Alkaline Serine Protease for long COVID
ALKALINE SERINE PROTEASE
What is alkaline serine protease?
Alkaline serine protease is a protease whose primary role is to break down proteins. It can be derived from the Neanthes japonica worm [[1]].
What does alkaline serine protease do in the body?
Alkaline serine protease breaks down proteins in the body. These proteins include inflammatory cytokines, the enzyme thrombin, which causes blood clots, and proteins such as the SARS-CoV-2 spike protein. Because of its anti-spike protein activity, alkaline serine protease represents a natural therapeutic against COVID-19 [[2]].
In animal studies, alkaline serine protease was found not toxic to organs, including the liver, the heart, and the kidneys [[3]].
How can alkaline serine protease help alleviate certain Long COVID symptoms and pathophysiology?
Researchers suggest that alkaline serine protease can act as a scavenger in the body, breaking down spike protein throughout the bloodstream due to its role in breaking down spike proteins. This can be helpful for Long COVID patients who still may have the virus in their system after the acute COVID-19 disease phase. An added feature of alkaline serine protease is that it is not toxic to organs such as the liver, heart, and kidneys, though it can reduce stroke risk [[4]]. Researchers hypothesize that alkaline serine protease can be used to prevent and treat heart and vascular inflammation and injuries resulting from the mRNA COVID vaccine in people with Long COVID [[5]].
Zinc for long COVID
ZINC
What is zinc?
The body needs only minimal amounts of zinc. It is a trace mineral, meaning humans do not produce it naturally. Therefore, we must get zinc from dietary sources or supplementation. Zinc deficiency may be a common feature in infectious diseases; a study found it was the most common deficiency in an infectious disease clinic [[1]]. Zinc deficiency, however, is also generally common worldwide, especially in the Global South nations [[2]]. Insufficient zinc intake is associated with an increased risk of respiratory tract infections, especially in older people [[3]].
What does zinc do in the body?
Zinc’s important roles include cell growth and reproduction, immune function, and metabolism. In addition to being an antioxidant and anti-inflammatory compound, zinc may decrease viral replication. In acute COVID-19 patients, zinc supplementation can improve lung function, improve mucus clearance, and reduce lung injury from ventilators in critical patients. Zinc deficiency may also be associated with anosmia (loss of smell) and dysgeusia (loss of taste), which can last for some time after acute COVID infection [[3]].
How can zinc help alleviate certain Long COVID symptoms and pathophysiology?
Researchers believe a potential reason for the persistence of Long COVID symptoms is that zinc deficiency is not adequately addressed in the conventional “standard of care” [[4]]. Zinc deficiency is linked to acute, persistent inflammation, which is a feature of Long COVID [[5]]. It can also affect certain types of lung cells and decrease lung barrier function [[6]]. Therefore, zinc supplementation may help reduce the body’s inflammatory response in Long COVID, particularly in the lungs.
Hyperbaric Oxygen Therapy for long COVID
HYPERBARIC OXYGEN THERAPY
What is hyperbaric oxygen therapy?
Hyperbaric oxygen therapy involves breathing in 100% oxygen under air pressure two to three times higher than normal air pressure. This allows your lungs to take in more oxygen than they can at normal air pressure. Hyperbaric oxygen therapy is typically an outpatient procedure that can be done in an individual unit for one patient within a chamber or a room for multiple people through a mask. This procedure is often used for wound healing or serious infections, as the extra oxygen can release growth factors and stem cells to promote healing and help fight bacteria.1
How can hyperbaric oxygen therapy help alleviate certain long COVID symptoms?
The mechanisms behind long COVID symptoms are not fully understood. Still, they are believed to be partly due to increased activation of proteins that promote clotting and hyperactive inflammatory and autoimmune responses. Hyperbaric oxygen therapy can improve circulation within our smallest blood vessels, inhibit the release of inflammatory mediators, inhibit autoimmune responses, and promote neurological repair.2 Hyperbaric oxygen therapy is proposed to improve the following long COVID symptoms: chronic fatigue; neurocognitive functions such as energy, sleep, pain, and psychiatric symptoms; and cardiac dysfunction such as shortness of breath.
What evidence supports the use of hyperbaric oxygen therapy for long COVID?
Several randomized control trials have studied the use of hyperbaric oxygen therapy for long COVID. The first evaluation of hyperbaric oxygen therapy for long COVID was a study done with ten patients who each received ten sessions over 12 days, each lasting 105 minutes with three 30-minute exposures to 100% oxygen. The study found a significant improvement in fatigue, cognition, information processing, executive function, attention, and verbal function.3 Another trial with 73 patients randomized to receive hyperbaric oxygen therapy daily for 40 sessions also saw significant improvement in energy, sleep, psychiatric symptoms, and pain.4
Other long-term effects of COVID include cardiac injury, such as inflammation in the heart and increased risk of arrhythmias, heart disease, heart failure, or stroke. One trial looked at the effect of hyperbaric oxygen therapy on cardiac function in long COVID patients in 60 patients randomized to receive 40 daily hyperbaric oxygen therapy sessions or placebo. The outcome of interest was global longitudinal strain (or GLS), which measures how well the heart is pumping blood to the rest of the body. The study found that GLS was significantly increased after hyperbaric oxygen therapy.5
What are some things to watch out for with hyperbaric oxygen therapy?
Hyperbaric oxygen therapy has risks, including middle ear injuries due to the higher air pressure, temporary nearsightedness, lung collapse, seizures (rarely), lowered blood sugar in people treated with insulin for diabetes, and a potential risk of fire.1 It is important to remove any hair or skin products that are petroleum-based, as they can pose a potential fire hazard.
An ongoing trial released interim safety data on 20 patients randomized to receive hyperbaric oxygen therapy or placebo and found that 60% of the participants experienced at least one adverse event.6 The most common adverse events were cough and chest pain or discomfort. All adverse events were temporary. No serious adverse events were reported.
Hyperbaric oxygen therapy cannot be used in patients with a collapsed lung. It should typically not be used in obstructive lung disease or a recent ear or thoracic (chest) surgery.
References:
1) Mayo Clinic Staff. Hyperbaric oxygen therapy. Mayo Clinic. Nov 4, 2022. Accessed November 5, 2023. https://www.mayoclinic.org/tests-procedures/hyperbaric-oxygen-therapy/about/pac-20394380
Active Clinical Trials: Long COVID, Hyperbaric oxygen | Card Results | ClinicalTrials.gov
Alpha-Lipoic Acid for long COVID
ALPHA-LIPOIC ACID
What is alpha-lipoic acid?
Alpha-lipoic acid, or ALA, sometimes called thiotic acid, is a fatty acid used as a supplement for many different health conditions. It is widely distributed in human cells across various cell types and is involved in producing energy [[1]].
What does alpha-lipoic acid do in the body?
ALA helps enzymes control metabolism and energy production and grow and develop new mitochondria [[1]]. It is also an antioxidant and anti-inflammatory substance. It is involved in controlling glucose levels, reducing oxidative stress in the body, and maintaining an antioxidant balance [[2]]. It is also known for its roles in preventing diabetic neuropathy and scavenging and neutralizing free radicals [[3]].
How can alpha-lipoic acid help alleviate certain Long COVID symptoms and pathophysiology?
ALA’s effects can help reduce damage to the body’s cells and tissues that occurs with COVID-19. Evidence shows that SARS-CoV-2, the virus that causes COVID-19, causes dysfunction in the body’s endothelial tissues, such as the lining of blood cells. Endothelial dysfunction includes oxidative stress, leading to endothelial cell injury. Functioning endothelial tissues are needed for cardiovascular health. ALA can reduce oxidative stress in the endothelial system, improving endothelial function. Therefore, it may counteract the endothelial damage in Long COVID [[3]].
ALA also improves mitochondrial function, helping new mitochondria develop, which makes energy expenditure more efficient on the cellular level, supporting the health of the body’s tissues. Lastly, by boosting glutathione, ALA can serve as an indirect means to support immune function [[3]].
Serrapeptase for long COVID
SERRAPEPTASE
What is serrapeptase?
While more research is needed to better understand serrapeptase, a few things are known about this compound, which is produced naturally within the intestines of silkworms [[1]]. Serrapeptase is a protease that breaks down proteins into amino acids, the building blocks of proteins. Silkworms use the compound to break down their cocoons when born [[2]]. Serrapeptase is also known as serratiopeptidase, serratiopeptidase, serralysin, and others [[1]].
What does serrapeptase do in the body?
Serrapeptase is known for its robust anti-inflammatory activity. As an analgesic (pain reliever), it can be used by itself or in conjunction with other drugs to treat inflammation, positioning it as an alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs), boasting fewer side effects. It has been used to treat chronic sinusitis, carpal tunnel syndrome, sprains, torn ligaments, and post-operative inflammation [[2]]. It is also an anti-edemic compound, meaning it prevents the abnormal collection of fluid in body tissues and the circulatory system. It is also fibrinolytic, meaning that it can eliminate fibrous scarring. It is also mucolytic, which breaks up mucus to help the lungs breathe more easily [[3]].
How can serrapeptase help alleviate certain Long COVID symptoms and pathophysiology?
Serrapeptase can be used as an anti-inflammatory, analgesic, and anti-edemic compound for patients with Long COVID. In the respiratory tract of Long COVID patients, serrapeptase’s mucolysis can help improve respiratory tract health by strengthening immune defenses. Lastly, anti-inflammatory effects can be beneficial for Long COVID patients as well. More data is needed to examine safety, tolerability, and mechanism of action [[2]].
Cimetidine for long COVID
CIMETIDINE
What is cimetidine?
Cimetidine is an H2-antihistamine used for heartburn, stomach ulcers, and acid reflux. It blocks histamine-2 receptors in the stomach, preventing the stomach from secreting as much acid. Famotidine (another H2-antihistamine in the same drug class) may be preferred over cimetidine due to its longer duration of action and higher potency.
How can cimetidine help alleviate certain long COVID symptoms?
Histamine is a chemical our immune system releases that causes allergy symptoms. Cells in our body called mast cells release histamine, and in some patients after COVID, they may release too much, leading to some of the symptoms of long COVID. Two types of drugs can block histamine in the body: H1- and H2-antihistamines, like cimetidine. Blocking histamine can lead to anti-inflammatory effects that cimetidine could theoretically be used for to relieve pulmonary and cardiovascular symptoms of long COVID.
What evidence supports cimetidine’s use for long COVID?
Cimetidine has been found to exhibit binding affinity to the SARS-CoV-2 virus that could result in some antiviral activity on a molecular level.1 However, human studies have not shown cimetidine to have protective properties against an active COVID infection; thus, it should not be used to treat it.2
There is a lack of evidence supporting cimetidine’s use for long COVID symptoms. Several studies have instead looked at the use of famotidine for the relief of cardiovascular and neurologic symptoms of long COVID, such as a fast heart rate, brain fog, and chest pain.3 While these two drugs are very similar, it is believed that famotidine has a unique non-histamine receptor-mediated property that cimetidine does not possess that allows it to relieve certain COVID symptoms.2 Therefore, it is likely more efficacious to trial famotidine instead.
What should you be aware of when taking cimetidine?
Although uncommon, cimetidine can cause headaches, dizziness, and drowsiness. It can also have some anti-androgenic effects at high doses, which, in rare cases, may cause enlarged breast tissue in men (also known as gynecomastia). Cimetidine may have more interactions with other drugs you may take compared to famotidine, so you should let your doctor or pharmacist know if you are frequently taking cimetidine.
References:
Ketotifen Eye Drops for long COVID
KETOTIFEN EYE DROPS
What is ketotifen?
Ketotifen is an antihistamine and mast cell stabilizer used as an eye drop to prevent and treat eye itching caused by allergies (also known as allergic conjunctivitis). An oral formulation of ketotifen is available to treat asthma and hives, but it is only available in the United States as an eye drop. It can be applied as one drop into the affected eye(s) twice daily every 8-12 hours and should not be used more than two applications daily.
How can ketotifen help alleviate certain long COVID symptoms?
Histamine is a chemical our immune system releases that causes allergy symptoms. Cells in our body called mast cells release histamine, and in some patients after COVID, they may release too much, leading to some of the symptoms of long COVID. Ketotifen prevents mast cells from releasing inflammatory mediators and blocks histamine in the body as a histamine type-1 blocker.
As an eye drop, ketotifen and similar products such as olopatadine (Pataday) can specifically relieve itchy eyes that certain COVID variants can cause. There have been some reports of the Omicron variant causing unusual symptoms such as itchy eyes or pink eye in some patients.1 While this is rarely reported outpatient, there may be up to 31.6% of hospitalized COVID patients experiencing conjunctivitis.2 If you are experiencing an isolated symptom of itchy eyes without other symptoms of COVID, however, it is likely not due to a COVID infection.
What evidence supports ketotifen’s use for long COVID?
The SARS-CoV-2 virus can cause extreme inflammatory outbreaks by activating mast cells in the respiratory tract and may cause an accumulation of mast cells. As a result, ketotifen has been studied to see if its mast cell stabilizer properties could be used for pulmonary inflammatory symptoms of COVID. Ketotifen has been found to reduce lung lesions in the early stages of an H5N1 infection and was studied to investigate its impact on a COVID infection.3, 4
While ketotifen was found to be useful for its anti-inflammatory and mast cell-stabilizing effects, it is important to note that these effects would only be significant enough in ketotifen taken orally, which is not currently available in the US. As an ophthalmic formulation, it is reserved for relieving conjunctivitis or itchy eyes due to COVID. More studies need to be conducted specifically on the use of ketotifen eye drops for long COVID symptoms.
What are some things to watch out for with ketotifen?
Ketotifen can cause some eye irritation or eye pain. Otherwise, it has minimal systemic absorption and relatively few side effects. If symptoms worsen or do not improve within three days, you should inform your provider and consider other options.
Additionally, soft contact lenses should be removed before using ketotifen. Ketotifen should not be used for irritation related to contact lenses. If you wear contact lenses, you should wait at least 10 minutes after using ketotifen before reinserting them.
References:
1) Korin M. Can Omicron cause itchy eyes? Experts explain. Prevention. Jan 20, 2022. Accessed October 31, 2023. https://www.prevention.com/health/a38830511/omicron-itchy-eyes/
Arginine for long COVID
ARGININE
What is arginine?
Arginine is an amino acid that possesses anti-inflammatory properties. Arginine plays a role in numerous biological processes [[1]]. Typically, our bodies make all the arginine we need. We
What does arginine do in the body?
Arginine works as a vasodilator, which means that it enlarges blood vessels to promote blood flow. It can treat angina, high blood pressure, and peripheral artery disease [[2]].
Arginine promotes nitric oxide formation, which increases blood flow and helps nerve cells talk to each other better [[3]]. Nitric oxide also serves as an antiviral agent with anti-inflammatory effects, may regulate endothelial and respiratory systems, protect cells, and exhibit anti-thrombotic properties [[1]], and reduces the activity of pro-inflammatory cytokines involved in the cytokine storm in severe COVID [[4]].
How can arginine help alleviate certain Long COVID symptoms and pathophysiology?
Research into Long COVID shows that long-hauler patients experience a variety of dysregulated cytokine processes long after the acute COVID-19 infection [[4]].
Severe COVID-19 patients taking oral arginine supplements with their regular treatment required less respiratory support and less time in the hospital. Arginine also modulates inflammation and supports endothelial function, so researchers believe it may also help improve Long COVID symptoms [[1]].
Together with the polyphenol hydroxytyrosol, arginine could prevent the formation of peroxy nitrate, a harmful substance involved in organ dysfunction in COVID-19 [[3]].
Is arginine safe for pregnancy and breastfeeding?
Arginine may cause complications during pregnancy, so it’s important to talk to your doctor to see if arginine supplementation could be right for you. It is also unclear whether arginine can be passed on to babies through breastmilk and what the effects might be [[5]].
Methylene Blue for long COVID
METHYLENE BLUE
What is methylene blue?
Methylene blue might be known for its vibrant blue color in high school chemistry labs, but it is also a medicine with many different uses. It can improve the body’s ability to take up oxygen and liver function, and it can also improve blood pressure and cardiac function in septic shock [[1]].
What does methylene blue do in the body?
Though methylene blue started as a textile dye, it has also been used for over a century as a medicinal compound. Methylene blue is low-cost and safe at low dosages [[2]]. Used to treat COVID-19, methylene blue can interact with the virus itself, blocking the viral replication process. Methylene in methylene blue can also interfere with pro-inflammatory cells and prevent the cytokine storm, which results from immune overreactivity, in the lungs [[2]]. Methylene blue is also a nitric oxide synthase inhibitor, which slows COVID-19 disease progression and increases oxygen saturation, improving COVID-19 outcomes [[2]].
How can methylene blue help alleviate certain Long COVID symptoms and pathophysiology?
Mitochondrial dysfunction plays a significant role in neurodegenerative disorders that involve inflammation and brain cell death. These disorders involve oxidative stress that contributes to inflammation of the endothelial tissues and disturbed metabolism, resulting from insult to the brain’s mitochondrial processes. Methylene blue protects mitochondria, whether in the context of stroke, neurodegeneration, or chemotherapy-induced neural injury. Therefore, methylene blue has attracted interest in reducing the cognitive and functional impairments in Long COVID. In a recent study, patients undergoing major surgery experienced a reduction in postoperative cognitive dysfunction when taking methylene blue, as opposed to controls [[3]]. These effects make methylene blue a promising therapeutic tool for improving cognition and brain metabolism processes in Long COVID and reducing inflammation, which is a feature of Long COVID
Cromolyn Sodium Nasal for long COVID
CROMOLYN SODIUM NASAL SPRAY
What is cromolyn sodium?
Cromolyn sodium is available as an over-the-counter nasal spray that can be used to prevent or treat seasonal or long-term allergy symptoms such as sneezing, wheezing, a stuffy or runny nose, and itching. It is a mast cell stabilizer that reduces inflammation in your nose. It can be applied as one spray in each nostril 3-4 times daily every 4-6 hours for up to 6 times daily. You can use it before exposure to allergens to prevent allergy symptoms. Cromolyn sodium should not be used to treat asthma, a sinus infection, or cold symptoms.
How can cromolyn sodium help alleviate certain long COVID symptoms?
Cells in our body called mast cells release histamine, a chemical that causes our allergy symptoms. With a COVID infection, mast cells can be overactivated and release excessive amounts of inflammatory mediators like histamine, leading to some of the symptoms of long COVID.1 Cromolyn sodium reduces the amount of histamine released from mast cells and blocks the release of other chemicals called cytokines that lead to inflammation. This allows it to be effective in decreasing the inflammatory effects of COVID.2
In addition, cromolyn may reduce neuroinflammation and improve cognitive function in long COVID patients. Inhaled cromolyn has been found to affect microglia directly (the brain’s primary immune cells) to reduce cytokine secretion, which may improve cognitive symptoms such as brain fog.2 It is important to note that the nasal formulation of cromolyn may not show the same effects as its oral or inhaled formulations because it has more of a local effect on the nasal passages.
What evidence supports cromolyn sodium’s use for long COVID?
It is unclear whether nasal cromolyn has enough systemic exposure to exhibit these neuro-inflammatory effects. Anecdotally, patients have reported improvement in post-COVID brain fog after using NasalCrom, but there are currently no studies specifically investigating the use of NasalCrom for cognitive symptoms of COVID.3
There is an ongoing Phase I trial of 10 patients studying the effects of adding cromolyn to the standard of care for hospitalized patients with COVID-19 pneumonia. Cromolyn will be given as a nebulized treatment four times a day for four days, followed by the intranasal spray for two weeks to assess its impact on symptom improvement.4
What should you be aware of when using cromolyn sodium?
Cromolyn can cause a burning or stinging sensation in the nose and sneezing. Less common side effects include headache, hoarseness, and post-nasal drip. Some may also experience an unpleasant aftertaste. If your symptoms do not improve within two weeks or if you are experiencing shortness of breath, wheezing, or chest tightness, you should stop using Cromolyn, as these symptoms may be due to another underlying condition.
References:
4) LongCovidPharmD. NasalCrom for Neuroinflammation? Studies, Surveys, & Supplements. November 23, 2022. Accessed October 31, 2023. https://pharmd.substack.com/p/nasalcrom-for-neuroinflammation
5) Michelson E. Cromolyn Sodium for Treatment of COVID-19 Pneumonia. ClinicalTrials.gov. February 14, 2023. Accessed October 31, 2023. https://clinicaltrials.gov/study/NCT05077917
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