Palmitoylethanolamide and Alpha-Lipoic Acid. Potential intervention for novel Covid-19 infection

Abel O. Sánchez MD¹, José M. Castellano MD, PhD², Guillermo Pérez Mendoza MD³

¹Physical Medicine and Rehabilitation Department, Insular University Hospital of Gran Canaria; ²Oral and Maxillofacial Surgery Department, Insular University Hospital of Gran Canaria; ³Pneumology Department, University Hospital of Gran Canaria Dr. Negrín. Las Palmas de Gran Canaria University, Spain.

Correspondence:

Abel Sánchez Fernández

Hospital Universitario Insular de Gran Canaria.

Avenida Marítima del Sur s/n, 35016, Las Palmas de Gran Canaria. España Telephone: +34 669604145

Fax: +34 928444101

E-mail: abelspin@gmail.com

ABSTRACT

Objective: The aim of this review was to evaluate the hypothesis that Palmitoylethanolamide and Alpha-Lipoic Acid could be considered as adjunctive therapy for prevention and treatment of viral respiratory infections, and also for Covid- 19.

Methods: To prove our hypothesis we have done an online search on PubMed with the keywords of Palmitoylethanolamide, Alpha-Lipoic acid, Influenza, Respiratory Infections, Covid-19 and Coronavirus.

Results: Palmitoylethanolamide has shown to be effective and safe in prevention ofviral respiratory infections. Palmitoylethanolamide also reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis.

Alpha-Lipoic acid could attenuate the increased susceptibility to human coronavirus infections. It might be expected to help prevent and control RNA virus infections.

They are generally well tolerated and serious adverse effects were not found in research populations.

Conclusions: Palmitoylethanolamide and Alpha-Lipoic Acid could be a safe andreliable treatment for viral respiratory infections and also for novel Covid-19. Preliminary suggestions for the daily dose that might be expected to be worthwhile for prevention and treatment of RNA virus infections are 600-1800 mg of Palmitoylethanolamide, and 600 mg of Alpha-Lipoic Acid.

Well-designed, randomized and placebo-controlled trials are needed to provide reliable estimates of its efficacy and is the successor work to our research.

Keywords: Palmitoylethanolamide. Alpha-Lipoic Acid. Influenza. Respiratory infections. Covid-19.

INTRODUCTION

Palmitoylethanolamide (PEA) belongs to the family of N-acylethanolamines (NAEs), endogenous biologically active lipids including the endogenous cannabinoid receptor ligand anandamide and the satiety factor oleoylethanolamide. It was identified in the 1950s as being an active anti-inflammatory agent in chicken egg yolk¹. Levi- Montalcini and her group discovered in 1993 PEA as a natural modulator of hyperactive mast cells, counteracting the pro-inflammatory actions of Nerve growth factor (NGF).

In the period 1970-1980 its safety and efficacy has been explored and documented in 6 double blind clinical trials in flu and respiratory infections in around 4000 patients². Several studies indicate that free PEA levels increase during inflammation. Concentrations of PEA in tissues and plasma have been published in various papers^3,4. Its inhibitory action on tumor necrosis factor (TNF)-𝛼 secretion is sufficiently documented⁵.

PEA was shown to significantly attenuate the degree of intestinal injury and inflammation and to inhibit proinflammatory cytokine production (TNF-𝛼, IL-1𝛽), adhesion molecules (ICAM-1, P-selectin) expression, and Nuclear factor- 𝜅B (NF-𝜅B) expression⁶. PEA also significantly decreases inflammation caused by ischemia- reperfusion injury, a pathological state characterized by a strong enhanced interleukin- cascade⁷.

Since 2008, PEA has been marketed as a food for special medical purposes in Italy and Spain and more recently introduced as food supplement in the United States.

Alpha-Lipoic acid (ALA) naturally exists in both animal and plant cells as a cofactor for mitochondrial alphaketo-dehydrogenase complex. Readily it is taken up by various cells, and transformed into a potent metabolic thiol antioxidant in mitochondria⁸. ALA is commercially available in Europe and the United States and has been suggested to have therapeutic value in pathologies associated with redox imbalances, such as diabetic and ischemia-reperfusion injury^9,10. In addition, ALA is shown to inhibit matrix metalloproteinases and disease activity by preventing the action of nuclear factor-κB (NF-κB) rather than by acting as an antioxidant in experimental autoimmune encephalitis¹¹. Alpha-Lipoic Acid affects signal transduction events and gene expression through redox-sensitive signaling pathways and transcription factors, under both normal and abnormal conditions^12,13. ALA also has the capability to enhance intracellular glutathione (GSH) levels¹⁴ and to normalize the oxidative stress induced by Dexamethasone¹⁵.

Infections with virulent influenza viruses together with an aberrant and excessive cytokine production are linked to increased morbidity and mortality. Furthermore, the impact of regulatory cytokines elevated in severe disease interleukin (IL)-10, IL-13 on the evolution of host immune responses to nvH1N1 infections may represent alternative therapeutics for controlling severe illness¹⁶.

Increased production of specific inflammatory cytokines, such as the tumor necrosis factor (TNF)-𝛼, IL-1, IL-6, and IL-10, is characteristic during an influenza infection. Viral RNA and a number of viral proteins with an intracellular location interfere with cellular signal transduction and transcription factor activity, thus promoting viral replication and expression of proinflammatory proteins¹⁷.

More virulent viruses are also associated with rapid and sustained induction of inflammatory cytokines and such an early dysregulation of the host response is seen as contributing to the severity and outcome of the infection^18,19.

The increased production of proinflammatory cytokines, hypercytokinemia, is thus a clear player in the disease progression and death of patients infected by influenza viruses^20,21.

SARS-CoV-2 induces excessive and prolonged cytokine/chemokine responses in some infected individuals, known as the cytokine storm. Cytokine storm causes Acute Respiratory Distress Syndrome or multiple organ dysfunction, which leads to physiological deterioration and death. Timely control of the cytokine storm in its early stage, as well as the reduction of lung inflammatory cell infiltration, is the key to improving the treatment success rate and reducing the mortality rate of patients with COVID-19²².

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first identified in Wuhan, China is responsible for the coronavirus disease outbreak of 2019 COVID-19, now declared a pandemic by the World Health Organization as of March of 2020. Among the CoV's known to cause human disease, the three most highly pathogenic of the group include the SARS coronavirus (SARS-CoV now named SARS-CoV-1), the Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) and SARS- CoV-2, the agent of COVID-19, identified in patients with severe pneumonia in Wuhan, China.

Although exposure to COVID-19 is asymptomatic or mild in most affected of younger age, those at highest risk for fulminant disease have been identified as having certain risk factors²³.

More than 1,2 million people have died worldwide in the COVID-19 pandemic as of November 7, 2020 according to recent data from Johns Hopkins University. Almost 50 million people worldwide have been infected with global mortality rates over time leveling off to a rate of 2.5% converging with current World Health Organization (WHO) estimates.

METHODS

We have done an online search on PubMed with the keywords of Palmitoylethanolamide, Alpha-Lipoic acid, Influenza, Respiratory Infections, Covid-19 and Coronavirus.

Hand searches of multiple reviews and clinical studies were made for completeness.

RESULTS

Palmitoylethanolamide Research

Keppel et al²⁴ reviewed the role of PEA as anti-inflammatory and therapeutic agent for influenza and the common cold and discussed 6 clinical trials in a total of nearly 4000 patients and volunteers where PEA's effectiveness and safety for the treatment in these indications was shown. They concluded that PEA should be reconsidered by clinicians as a new treatment modality for the flu and respiratory infections due to its documented efficacy and more importantly its very benign side effect profile. Finally, they reported that the ease of application of PEA offers the possibility to have a quick therapeutic answer ready in case of a flu epidemic, especially in cases of a mismatch between circulating strains and the recommendations from WHO²⁴.

Davis et al²⁵ reported in their systematic review that PEA has demonstrated significant analgesic benefits with very few adverse effects. Initial interests in PEA were related to influenza A and the management of Rheumatic fever, which have largely been ignored over the past 3 decades. What is fairly remarkable is PEA safety in both animal studies and clinically. No drug interactions were reported²⁵.

Esposito et Cuzzocrea²⁶ reported that PEA has been shown to inhibit peripheral inflammation and mast-cell degranulation, as well as to exert neuroprotective and antinociceptive effects in rats and mice. Recent data have demonstrated that PEA may play a key role in the regulation of complex systems involved in the inflammatory response, pruritus, neurogenic and neuropathic pain. They finally concluded that PEA could be a novel treatment for several inflammatory diseases and trauma. It is important to note that PEA lacks both acute and chronic toxicity, and is not associated with gastric mucosal lesions²⁶.

Masek et al²⁷ conducted two large scale, double-blind field trials to test the efficacy of Impulsin (N-2-hydroxyethyl palmitamide) in reducing the incidence and severity of respiratory tract infections in soldiers. The results suggested that repeated daily intake of Impulsin 30 mg per kg helped to prevent viral respiratory tract infections, since it produced a statistically significant reduction in the incidence of illness. Prophylactic treatment with Impulsin markedly diminished the number of episodes of fever, headache and sore throat, while catarrhal symptoms were much less affected^24,27.

Ameli et al²⁸ reported that modulating of the inmune system may have a critical role in prevention of recurrent respiratory infections (RRI). Sinerga, a dietary supplement (containing: palmitoylethanolamide, Kluyveromyces marxianus B0399, bovine colostrum, and phenylalanine), significantly reduced the number of respiratory infection in allergic children with RRI²⁸.

Nigro et al²⁹ reported that PEA can be effective in RRI. In their retrospective observational clinical study, 167 children, aged 3 to 7 years, of both sexes, with a clinical history of recurrent respiratory infections (RRI), administered with bacterial extracts of first and second generation or Sinerga were observed. The goal of the study was to observe the effect on the frequency of episodes of respiratory infection that had resulted in a prescription for antibiotics. The results showed a greater reduction in the frequency of respiratory infections with antibiotic therapy in the group of children supplemented with Sinerga than in the group treated with bacterial extracts²⁹.

Di Paola et al³⁰ examined the effects of Palmitoylethanolamide in mice subjected to idiopathic pulmonary fibrosis, induced by a single intratracheal administration of saline with bleomycin sulphate. Compared to bleomycin-treated mice, animals that received also PEA had significantly decreased weight loss, mortality, inflammation, lung damage at the histological level, and lung fibrosis at 7 and 21 days. This study demonstrated that PEA (3 and 10mg/kg) reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis³⁰

Gigante et al³¹ reported that Sodium Chromo-Gycate (SCG) and/or PEA suppress MC activation and pro-inflammatory mediators release, playing an anti-inflammatory therapeutic role in the inflamed lung of patients with COVID-19³¹.

Paladini et al³² reported that among innovative therapies for treating chronic pain, PEA seems to come to the forefront owing to its high efficacy/risk ratio and lack of both tolerance induction and interference with other potential therapies for pain and/or co- morbid conditions³².

Artukoglu et al³³ meta-analysis provided preliminary evidence that PEA may be a useful treatment for pain and is generally well tolerated. PEA represents a potentially promising treatment for pain that may offer several advantages over currently available treatments³³.

Kepple³⁴ reported that recommended starting treatment dose for pain is: twice daily 600 mg PEA, 10 days or, in the case of central neuropathic pain 20-30 days. After the initial loading dose phase, if pain is reduced at least 30-50%, a lower dose can be selected. He also concluded that, consistently, the effective dose range has been between 10 and 30mg PEA/kg body weight without relevant side effects³⁴.

Alpha-Lipoic acid Research

Zhang et al³⁵ reported that Reactive oxygen species (ROS) play a crucial role in the inflammatory response and cytokine outbreak, such as during virus infections, diabetes, cancer, cardiovascular diseases, and neurodegenerative diseases. Therefore, antioxidant is an important medicine to ROS-related diseases. They compared and analyzed all kinds of mitochondrion-permeable antioxidants, including alfa-lipoic acid. They concluded that, antioxidant drugs should be used carefully for chronic diseases, especially for diabetes and Alzheimer's disease, when a certain level of ROS is required for normally cellular functions. However, for ROS-burst-mediated acute diseases, mitochondrion-permeable antioxidants should be used in the early stage³⁵. In their previous review of treatment for avian influenza infection, a large drug combination (including antioxidants, protectant of mitochondrial membrane permeability, immunomodulators, protease inhibitors, and antiviral drugs) was proposed, which mainly focused on cytokine control. Antioxidant was the most important medicine suggested. They also reported that neutrophil aggregation and oxidative-damage to alveolar epithelial membrane result in acute respiratory distress syndrome (ARDS) finally³⁶.

Erol et al³⁷ concluded in their study that Antioxidant vitamins, such as ALA, vit E and vit C, may be useful for premedication of Acute Respiratory Distress Syndrome (ARDS) and similar disorders. They also reported that reactive oxygen species (ROS) play a key role in acute respiratory distress syndrome pathophysiology and constitute the base of damage process³⁷.

Wu et al³⁸ demonstrated that oxidative stress increases susceptibility of glucose-6- phosphate-dehydrogenase (G6PD) deficient cells to viral infection and is ameliorated by antioxidant agents, such as lipoic acid. These data provide further evidence that host redox status is important in viral infectivity. Increased viral infection in G6PD- deficient cells may be partly attributable to increased viral receptors in these cells or increased production of viral particles. Moreover, this finding also suggests that antioxidant treatment may protect G6PDdeficient subjects from viral infection³⁸.

Hummel et al³⁹ unblinded, prospective clinical trial concluded that alpha lipoic acid may be helpful in patients with olfactory loss after upper respiratory tract infection. They studied a total of 23 patients (13 women, 10 men). Alpha-lipoic acid was used orally at a dose of 600 mg/day and it was prescribed for an average period of 4.5 months. Possible mechanisms of actions included the release of nerve growth factor and antioxidative effects³⁹.

Horowitz et al²³ concluded that Oral and IV glutathione, glutathione precursors (N- acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking nuclear factor-κB and addressing "cytokine storm syndrome" and respiratory distress in patients with COVID-19 pneumonia. NF-κ has been shown to be required for transcription of the genes for many of the pro-inflammatory mediators associated with Acute Respiratory Distress Syndrome. An intact inflammatory response, in which NF-κB plays a major role, is also required for appropriate host defense against viruses and in the later stages of bacterial pneumonia. In preclinical models of sepsis and acute lung injury, associated with rapid and large increases in pro-inflammatory cytokines and other mediators, suppression of NF-κB activation has been shown to result in improved survival. N-acetyl-cysteine, Alpha-lipoic acid and glutathione all inhibit TNF-α-induced NF-kappa activation²³.

Bai et al⁴⁰ demonstrated that ALA is an attractive therapeutic agent candidate for influenza A virus inhibiting its spread in vitro through a mechanism that blocking p65 translocation, up modulating of Interferon-α and reducing apoptosis⁴⁰.

McCarty et al⁴¹ concluded in his recent review that Alpha-Lipoic acid might be expected to help prevent and control RNA virus infections by amplifying the signaling functions of Toll like receptor 7 (TLR7) and mitochondrial antiviral-signaling protein (MAVS) in evoking type 1 interferon production⁴¹.

Saboori et al⁴² meta-analysis showed that Alpha-lipoic acid supplementation could significantly decrease C-Reactive Protein level in patients with elevated levels of this inflammatory marker⁴².

Koh EH et al⁴³ did not find major side effect in their study of 360 subjects with Alpha-lipoic acid at a dosage of 1800 mg/d. Itching sensation or urticaria was the most common adverse event. Overall, the percentage of subjects with at least 1 adverse event during the treatment did not differ among the 1200 and 1800 mg/d alpha-lipoic acid groups and placebo group (24, 24, and 20%, respectively). Severe unexpected adverse events were not observed, as determined by physical examination, clinical laboratory tests, and electrocardiograms. No deaths occurred during this study⁴³.

Cremer et al⁴⁴ reported that administration of 31.6 or 61.9mg ALA/kg body weight (bw)/day for 4 weeks to male/female Wistar rats did not show any adverse effects. Only the high-dose of 121mg ALA/kg bw was associated with slight alterations in liver enzymes as well as histopathological effects on the liver and mammary gland. The results of these studies support the safety of ALA. The no-observed-adverse-effect level is considered to be 61.9mg/kg bw/day⁴⁴.

Teicher et al⁴⁵ concluded that the pharmacokinetics of alpha-lipoic acid are not influenced by creatinine clearance and are unaffected in subjects with severely reduced kidney function or end-stage renal disease. Hemodialysis did not significantly contribute to the clearance of alpha-lipoic acid. Hence, dose adjustment of alpha-lipoic acid is not necessary in patients with renal dysfunction⁴⁵.

DISCUSSION

We have used Palmitoylethanolamide and Alpha-Lipoic Acid to treat neuropathic pain for years with very good results and no serious adverse events have been reported. We generally recommend 600-1200mg of PEA and 400-600mg of ALA per day.

It has been published in various papers that overactive and no functional hyper induction of proinflammatory cytokines might play a key role in the symptomatology and may lead to increased morbidity and mortality in RNA virus infections^16-19.

It has been also published that SARS-CoV-2 induces a cytokine storm in some infected individuals and causes Acute Respiratory Distress Syndrome or multiple organ dysfunction, which leads to physiological deterioration and death. Timely control of the cytokine storm in its early stage is the key to improving the treatment success rate and reducing the mortality rate of patients with COVID-19²².

Palmitoylethanolamide is widely known for its anti-inflammatory activity. Studies suggests that it could helped to prevent viral respiratory tract infections^27-29.

Alpha-lipoic acid has demonstrated to be an attractive candidate for influenza A virus and might be expected to help prevent and control RNA virus infections as host redox status is important in viral infectivity⁴¹. ALA may also represent a novel treatment approach for blocking NF-κB and addressing "cytokine storm syndrome" and respiratory distress in patients with COVID-19 pneumonia²³.

Based on data known to date, we hypothesize that PEA and ALA combination could be a safe and reliable therapy for COVID-19 infection.

CONCLUSIONS

Palmitoylethanolamide and Alpha-Lipoic Acid could be a safe and reliable treatment for viral respiratory infections and also for novel Covid-19.

Preliminary suggestions for the daily dose that might be expected to be worthwhile for prevention and treatment of Covid-19 infections are 600-1800 mg of PEA, and 600 mg of ALA.

Well-designed, randomized and placebo-controlled trials are needed to provide reliable estimates of its efficacy and is the successor work to our research.

CONFLICT OF INTEREST STATEMENT

This manuscript was prepared in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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