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 in need of treatment for symptoms caused by a viral infection of the lungs or lower respiratory tract, in particular respiratory distress and chest pain.A further object of the present invention is the use of creatine or a creatine derivative as a dietary supplement for preparing a diet for a patient suffering from respiratory distress and chest or lung pain after a viral infection. [Background technology]

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

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

[0004] Typical symptoms that persist after SARS-CoV-2 infection include fatigue (e.g., postviral fatigue syndrome (PVFS) and chronic fatigue syndrome (CFS)), breathing problems or shortness of breath (dyspnea), lung or chest pain, joint pain, muscle pain or headache, difficulty concentrating or remembering, sleep problems (insomnia), 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] As reported in a study by Manal S., Barnett J., Brill S., et al. (Thorax, 2021; 76, 396-398), in severe cases of COVID-19, more than 50% of patients suffer from respiratory distress 8 weeks or more after discharge from the hospital. These findings are confirmed by a study by Halpin SJ, McIvor C., et al. (J. Med. Virol. 2021; 93, 1013-1022). More than 60% of patients who received intensive medical treatment suffered from respiratory distress 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 find it difficult to get enough air or feel short of breath. They may need to rest frequently during activity or feel as if their upper body and muscles are working harder than usual 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 exhausting.

[0008] Post-COVID people often 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 innovation and emphasize 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 support immune cell function. The micronutrients with the strongest evidence for immune support are vitamins C, D, and zinc.

[0009] Practical medical treatment strategies for patients suffering from Long COVID are summarized in Deutsches Arzteblatt 2020; 49, 117 and are based on primary care recommendations for Long Covid described in Greenhalgh, T.; Knight M., A`Court C.; BMJ 2020; 370, 3026. Medical management is limited to symptomatic treatment, such as treating fever with paracetamol and considering antibiotics for secondary infections.

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

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

[0012] Creatine is methylguanidinoacetic acid, typically available from animal foods and / or naturally produced in the body from the amino acids arginine, glycine, and methionine. Creatine synthesis in the body provides approximately half of the daily requirement. The remaining creatine, needed to maintain normal tissue levels, can be obtained from animal foods such as fish and meat or from dietary supplements. Creatine plays a key role in the energy metabolism of all cells in the body. Creatine primarily functions as a metabolic intermediary for energy transfer by facilitating the recycling of ATP, the energy source used and stored at the cellular level.Therefore, creatine is found in high concentrations in organs with high energy metabolism, with ~95% of the creatine in the human body stored in skeletal muscle and the remaining 5% in the brain, liver, kidneys, and testes (McCall, W., Persky, AM. Pharmacokinetics of creatine. Subcell Biochem 2007, 46, 261-273; Bonilla, DA et al., Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review. Nutrients 2021, 13, 1238; Brosnan, ME et al., The role of dietary creatine. Amino Acids 2016, 48, 1785-1791; Harris, R. Creatine in health, medicine, and sport: An introduction to a meeting held at Downing College, University of Cambridge, July 2010, Amino Acids 2011, 40, 1267; Harris, RCet al. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 1992, 83, 367-374; Kreider, RB; Stout, JR Creatine in Health and Disease. Nutrients 2021, 13, 447; Ostojic, SM; Forbes, SC Perspective: Creatine, a Conditionally Essential Nutrient: Building the Case. Adv. Nutr. 2021, 00, 1-4).

[0013] Creatine administration has therefore been considered a supportive measure for the treatment of various diseases. Ostojic, SM et al., in particular, described a dietary treatment for chronic fatigue syndrome (CFS) containing guanidinoacetic acid (GAA) (Nutrients 2016, 8, 72). The combined administration of creatine and coenzyme Q10 for the treatment of COPD patients was described in Marinari, S. et al., Multidisciplinary Respiratory Medicine 2013, 8:40. The efficacy of creatine in the treatment of postviral fatigue syndrome (PVFS) has been 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 this, the problem that the present invention aims to solve is to improve recovery from respiratory problems (dyspnea) and / or chest, lung and body pain caused by viral infections, particularly 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, pulmonary 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, pulmonary fatigue and body pain after viral infection, e.g., post-Covid.

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

[0017] Postviral fatigue syndrome (PVFS) is a long-term, mysterious neurological disorder characterized by an inability to participate in previously normal activities, lasting for more than six months, and accompanied by fatigue, postexertional malaise, and unrefreshing sleep. 。P VFS-related symptoms are particularly common after infection with members of the coronavirus family (SARS-CoV2), often leading to post-COVID fatigue syndrome.

[0018] Thus, a first embodiment of the present 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 after a viral infection, in particular after 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 a physiologically acceptable derivative thereof and / or its salt and / or adduct 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 bodily pain after 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 it was previously thought that creatine could not cross the blood-brain barrier. However, within the framework of the present invention, it has been found that long COVID or post-COVID causes changes in the blood-brain barrier, and that, particularly in the post-COVID situation, creatine uptake and enrichment in brain regions such as the thalamus, gray matter, and white matter has been observed.

[0023] Furthermore, the inventors of the present application have found that patients with long COVID who do not receive creatine supplementation exhibit low levels of creatine in the brain. Within the framework of the present invention, it has been found that the concentration of total creatine in the brain, particularly in the thalamus, white matter, and gray matter, is significantly reduced in patients with long COVID compared with baseline values ​​in the general population. Therefore, without being bound by any theory, it is believed that one of the effects and / or causes of long COVID is the depletion of creatine in brain regions, and therefore a decrease in creatine levels in such brain regions. Based on the present finding that creatine can cross the blood-brain barrier in patients with long COVID, creatine levels in brain regions can be enriched and / or increased by the addition of creatine.

[0024] Particularly surprising is that while total brain creatine concentrations in long COVID patients were found to be reduced compared to baseline values ​​in the general population, significant enrichment of creatine was found in the brains of post-COVID patients, particularly in the thalamus, gray matter, and / or white matter, while no increase in brain creatine was observed or only a very small increase of up to approximately 5% was observed in healthy subjects after creatine supplementation. Ostensibly, long COVID causes brain creatine depletion and simultaneously alters the properties of the blood-brain barrier, allowing supplemented creatine to pass through, resulting in a significant increase in brain creatine after creatine supplementation. Surprisingly, according to the present invention, enrichment of brain creatine was found after creatine supplementation, indicating that creatine in long COVID patients can cross the blood-brain barrier. Notably, supplementation with creatine alone, i.e., creatine without any transporters or supplements known to alter the blood-brain barrier, was found to result in enrichment of creatine in the brain.

[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 exercise. This is because total tissue creatine concentrations remain largely unresponsive to physical and / or respiratory exercise (or even decline from baseline levels), suggesting long-term impairment of tissue bioenergetics in the post-COVID period. Therefore, post-COVID recovery can be supported by creatine administration to improve tissue creatine levels, for example, in muscle and throughout the brain. Furthermore, the physical condition of post-COVID patients can be improved, including reduced physical fatigue, respiratory impairment, pulmonary (chest) pain, and pulmonary fatigue. Furthermore, subjects receiving creatine in combination with physical and / or respiratory exercise also experienced a longer time to exhaustion. Therefore, the physical condition of post-COVID patients can be significantly improved by combining creatine administration with physical and / or respiratory exercise.

[0026] Creatine's effects 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 muscle 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). Furthermore, exercise may upregulate the sodium-potassium pump, which activates a specific creatine transporter (CT1), potentially 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 may not only support post-COVID patient recovery with creatine administration, but also minimize the undesirable effects of physical exercise, such as respiratory exercise, on patients (e.g., increased physical fatigue). Research evidence suggests that exercise enhances creatine accumulation in target tissues following creatine supplementation, suggesting a synergistic effect between creatine, particularly 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 comprising creatine. The terms "creatine composition," "creatine-containing composition," or "composition comprising creatine" also include physiologically acceptable creatine derivatives, creatine salts, and / or creatine adducts, unless expressly stated otherwise.

[0028] The creatine-containing composition of the present invention is particularly useful for supporting recovery from typical symptoms following viral infections, such as respiratory distress and chest pain. Respiratory distress or dyspnea is characterized by shortness of breath, impairing the ability to inhale and exhale. Respiratory distress can occur as a result of several acute and chronic cardiopulmonary conditions, including asthma, chronic obstructive pulmonary disease (COPD), heart disease, and pneumonia. In such cases, respiratory distress is a respiratory disease, while post-COVID-19 is classified as a neurological disease. For example, in COPD, a respiratory disease, oxidative stress plays an important role, and its treatment often includes antioxidants such as coenzyme Q10. However, shortness of breath is one of the most common symptoms following viral infections, particularly coronavirus infections such as SARS-CoV-2. In such cases, shortness of breath and respiratory distress associated with viral infections, particularly SARS-CoV-2 infection, often persist for weeks to months in patients who survive the viral infection. Thus, the underlying causes and mechanisms of classic COPD, a respiratory disease, and post-COVID-19-related respiratory distress, a neurological disease, appear to be distinct. 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 or lung pain are asthma, chronic obstructive pulmonary disease, and especially bacterial or viral infections of the pleura (pleurisy) and other thoracic tissues. Chest pain is observed as a persistent condition after viral infections, such as SARS-CoV-2 infection. Chest 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, pain can also radiate to the neck or shoulders.

[0030] Acute and chronic viral infections that cause breathing problems and / or pulmonary fatigue, including 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 a 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) caused in particular by viral infections. Chest pain within the meaning of the present invention includes pleural pain and thoracic chest pain (lung pain) caused in particular by viral infections.

[0032] According to the present invention, a pharmaceutical composition containing creatine or a physiologically acceptable derivative thereof and / or a salt and / or adduct thereof is intended for use in treating one condition selected from the group consisting of physical fatigue, respiratory problems, shortness of breath (dyspnea), chest pain, lung pain, pulmonary fatigue, and body pain, particularly in post-COVID patients. Post-COVID symptoms are specifically referred to herein as symptoms and / or conditions that persist or occur after initial recovery from acute COVID infection. One of the challenges associated with finding an appropriate treatment for PVFS, particularly post-COVID, is the variability, multiplicity, diversity, and ambiguity of post-COVID-related symptoms, as well as the uncertainty regarding the cause of the symptoms. This complicates both post-COVID treatment and predicting which drugs or treatments will work in post-COVID treatment. Post-COVID manifestations can manifest as many different conditions and symptoms, including pulmonary disease, neurological symptoms and conditions such as headache, loss of smell and taste, 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 dysfunction, and thromboembolism; renal failure; and skin conditions. A uniform clinical picture cannot be defined, particularly regarding long-term effects, and the underlying mechanisms are unclear. Post-COVID patients report disparate symptoms that persist for weeks to months. Commonly reported complaints and symptoms include fatigue, tiredness, mental exhaustion, exhaustion, decreased recovery, memory impairment, sleep disturbances, muscle weakness, muscle pain, and psychological problems such as depression and anxiety. Other reported symptoms include regional lung function decline, decreased pulmonary function, decreased renal function, and myocardial inflammation. While this list is by no means definitive, it illustrates the diversity and variability of conditions and symptoms associated with post-COVID. It is currently unknown what causes COVID or post-COVID symptoms to develop in these conditions, and therefore, there is no cross-applicability of known treatments for similar symptoms, making it difficult to provide appropriate treatments for post-COVID.

[0033] In accordance with the present invention, it has now surprisingly been found that pharmaceutical compositions containing creatine or physiologically acceptable derivatives thereof and / or salts and / or adducts thereof are effective in treating specific conditions selected from the group consisting of physical fatigue, respiratory problems, shortness of breath (dyspnea), chest pain, lung pain, pulmonary fatigue, and body pain associated with post-COVID. As outlined above, the causes of the numerous and varied symptoms associated with post-COVID are unknown, and therefore effective treatments are unpredictable. Furthermore, the conditions that cause the various symptoms, as well as the symptoms, appear to be numerous. In the tests and experiments underlying the present invention, it has now surprisingly been found that providing creatine specifically improves conditions related to physical fatigue, respiratory problems, 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 infections is dramatically improved by the 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 and N-methyl-N-guanylglycine. Creatine is also available in large quantities from animal foods or as a food supplement. Creatine monohydrate, which can be prepared with very high purity, is preferably used in food supplements.

[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. The physiologically acceptable creatine derivative is preferably selected from the group consisting of creatine, creatine hydrate, creatine C1-C5-alkyl esters, creatine esters or amides such as N-C1-C5-alkylamides, creatine phosphate, creatinol-O-phosphate, or a mixture thereof.

[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 salts, the corresponding potassium salts, sodium salts, calcium salts, magnesium salts, the corresponding L-carnitine adducts, acetyl-L-carnitine adducts, taurine adducts, betaine adducts, choline adducts, methionine adducts or mixtures thereof.

[0037] As used herein, the term respiratory exercise also 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 alleviating symptoms of dyspnea. Breathing exercises are recommended during the acute management of various lung diseases, including 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 through breathing exercises. Respiratory muscles include the inspiratory muscles, such as the diaphragm, and the external intercostal muscles, such as the external intercostal muscles and intercartilaginous 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 into the accessory inspiratory muscles. This muscle group supports inspiration through the lungs and includes the superior serratus posterior, inferior serratus posterior, pectoralis minor and major, sternocleidomastoid, and erector spinae.

[0040] The expiratory muscles include the internal intercostal muscles (intercostalis interna, intercostalis), the muscles of the lower lip (subcostalis), and accessory expiratory muscles such as the oblique abdominal muscles, transverse abdominis, transverse thoracic muscles, latissimus dorsi, quadratus lumborum, and rectus abdominis.

[0041] Creatine treatment can be initiated during viral infection, preferably within about 3 months (12 weeks) after infection. Preferably, creatine administration is initiated between 2 weeks and 8 weeks after infection. Furthermore, creatine administration should most preferably be initiated within 4 weeks before or simultaneously with 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 respiratory muscle training with breathing exercises, should be initiated as soon as possible, provided the patient's health permits. Rehabilitation, physical exercise and / or breathing exercises usually begin within 20 weeks, preferably within 12 weeks, and most preferably within 6 weeks after the infection has subsided.

[0043] Creatine supplementation typically lasts between one week and twelve months or longer, preferably between one and eight months, and especially between three and six months, depending on the condition of the subject requiring it.

[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 typically recommended for sportsmen and women.

[0045] Preferably, the administration of creatine is divided into an accumulation phase and a maintenance phase, with the daily dose of creatine in the composition ranging from 10 g to 30 g in the initial accumulation phase and from 7 g to 15 g in the subsequent maintenance phase, the accumulation phase lasting up to 3 weeks, preferably between 3 and 14 days, particularly between 5 and 10 days, and the maintenance phase lasting from 1 week to 12 months, preferably between 2 and 8 months, particularly 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 with breakfast, or in divided doses administered 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 set forth above.

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

[0050] In particular, granules or powders containing creatine compositions are used in the form of aqueous suspensions or water-soluble solutions. Pure creatine and some creatine derivatives have low solubility. For example, the solubility of creatine is 17 g / L (20°C). Poorly soluble creatine and its derivatives can be used in the form of aqueous suspensions. A disadvantage of aqueous suspensions is that they often separate before ingestion. Therefore, water-soluble granules or powders are usually preferred. To increase the water solubility of creatine or creatine derivatives, water-soluble salts or adducts of creatine can be used. To increase water solubility, the use of acids or complexing agents may be useful, particularly to provide the corresponding creatine salts or creatine derivative salts. Examples of suitable acids (e.g., carboxylic acids) and complexing agents are selected from the group consisting of malic acid, aspartic acid, ascorbic acid, succinic acid, pyruvic acid, fumaric acid, gluconic acid, alpha-ketoglutaric acid, oxalic acid, acetic acid, formic acid, sulfuric acid, hydrochloric acid, L-carnitine, acetyl-L-carnitine, taurine, betaine, choline, and lipoic acid. Peptides and amino acids may also be useful in increasing the solubility of creatine and creatine derivatives. Sodium, potassium, calcium, and magnesium salts may also be used to increase the water solubility of creatine or creatine derivatives.

[0051] The molar ratio of creatine or creatine derivative to the acid or complexing agent is usually in the range of 5:1 to 1:5, preferably in the range of 2:1 to 1:2, in particular in the range of 1.3:1 to 1:1.3.

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

[0053] The creatine composition used according to the present invention can 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 hydroxypropyl cellulose or hydroxyethyl cellulose); microcrystalline cellulose; sugar alcohols such as xylitol, sorbitol, or mannitol; peptides such as gelatin; and polymers (e.g., polyvinylpyrrolidone, polyethylene glycol, etc.) are common binders or fillers for tablets.

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

[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 can be absorbed by the body. Examples of disintegrants include cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone) and cross-linked sodium carboxymethylcellulose (croscarmellose sodium). Other suitable disintegrants are, for example, modified starches or sodium starch glycolate.

[0059] Flavorings can be used to mask unpleasant-tasting tablet ingredients. Furthermore, the ingredients may increase patient acceptance of the tablet. Flavorings can be natural, such as fruit extracts, or artificial. For example, natural extracts of vanilla, peach, apricot, raspberry, mint, anise, or cherry can be used as flavorings. Antacid compounds or cough syrups are also suitable.

[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 are made with cellulose ethers, especially hydroxypropyl methylcellulose (HPMC) film coatings. However, other coating materials are also useful, such as synthetic polymers, shellac, vegetable fibers, waxes, fatty acids, or polysaccharides. Capsules are usually coated with gelatin.

[0062] Particularly useful coatings for tablets in connection with the invention disclosed herein are cross-linked sodium carboxymethylcellulose (croscarmellose sodium), silicified microcrystalline cellulose, agglomerated anhydrous lactose and lactitol monohydrate.

[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% carbohydrates; 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% carbohydrates; 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 containing 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 in accordance with the present invention.

[0066] Preferred granules or powders according to the invention described contain 10 wt% to 100 wt%, preferably 30 wt% to 99 wt% of creatine, creatine derivatives or salts thereof or adducts thereof.

[0067] The application of creatine, a creatine derivative, or a salt thereof, or an adduct thereof in combination with an anti-inflammatory drug can support recovery from respiratory problems (dyspnea) and / or chest pain, lung pain, lung fatigue, and body pain caused by viral infections. Anti-inflammatory drugs include, for example, nonsteroidal drugs such as aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, and indomethacin, and steroidal drugs such as corticosteroids such as cortisone, hydrocortisone, and prednisone.

[0068] Creatine, creatine derivatives or their salts or their adducts can be advantageously combined with neuroprotective agents.Preferred neuroprotective agents include glutamate excitotoxicity inhibitors such as ginsenoside, riluzole, progesterone, estrogen, memantine or simvastatin; stimulants such as caffeine; growth factors such as IGF-1 and CNTF; nitric oxide synthase inhibitors; and caspase inhibitors or erythropoietin.

[0069] Creatine, a creatine derivative or a salt thereof or an adduct thereof may also be combined with a drug for the treatment of a viral infection, especially if the administration of creatine is initiated in the acute phase of the viral infection. For the treatment of COVID-19, drugs from the following groups are available: Radivrio (molnupiravir), Olumiant (baricitinib), (tixagevimab / silgavimab), Kineret (anakinra), Paxlobid (PF-07321332 / ritonavir), Resiquilona (regdanvimab), Roactemra (tocilizumab), Lonaprev (casirivimab / imdevimab), Veklury (remdesivir), and Zevdi (sotrobimab). For the treatment of influenza, drugs such as Rapivab (peramivir), Relenza (zanamivir), Tamiflu (oseltamivir phosphate), and Xofluza (baloxavir marboxil) are suitable. For the treatment of adenovirus, cidofovir, ribavirin, ganciclovir, and vidarabine are useful.

[0070] Creatine, creatine derivatives, or their salts or 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 adducts, can be administered without the additional administration of such compounds, particularly without the co-administration of ubiquinone 10 (coenzyme Q-10).

[0071] Creatine, creatine derivatives, or salts thereof, or adducts thereof, are preferably used in combination with a pain-relieving, anti-inflammatory diet according to a preferred embodiment of the present invention. A preferred diet should provide all the nutrients necessary for normal energy metabolism and healthy functioning of the nervous system. A particularly suitable diet should include vitamins, minerals, unsaturated fatty acids, amino acids, antioxidants, phytonutrients, and secondary plant metabolites, including essential or semi-essential nutrients.

[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 of 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, Referenzwerte fur die Nahrstoffzufuhr, 2. Auflage, 7. Aktualisierte Ausgabe, 2021).

[0075] A further group of nutrients useful in a pain-relieving, anti-inflammatory diet are unsaturated fatty acids, particularly the omega-3 fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-lipoic acid and lecithin.

[0076] A preferred diet should also be rich in amino acids selected from the group consisting of L-tyrosine, arginine, and glycine. Additional amino acids, such as theanine, cystine, taurine, or mixtures thereof, are also abundant in a preferred diet.

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

[0079] A suitable diet can include plants, especially herbs, spices, fruits, vegetables, and legumes, or their extracts, oils, powders, or composites, such as Boswellia serrata, Curcuma longa, grape seeds (especially those containing OPCs), or Devil's Claw. Additionally, tomatoes, olive oil, green leafy vegetables such as spinach, kale, and collard greens, nuts such as almonds and walnuts, and fruits such as strawberries, blueberries, cherries, and oranges are also considered anti-inflammatory foods. Fatty fish such as salmon, mackerel, tuna, and sardines also have anti-inflammatory properties.

[0080] The nutrients recommended for a pain-reducing and anti-inflammatory diet can be supplied by making appropriate food choices or by adding the respective ingredients via dietary supplements. Description of the image: [Brief explanation of the drawings]

[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, and the right column represents the placebo group. [Figure 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. [Example]

[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 symptoms after SARS-CoV-2 infection. The study employed a parallel-group, randomized, placebo-controlled, double-blind design. The allocation ratio to the experimental (creatine) and control (placebo) groups was set at 1:1. Patients were eligible for inclusion in the study: age 18–65 years, a positive COVID-19 test (documented by a valid PCR or antigen test) within the past 3 months, moderate to severe fatigue, and at least one additional COVID-19-related symptom selected from the following: loss of smell, loss of taste, breathing 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 the 4 weeks prior to the start of the study.

[0083] This study was conducted in accordance with the Declaration of Helsinki (7th edition). The previously published data were collected from October 2021 to January 2022 at the FSPE Applied Bioenergetics Lab at Novi Sad University. The experimental (creatine) group received 4 grams of creatine monohydrate per day, while the control (placebo) group received the same amount of inulin. Participants received the intervention once daily at breakfast. They were asked to stir either the experimental or control powder into 250 mL of lukewarm water and ingest it immediately. Both interventions were similar in appearance, texture, and sensory characteristics. Creatine monohydrate was provided by Alzchem Trostberg GmbH (Trostberg, Germany). The intervention period was 6 months, and participants were asked to refrain from using other dietary supplements during the study period. All outcome measures were measured at baseline (pre-treatment), 3 months, and 6 months. The primary outcomes were changes in vastus medialis creatine levels 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), with an effect size of 0.50 (medium effect), an alpha error probability of 0.05, a power of 0.80 for the two groups, and two (3-month) and three (6-month) measurements of each study outcome.

[0084] At this point, 12 participants had been randomly assigned to receive the intended treatment and analyzed for the primary outcome: 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. Creatine tissue levels were measured by proton magnetic resonance spectroscopy (1.5 T Avanto scanner, Siemens, Erlangen, Germany) using a matrix head coil in circular polarization mode, and metabolite spectra of skeletal muscle and specific brain regions (vastus medialis, thalamus, frontal lobe, precentral, paracentral, and parietal lobe white and gray matter) were processed as previously described (Appl Physiol Nutr Metab. 2016 Sep, 41(9):1005-7.).

[0086] Statistical method: Data were first analyzed for normality of distribution using the Shapiro-Wilk test and for homogeneity of variance using the Bartlett test. When homogeneity of variance was verified for normally distributed data, summary measures of the interaction effect (time vs. intervention) were compared using a two-way ANOVA with repeated measures. When non-homogeneity of variance was confirmed, data were compared using the Friedmann test. For the two-way ANOVA and Friedmann test, post-hoc LSD and Wilcoxon tests were used to identify differences between individual sample pairs, respectively. The significance level was set at P ≤ 0.05. Effect sizes after the intervention were assessed using the Cohen statistic, with d ≥ 0.8 indicating a large effect. Data were analyzed using the statistical package SPSS version 24.0 for Mac (IBM SPSS Statistics, Chicago, IL).

[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 the white matter (brain), thalamus, vastus medialis, and gray matter (brain) after 3 and 6 months of intervention with 4 grams of creatine per day compared to creatine levels in the placebo group.

[0088] [Table 1]

[0089] The percent difference between creatine levels at 3 months and the corresponding baseline levels in the white matter (brain), gray matter (brain), thalamus, and vastus medialis, calculated from Table 1, is shown in Figure 1. The left column represents the creatine-treated patient group, and the right column represents the placebo group. For white matter and gray matter values, the mean values ​​were determined from Table 1.

[0090] A randomized controlled trial found that creatine administration for 3 months resulted in accumulation in the brain and vastus medialis muscle. Creatine supplementation maintained increased creatine levels for at least another 3 months. No changes in tissue creatine levels were observed in the placebo group.

[0091] Participants in the experimental group experienced increases in tissue total creatine levels in all 14 regions assessed in the study, with the highest increases observed in the vastus medialis (P = < 0.01), left frontal lobe white matter (P = 0.01), and right parietal lobe white matter (P = 0.01) at 6-month follow-up. Tissue creatine levels remained unchanged in the placebo group throughout the study. A two-way ANOVA with repeated measures revealed significant differences between interventions (treatment by time interaction) in tissue creatine levels (P < 0.05), with the creatine group demonstrating superior enhancement of creatine levels in the vastus medialis, left frontal lobe white matter, and right parietal lobe white matter compared with the placebo group. Furthermore, strong interaction effects between interventions were reported in several other regions, including the right frontal lobe white matter, right paracentral lobule white matter, left parietal lobe white matter, and left medial parietal gray matter (P < 0.20).

[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 lobe white matter (1.25 at 3 months and 1.32 at 6 months), right paracentral gray matter (0.88 at 3 months), left parietal lobe white matter (0.92 at 3 months and 1.17 at 6 months), parietal lobe white matter (1.99 at 3 months and 1.74 at 6 months), left parietal lobe mesial gray matter (0.84 at 6 months), and right parietal lobe mesial gray matter (1.17 at 3 months and 1.06 at 6 months), with 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, decreased activity, and decreased motivation, was assessed using the Multidimensional Fatigue Inventory (MFI-20) test (Smets EM et al., J. Psychosom. Res. 1995, 39(3), 315). The results of the VAS scale survey and MFI-20 test are summarized in Table 2.

[0096] [Table 2]

[0097] In the tests carried out, patients were required to report a score for the symptoms shown in Table 2. Thus, the higher the score, the greater the respective symptom experienced by the interviewed patient. Consequently, the lower the given value, the greater the relief effect for each symptom. As can be seen from Table 2, improvements in physical fatigue were observed in the creatine group, but not in the placebo group.

[0098] [Table 3]

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

[0100] Significant interaction effects (time vs. treatment) were observed for all symptoms assessed (P<0.05). Cohen's effect sizes for primary and secondary outcomes after creatine supplementation were also demonstrated for respiratory disturbances (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 administration for three months resulted in accumulation in skeletal muscle and the brain. Increased endurance in the creatine group was superior to that in the placebo group (Table 5). The improved endurance was accompanied by a reduction in bodily and pulmonary pain, particularly recovery from respiratory problems. The improved endurance was also accompanied by a reduction in fatigue symptoms, particularly mental fatigue and loss of motivation, compared with 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, creatine administration achieved smaller improvements in fatigue symptoms, such as physical fatigue and decreased activity, compared with the placebo group. Furthermore, creatine did not cause 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 symptoms after SARS-CoV-2 infection. Eight post-COVID patients (age 33.5 ± 9.9 years, weight 72.3 ± 14.5 kg, height 168.6 ± 11.0 cm; four women) with moderate fatigue and respiratory problems or lung pain and pulmonary fatigue volunteered to participate in this randomized controlled trial. All patients were randomized to receive 4 grams of creatine monohydrate daily plus breathing exercises (2–3 times daily for 10–15 minutes) (experimental group) or breathing exercises alone (control group) for a 3-month intervention period using a double-blind, parallel-group design.

[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 each patient and may include, for example, modified segmental breathing, breathing exercises to strengthen respiratory and expiratory muscles, inspiratory muscle training, bed mobility exercises, stretching, gymnastics, and / or walking. The intensity of exercise is initially low and gradually increased without placing significant strain on the patient.

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

[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 after this complex condition.

[0111] Respiratory disturbances and lung pain were reduced to zero in both groups at the 3-month follow-up, while lung fatigue significantly decreased by 84% in the creatine group and 74% in the control group (P<0.05). A repeated-measures Friedman ANOVA test revealed a significant difference between the groups for lung fatigue (P=0.03), with participants in the creatine group experiencing better relief of lung fatigue than those in the control group. The Cohen's effect size for lung fatigue was 2.97, suggesting a significant effect of creatine monohydrate and breathing exercises (Table 6). This outcome was also confirmed by the results of a VAS scale survey of physical fatigue. In particular, physical fatigue was significantly improved by creatine administration combined with breathing exercises (Table 5). Compared with the control group (breathing exercise group), no significant improvement was achieved with creatine plus breathing exercises for mental fatigue or decreased motivation.

[0112] Example 3: Exhaustion test Patients' time to exhaustion was assessed by a motorized treadmill incremental exhaustion test. 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). Treadmill assessment results are shown in Tables 7 and 8.

[0113] [Table 7]

[0114] In patients suffering from postviral fatigue syndrome after SARS-CoV-2 infection, time to exhaustion was significantly increased. The time to exhaustion in the creatine group increased by 7.3% compared to 2.1% after placebo. 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 extending time to exhaustion after 3 and 6 months of creatine administration.Improvements in endurance were accompanied by decreases in bodily and pulmonary pain, particularly recovery from respiratory problems.

[0116] [Table 8]

[0117] The mean time to exhaustion significantly improved by 54 seconds after administration in the experimental group (P = 0.05), with creatine monohydrate and breathing exercises superior to breathing exercises in extending 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, while the placebo group remained at stage 5. The data demonstrate a synergistic effect of creatine monohydrate and breathing exercises compared with 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 impairment, 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 or smell, body pain, respiratory problems, difficulty concentrating, headache, lung pain, or fatigue) volunteered to participate in this randomized, controlled, parallel-group intervention study. All patients were assigned to receive either powdered creatine monohydrate (experimental group: creatine (Creapure®) 8 grams per day) or glucose (control group: glucose 3 grams per day) in a double-blind, parallel-group design during the 8-week intervention period. All participants refrained from using other dietary supplements during the study period. Detailed information about the experimental protocol and test procedures used in this study is provided 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 gray matter (brain) after creatine intervention compared to the glucose group.

[0121] [Table 9]

[0122] Creatine levels in the white matter (brain), gray matter (brain), thalamus, and vastus medialis muscle after 8 weeks were increased in the experimental group compared to the control group.The results confirmed the results 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 postviral 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. Lung pain was significantly reduced by 67% in the creatine cohort compared to a 50% increase in the glucose cohort.

[0127] Therefore, several post-COVID-19 related symptoms, 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 the 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 reductions 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 reductions 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 calculating effect sizes when pre- and / or post-values ​​are equal to zero. Abbreviations: GF: general fatigue, PF: physical fatigue, RM: decreased motivation, RA: decreased 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 creatine hydrate and / or a salt thereof for use in treating one of the conditions selected from the group consisting of physical fatigue and respiratory problems after SARS-CoV-2 infection and / or increasing the time to exhaustion after SARS-CoV-2 infection.

2. 2. The pharmaceutical composition of claim 1, wherein the physical fatigue and / or respiratory problems are caused by SARS-CoV-2 infection or are post-COVID symptoms after SARS-CoV-2 infection.

3. 3. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of respiratory disorders and / or physical fatigue in combination with physical and / or respiratory exercise.

4. 3. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of physical fatigue in a subject performing physical and / or respiratory exercise.

5. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition is for use in combination with breathing exercises to strengthen the respiratory muscles, including strengthening the diaphragm, external intercostal muscles and expiratory muscles.

6. 3. The pharmaceutical composition of claim 1 or 2, 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. 3. The pharmaceutical composition of claim 1, wherein the salt of creatine is selected from the group consisting of the corresponding acetate, citrate, maleate, fumarate, tartrate, malate, pyruvate, ascorbate, succinate, aspartate, lactate, oxalate, formate, benzoate, phosphate, sulfate, chloride, hydrochloride, and the corresponding potassium, sodium, calcium, and magnesium salts.

8. 3. The pharmaceutical composition of claim 1, wherein the composition comprises creatine monohydrate.

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

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

11. A composition comprising creatine or creatine hydrate and / or a salt thereof as a dietary supplement for supporting recovery from one of the conditions selected from the group consisting of physical fatigue and respiratory problems after SARS-CoV-2 infection and / or increasing the time to exhaustion after SARS-CoV-2 infection.

12. 12. The composition of claim 11, wherein the physical fatigue and / or respiratory problems are caused by a coronavirus infection of the lungs or lower respiratory system or are post-COVID symptoms following SARS-CoV-2 infection.

13. 13. The composition of claim 11 or 12, wherein the composition is used in combination with physical and / or respiratory exercises to strengthen the respiratory muscles, including strengthening the diaphragm, external intercostal muscles and expiratory muscles.

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

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

16. The composition of claim 11 or 12, wherein the composition comprises creatine monohydrate.

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