoglobin from the circulation [31]
What does ascorbic acid have to do with haptoglobin?
Even though haptoglobin can bind cell-free hemoglobin, to maintain these heme in a stable form, haptoglobin must depend on reductants (antioxidants) like ascorbic acid in plasma to maintain the free heme in a reduced, stable, unreactive ferrous (Fe2+) redox state [31, 45]. As demonstrated by Shaver et al. in 2016, free heme without iron ion centers do not inflict as much damage [41]. Heme iron when maintained in the unreactive ferrous (Fe2+) redox state remains stable. Thus the key in controlling the deranged production of cell-free heme in the course of ARDS is to prevent the oxidation of heme to the Ferrous (Fe2+) redox state which is more stable than ferric (Fe3+) redox state. The key to the stability of heme is the maintenance of iron ions in the ferrous (Fe2+) redox state. In the ferric form, hemoglobin have been seen to lose heme to form free heme at substantially higher rates than ferrous forms [47].
The Advantage of the Haptoglobin Hp2/Hp2 Polymorphism in COVID-19
There are two co-dominant alleles of the Haptoglobin (Hp) gene. Hp1 and Hp2 have three genotypes: Hp1/Hp1, Hp1/Hp2 and Hp2/Hp2. Interestingly, a correlation with the severity of malaria has been observed where 74% of non-severe malaria patients have the Hp2/Hp2 genotype, while 31% of the carriers of this same Hp2/Hp2 allele exhibited severe malaria symptoms [44]. Malaria patients with Hp2/Hp2 alleles may have a distinct advantage where their haptoglobin binds cell-free hemoglobin more effectively.
But why do 31% of patients with the same genotype still develop severe malaria? The question may be answered in another study that showed that the Hp2-2 genotype, when compared to the Hp-1 allele, had lower serum ascorbic levels if they did not supplement with adequate vitamin C [44]. What does ascorbic acid have to do with haptoglobin?
Even though haptoglobin can bind cell-free hemoglobin, to maintain these heme in a stable form, haptoglobin must depend on reductants (antioxidants) like ascorbic acid in plasma to maintain the free heme in a reduced, stable, unreactive ferrous (Fe2+) redox state [31, 45].
Critically ill patients with ARDS are extremely difficult to oxygenate as their lungs are filled with fluid and cell-free hemoglobin (CFH) occupying most of the airspace
A Call for Immediate Attention To The Use of Oral Ascorbic Acid in COVID-19 Patients
The Shanghai Medical Association and the Shanghai city government now officially endorse the use of vitamin C for the treatment of COVID-19 infections.
Critically ill patients in sepsis, trauma, burns, or ischemia/reperfusion injury exhibit extremely low levels of plasma ascorbic acid [100, 101, 102]. The rapid depletion of ascorbic acid in plasma of critically ill patients has a direct impact on the highly conserved eukaryotic transmembrane enzyme known as Cytochrome b561 (Cytb561). Cytb561 is ascorbate-dependent. That means this transmembrane enzyme uses ascorbate EXCLUSIVELY for its role in the recycling of ascorbate [73]. Cytb561 is also a ferrireductase enzyme responsible for the reduction of iron ions from the oxidized ferric state to the reduced ferrous state [74]. COVID-19 ARDS patients are difficult to oxygenate because of systematic destruction of red blood cells resulting in cell-free heme that have oxidized iron ions in the ferric state. Under normal conditions, the iron ions in heme can be reduced by Cytb561. So why are COVID-19 patients unable to maintain stable heme?
Only iron ions in hemoglobin that are in the ferrous form can bind and transport oxygen. A functional hemoglobin carries four iron ions and four oxygen molecules. Heme is the protein that carries BOTH iron AND oxygen [76]. Hemoglobin in red blood cells are active only when the iron in the heme is in the ferrous reduced state. In this state, the heme is able to bind oxygen reversibly. When the iron in heme is oxidized to the ferric state, the heme is inactivated, and the hemoglobin becomes cell-free hemoglobin that can cause hemolysis and ARDS in COVID-19 [32].
Without adequate ascorbic acid, heme will rapidly oxidize and become cell-free hemoglobin. This is the reason why even young adults in good health and no underlying health conditions can develop ARDS quickly upon COVID-19 infection [50, 57].
Sodium ascorbate is the form used in all intravenous Vitamin C applications. The extremely low pH of ascorbic acid (1.0 to 2.5 at 25 °C, 176 g/L in water) renders it unsuitable for intravenous injections [80]. All intravenous ascorbic acid has to be adjusted with buffers to raise pH between 5.5 to 7.0, using sodium bicarbonate [79, 81, 82]. When ascorbic acid is combined with sodium bicarbonate, sodium ascorbate is created. Hospitals in China and the rest of the world treat COVID-19 patients with IV C in the molecular form of sodium ascorbate. Clinical trials conducted on Vitamin C also use IV C in the form of sodium ascorbate [83].
It is entirely possible that the sodium ascorbate molecule may not be in the preferred form that is utilized by our REDOX systems. There has actually been no evidence that compare side-by-side the difference in results of plasma concentration from oral ascorbic acid and sodium ascorbate (both IV C and oral), until the ground-breaking paper released by Owen Fonorow and Steve Hickey on March 13th, 2020 [94].
Fonorow and Hickey exploited this feature and used glucose meters to measure minute-by-minute results of the two different forms of vitamin C – ascorbic acid and sodium ascorbate in different combinations of oral/oral and oral/IV C. The results from their study are truly remarkable and should be considered as a landmark moment in orthomolecular medicine due to the way their observations could be interpreted [94]. When 10 grams of ascorbic acid was ingested orally, compared to 11.3 grams of sodium ascorbate (to account for additional weight of sodium in the compound) taken by mouth, Fonorow and Hickey obtained a totally UNEXPECTED result showing that oral ascorbic acid is absorbed more efficiently and in higher quantities than sodium ascorbate.
A common misunderstanding about ascorbic acid absorption in the intestines is that there is an upper limit of about 200 milligrams, above which, the body would not be able to transport and utilize the molecule. This is the reason why intravenous delivery is the preferred method as it is believed to be able to provide a higher bioavailability.
If you look at the oral/IV C chart above, what do you observe? There is a distinct spike within 2 to 8 minutes after a single ingestion of 10 g ascorbic acid. The highest level is more than DOUBLE that achieved by IV C at the same minute mark. Why would the body absorb ascorbic acid better than sodium ascorbate?
This remarkable study by Fonorow and Hickey (March 2020) not only showed that oral ascorbic acid is fully absorbed and utilized in high quantities, it also revealed the true nature of ascorbic acid as a REDOX molecule.
COVID-19 patients should be afforded the most efficacious treatment using oral supplementation of ascorbic acid to reduce hypoxia and lower cell-free hemoglobin, the main cause for ARDS in COVID-19.
The combined oral ascorbic acid AND intravenous sodium ascorbate treatment may confer COVID-19 patients the best of both worlds.
The following supplementation guide for oral ascorbic acid is offered as informational purposes only, and should NOT be considered as MEDICAL ADVICE.
Initial onset of symptoms:
3 to 5 g in one dose, followed by 1 g every 30 to 60 mins for the following 3 hours. Repeat this cycle until symptoms subside.
Milder cases:
2 to 5 g in one dose, followed by 1 g every hour for the following 4 – 6 hours. Repeat this cycle until symptoms subside.
Severe/critical cases:
10 g in one dose, followed by 2 g every 15 to 30 mins for the following 2 hours. Repeat this cycle until symptoms improve.
Stomach Acidity
Patients exhibiting stomach discomforts can be given acidic beverages together with oral ascorbic acid. Lower pH will facilitate faster absorption. High pH in stomach acids can slow or even prevent speedy absorption of ascorbic acid. Examples of acidic beverages may include fresh squeezed lemon/lime in water, apple cider vinegar (1 tbs in 2-3 oz water).
Importance of Sodium ions in Ascorbic Acid Transport
The transport of ascorbic acid is dependent upon the sodium electrochemical gradient generated across the plasma membrane by Na+/K+ ATPase. Theoretically, ascorbate should significantly reduce quenching of NO, raising NO levels, thus stabilizing blood pressure.
Inhibition of SVCT by Flavonoids
The flavonoid quercetin has been demonstrated to inhibit transport of ascorbate by SVCT1. Supplementation of quercetin may need to be reconsidered when using oral ascorbic acid during COVID-19 treatment.
Ascorbic Acid Recommendations for Children
Children infected by COVID-19 should, under normal circumstances, recover quickly. However, they may be asymptomatic and have high transmissibility. Upon infection children should be given oral ascorbic acid in the following dosages:
Ages Under 9
Initial dose – 200 mg per 10 lb. body weight
Subsequent doses – 100 mg per 10 lb. body weight
Follow the time schedule under mild cases for adults. If symptoms worsen, change to the time schedule for severe cases.
Ages Between 10 – 15
Initial dose – 300 mg per 10 lb. body weight
Subsequent doses – 200 mg per 10 lb. body weight
Follow the time schedule under mild cases. If symptoms worsen, change to the time schedule for severe cases.
Above 15 – treat as adult
In conclusion, with proper attention to social distancing, adequate nutrition, sleep, exercise and supplementation with ascorbic acid and melatonin, in time, COVID-19 may actually become ‘just another flu’ after all.
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