Tag: anti-inflammatories

Use of 1-MNA to Improve Exercise Tolerance and Fatigue in Patients after COVID-19

Abstract:

COVID-19 is not only a short-term infection, as patients (pts) recovering from SARS-CoV-2 infection complain of persisting symptoms, which may lead to chronic fatigue syndrome. There is currently no evidence that nutritional supplements can assist in the recovery of pts with chronic fatigue syndrome. 1-Methylnicotinamide (1-MNA) is an endogenic substance that is produced in the liver when nicotinic acid is metabolized. 1-MNA demonstrates anti-inflammatory and anti-thrombotic properties. Therefore, we investigated whether 1-MNA supplements could improve exercise tolerance and decrease fatigue among patients recovering from SARS-CoV-2.

Methods: The study population was composed of 50 pts who had recovered from symptomatic COVID-19. The selected pts were randomized into two groups: Gr 1 (NO-1-MNA)-without supplementation; Gr 2 (1-MNA) with 1-MNA supplementation. At the beginning of the study (Phase 0), in both groups, a 6-minute walk test (6MWT) was carried out and fatigue assessment was performed using the Fatigue Severity Scale (FSS). Both FSS and 6MWT were repeated after 1 month.

Results: A significant improvement in the mean distance covered in the 6MWT was noted at follow-up in Gr 1-MNA, compared with Gr NO-1-MNA. We also noted that in Gr 1-MNA, the 6MWT distance was significantly higher after 1 month of supplementation with 1-MNA, compared with the beginning of the study (515.18 m in Phase 0 vs. 557.8 m in Phase 1; p = 0.000034). In Gr 1-MNA, significantly more pts improved their distance in the 6MWT (23 out of 25 pts, equal to 92%), by a mean of 47 m, compared with Gr NO-1-MNA (15 of 25 pts, equal to 60%) (p = 0.0061). After one month, significantly more patients in the group without 1-MNA had severe fatigue (FSS ≥ 4) compared with the group with supplementation (Gr 1-MNA = 5 pts (20%) vs. Gr NO-1-MNA = 14pts (56%); p = 0.008).

Conclusions: 1-MNA supplementation significantly improved physical performance in a 6-min walk test and reduced the percentage of patients with severe fatigue after COVID-19. The comprehensive action of 1-MNA, including anti-inflammatory and anticoagulant effects, may be beneficial for the recovery of patients with persistent symptoms of fatigue and low tolerance to exercise after COVID-19.

Source: Chudzik M, Burzyńska M, Kapusta J. Use of 1-MNA to Improve Exercise Tolerance and Fatigue in Patients after COVID-19. Nutrients. 2022 Jul 22;14(15):3004. doi: 10.3390/nu14153004. PMID: 35893858.  https://www.mdpi.com/2072-6643/14/15/3004/htm (Full text)

The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study

Abstract:

COVID-19 can cause symptoms that last weeks or months after the infection has gone, with a significant impairment of quality of life. Palmitoylethanolamide (PEA) is a naturally occurring lipid mediator that has an entourage effect on the endocannabinoid system mitigating the cytokine storm. The aim of this retrospective study is to evaluate the potential efficacy of PEA in the treatment of long COVID.
Patients attending the Neurological Out Clinic of the IRCCS Centro Neurolesi Bonino-Pulejo (Messina, Italy) from August 2020 to September 2021 were screened for potential inclusion in the study. We included only long COVID patients who were treated with PEA 600 mg two times daily for about 3 months. All patients performed the post-COVID-19 Functional Status (PCFS) scale. Thirty-three patients (10 males, 43.5%, mean age 47.8 ± 12.4) were enrolled in the study. Patients were divided into two groups based on hospitalization or home care observation. A substantial difference in the PCFS score between the two groups at baseline and after treatment with PEA were found. We found that smoking was a risk factor with an odds ratio of 8.13 CI 95% [0.233, 1.167]. Our findings encourage the use of PEA as a potentially effective therapy in patients with long COVID.
Source: Raciti L, De Luca R, Raciti G, Arcadi FA, Calabrò RS. The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study. Medical Sciences. 2022; 10(3):37. https://doi.org/10.3390/medsci10030037  https://www.mdpi.com/2076-3271/10/3/37/htm (Full text)

Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study

Abstract:

Despite the increasing prevalence of patients with Long Covid Syndrome (LCS), to date the pathophysiology of the disease is still unclear, and therefore diagnosis and therapy are a complex effort without any standardization. To address these issues, we performed a broad exploratory screening study applying state-of-the-art post-genomic profiling methods to blood plasma derived from three groups: 1) healthy individuals vaccinated against SARS-CoV-2 without exposure to the full virus, 2) asymptomatic fully recovered patients at least three months after SARS-CoV-2 infection, 3) symptomatic patients at least 3 months after a SARS-CoV-2 infection, here designated as Long Covid Syndrome (LCS) patients.

Multiplex cytokine profiling indicated slightly elevated cytokine levels in recovered individuals in contrast to LCS patients, who displayed lowest levels of cytokines. Label-free proteome profiling corroborated an anti-inflammatory status in LCS characterized by low acute phase protein levels and a uniform down-regulation of macrophage-derived secreted proteins, a pattern also characteristic for chronic fatigue syndrome (CFS).

Along those lines, eicosanoid and docosanoid analysis revealed high levels of omega-3 fatty acids and a prevalence of anti-inflammatory oxylipins in LCS patients compared to the other study groups. Targeted metabolic profiling indicated low amino acid and triglyceride levels and deregulated acylcarnithines, characteristic for CFS and indicating mitochondrial stress in LCS patients. The anti-inflammatory osmolytes taurine and hypaphorine were significantly up-regulated in LCS patients.

In summary, here we present evidence for a specific anti-inflammatory and highly characteristic metabolic signature in LCS which could serve for future diagnostic purposes and help to establish rational therapeutic interventions in these patients.

Source: Johannes J Kovarik, Andrea Bileck, Gerhard Hagn, Samuel M Meier Menches, Tobias Frey, Anna Kaempf, Marlene Hollenstein, Tarik Shoumariyeh, Lukas Skos, Birgit Reiter, Marlene C Gerner, Andreas Spannbauer, Ena Hasimbegovic, Doreen Schmidl, Gerhard Garhoefer, Mariann Gyoengyoesi, Klaus G Schmetterer, Christopher Gerner. Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study. medRxiv 2022.07.11.22277499; doi: https://doi.org/10.1101/2022.07.11.22277499 (Full study available as PDF file)

Comments to “Fluvoxamine and long COVID-19: a new role for sigma-1 receptor (S1R) agonists” by Khani and Entezari-Maleki

To the Editor:

The coronavirus disease 2019 (COVID-19) pandemic causes short-term and long-term health problems in survivors after infection of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2). A recent systematic review using 57 studies with 250,351 survivors of COVID-19 shows that the median proportion of COVID-19 survivors experiencing at least 1 PASC (post-acute sequelae of COVID-19) was 54% at 1 month (short-term), 55% at 2–5 months (intermediate-term), and 54% at 6 or more months (long-term) [1]. The most common sequelae involved neurologic symptoms (i.e., headaches, memory deficits, difficulty concentrating, cognitive impairment), psychiatric symptoms (i.e., depression, anxiety, sleep disorders), pulmonary abnormalities (i.e., dyspnea, cough, increased oxygen requirement, pulmonary diffusion abnormalities, chest imaging abnormalities), and functional mobility impairment (i.e., impairment in general functioning, mobility decline, reduced exercise tolerance). However, there are no therapeutic drugs for long-term symptoms in survivors of COVID-19.

The precise mechanisms underlying SARS-CoV-2 induced long-term detrimental effects remain unclear. Infection of SARS-CoV-2 can damage endothelial cells leading to inflammation, thrombi and brain damage. SARS-CoV-2-associated systemic inflammation leads to decreased monoamines and neurotrophic factors, and microglial activation in the brain, resulting in long-term neurological and psychiatric symptoms in COVID-19 survivors [2]. A retrospective study of Wuhan University (Wuhan, China) reported that patients with Epstein-Barr virus (EBV)/SARS-CoV-2 coinfection have about 3-fold risk of having a fever symptom than patients with SARS-CoV-2 infection alone, and that levels of C-reactive protein and aspartate aminotransferase in patients with EBV/SARS-CoV-2 coinfection were higher than those in patients with SARS-CoV-2 infection alone [3]. This report suggests that EBV reactivation may be associated with the severity of clinical symptoms after SARS-CoV-2 infection.

Interestingly, approximately 67% of patients (20/30) with long-term sequelae of COVID-19 were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse IgG or EBV viral capsid antigen IgM [4]. Thus, EBV reactivation may play a role in long-term symptoms in COVID-19 survivors although further study using a large sample size is needed. The authors suggest that most of long-lasting symptoms in COVID-19 survivors following the recovery from SARS-CoV-2 infection might not be directly affected by the virus but probably result from SARS-CoV-2-associated inflammation and EBV reactivation [4].

In the issue, Khani and Entezari-Maleki proposed that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), may be a new therapeutic drug for long-term consequences of COVID-19 survivors [5]. Fluvoxamine has been demonstrated to prevent clinical deterioration in early-stage subjects with COVID-19 [6]. In addition of serotonin transporter inhibition, sigma-1 receptor chaperone in the endoplasmic reticulum (ER) and acid sphingomyelinase might play a role in the mechanisms of beneficial action of fluvoxamine for patients with SARS-CoV-2 infection [6,7,8]. It is also reported that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory actions by the prevention of inositol requiring enzyme 1α (IRE1) and X-box binding protein-1 (XBP-1) pathway [9]. Collectively, it is likely that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory effects through sigma-1 receptor/IRE1/XBP-1 pathway in the ER [6,7,8,9].

Among the SSRIs, fluvoxamine was the most potent at sigma-1 receptor in the brain [6,7,8]. Given the link between EBV reactivation and XBP-1 [10], it is possible that the potent sigma-1 receptor agonist fluvoxamine may have beneficial effects for long-term consequences in COVID-19 survivors through sigma-1 receptor/IRE1/XBP-1 pathway [4]. Therefore, it is of great interest to examine whether fluvoxamine can improve long-term sequelae in COVID-19 survivors.

Source: Hashimoto Y, Suzuki T, Hashimoto K. Comments to “Fluvoxamine and long COVID-19: a new role for sigma-1 receptor (S1R) agonists” by Khani and Entezari-Maleki. Mol Psychiatry. 2022 Apr 6:1–2. doi: 10.1038/s41380-022-01546-2. Epub ahead of print. PMID: 35388183; PMCID: PMC8985059. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985059/ (Full text)

The use of amantadine in the prevention of progression and treatment of COVID-19 symptoms in patients infected with the SARS-CoV-2 virus (COV-PREVENT): Study rationale and design

Abstract:

Background: COVID-19, a disease caused by infection with the SARS-CoV-2 virus, is asymptomatic or mildly symptomatic in most cases. Some patients, usually burdened with risk factors develop acute respiratory failure and other organ dysfunction. In such cases, the mortality rate is very high despite the use of intensive therapy. Amantadine has complex activity including antiviral, antiinflammatory and dopaminergic effects. This clinical trial will assess the efficacy and safety of amantadine in the prevention of COVID-19 progression toward acute respiratory failure and neurological complications.

Methods and results: The trial will enroll 200 patients who are positive for SARS-CoV-2 infection and have one or more risk factors for worsening the disease. These patients will be included as hospitalized or ambulatory subjects for early treatment of illness. The recruitment will take place in 8 centers covering different regions of Poland. For 14 days they will be given either 200 mg of amantadine a day or placebo. Our hypothesis is a considerable reduction in the number of patients with progression toward respiratory insufficiency or neurological complications thanks to the treatment of amantadine.

Conclusions: Demonstrating the efficacy and safety of amantadine treatment in improving the clinical condition of patients diagnosed with COVID-19 is of great importance in combating the effects of the pandemic. It has potential to influence on the severity and course of neurological complications, which are very common and persist long after the infection as long-COVID syndrome.

Clinical trial registration: www.

Clinicaltrials: gov identification no. NCT04854759; Eudra CT number: 2021-001144-98 (dated 27 February 2021).

Source: Rejdak K, Fiedor P, Bonek R, Goch A, Gala-Błądzińska A, Chełstowski W, Łukasiak J, Kiciak S, Dąbrowski P, Dec M, Król ZJ, Papuć E, Zasybska A, Segiet A, Grieb P. The use of amantadine in the prevention of progression and treatment of COVID-19 symptoms in patients infected with the SARS-CoV-2 virus (COV-PREVENT): Study rationale and design. Contemp Clin Trials. 2022 Apr 4;116:106755. doi: 10.1016/j.cct.2022.106755. Epub ahead of print. PMID: 35390511; PMCID: PMC8978450. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978450/ (Full text)

Does Dietary Coenzyme Q10 plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neuroinflammatory, multifaceted chronic disorder of unknown cause. Accumulating data indicates a link between a redox imbalance, mitochondrial dysfunction, and inflammation status in ME/CFS. CoQ10 and selenium as effective antioxidant and anti-inflammatory agents have shown potential clinical implications in chronic diseases; however, their therapeutic benefits on ME/CFS remain elusive.

This open-label exploratory study aimed to evaluate the effectiveness of combined CoQ10 plus selenium supplementation on clinical features and circulating biomarkers in ME/CFS. Twenty-seven ME/CFS patients received an oral combination of 400 mg of CoQ10 and 200 µg of selenium daily for 8-weeks. The primary endpoint was patient-reported changes in outcome measures from baseline to 8 weeks post-intervention.

Secondary endpoint included changes in circulating biomarkers from baseline to each participant. After an 8-week intervention, a significant improvement was found for overall fatigue severity (p = 0.021) and global quality of life (p = 0.002), while there was no significant effect on the sleep disturbances (p = 0.480) among participants. After 8-weeks’ intervention, there was significantly increased total antioxidant capacity, and there were reduced lipoperoxides levels from the participants (p < 0.0001 for both). Circulating cytokine levels decreased significantly (p < 0.01 for all), but with no significant changes on the CRP, FGF21, and NT-proBNP biomarkers after supplementation.

Based on these findings, we hypothesized that long-term supplementation of combined CoQ10 and selenium may indicate a potentially beneficial synergistic effect in ME/CFS.

Source: Castro-Marrero J, Domingo JC, Cordobilla B, Ferrer R, Giralt M, Sanmartin-Sentañes R, Alegre-Martin J. Does Dietary Coenzyme Q10 plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Antioxid Redox Signal. 2022 Mar 1. doi: 10.1089/ars.2022.0018. Epub ahead of print. PMID: 35229657. https://pubmed.ncbi.nlm.nih.gov/35229657/

Levocetirizine and montelukast in the COVID-19 treatment paradigm

Abstract:

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of ‘Long COVID,’ thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March – November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed.

Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.

Source: May BC, Gallivan KH. Levocetirizine and montelukast in the COVID-19 treatment paradigm. Int Immunopharmacol. 2021 Dec 15;103:108412. doi: 10.1016/j.intimp.2021.108412. Epub ahead of print. PMID: 34942461; PMCID: PMC8673734. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673734/ (Full text)

Improvement Effects of Myelophil on Symptoms of Chronic Fatigue Syndrome in a Reserpine-Induced Mouse Model

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with various symptoms, such as depression, pain, and fatigue. To date, the pathological mechanisms and therapeutics remain uncertain. The purpose of this study was to investigate the effect of myelophil (MYP), composed of Astragali Radix and Salviaemiltiorrhizae Radix, on depression, pain, and fatigue behaviors and its underlying mechanisms.

Reserpine (2 mg/kg for 10 days, intraperitoneally) induced depression, pain, and fatigue behaviors in mice. MYP treatment (100 mg/kg for 10 days, intragastrically) significantly improved depression behaviors, mechanical and thermal hypersensitivity, and fatigue behavior. MYP treatment regulated the expression of c-Fos, 5-HT1A/B receptors, and transforming growth factor β (TGF-β) in the brain, especially in the motor cortex, hippocampus, and nucleus of the solitary tract. MYP treatment decreased ionized calcium binding adapter molecule 1 (Iba1) expression in the hippocampus and increased tyrosine hydroxylase (TH) expression and the levels of dopamine and serotonin in the striatum. MYP treatment altered inflammatory and anti-oxidative-related mRNA expression in the spleen and liver.

In conclusion, MYP was effective in recovering major symptoms of ME/CFS and was associated with the regulation of dopaminergic and serotonergic pathways and TGF-β expression in the brain, as well as anti-inflammatory and anti-oxidant mechanisms in internal organs.

Source: Song JH, Won SK, Eom GH, Lee DS, Park BJ, Lee JS, Son CG, Park JY. Improvement Effects of Myelophil on Symptoms of Chronic Fatigue Syndrome in a Reserpine-Induced Mouse Model. Int J Mol Sci. 2021 Sep 22;22(19):10199. doi: 10.3390/ijms221910199. PMID: 34638540. https://pubmed.ncbi.nlm.nih.gov/34638540/

α-1 antitrypsin and chronic fatigue syndrome: a case study from pathophysiology to clinical practice

Abstract:

SUMMARY

BACKGROUND: Several lines of evidence support the involvement of inflammatory and immunologic abnormalities in chronic fatigue syndrome (CFS). Since recent studies have shown that α-1 antitrypsin (AAT) possesses anti-inflammatory properties, the potential therapeutic effect of AAT treatment on CFS has been investigated.

CASE PRESENTATION: A 49-year-old woman diagnosed with CFS was treated with intravenous infusions of a human plasma-derived AAT concentrate (60 mg/kg body weight weekly for 8 consecutive weeks). The patient’s monocyte elastase, a regulator of inflammatory processes, was 1170 U/mg. At completion of treatment, improvement in maximal workload was observed (54.0-71.7% of predicted). Additionally, amelioration in working memory (scores: 83-94) and perceptual organization (scores: 75-83) were detected on the Wechsler Adult Intelligence Scale-III test. Monocyte elastase decreased to a normal range (<150 U/mg). Improvement in functional capacity allowed the patient to work in part-time employment.

CONCLUSION: These findings suggest a possible role for AAT in the treatment of CFS.

 

Source: Alegre J, Camprubí S, García-Quintana A. α-1 antitrypsin and chronic fatigue syndrome: a case study from pathophysiology to clinical practice.Pain Manag. 2013 Mar;3(2):119-22. doi: 10.2217/pmt.12.84. https://www.ncbi.nlm.nih.gov/pubmed/24645995