Compositions containing creatine for use in treating respiratory disorders

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, especially in combination with respiratory exercise, of respiratory disorders, chest pain, body pain, etc., following viral infection. 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 diet to support recovery from respiratory disorders, chest pain, body pain, etc., due to respiratory exercise, following viral infection of the lungs or lower respiratory system.

Description

[Technical field]

[0001] Technical fields: The present invention relates to a pharmaceutical composition comprising creatine for use in a subject who needs to treat symptoms caused by viral infection of the lungs or lower respiratory tract, particularly respiratory disorders and chest pain.A further object of the present invention is the use of creatine or a creatine derivative as a dietary supplement for the preparation of diet for patients suffering from respiratory disorders and chest or lung pain after viral infection. [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 fatigue (e.g., Postviral Fatigue Syndrome (PVFS) and Chronic Fatigue Syndrome (CFS)), breathing problems or shortness of breath (dyspnea), lung or chest pain, joint or muscle pain or headache, impaired 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. These symptoms often persist for several months.

[0005] In the severe course of the disease, more than 50% of COVID patients suffer from respiratory distress 8 weeks after discharge, as reported in a study by Manal S., Barnett J., Brill S, et al. (Thorax, 2021; 76, 396-398). These findings are confirmed in a study by Halpin SJ, McIvor C., et al. (J. Med. Virol. 2021; 93, 1013-1022). More than 60% of patients who underwent intensive medical treatment suffered from respiratory problems an average of 48 days after discharge.

[0006] The conditions described are summarized under the term "Post-COVID-19 syndrome" or "Long-COVID-19", hereafter referred to as "Post-COVID".

[0007] Subjects with respiratory problems often feel unable to get enough air or short of breath. They may need to rest frequently during activities or feel as though their upper body and muscles are working harder than normal to breathe. Recommendations for these subjects are usually limited to advice on actions such as ensuring regular rest periods, breaking large tasks into smaller ones, and slowly increasing exercise. For subjects suffering from these symptoms, the situation can be very fatiguing.

[0008] Post-COVID people often additionally experience muscle pain, joint pain (body pain) or chest / lung pain. Unfortunately, to date, no specific treatment has been found to cure this virus. Moscatelli, F. et al., discuss the role of nutritional inventions and highlight the fact that strong data from clinical trials are needed to support such assumptions (Nutrients 2021; 13, 976-988). Adequate nutrition is necessary to enable a strong response against pathogens and to support immune cell function. The micronutrients with the strongest evidence for immune support are vitamins C, D and zinc.

[0009] A practical medical treatment strategy for patients suffering from Long COVID is summarized in Deutsches Arzteblatt 2020; 49, 117 and is based on the primary care recommendations for Long Covid outlined in Greenhalgh, T.; Knight M., A`Court C.; BMJ 2020; 370, 3026. Medical management is limited to symptomatic treatment, including treatment of fever with paracetamol and consideration of antibiotics for secondary infections.

[0010] To improve the recovery of patients with respiratory problems or lung pain, pulmonary rehabilitation treatment should be provided as soon as possible. Pulmonary rehabilitation is considered one of the most important interventions in post-COVID treatment so far.

[0011] Suitable pulmonary rehabilitation procedures are described in Wang TJ et al. (Am. J. Phys. Med. Rehabil., 2020 Sep; 99(9), 769-774).

[0012] 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).

[0013] 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 combined administration of creatine and coenzyme Q10 for the treatment of COPD patients is described in Marinari, S. et al., Multidisciplinary Respiratory Medicine 2013, 8:40. The efficacy of creatine in the treatment of postviral fatigue syndrome (PVFS) is described in Ostojic, SM Nutrients 2021, 13, 503; Ostojic, SM, Therapeutic Advances in Respiratory Disease, 2020, Vol. 14, 1-2 and Kreider RB et al., Nutrients 2021, 13, 447.

[0014] Starting from here, the problem that the present invention aims to solve is to improve recovery from respiratory disorders (dyspnea) and / or chest, lung and body pain caused by viral infection, in particular when these conditions are symptoms of Post-Viral Fatigue Syndrome (PVFS). Summary of the Invention

[0015] Description of the invention: The problem is solved by administering creatine to patients in need of it: Creatine supports recovery from physical fatigue and / or breathing problems (e.g. dyspnea) and / or chest pain, lung pain, lung fatigue and body pain caused by viral infection, and in particular supports recovery from physical fatigue and / or breathing problems (e.g. dyspnea) and / or chest pain, lung pain, lung fatigue and body pain after viral infection, e.g. post-Covid.

[0016] The administration of creatine is particularly useful in combination with pulmonary rehabilitation measures, in particular breathing exercises and / or physical exercises, for patients suffering from physical fatigue and / or respiratory disorders (e.g. dyspnea) and / or chest or lung pain and / or lung fatigue and / or body pain after a viral infection, e.g. post-Covid. The combination of pulmonary rehabilitation measures, such as training of the respiratory muscles with breathing exercises, with the simultaneous administration of creatine significantly improves the recovery of patients suffering from respiratory disorders or chest or lung pain or lung fatigue, in particular post-COVID patients, compared to the intake of creatine or the application of breathing exercises alone.

[0017] Post-viral fatigue syndrome (PVFS) is a long-lasting 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. Symptoms related to PVFS are particularly common following infection with members of the coronavirus family (SARS-CoV2), often leading to post-COVID fatigue syndrome. Symptoms related to PVFS are particularly common following infection with members of the coronavirus family (SARS-CoV2), often leading to post-COVID fatigue syndrome.

[0018] 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 physical fatigue, respiratory disorders, shortness of breath (dyspnea), chest / lung pain, pulmonary fatigue and body pain following a viral infection, in particular a COVID-19 infection.

[0019] In a preferred embodiment of the invention, a pharmaceutical composition comprising creatine or a physiologically acceptable derivative thereof and / or a salt thereof and / or an adduct thereof is used in combination with respiratory and / or physical exercise to treat respiratory disorders, shortness of breath (dyspnea) and / or chest (lung) pain and / or pulmonary fatigue.

[0020] 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 physical fatigue, breathing problems, shortness of breath (dyspnea) or chest / lung pain, pulmonary fatigue and / or body pain following a viral infection of the lungs or lower respiratory system, preferably in combination with physical and / or respiratory exercise.

[0021] Creatine administration can detect a significant increase in creatine concentrations in the muscles and brains of post-COVID patients.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] The significant increase in creatine concentrations in muscle and brain of post-COVID patients is particularly surprising for those treated with physical and / or respiratory exercises, because total tissue creatine concentrations remain largely unresponsive (or even decline from baseline levels) to physical and / or respiratory exercises, suggesting long-term impairment of tissue bioenergetics in post-COVID. Recovery from post-COVID can therefore be supported by creatine administration to improve tissue creatine levels, for example in muscles and throughout the brain. Furthermore, the physical condition of post-COVID patients can be improved, including reduced physical fatigue, reduced respiratory impairment, reduced pulmonary (chest) pain, and reduced pulmonary malaise. Subjects who received creatine in combination with physical and / or respiratory exercise also have a longer time to exhaustion. Thus, the physical condition of post-COVID patients can be significantly improved by the combination of creatine administration with physical and / or respiratory exercises.

[0026] The effects of creatine may be enhanced if individuals participate in exercise while taking the supplement. Respiratory exercise induces hyperemia, increasing tissue perfusion and enhancing creatine delivery to target cells (Ribeiro F, Longobardi I, Perim P, Duarte B, Ferreira P, Gualano B, Roschel H, Saunders B. Timing of creatine supplementation around exercise: a real concern? Nutrients. 2021;13(8):2844). Exercise enhances the increase in intramuscular creatine during creatine supplementation, with greater increases in exercised than non-exercised body parts (Robinson TM, Sewell DA, Hultman E, Greenhaff PL. Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol. 1999;87(2):598-604). In addition, exercise may upregulate the sodium-potassium pump that activates a specific creatine transporter (CT1), increasing the amount of creatine delivered to specific cells (Odoom JE, Kemp GJ, Radda GK The regulation of total creatine content in a myoblast cell line. Mol. Cell. Biochem. 1996;158:179-188). Without being bound by theory, these effects not only support post-COVID patient recovery with creatine administration, but also minimize the undesirable effects of physical exercise in patients, such as respiratory exercise (e.g., increased physical fatigue). Evidence from studies suggests that exercise enhances creatine accumulation in target tissues with creatine supplementation, implying a synergistic effect between creatine, especially creatine monohydrate, and respiratory exercise.

[0027] 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.

[0028] The creatine-containing composition of the present invention is particularly useful for supporting recovery from typical symptoms after viral infections, such as respiratory problems and chest pain. Respiratory problems or dyspnea are characterized by shortness of breath, which impairs the ability to inhale and exhale. Respiratory problems can occur as a result of several acute and chronic cardiopulmonary conditions, such as asthma, chronic obstructive pulmonary disease (COPD), heart disease, and pneumonia. In such cases, respiratory problems are respiratory diseases, while post-Covid is classified as a neurological disease. For example, in COPD, a respiratory disease, oxidative stress plays a key role, so its treatment often includes antioxidants such as coenzyme Q10. However, shortness of breath is one of the most common conditions after viral infections, especially after coronavirus infections such as SARS-CoV-2 infection. In such cases, shortness of breath and respiratory problems associated with viral infections, especially SARS-CoV-2 infections, often persist for weeks to months in patients who have overcome the viral infection. Thus, the causes and mechanisms underlying classical COPD, a respiratory disease, and respiratory problems associated with post-Covid, a neurological disease, are seemingly different. Respiratory problems are further accompanied by reduced blood oxygen levels, which can be observed over the long term and can impair overall health.

[0029] Chest pain (lung pain) is a sharp, throbbing sensation that occurs when breathing, coughing or sneezing. The most common cases of chest pain or lung pain are asthma, chronic obstructive pulmonary disease, especially bacterial or viral infections of the pleura (pleurisy) and other thoracic tissues. Chest (lung) pain is observed as a persistent condition after viral infections, for example SARS-CoV-2 infection. Chest (lung) pain can persist for a long time or become chronic, and is often accompanied by coughing, breathing problems and wheezing. When pleural inflammation occurs near the diaphragm, the pain can also radiate to the neck or shoulders.

[0030] Acute and chronic viral infections that cause breathing problems and / or pulmonary fatigue, some chest (lung) pain, include influenza A or B viruses (e.g., H1N1, H5N1), enteroviruses, respiratory syncytial viruses, parainfluenza, adenoviruses, and coronaviruses (e.g., SARS, MERS, SARS-CoV-2). The condition may last for weeks or months. For example, after SARS-CoV-2 infection, shortness of breath may last from two weeks to a year or longer.

[0031] Respiratory disorders within the meaning of the present invention include shortness of breath (dyspnea) especially caused by viral infections. Chest pain within the meaning of the present invention includes pleural pain and thoracic chest pain (lung pain) especially caused by viral infections.

[0032] According to the present invention, the pharmaceutical composition comprising creatine or its physiologically acceptable derivatives and / or their salts and / or adducts is for use in the treatment of one of the conditions selected from the group of physical fatigue, respiratory disorders, shortness of breath (dyspnea), chest pain, lung pain, pulmonary fatigue and body pain in particular in post-COVID patients. In particular, symptoms and / or conditions that persist or develop after initial recovery from acute COVID infection are referred to as post-COVID. One of the difficulties associated with finding an appropriate treatment for PVFS, particularly post-COVID, is the change, multiplicity, diversity and ambiguity of symptoms associated with post-COVID, and at the same time the uncertainty regarding the cause of the symptoms. This complicates both the treatment of post-COVID and predicting what drugs or treatments will work in the treatment of post-COVID. Post-COVID manifestations can manifest as many different conditions and symptoms, including pulmonary disease, neurological symptoms and conditions such as headache, nasal anosmia, taste disorder, dizziness, confusion, disorientation and other disorders; neuropsychiatric disorders, gastrointestinal symptoms such as stroke, nausea, loss of appetite, vomiting and diarrhea; cardiovascular diseases such as myocarditis, heart failure, cardiac insufficiency and thromboembolism; rhenal failure; and skin conditions. No uniform clinical picture can be defined, especially regarding long-term effects, and the underlying mechanisms are unclear. Post-COVID patients complain of quite different symptoms that last for weeks to months. Commonly reported complaints and symptoms include fatigue, tiredness, mental fatigue, exhaustion, reduced recovery, memory impairment, sleep disorders, muscle weakness, muscle pain and mental problems such as depressive and anxiety symptoms. 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 change of conditions and symptoms associated with post-COVID. It is currently unknown what causes COVID or post-COVID to cause these conditions, therefore providing an appropriate treatment for post-COVID is difficult as there is no cross-applicability of known treatments for similar conditions.

[0033] 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 in treating certain conditions selected from the group of physical fatigue, respiratory disorders, shortness of breath (dyspnea), chest pain, lung pain, pulmonary fatigue and body pain associated with 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 numerous. In the tests and experiments underlying the present invention, it has now surprisingly been found that the provision of creatine specifically improves conditions related to physical fatigue, respiratory disorders, shortness of breath (dyspnea), chest pain, lung pain, pulmonary fatigue and body pain in post-Covid patients.

[0034] The recovery of patients suffering from respiratory problems or chest (lung) pain or pulmonary fatigue after viral infection is surprisingly improved by administration of creatine, especially in combination with respiratory exercises. 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 furthermore 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.

[0035] 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 -alkylamides, creatine phosphate, creatinol-O-phosphate or mixtures thereof.

[0036] 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.

[0037] As used herein, the term respiratory exercise includes physical exercise as well as pulmonary rehabilitation.

[0038] Pulmonary rehabilitation is part of the management of people with lung problems due to respiratory disease or other conditions. Pulmonary rehabilitation includes exercise training, health education and breathing techniques aimed at improving reduced lung function and improving symptoms of dyspnea. Breathing exercises are recommended during the acute management of various lung diseases, such as COVID-19 (Wang, TJ et al., PM&R and Pulmonary Rehabilitation for COVID-19, Am J Phys Med Rehab, 2020 Sep;99(9):769-774. doi: 10.1097 / PHM.0000000000001505).

[0039] Pulmonary rehabilitation involves training the respiratory and expiratory muscles with breathing exercises. Respiratory muscles include the inspiratory muscles, such as the diaphragm, and the external intercostal muscles, such as the external intercostal muscles and interchondral muscles, which attach between the ribs. The diaphragm and external intercostal muscles are one of the most important groups of respiratory muscles. The inspiratory muscles are further grouped together as accessory muscles of inspiration. This group of muscles supports the intake of air through the lungs and includes the serratus posterior superior and inferior, pectoralis minor and major, sternocleidomastoid, and erector spinae.

[0040] The expiratory muscles include the internal intercostal muscles (intercostal muscles, intercostal muscles), the muscles of the labium inferior (subcostal muscles), and accessory expiratory muscles such as the oblique abdominal muscles, transverse abdominis, transverse thoracic muscles, latissimus dorsi, quadratus lumborum, and rectus abdominis.

[0041] Treatment with creatine can be started already during viral infection, preferably within about 3 months (12 weeks) after infection. Preferably, creatine administration is started in the period from 2 weeks after infection to 8 weeks after infection. Furthermore, creatine administration should most preferably be started within 4 weeks before physical exercise and / or respiratory exercise including pulmonary rehabilitation is started or at the same time as physical exercise and / or respiratory exercise including pulmonary rehabilitation. However, creatine administration after the start of physical exercise and / or respiratory exercise including pulmonary rehabilitation is also possible.

[0042] Pulmonary rehabilitation measures, such as training of the respiratory muscles with breathing exercises, should be started as soon as possible, provided the patient's health status permits. Rehabilitation, physical exercises and / or breathing exercises are usually started within 20 weeks, preferably within 12 weeks, and most preferably within 6 weeks after the infection has subsided.

[0043] The period of creatine supplementation will usually last between one week and twelve months or more, preferably between one month and eight months, particularly between three and six months, depending on the condition of the subject in need thereof.

[0044] 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.

[0045] 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 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 12 months, preferably between 2 and 8 months, in particular between 3 and 6 months.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] The creatine compositions described herein may be administered orally, preferably in the form of tablets, coated tablets, capsules, granules or powders.

[0050] 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.

[0051] 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.

[0052] The granules and powder can also be used in the preparation of food to support recovery from physical fatigue, breathing problems, shortness of breath, chest / lung pain, pulmonary fatigue, and body pain after viral infection, especially in post-COVID patients.

[0053] The creatine composition used according to the invention may further be applied in the form of tablets.

[0054] 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.

[0055] 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.

[0056] Typical suitable preservatives are, for example, cysteine, methionine, citric acid, sodium citrate, tartrazine 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] Suitable pigments and colorants are, for example, food dyes.

[0061] 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.

[0062] 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.

[0063] 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% carbohydrate; 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.

[0064] 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% carbohydrate; 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.

[0065] 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 and pigments may be part of the creatine compositions used according to the present invention.

[0066] 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.

[0067] In combination with creatine, a creatine derivative or its salt or adduct, an anti-inflammatory drug can be applied to support recovery from respiratory problems (dyspnea) and / or chest pain, lung pain, lung fatigue, and body pain caused by viral infection.Anti-inflammatory drugs are, 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.

[0068] 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.

[0069] 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: Radivrio (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.

[0070] Creatine, creatine derivatives or their salts or their adducts can be administered in combination with creatine precursors such as guanidinoacetate / guanidinoacetic acid, and / or methyl group donors such as arginine, glycine, methionine, or other compounds or precursors useful in cellular energy pathways.However, in a preferred embodiment, creatine, creatine derivatives or their salts or their adducts are applied without additional administration of such compounds, in particular without co-administration of ubiquinone 10 (coenzyme Q-10).

[0071] 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.

[0072] 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).

[0073] The important minerals are selected from the group: magnesium, calcium, potassium, sodium, copper, manganese, zinc, selenium, and boric acid / boron.

[0074] 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).

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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).

[0079] 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), or Devil'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.

[0080] 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]

[0081] [Figure 1] 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's effect sizes (GF: general fatigue, PF: physical fatigue, RM: decreased motivation, RA: decreased activity, MF: mental fatigue, BOA: bodily pain, BRD: dyspnea, LUP: lung pain, MAL: fatigue) of creatine administration in post-COVID patients. EXAMPLES

[0082] 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 the 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 additional COVID-19-related symptom selected from the group of loss of smell, loss of taste, 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.

[0083] 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. Primary outcomes were changes in vastus medialis creatine and brain creatine levels at baseline and 6-month follow-up.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 measurements (at 3 months and 3 months follow-up) of each study outcome.

[0084] At this point, 12 participants had been randomly assigned to receive the intended treatment and were included in the analysis of the primary outcomes: 6 in the experimental group and 6 in the control group. Recruited participants reported no major side effects from either intervention so far.

[0085] 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.).

[0086] 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).

[0087] Changes in tissue creatine levels 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.

[0088] [Table 1]

[0089] 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.

[0090] 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.

[0091] 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 white matter (P=0.01), and right parietal 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 white matter, and right parietal white matter6 than the placebo group. Furthermore, strong interaction effects between the interventions were reported in several other sites, including the right frontal white matter, right paracentral white matter, left parietal white matter, and left medial parietal gray matter (P<0.20).

[0092] 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), 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).

[0093] In summary, creatine was enriched in the brains of post-COVID patients after creatine supplementation and was found to cross the blood-brain barrier.

[0094] Effect of creatine as a nutritional supplement on post-COVID patients.

[0095] Patient-reported outcomes regarding COVID-19-related signs and symptoms (e.g., respiratory problems, lung pain, and body pain) 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 Table 2.

[0096] [Table 2]

[0097] The tests carried out require the patient to report a score of the symptoms shown 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 relieving the respective symptom. As can be seen from Table 2, an improvement in terms of physical fatigue was observed in the creatine group, but not in the placebo group.

[0098] [Table 3]

[0099] After three months, breathing problems (dyspnea) were significantly reduced in 78% of participants taking creatine compared to 55% after placebo. Bodily pain was slightly reduced in 73.3% of participants taking creatine compared to 69% after placebo. Lung pain was significantly reduced in the creatine cohort.

[0100] Significant interaction effects (time vs. treatment) were found for all symptoms assessed (P<0.05). Cohen effect sizes for primary and secondary outcomes after creatine supplementation were also demonstrated for respiratory disturbance (0.89 at 3 months and 1.25 at 6 months), lung pain (0.99 at 6 months), and bodily pain (1.77 at 3 months and 3.03 at 6 months), with strong effect sizes for creatine (d≥0.8).

[0101] A randomized controlled trial found that creatine was accumulated in skeletal muscle and the brain after 3 months of administration. The increase in endurance in the creatine group was superior to the placebo group (Table 5). The increase in endurance was accompanied by a decrease in bodily and pulmonary pain, especially recovery from respiratory disorders. The increase in endurance was further accompanied by 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 shown in Table 2, with regard to fatigue symptoms such as physical fatigue and reduced activity, a smaller improvement was achieved by creatine administration compared to the placebo group. Furthermore, creatine did not cause any significant side effects.

[0102] 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.

[0103] 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.

[0104] Detailed information regarding the experimental protocols and test procedures used is provided in Example 1.

[0105] All volunteers completed the study, and no participants reported side effects from either intervention. Changes in study outcomes over the course of the study are shown in Tables 5 and 6. Increases in tissue total creatine levels in several brain sites and vastus medialis are provided in Table 4.

[0106] [Table 4]

[0107] [Table 5]

[0108] [Table 6]

[0109] 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.

[0110] 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.

[0111] Respiratory disorders and pulmonary pain were reduced to zero in both groups at the 3-month follow-up, whereas pulmonary fatigue was significantly reduced by 84% in the creatine group and 74% in the control group (P<0.05). Friedman / ANOVA test with repeated measures showed a significant difference between the groups for pulmonary fatigue (P=0.03), with participants in the creatine group being better at reducing pulmonary fatigue than those in the control group. Cohen's effect size for pulmonary fatigue was 2.97, suggesting a large effect of creatine monohydrate and breathing exercises (Table 6). The outcome was also confirmed by the results of the VAS scale survey on physical fatigue. In particular, physical fatigue is significantly improved by creatine administration combined with breathing exercises (Table 5). As for mental fatigue and reduced motivation, no significant improvement is achieved by creatine + breathing exercises compared to the control group (breathing exercise group).

[0112] Example 3: Exhaustion Test Patients' time to exhaustion was assessed by a motorized treadmill incremental exhaustion test. The treadmill speed and gradient were increased every 3 minutes, starting at 2.7 km / h (1.7 miles per hour) at a 10% gradient and increasing to 9.7 km / h (6 miles per hour) at a 22% gradient in stage 7 (Will PM and Walter JD, Am Heart. J., 1999 Dec, 138, 1033). The treadmill evaluation results are shown in Tables 7 and 8.

[0113] [Table 7]

[0114] In patients suffering from post-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.

[0115] Time to exhaustion increased in the creatine group, and creatine outperformed placebo in increasing time to exhaustion after 3 and 6 months of creatine treatment.Improvements in endurance were accompanied by decreases in bodily and pulmonary pain, particularly recovery from respiratory failure.

[0116] [Table 8]

[0117] The mean time to exhaustion improved significantly in the experimental group by 54 seconds after administration (P=0.05), with creatine monohydrate and breathing exercises superior to breathing exercises in increasing the time to exhaustion (P=0.11). Cohen's effect size for time to exhaustion was 0.36. The creatine plus breathing exercise group reached stage 6 on the treadmill test, whereas the placebo group remained at stage 5. The data show a synergistic effect of creatine monohydrate and breathing exercises compared to the placebo group.

[0118] Conclusion: Creatine monohydrate and breathing exercises can be recommended as a well-tolerated intervention that significantly improves tissue creatine levels and several clinical features (e.g., respiratory distress, lung pain, pulmonary fatigue, and time to exhaustion) in patients with post-COVID fatigue syndrome, when administered, for example, during a 3-month treatment period.

[0119] Example 4: Creatine supplementation compared to glucose administration: Ten male and female PCFS patients with moderate fatigue and at least one additional COVID-related symptom (e.g., loss of taste, loss of smell, body pain, breathing 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 powdered creatine monohydrate (experimental group: creatine (Creapure®) 8 grams per day) or glucose (control group: glucose 3 grams 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 protocol and test procedures used in this study is described in Example 1.

[0120] Changes in tissue creatine levels in patients suffering from post-COVID are shown in Table 9. The table shows changes in tissue creatine levels in white matter (brain), thalamus, vastus medialis and grey matter (brain) after creatine intervention compared to the glucose group.

[0121] [Table 9]

[0122] Creatine levels in white matter (brain), gray matter (brain), thalamus, and vastus medialis after 8 weeks are increased in the experimental group compared to the control group. The results confirm the outcomes of Examples 1 (Table 1) and 2 (Table 4).

[0123] Patient-reported outcomes for signs and symptoms related to COVID-19 (e.g., breathing problems, lung pain, body pain, and post-viral fatigue) were assessed using a VAS scale (Tables 10 and 11).

[0124] [Table 10]

[0125] [Table 11]

[0126] After 8 weeks, respiratory distress (dyspnea) was significantly reduced by 85% after creatine compared to 43% after glucose, bodily pain was reduced by 71% after creatine compared to 50% after glucose, and lung pain was significantly reduced by 67% in the creatine cohort compared to an increase of 50% in the glucose cohort.

[0127] Thus, several symptoms related to post-COVID, such as body pain, lung pain and respiratory distress, were significantly reduced in the experimental group (creatine) at 8 weeks of follow-up (P ≤ 0.05); Cohen's effect size (d) for reduction of respiratory distress, body pain and lung fatigue exceeded the threshold of 0.80, suggesting a large effect of creatine. Participants in the experimental group (creatine) had better reduction in body pain and lung pain than participants in the control group (glucose) (P ≤ 0.20), and participants in the experimental group also had better reduction in respiratory distress than participants in the control group.

[0128] Cohen's effect sizes (d) for all outcomes in the creatine group were assessed and are reproduced in Table 12 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. Abbreviations: GF: general fatigue, PF: physical fatigue, RM: reduced motivation, RA: reduced activity, MF: mental fatigue, BOA: bodily pain, BRD: respiratory disorder, LUP: lung pain, MAL: malaise.

[0129] [Table 12]

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 treating one of the symptoms selected from the group consisting of physical fatigue, respiratory disorders, shortness of breath (dyspnea), chest pain, lung pain, pulmonary fatigue and body pain following a viral infection.

2. 2. The pharmaceutical composition of claim 1, wherein the physical fatigue, breathing problems, shortness of breath (dyspnea), chest pain, lung pain or pulmonary fatigue are symptoms caused by coronavirus infection or are post-COVID symptoms.

3. 3. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of respiratory disorders, shortness of breath (dyspnea), chest pain, lung pain or pulmonary fatigue in combination with physical and / or respiratory exercise.

4. A pharmaceutical composition according to any one of claims 1 to 3 for use in the treatment of physical fatigue in a subject performing physical and / or respiratory exercise.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the composition is for use in combination with breathing exercises to strengthen the respiratory muscles, including strengthening the diaphragm, the external intercostal muscles and the expiratory muscles.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the composition is for use in combination with respiratory exercise, and the respiratory exercise is gradually increased as tolerated by the subject in need thereof.

7. Physiologically acceptable creatine derivatives include creatine, creatine hydrate, creatine C １ -C ５ -Alkyl ester, N-C １ -C ５ 7. The pharmaceutical composition of claim 1, wherein the creatine ester or amide, such as -alkylamide, guanidinoacetic acid, creatinol, creatinol-O-phosphate or mixtures thereof.

8. 8. 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.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the composition comprises creatine monohydrate.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the daily dose of creatine in the composition ranges from 7 g to 30 g.

11. 10. The pharmaceutical composition of any one of claims 1 to 9, 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.

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 to support recovery from one of the conditions selected from the group consisting of physical fatigue, breathing problems, shortness of breath (dyspnea), chest pain, lung pain, lung fatigue and body pain following a viral infection.

13. 13. The use of claim 12, wherein the physical fatigue, breathing problems, chest pain, lung pain or pulmonary fatigue are caused by coronavirus infection of the lungs or lower respiratory system or are post-COVID symptoms.

14. 14. Use according to claim 12 or 13, wherein the composition is used in combination with physical and / or respiratory exercises to strengthen the respiratory muscles, including strengthening the diaphragm, the external intercostal muscles and the expiratory muscles.

15. The use according to any one of claims 12 to 14, wherein the daily dose of creatine in the composition ranges from 7 g to 30 g.

16. 16. The use according to any one of claims 12 to 15, 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 12 to 16, wherein the composition used comprises creatine monohydrate.

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