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Ivabradine for long COVID

IVABRADINE

What is Ivabradine?

Ivabradine is a medication used to treat heart conditions.

 

What does Amantading do in the body?

Ivabradine slows the electrical conduction in the heart which subsequently slows the heart rate.

 

How can Ivabradine help alleviate certain long COVID symptoms and pathophysiology?

The use of ivabradine in long COVID (post-acute sequelae of SARS-CoV-2 infection, PASC) is based on limited but emerging scientific evidence. According to the 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 by the American College of Cardiology, ivabradine has been used in patients with severe fatigue exacerbated by beta-blockers and calcium-channel blockers.

This recommendation is based on a small trial involving 22 patients with postural orthostatic tachycardia syndrome (POTS). The trial found that ivabradine improved heart rate and quality of life over one month[1]. Additionally, a perspective article suggests that ivabradine may be helpful in managing COVID-19-related cardiovascular complications due to its heart rate-lowering effects and various additional benefits, such as anti-inflammatory and anti-oxidant actions[2]. However, these findings are preliminary and derived from small-scale studies or theoretical benefits rather than large, randomized controlled trials specifically targeting long COVID. While there is some evidence supporting the use of ivabradine for managing cardiovascular symptoms in long COVID, it is primarily based on small studies and expert opinion. More extensive clinical trials are needed.

 

 

1.Gluckman TJ, Bhave NM, Allen LA, et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and other Myocardial involvement, Post-Acute Sequelae of SARS-COV-2 Infection, And return to play. Journal of the American College of Cardiology. 2022;79(17):1717-1756. doi:10.1016/j.jacc.2022.02.003

2.Baka T, Repova K, Luptak I, Simko F. Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A perspective. Current Pharmaceutical Design. 2022;28(19):1581-1588. doi:10.2174/1381612828666220328114236

Amantadine for long COVID

AMANTADINE

 

What is Amantadine?

Amantadine is a medication used to treat abnormal movements in conditions such as Parkinson’s disease.

 

What does Amantadine do in the body?

Amantadine has mild effects on dopamine neurons, but we’re not sure exactly how it works for Parkinson’s. It also seems to stop a virus from infecting cells, but we don’t fully understand how it works.  While Amantadine has some antiviral properties, it is no longer recommended as an antiviral in clinical practice. [1]

 

How can Amantadine help alleviate certain long COVID symptoms and pathophysiology?

When it comes to long COVID, especially post-COVID-19 fatigue, there’s limited but hopeful evidence for using amantadine. One study found that patients who took amantadine for two weeks had less fatigue compared to those who didn’t, as measured by the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS). [2] However, other studies looked at different aspects of COVID-19 and how amantadine is used to treat it.

For example, one study found no significant improvements in fatigue among unvaccinated patients with early, mild to moderate COVID-19. [3] Another study emphasized the need for more standardized and robust studies on long COVID.[4]. The treatment has also been considered for fatigue in other conditions, such as Multiple Sclerosis. A Cochrane Database of Systematic Reviews found that amantadine is generally well-tolerated. However, the evidence supporting its effectiveness in reducing MS-related fatigue is still limited and inconsistent [5].  While Amantadine has the potential to reduce post-COVID-19 fatigue, but we need more large-scale, well-controlled studies to confirm its effectiveness and safety in this context.

 

1.Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal InfluenzaaClinical Infectious Diseases. 2018;68(6):e1-e47. doi:10.1093/cid/ciy866

2.Harandi AA, Pakdaman H, Medghalchi A, et al. A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue. Scientific Reports. 2024;14(1). doi:10.1038/s41598-024-51904-z

3Rejdak K, Fiedor P, Bonek R, et al. Amantadine in unvaccinated patients with early, mild to moderate COVID‐19: A randomized, placebo‐controlled, double‐blind trial. European Journal of Neurology. 2023;31(1). doi:10.1111/ene.16045

4.Chee YJ, Fan BE, Young BE, Dalan R, Lye DC. Clinical trials on the pharmacological treatment of long COVID: A systematic review. Journal of Medical Virology. 2022;95(1). doi:10.1002/jmv.28289

 

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Pollen-Based Herbal Extracts for long COVID

POLLEN-BASED HERBAL EXTRACTS

 

What is a pollen-based herbal extract?

Pollen is a powder produced by flowers when they are reproducing. Flowers reproduce when the pollen spreads around to fertilize other plants. You may know pollen from its status as a springtime allergen. The exact mixture of bioactive substances in pollen depends on its plant source, the activity of bees (who pollinate flowers), climate, and other agricultural variables. However, pollen typically contains nutrients such as amino acids, carbohydrates, and minerals [[1]].

 

One type of pollen-based herbal extract is purified cytoplasm of pollen. The cytoplasm of a cell, such as pollen, refers to the material within it, excluding the nucleus—in other words, the different components found within the cell. Purified cytoplasm of pollen, or PCP, is one pollen-based herbal extract used to support menopausal women’s health [[2]].

 

What does pollen-based herbal extract do in the body?

The exact mechanisms behind PCP are not understood. Still, researchers believe it may act as a selective serotonin reuptake inhibitor (SSRI) to increase the availability of the neurotransmitter serotonin in the brain, particularly in the hypothalamus cells. Indeed, precursors to serotonin can be found in PCP. The hypothalamus regulates the brain, controlling temperature perception, sleep-wake cycles, appetite, and overall balance of the body’s functioning. Studies of PCP supplements improved sleep quality and quality of life, reducing hot flashes, fatigue, and other menopause symptoms in women [[2]].

 

How can pollen-based herbal extract help alleviate certain Long COVID symptoms and pathophysiology? 

Researchers believe PCP could be used to reduce some of the common symptoms experienced by COVID long-haulers. Symptoms commonly experienced by people with Long COVID include fatigue, muscle weakness, and difficulty sleeping, as well as anxiety or depression. PCP, given its successes in treating these symptoms in menopausal women without the side effects of SSRIs.

 

Benfotiamine for long COVID

BENFOTIAMINE

 

What is benfotiamine?

Benfotiamine is derived from thiamine or vitamin B1. While vitamin B1 is water-soluble, benfotiamine is fat-soluble and can be naturally found in roasted garlic [[1]].

 

What does benfotiamine do in the body?

Benfotiamine is a powerful antioxidant and anti-inflammatory compound relevant to several diseases. Benfotiamine has helped prevent complications from diabetes as well as inflammatory complications of diabetes. Conditions that benefited from benfotiamine include a type of eye inflammation called uveitis and endotoxemia. Endotoxemia is involved not only in diabetes but also in other chronic diseases. It may contribute to low-grade inflammation that affects people with diabetes, dysregulating inflammation and triggering weight gain and diabetes [[1], [2]].

 

 

How can benfotiamine help alleviate certain Long COVID symptoms and/or pathophysiology? 

Relevant to COVID-19, benfotiamine could potentially reduce neurological complications by reducing amyloid beta deposition and tau activity, which are markers of neurodegeneration. Inflammatory complications that can be improved with benfotiamine include reductions in the activation of immune cells such as cytokines, as well as genes and molecular cascades upregulated during inflammation. Metabolic activity can be improved with benfotiamine through improvements and efficiencies gained in the Krebs cycle. Overall, for COVID-19, these effects reduce immune cell activation and decrease the cytokine storm. They also reduce oxidative stress and other complications associated with diabetes for COVID-19 patients. While it is unclear which of these improvements occur during the acute versus chronic phase of COVID-19, benfotiamine is a promising compound in this realm [[3]].

Selenium for long COVID

SELENIUM

 

What is selenium?

Selenium is an essential trace element, meaning our bodies only need a small amount [[1]]. We can get selenium from the foods we eat or from supplements [[2]].

 

Selenium intake is essential to ensure the proper function of selenoproteins, which get their name, in part, from selenium [[3]]. Selenium is a crucial aspect of selenoproteins, which help make DNA and are involved in the antiviral response. More generally, selenoproteins protect against cell damage [1]]. Selenium supplements support the innate immune system and help regulate the secretion of pro-inflammatory molecules [[2]].

 

What does selenium do in the body?

Selenium is involved in the brain, hormones, heart, blood vessels, and immune functions. Our bodies also need selenium for antioxidant processes. Selenium deficiency increases susceptibility to COVID-19. Dietary selenium is necessary for proper immune function and may protect against certain diseases, such as cancers, asthma, and heart disease [[4]]. Selenium is thought to prevent cancer cells from growing and spreading due to its ability to shut down the cancer cell cycle, promote cell death of tumor cells, and initiate DNA repair [[5]].

 

How can selenium help alleviate certain Long COVID symptoms and pathophysiology? 

Low selenium levels in COVID-19 are linked to increased tissue damage and Long COVID symptoms [[2]]. Low selenium levels may increase susceptibility to COVID-19, influence disease severity, and contribute to post-acute COVID symptoms, such as Long COVID. Many studies show that selenium concentration in COVID-19 patients is lower than in people who do not have COVID-19. Selenium concentration in COVID-19 is also linked to the severity and mortality of the disease [[2]].

 

Vitamin B1 for long COVID

THIAMINE (VITAMIN B1)

 

What is thiamine?

Thiamine, also called vitamin B1, belongs to the group of vitamins known as the B vitamins. Like the other B vitamins, thiamine converts food into fuel for our cells. More specifically, thiamine helps break down carbohydrates we eat into energy [[1]].

 

What does thiamine do in the body?

Thiamine is essential for nervous system function because it helps brain cells communicate better, both in terms of the insulation needed for brain cells to communicate and the propagation of neural signals itself. Thiamine deficiency can lead to neurological issues such as memory problems, seizures, delirium, and more. Thiamine also has antioxidant properties; the body needs more during a viral illness. Continual dietary supplementation is vital because the body can only store a limited amount of thiamine and has a relatively short half-life [[2]].

 

How can thiamine help alleviate certain Long COVID symptoms and/or pathophysiology? 

Research shows that thiamine depletion occurs in critical illness, including acute COVID-19 [[2]], and that this depletion is associated with an almost 50% increase in mortality [[1]]. One study found that the lower a patient’s vitamin B1 is, the larger the systemic inflammatory response, which is linked to adverse clinical outcomes in COVID-19 and is a risk factor for developing Long COVID [[3]].

 

Beyond thiamine’s role in dampening inflammation in acute illness, Long COVID symptoms resemble those of beriberi, or thiamine deficiency [[4]]. Many of the symptoms of beriberi involve the nervous system, which can be affected by long COVID. Therefore, sufficient thiamine intake may be essential to treat Long COVID symptoms, and potentially, especially those Long COVID symptoms that affect the nervous system.

 

Systemic Proteolytic Enzymes for long COVID

SYSTEMIC PROTEOLYTIC ENZYMES 

 

What are systemic proteolytic enzymes?                                                                                            

We previously discussed bromelain’s utility in reducing inflammation. Bromelain, discussed in this guide, belongs to a larger class of systemic proteolytic enzymes, or SPEs. SPEs break down proteins to help facilitate normal body processes such as digestion or pain relief. They can also be used to reduce swelling and help with wound healing cleanup [[1]].

 

Other SPEs include lysozyme, catalase, and papain. SPEs break down proteins into smaller fragments and, ultimately, into amino acids, which are the building blocks of proteins and other vital molecules the body uses for various purposes [[2]].

 

What do systemic proteolytic enzymes do in the body?

SPEs can be taken as oral supplements or applied to the skin. Applied to the skin, they can aid in cleaning up tissue from wounds to support healthy wound healing [[1]].

 

As a supplement, SPEs can work in the body to perform a variety of processes related to immune health, digestion, and more. Regarding COVID-19 and its impact on the immune system in Long COVID, SPEs are known immune system modulators. SPEs work to combat oxidative stress and prevent cell and tissue damage [[2]].

 

How can systemic proteolytic enzymes help alleviate certain Long COVID symptoms and pathophysiology? 

SPEs may be able to break down the spike proteins in SARS-CoV-2, the virus that causes COVID-19 [[2]]. They may also be able to unfold coronavirus proteins. SPE’s antiviral properties can be helpful because the virus can persist in Long COVID patients after the acute phase.

 

Ibuprofen for long COVID

IBUPROFEN

What is ibuprofen?

Ibuprofen is a nonsteroidal anti-inflammatory (NSAID) medication commonly used to relieve pain and reduce fevers. Unlike acetaminophen, it also has some anti-inflammatory properties and can be used for inflammatory diseases such as osteoarthritis and rheumatoid disorders.

How can ibuprofen help alleviate certain long COVID symptoms?

Ibuprofen works by reversibly inhibiting enzymes in our body called COX-1 and COX-2 that help reduce fever, pain, and inflammation. It is also believed to reduce pro-inflammatory substances called cytokines and inhibit the activation of other immune cells that can cause inflammation.

The prevalence of post-COVID pain is estimated to be up to 63.3%, and patients with chronic pain can have exacerbated symptoms after COVID.1 There are multiple possible mechanisms behind post-COVID pain. Post-COVID pain may be caused by the virus entering and attacking musculoskeletal and nervous systems, including the brain. Persistent inflammation from overactivated inflammatory pathways and excessive activation of blood clotting can also contribute to pain. Various types of pain can also be caused by COVID, such as headaches, neuropathic pain, musculoskeletal pain, chest pain, arthralgia, and fibromyalgia.

While other prescription medications are typically used to treat headaches, neuropathic pain, chest pain, and fibromyalgia, ibuprofen can be used to relieve short-term headaches, musculoskeletal pain, arthralgia, and myalgias that persist or worsen after COVID; however, it should not be used to treat COVID or to reduce the duration of COVID symptoms. Post-COVID headache can also be treated first-line with acetaminophen or NSAIDs like ibuprofen.2

What evidence supports ibuprofen’s use for long COVID?

Early on in the pandemic, anecdotal reports suggested that NSAIDs could potentially increase susceptibility to COVID due to their ability to increase expression of ACE2 receptors that are targeted by the SARS-CoV-2 virus.3 However, several studies have since debunked this theory and have shown that the use of NSAIDs is not associated with increased COVID severity or risk of all-cause mortality.4

A survey of 696 COVID patients in Italy reported that the use of standard analgesics such as ibuprofen in the post-acute phase of COVID had a temporary reduction in pain severity.5 NSAIDs can also be effective in managing migraines and are commonly used for headaches as well.6 While there are few studies investigating the use of ibuprofen for long COVID pain, the use of NSAIDs for pain is well-established and can be used safely in many patients post-COVID. Chronic use of NSAIDs, however, should be discussed with a healthcare provider. 

 

What are some things to be aware of when taking ibuprofen? 

Ibuprofen is not recommended in people at risk for or with existing cardiovascular disease, GI disease, kidney impairment, chronic liver disease, or people at higher risk of bleeding. Use of NSAIDs is associated with an increased risk of serious cardiovascular events such as heart attacks and strokes. New-onset hypertension can also occur with NSAIDs and can exacerbate heart failure. There is also a higher risk of gastrointestinal adverse events such as gastrointestinal bleeding or ulcers. Do not take ibuprofen for more than 10-15 days per month for headaches. Ibuprofen should be taken with food, and you should let your doctor know if you are taking ibuprofen regularly for long COVID symptoms.

 

References:

1)      El-Tallawy SN, Perglozzi JV, Ahmed RS, Kaki AM, Nagiub MS, LeQuang JK, Hadarah MM. Pain Management in the Post-COVID Era-An Update: A Narrative Review. Pain Ther. 2023 Apr;12(2):423-448. doi: 10.1007/s40122-023-00486-1

2)     Chhabra N, Grill MF, Singh RBH. Post-COVID Headache: A Literature Review. Curr Pain Headache Rep. 2022 Nov;26(11):835-842. doi: 10.1007/s11916-022-01086-y

3)     Kushner, P., McCarberg, B.H., Grange, L. et al. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. npj Prim. Care Respir. Med. 32, 35 (2022)

4)     Reese JT, Coleman B, Chan L, Blau H, Callahan TJ, Cappelletti L, Fontana T, Bradwell KR, Harris NL,      Casiraghi E, Valentini G, Karlebach G, Deer R, McMurry JA, Haendel MA, Chute CG, Pfaff E, Moffitt R, Spratt H, Singh J, Mungall CJ, Williams AE, Robinson PN. NSAID use and clinical outcomes in COVID-19 patients: A 38-center retrospective cohort study. medRxiv [Preprint]. 2021 Dec 22:2021.04.13.21255438. doi: 10.1101/2021.04.13.21255438

5)     Galluzzo V, Zazzara MB, Ciciarello F, Tosato M, Bizzarro A, Paglionico A, Varriano V, Gremese E, Calvani R, Landi F on behalf of Gemelli against COVID-19 Post-Acute Care Team. Use of First-Line Oral Analgesics during and after COVID-19: Results from a Survey on a Sample of Italian 696 COVID-19 Survivors with Post-Acute SymptomsJ Clin Med. 2023; 12(8):2992.

6)    Arca KN, Smith JH, Chiang CC, Starling AJ, Robertson CE, Halker Singh RB, Schwedt TJ, Kissoon NR, Garza I, Rozen TD, Boes CJ, Whealy MA, VanderPluym JH. COVID-19 and Headache Medicine: A Narrative Review of Non-Steroidal Anti-Inflammatory Drug (NSAID) and Corticosteroid Use. Headache. 2020 Sep;60(8):1558-1568. doi: 10.1111/head.13903

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