Prescription Sulodexide Improves Some Post-Covid Symptoms
And Can Healing Proteoglycans be Boosted Nutritionally?
Sulodexide was shown to reduce chest pains, palpitations, and blood vessel function in a 21-day study of Long Haulers conducted in Tunisia. Chest pain and palpitations were reduced 40-50% compared to a placebo, and blood vessel function was much better in the group receiving Sulodexide.
“Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study.” Frontiers in Cardiovascular Medicine, 12 May 2022. PMID 35647070, Full Article.
So what is Sulodexide? It is a mix of 2 different Proteoglycans found in the body. Proteoglycans are sugar-amino compounds that are critical to many soft tissues.
One of the compounds in Sulodexide is a form of heparin sulfate. The other ingredient is dermatan sulfate. Sulodexide is a mixture of 4 parts of low molecular weight heparin and 1 part dermatan sulfate.
Heparin is a polysaccharide that has an anti-coagulant effect in the blood. It is often given when a person in the ER is having a heart attack or stroke. This observation is consistent with other data that shows that many Long Haulers have increased coagulation and blood clots. Heparin also has a very high surface area also acts as a ‘sponge’ in the blood, and binds up many charged molecules or particles.
Our bodies naturally produce Heparin, and it can be sourced from animal products (beef, pork). The “low molecular weight” (LMW) form used in the Tunisian study has been partially broken down and filtered, and is more standardized and predictable compared to regular heparin. It is also easier to administer the LMW form of heparin … the smaller molecules can be taken orally or injected under the skin — patients can self-administer those forms. Plain (high molecular weight) heparin is generally administered intravenously, which is something typically done in a clinic or hospital setting.
Dermatan sulfate is sometimes referred to as chondroitin sulfate B (although technically, it may not be chondroitin in a strict chemical sense). The word dermatan refers to the derma, the skin — and dermatan is indeed an important component of the skin.
Proteoglycans
Proteoglycans are molecules made from amino compounds and specialized sugars. They can take the form of nano-sized chains or blocks. And some of these proteoglycans are quite important. Here are 5 common proteoglycans:
Heparin Sulfate
Keratin Sulfate
Dermatan Sulfate
Chondroitin Sulfate
Hyaluronic Acid
Will Ordinary Chondroitin Sulfate Work?
The Chondroitin supplements that people take over OTC are similar to the dermatan-sulfate component of Sulodexide. I would not expect that OTC Chondroitin would have exactly the same effect, but it might be of some support to the healing process.
The blood vessels and other tissues in the body contain a lot of collagen proteins and proteoglycan compounds like chondroitin, hyaluronic acid, and heparin. During the inflammatory and immune storms of Covid (and other types of infection), the blood vessels can be damaged. That damage tends to heal over time, but providing the building blocks the body needs for repair might speed the convalescence.
Ordinary chondroitin may not be effectively absorbed - some forms have been processed to break big chondroitin chains down into smaller ones that are more likely to move from the gut into the blood.
There is no OTC form of heparin, which makes up most of the Sulodexide formula. And (as mentioned previously) heparin needs to be injected, it has a very low oral availability. But there is a rationale for increasing heparin production in the body by making sure the essential precursors needed to make heparin are present in adequate amounts.
Dietary Support - Glucuronic Acid, NA-Glucosamine, And Sulfate
In order to make the five proteoglycans listed above (Heparin-Sulfate, Keratin-Sulfate, Dermatan-Sulfate, Chondroitin-Sulfate, and Hyaluronic acid) the body needs 3 compounds: 1) glucuronic acid, and 2) N-Acetyl-Glucosamine, and 3) Sulfate.
Under ordinary circumstances, the body is assumed to have enough of these molecular building blocks to maintain good health. But these assumptions might not always hold true… there might be times when a person is ‘conditionally deficient’ in one or more of them… perhaps after an illness, or as we age and produce less of these compounds, or if we have a particular genetic configuration that means we produce less or absorb less of them from food. And that might slow our healing. So it is a plausible hypothesis that boosting our intakes of the 3 precursors ~might~ boost production and work in a way similar to Sulodexide. Not proven. Not guaranteed. But a fairly low risk and affordable biohack that people might consider if Sulodexide is not available due to geographic or economic reasons.
» Glucuronic Acid
Glucuronic acid is made from glucose. Our body has a metabolic pathway for making it, some microbes can make it, and it can be cooked up in a lab by heating glucose with nitric acid.
Kombucha is a fermented beverage that is rich in glucuronic acid - it may contain up to 2.3 grams per liter (2300 mg) per liter, according to one study. 1 Okra slime contains 2.5% glucuronic acid on a dry weight basis.2 Gum Arabic and Xanthan gum also contain a fairly large amount of glucuronic acid. The polysaccharides in okra, gum Arabic, and xanthan gum also might have some beneficial effects on the immune system, as do the polysaccharides from seaweed.
I have gone through periods in the past where I drank kombucha regularly. The beverage has much less sugar than other sweetened beverages, but a fair dose of sour and fruit flavors. A bottle of kombucha per day isn’t cheap … it could run $2 to $3 for twelve or sixteen ounces, less if bought in bulk at Costco or Sams Club. There is also the option of brewing your own. I have done a fair amount of fermentation in the past, but haven’t done kombucha (which is basically fermented sweet tea). There have been a few widely scattered cases of people brewing up kombucha that makes them ill, but I think the situation is comparable to making cheese… Cheese is not an incredibly dangerous food, but people get sick (and even die) every year from cheese that fermented sideways. If a person wants to brew their own ‘bouch’ its an option, but additional research is needed to ensure a safe product. I might get around to brewing it someday, but haven’t yet. People suffering from a chronic condition that zaps their energy and focus might want to spring for a few weeks of the store bought stuff.
Side Note: Many people on the internet use the term “detoxification” in a vague, non-technical way, and the skeptics love to poke at them for that. But the glucuronic acid in kombucha actually is one compound the body does use for specific detoxification processes. For example, bilirubin is normally tagged with 2 glucuronic acid molecules and then it can be excreted by the liver into the bile. When a newborn infant doesn’t turn on the genes to make adequate glucuronic acid, bilirubin builds up in the blood, becomes toxic, and causes disease. Usually, this issue corrects itself and the doctor assures the anxious mother that the yellow eyes (jaundice) will return to a more normal white, but if an infant has a genetic system that keeps the glucuronic acid levels low, serious problems follow. Glucuronic acid is needed both to detoxify molecules in the liver and to build proteoglycans.
» N-Acetyl-Glucosamine (NAG)
A variety of glucosamine preparations are sold as supplements to support the cartilage systems of the body. The levels of this nutrient drops as we age - the body seems to gradually lose the ability to synthesize this over time. 3 The N-Acetyl form of glucosamine (NAG) is the most active, it is what is immediately needed to build proteoglycans.
Glucosamine is typically produced from either shrimp cells, or by vats of bacteria. The N-Acetyl-Glucosamine form of it is normally present in breastmilk: shortly after birth, a breastfed infant is consuming around 1.5 grams (1500 mg) of NAG in a liter of breast milk, and that drops to around 650 mg per liter at the 3 month mark. 4
Adults taking NAG for arthritis are typically consuming 700 mg to 2000 mg per day. If we set 2000 mg per day for comparison purposes, that might cost 50 cents to one dollar per day when taking capsules. If buying NAG powder in bulk, the cost drops to around 20 cents per day. In my general experience, supplements that are in the N-acetyl form tend to have a sharp, acidic taste (in a small amount of the compound, the acetyl groups split off and create a vinegary taste. I haven’t used the N-Acetyl form (only regular glucosamine in tablets), I cannot say how strong the flavor is, or how easy it is to mask the flavor in a smoothie.
» Sulfate Deficiency?
Most researchers assume that the body always has plenty of sulfate, and relatively little research has been done to see how much SO4- is actually needed. People get a fair amount of sulfur from protein, and from particular vegetables (like cabbage and broccoli). But Sulfur can exist in several forms of the body, and some people may be better at others at processing it and moving it around to where it is needed — especially if levels are low.
One controversial hypothesis that came from an MIT researcher is that a deficiency of sulfate is a major contributor to heart disease. This idea states that cholesterol needs to be in a sulfated form to work properly … this thinking is that when cholesterol (an essential building block in the body) is laid down on an artery and it gets sulfated, it is stabilized, and forms a smooth surface that is resistant to problems. But when the cholesterol is not sulfated, layers and layers of additional cholesterol get laid down on top of that, and it forms a rough surface that impedes blood flow, it messes up nitric oxide levels, and the blood vessels no longer work properly, and the plaque can get so thick that clumps of it can break off and cause heart attacks and strokes. Here’s part of the theory:
We argue that the sulfate anions attached to the glycosaminoglycans in the glycocalyx are essential in maintaining the structured water that is crucial for vascular endothelial health and erythrocyte mobility through capillaries. Sulfate depletion leads to cholesterol accumulation in atheromas, … We argue that low (less negative) zeta potential due to insufficient sulfate anions leads to hypertension and thrombosis, because these responses can increase streaming potential and induce nitric-oxide mediated vascular relaxation, promoting oxygen delivery.
“A novel hypothesis for atherosclerosis as a cholesterol sulfate deficiency syndrome.” Theoretical Biology and Medical Modelling. 27 May 2015. PMID 26014131.
The theory also states that when sulfate levels are low, sulfate might be stripped off of cholesterol in the arteries for use elsewhere… the destruction of the artery lining might be a disease process that is negative, but less negative that not getting sulfate to other critical systems of the body.
This theory is provocative, but remains largely untested. I think it is plausible that low sulfate levels might reduce the formation and function of proteoglycans. If the body is struggling to make more heparin and dermatan, and there is not enough sulfate to convert them to the active sulfated forms, the body’s needs are not being met.
Sulfate is naturally found in many mineral waters, and we get some from food. One familiar compound called Epsom Salts is magnesium sulfate. It is a good source of both magnesium and sulfate, but there is one important thing to consider about Epsom Salts… too much of it has a laxative effect. Magnesium sulfate has a low rate of absorption from the gut into the blood. When it stays in the gut, it holds water. It holds the water all of the way down, softening the stool and possibly making it very liquid. This side effect makes it difficult to quickly boost sulfate levels in the body by taking epsom salts. Taking lower doses will increase magnesium and sulfate in the blood, but it takes time.
Magnesium sulfate is sometimes given intravenously to pregnant women who develop high blood pressure. That avoids the laxative effects. The conventional wisdom is that the magnesium is what brings down the elevated blood pressure - but the sulfate might also play a role.
The San Pellegrino brand of mineral water contains 420 mg of sulfate per liter, according to their 2021 chemical analysis report. The most common form of magnesium salt (magnesium sulfate heptahydrate) is approximately 39% sulfate by weight. So just a bit more over 1 gram of Epsom salt contains 400 mg of sulfate… that is somewhere between 1/8th and 1/4th of a teaspoon per liter of water.
Drinking a liter or two of water with this amount of Epsom salt each day is fairly safe and costs very little - literally pennies per month. It supplies both sulfate and magnesium (which many people are short on). If taking Epsom salts internally, look for the USP designation (US Pharmacopeia)... it indicates that the product has a level of purity that may not be found with other forms of the salt. Other grades might be suitable for bathing or gardening, but not for direct consumption.
Other References
“Sulodexide.” Wikipedia. https://en.wikipedia.org/wiki/Sulodexide
“Chondroitin Sulfate.” Wikipedia. https://en.wikipedia.org/wiki/Chondroitin_sulfate
“Low-Molecular-Weight Heparin.” https://en.wikipedia.org/wiki/Low-molecular-weight_heparin
“Dermatan Sulfate.” https://en.wikipedia.org/wiki/Dermatan_sulfate
“Changes in content of organic acids and tea polyphenols during kombucha tea fermentation.” Food Chemistry, 2007, https://www.sciencedirect.com/science/article/abs/pii/S0308814606004250
“Composition, physicochemical properties, and anti-fatigue activity of water-soluble okra (Abelmoschus esculentus) stem pectins.” International Journal of Macromolecules, 15 Dec 2020, PMID 33115649.
“Effect of N-acetylglucosamine administration on cartilage metabolism and safety in healthy subjects without symptoms of arthritis.” Experimental and Therapeutic Medicine, Apr 2017. PMID 28413518.
“Glucosamine.” Drugs and Lactation Database (LactMed), 17 May 2021. PMID 30000928.