Compositions containing creatine for use in treating post-viral fatigue syndrome

Abstract

The present invention relates to a pharmaceutical composition comprising creatine or a physiologically acceptable derivative thereof and / or a salt thereof and / or an adduct thereof for use in the treatment of PVFS, in particular PVFS accompanied by mental fatigue, decreased motivation, decreased activity or decreased concentration.A further embodiment of the present invention relates to the use of a composition comprising creatine or a physiologically acceptable derivative thereof and / or a salt thereof and / or an adduct thereof as a dietary supplement for the preparation of a food that supports recovery from PVFS.

Description

[Technical Field]

[0001] Technical fields: The present invention relates to a pharmaceutical composition comprising creatine for use in a subject in need of treatment for post-viral fatigue syndrome (PVFS) caused by a viral infection of the lungs or lower respiratory tract. A further object of the present invention is the use of creatine or a creatine derivative as a dietary supplement for preparing a diet for a patient suffering from PVFS. [Background technology]

[0002] Description of the Prior Art: Although COVID-19 is considered primarily a lung disease, it can also harm other organs, such as the heart, vasculature, kidneys, and brain. Organ damage increases the risk of sequelae such as cognitive impairment, cardiac complications (myocarditis), chronic kidney damage, stroke, thrombosis, and Guillain-Barré syndrome.

[0003] Most people infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) recover within a few weeks, but some people with mild illness continue to experience a range of symptoms after their initial recovery.

[0004] Typical symptoms that persist after SARS-CoV-2 infection include fatigue (e.g., postviral fatigue syndrome (PVFS) and chronic fatigue syndrome (CFS)), breathing problems or shortness of breath (dyspnea), lung or chest pain, joint pain, muscle pain or headache, difficulty concentrating or remembering, sleep problems (insomnia), and loss of smell (anosmia) or taste (dysgeusia), with fatigue, breathing problems (dyspnea) and chest pain being the most commonly reported symptoms after acute SARS-CoV-2 infection.

[0005] PVFS is a complex, long-term disability characterized by the inability to participate in routine activities of daily living that were possible before the viral infection, lasting at least three months. In addition to other adverse effects, coronavirus infection is often associated with PVFS.

[0006] In severe cases of the disease, approximately 70% of COVID patients suffer from fatigue during the acute phase of infection, and the symptoms often persist even after the patient has recovered from the infection (Manal S., Barnett J., Brill S. et al. (Thorax, 2021; 76, 396-398), Halpin SJ, McIvor C., et al. (J. Med. Virol. 2021; 93, 1013-1022, Carfi A., et al. JAMA, Vol. 324, No. 6, 603-605, 2020).

[0007] The conditions described are summarized under the term "Post-COVID-19 syndrome" or "Long-COVID-19", hereafter referred to as "Post-COVID".

[0008] People with post-viral fatigue syndrome report physical and mental exhaustion, including decreased activity, decreased motivation, poor memory, poor concentration, poor sleep quality, emotional lability, and in some cases depression. Recommendations for these people are typically limited to behavioral advice to support recovery, such as initially exercising less and gradually increasing activity, and maintaining routine daily activities (e.g., eating, sleeping).

[0009] Practical medical treatment strategies for patients suffering from Long COVID are summarized in Deutsches Arzteblatt 2020; 49, 117 and are based on the Long COVID primary care recommendations described in Greenhalgh, T.; Knight M., A`Court C.; BMJ 2020; 370, 3026.

[0010] Moscatelli, F. et al. (Nutrients 2021; 13, 976-988) discuss the role of nutritional inventions and emphasize the fact that strong data from clinical trials are needed to support such assumptions. Adequate nutrition is necessary to support immune cell function, enabling them to engage in a strong response against pathogens. The micronutrients with the strongest evidence for immune support are vitamins C, D and zinc.

[0011] Creatine is methylguanidinoacetic acid, typically available from animal foods and / or naturally produced in the body from the amino acids arginine, glycine, and methionine. Creatine synthesis in the body provides approximately half of the daily requirement. The remaining creatine, needed to maintain normal tissue levels, can be obtained from animal foods such as fish and meat or from dietary supplements. Creatine plays a key role in the energy metabolism of all cells in the body. Creatine primarily functions as a metabolic intermediary for energy transfer by facilitating the recycling of ATP, the energy source used and stored at the cellular level.Therefore, creatine is found in high concentrations in organs with high energy metabolism, with ~95% of the creatine in the human body stored in skeletal muscle and the remaining 5% in the brain, liver, kidneys, and testes (McCall, W., Persky, AM. Pharmacokinetics of creatine. Subcell Biochem 2007, 46, 261-273; Bonilla, DA et al., Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review. Nutrients 2021, 13, 1238; Brosnan, ME et al., The role of dietary creatine. Amino Acids 2016, 48, 1785-1791; Harris, R. Creatine in health, medicine, and sport: An introduction to a meeting held at Downing College, University of Cambridge, July 2010, Amino Acids 2011, 40, 1267; Harris, RCet al. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 1992, 83, 367-374; Kreider, RB; Stout, JR Creatine in Health and Disease. Nutrients 2021, 13, 447; Ostojic, SM; Forbes, SC Perspective: Creatine, a Conditionally Essential Nutrient: Building the Case. Adv. Nutr. 2021, 00, 1-4).

[0012] Creatine administration has therefore been considered a supportive measure for the treatment of various diseases. In particular, Ostojic, SM et al. described a dietary treatment for chronic fatigue syndrome (CFS) containing guanidinoacetic acid (GAA) (Nutrients 2016, 8, 72). The efficacy of creatine in the treatment of postviral fatigue syndrome (PVFS) is described in Ostojic, SM Nutrients 2021, 13, 503; Kreider RB et al., Nutrients 2021, 13, 447; and Ostojic, SM Nutritional Neuroscience, An International Journal of Diet, Nutrition and the Nervous System, vol. 25, no. 4, 2022, 884-885.

[0013] S. Marinari et al., Effects of neutraceutical diet integration, with coenzyme Q 10 (Q-Ter multicomposite) and creatine, on dyspnea, exercise tolerance, and quality of life in COPD patients with chronic respiratory failure, Multidisciplinary Respiratory Medicine 2013, 8:40 10This study examines nutritional supplementation using creatine. While COPD is a respiratory disease, PVFS, especially post-COVID, is a neurological disease. SM Ostojic, "Can creatine help in pulmonary rehabilitation after COVID-19?", Ther. Adv. Respir. Dis. 2020, Vol. 14:1-2, raises the question of whether creatine supplementation can support pulmonary rehabilitation in COVID-19. Z. Naureen et al., European Review for Medical and Pharmacological Sciences, 2021, 25 (1 Suppl): 67-73, provide food supplement suggestions for managing post-COVID syndrome. They propose a food supplement composition containing vitamin C, acetyl-L-carnitine, hydroxytyrosol / olive polyphenols, thiamin, vitamin B6, folic acid, vitamin D3, and vitamin B12. L. Barrea et al., Nutrients 2022, 14, 1305, provide food recommendations for post-COVID-19 syndrome. In relation to post-COVID-19 fatigue syndrome, the authors recommend the use of vitamin C, B vitamins, sodium, magnesium, zinc, folate, L-carnitine, L-tryptophan, essential fatty acids, and coenzyme Q. 10 We speculate that there is evidence that deficiencies of several nutrients, such as:

[0014] Therefore, the problem that the present invention aims to solve is to improve recovery from postviral fatigue syndrome (PVFS), for example caused by the SARS-CoV-2 virus, in particular in patients suffering from PVFS accompanied by mental fatigue, loss of motivation, reduced activity, or reduced concentration. Summary of the Invention

[0015] Description of the invention: This problem can be solved by administering creatine to patients in need. Creatine supports recovery from PVFS, especially when PVFS is caused by the SARS-CoV-2 virus. In particular, creatine administration can improve the mental state of patients suffering from PVFS and / or extend the time to exhaustion. The mental state of patients includes parameters such as mental fatigue, loss of motivation, and impaired concentration.

[0016] Postviral fatigue syndrome (PVFS) is a long-term, enigmatic neurological disorder. PVFS is characterized by an inability to participate in previously normal daily activities, persisting for more than six months, and accompanied by fatigue, post-exertional malaise, and unrefreshing sleep. PVFS-related symptoms are particularly common after infection with members of the coronavirus family (SARS-CoV2), often leading to post-COVID fatigue syndrome.

[0017] The inventors of the present application have surprisingly found that creatine is effective in improving mental conditions such as mental fatigue, loss of motivation, and impaired concentration in patients, as well as in extending the time to exhaustion in patients suffering from PVFS. This effect is supported by a strong enrichment of creatine in the thalamus, gray matter, and especially white matter of the brains of patients suffering from post-COVID (see Figure 1). This enrichment is achieved by administering creatine supplementation to patients in need.

[0018] This is surprising, since it was previously thought that creatine could not cross the blood-brain barrier. However, within the framework of the present invention, it has been found that long COVID or post-COVID causes changes in the blood-brain barrier, and that, particularly in the post-COVID situation, creatine uptake and enrichment in brain regions such as the thalamus, gray matter, and white matter has been observed.

[0019] Furthermore, the inventors of the present application have found that patients with long COVID who do not receive creatine supplementation exhibit low levels of creatine in the brain. Within the framework of the present invention, it has been found that the concentration of total creatine in the brain, particularly in the thalamus, white matter, and gray matter, is significantly reduced in patients with long COVID compared with baseline values ​​in the general population. Therefore, without being bound by any theory, it is believed that one of the effects and / or causes of long COVID is the depletion of creatine in brain regions, and therefore a decrease in creatine levels in such brain regions. Based on the present finding that creatine can cross the blood-brain barrier in patients with long COVID, creatine levels in brain regions can be enriched and / or increased by the addition of creatine.

[0020] Particularly surprising is that while total brain creatine concentrations in long COVID patients were found to be reduced compared to baseline values ​​in the general population, significant enrichment of creatine was found in the brains of post-COVID patients, particularly in the thalamus, gray matter, and / or white matter, while no increase in brain creatine was observed or only a very small increase of up to approximately 5% was observed in healthy subjects after creatine supplementation. Ostensibly, long COVID causes brain creatine depletion and simultaneously alters the properties of the blood-brain barrier, allowing supplemented creatine to pass through, resulting in a significant increase in brain creatine after creatine supplementation. Surprisingly, according to the present invention, enrichment of brain creatine was found after creatine supplementation, indicating that creatine in long COVID patients can cross the blood-brain barrier. Notably, supplementation with creatine alone, i.e., creatine without any transporters or supplements known to alter the blood-brain barrier, was found to result in enrichment of creatine in the brain.

[0021] Thus, the present invention can treat brain-related symptoms of Long COVID, such as mental fatigue, loss of motivation, difficulty concentrating and / or time to exhaustion, which are all neurological conditions.

[0022] One of the challenges of finding appropriate treatments for PVFS, especially post-COVID, is the variability, multiplicity, diversity, and ambiguity of post-COVID-19 symptoms, along with uncertainty about their causes. This complicates both post-COVID treatment and predicting which medications and treatments will work for post-COVID treatment. Post-COVID manifestations include many different conditions and symptoms, such as pulmonary disease, neurological symptoms and conditions (e.g., headache, nasal anosmia, taste disorders, dizziness, confusion, disorientation, and other disorders), neuropsychiatric disorders, gastrointestinal symptoms (e.g., stroke, nausea, loss of appetite, vomiting, and diarrhea), cardiovascular diseases (e.g., myocarditis, heart failure, cardiac dysfunction, and thromboembolism), renal failure, and skin conditions. It is not possible to define a uniform clinical picture, particularly with regard to long-term effects, and the underlying mechanisms remain unclear. Post-COVID patients report disparate symptoms that persist for weeks to months. Commonly reported complaints and symptoms include fatigue, tiredness, mental fatigue, exhaustion, decreased recovery, memory impairment, sleep disturbances, muscle weakness, muscle pain, and mental health issues such as depression and anxiety. Other reported symptoms include decreased regional lung function, decreased pulmonary function, decreased renal function, and myocardial inflammation. While this list is by no means definitive, it illustrates the diversity and variability of conditions and symptoms associated with post-COVID. It is currently unknown what causes COVID or post-COVID to cause these conditions and symptoms. Therefore, there is no cross-applicability of known treatments for similar symptoms, making it difficult to provide appropriate treatments for post-COVID.

[0023] According to the present invention, it has now surprisingly been found that pharmaceutical compositions containing creatine or physiologically acceptable derivatives thereof and / or salts and / or adducts thereof are effective in treating specific conditions selected from the group consisting of post-COVID-19-related mental fatigue, loss of motivation, and impaired concentration, and are also suitable for extending the time to post-COVID exhaustion. As outlined above, the causes of the numerous and varied symptoms associated with post-COVID-19 are unknown, and therefore effective treatments cannot be predicted. Furthermore, the conditions that cause the various symptoms, as well as the symptoms, appear to be numerous. In the tests and experiments underlying the present invention, it has now surprisingly been found that providing creatine improves the mental state of post-COVID patients, specifically improving conditions of mental fatigue, loss of motivation, and impaired concentration. Significant improvements were observed, particularly with regard to mental fatigue.

[0024] A first embodiment of the present invention is therefore a pharmaceutical composition comprising creatine or a physiologically acceptable derivative thereof and / or a salt thereof and / or an adduct thereof for use in the treatment of PVFS, in particular PVFS caused by SARS-CoV-2, according to claim 1.

[0025] A second embodiment of the invention is the use of creatine or its physiologically acceptable derivatives and / or salts thereof and / or adducts thereof as a dietary supplement or supplement for the preparation of a diet to support recovery from PVFS, particularly when PVFS is caused by SARS-CoV-2 and when PVFS is accompanied by symptoms selected from the group consisting of mental fatigue, loss of motivation or decreased concentration. Thus, the mental state of subjects, particularly those suffering from post-COVID fatigue (PCFS), can be improved by the administration of creatine.

[0026] A further embodiment of the present invention is the administration of creatine in combination with glucose. Glucose promotes creatine uptake in the brain compared to creatine taken alone. The present invention surprisingly found that creatine administered alone crosses the blood-brain barrier and enriches in brain regions in post-COVID patients, but also found that adjunctive administration of glucose can further enhance creatine uptake in the brain. Surprisingly, the time to exhaustion in post-COVID patients can be extended by administering glucose in addition to creatine compared to creatine alone, whereas the time to exhaustion is shortened by administering glucose alone.

[0027] Glucose is preferably administered in combination with creatine.This preferably means within 1 hour before and within 1 hour after creatine administration.Particularly preferably, within 30 minutes, 15 minutes, 10 minutes or 5 minutes before creatine intake, and within 30 minutes, 15 minutes, 10 minutes or 5 minutes after creatine intake.Most preferably, creatine and glucose are administered together.The daily dose of glucose administered in combination with creatine is preferably in the range of 1g to 10g, particularly between 2g and 7g and 5g.The daily dose of glucose can be administered once a day, for example, at breakfast, or 2, 3, 4 or 5 times a day.

[0028] In a further embodiment of the present invention, a pharmaceutical composition or dietary supplement containing creatine or a physiologically acceptable derivative thereof and / or its salt and / or its adduct is used in combination with pulmonary rehabilitation, particularly respiratory exercise, for the treatment of PVFS. As used herein, the term "respiratory exercise" includes physical exercise and also includes pulmonary rehabilitation. Pulmonary rehabilitation is preferably performed according to Wang TJ et al., Am J Phys Med Rehabil, 2020, Jun 11 (DOI 10.1097 / PHM. 0000000000001505 / PMCID: 7315835). Pulmonary rehabilitation is tailored to each patient and may include, for example, modified segmental breathing, respiratory exercises to strengthen lung muscles, bed mobility, stretching, gymnastics, and / or walking. The intensity of exercise is initially low and gradually increased without placing a significant strain on the patient. The frequency of exercise is, for example, 2 to 4 times a day for 10 to 15 minutes. The duration of exercise can be gradually increased. Pulmonary rehabilitation measures, such as training the respiratory and expiratory muscles with breathing exercises, should be initiated as soon as the patient's health permits, usually within 20 weeks, preferably within 12 weeks, and most preferably within 6 weeks after the infection has resolved.

[0029] Hereinafter, the pharmaceutical composition of the first embodiment and the composition used as a dietary supplement of the second embodiment are also referred to as creatine compositions, creatine-containing compositions, or compositions comprising creatine. The terms "creatine composition," "creatine-containing composition," or "composition comprising creatine" also include physiologically acceptable creatine derivatives, creatine salts, and / or creatine adducts, unless expressly stated otherwise.

[0030] The creatine-containing composition of the present invention is particularly useful for supporting recovery from fatigue syndrome after viral infections, such as SARS-CoV-2 infection, especially when post-viral fatigue syndrome is accompanied by mental fatigue, loss of motivation, and impaired concentration. However, PVFS is one of the most common conditions post-COVID. Fatigue syndrome often persists for weeks, months, or even longer in patients who have survived SARS-CoV-2 infection and can significantly impair overall health.

[0031] Acute and chronic viral infections that can cause PVFS include coronaviruses (e.g., SARS, MERS, SARS-CoV-2), Epstein-Barr virus, cytomegalovirus, and coxsackievirus. Postviral fatigue syndrome can last for weeks to months. For example, after SARS-CoV-2 infection, PVFS can persist for a year or longer.

[0032] The recovery of patients suffering from PVFS is dramatically improved by the administration of creatine, especially in combination with glucose. Creatine, also known as methylguanidinoacetic acid, occurs naturally in animals and humans. Other names for creatine are N-(aminoiminomethyl)-N-methyl-glycine and N-methyl-N-guanylglycine. Creatine is also available in large quantities from animal foods or as a food supplement. Creatine monohydrate, which can be prepared with very high purity, is preferably used in food supplements.

[0033] In addition to creatine, physiologically acceptable creatine derivatives can also be used according to the present invention. Such creatine derivatives can be naturally occurring compounds such as creatine phosphate, or prodrugs of creatine that can release creatine under physiological conditions, such as creatine esters. In the context of the present invention, guanidinoacetic acid (GAA) is also included in the group of suitable creatine derivatives. The physiologically acceptable creatine derivative is preferably selected from the group consisting of creatine, creatine hydrate, creatine C1-C5-alkyl esters, creatine esters or amides such as N-C1-C5-alkylamides, creatine phosphate, creatinol-O-phosphate, or a mixture thereof.

[0034] Suitable creatine salts, creatine adducts, physiologically acceptable salts of creatine derivatives and physiologically acceptable adducts of creatine derivatives are preferably selected from the group consisting of the corresponding acetate, citrate, maleate, fumarate, tartrate, malate, pyruvate, ascorbate, succinate, aspartate, lactate, oxalate, formate, benzoate, phosphate, sulfate, chloride, hydrochloride salts, the corresponding potassium salts, sodium salts, calcium salts, magnesium salts, the corresponding L-carnitine adducts, acetyl-L-carnitine adducts, taurine adducts, betaine adducts, choline adducts, methionine adducts or mixtures thereof.

[0035] Creatine treatment can begin during viral infection, preferably within about 3 months (12 weeks) after infection. Creatine supplementation typically lasts between 1 week and 18 months or longer, preferably between 1 month and 12 months, and particularly between 3 and 8 months, depending on the condition of the individual requiring it.

[0036] The amount of creatine administered ranges from 3 g to 30 g per day. Preferably, the dosage ranges from 7 g to 25 g, and most preferably between 8 g and 20 g, which is higher than the amount typically recommended for sportsmen and women.

[0037] Preferably, the administration of creatine is divided into an accumulation phase and a maintenance phase, with the daily dose of creatine in the composition ranging from 10 g to 30 g in the initial accumulation phase and from 7 g to 15 g in the subsequent maintenance phase, the accumulation phase lasting up to 3 weeks, preferably between 3 and 14 days, particularly between 5 and 10 days, and the maintenance phase lasting from 1 week to 18 months, preferably between 2 and 12 months, particularly between 3 and 8 months.

[0038] The accumulation phase is usually the first phase. However, additional accumulation phases, for example having a duration between 1 and 7 days, can be integrated into the maintenance phase.

[0039] The daily creatine dose can be administered once a day, for example with breakfast, or in divided doses administered two, three, four or five times a day.

[0040] When a combination of creatine and glucose is administered, the weight ratio of creatine to glucose is preferably in the range of 1:5 to 5:1, more preferably between 1:3 and 3:1, especially 1:1 to 1:3.

[0041] When the administered creatine composition comprises a creatine derivative, prodrug, adduct or salt, the amount of creatine moiety contained therein is apparent for a daily dosage within the ranges set forth above.

[0042] The creatine compositions described herein can be administered orally, preferably in the form of tablets, coated tablets, capsules, granules or powders.

[0043] In particular, granules or powders containing creatine compositions are used in the form of aqueous suspensions or water-soluble solutions. Pure creatine and some creatine derivatives have low solubility. For example, the solubility of creatine is 17 g / L (20°C). Poorly soluble creatine and its derivatives can be used in the form of aqueous suspensions. A disadvantage of aqueous suspensions is that they often separate before ingestion. Therefore, water-soluble granules or powders are usually preferred. To increase the water solubility of creatine or creatine derivatives, water-soluble salts or adducts of creatine can be used. To increase water solubility, the use of acids or complexing agents may be useful, particularly to provide the corresponding creatine salts or creatine derivative salts. Examples of suitable acids (e.g., carboxylic acids) and complexing agents are selected from the group consisting of malic acid, aspartic acid, ascorbic acid, succinic acid, pyruvic acid, fumaric acid, gluconic acid, alpha-ketoglutaric acid, oxalic acid, acetic acid, formic acid, sulfuric acid, hydrochloric acid, L-carnitine, acetyl-L-carnitine, taurine, betaine, choline, and lipoic acid. Peptides and amino acids may also be useful in increasing the solubility of creatine and creatine derivatives. Sodium, potassium, calcium, and magnesium salts may also be used to increase the water solubility of creatine or creatine derivatives.

[0044] The molar ratio of creatine or creatine derivative to the acid or complexing agent is usually in the range of 5:1 to 1:5, preferably in the range of 2:1 to 1:2, in particular in the range of 1.3:1 to 1:1.3.

[0045] The granules and powder can also be used in the preparation of food to support recovery from PVFS, especially by improving the mental state of patients suffering from PVFS.

[0046] The creatine composition used according to the present invention can further be applied in the form of tablets.

[0047] The creatine composition may be tableted as is or in the form of a formulation containing excipients, such as pharmacologically inactive ingredients such as binders, fillers, antioxidants, preservatives, stabilizers, anti-caking agents, lubricants, disintegrants, flavors, pigments, etc.

[0048] A wide variety of compounds can be used as binders or fillers. Dibasic calcium phosphate; saccharides such as lactose and sucrose; polysaccharides and their derivatives such as starch, cellulose, modified cellulose, and cellulose ethers (such as hydroxypropyl cellulose or hydroxyethyl cellulose); microcrystalline cellulose; sugar alcohols such as xylitol, sorbitol, or mannitol; peptides such as gelatin; and polymers (e.g., polyvinylpyrrolidone, polyethylene glycol, etc.) are common binders or fillers for tablets.

[0049] Typical suitable preservatives are, for example, cysteine, methionine, citric acid, sodium citrate, tetrazine or synthetic preservatives such as parabens (methylparaben and propylparaben) and benzoic acid. Suitable antioxidants may be selected from the group of vitamin A, vitamin C, vitamin E, retinyl palmitate, and selenium.

[0050] Lubricants and anti-caking agents reduce the adhesiveness of granules or powders and prevent them from sticking together during tablet compression. They are also used to protect tablets from sticking. The most commonly used anti-caking agents are magnesium stearate, stearic acid, or stearin, although magnesium or calcium salts of other fatty acids may be used instead or in addition. Common mineral lubricants are, for example, talc or silica.

[0051] Disintegrants swell and dissolve when wet, causing the tablet to break down in the digestive tract or at a specific stage of the digestive process, releasing the components that can be absorbed by the body. Examples of disintegrants include cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone) and cross-linked sodium carboxymethylcellulose (croscarmellose sodium). Other suitable disintegrants are, for example, modified starches or sodium starch glycolate.

[0052] Flavorings can be used to mask unpleasant-tasting tablet ingredients. Furthermore, the ingredients may increase patient acceptance of the tablet. Flavorings can be natural, such as fruit extracts, or artificial. For example, natural extracts of vanilla, peach, apricot, raspberry, mint, anise, or cherry can be used as flavorings. Antacid compounds or cough syrups are also suitable.

[0053] Suitable pigments and colorants are, for example, food dyes.

[0054] Tablet coatings protect tablet ingredients from deterioration due to moisture in the air and make large or unpleasant-tasting tablets easier to swallow. Most coated tablets are made with cellulose ethers, especially hydroxypropyl methylcellulose (HPMC) film coatings. However, other coating materials are also useful, such as synthetic polymers, shellac, vegetable fibers, waxes, fatty acids, or polysaccharides. Capsules are usually coated with gelatin.

[0055] Particularly useful coatings for tablets in connection with the invention disclosed herein are cross-linked sodium carboxymethylcellulose (croscarmellose sodium), silicified microcrystalline cellulose, agglomerated anhydrous lactose and lactitol monohydrate.

[0056] The preferred tablets are at least a) 10 wt% to 100 wt%, preferably 30 wt% to 99 wt%, of creatine, a creatine derivative or a salt thereof or an adduct thereof; b) 0 to 80 wt % of a carbohydrate, preferably glucose; c) 0 to 20 wt % of an anti-caking agent selected from fatty acids or fatty acid salts, in particular magnesium stearate; d) 0 to 20 wt% of an antacid, preferably citric acid; e) 0 to 20 wt. % fatty acids, preferably coconut oil; f) 0 to 5 wt% fragrance Includes:

[0057] A preferred capsule contains at least a) 10 wt% to 95 wt%, preferably 30 wt% to 80 wt%, of creatine, a creatine derivative, or a salt thereof, or an adduct thereof b) 0 to 80 wt % of a carbohydrate, preferably glucose; c) 0 to 20 wt. % of an anti-caking agent selected from fatty acids or fatty acid salts, in particular magnesium stearate; d) 0 to 5 wt% fragrance; e) 5 to 90 wt% gelatin Includes:

[0058] The listed ingredients may be useful not only for tablets but also for granules or powders containing creatine or creatine derivatives or their salts or adducts. In particular, binders, fillers, antioxidants, preservatives, stabilizers, anti-caking agents, lubricants, disintegrants, flavors, pigments, and carbohydrates may be part of the creatine compositions used in accordance with the present invention. Preferably, the granules or powders contain a combination of creatine and glucose.

[0059] Preferred granules or powders according to the invention described contain 10 wt% to 100 wt%, preferably 30 wt% to 99 wt% of creatine, creatine derivatives or salts thereof or adducts thereof.

[0060] Particularly preferred tablets, capsules, granules or powders contain between 10 and 80% by weight glucose, preferably between 30 and 70% by weight. The preferred ratio of creatine:glucose in the composition ranges from 1:3 to 3:1, most preferably between 1:2 and 2:1.

[0061] Creatine and glucose can be formulated together, for example, as tablets, capsules, or granules, but the combination can also be administered in the form of a mixture of compounds, for example, powder.In addition, creatine and glucose can be taken separately, preferably with a time difference of less than 2 hours, most preferably less than 1 hour, or less than 30 minutes.It is advantageous to administer creatine and glucose together.However, it is more preferable to take creatine in the first stage and administer glucose in the second stage.

[0062] In combination with creatine, a creatine derivative, or a salt thereof, or an adduct thereof, an anti-inflammatory drug can be used, such as a non-steroidal drug such as aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, or a steroidal drug such as a corticosteroid such as cortisone, hydrocortisone, and prednisone.

[0063] Creatine, creatine derivatives or their salts or their adducts can be advantageously combined with neuroprotective agents.Preferred neuroprotective agents include glutamate excitotoxicity inhibitors such as ginsenoside, riluzole, progesterone, estrogen, memantine or simvastatin; stimulants such as caffeine; growth factors such as IGF-1 and CNTF; nitric oxide synthase inhibitors; and caspase inhibitors or erythropoietin.

[0064] Creatine, a creatine derivative or a salt thereof or an adduct thereof may also be combined with a drug for the treatment of a viral infection, especially if the administration of creatine is initiated in the acute phase of the viral infection. For the treatment of COVID-19, drugs from the following groups are available: Radibrio (molnupiravir), Olumiant (baricitinib), tixagevimab / silgavimab, Kineret (anakinra), Paxlobid (PF-07321332 / ritonavir), Resiquilona (regdanvimab), Roactemra (tocilizumab), Lonaprev (casirivimab / imdevimab), Veklury (remdesivir), and Zevdi (sotrobimab). For the treatment of influenza, drugs such as Rapivab (peramivir), Relenza (zanamivir), Tamiflu (oseltamivir phosphate), and Xofluza (baloxavir marboxil) are suitable. For the treatment of adenovirus, cidofovir, ribavirin, ganciclovir, and vidarabine are useful.

[0065] Creatine, creatine derivatives, or salts thereof, or adducts thereof, are preferably used in combination with a pain-relieving, anti-inflammatory diet according to a preferred embodiment of the present invention. A preferred diet should provide all the nutrients necessary for normal energy metabolism and healthy functioning of the nervous system. A particularly suitable diet should include vitamins, minerals, unsaturated fatty acids, amino acids, antioxidants, phytonutrients, and secondary plant metabolites, including essential or semi-essential nutrients.

[0066] A pain-relieving and anti-inflammatory diet should include sufficient amounts of vitamins, especially vitamin C, vitamin D, vitamin E, vitamin K and the group of B vitamins (thiamine, riboflavin, nicotinamide, pantothenic acid, pyridoxine, biotin, folic acid, and / or vitamin B12).

[0067] The important minerals are selected from the group of magnesium, calcium, potassium, sodium, copper, manganese, zinc, selenium, and boric acid / boron.

[0068] Vitamins and minerals must be present in sufficient amounts in the diet to prevent deficiency symptoms. Appropriate recommendations for daily amounts of these nutrients are published by the German Society for Nutrition (Deutsche Gesellschaft fur Ernahrung eV, Referenzwerte fur die Nahrstoffzufuhr, 2. Auflage, 7. Aktualisierte Ausgabe, 2021).

[0069] A further group of nutrients useful in a pain-relieving, anti-inflammatory diet are unsaturated fatty acids, particularly the omega-3 fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-lipoic acid and lecithin.

[0070] A preferred diet should also be rich in amino acids selected from the group consisting of L-tyrosine, arginine, and glycine. Additional amino acids, such as theanine, cystine, taurine, or mixtures thereof, are also abundant in a preferred diet.

[0071] Additional compounds that reduce pain and should be present in an anti-inflammatory diet are N-acetyl-L-cysteine, gamma-aminobutyric acid (GABA), S-adenosylmethionine (SAMe), ubiquintol (coenzyme Q10), NADH, resveratrol, lutein, lycopene, choline, and carnitine.

[0072] Particularly useful phytonutrients for pain relief and anti-inflammatory diets, such as secondary plant metabolites, include antioxidants, anthocyanidins, flavonoids, flavones, isoflavones, catechins, anthocyanidins, isothiocyanates, carotenoids, allyl sulfides, polyphenols, resveratrol, lutein, and lycopene. Particularly preferred secondary plant metabolites are oligomeric procyanidins and oligomeric proanthocyanidins (OPCs).

[0073] A suitable diet may include plants, particularly herbs, spices, fruits, vegetables, and legumes, or their extracts, oils, powders, or composites, such as Boswellia serrata, Curcuma longa, grape seeds (especially those containing OPCs), devil's claw, or cat's claw. Additionally, tomatoes, olive oil, green leafy vegetables such as spinach, kale, and collard greens, nuts such as almonds and walnuts, and fruits such as strawberries, blueberries, cherries, and oranges are also considered anti-inflammatory foods. Fatty fish such as salmon, mackerel, tuna, and sardines also have anti-inflammatory properties.

[0074] The nutrients recommended for a pain-reducing and anti-inflammatory diet can be supplied by making appropriate food choices or by adding the respective ingredients via dietary supplements. Description of the image: [Brief explanation of the drawings]

[0075] [Figure 1] Changes in tissue creatine levels in patients suffering from post-COVID. The left column represents the creatine-treated group, and the right column represents the placebo group. [Figure 2] Figure 2 illustrates the calculated Cohen effect size of creatine administration in post-COVID patients. [Example]

[0076] Working Example: Example 1: A study was conducted to evaluate the efficacy and safety of creatine supplementation via dietary supplements in patients suffering from post-COVID symptoms after SARS-CoV-2 infection. The study employed a parallel-group, randomized, placebo-controlled, double-blind design. The allocation ratio to the experimental (creatine) and control (placebo) groups was set at 1:1. Patients were eligible for inclusion in the study: age 18–65 years, a positive COVID-19 test (documented by a valid PCR or antigen test) within the past 3 months, moderate to severe fatigue, and at least one additional post-COVID-19-related symptom, such as anosmia, taste disturbance, respiratory problems, lung pain, body pain, headache, and difficulty concentrating. Exclusion criteria were other pulmonary and cardiovascular conditions and a history of dietary supplement use within 4 weeks prior to the start of the study.

[0077] This study was conducted in accordance with the Declaration of Helsinki (7th edition). The previously published data were collected from October 2021 to January 2022 at the FSPE Applied Bioenergetics Lab at Novi Sad University. The experimental (creatine) group received 4 grams of creatine monohydrate per day, while the control (placebo) group received the same amount of inulin. Participants received the intervention once daily at breakfast. They were asked to stir either the experimental or control powder into 250 mL of lukewarm water and ingest it immediately. Both interventions were similar in appearance, texture, and sensory characteristics. Creatine monohydrate was provided by Alzchem Trostberg GmbH (Trostberg, Germany). The intervention period was 6 months, and participants were asked to refrain from using other dietary supplements during the study period. All outcome measures were measured at baseline (pre-treatment), 3 months, and 6 months. The primary outcomes were the change in creatine levels at baseline and at 3- and 6-month follow-up, respectively. The minimum sample size (n = 12) was calculated using power analysis (G*Power 3.1.9.3, Heinrich-Heine-Universitat Düsseldorf), with an effect size of 0.50 (medium effect), an alpha error probability of 0.05, a power of 0.80 for the two groups, and two (3-month) and three (6-month) measurements of each study outcome.

[0078] At this point, the number of participants who had been randomized, received the intended treatment, and were included in the primary outcome analysis was 12, six in the experimental group and six in the control group.Recruited participants reported no major side effects from either intervention so far.

[0079] Creatine accumulation in skeletal muscle of post-COVID patients. Creatine tissue levels were measured by proton magnetic resonance spectroscopy (1.5 T Avanto scanner, Siemens, Erlangen, Germany) using a matrix head coil in circular polarization mode, and metabolite spectra of skeletal muscle and specific brain regions (vastus medialis, thalamus, frontal lobe, precentral, paracentral, and parietal lobe white and gray matter) were processed as previously described (Appl Physiol Nutr Metab. 2016 Sep, 41(9):1005-7.).

[0080] Statistical method: Data were first analyzed for normality of distribution using the Shapiro-Wilk test and for homogeneity of variance using the Bartlett test. When homogeneity of variance was verified for normally distributed data, summary measures of the interaction effect (time vs. intervention) were compared using a two-way ANOVA with repeated measures. When non-homogeneity of variance was confirmed, data were compared using the Friedmann test. For the two-way ANOVA and Friedmann test, post-hoc LSD and Wilcoxon tests were used to identify differences between individual sample pairs, respectively. The significance level was set at P ≤ 0.05. Effect sizes after the intervention were assessed using the Cohen statistic, with d ≥ 0.8 indicating a large effect. Data were analyzed using the statistical package SPSS version 24.0 for Mac (IBM SPSS Statistics, Chicago, IL).

[0081] Changes in tissue creatine levels after 3 months in patients suffering from post-COVID are summarized in Table 1. The table shows changes in tissue creatine levels in the white matter (brain), thalamus, vastus medialis, and gray matter (brain) after 3 and 6 months of intervention with 4 grams of creatine per day compared to creatine levels in the placebo group.

[0082] [Table 1]

[0083] The percent difference between creatine levels at 3 months and the corresponding baseline levels in the white matter (brain), gray matter (brain), thalamus, and vastus medialis, calculated from Table 1, is shown in Figure 1. The left column represents the creatine-treated patient group, and the right column represents the placebo group. For white matter and gray matter values, the mean values ​​were determined from Table 1.

[0084] A randomized controlled trial found that creatine administration for 3 months resulted in accumulation in the brain and vastus medialis muscle. Creatine supplementation maintained increased creatine levels for at least another 3 months. No changes in tissue creatine levels were observed in the placebo group.

[0085] Participants in the experimental group experienced increases in tissue total creatine levels in all 14 regions assessed in the study, with the highest increases observed in the vastus medialis (P = < 0.01), left frontal lobe white matter (P = 0.01), and right parietal lobe white matter (P = 0.01) at 6-month follow-up. Tissue creatine levels remained unchanged in the placebo group throughout the study. A two-way ANOVA with repeated measures revealed significant differences between interventions (treatment by time interaction) in tissue creatine levels (P < 0.05), with the creatine group demonstrating superior enhancement of creatine levels in the vastus medialis, left frontal lobe white matter, and right parietal lobe white matter compared with the placebo group. Furthermore, strong interaction effects between interventions were reported in several other regions, including the right frontal lobe white matter, right paracentral lobule white matter, left parietal lobe white matter, and left medial parietal gray matter (P < 0.20).

[0086] Furthermore, Cohen's effect sizes for the primary and secondary outcomes after creatine supplementation demonstrated elevated brain levels in the thalamus (0.82 at 3 months), right frontal lobe white matter (1.25 at 3 months and 1.32 at 6 months), right paracentral gray matter (0.88 at 3 months), left parietal lobe white matter (0.92 at 3 months and 1.17 at 6 months), left temporal lobe white matter (0.92 at 3 months and 1.17 at 6 months), parietal lobe white matter (1.99 at 3 months and 1.74 at 6 months), left parietal lobe mesial gray matter (0.84 at 6 months), and right parietal lobe mesial gray matter (1.17 at 3 months and 1.06 at 6 months), with a strong effect size for creatine (d ≥ 0.8).

[0087] In summary, creatine was enriched in the brains of post-COVID patients after creatine supplementation and was found to cross the blood-brain barrier.

[0088] Effect of creatine as a nutritional supplement on post-COVID patients.

[0089] Patient-reported outcomes regarding COVID-19-related signs and symptoms (e.g., headache, difficulty concentrating, anosmia, and dysgeusia) were assessed using a VAS scale (Table 3). Fatigue, including the group states of general fatigue, physical fatigue, metal fatigue, decreased activity, and decreased motivation, was assessed using the Multidimensional Fatigue Inventory (MFI-20) test (Smets EM et al., J. Psychosom. Res. 1995, 39(3), 315). The results of the VAS scale survey and MFI-20 test are summarized in Tables 2 and 3.

[0090] [Table 2]

[0091] In the test carried out, the patient is required to report a score for the symptoms shown in Table 2. Thus, the higher the score, the greater the respective symptom experienced by the interviewed patient. Consequently, the lower the given value, the greater the relief effect for the respective symptom. As can be seen from Table 2, a fairly significant improvement in mental fatigue was observed in the creatine group, but not in the placebo group. Furthermore, a specific improvement was observed in the symptom of decreased motivation.

[0092] [Table 3]

[0093] As can be seen from Table 3, the creatine group achieved a significant improvement in the condition of poor concentration.

[0094] Additionally, patients' time to exhaustion was assessed by a ramp-to-exhaustion test on a motorized treadmill. The treadmill speed and gradient increased every 3 minutes, starting at 2.7 km / h (1.7 miles / hour) at a 10% gradient and increasing to 9.7 km / h (6 miles / hour) at a 22% gradient in stage 7 (Will PM and Walter JD, Am Heart. J., 1999 Dec, 138, 1033). The results of the treadmill assessment are provided in Table 4.

[0095] [Table 4]

[0096] Patients suffering from viral fatigue syndrome after SARS-CoV-2 infection experienced a significant increase in time to exhaustion. The time to exhaustion in the creatine group increased by 7.3% compared with 2.1% after placebo. More importantly, the creatine group achieved stage 6 in the treadmill test, while the placebo group remained at stage 5. The improvement in endurance was further associated with a reduction in fatigue symptoms, particularly mental fatigue and loss of motivation compared with increases in the placebo group. Loss of motivation worsened during the observation period in the placebo group, whereas it slightly improved in the creatine cohort. According to the results shown in Table 2, creatine administration achieved smaller improvements in fatigue symptoms, such as physical fatigue and reduced activity, compared with the placebo group. Furthermore, creatine did not cause any significant side effects.

[0097] Example 2: Combining Creatine Supplementation with Pulmonary Rehab: A second study was conducted to evaluate the efficacy and safety of creatine supplementation from dietary supplements in patients suffering from post-COVID symptoms after SARS-CoV-2 infection. Eight post-COVID patients (age 33.5 ± 9.9 years, weight 72.3 ± 14.5 kg, height 168.6 ± 11.0 cm; four women) with moderate fatigue and respiratory problems or lung pain and pulmonary fatigue volunteered to participate in this randomized controlled trial. All patients were randomized to receive 4 grams of creatine monohydrate daily plus breathing exercises (2–3 times daily for 10–15 minutes) (experimental group) or breathing exercises alone (control group) for a 3-month intervention period using a double-blind, parallel-group design.

[0098] Pulmonary rehabilitation is performed according to Wang TJ et al., Am J Phys Med Rehabil, 2020, Jun 11 (DOI 10.1097 / PHM.0000000000001505 / PMCID: 7315835). Pulmonary rehabilitation is tailored to each patient and may include, for example, modified segmental breathing, breathing exercises to strengthen respiratory and expiratory muscles, inspiratory muscle training, bed mobility exercises, stretching, gymnastics, and / or walking. The intensity of exercise is initially low and gradually increased without placing significant strain on the patient.

[0099] Detailed information regarding the experimental protocols and test procedures used is provided in Example 1.

[0100] All volunteers completed the study, and no participants reported side effects from either intervention. Changes in study outcomes over the course of the study are shown in Table 6. Increases in tissue total creatine levels in several brain regions and vastus medialis muscle are provided in Table 5.

[0101] [Table 5]

[0102] [Table 6]

[0103] Participants in the creatine group experienced increases in tissue total creatine levels in all 14 sites assessed in our study, with significant increases observed at 3-month follow-up in the vastus medialis (P = 0.04), thalamus (P = 0.03), right frontal lobe gray matter (P = 0.04), right precentral white matter (P = 0.01), right paracentral lobule gray matter (P = 0.03), and left medial parietal gray matter (P = 0.01). Cohen's effect sizes (d) for the increases in creatine in these six sites ranged from 0.77 (vastus medialis) to 1.76 (right frontal lobe gray matter), suggesting that creatine monohydrate and breathing exercises had a substantial effect on muscle and brain creatine amplification. In the control group, no increase in total creatine levels was observed in any region (except for a non-significant increase in the left precentral white matter); in addition, in the control group, creatine levels significantly decreased in the right frontal gray matter and left medial parietal gray matter at the 3-month follow-up (P<0.05). Furthermore, a two-way ANOVA with repeated measures revealed significant between-group differences in the changes in total creatine levels in four brain regions (P<0.05), with participants in the experimental group demonstrating greater enhancement of brain creatine concentrations in the left frontal gray matter, right frontal gray matter, right precentral white matter, and left medial parietal gray matter than participants in the control group.

[0104] At 3-month follow-up, total tissue creatine concentrations remained largely unresponsive to respiratory exercise (or even declined from baseline levels), suggesting long-term impairment in tissue bioenergetics after this complex condition.

[0105] Example 3: Creatine supplementation combined with glucose administration: Fifteen male and female PCFS patients (age 39.7 ± 16.0 years, weight 74.0 ± 9.7 kg, height 173.9 ± 8.8 cm; 9 females) with moderate fatigue and at least one additional COVID-related symptom (e.g., taste disorder, anosmia, body pain, respiratory problems, difficulty concentrating, headache, lung pain, fatigue) volunteered to participate in this randomized, controlled, parallel-group, interventional study. All patients were assigned to receive a creatine monohydrate and glucose powder mixture (experimental group 1: 8 grams of creatine (Creapure®) and 3 grams of glucose per day), creatine monohydrate (experimental group 2: 8 grams of creatine (Creapure®) per day), or glucose (control group: 3 grams of glucose per day) in a double-blind, parallel-group design during the 8-week intervention period. All participants refrained from using other dietary supplements during the study period. Detailed information about the experimental protocols and testing procedures used in this study is provided in Example 1.

[0106] All volunteers completed the study, and no participants reported any side effects with either intervention. Changes in tissue creatine levels in patients suffering from post-COVID are shown in Table 7. The table shows changes in tissue creatine levels in the white matter (brain), thalamus, vastus medialis, and gray matter (brain) after creatine + glucose intervention or creatine intervention compared with the control group (glucose administration).

[0107] [Table 7]

[0108] In experimental group 1, after 8 weeks of intervention, total creatine levels increased in all 14 regions, with levels significantly elevated compared to baseline concentrations in 8 regions, including the vastus medialis, thalamus, right frontal gray matter, left and right precentral white matter, right paracentral gray matter, left parietal white matter, and right medial parietal gray matter (P ≤ 0.05). Cohen's effect sizes (d) varied by region, with moderate or large effects for creatine monohydrate plus glucose in the right frontal gray matter (d = 0.54), left precentral white matter (d = 0.66), right precentral white matter (d = 0.60), left parietal white matter (d = 0.97), and right parietal white matter (d = 0.77). In experimental group 2, after 8 weeks of intervention, creatine concentrations significantly increased in three regions, including the vastus medialis and the medial parietal gray matter (P ≤ 0.05); the effect exceeded the moderate effect threshold only in the medial parietal gray matter (d = 0.65). In the control group (glucose group), no significant changes in creatine levels were observed (P > 0.05), and creatine levels decreased from baseline in 10 of 14 regions evaluated (71.4%). A two-way ANOVA with repeated measures (treatment × time interaction) revealed significant between-group differences in changes in total creatine levels in the right precentral white matter and left paracentral gray matter (P ≤ 0.05), with experimental groups 1 and 2 demonstrating superior increases in creatine levels in these two regions. There was a strong trend toward superior creatine levels in other regions, including the vastus medialis, left precentral white matter, right paracentral gray matter, left parietal white matter, left medial parietal gray matter, and right medial parietal gray matter (P<0.20). A two-way ANOVA with repeated measures (treatment by time interaction) revealed significant between-group differences in changes in total creatine concentrations in the right precentral white matter and left paracentral gray matter (P<0.05). Experimental groups 1 and 2 outperformed the control group in increasing creatine levels in these two regions. There was a strong trend toward superior creatine concentrations in other regions, including the vastus medialis, left precentral white matter, right paracentral gray matter, left parietal white matter, left medial parietal gray matter, and right medial parietal gray matter (P<0.20).

[0109] Patient-reported outcomes regarding COVID-19-related signs and symptoms (e.g., headache, difficulty concentrating, anosmia, and dysgeusia) were assessed using a VAS scale. Fatigue, including the group states of general fatigue, physical fatigue, metal fatigue, decreased activity, and decreased motivation, was assessed using the Multidimensional Fatigue Inventory (MFI-20 test; Smets EM et al., J. Psychosom. Res. 1995, 39(3), 315). The results of the VAS scale survey and MFI-20 test are summarized in Tables 8 and 9.

[0110] [Table 8]

[0111] [Table 9]

[0112] Additionally, the patient's time to exhaustion was assessed by incremental exhaustion testing on a motorized treadmill, as described in Example 1.

[0113] [Table 10]

[0114] Patients suffering from postviral fatigue syndrome after SARS-CoV-2 infection showed a significant prolongation of time to exhaustion. Time to exhaustion in the creatine group was increased by 20 seconds in experimental group 2 (creatine group) after administration (P=0.03). More importantly, the combined intake of creatine and glucose prolonged time to exhaustion in the treadmill test by 27 seconds, which is unexpected given the worsening time to exhaustion after glucose ingestion (-7 seconds). In experimental group 2, fatigue scores in the activity reduction subdomain were significantly reduced in conjunction with improvements in endurance (P=0.008), with a d=1.52 suggesting a significant effect of creatine monohydrate on this condition. Improvements in endurance were further accompanied by improvements in mental fatigue and demotivation.

[0115] Several symptoms associated with post-COVID fatigue (PCFS), such as poor concentration and general fatigue, were significantly reduced in experimental group 1 (creatine + glucose) at 8-week follow-up (P ≤ 0.05); the Cohen effect size (d) for the reduction in poor concentration was 0.80, suggesting a significant effect of creatine monohydrate and glucose on this outcome. Furthermore, poor concentration and general fatigue were significantly reduced in experimental group 2 after administration (P ≤ 0.05); the Cohen effect sizes for these variables exceeded the threshold of 0.80, suggesting a significant effect of creatine monohydrate. Participants receiving the control intervention did not experience significant changes in most variables at 8-week follow-up (P > 0.05).

[0116] Conclusion: Creatine monohydrate, administered with or without glucose for 8 weeks, can be recommended as a well-tolerated intervention for improving tissue bioenergetics and several clinical features in patients suffering from post-COVID fatigue syndrome. The effects of creatine monohydrate (with or without glucose) were superior to control interventions in terms of increasing creatine levels in skeletal muscle and several brain regions (including both white and gray matter) and reducing patient-reported symptoms, such as concentration problems and general fatigue. Creatine monohydrate also improved time to exhaustion and reduced specific fatigue subdomains (e.g., reduced activity). Furthermore, glucose enhanced the ability of creatine monohydrate to improve creatine levels in specific regions throughout the brain, but had no effect on most patient-reported outcomes with post-COVID fatigue syndrome. However, combined creatine and glucose supplementation improved endurance, despite neutral patient-reported outcomes.

[0117] Cohen's effect sizes (d) for all outcomes in experimental group 1 (EXP1, creatine + glucose) and experimental group 2 (EXP2, creatine) were assessed and are reproduced in Table 11 and Figure 2. Effects are categorized as small (d = 0.2), medium (d = 0.5, dashed lines), and large (d ≥ 0.8). Missing values ​​are due to statistical limitations in calculating effect sizes when pre- and / or post-values ​​are equal to zero.

[0118] Abbreviation: GF, general fatigue; PF, physical fatigue; RM, decreased motivation; RA, decreased activity; MF, mental fatigue; AGE, taste disorder; ANO, anosmia; DCN, decreased concentration; and HAD, headache.

[0119] [Table 11]

Claims

1. A pharmaceutical composition comprising creatine or creatine hydrate and / or a salt thereof for use in the treatment of postviral fatigue syndrome (PVFS) following SARS-CoV-2 infection accompanied by a condition selected from the group consisting of mental fatigue, loss of motivation and / or decreased concentration.

2. 2. The pharmaceutical composition of claim 1, wherein PVFS is a symptom caused by a coronavirus infection or post-COVID after SARS-CoV-2 infection.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition is used in combination with glucose.

4. 3. The pharmaceutical composition of claim 1, wherein the salt of creatine is selected from the group consisting of the corresponding acetate, citrate, maleate, fumarate, tartrate, malate, pyruvate, ascorbate, succinate, aspartate, lactate, oxalate, formate, benzoate, phosphate, sulfate, chloride, hydrochloride, and the corresponding potassium, sodium, calcium, and magnesium salts.

5. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises creatine monohydrate.

6. 3. The pharmaceutical composition of claim 1, wherein the daily dose of creatine in the composition is in the range of 7 g to 30 g.

7. 3. The pharmaceutical composition of claim 1, wherein the daily dose of creatine in the composition is an accumulation dose ranging from 10 g to 30 g during an initial accumulation phase and a maintenance dose ranging from 7 g to 15 g during a subsequent maintenance phase, the accumulation phase having a duration of up to 3 weeks and the maintenance phase having a duration of 1 month to 12 months.

8. The pharmaceutical composition of claim 1 in combination with glucose.

9. 9. The pharmaceutical composition of claim 8 in combination with glucose, wherein the glucose is for administration within 1 hour before and 1 hour after administration of creatine.

10. 9. The pharmaceutical composition of claim 8 in combination with glucose, wherein the daily dose of glucose in the composition is in the range of 1 g to 10 g.

11. Use of a composition comprising creatine or creatine hydrate and / or a salt thereof as a dietary supplement or supplement for the preparation of food to support recovery from PVFS after SARS-CoV-2 infection accompanied by conditions selected from the group consisting of mental fatigue, decreased motivation, decreased activity and / or decreased concentration.

12. 12. The use of claim 11, wherein PVFS is a symptom caused by a coronavirus infection or post-COVID after SARS-CoV-2 infection.

13. 13. Use according to claim 11 or 12, wherein the daily dose of creatine in the composition is in the range of 7 g to 30 g.

14. 13. Use according to claim 11 or 12, wherein the daily dose of creatine in the composition is an accumulation dose ranging from 10 g to 30 g during an initial accumulation phase and a maintenance dose ranging from 7 g to 15 g during a subsequent maintenance phase, the accumulation phase having a duration of up to 3 weeks and the maintenance phase having a duration of 1 month to 12 months.

15. 13. Use according to claim 11 or 12, wherein the composition used comprises creatine monohydrate.

16. The use of claim 11 in combination with glucose.

17. 17. The use of claim 16, wherein glucose is administered within 1 hour before and 1 hour after creatine administration.

18. 17. The use of claim 16, wherein the daily dose of glucose administered in combination with creatine is in the range of 1 g to 10 g.

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