Compositions comprising creatine for treatment of post-viral fatigue syndrome

Abstract

The present invention relates to a pharmaceutical composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof for use in the treatment of PVFS, in particular PVFS associated with mental fatigue, impaired motility, reduced activity or difficulty in concentration of attention. Another embodiment of the present invention relates to the use of a composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof as a dietary supplement for the preparation of a diet for supporting a recovered diet from PVFS.

Description

Field of the invention:

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

[0002] Although COVID-19 is considered a disease that primarily affects the lungs, it can also damage other organs, including, for example, the heart, vascular system, kidneys, and brain. Organ damage increases the risk of sequelae such as cognitive impairment, cardiac complications (myocarditis), chronic renal impairment, stroke, thrombosis, and Guillain-Barré syndrome.

[0003] However, most people who are infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) recover within a few weeks. But some people, even those with milder forms of the disease, continue to experience the symptoms after they initially recover.

[0004] Typical symptoms that may persist after SARS-CoV-2 infection include fatigue (such as post-viral fatigue syndrome (PVFS) or chronic fatigue syndrome (CFS)), difficulty breathing or shortness of breath (dyspnea), lung or chest pain, joint pain, muscle pain or headache, difficulty with concentration and memory, sleep problems (insomnia), loss of smell (anosmia) or loss of taste (anosmia), among which fatigue, dyspnea and chest pain are the most commonly reported symptoms after acute SARS-CoV-2 infection.

[0005] PVFS is a complex, long-term condition characterized by an inability to participate in routine activities of daily life that were possible before the viral infection, lasting at least 3 months. Coronavirus infection is often associated with PVFS, in addition to other negative consequences.

[0006] In severe courses, approximately 70% of COVID patients suffer from fatigue during the acute phase of infection, with the symptom often persisting after the patient recovers 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 described condition is summarized by the term “post-COVID-19 syndrome” or “long-COVID-19”, hereafter referred to as post-COVID.

[0008] People with post-viral fatigue syndrome complain of physical and mental exhaustion, including decreased activity, reduced motivation, poor memory, difficulty concentrating, restless sleep, mood swings, and in some cases, depression. Advice for these people is usually limited to behavioral advice, such as keeping exercise low in intensity at first and increasing activity slowly, maintaining a routine of daily activities (eating, sleeping, etc.) to support recovery.

[0009] In Deutsches Practical medical strategies for patients with long COVID are summarized in 2020;49,117 and are based on initial 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 emphasize the fact that strong data from clinical trials are needed to support any such hypothesis. Adequate nutrition is required to support immune cell function to allow a strong response to pathogens. The micronutrients with the strongest evidence of immune support are vitamins C, D, and zinc.

[0011] Creatine is a methylguanidinoacetic acid that is commonly available from animal foods and / or is naturally produced in the body from the amino acids arginine, glycine, and methionine. Endogenous creatine synthesis provides about half of the daily requirement. The remaining amount of creatine required to maintain normal tissue creatine levels is obtained in the diet from animal products (such as fish or meat) or dietary supplements. Creatine plays a vital role in the energy metabolism of every cell in the body. It acts as a metabolic intermediate for energy transfer primarily by promoting the recycling of ATP, which is a source of energy for use and storage at the cellular level.Therefore, high concentrations of creatine are found in organs with high energy turnover, with ~95% of human creatine stored in skeletal muscle and the remaining 5% stored 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, RC et al., Elevation of creatine in resting and exercised muscle of normal subjects by creatinesupplementation.Clin.Sci.1992,83,367-374; Kreider, RB; Stout,JRCreatine inHealth 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 an auxiliary measure for the treatment of various diseases. In particular, Ostojic, SM et al., for example, describe a dietary treatment for chronic fatigue syndrome (CFS) containing guanidinoacetic acid (GAA) (Nutrients 2016, 8, 72). The effectiveness of creatine in the treatment of post-viral fatigue syndrome (PVFS) is discussed in Ostojic, SM Nutritions 2021, 13, 503; Kreider RB et al., Nutritions 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 is about the use of creatine and coenzyme Q 10Study on dietary supplementation. COPD is a respiratory disease, while PVS and especially after COVID are neurological diseases. SMOstojic, 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 Supplement): 67-73 proposed food supplements for controlling post-COVID syndrome. Among them, a food supplement composition containing vitamin C, acetyl-L-carnitine, hydroxytyrosol / olive polyphenols, thiamine, vitamin B6, folic acid, vitamin D3 and vitamin B12 is suggested. L. Barrea et al., Nutrients 2022, 14, 1305 gives dietary recommendations for post-COVID-19 syndrome. Regarding post-COVID-19 fatigue syndrome, the authors postulate that there is evidence that deficiencies in certain nutrients appear to be important, including vitamin C, B vitamins, sodium, magnesium, zinc, folate, L-carnitine, L-tryptophan, essential fatty acids, and coenzyme Q 10 .

[0014] Starting from this, the problem to be solved by the present invention is to improve the recovery of post-viral fatigue syndrome (PVFS) caused by, for example, the SARS-CoV-2 virus, in particular in patients with PVFS associated with mental fatigue, reduced motivation, decreased activity or difficulty concentrating. Summary of the invention:

[0015] This problem is solved by administering creatine to patients in need thereof. Creatine supports recovery from PVFS, especially when PVFS is caused by the SARS-CoV-2 virus. In particular, the mental state of patients suffering from PVFS can be improved by administering creatine, and / or the time to exhaustion can be increased. The mental state of the patient includes parameters such as mental fatigue, reduced motivation and difficulty concentrating.

[0016] Post-viral fatigue syndrome (PVFS) is a puzzling long-term neurological condition. PVFS is characterized in particular by the inability to participate in daily activities that were possible before the illness, lasting for more than six months, accompanied by fatigue, post-exertional malaise, and restless sleep. PVFS-related symptoms are often found especially after infection with members of the coronavirus family (SARS-CoV2), leading in many cases to post-COVID fatigue syndrome.

[0017] The inventors of the present application surprisingly found that creatine is effective in improving conditions related to the patient's mental state (such as mental fatigue, reduced motivation and difficulty concentrating) and increasing the time to exhaustion in patients with PVFS. This effect is supported by the finding that a strong enrichment of creatine in the thalamus, gray matter and especially white matter of the brain in patients after COVID (see Figure 1 ). The enrichment is achieved by supplementing creatine in patients in need thereof.

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

[0019] In addition, the inventors of the present application found that, without creatine supplementation, long COVID patients showed only low levels of creatine in the brain. Within the framework of the present invention, it was found that the total creatine concentration in the brain of long COVID patients, especially in the thalamus, white matter and gray matter, was significantly reduced compared to the reference values ​​of the general population. Therefore, without being bound by any theory, it is assumed that one of the effects and / or causes of long COVID is the depletion of creatine in brain regions, resulting in a decrease in creatine levels in these brain regions. Through the discovery of the present invention, that creatine is able to cross the blood-brain barrier of long COVID patients, creatine levels in brain regions can be enriched and / or increased by adding creatine.

[0020] It is particularly surprising that, on the one hand, total creatine concentrations in the brain of long COVID patients were found to be reduced compared to reference values ​​for the general population, and on the other hand, in post-COVID patients, a significant enrichment of creatine was found in the brain, in particular in the thalamus, gray matter and / or white matter, whereas after creatine supplementation, no increase in creatine in the brain was seen in normal healthy people, or only a very small maximum increase of about 5% was seen. It appears that long COVID leads to a depletion of brain creatine and at the same time changes the properties of the blood-brain barrier, allowing the supplemented creatine to pass through and leading to a significant increase in creatine in the brain after creatine supplementation. Surprisingly, according to the present invention, the enrichment of creatine in the brain after creatine supplementation was found to indicate that creatine in long COVID patients can pass the blood-brain barrier. In particular, it was found that creatine supplementation alone, i.e. creatine supplementation without the addition of any transporters or adjuvants known to modify the blood-brain barrier, leads to an enrichment of creatine in the brain.

[0021] Thus, according to the present invention, prolonged brain-related COVID symptoms such as mental fatigue, decreased motivation, difficulty concentrating, and / or exhaustion (all of which are neurological conditions) can be treated.

[0022] One of the difficulties associated with finding appropriate treatment for PVFS, especially post-COVID, is the diversity, multiplicity, variety, and ambiguity of symptoms associated with post-COVID, as well as the uncertainty of the causes of the symptoms. This complicates post-COVID treatment and the prediction of which agent or treatment may work in post-COVID treatment. Post-COVID manifestations can appear as many different conditions and symptoms, including pulmonary conditions, neurological symptoms and conditions such as headache, nasal smell disorders, impaired taste, dizziness, confusion, disorientation and other injuries, neuropsychiatric disorders, stroke, gastrointestinal symptoms such as nausea, loss of appetite, vomiting, diarrhea, etc.; cardiovascular diseases including myocarditis, cardiac insufficiency, heart failure, and thromboembolic events; renal insufficiency; dermatological manifestations. In particular, for long-term effects, a consistent clinical phenomenon cannot be determined, and the underlying mechanism is unclear. Post-COVID patients report quite different symptoms that last for weeks or even months. Frequently reported complaints or symptoms include fatigue, tiredness, mental fatigue, syndrome, impaired elasticity, memory problems, sleep problems, muscle weakness, muscle pain, and mental problems (such as depressive symptoms and anxiety). Other symptoms reported include worsening lung function, worsening lung function, worsening kidney function, and myocardial inflammation. However, this list is by no means definitive and shows the diversity and variety of conditions and symptoms associated with post-COVID. Even more unknown to date are the causes of those conditions and symptoms caused by COVID or post-COVID. Therefore, providing suitable post-COVID treatments is difficult because the mutual applicability of known treatments for similar symptoms does not exist.

[0023] According to the present invention, it has now surprisingly been found that a pharmaceutical composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof is effective for treating a specific condition selected from mental fatigue, reduced motivation, and difficulty concentrating associated with post-COVID, and is further suitable for increasing the time of exhaustion in post-COVID patients. As outlined above, the causes of many different symptoms associated with post-COVID are unclear and, therefore, effective treatment is unpredictable. In addition, it seems that not only are there quite a lot of symptoms, but also quite a lot of conditions that cause various symptoms. In the tests and experiments that form the basis of the present invention, it has now been found that the provision of creatine particularly improves the mental state of post-COVID patients, in particular improves the state of mental fatigue, reduced motivation and difficulty concentrating. In particular, significant improvements were found in terms of mental fatigue.

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

[0025] A second embodiment of the present invention is the use of creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof as a dietary supplement or as a supplement for the preparation of a diet that supports recovery from PVFS, in particular when PVFS is caused by SARS-CoV-2 and when PVFS is associated with symptoms selected from the group consisting of mental fatigue, decreased motivation or difficulty concentrating. Thus, the mental status of subjects suffering from post-COVID fatigue (PCFS) in particular can be improved by administering creatine.

[0026] Another embodiment of the present invention is the combined administration of creatine and glucose. Glucose supports the uptake of creatine in the brain compared to taking creatine alone. Although it has been found according to the present invention that creatine administered alone can surprisingly cross the blood-brain barrier of post-COVID patients and is therefore enriched in brain areas, it has also been found that the uptake of creatine in the brain can be further enhanced by supplementing with glucose. Surprisingly, the time to exhaustion in post-COVID patients can be increased by administering glucose in addition to creatine compared to creatine alone, although glucose alone reduces the time to exhaustion.

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

[0028] In another embodiment of the present invention, a pharmaceutical composition or dietary supplement comprising creatine or its physiologically acceptable derivatives and / or salts and / or adducts is combined with pulmonary rehabilitation and in particular with breathing exercises for the treatment of PVFS. As used herein, the term breathing exercises includes physical exercise, and also includes pulmonary rehabilitation. Preferably, according to Wang TJ et al., Am J Phys Med Rehabil, June 11, 2020 (DOI 10.1097 / PHM.0000000000001505 / PMCID:7315835), pulmonary rehabilitation is performed. Pulmonary rehabilitation is tailored for each patient and includes, for example, improved segmented breathing, breathing exercises for strengthening lung muscles, bed activity exercises, stretching, gymnastics and / or walking. The degree of exercise is low at the beginning, and then slowly increases without subjecting the patient to greater efforts. The frequency of exercise is, for example, 2 to 4 times a day, 10 to 15 minutes each time. Exercise time can be slowly increased. If the patient's health permits, pulmonary rehabilitation measures, such as breathing exercises to train the respiratory and expiratory muscles, should be started as soon as possible. Rehabilitation is usually started within 20 weeks, preferably within 12 weeks, and most preferably within 6 weeks after the infection resolves.

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

[0030] The compositions of the invention comprising creatine are particularly useful for supporting recovery from fatigue syndrome following viral infections such as SARS-CoV-2 infection, especially when the fatigue syndrome following viral infection is associated with mental fatigue, reduced motivation and difficulty concentrating. However, PVFS is one of the most commonly occurring post-COVID conditions. Fatigue syndrome often persists for weeks, months or even longer in patients who have overcome SARS-CoV-2 infection and can significantly compromise overall health.

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

[0032] By administering creatine, particularly in combination with glucose, recovery of patients with PVFS can be surprisingly improved. 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-guanidinoglycine. Creatine can also be obtained from animal foods or as a food supplement in higher amounts. In food supplements, creatine monohydrate is preferably used, which can be prepared in 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 creatine prodrugs that can release creatine under physiological conditions, such as creatine esters. In the description of the present invention, guanidinoacetic acid (GAA) is also included in the group of suitable creatine derivatives. Physiologically acceptable creatine derivatives are preferably selected from the group consisting of: creatine, creatine hydrate, creatine ester or amide, including creatine C1-C5-alkyl esters, N-C1-C5-alkyl amides, creatine phosphate, inositol-O-phosphate or its mixture.

[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 acetates, citrates, maleates, fumarates, tartrates, malates, pyruvates, ascorbates, succinates, aspartates, lactates, oxalates, formates, benzoates, phosphates, sulfates, chlorides, hydrochlorides, the corresponding potassium, sodium, calcium, magnesium salts, the corresponding L-carnitine, acetyl-L-carnitine, taurine, betaine, choline, methionine adducts or mixtures thereof.

[0035] Treatment with creatine can already be started during viral infection, preferably within about three months (12 weeks) after infection. The duration of creatine supplementation generally lasts from 1 week to 18 months or more, preferably from 1 to 12 months, in particular from 3 to 8 months, depending on the symptoms of the subject in need.

[0036] The amount of creatine to be administered is in the range of 3 g to 30 g per day. Preferably, the dosage is in the range of 7 g to 25 g, most preferably between 8 g and 20 g, which is higher than the dosage usually recommended for athletes or sportswomen.

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

[0038] The build-up period is typically the initial period. However, additional build-up periods, such as build-up periods lasting between 1 and 7 days, may be incorporated into the maintenance period.

[0039] The daily creatine dose may be administered once a day, for example during breakfast, or in 2, 3, 4 or 5 divided doses a day.

[0040] If 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, in particular from 1:1 to 1:3.

[0041] If the administered creatine composition comprises a creatine derivative, prodrug, adduct or salt, the amount of the creatine moiety comprised therein is decisive for the daily dosage within the above-mentioned range.

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

[0043] In particular, the granules or powders comprising the creatine composition are used in aqueous suspension or water-soluble form. Pure creatine and several creatine derivatives have low solubility. For example, the solubility of creatine is 17 g / L (at 20° C.). Creatine and its low-solubility derivatives can be used in the form of aqueous suspensions. The disadvantage of aqueous suspensions is usually that they separate before ingestion. Therefore, water-soluble granules or powders are generally preferred. In order to increase the water solubility of creatine or creatine derivatives, their water-soluble salts or adducts can be used. In order to increase water solubility, the use of acids or complexing agents in particular can help provide the corresponding creatine salts or creatine derivative salts. Examples of suitable acids (including carboxylic acids) and complexing agents are selected from malic acid, aspartic acid, ascorbic acid, succinic acid, pyruvic acid, fumaric acid, gluconic acid, α-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 can also help increase the solubility of creatine and creatine derivatives. Sodium, potassium, calcium and magnesium salts can also be used to increase the water solubility of creatine or creatine derivatives.

[0044] The molar ratio of creatine or creatine derivatives to the above-mentioned acids or complexing agents is generally 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 powders may also be used to prepare food products that support recovery from PVFS, particularly by improving the mental status of patients suffering from PVFS.

[0046] The creatine composition used according to the present invention may further be administered in the form of a tablet.

[0047] The creatine composition can be tableted as is or in the form of a preparation containing excipients. Suitable excipients are, for example, pharmacologically inactive ingredients such as binders, fillers, antioxidants, preservatives, stabilizers, anti-caking agents, lubricants, disintegrants, flavoring agents, pigments, etc.

[0048] As binders or fillers, a variety of compounds can be used. Dicalcium phosphate; sugars, including lactose and sucrose; polysaccharides and their derivatives, including 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; polymers, such as polyvinyl pyrrolidone, polyethylene glycol, etc. are commonly used binders or fillers for tablets.

[0049] Typical suitable preservatives are for example cysteine, methionine, citric acid, sodium citrate, triazines or synthetic preservatives such as parabens, including methyl and propyl paraben, 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 adhesion in granules or powders, thereby preventing sticking to tablet punches. They are also used to help protect tablets from sticking. The most commonly used anti-caking agents are magnesium stearate, stearic acid or stearin, but magnesium or calcium salts of other fatty acids may also be used alternatively or in addition. For example, common mineral lubricants are talc or silica.

[0051] Disintegrants swell and dissolve when wet, causing the tablet to disintegrate in the digestive tract or at a specific point in the digestive process, releasing the ingredients for absorption by the body. Examples of disintegrants include cross-linked polymers, such as cross-linked polyvinyl pyrrolidone (crospovidone) and cross-linked sodium carboxymethylcellulose (croscarmellose sodium). Other suitable disintegrants are, for example, modified starch or sodium starch glycolate.

[0052] Flavoring agents can be used to mask unpleasant tablet ingredients. In addition, the ingredients can 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 flavoring agents. Antacid compounds or cough syrups are also suitable.

[0053] Suitable pigments and colors are, for example, food colorings.

[0054] Tablet coatings protect tablet ingredients from deterioration due to moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a film coating of cellulose ethers, especially hydroxypropylmethylcellulose (HPMC), is used. However, other coating materials are also useful, such as synthetic polymers, shellac, plant fibers, waxes, fatty acids, or polysaccharides. Capsules are commonly coated with gelatin.

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

[0056] Preferably the tablet comprises at least

[0057] a) 10 to 100% by weight, preferably 30 to 99% by weight, of creatine, a creatine derivative or a salt or adduct thereof;

[0058] b) 0 to 80% by weight of carbohydrates, preferably comprising glucose;

[0059] c) 0 to 20% by weight of an anti-caking agent selected from fatty acids or fatty acid salts, in particular magnesium stearate;

[0060] d) 0 to 20% by weight of an acidulant, preferably citric acid;

[0061] e) 0 to 20% by weight of fatty acids, preferably coconut oil;

[0062] f) 0 to 5% by weight of flavoring agents.

[0063] Preferably the capsule contains at least

[0064] a) 10 to 95% by weight, preferably 30 to 80% by weight, of creatine, creatine derivatives or salts or adducts thereof

[0065] b) 0 to 80% by weight of carbohydrates, preferably comprising glucose;

[0066] c) 0 to 20% by weight of an anti-caking agent selected from fatty acids or fatty acid salts, in particular magnesium stearate,

[0067] d) 0 to 5% by weight of flavoring agents;

[0068] e) 5 to 90% by weight of gelatin.

[0069] The composition can be used not only in tablets, but also in granules or powders containing creatine or creatine derivatives or salts or adducts thereof. In particular, binders, fillers, antioxidants, preservatives, stabilizers, anti-caking agents, lubricants, disintegrants, flavoring agents, pigments and carbohydrates can be part of the creatine composition used according to the invention. Preferably, the granules or powders contain a combination of creatine and glucose.

[0070] Preferred granules or powders in connection with the invention contain 10 to 100 wt. %, preferably 30 to 99 wt. % of creatine, a creatine derivative or a salt or adduct thereof.

[0071] Particularly preferred tablets, capsules, granules or powders contain 10 to 80 wt% glucose, preferably between 30 and 70 wt% glucose. The preferred ratio of creatine:glucose in the composition is in the range of 1:3 to 3:1, most preferably between 1:2 and 2:1.

[0072] Creatine and glucose can be formulated together, for example, in tablets, capsules or granules, but the combination can also be administered as a mixture of compounds, for example in the form of a powder. Another possibility is to take creatine monohydrate and glucose separately, preferably with a time lag of less than 2 hours, most preferably less than 1 hour or even less than 30 minutes. It is advantageous to administer creatine and glucose together. However, it is more preferred to take creatine in a first step and then administer glucose in a second step.

[0073] Anti-inflammatory drugs can be administered in combination with creatine, creatine derivatives or salts or adducts thereof. Anti-inflammatory drugs are, for example, non-steroidal drugs such as aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, etc., or steroids such as corticosteroids, including cortisone, hydrocortisone and prednisone.

[0074] Further combinations of creatine, creatine derivatives or salts or adducts thereof with neuroprotective drugs may be advantageous. Preferred neuroprotective agents include glutamate excitotoxicity inhibitors such as ginsenosides, riluzole, progesterone, estrogen, memantine or simvastatin; stimulants such as caffeine; growth factors such as IGF-1, CNTF; nitric oxide synthase inhibitors; and caspase inhibitors or erythropoietin.

[0075] Combination of creatine, creatine derivatives or salts or adducts thereof with drugs for the treatment of viral infections is also possible, in particular if the administration of creatine is started during the acute phase of the viral infection.

[0076] For the treatment of COVID-19, for example, the following group of drugs can be used: Lagevrio (monuprivir), Olumiant20 (baricitinib), tesagvir / segavir, Kineret (anakinra), Paxlovid (PF-07321332 / ritonavir), Regkirona (redanvir), RoActemra (tocilizumab), Ronapreve (casirivimab / imidavimab), Veklury (remdesiviv), Xevudy (sotrovimab). For the treatment of influenza, Rapivab (peramivir), Relenza (zanamivir), Tamiflu (oseltamivir phosphate), Xofluza (baloxavir mapositate) are suitable drugs. For the treatment of adenovirus, cidofovir, ribavirin, ganciclovir and vidarabine are useful drugs.

[0077] According to a preferred embodiment of the present invention, creatine, creatine derivatives or salts or adducts thereof are preferably used in combination with a pain-relieving, anti-inflammatory diet. Preferably, the diet should provide all nutrients for normal energy metabolism and healthy function of the nervous system. Particularly suitable diets should contain vitamins, minerals, unsaturated fatty acids, amino acids, secondary plant metabolites, including antioxidants, phytonutrients or essential or semi-essential nutrients.

[0078] For pain relief, anti-inflammatory diets, especially vitamin C, vitamin D, vitamin E, vitamin K, and B vitamins (thiamine, riboflavin, niacinamide, pantothenic acid, pyridoxine, biotin, folic acid, and / or vitamin B 12 ) should be administered in sufficient amounts.

[0079] Important minerals are selected from the group of magnesium, calcium, potassium, sodium, copper, manganese, zinc, selenium and boric acid / boron.

[0080] Vitamins and minerals should be present in the diet in sufficient quantities so that no deficiency symptoms occur. The German Nutrition Society gives appropriate recommendations for the daily amounts of these nutrients (Deutsche Gesellschaft für eV,Reference for this 2.Auflage,7.Aktualisierte Ausgabe,2021).

[0081] Another useful group of nutrients for 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.

[0082] The preferred diet should also be enriched with amino acids selected from the group of L-tyrosine, arginine and glycine. Additional amino acids are enriched in the preferred diet, such as theanine, cystine, taurine or mixtures thereof.

[0083] Other compounds that should be present in a pain-relieving, anti-inflammatory diet are N-acetyl-L-cysteine, gamma-amino-butyric acid (GABA), S-adenosylmethionine (SAMe), ubiquinol (Coenzyme Q10), NADH, resveratrol, lutein, lycopene, choline, and carnitine.

[0084] Phytonutrients particularly useful in pain relief, anti-inflammatory diets include secondary plant metabolites, such as antioxidants, anthocyanidines, flavonoids, flavonoids, isoflavonoids, catechins, anthocyanidins, isothiocyanates, carotenoids, allyl sulfides, polyphenols, resveratrol, lutein or lycopene. Particularly preferred secondary plant metabolites are oligomeric proanthocyanidins and oligomeric proanthocyanidins (OPC).

[0085] For the preferred diet, plants, in particular herbs, spices, fruits, vegetables and legumes, or extracts, oils, powders or compounds thereof may also be used, for example from groupboswellia serrata, turmeric, 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 or fruits (such as strawberries, blueberries, cherries and oranges) are considered anti-inflammatory foods. Fatty fish like salmon, mackerel, tuna and sardines also have anti-inflammatory effects.

[0086] The recommended nutrients for a pain-relieving, anti-inflammatory diet can be provided by selecting appropriate foods or by adding the corresponding components through nutritional supplements.

[0087] Description of the drawings:

[0088] Figure 1 : Changes in tissue creatine levels in patients after COVID. The left column represents the group of patients who received creatine and the right column represents the placebo group. Figure 2 Described are the calculated Cohen effect sizes for creatine administration in post-COVID patients. Specific implementation method:

[0089] Embodiment 1:

[0090] A study was conducted to evaluate the efficacy and safety of creatine supplementation via dietary supplementation in patients with post-COVID following SARS-CoV-2 infection. The study adopted a parallel-group, randomized placebo-controlled, double-blind design. The allocation ratio of the experimental group (creatine) and the control group (placebo) was set at 1:1. The eligibility criteria for patients included in this trial were: age 18-65 years, positive COVID-19 test in the past 3 months (as demonstrated by a valid PCR or antigen test), moderate to severe fatigue, and at least one of the other COVID-19 related symptoms such as anosmia, loss of taste, dyspnea, lung pain, body pain, headache, and difficulty concentrating. Exclusion criteria were other pulmonary and cardiovascular conditions, and a history of dietary supplement use in the 4 weeks before the start of the trial.

[0091] The study was conducted in accordance with the Declaration of Helsinki (7th edition). The data presented here were collected from October 2021 to January 2022 at the FSPE Applied Bioenergy Laboratory at the University of Novi Sad, Serbia. The experimental (creatine) group received 4 g of creatine monohydrate per day, while the control (placebo) group received an equal amount of inulin. Participants were asked to perform the intervention once a day at breakfast by stirring the experimental or control powder in 250 ml of warm water and drinking it immediately. Both interventions were similar in appearance, texture and sensory characteristics. Creatine monohydrate was provided by AlzchemTrostberg GmbH (Trostberg, Germany). The intervention duration was 6 months, and participants were asked to avoid the use of any other dietary supplements during the trial. All measurements were determined at baseline (before administration) and after 3 and 6 months. The primary outcome was the change in brain creatine levels at baseline and at 3 and 6-month follow-up. The minimum sample size (n = 12) was analyzed using power analysis (G*Power 3.1.9.3, Heinrich-Heine-University Düsseldorf Düsseldorf)) with an effect size of 0.50 (medium effect), an alpha error probability of 0.05, and a power of 0.80 for both groups, with two measurements (3 months) and three measurements (6 months follow-up), respectively.

[0092] The total number of participants who were randomly assigned, received the intended treatment, and analyzed for the primary outcome was 12, 6 in the experimental group and 6 in the control group. The recruited participants reported no significant side effects from either intervention so far.

[0093] Creatine accumulation in skeletal muscle of post-COVID patients.

[0094] Creatine tissue levels were measured with proton magnetic resonance spectroscopy (1.5T Avanto scanner, Siemens, Erlangen, Germany) using a matrix head coil in circular polarization mode, with metabolite profiles in skeletal muscle and specific regions of the brain (vastus medialis, thalamus, frontal, precentral, paracentral, and parietal white and gray matter) processed as previously described (Appl Physiol Nutr Metab. 2016 Sep; 41(9): 1005-7.).

[0095] Statistical methods:

[0096] Initially, the data were analyzed for normality of distribution using the Shapiro-Wilk test and for homogeneity of variance using the Bartlett test. When homogeneous variances were verified for normally distributed data, summary measures of interaction effects (time vs. intervention) were compared with repeated measures by two-way ANOVA. When non-homogeneous differences were identified, data were compared using the Friedmann test. Post hoc LSD tests and Wilcoxon tests were used to determine differences between individual sample pairs for two-way ANOVA and Friedmann tests, respectively. The significance level was set at P ≤ 0.05. Effect sizes after intervention were assessed using the Cohen statistic, where d ≥ 0.8 indicated a larger effect. Data were analyzed using the statistical package SPSS 24.0 for Mac (IBM SPSS Statistics, Chicago, IL).

[0097] Table 1 summarizes the changes in tissue creatine levels after 3 months in patients with COVID. The table shows the changes in tissue creatine levels in the white matter (brain), thalamus, vastus medialis, and gray matter (cerebrum) after 3 and 6 months of intervention with 4 g creatine per day compared to creatine levels in the placebo group.

[0098] Table 1. Changes in tissue creatine levels (mM)

[0099]

[0100] Figure 1 The percentage difference in creatine levels after three months from the corresponding baseline levels in the white matter (cerebrum), gray matter (cerebrum), thalamus and vastus medialis muscle calculated from Table 1 is shown in FIG. The left column represents the patient group receiving creatine and the right column represents the placebo group. For the values ​​in the white matter and gray matter, the mean values ​​were determined from Table 1.

[0101] In a randomized controlled trial, creatine was found to accumulate in the brain and vastus medialis muscle when administered for 3 months. The elevated creatine levels could be maintained for at least another 3 months with supplemental creatine administration. No changes in tissue creatine values ​​were found in the placebo group.

[0102] Participants in the experimental group experienced increases in total tissue creatine levels in all fourteen (14) sites assessed in the study, with higher increases at 6-month follow-up found in the vastus medialis (P = < 0.01), left frontal white matter (P = 0.01), and right parietal white matter (P = 0.01). Tissue creatine values ​​did not change in the placebo group throughout the trial. A two-way ANOVA with repeated measures revealed significant differences between interventions in tissue creatine levels (treatment vs. time interaction) (P < 0.05), with the creatine group being superior to the placebo group in increasing creatine levels in the vastus medialis, left frontal white matter, and right parietal white matter. In addition, strong interactions between interventions were reported in several other sites, including the right frontal white matter, right paracentral gray matter, left parietal white matter, and left medial parietal gray matter (P < 0.20).

[0103] Furthermore, 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), parietal white matter (1.99 at 3 months and 1.74 at 6 months), left parietal gray matter (0.84 at 6 months), and right parietal gray matter (1.17 at 3 months and 1.06 at 6 months) confirmed Cohen effect sizes for the primary and secondary outcomes after creatine intake and strong effect sizes for creatine (d ≥ 0.8).

[0104] In conclusion, creatine was found to be enriched in the brains of post-COVID patients following creatine supplementation and thus cross the blood-brain barrier.

[0105] Effects of creatine as a nutritional supplement in post-COVID patients.

[0106] The results of COVID-19 related signs and symptoms (e.g., headache, difficulty concentrating, anosmia, anosmia) reported by patients were evaluated using the VAS scale. Fatigue was assessed using the Multidimensional Fatigue Inventory Test (MFI-20 test, Smets EM et al., J. Psychosom. Res. 1995, 39 (3), 315), including the conditions of the group of general fatigue, physical fatigue, metal fatigue, reduced activity, and reduced motivation. The results of the VAS scale survey and the MFI-20 test are summarized in Tables 2 and 3.

[0107] Table 2:

[0108]

[0109] In the tests performed, the patients should report the scores of the symptoms given in Table 2. Therefore, the higher the score, the more severe the corresponding symptom experienced by the interviewed patient. Therefore, the lower the value given, the better the relief effect of the corresponding symptom. As can be seen from Table 2, a quite significant improvement was observed in the creatine group with respect to mental fatigue, which was not observed in the placebo group. In addition, a certain improvement was also seen with respect to symptom reduction in motivation.

[0110] Table 3:

[0111]

[0112] As can be seen from Table 3, in the creatine group, the condition of difficulty in concentration could be significantly improved.

[0113] In addition, the patient's time to exhaustion was assessed by performing an incremental test on a motorized treadmill until exhaustion. The speed and slope of the treadmill were increased every three minutes, starting with a 10% slope, 2.7 km / h (1.7 miles / hour), and rising to the 7th stage, reaching a 22% slope, 9.7 km / h (6 miles / hour) (Will PM and Walter JD, Am Heart. J., December 1999, 138, 1033). The results of the treadmill assessment are provided in Table 4.

[0114] Table 4:

[0115]

[0116] In patients with post-viral fatigue syndrome after SARS-CoV-2 infection, the time to exhaustion increased significantly. The time to exhaustion increased by 7.3% in the creatine group compared to 2.1% after taking a placebo. More importantly, the creatine group reached stage 6 in the treadmill test, while the placebo group remained at stage 5. The improvement in endurance was associated with a reduction in fatigue symptoms, especially a reduction in mental fatigue and decreased motivation, compared to the increase in the placebo group. The decreased motivation in the placebo group worsened during the observation period, compared to the slight improvement in the creatine cohort. According to the results shown in Table 2, smaller improvements in fatigue symptoms (such as physical fatigue) and reduced activity were achieved by creatine administration compared to the placebo group. In addition, creatine did not cause major side effects.

[0117] Embodiment 2:

[0118] Combining Creatine Supplementation with Pulmonary Rehabilitation:

[0119] A second study was conducted to evaluate the efficacy and safety of creatine supplementation via dietary supplementation in patients with post-COVID following SARS-CoV-2 infection. Eight male and female post-COVID patients (age 33.5±9.9 years, weight 72.3±14.5 kg, height 168.6±11.0 cm; 4 women) with moderate fatigue and dyspnea or lung pain and discomfort volunteered to participate in this randomized controlled trial. During the 3-month intervention period, all patients were assigned in a double-blind parallel-group design to receive either 4 g of creatine monohydrate per day plus breathing exercises (2-3 times per day for 10-15 minutes each time) (experimental group) or breathing exercises alone (control group).

[0120] According to Wang TJ et al., Am J Phys Med Rehabil, 2020, Jun 11 (DOI 10.1097 / PHM.0000000000001505 / PMCID:7315835), pulmonary rehabilitation is performed. Pulmonary rehabilitation is tailored for each patient and includes, for example, improved segmented breathing, breathing exercises for strengthening respiratory and expiratory muscles, inspiratory muscle training, bed activity exercises, stretching, gymnastics and / or walking. The degree of exercise is low at the beginning and then slowly increases without requiring the patient to make greater efforts.

[0121] Detailed information on the experimental protocol and testing procedures used are described in Example 1.

[0122] All volunteers completed the trial and no participant reported adverse effects from either intervention. Changes in the study results during the trial are shown in Table 6. Table 5 provides the increase in total tissue creatine levels in several brain sites and the vastus medialis muscle.

[0123] Table 5: Changes in tissue creatine levels (mM)

[0124]

[0125]

[0126] Table 6:

[0127]

[0128] For all fourteen (14) sites assessed in our study, participants in the creatine group experienced increases in total tissue creatine levels, with significant increases found in the vastus medialis (P = 0.04), thalamus (P = 0.03), right anterior 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) at 3-month follow-up. The Cohen effect sizes (d) for creatine increases in the six sites ranged from 0.77 (vastus medialis) to 1.76 (right frontal gray matter), suggesting that creatine monohydrate plus breathing exercises had a sizeable effect on increasing muscle and brain creatine. No increases in total creatine levels were found in any of the control groups (except for a non-significant increase in the left precentral white matter); in addition, creatine levels in the right frontal gray matter and left medial parietal gray matter were significantly decreased in the control group at 3-month follow-up (P < 0.05). Furthermore, two-way ANOVA with repeated measures revealed significant differences in the changes in total creatine levels between the groups at four brain sites (P < 0.05), with participants from the experimental group outperforming those from the control group in increasing brain creatine concentrations at the left frontal gray matter, right anterior lobe gray matter, right precentral white matter, and left parietal gray matter.

[0129] Total tissue creatine concentrations at the 3-month follow-up remained largely unresponsive to breathing exercise (even further reduced from baseline levels), suggesting long-term disturbances in tissue bioenergetics following this complex condition.

[0130] Embodiment 3:

[0131] Combination of creatine supplementation and glucose administration:

[0132] 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 women) with moderate fatigue and at least one additional COVID-related symptom (e.g., loss of taste, loss of smell, body pain, dyspnea, difficulty concentrating, headache, lung pain, malaise) volunteered to participate in this randomized controlled parallel-group intervention trial. All patients were assigned in a double-blind parallel-group design to receive a powdered mixture of creatine monohydrate and glucose three times daily during an 8-week intervention interval (experimental group 1; 8 g creatine per day) and 3 g glucose), creatine monohydrate (experimental group 2; 8 g creatine per day or glucose (control group; 3 g glucose per day). All participants avoided taking any other dietary supplements during the study. Detailed information on the experimental protocol and testing procedures used in this study is described in Example 1.

[0133] All volunteers completed the trial and no participant reported side effects of either intervention. Changes in tissue creatine levels in post-COVID patients are described in Table 7. The table shows changes in tissue creatine levels in white matter (brain), thalamus, vastus medialis, and gray matter (brain) after creatine + glucose intervention or creatine intervention compared to the control group (glucose administration).

[0134] Table 7:

[0135]

[0136]

[0137] In experimental group 1, total creatine levels increased at all 14 sites after 8 weeks of intervention, with levels significantly higher than baseline concentrations at 8 sites (including vastus medialis muscle, thalamus, right frontal gray matter, left and right precentral white matter, right paracentral white matter, left parietal white matter, and right medial parietal white matter) (P ≤ 0.05). Cohen effect sizes (d) varied by site, with medium or large effects of creatine monohydrate plus glucose showing increases 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). After 8 weeks of intervention, creatine concentrations in three sites (including the vastus medialis and left and right medial parietal gray matter) of experimental group 2 increased significantly (P≤0.05); only in the medial parietal gray matter was the effect above the threshold for a medium effect (d=0.65). No significant changes in creatine levels were found in the control group (glucose group) (P>0.05), and creatine levels decreased relative to baseline levels in 10 of the 14 sites evaluated (71.4%). Repeated measures two-way ANOVA (treatment by time interaction) revealed significant differences in changes in total creatine levels in the right precentral white matter and left paracentral gray matter between groups (P≤0.05), with experimental groups 1 and 2 having increased creatine levels in these two sites more than the control group. A strong trend toward higher creatine levels was also observed for other sites, such as the vastus medialis, left precentral white matter, right paracentral white matter, left parietal white matter, left medial parietal gray matter, and right medial parietal gray matter (P<0.20).

[0138] The results of COVID-19 related signs and symptoms (e.g., headache, difficulty concentrating, anosmia, anosmia) reported by patients were evaluated using the VAS scale. Fatigue was evaluated using the Multidimensional Fatigue Inventory Test (MFI-20 test, Smets EM et al., J. Psychosom. Res. 1995, 39 (3), 315), including the conditions of the group of general fatigue, physical fatigue, metal fatigue, reduced activity, and reduced motivation. The results of the VAS scale survey and the MFI-20 test are summarized in Tables 8 and 9.

[0139] Table 8:

[0140]

[0141] Table 9:

[0142]

[0143] Additionally, as described in Example 1, the patient's time to exhaustion was assessed by performing an incremental test on a motorized treadmill until exhaustion.

[0144] Table 10:

[0145]

[0146] In patients with post-viral fatigue syndrome after SARS-CoV-2 viral infection, the time to exhaustion increased significantly. In experimental group 2 (creatine group), after administration, the time to exhaustion in the creatine group increased by 20 seconds (P = 0.03). More importantly, by combining creatine and glucose intake, the time to exhaustion in the treadmill test increased to 27 seconds, which is contrary to expectations considering the deterioration of the time to exhaustion after glucose intake (-7 seconds). In experimental group 2, the improvement in endurance was accompanied by a significant decrease in fatigue scores with reduced activity subdomains (P = 0.008), where d = 1.52 suggested that creatine monohydrate had a great effect on this condition. The improvement in endurance was further associated with improvements in mental fatigue and reduced motivation.

[0147] At the 8-week follow-up, several post-COVID fatigue (PCFS)-related symptoms, including difficulty concentrating and general malaise, were significantly reduced in experimental group 1 (creatine + glucose) (P≤0.05); the Cohen effect size (d) for reducing difficulty concentrating was 0.80, indicating that creatine monohydrate plus glucose had a large effect on this outcome. In addition, difficulty concentrating and general malaise were significantly reduced in experimental group 2 after administration (P≤0.05); the Cohen effect sizes for these variables were above the threshold of 0.80, indicating that creatine monohydrate had a large effect. At the 8-week follow-up, participants who received the control intervention did not experience significant changes in most variables (P>0,05).

[0148] in conclusion:

[0149] Administration of creatine monohydrate with or without glucose for eight weeks can be recommended as a well-tolerated intervention to improve tissue bioenergetics and several clinical features in patients with post-COVID fatigue syndrome. Creatine monohydrate (with or without glucose) was superior to control intervention in increasing creatine levels in skeletal muscle and several brain sites (including white and gray matter), patient-reported symptoms (including reductions in concentration problems), and general malaise. Creatine monohydrate also increased time to exhaustion and reduced specific fatigue subdomains (e.g., decreased activity). Glucose also enhanced the ability of creatine monohydrate to increase creatine levels in specific sites of the brain, but not for most patient-reported outcomes in post-COVID fatigue syndrome. However, despite no differences in patient-reported outcomes, combined intake of creatine and glucose may improve endurance.

[0150] In Table 11 and Figure 2 Cohen effect sizes (d) for all outcomes in Experimental Group 1 (EXP1, creatine + glucose) and Experimental Group 2 (EXP2, creatine) were estimated and reproduced in Figure 2. Effects were 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 calculating effect sizes when the pre- and / or post-values ​​are equal to zero.

[0151] abbreviation:

[0152] GF, general fatigue; PF, physical fatigue; RM, reduced motivation; RA, decreased activity; MF, mental fatigue; AGE, anosmia; ANO, anosmia; DCN, difficulty concentrating; and HAD, headache.

[0153] Table 11:

[0154] Cohen effect (d), Experiment 1 Cohen effect (d), Experiment 2 General fatigue (GE) 0.49 0.44 Physical Fatigue (PF) 0.47 0.83 Power reduction (RM) 0.11 1.07 Reduced activity (RA) 1.15 1.52 Mental Fatigue (MF) 0.11 1.32 Breathlessness (BRD) 0.34 0.96 Loss of taste (AGE) 0.34 Anosmia (ANO) 0.44 Difficulty concentrating (DCN) 0.80 1.37 Headache (HAD) 1.12 0.93 Discomfort (MAL) 0.47 1.81

Claims

1. A pharmaceutical composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof for use in the treatment of post-viral fatigue syndrome (PVFS) associated with a condition selected from the group consisting of mental fatigue, decreased motivation, and difficulty concentrating and / or for increasing the time to exhaustion.

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

3. The pharmaceutical composition of claim 1 or 2, wherein the composition is used in combination with glucose, preferably to increase the time to exhaustion in a subject suffering from post-COVID fatigue syndrome (PCFS).

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the physiologically acceptable creatine derivative is selected from the group consisting of creatine, creatine hydrates, creatine esters or amides, including creatine C1-C5-alkyl esters, N-C1-C5-alkyl amides, guanidinoacetic acid, inositol, inositol-O-phosphate or mixtures thereof.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the creatine salts and adducts or the physiologically acceptable salts and adducts of creatine derivatives are selected from the group consisting of the corresponding acetates, citrates, maleates, fumarates, tartrates, malates, pyruvates, ascorbates, succinates, aspartates, lactates, oxalates, formates, benzoates, phosphates, sulfates, chlorides, hydrochlorides, the corresponding potassium, sodium, calcium, magnesium salts, the corresponding L-carnitine, acetyl-L-carnitine, taurine, betaine, choline, methionine adducts or mixtures thereof.

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

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the daily dose of creatine in the composition is in the range of 7 g and 30 g.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the daily dose of creatine in the composition is a cumulative dose in the range of 10 g to 30 g for an initial build-up period and a maintenance dose in the range of 7 g to 15 g for a subsequent maintenance period, wherein the build-up period has a duration of up to 3 weeks and the maintenance period has a duration of 1 month to 12 months.

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

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

11. A pharmaceutical composition according to 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 and / or salt and / or adduct thereof as a dietary supplement or as a supplement for preparing a diet, which supports recovery from PVFS associated with a condition selected from the group of mental fatigue, decreased motivation, reduced activity, difficulty concentrating, and increases the time to exhaustion.

13. The use of claim 9, wherein the PVFS is caused by coronavirus infection or is a symptom after COVID.

14. The use of claim 9 or 10, wherein the composition is used in combination with glucose, preferably for increasing the time to exhaustion in a subject 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 is in the range of 7 g to 30 g.

16. The use of any one of claims 9 to 12, wherein the daily dose of creatine in the composition is a cumulative dose in the range of 10 g to 30 g for an initial build-up period and a maintenance dose in the range of 7 g to 15 g for a subsequent maintenance period, wherein the build-up period has a duration of up to 3 weeks and the maintenance period has a duration of 1 month to 12 months.

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

20. The use of claim 18 or 19, 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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