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

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 the preparation of a diet for patients suffering from PVFS. [Background technology]

[0002] Description of the Prior Art: Although COVID-19 is considered primarily a pulmonary disease, it can also harm other organs, for example 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, for example, 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, decreased concentration or memory, sleep problems (insomnia), loss of smell (anosmia) or loss of 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 disorder characterized by an inability to participate in routine activities of daily living that were possible before the viral infection, lasting for at least three months. In addition to other adverse effects, coronavirus infection is often associated with PVFS.

[0006] In the severe course 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 reduced activity, decreased motivation, poor memory, poor concentration, poor sleep quality, emotional lability, and in some cases depression. Recommendations for these people are usually limited to behavioral advice to support recovery, such as initially exercising less and gradually increasing activity, and maintaining routine daily activities (eating, sleeping, etc.).

[0009] Practical medical treatment strategies for patients suffering from Long COVID are summarized in Deutsches Arzteblatt 2020; 49, 117 and are based on the primary care recommendations for Long COVID 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 highlight 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, which is usually 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 amount of creatine required to maintain normal creatine levels in tissues 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 functions primarily as a metabolic intermediary in energy transfer by facilitating the recycling of ATP, the energy source used and stored at the cellular level.Creatine is therefore 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] Therefore, the administration of creatine has been considered as a supportive measure for the treatment of various diseases. In particular, Ostojic, SM et al., for example, describe a dietary treatment for chronic fatigue syndrome (CFS) that includes guanidinoacetic acid (GAA) (Nutrients 2016, 8, 72). The efficacy of creatine in the treatment of post-viral 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 is a study on 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 back up pulmonary rehabilitation in COVID-19. Z. Naureen et al., European Review for Medical and Pharmacological Sciences, 2021, 25 (1 Suppl): 67-73 provides food supplement suggestions for the management of post-COVID syndrome. There, a food supplement composition containing vitamin C, acetyl-L-carnitine, hydroxytyrosol / olive polyphenols, thiamine, vitamin B6, folic acid, vitamin D3 and vitamin B12 is proposed. L. Barrea et al., Nutrients 2022, 14, 1305 provides 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, folic acid, L-carnitine, L-tryptophan, essential fatty acids and coenzyme Q. 10 They 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 post-viral 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: The problem is solved by administering creatine to patients who need it. Creatine supports recovery from PVFS, especially when PVFS is caused by the SARS-CoV-2 virus, and among other things, administration of creatine can improve the mental state of patients suffering from PVFS and / or extend the time to exhaustion. The mental state of the patient includes parameters such as mental fatigue, decreased motivation, and decreased concentration.

[0016] Postviral fatigue syndrome (PVFS) is a long-term and mysterious neurological disorder. PVFS is specifically characterized by an inability to participate in everyday activities that were possible before the onset of illness, lasting for more than six months, and accompanied by fatigue, post-exertional malaise, and unrefreshing sleep. PVFS-related symptoms are common following infection, especially 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 conditions involving the patient's mental state, such as mental fatigue, lack of motivation and concentration, as well as in extending the time to exhaustion in patients suffering from PVFS. This effect is confirmed by a strong enrichment of creatine in the thalamus, grey matter and especially the white matter of the brain of patients suffering from post-COVID (see Figure 1). This enrichment is achieved by administering supplemental creatine to patients in need of it.

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

[0019] Furthermore, the inventors of the present application found that Long COVID patients who do not supplement with creatine only show low levels of creatine in the brain. Within the framework of the present invention, it was found that the concentration of total creatine in the brain, particularly in the thalamus, white matter and grey matter, is significantly reduced in Long COVID patients compared to the baseline values ​​of 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 thus the reduction of creatine levels in such brain regions. Due to the finding of the present invention that creatine can cross the blood-brain barrier in Long COVID patients, creatine levels in brain regions can be enriched and / or increased by the addition of creatine.

[0020] Particularly surprising is that while the total brain creatine concentration of Long COVID patients is found to be reduced compared to the baseline values ​​of the general population, on the one hand, a significant enrichment of creatine in the brain, especially in the thalamus, grey matter and / or white matter of Post COVID patients is found, on the other hand, no increase in brain creatine is found or only a very small increase of up to about 5% is found in the healthy population after creatine supplementation. Ostensibly, Long COVID causes a depletion of creatine in the brain and at the same time alters the properties of the blood-brain barrier so that the supplemented creatine can pass, resulting in a significant increase in brain creatine after creatine supplementation. Surprisingly, according to the present invention, an enrichment of brain creatine after creatine supplementation is found, indicating that creatine in Long COVID patients can pass the blood-brain barrier. In particular, it is found that supplementation with creatine alone, i.e. without any transporters or auxiliary agents known to alter the blood-brain barrier, leads to an 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 difficulties associated with finding an appropriate treatment for PVFS, especially post-COVID, is the change, multiplicity, diversity and ambiguity of symptoms associated with post-COVID, and at the same time the uncertainty about the cause of symptoms. This complicates both the treatment of post-COVID and predicting what drugs and treatments will work to treat post-COVID. The emergence of post-COVID is characterized by many different conditions and symptoms, including pulmonary disease, neurological symptoms and conditions such as headache, nasal anosmia, taste disorder, dizziness, mental confusion, disorientation and other disorders, neuropsychiatric disorders, gastrointestinal symptoms such as stroke, nausea, anorexia, vomiting, diarrhea; cardiovascular diseases such as myocarditis, heart failure, cardiac dysfunction and thromboembolism; renal (rhenal) failure; skin symptoms, etc., which appear as various symptoms. Especially with regard to the long-term effects, a uniform clinical picture cannot be defined and the underlying mechanisms are unclear. Post-COVID patients complain of completely different symptoms that last for weeks to months. Commonly reported complaints and symptoms include fatigue, tiredness, mental fatigue, exhaustion, reduced recovery, memory problems, sleep disorders, muscle weakness, muscle pain, and mental problems such as depression and anxiety. Other symptoms reported include reduced lung area function, reduced pulmonary function, reduced renal function, and myocardial inflammation. This list is by no means conclusive, but it illustrates the diversity and variation of conditions and symptoms associated with post-COVID. It is currently unknown what causes COVID or post-COVID to cause these condition symptoms. Therefore, it is difficult to provide an appropriate treatment for post-COVID, as there is no cross-applicability of known treatments for similar symptoms.

[0023] According to the present invention, it has now surprisingly been found that pharmaceutical compositions comprising creatine or its physiologically acceptable derivatives and / or their salts and / or adducts are effective for the treatment of certain conditions selected from the group of mental fatigue, lack of motivation, and poor concentration associated with post-COVID, and are also suitable for extending the time to exhaustion in post-COVID. As outlined, the causes of the numerous and varied symptoms associated with post-COVID are unknown, and therefore effective treatments cannot be predicted. Moreover, not only the symptoms, but also the conditions that cause the various symptoms appear to be very numerous. In the tests and experiments on which the present invention is based, it has now surprisingly been found that the provision of creatine improves the mental state of post-Covid patients, specifically improving the conditions of mental fatigue, lack of motivation, and poor concentration. Significant improvements have been found, particularly with regard to mental fatigue.

[0024] Thus, a first embodiment of the invention is 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, in particular when PVFS is caused by SARS-CoV-2 and when PVFS is accompanied by symptoms selected from the group of mental fatigue, loss of motivation or loss of concentration. Thus, the mental state of subjects, especially those suffering from Post-COVID Fatigue (PCFS), can be improved by administration of creatine.

[0026] A further embodiment of the present invention is the administration of creatine in combination with glucose. Glucose enhances creatine uptake in the brain compared to creatine taken alone. In the present invention, it has been found that creatine administered alone surprisingly crosses the blood-brain barrier and is enriched in brain regions in post-COVID patients, but also that creatine uptake in the brain can be further enhanced by the adjunctive administration of glucose. Surprisingly, the time to exhaustion in post-COVID patients can be extended by administering glucose in addition to creatine compared to creatine alone, but the time to exhaustion is shortened by administration of 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 1 g to 10 g, particularly between 2 g and 7 g and 5 g. The daily dose of glucose can be administered once a day, for example at breakfast, or divided into 2, 3, 4 or 5 times a day.

[0028] In a further embodiment of the present invention, a pharmaceutical composition or dietary supplement comprising creatine or a physiologically acceptable derivative thereof and / or its salt and / or its adduct is used in combination with pulmonary rehabilitation, in particular respiratory exercises, for the treatment of PVFS. As used herein, the term respiratory exercise includes physical exercises 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 the individual patient and may include, for example, modified segmental breathing, respiratory exercises to strengthen the lung muscles, bed movement exercises, stretching, gymnastics, and / or walking. The intensity of exercise is low at the beginning and gradually increased without placing a significant burden 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 started 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 subsided.

[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 that include creatine. The terms "creatine compositions", "creatine-containing compositions" or "compositions that include 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 a viral infection, such as SARS-CoV-2 infection, especially when the post-viral fatigue syndrome is accompanied by mental fatigue, loss of motivation, and poor concentration. However, PVFS is one of the most common conditions post-COVID. Fatigue syndrome often persists for weeks, months, or 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 surprisingly 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 or N-methyl-N-guanylglycine. Creatine is also available in large quantities from animal foods or as a food supplement. In food supplements, creatine monohydrate is preferably used, which can be prepared with very high purity.

[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. Physiologically acceptable creatine derivatives are preferably creatine, creatine hydrate, creatine C. 1 -C 5 -Alkyl ester, NC 1 -C 5 creatine esters or amides such as creatine-O-alkylamides, creatine phosphate, creatinol-O-phosphate or mixtures 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, the corresponding potassium salt, sodium salt, calcium salt, magnesium salt, the corresponding L-carnitine adduct, acetyl-L-carnitine adduct, taurine adduct, betaine adduct, choline adduct, methionine adduct or mixtures thereof.

[0035] Treatment with creatine can begin already during viral infection, preferably within about 3 months (12 weeks) after infection. The creatine supplementation period usually lasts between 1 week and 18 months or more, preferably between 1 month and 12 months, in particular between 3 and 8 months, depending on the condition of the subject in need of 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 generally recommended for sportsmen and women.

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

[0038] The accumulation phase is usually the first phase. However, an additional accumulation phase, 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 at breakfast, or it can be administered in divided doses, 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 given above.

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

[0043] In particular, the granules or powders containing the creatine composition are used in the form of an aqueous suspension or water-soluble. The solubility of pure creatine and some creatine derivatives is low. For example, the solubility of creatine is 17 g / L (20°C). Creatine and its derivatives with low solubility can be used in the form of an aqueous suspension. The 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 the water solubility, the use of acids or complexing agents may be useful, especially to provide the corresponding creatine salts or creatine derivative salts. Examples of suitable acids (such as carboxylic acids) and complexing agents are selected from the group 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 said acid or complexing agent is usually in the range of from 5:1 to 1:5, preferably in the range of from 2:1 to 1:2, in particular in the range of from 1.3:1 to 1:1.3.

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

[0046] The creatine composition used according to the invention may 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 hydroxypropylcellulose or hydroxyethylcellulose); 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-adherents reduce the adhesion of granules or powders and prevent them from sticking during tablet compression. They are also used to protect tablets from sticking. The most commonly used anti-adherents 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 are 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. In addition, the ingredients may increase the patient's 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 use 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 accordance 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 for tablets as well as granules or powders that contain 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 composition used according to 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 10wt% to 100wt%, preferably 30wt% to 99wt% creatine, a creatine derivative or a salt thereof or an adduct 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 as a powder.Furthermore, creapure 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 preferred to take creatine in the first stage and administer glucose in the second stage.

[0062] In combination with creatine, creatine derivatives or their salts or adducts, anti-inflammatory drugs can be applied, for example non-steroidal drugs such as aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, and steroidal drugs such as corticosteroids such as cortisone, hydrocortisone, and prednisone.

[0063] Further combination of creatine, creatine derivative or its salt or its adduct with neuroprotective agent is advantageous.Preferred neuroprotective agent includes glutamate excitotoxicity inhibitor such as ginsenoside, riluzole, progesterone, estrogen, memantine or simvastatin; stimulant such as caffeine; growth factor such as IGF-1, CNTF; nitric oxide synthase inhibitor; and caspase inhibitor or erythropoietin.

[0064] A combination of creatine, a creatine derivative or a salt thereof or an adduct thereof with an agent for the treatment of a viral infection is also possible, especially when the administration of creatine is started in the acute phase of a viral infection. For the treatment of COVID-19, drugs from the following groups are available, for example: Rajebrio (molnupiravir), Olumiant (baricitinib), tixagevimab / silgavimab, Kineret (anakinra), Paxlovid (PF-07321332 / ritonavir), Resiquilona (regdanvimab), Roactemra (tocilizumab), Lonaprev (casirivimab / imdevimab), Veklury (remdesivir), Zevdi (sotrobimab). For the treatment of influenza, suitable drugs are Rapivir (peramivir), Relenza (zanamivir), Tamiflu (oseltamivir phosphate), and Xofluza (baloxavir marboxil). For the treatment of adenoviruses, cidofovir, ribavirin, ganciclovir, and vidarabine.

[0065] Creatine, creatine derivatives or their salts or adducts are preferably used in combination with a pain-relieving, anti-inflammatory diet according to the preferred embodiment of the present invention.A preferred diet should provide all the nutrients for normal energy metabolism and healthy function of the nervous system.A particularly suitable diet should include vitamins, minerals, unsaturated fatty acids, amino acids, antioxidants, phytonutrients, 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: 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, References fur die Nahrstoffzufuhr, 2. Auflage, 7. Aktualisierte Ausgabe, 2021).

[0069] A further group of nutrients useful in the pain relieving and anti-inflammatory diet are the 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 of L-tyrosine, arginine and glycine. Additional amino acids, such as theanine, cystine, taurine, or mixtures thereof, are also included in the preferred diet in abundance.

[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, are, for example, antioxidants, anthocyanidins, flavonoids, flavones, isoflavones, catechins, anthocyanidins, isothiocyanates, carotenoids, allyl sulfides, polyphenols, resveratrol, lutein, or lycopene.Particularly preferred secondary plant metabolites are oligomeric procyanidins and oligomeric proanthocyanidins (OPCs).

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

[0074] The nutrients recommended for the pain-relieving 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 description of the drawings]

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

[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 after SARS-CoV-2 infection. The study employed a parallel-group randomized placebo-controlled double-blind design. The allocation ratio to the experimental group (creatine) and control group (placebo) was set at 1:1. Eligibility criteria for patients included in the study were: age 18–65 years, 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 of the additional post-COVID-19 related symptoms such as anosmia, taste disorder, 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] The study was conducted in accordance with the Declaration of Helsinki (7th edition). The data published so far were collected from October 2021 to January 2022 at the FSPE Applied Bioenergetics Lab at the University of Novi Sad. The experimental (creatine) group received 4 grams of creatine monohydrate per day, while the control (placebo) group received the same amount of inulin. Participants were asked to take the intervention once daily at breakfast by stirring the experimental or control powder in 250 mL of lukewarm water and consuming it immediately after. 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 (before 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) and was set at an effect size of 0.50 (medium effect), alpha error probability of 0.05, power of 0.80 for the two groups, and two (3-month) and three (6-month follow-up) measurements of the study outcomes, respectively.

[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. Tissue levels of creatine 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 with the Shapiro-Wilk test and for homogeneity of variance with the Bartlett test. When homogeneity of variance was verified for normally distributed data, summary measures of interaction effects (time vs. intervention) were compared by two-way ANOVA with repeated measures. When non-homogeneity of variance was identified, data were compared using Friedmann's test. For two-way ANOVA and Friedmann tests, post-hoc LSD and Wilcoxon tests were used to identify differences between individual pairs of samples, respectively. The significance level was set at P ≤ 0.05. Post-intervention effect sizes were assessed by Cohen statistics, 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 white matter (brain), thalamus, vastus medialis and grey 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 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 patients, 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 was accumulated in the brain and vastus medialis after 3 months of administration. With creatine supplementation, increased creatine levels could be maintained for at least another 3 months. No changes in tissue creatine were observed in the placebo group.

[0085] Participants in the experimental group experienced increases in tissue total creatine levels in all 14 sites assessed in the study, with higher increases 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. The placebo group showed no change in tissue creatine levels throughout the study. Two-way ANOVA with repeated measures revealed significant differences between the interventions (treatment by time interaction) in tissue creatine levels (P<0.05), with the creatine group demonstrating better enhancement of creatine levels in the vastus medialis, left frontal lobe white matter, and right parietal lobe white matter than the placebo group. Furthermore, strong interaction effects between the interventions were reported in several other sites, including the right frontal lobe white matter, right paracentral lobe white matter, left parietal lobe white matter, and left parietal lobe medial gray matter (P<0.20).

[0086] Furthermore, Cohen effect sizes for primary and secondary outcomes after creatine supplementation demonstrated elevated brain levels in the thalamus (0.82 at 3 months), right frontal white matter (1.25 at 3 months and 1.32 at 6 months), right paracentral gray matter (0.88 at 3 months), left parietal white matter (0.92 at 3 months and 1.17 at 6 months), left parietal white matter (0.92 at 3 months and 1.17 at 6 months), parietal white matter (1.99 at 3 months and 1.74 at 6 months), left parietal messial gray matter (0.84 at 6 months), and right parietal messial gray matter (1.17 at 3 months and 1.06 at 6 months), with strong effect sizes 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 taste disorder) were assessed using a VAS scale (Table 3). Fatigue, including the group states of general fatigue, physical fatigue, metal fatigue, reduced activity, and reduced motivation, was assessed using the Multidimensional Fatigue Inventory Test (MFI-20 test, Smets EM et al., J. Psychosom. Res. 1995, 39(3), 315). The results of the VAS scale survey and the MFI-20 test are summarized in Tables 2 and 3.

[0090] [Table 2]

[0091] The tests carried out require the patient to report a score for the symptoms presented in Table 2. Thus, the higher the score, the greater the respective symptom is experienced by the interviewed patient. As a consequence, the lower the value given, the greater the effect of alleviating the respective symptom. As can be seen from Table 2, a fairly significant improvement in terms of mental fatigue was observed in the creatine group, but not in the placebo group. Furthermore, a particular improvement is seen in the symptom of decreased motivation.

[0092] [Table 3]

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

[0094] Additionally, patients were assessed for time to exhaustion by a progressive 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) with a 10% gradient and increasing to 9.7 km / h (6 miles / hour) with 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] In patients suffering from viral fatigue syndrome after SARS-CoV-2 virus infection, the time to exhaustion is significantly increased. The time to exhaustion in the creatine group increased by 7.3% compared to 2.1% after placebo intake. More importantly, the creatine group achieved stage 6 in the treadmill test, while the placebo group remained at stage 5. The improvement in endurance is further associated with a reduction in fatigue symptoms, especially mental fatigue and loss of motivation compared to the increase in the placebo group. Loss of motivation worsened during the observation period in the placebo group, whereas it improved slightly in the creatine cohort. According to the results presented in Table 2, in terms of fatigue symptoms such as physical fatigue and reduced activity, a smaller improvement is achieved by creatine administration compared to the placebo group. Moreover, 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 after SARS-CoV-2 infection. Eight post-COVID patients (age 33.5 ± 9.9 years, weight 72.3 ± 14.5 kg, and height 168.6 ± 11.0 cm, 4 women) of both sexes with moderate fatigue and respiratory disorders, or lung pain and pulmonary fatigue, volunteered to participate in this randomized controlled trial. All patients were assigned in a double-blind parallel-group design to receive either 4 grams of creatine monohydrate per day plus breathing exercises (2-3 times per day, 10-15 min) (experimental group) or breathing exercises alone (control group) during the 3-month intervention period.

[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 the individual 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 low at the beginning and gradually increased without placing a significant burden 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 with 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 sites and vastus medialis 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 at 3-month follow-up in the vastus medialis (P = 0.04), thalamus (P = 0.03), right frontal gray matter (P = 0.04), right precentral white matter (P = 0.01), right paracentral 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 gray matter), suggesting that creatine monohydrate and breathing exercises had a sizeable 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 were significantly decreased in the right frontal gray matter and the left medial parietal gray matter at the 3-month follow-up (P<0.05). Furthermore, two-way ANOVA with repeated measures revealed significant between-group differences in the changes in total creatine levels in the four brain regions (P<0.05), with the experimental group participants showing 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 the control group participants.

[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 following 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, poor concentration, headache, lung pain, fatigue) volunteered to participate in this randomized controlled parallel group intervention study. All patients were assigned in a double-blind parallel group design to receive tid administration of a powder mixture of creatine monohydrate and glucose (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) 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 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 white matter (brain), thalamus, vastus medialis and grey matter (brain) after creatine + glucose intervention or creatine intervention compared to 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 sites, with levels significantly elevated (P ≤ 0.05) compared with baseline concentrations in 8 sites, including 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. Cohen effect sizes (d) varied by site, with moderate or large effects in 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) for creatine monohydrate plus glucose. In experimental group 2, after 8 weeks of intervention, creatine concentrations increased significantly (P ≤ 0.05) in three sites, including vastus medialis and left and right medial parietal gray matter; 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 in 10 of 14 sites evaluated (71.4%) decreased from baseline levels. Two-way ANOVA with repeated measures (treatment by 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 being superior to the control group in increasing creatine levels in these two sites. There was a strong trend towards superior creatine levels in other locations, including 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). Two-way ANOVA with repeated measures (treatment by time interaction) revealed significant between-group differences in the change in total creatine concentration in right precentral white matter and left paracentral gray matter (P<0.05). Experimental groups 1 and 2 were superior to the control group in increasing creatine levels in these two locations. There was a strong trend towards superior creatine concentrations in other locations, including 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, poor concentration, anosmia, and dysgeusia) were assessed using a VAS scale. Fatigue, including the group states of general fatigue, physical fatigue, metal fatigue, reduced activity, and reduced 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 the MFI-20 test are summarized in Tables 8 and 9.

[0110] [Table 8]

[0111] [Table 9]

[0112] In addition, 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] In patients suffering from post-viral fatigue syndrome after SARS-CoV-2 virus infection, the time to exhaustion is significantly prolonged. The time to exhaustion in the creatine group is prolonged by 20 sec. in experimental group 2 (creatine group) after administration (P=0.03). More importantly, the intake of a combination of creatine and glucose prolongs the time to exhaustion in the treadmill test by 27 sec., which is contrary to expectations, considering that the time to exhaustion is worsened after glucose intake (-7 sec.). In experimental group 2, the fatigue score in the reduced activity subdomain was significantly reduced with the improvement in endurance (P=0.008), d=1.52, suggesting a greater effect of creatine monohydrate on this condition. The improvement in endurance is further accompanied by an improvement 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 weeks of follow-up (P ≤ 0.05); the Cohen effect size (d) for the reduction in poor concentration was 0.80, suggesting a large 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 large effect of creatine monohydrate. Participants who received the control intervention did not experience significant changes in most variables at 8 weeks of 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 to improve tissue bioenergetics and some 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 sites (including both white and grey matter) and patient-reported symptoms such as reduced 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 sites throughout the brain, but had no effect on most patient-reported outcomes with post-COVID fatigue syndrome. However, endurance was improved with the combined intake of creatine and glucose, despite patient-reported outcomes being neutral.

[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 classified as small (d = 0.2), medium (d = 0.5, dashed line) and large (d ≥ 0.8). Missing values ​​are due to statistical limitations in the calculation of 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 a physiologically acceptable derivative thereof and / or a salt thereof and / or an adduct thereof for use in the treatment of post-viral fatigue syndrome (PVFS) accompanied by conditions selected from the group consisting of mental fatigue, loss of motivation and decreased concentration and / or for use in prolonging the time to exhaustion.

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

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition is used in combination with glucose, preferably for extending the time to exhaustion in a subject suffering from Post-COVID Fatigue Syndrome (PCFS).

4. Physiologically acceptable creatine derivatives include creatine, creatine hydrate, creatine C １ -C ５ -Alkyl ester, N-C １ -C ５ 4. The pharmaceutical composition of claim 1, wherein the creatine ester or amide, such as -alkylamide, guanidinoacetic acid, creatinol, creatinol-O-phosphate or mixtures thereof.

5. 5. The pharmaceutical composition of claim 1, wherein the salts and adducts of creatine or physiologically acceptable creatine derivatives are 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, the corresponding potassium, sodium, calcium, magnesium salts, the corresponding L-carnitine adducts, acetyl-L-carnitine adducts, taurine adducts, betaine adducts, choline adducts, methionine adducts or mixtures thereof.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the composition comprises creatine monohydrate.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the daily dose of creatine in the composition ranges from 7 g to 30 g.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, 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.

9. The pharmaceutical composition according to any one of claims 1 to 8, in combination with glucose.

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

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

12. 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 or supplement for the preparation of a food for supporting recovery from PVFS accompanied by conditions selected from the group consisting of mental fatigue, decreased motivation, decreased activity, and decreased concentration, as well as improving time to exhaustion.

13. 10. The use of claim 9, wherein PVFS is caused by coronavirus infection or is a post-COVID symptom.

14. 11. Use according to claim 9 or 10, wherein the composition is used in combination with glucose, preferably for extending the time of exhaustion in subjects suffering from Post-COVID Fatigue Syndrome (PCFS).

15. The use according to any one of claims 9 to 11, wherein the daily dose of creatine in the composition ranges from 7 g to 30 g.

16. 13. The use according to any one of claims 9 to 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.

17. Use according to any one of claims 9 to 13, wherein the composition used comprises creatine monohydrate.

18. The use according to any one of claims 12 to 17 in combination with glucose.

19. 20. The use of claim 18, wherein glucose is administered within 1 hour before and 1 hour after creatine administration.

20. 20. The use of claim 18 or 19, wherein the daily dose of glucose used in combination with glucose is in the range of 1 g to 10 g.

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