Compositions comprising creatine for treatment of dyspnea

Abstract

The present invention relates to a pharmaceutical composition comprising creatine or a physiologically acceptable derivative thereof and / or a salt and / or adduct thereof for use in the treatment of dyspnea, chest pain, body pain, etc. following viral infections, in particular in combination with respiratory exercise. Another embodiment of the invention relates to the use of a composition comprising creatine or a physiologically acceptable derivative thereof and / or a salt and / or adduct thereof as a dietary supplement, the dietary supplement is used for preparing a diet for supporting recovery from dyspnea, chest pain, body pain and the like through respiratory exercise after lung or lower respiratory system virus infection.

Description

Technical field:

[0001] The present invention relates to a pharmaceutical composition comprising creatine for use in treating symptoms caused by viral infections of the lungs or lower respiratory system, in particular dyspnea and chest pain, in a subject in need thereof. Another object of the present invention is the use of creatine or a creatine derivative as a dietary supplement for the preparation of a diet for consumption by patients suffering from dyspnea and chest or lung pain following a viral infection. Background technology:

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

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

[0004] Typical symptoms that may persist after SARS-CoV-2 infection include fatigue (e.g., post-viral fatigue syndrome (PVFS) or chronic fatigue syndrome (CFS)), difficulty breathing or shortness of breath (dyspnea), lung or chest pain, joint pain, muscle pain or headache, concentration and memory difficulties, sleep problems (insomnia), loss of smell (anosmia) or loss of taste (anosmia), etc. Among them, fatigue, difficulty breathing (dyspnea) and chest pain are the most reported symptoms after acute SARS-CoV-2 infection. In many cases, these symptoms sometimes last for months.

[0005] According to a study by Manal S., Barnett J., Brill S et al. (Thorax, 2021; 76, 396-398), during severe illness, more than 50% of COVID patients suffered dyspnea within 8 weeks after discharge. These findings were confirmed by a survey by Halpin S.J., McIvor C. et al. (J. Med. Virol. 2021; 93, 1013-1022). More than 60% of patients who received strict medical treatment subsequently suffered dyspnea for an average of 48 days after discharge.

[0006] The described condition is summarized by the term “post-COVID-19 syndrome” or “long-COVID-19”, hereafter referred to as post-COVID.

[0007] Subjects with dyspnea often do not get enough air or feel out of breath. They need to take frequent breaks during activity or feel that upper body and muscle movements are more labored than normal breathing. Advice for these subjects is usually limited to behavioral advice, such as allowing regular breaks, breaking large tasks into smaller ones, and slowly increasing the amount of exercise. For subjects with these symptoms, the situation can be very exhausting.

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

[0009] In Deutsches A practical medical strategy for patients with long COVID is summarized in 2020;49,117 and is based on initial care recommendations for long Covid described in Greenhalgh, T.; Knight M., A`Court C.; BMJ 2020;370,3026. Medical treatment is limited to symptomatic treatment, such as acetaminophen for fever and consideration of antibiotics for secondary infection.

[0010] To improve recovery in patients with dyspnea or lung pain, pulmonary rehabilitation should be applied as early as possible. So far, pulmonary rehabilitation is considered one of the most important interventions in post-COVID care.

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

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

[0013] Therefore, the administration of creatine has been considered as an auxiliary measure for the treatment of various diseases. In particular, Ostojic, SM et al., for example, described a dietary treatment for chronic fatigue syndrome (CFS) containing guanidinoacetic acid (GAA) (Nutrients 2016, 8, 72). In Marinari, S. et al., Multidisciplinary Respiratory Medicine 2013, 8:40, the combination of creatine and coenzyme Q10 was described for the treatment of COPD patients. In Ostojic, SM Nutrients 2021, 13, 503; Ostojic, SM, Therapeutic Advances in Respiratory Disease, 2020, Vol. 14, Issue 1-2 and Kreider RB et al., Nutrients 2021, 13, 447, the effectiveness of creatine in the treatment of post-viral fatigue syndrome (PVFS) was discussed.

[0014] Starting from this, the problem to be solved by the present invention is to improve the recovery from dyspnea and / or chest pain, lung pain 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] This problem is solved by administering creatine to patients in need thereof. Creatine supports recovery from body fatigue and / or breathlessness (e.g., dyspnea) and / or chest pain, lung pain, lung discomfort and body aches caused by viral infections, and in particular supports recovery from body fatigue and / or breathlessness (e.g., dyspnea) and / or chest pain, lung pain, lung discomfort and body aches following viral infections (e.g., post-Covid).

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

[0017] Post-viral fatigue syndrome (PVFS) is a puzzling long-term neurological condition. PVFS is characterized in particular by the inability to participate in daily activities that were possible before the illness, lasting for more than six months, accompanied by fatigue, post-exertional malaise, and unrefreshing sleep. PVFS-related symptoms are often found especially after infection with members of the coronavirus family (SARS-CoV2), leading in many cases to post-COVID fatigue syndrome.

[0018] Therefore, a first embodiment of the present invention is a pharmaceutical composition for treating physical fatigue, dyspnea, shortness of breath (dyspnea), chest / lung pain, lung discomfort and body pain after viral infection, in particular COVID-19 infection, comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof.

[0019] In a preferred embodiment of the invention, a pharmaceutical composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof is used for the treatment of dyspnea, shortness of breath (dyspnea) and / or chest (lung) pain and / or lung discomfort in combination with breathing exercises and / or physical exercise.

[0020] A second embodiment of the invention is the use of creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof as a dietary supplement or as a supplement for the preparation of a diet that supports recovery from physical fatigue, dyspnea, shortness of breath (dyspnea), or chest / lung pain, lung discomfort and / or body pain following a viral infection of the lungs or lower respiratory system, preferably in combination with physical exercise and / or respiratory exercises.

[0021] By administering creatine, a significant increase in creatine concentrations in the muscles and brain of post-COVID patients could be detected.

[0022] This is surprising, as it was previously believed that creatine could not cross the blood-brain barrier. However, within the framework of the present invention, it has been found that it appears that long COVID or post-COVID causes changes in the blood-brain barrier, whereby creatine uptake and enrichment in brain regions such as the thalamus, gray matter and white matter are observed, especially in the post-COVID situation.

[0023] In addition, the inventors of the present application found that, without supplementing creatine, long COVID patients only showed low levels of creatine in the brain. Within the framework of the present invention, it was found that the total creatine concentration in the brain, especially the thalamus, white matter and gray matter of long COVID patients was significantly reduced compared with the reference value of the general population. Therefore, without being bound by any theory, it is assumed that one of the effects and / or causes of long COVID is the depletion of creatine in the brain region, resulting in a reduction in creatine levels in these brain regions. Through the discovery of the present invention (i.e., creatine can pass through the blood-brain barrier of long COVID patients), creatine levels in the brain region can be enriched and / or increased by adding creatine.

[0024] It is particularly surprising that, on the one hand, total creatine concentrations in the brain of long COVID patients were found to be reduced compared to reference values ​​for the general population, and on the other hand, in post-COVID patients, creatine was found to be significantly enriched in the brain, especially in the thalamus, gray matter and / or white matter, while after creatine supplementation, no increase in creatine in the brain was seen in normal healthy people, or only a very small maximum increase of about 5% was seen. It seems that long COVID leads to a depletion of brain creatine and at the same time changes the properties of the blood-brain barrier so that the supplemented creatine can pass through and leads to a significant increase in creatine in the brain after creatine supplementation. Surprisingly, according to the present invention, creatine was found to be enriched in the brain after creatine supplementation, indicating that creatine in long COVID patients can pass the blood-brain barrier. In particular, it was found that creatine supplementation alone, i.e. creatine supplementation without the addition of any transporters or adjuvants known to modify the blood-brain barrier, leads to an enrichment of creatine in the brain.

[0025] The significant increase in creatine concentrations in the muscles and brain of post-COVID patients is particularly surprising for patients treated with physical and / or respiratory exercises, as total tissue creatine concentrations remain essentially unresponsive to physical and / or respiratory exercises (even further reduced from baseline levels), suggesting a long-term disturbance in tissue bioenergetics after COVID. Therefore, recovery from post-COVID is supported by administering creatine to increase tissue creatine levels, for example in muscle and throughout the brain. In addition, the physical condition of post-COVID patients, such as reduced physical fatigue, reduced dyspnea, reduced lung (chest) pain, and reduced lung discomfort, may also be improved. In addition, the time to exhaustion of subjects receiving creatine in combination with physical and / or respiratory exercises is increased. Therefore, the physical condition of post-COVID patients can be significantly improved by combining creatine administration with physical and / or respiratory exercises.

[0026] The effect of creatine is enhanced if the individual exercises during the supplementation period. Respiratory exercise can induce hyperemia, which increases tissue perfusion and enhances the delivery of creatine 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 promotes the increase in intramuscular creatine during creatine uptake, and the increase in exercised body parts is greater than that in unexercised 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 can upregulate the sodium-potassium pump that activates a specific creatine transporter (CT1) and enable more creatine to be delivered to specific cells (Odoom JE, Kemp GJ, Radda GK Theregulation of total creatine content in a myoblast cellline. Mol. Cell. Biochem. 1996; 158: 179-188). It is speculated that, without being bound by theory, these effects not only support the recovery of patients after COVID by creatine administration, but also minimize the adverse effects (e.g., increased physical fatigue) of patient physical exercise (including breathing exercise). Evidence from research shows that exercise combined with creatine supplementation enhances creatine accumulation in target tissues, which means the synergistic effect of creatine (especially creatine monohydrate) plus breathing exercise.

[0027] The pharmaceutical composition of the first embodiment and the composition used as a dietary supplement of the second embodiment are also referred to below as creatine composition, creatine-containing composition or composition comprising creatine. Unless expressly stated otherwise, the term "creatine composition", "creatine-containing composition" or "composition comprising creatine" also includes physiologically acceptable creatine derivatives, creatine salts and / or creatine adducts.

[0028] The creatine-containing composition of the present invention is particularly useful for supporting recovery from typical symptoms (such as dyspnea and chest pain) after viral infection. Dyspnea or dyspnea is characterized by shortness of breath and impaired ability to inhale or exhale. Dyspnea can occur as a result of several acute and chronic cardiopulmonary diseases (including asthma, chronic obstructive pulmonary disease (COPD), heart disease, pneumonia, etc.). In such cases, dyspnea is a respiratory disease, and is classified as a neurological disease after Covid. For example, in COPD as a respiratory disease, oxidative stress plays a key role, so its treatment generally includes antioxidants such as coenzyme Q10. However, shortness of breath is one of the most common diseases after viral infection, especially coronavirus infection (including SARS-CoV-2 infection). In such cases, shortness of breath or dyspnea associated with viral infection, especially SARS-CoV-2 infection, usually lasts for weeks or months in patients who overcome viral infection. Therefore, the causes and mechanisms of typical COPD as a respiratory disease and dyspnea associated with Covid as a neurological disease seem to be different. Breathing difficulties can also be associated with low blood oxygen levels observed over longer periods of time and compromise overall health.

[0029] Chest pain (lung pain) is a sharp, stabbing pain that occurs during breathing, coughing or sneezing. The most common cases of chest pain or lung pain are asthma, chronic obstructive pulmonary disease, and especially bacterial or viral infections of the pleura (pleurisy) or other chest tissues. For example, chest (lung) pain is observed as a persistent symptom after viral infections such as SARS-CoV-2 infection. Chest (lung) pain may last for a long time or may be chronic, often accompanied by coughing, difficulty breathing and wheezing. When pleural inflammation occurs near the diaphragm, the pain may also involve the neck or shoulders.

[0030] Several acute and chronic viral infections that cause breathing difficulties and / or pulmonary discomfort, chest (lung) pain include influenza A or B viruses (e.g., H1N1, H5N1), enteroviruses, respiratory syncytial viruses, parainfluenza viruses, adenoviruses, and coronaviruses (e.g., SARS, MERS, SARS-CoV-2). The symptoms can last for weeks or months. For example, after SARS-CoV-2 infection, breathing difficulties can last from 2 weeks to 1 year or even longer.

[0031] Dyspnea in the sense of the present invention includes in particular dyspnea caused by viral infections.Chest pain in the sense of the present invention includes in particular pleuritic chest pain and thoracal chest pain (lung pain) caused by viral infections.

[0032] According to the present invention, a pharmaceutical composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof is particularly useful for treating one of the following conditions in a post-COVID patient selected from the group consisting of: physical fatigue, dyspnea, dyspnea, chest pain, lung pain, lung discomfort and body pain. In this article, specific symptoms and / or conditions that persist or appear after the initial recovery of acute COVID infection are referred to as post-COVID. One of the difficulties associated with finding a suitable treatment for PVFS, especially post-COVID, is the diversity, multiplicity, variety and ambiguity of symptoms associated with post-COVID, as well as the uncertainty of the causes of the symptoms. This complicates post-COVID treatment and the prediction of which agent or treatment method may work in post-COVID treatment. Post-COVID manifestations can appear as many different conditions and symptoms, including pulmonary conditions, neurological symptoms and conditions such as headache, nasal olfactory disorders, impaired taste, dizziness, confusion, disorientation and other injuries, neuropsychiatric disorders, stroke, gastrointestinal symptoms such as nausea, loss of appetite, vomiting, diarrhea, etc.; cardiovascular diseases including myocarditis, cardiac insufficiency, heart failure and thromboembolic events; renal insufficiency; dermatological manifestations. Especially for long-term effects, consistent clinical phenomena cannot be determined, and the underlying mechanism is unclear. Patients report quite different symptoms after COVID, which last for weeks or even months. Frequently reported complaints or symptoms include fatigue, tiredness, mental fatigue, exhaustion, impaired elasticity, memory problems, sleep problems, muscle weakness, muscle pain and mental problems (such as depressive symptoms and anxiety). Other symptoms reported include worsening lung function, worsening lung function, worsening renal function and myocardial inflammation. However, this list is by no means definitive, and it shows the diversity and diversification of the illnesses and symptoms related to COVID. So far, it is more unknown to be the causes of those illnesses and symptoms caused by COVID or after COVID. Therefore, it is difficult to provide suitable treatment after COVID because the mutual applicability of known treatments for similar symptoms does not exist.

[0033] According to the present invention, it has now surprisingly been found that a pharmaceutical composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof can be effectively used to treat specific conditions selected from the group consisting of: physical fatigue, dyspnea, shortness of breath (dyspnea), chest pain, lung pain, lung discomfort and body pain associated with post-COVID. As outlined above, the causes of many different symptoms associated with post-COVID are unclear and, therefore, effective treatment is unpredictable. In addition, it seems that not only are there quite a lot of symptoms, but also there are quite a lot of conditions that cause various symptoms. In the tests and experiments that serve as the basis of the present invention, it has now surprisingly been found that the provision of creatine specifically improves conditions associated with physical fatigue, dyspnea, shortness of breath (dyspnea), chest pain, lung pain, lung discomfort and body pain in post-Covid patients.

[0034] The recovery of patients who suffer from dyspnea or chest (lung) pain or pulmonary discomfort after a viral infection can be surprisingly improved by administering creatine, particularly in combination with breathing 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-guanidinoglycine. Creatine can also be obtained from animal foods or in higher amounts as a food supplement. In food supplements, preferably creatine monohydrate is used, which can be prepared in 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 creatine prodrugs capable of releasing creatine under physiological conditions, such as creatine esters. In the present specification, guanidinoacetic acid (GAA) is also included in the group of suitable creatine derivatives. Physiologically acceptable creatine derivatives are preferably selected from the group consisting of: creatine, creatine hydrate, creatine esters or amides, including creatine C 1 -C 5 -Alkyl ester, NC 1 -C 5 -alkylamides, creatine phosphate, inositol-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 acetates, citrates, maleates, fumarates, tartrates, malates, pyruvates, ascorbates, succinates, aspartates, lactates, oxalates, formates, benzoates, phosphates, sulfates, chlorides, hydrochlorides, the corresponding potassium, sodium, calcium, magnesium salts, the corresponding L-carnitine, acetyl-L-carnitine, taurine, betaine, choline, methionine adducts or mixtures thereof.

[0037] The term breathing exercise as used herein includes physical exercise as well as pulmonary rehabilitation.

[0038] Pulmonary rehabilitation is an integral part of the management of people with respiratory diseases or lung problems caused by other conditions. Pulmonary rehabilitation includes exercise training, health education, and breathing techniques designed to improve decreased lung function and improve 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 includes training the respiratory and expiratory muscles through breathing exercises. The respiratory muscles include the inspiratory muscles, such as the diaphragm and the external intercostal muscles attached between the ribs, such as the external intercostal muscles and the intercostal muscles (musculi intercartilaginei). The diaphragm and the external intercostal muscles are one of the most important respiratory muscle groups. Other inspiratory muscles are summarized as the auxiliary muscles of inspiration. This group of muscles supports the inspiration through the lungs and includes the posterior superior serratus, posterior inferior serratus, pectoralis minor and major muscles, sternocleidomastoid muscles and erector spinae. Includes the upper posterior serratus, the lower posterior serratus, the pectoralis minor and major muscles, the sternocleidomastoid muscles and the erector spinae.

[0040] The expiratory muscles include the internal intercostal muscles (internal and innermost intercostal muscles), the subcostal muscles (subcostal muscles), and the accessory exhalation muscles, such as the internal obliques, transverse abdominis, transverse thoracis, latissimus dorsi, quadratus lumborum, and rectus abdominis.

[0041] Treatment with creatine can be started during viral infection, preferably within about three months (12 weeks) after infection. Preferably, creatine administration is started within a time range of 2 weeks after infection to 8 weeks after infection. In addition, the administration of creatine should most preferably be started within 4 weeks before the start of physical exercise and / or breathing exercises including pulmonary rehabilitation, or simultaneously with physical exercise and / or breathing exercises including pulmonary rehabilitation. However, it is also possible to administer creatine after the start of physical exercise and / or breathing exercises including pulmonary rehabilitation.

[0042] As soon as the patient's health status allows, pulmonary rehabilitation measures, such as training the respiratory muscle system through breathing exercises, should be started as soon as possible. Rehabilitation, physical exercise and / or breathing exercises are usually started within 20 weeks, preferably within 12 weeks, and most preferably within 6 weeks after the infection resolves.

[0043] The duration of creatine supplementation generally lasts from 1 week to 12 months or longer, preferably 1 to 8 months, especially 3 to 6 months, depending on the symptoms of the subject in need thereof.

[0044] The amount of creatine to be administered is in the range of 3 g to 30 g per day. Preferably, the dosage is in the range of 7 g to 25 g, most preferably between 8 g and 20 g, which is higher than the dosage usually recommended for athletes or sportswomen.

[0045] Preferably, the administration of creatine is divided into a build-up phase and a maintenance phase, wherein the daily dose of creatine in the composition is in the range of 10 g to 30 g in the initial build-up phase and in the range of 7 g to 15 g in the subsequent maintenance phase. The build-up phase has a duration of up to 3 weeks, preferably between 3 and 14 days, in particular between 5 and 10 days, and the maintenance phase has a duration of 1 week to 12 months, preferably between 2 and 8 months, in particular between 3 and 6 months.

[0046] The build-up period is typically the initial period. However, additional build-up periods, such as build-up periods lasting between 1 and 7 days, may be incorporated into the maintenance period.

[0047] The daily creatine dose may be administered once daily, for example during breakfast, or 2, 3, 4 or 5 times a day.

[0048] If the administered creatine composition comprises a creatine derivative, prodrug, adduct or salt, the amount of the creatine moiety comprised therein is decisive for the daily dosage within the above-mentioned range.

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

[0050] In particular, the granules or powders comprising the creatine composition are used in aqueous suspension or water-soluble form. Pure creatine and several creatine derivatives have low solubility. For example, the solubility of creatine is 17 g / L (at 20° C.). Creatine and its low-solubility derivatives can be used in the form of aqueous suspensions. The disadvantage of aqueous suspensions is usually that they separate before ingestion. Therefore, water-soluble granules or powders are generally preferred. In order to increase the water solubility of creatine or creatine derivatives, their water-soluble salts or adducts can be used. In order to increase water solubility, the use of acids or complexing agents in particular can help provide the corresponding creatine salts or creatine derivative salts. Examples of suitable acids (including carboxylic acids) and complexing agents are selected from malic acid, aspartic acid, ascorbic acid, succinic acid, pyruvic acid, fumaric acid, gluconic acid, α-ketoglutaric acid, oxalic acid, acetic acid, formic acid, sulfuric acid, hydrochloric acid, L-carnitine, acetyl-L-carnitine, taurine, betaine, choline and lipoic acid. Peptides and amino acids can also help increase the solubility of creatine and creatine derivatives. Sodium, potassium, calcium and magnesium salts can also be used to increase the water solubility of creatine or creatine derivatives.

[0051] The molar ratio of creatine or creatine derivatives to the above-mentioned acids or complexing agents is generally in the range of 5:1 to 1:5, preferably in the range of 2:1 to 1:2, in particular in the range of 1.3:1 to 1:1.3.

[0052] The granules and powders may also be used to prepare foods that support recovery from physical fatigue, difficulty breathing, shortness of breath, chest / lung pain, lung discomfort and body aches following viral infection, particularly in post-COVID patients.

[0053] The creatine composition used according to the present invention may further be administered in the form of a tablet.

[0054] The creatine composition can be tableted as is or in the form of a preparation containing excipients. Suitable excipients are, for example, pharmacologically inactive ingredients such as binders, fillers, antioxidants, preservatives, stabilizers, anti-caking agents, lubricants, disintegrants, flavoring agents, pigments, etc.

[0055] As binders or fillers, a variety of compounds can be used. Dicalcium phosphate; sugars, including lactose and sucrose; polysaccharides and their derivatives, including starch, cellulose, modified cellulose and cellulose ethers, such as hydroxypropyl cellulose or hydroxyethyl cellulose; microcrystalline cellulose; sugar alcohols, such as xylitol, sorbitol or mannitol; peptides, such as gelatin; polymers, such as polyvinyl pyrrolidone, polyethylene glycol, etc. are commonly used binders or fillers for tablets.

[0056] Typical suitable preservatives are for example cysteine, methionine, citric acid, sodium citrate, triazines or synthetic preservatives such as parabens, including methyl and propyl paraben, and benzoic acid. Suitable antioxidants may be selected from the group of vitamin A, vitamin C, vitamin E, retinyl palmitate and selenium.

[0057] Lubricants and anti-caking agents reduce adhesion in granules or powders, thereby preventing adhesion to tablet punches. They are also used to help protect tablets from sticking. The most commonly used anti-caking agents are magnesium stearate, stearic acid or stearin, but magnesium or calcium salts of other fatty acids may also be used alternatively or in addition. For example, common mineral lubricants are talc or silica.

[0058] Disintegrants swell and dissolve when wet, causing the tablet to disintegrate in the digestive tract or at a specific point in the digestive process, releasing the ingredients for absorption by the body. Examples of disintegrants include cross-linked polymers, such as cross-linked polyvinyl pyrrolidone (crospovidone) and cross-linked sodium carboxymethylcellulose (croscarmellose sodium). Other suitable disintegrants are, for example, modified starch or sodium starch glycolate.

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

[0060] Suitable pigments and colors are, for example, food colorings.

[0061] Tablet coatings protect tablet ingredients from deterioration due to moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a film coating of cellulose ethers, especially hydroxypropylmethylcellulose (HPMC), is used. However, other coating materials are also useful, such as synthetic polymers, shellac, plant fibers, waxes, fatty acids, or polysaccharides. Capsules are commonly coated with gelatin.

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

[0063] Preferably the tablet comprises at least

[0064] a) 10 to 100% by weight, preferably 30 to 99% by weight, of creatine, a creatine derivative or a salt or adduct thereof;

[0065] b) 0 to 80% by weight of carbohydrates;

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

[0067] d) 0 to 20% by weight of an acidulant, preferably citric acid;

[0068] e) 0 to 20% by weight of fatty acids, preferably coconut oil;

[0069] f) 0 to 5% by weight of flavoring agents.

[0070] Preferably the capsule contains at least

[0071] a) 10 to 95% by weight, preferably 30 to 80% by weight, of creatine, creatine derivatives or salts or adducts thereof

[0072] b) 0 to 80% by weight of carbohydrates;

[0073] c) 0 to 20% by weight of an anti-caking agent selected from fatty acids or fatty acid salts, in particular magnesium stearate,

[0074] d) 0 to 5% by weight of flavoring agents;

[0075] e) 5 to 90% by weight of gelatin.

[0076] The ingredients can be used not only for tablets, but also for granules or powders containing creatine or creatine derivatives or salts or adducts thereof. In particular, binders, fillers, antioxidants, preservatives, stabilizers, anti-caking agents, lubricants, disintegrants, flavoring agents and pigments can be part of the creatine composition used according to the present invention.

[0077] Preferred granules or powders in connection with the invention contain 10 to 100 wt. %, preferably 30 to 99 wt. % of creatine, a creatine derivative or a salt or adduct thereof.

[0078] In combination with creatine, creatine derivatives or salts or adducts thereof, anti-inflammatory drugs can be used to support recovery from dyspnea and / or chest pain, lung pain, lung discomfort and body pain caused by viral infections. Anti-inflammatory drugs are, for example, non-steroidal drugs such as aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, etc., or steroids such as corticosteroids, including cortisone, hydrocortisone and prednisone.

[0079] Further combinations of creatine, creatine derivatives or salts or adducts thereof with neuroprotective drugs may be advantageous. Preferred neuroprotective agents include glutamate excitotoxicity inhibitors such as ginsenosides, riluzole, progesterone, estrogen, memantine or simvastatin; stimulants such as caffeine; growth factors such as IGF-1, CNTF; nitric oxide synthase inhibitors; and caspase inhibitors or erythropoietin.

[0080] Combination of creatine, creatine derivatives or salts or adducts thereof with drugs for the treatment of viral infections is also possible, in particular when the administration of creatine is started during the acute phase of the viral infection.

[0081] For the treatment of COVID-19 disease, for example, drugs of the group of Lagevrio (monuprivir), Olumiant (baricitinib), (tesagvir / sigavir), Kineret (anakinra), Paxlovid (PF-07321332 / ritonavir), Regkirona (redanvir), RoActemra (tocilizumab), Ronapreve (casirivimab / imidavimab), Veklury (remdesiviv), Xevudy (sotrovimab) can be used. For the treatment of influenza, Rapivab (peramivir), Relenza (zanamivir), Tamiflu (oseltamivir phosphate), Xofluza (baloxavir mapositate) are suitable drugs. For the treatment of adenovirus, cidofovir, ribavirin, ganciclovir and vidarabine are useful drugs.

[0082] Creatine, creatine derivatives or salts or adducts thereof may be administered in combination with creatine precursors such as guanidinoacetate / guanidinoacetic acid and / or methyl donors (such as arginine, glycine, methionine, etc.) or other compounds or precursors useful in the energy pathways of cells. However, in a preferred embodiment, creatine, creatine derivatives or salts or adducts thereof are administered without additional administration of such compounds, in particular without co-administration of ubiquinone 10 (coenzyme Q-10).

[0083] According to a preferred embodiment of the present invention, creatine, creatine derivatives or salts or adducts thereof are preferably used in combination with a pain-relieving, anti-inflammatory diet. Preferably, the diet should provide all nutrients for normal energy metabolism and healthy function of the nervous system. Particularly suitable diets should contain vitamins, minerals, unsaturated fatty acids, amino acids, secondary plant metabolites, including antioxidants, phytonutrients or essential or semi-essential nutrients.

[0084] For pain relief, anti-inflammatory diets, especially vitamin C, vitamin D, vitamin E, vitamin K, and B vitamins (thiamine, riboflavin, niacinamide, pantothenic acid, pyridoxine, biotin, folic acid, and / or vitamin B 12 ) should be administered in sufficient amounts.

[0085] Important minerals are selected from the group of magnesium, calcium, potassium, sodium, copper, manganese, zinc, selenium and boric acid / boron.

[0086] Vitamins and minerals should be present in the diet in sufficient quantities so that no deficiency symptoms occur. The German Nutrition Society gives appropriate recommendations for the daily amounts of these nutrients (Deutsche Gesellschaft für eV, Refer to first 2.Auflage,7.Aktualisierte Ausgabe,2021).

[0087] Another useful group of nutrients for a pain-relieving, anti-inflammatory diet are unsaturated fatty acids, particularly the omega-3 fatty acids; docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-lipoic acid, and lecithin.

[0088] The preferred diet should also be enriched with amino acids selected from the group of L-tyrosine, arginine and glycine. Additional amino acids are enriched in the preferred diet, such as theanine, cystine, taurine or mixtures thereof.

[0089] Other compounds that should be present in a pain-relieving, anti-inflammatory diet are N-acetyl-L-cysteine, gamma-amino-butyric acid (GABA), S-adenosylmethionine (SAMe), ubiquinol (Coenzyme Q10), NADH, resveratrol, lutein, lycopene, choline, and carnitine.

[0090] Particularly useful phytonutrients in the pain-relieving, anti-inflammatory diet include secondary plant metabolites, such as antioxidants, anthocyanidines, flavonoids, flavonoids, isoflavones, catechins, anthocyanidins, isothiocyanates, carotenoids, allyl sulfides, polyphenols, resveratrol, lutein or lycopene. Particularly preferred secondary plant metabolites are oligomeric proanthocyanidins and oligomeric proanthocyanidins (OPC).

[0091] For the preferred diet, plants, in particular herbs, spices, fruits, vegetables and legumes, or extracts, oils, powders or compounds thereof, such as extracts, oils, powders or compounds from groupboswellia serrata, turmeric, grape seeds (especially containing OPCs) or devil's claw, can also be used. In addition, tomatoes, olive oil, green leafy vegetables (such as spinach, kale and collards), nuts such as almonds and walnuts or fruits (such as strawberries, blueberries, cherries and oranges) are considered anti-inflammatory foods. Fatty fish like salmon, mackerel, tuna and sardines also have anti-inflammatory effects.

[0092] The recommended nutrients for a pain-relieving, anti-inflammatory diet can be provided by selecting appropriate foods or by adding the corresponding components through nutritional supplements.

[0093] Description of the drawings:

[0094] Figure 1 : Changes in tissue creatine levels in patients post-COVID. The left column represents the group of patients who received creatine and the right column represents the placebo group. Figure 2 The calculated Cohen effect sizes (GF, general fatigue; PF, physical fatigue; RM, reduced motivation; RA, reduced activity; MF, mental fatigue; BOA, bodily pain; BRD, dyspnea; LUP, lung pain; and MAL, malaise) of creatine administration in post-COVID patients are described. Specific implementation method:

[0095] Embodiment 1:

[0096] A study was conducted to evaluate the efficacy and safety of creatine supplementation via dietary supplementation in patients with post-COVID following SARS-CoV-2 infection. The study adopted a parallel-group, randomized placebo-controlled, double-blind design. The allocation ratio of the experimental group (creatine) and the control group (placebo) was set at 1:1. The eligibility criteria for patients included in this trial were: age 18-65 years, positive COVID-19 test in the past 3 months (as demonstrated by a valid PCR or antigen test), moderate to severe fatigue, and at least one other COVID-19 related symptom selected from anosmia, loss of taste, dyspnea, lung pain, body pain, headache, and difficulty concentrating. Exclusion criteria were other pulmonary and cardiovascular conditions, and a history of dietary supplement use in the 4 weeks before the start of the trial.

[0097] The study was conducted in accordance with the Declaration of Helsinki (7th edition). The data presented here were collected from October 2021 to January 2022 at the FSPE Applied Bioenergy Laboratory at the University of Novi Sad, Serbia. The experimental (creatine) group received 4 g of creatine monohydrate per day, while the control (placebo) group received an equal amount of inulin. Participants were asked to perform the intervention once a day at breakfast by stirring the experimental or control powder in 250 ml of warm water and drinking it immediately. Both interventions were similar in appearance, texture and sensory characteristics. Creatine monohydrate was provided by AlzchemTrostberg GmbH (Trostberg, Germany). The intervention duration was 6 months, and participants were asked to avoid the use of any other dietary supplements during the trial. All outcomes were measured at baseline (before administration) and after 3 and 6 months. The primary outcomes were changes in creatine levels in the vastus medialis muscle and in the brain at baseline and 6-month follow-up. The minimum sample size (n = 12) was analyzed using power analysis (G*Power 3.1.9.3, Heinrich-Heine-University Düsseldorf Düsseldorf)) with an effect size of 0.50 (medium effect), an alpha error probability of 0.05, and a power of 0.80 for both groups, with two measurements (3 months) and three measurements (6 months follow-up), respectively.

[0098] The total number of participants who were randomized, received the intended treatment, and analyzed for the primary outcome at this time was 12, 6 in the experimental group and 6 in the control group. The recruited participants reported no significant side effects from either intervention so far.

[0099] Creatine accumulation in skeletal muscle of post-COVID patients.

[0100] Creatine tissue levels were measured with proton magnetic resonance spectroscopy (1.5T Avanto scanner, Siemens, Erlangen, Germany) using a matrix head coil in circular polarization mode, with metabolite profiles in skeletal muscle and specific regions of the brain (vastus medialis, thalamus, frontal, precentral, paracentral, and parietal white and gray matter) processed as previously described (Appl Physiol Nutr Metab. 2016 Sep; 41(9): 1005-7.).

[0101] Statistical methods:

[0102] Initially, the data were analyzed for normality of distribution using the Shapiro-Wilk test and for homogeneity of variance using the Bartlett test. When homogeneous variances were verified for normally distributed data, summary measures of interaction effects (time vs. intervention) were compared with repeated measures by two-way ANOVA. When non-homogeneous differences were identified, data were compared using the Friedmann test. Post hoc LSD tests and Wilcoxon tests were used to determine differences between individual sample pairs for two-way ANOVA and Friedmann tests, respectively. The significance level was set at P ≤ 0.05. Effect sizes after intervention were assessed using the Cohen statistic, where d ≥ 0.8 indicated a larger effect. Data were analyzed using the statistical package SPSS version 24.0 for Mac (IBM SPSS Statistics, Chicago, IL).

[0103] Changes in tissue creatine levels in post-COVID patients are summarized in Table 1. The table shows changes in tissue creatine levels in the white matter (cerebrum), thalamus, vastus medialis, and gray matter (brain) after 3 and 6 months of intervention with 4 g creatine per day compared to creatine levels in the placebo group.

[0104] Table 1. Changes in tissue creatine levels (mM)

[0105]

[0106] Figure 1 The percentage difference in creatine levels after three months from the corresponding baseline levels in the white matter (cerebrum), gray matter (cerebrum), thalamus and vastus medialis muscle calculated from Table 1 is shown in FIG. The left column represents the patient group receiving creatine and the right column represents the placebo group. For the values ​​in the white matter and gray matter, the mean values ​​were determined from Table 1.

[0107] In a randomized controlled trial, creatine was found to accumulate in the brain and vastus medialis muscle when administered for 3 months. The elevated creatine levels could be maintained for at least another 3 months with supplemental creatine administration. No changes in tissue creatine values ​​were found in the placebo group.

[0108] Participants in the experimental group experienced increases in total tissue creatine levels in all fourteen (14) sites assessed in the study, with higher increases at 6-month follow-up found in the vastus medialis (P = < 0.01), left frontal white matter (P = 0.01), and right parietal white matter (P = 0.01). Tissue creatine values ​​did not change in the placebo group throughout the trial. A two-way ANOVA with repeated measures revealed significant differences between interventions in tissue creatine levels (treatment vs. time interaction) (P < 0.05), with the creatine group being superior to the placebo group in increasing creatine levels in the vastus medialis, left frontal white matter, and right parietal white matter. In addition, strong interactions between interventions were reported in several other sites, including the right frontal white matter, right paracentral gray matter, left parietal white matter, and left medial parietal gray matter (P < 0.20).

[0109] Furthermore, elevated brain levels in the thalamus (0.82 at 3 months), right frontal white matter (1.25 at 3 months and 1.32 at 6 months), right paracentral gray matter (0.88 at 3 months), left parietal white matter (0.92 at 3 months and 1.17 at 6 months), parietal white matter (1.99 at 3 months and 1.17 at 6 months), left parietal gray matter (0.84 at 6 months), and right parietal gray matter (1.17 at 3 months and 1.06 at 6 months) confirmed Cohen effect sizes for the primary and secondary outcomes after creatine intake and strong effect sizes for creatine (d ≥ 0.8).

[0110] In conclusion, creatine was found to be enriched in the brains of post-COVID patients following creatine supplementation and thus cross the blood-brain barrier.

[0111] Effects of creatine as a nutritional supplement in post-COVID patients.

[0112] The results of COVID-19-related signs and symptoms (such as dyspnea, lung pain, body pain, etc.) reported by patients were evaluated using the VAS scale (Table 3). Fatigue was assessed using the Multidimensional Fatigue Inventory Test (MFI-20 test, Smets EM et al., J. Psychosom. Res. 1995, 39 (3), 315), including the conditions of general fatigue, physical fatigue, metal fatigue, reduced activity, and reduced motivation groups. The results of the VAS scale survey and the MFI-20 test are summarized in Table 2.

[0113] Table 2:

[0114]

[0115] In the tests performed, the patients should report the scores of the symptoms given in Table 2. Therefore, the higher the score, the more severe the corresponding symptom experienced by the interviewed patient. Therefore, the lower the value given, the better the relief effect of the corresponding symptom. As can be seen from Table 2, an improvement was observed in the creatine group with respect to physical fatigue, which was not observed in the placebo group.

[0116] Table 3:

[0117]

[0118] After 3 months, dyspnea was significantly reduced by 78% with creatine, compared to 55% with placebo. Body pain was slightly reduced by 73.3% with creatine, compared to 69% with placebo. Pulmonary pain was significantly reduced in the creatine group.

[0119] Significant interaction effects (time vs treatment) were found for all symptoms assessed (P<0.05). Cohen effect sizes and strong effect sizes for creatine (d≥0.8) were also demonstrated for the primary and secondary outcomes of dyspnea (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) after creatine intake.

[0120] In a randomized controlled trial, it was found that creatine accumulated in skeletal muscle and brain after 3 months of administration. The increase in endurance in the creatine group was superior to that in the placebo group (Table 5). The improved endurance was associated with the reduction of body pain and lung pain, particularly associated with recovery from dyspnea. Compared with the increase in the placebo group, the improved endurance was also associated with a reduction in fatigue symptoms, particularly with a reduction in mental fatigue and decreased motivation. Compared with the slight improvement in the creatine group, the decreased motivation in the placebo group increased during the observation period. According to the results shown in Table 2, creatine administration achieved a smaller improvement in fatigue symptoms (such as physical fatigue) and decreased activity compared to the placebo group. In addition, creatine did not cause major side effects.

[0121] Embodiment 2:

[0122] Combining Creatine Supplementation with Pulmonary Rehabilitation:

[0123] A second study was conducted to evaluate the efficacy and safety of creatine supplementation via dietary supplementation in patients with post-COVID following SARS-CoV-2 infection. Eight male and female post-COVID patients (age 33.5±9.9 years, weight 72.3±14.5 kg, height 168.6±11.0 cm; 4 women) with moderate fatigue and dyspnea or lung pain, pulmonary discomfort volunteered to participate in this randomized controlled trial. During the 3-month intervention period, all patients were assigned in a double-blind parallel-group design to receive either 4 g of creatine monohydrate per day plus breathing exercises (2-3 times per day for 10-15 minutes each time) (experimental group) or breathing exercises alone (control group).

[0124] According to Wang TJ et al., Am J Phys Med Rehabil, 2020, Jun 11 (DOI 10.1097 / PHM.0000000000001505 / PMCID:7315835), pulmonary rehabilitation is performed. Pulmonary rehabilitation is tailored for each patient and includes, for example, improved segmented breathing, breathing exercises for strengthening respiratory and expiratory muscles, inspiratory muscle training, bed activity exercises, stretching, gymnastics and / or walking. The degree of exercise is low at the beginning and then slowly increases without requiring the patient to make greater efforts.

[0125] Detailed information on the experimental protocol and testing procedures used are described in Example 1.

[0126] All volunteers completed the trial and no participant reported adverse effects from either intervention. Changes in the study results during the trial are shown in Tables 5 and 6. Table 4 provides the increase in total tissue creatine levels in several brain sites and the vastus medialis muscle.

[0127] Table 4: Changes in tissue creatine levels (mM)

[0128]

[0129] Table 5:

[0130]

[0131] Table 6

[0132]

[0133] For all fourteen (14) sites assessed in our study, participants in the creatine group experienced increases in total tissue creatine levels, with significant increases found in the vastus medialis (P = 0.04), thalamus (P = 0.03), right anterior gray matter (P = 0.04), right precentral white matter (P = 0.01), right paracentral gray matter (P = 0.03), and left medial parietal gray matter (P = 0.01) at 3-month follow-up. The Cohen effect sizes (d) for creatine increases in the six sites ranged from 0.77 (vastus medialis) to 1.76 (right frontal gray matter), suggesting that creatine monohydrate plus breathing exercises had a sizeable effect on increasing muscle and brain creatine. No increases in total creatine levels were found in any of the control groups (except for a non-significant increase in the left precentral white matter); in addition, creatine levels in the right frontal gray matter and left medial parietal gray matter were significantly decreased in the control group at 3-month follow-up (P < 0.05). Furthermore, two-way ANOVA with repeated measures revealed significant differences in the changes in total creatine levels between the groups at four brain sites (P < 0.05), with participants from the experimental group outperforming those from the control group in increasing brain creatine concentrations at the left frontal gray matter, right anterior lobe gray matter, right precentral white matter, and left parietal gray matter.

[0134] Total tissue creatine concentrations at the 3-month follow-up remained largely unresponsive to breathing exercise (even further reduced from baseline levels), suggesting long-term disturbances in tissue bioenergetics following this complex condition.

[0135] At the 3-month follow-up, dyspnea and lung pain in both groups were reduced to zero, while lung discomfort in the creatine group was significantly reduced by 84%, while lung discomfort in the control group was significantly reduced by 74% (P<0.05). The Friedman / ANOVA test for repeated measures revealed a significant difference in lung discomfort between the groups (P=0.03), with participants in the creatine group being superior to those in the control group in terms of reduction in lung discomfort. The Cohen effect size for lung discomfort was 2.97, indicating a greater effect of creatine monohydrate plus breathing exercises (Table 6). The results of the VAS scale survey on physical fatigue confirmed this result. In particular, physical fatigue was significantly improved by the administration of creatine combined with breathing exercises (Table 5). Compared with the control group (breathing exercise group), creatine + breathing exercises did not significantly improve mental fatigue and decreased motivation.

[0136] Example 3: Exhaustive Study

[0137] The time of exhaustion of the patient is assessed by performing an incremental test on a motorized treadmill until exhaustion. The speed and slope of the treadmill are increased every three minutes, starting with a slope of 10%, 2.7 km / h (1.7 miles / hour), rising to the 7th stage, reaching a slope of 22%, 9.7 km / h (6 miles / hour) (Will PM and Walter JD, Am Heart. J., December 1999, 138, 1033). The results of the treadmill assessment are provided in Tables 7 and 8.

[0138] Table 7:

[0139]

[0140] In patients with post-viral fatigue syndrome following SARS-CoV-2 infection, time to exhaustion increased significantly. The creatine group increased time to exhaustion by 7.3% compared to a 2.1% increase after taking a placebo. More importantly, the creatine group reached stage 6 on the treadmill test, while the placebo group remained at stage 5.

[0141] After 3 and 6 months of creatine administration, the time to exhaustion increased in the creatine group, with the creatine group outperforming the placebo group in extending the time to exhaustion. The improvement in endurance was associated with a decrease in body and lung pain, particularly in recovery from dyspnea.

[0142] Table 8:

[0143]

[0144] After administration, the mean time to exhaustion in the experimental group was significantly improved by 54 seconds (P=0.05), with creatine monohydrate plus breathing exercise being superior to breathing exercise in prolonging the time to exhaustion (P=0.11). The Cohen effect size for the time to exhaustion was 0.36. The creatine + breathing exercise group reached stage 6 in the treadmill test, with the placebo group remaining at stage 5. This data illustrates the synergistic effect of creatine monohydrate plus breathing exercise compared to the placebo group.

[0145] in conclusion:

[0146] For example, creatine monohydrate plus breathing exercises can be recommended as a well-tolerated intervention to significantly improve tissue creatine levels and several clinical features (including dyspnea, lung pain, lung discomfort, and time to exhaustion) in patients with post-COVID fatigue syndrome when administered during a 3-month treatment period.

[0147] Embodiment 4:

[0148] Creatine supplementation compared to glucose administration:

[0149] Ten male and female PCFS patients with moderate fatigue and at least one additional COVID-related symptom (e.g., loss of taste, anosmia, body pain, dyspnea, difficulty concentrating, headache, lung pain, malaise) volunteered to participate in this randomized controlled parallel-group intervention trial. All patients were assigned in a double-blind parallel-group design to receive powdered creatine monohydrate three times daily during an 8-week intervention interval (experimental group; 8 g creatine per day) ) or glucose (control group; 3 g glucose per day). All participants avoided any other dietary supplements during the study period. Detailed information on the experimental protocol and testing procedures used in this study is described in Example 1.

[0150] The changes in tissue creatine levels in post-COVID patients are described in Table 9. The table shows the changes in tissue creatine levels in white matter (brain), thalamus, vastus medialis, and gray matter (brain) after creatine intervention compared to the glucose group.

[0151] Table 9: Changes in tissue creatine levels (mM)

[0152]

[0153] After 8 weeks, creatine levels were increased in the white matter (brain), gray matter (brain), thalamus and vastus medialis muscle in the experimental group compared to the control group. The results confirmed the results of Examples 1 (Table 1) and 2 (Table 4).

[0154] The outcomes of patient-reported COVID-19-related signs and symptoms (e.g., dyspnea, lung pain, body aches, and post-viral fatigue) were assessed using the VAS scale (Tables 10 and 11).

[0155] Table 10:

[0156]

[0157] Table 11:

[0158]

[0159] After 8 weeks, dyspnea was significantly reduced by 85% with creatine, compared to 43% with glucose. Body pain was reduced by 71% with creatine, compared to 50% with glucose. Lung pain was significantly reduced by 67% in the creatine group, compared to a 50% increase in the glucose group.

[0160] Thus, at the 8-week follow-up, several post-COVID-related symptoms such as body pain, lung pain, and dyspnea were significantly reduced in the experimental group (creatine group) (P≤0.05); the Cohen effect size (d) for reducing dyspnea, body pain, and lung discomfort was above the threshold of 0.80, indicating a large effect of creatine. Participants in the experimental group (creatine) were superior to those in the control group (glucose) in reducing body pain and lung pain (P≤0.20), and participants in the experimental group were also superior to those in the control group in reducing dyspnea.

[0161] In Table 12 and Figure 2 Cohen effect sizes (d) for all outcomes in the creatine group were estimated and reproduced in . Effects were categorized as small (d = 0.2), medium (d = 0.5, dashed line), and large (d ≥ 0.8). Missing values ​​are due to statistical limitations in calculating effect sizes when the pre- and / or post-values ​​are equal to zero. Abbreviations: GF, general fatigue; PF, physical fatigue; RM, reduced motivation; RA, reduced activity; MF, mental fatigue; BOA, bodily pain; BRD, dyspnea; LUP, lung pain; and MAL, malaise.

[0162] Table 12:

[0163] Cohen effect (d) General fatigue (GE) 0,44 Physical Fatigue (PF) 0,83 Power reduction (RM) 1,07 Reduced activity (RA) 1,52 Mental Fatigue (MF) 1,32 Breathlessness (BRD) 0,96 Body pain (BOA) 1,11 Lung pain (LUP) 0,64 Discomfort (MAL) 1,81

Claims

1. A pharmaceutical composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof for use in treating one of the conditions selected from the group consisting of physical fatigue after viral infection, dyspnea, shortness of breath (dyspnea), chest pain, lung pain, lung discomfort and body pain.

2. The pharmaceutical composition of claim 1, wherein the physical fatigue, dyspnea, shortness of breath (dyspnea), chest pain, lung pain, or lung discomfort is caused by a coronavirus infection or is a post-COVID symptom.

3. The pharmaceutical composition of claim 1 or 2, for use in combination with physical exercise and / or breathing exercises to treat dyspnea, shortness of breath (dyspnea), chest pain, lung pain or lung discomfort.

4. The pharmaceutical composition according to any one of claims 1 to 3, which is used for treating physical fatigue in a subject who performs physical exercise and / or breathing exercise.

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

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the composition is for use in combination with breathing exercises, and wherein the breathing exercises are gradually increased as the subject in need thereof is able to tolerate.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the physiologically acceptable creatine derivative is selected from the group consisting of creatine, creatine hydrates, creatine esters or amides, including creatine C1-C5-alkyl esters, N-C1-C5-alkyl amides, guanidinoacetic acid, inositol, inositol-O-phosphate or mixtures thereof.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the creatine salts and adducts or the physiologically acceptable salts and adducts of creatine derivatives are selected from the group consisting of the corresponding acetates, citrates, maleates, fumarates, tartrates, malates, pyruvates, ascorbates, succinates, aspartates, lactates, oxalates, formates, benzoates, phosphates, sulfates, chlorides, hydrochlorides, the corresponding potassium, sodium, calcium, magnesium salts, the corresponding L-carnitine, acetyl-L-carnitine, taurine, betaine, choline, methionine adducts or mixtures thereof.

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

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

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

12. Use of a composition comprising creatine or a physiologically acceptable derivative and / or salt and / or adduct thereof as a dietary supplement for supporting recovery from one of the conditions selected from the group consisting of: physical fatigue after a viral infection, dyspnea, shortness of breath (dyspnea), chest pain, lung pain, lung discomfort and body pain.

13. The use of claim 12, wherein the body fatigue, dyspnea, chest pain, lung pain or lung discomfort is caused by coronavirus infection of the lungs or lower respiratory system, or is a post-COVID symptom.

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

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

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

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

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