Creatine compound for the prophylaxis and treatment of creatine deficiency and the symptoms associated therewith in hemodialysis patients

Abstract

A creatine compound, selected from the following groups: (i) creatine and the pharmaceutically acceptable salts thereof; (ii) (phospho)creatine compounds; (iii) (phospho)creatine derivatives; (iv) creatine precursors, (v) creatine analogues; and mixtures thereof, is used for the prophylaxis and treatment of creatine deficiency and the symptoms associated therewith in hemodialysis patients. The creatine compound is added to a hemodialysis solution intended for the patient in such an amount that the blood, which is returned to the patient from a dialysis device simultaneously connected to the patient, has a concentration of 400-1100 μM of creatine compound in the blood plasma at a blood flow rate, from the dialysis device into the patient, of 100 ml / min to 500 ml / min.

Description

[0001] Creatine compound for the prophylaxis and treatment of creatine deficiency and its associated symptoms in hemodialysis patients

[0002] The present invention relates to a creatine compound for use in the prophylaxis and treatment of creatine deficiency in patients with chronic kidney disease (hereinafter: dialysis patients) and the associated symptoms, according to the preamble of claim 1. In particular, it relates to a dosage guideline for the intradialytic administration of creatine during hemodiafiltration (hemodialysis and hemofiltration) for the treatment of creatine deficiency, such as occurs, for example, in patients who are dependent on hemodialysis as chronic renal replacement therapy.

[0003] Creatine is a naturally occurring guanidino compound, of which the body produces approximately 50% of its daily requirement. The remaining 50% must be obtained through diet by consuming meat from vertebrates, including fish. Endogenous creatine synthesis occurs in a two-step process from arginine, glycine, and S-adenosylmethionine (SAM). The first step, producing the precursor to creatine, guanidinoacetic acid (GAA), is primarily carried out in the kidneys with the help of the enzyme L-arginine:glycine amidinotransferase (AGAT). The second step, from GAA to the end product, creatine, then takes place mainly in the liver. From there, creatine is released into the bloodstream and subsequently taken up by target organs (muscle tissue, heart, brain, etc.) into the corresponding cells via an active, specific creatine transporter.

[0004] The more or less impaired kidney function in dialysis patients results, among other things, in reduced or even absent levels and activity of the AGAT enzyme in the kidneys. This impairment of the body's own endogenous synthesis of GAA, a creatine precursor, ultimately leads to a creatine deficiency in the bodies of dialysis patients, who depend on recurring dialysis treatments for survival. In addition, the unimpeded loss of plasma creatine into the dialysis fluid during dialysis exacerbates the already existing general, chronic creatine depletion in dialysis patients. This creatine deficiency is further aggravated by the reduced intake of dietary creatine from meat and fish, because dialysis patients generally consume less meat and / or fish due to loss of appetite and prefer a more plant-based diet.Due to all these factors, a general chronic creatine deficiency results in the bodies of dialysis patients. This is all the more pronounced because the normal non-enzymatic conversion of endogenous creatine to uremic creatinine (Crn), which occurs at approximately 1.6–1.7% of the body's creatine pool per day and cannot be influenced within physiological limits, proceeds at a constant rate, and this creatinine is removed via dialysis. Because of this imbalance between the production and uptake rate of creatine, as well as the constant rate of creatine to creatinine breakdown, dialysis patients demonstrably present with a significantly more pronounced creatine deficiency in the bodies compared to the general population.

[0005] To compensate for the lack of kidney function in dialysis patients, life-saving dialysis treatment must be continued for life. Unfortunately, compared to the general population, the health-related quality of life (HRQoL) of dialysis patients is significantly lower, while their mortality rate is higher compared to healthy individuals. Besides the proven non-modifiable risk factors for mortality and low HRQoL (e.g., age and genetics), there are also risk factors for dialysis patients that are potentially modifiable, such as nutritional status and / or care.

[0006] The creatine deficiency generally observed in dialysis patients is one such modifiable risk factor that negatively affects several important causes of poor HRQoL, such as protein energy wasting (PEW), sarcopenia, chronic fatigue, muscle weakness, depression, cognitive impairment, as well as increased susceptibility and higher risk for an adverse course of infectious diseases.

[0007] The factors mentioned above that contribute to poor HRQoL are also reflected in the increased frailty syndrome of dialysis patients. These include increased muscle loss, progressive muscle weakness, and impaired neuromuscular coordination, leading to a higher incidence of falls and fractures. Additional complications result in delayed or prolonged bone and wound healing, often necessitating longer hospital stays. Consequently, compared to the general population, dialysis patients have a significantly higher incidence of complications, including death. Creatine can be beneficial in this context, as it can slow muscle loss during prolonged immobilization, such as with fixed fractures, and promote faster and better healing of fractures and wounds.

[0008] Due to the almost ubiquitous presence of creatine in all body cells, as well as its important function as an energy storage and energy transport form within many cell types, a creatine deficiency manifests itself in a variety of often simultaneously occurring symptoms, thus forming the so-called "creatine deficiency".

[0009] Creatine deficiency manifests itself in a range of physical symptoms. Replenishing or maintaining the creatine pool in the body of dialysis patients to a normal, healthy level, which is achieved through intradialytic administration of creatine at the dose disclosed herein, can positively influence a number of these symptoms:

[0010] Creatine is essential for the normal functioning of the central nervous system, particularly neurons. These exhibit a very high and highly fluctuating energy consumption, primarily due to their various energy-intensive ion pumps. Furthermore, the intracellular transport of organelles and substances over the long distances along the axons consumes a significant amount of energy.

[0011] Complex fatigue syndromes such as Chronic Fatigue Syndrome or ME / CFS (Myalgic Encephalomyelitis) can be positively influenced by intradialytic creatine administration.

[0012] Cognitive impairments of working memory, long-term memory, mental performance, intelligence tests, brain fog, concentration problems and reduced stress resistance can be reduced by intradialytic creatine administration.

[0013] Coordination disorders, depression, sleep disorders such as difficulty falling asleep, difficulty staying asleep, daytime sleepiness and reduced sleep quality can be reduced by intradialytic creatine administration.

[0014] Intradialytic creatine administration also leads to a certain degree of protection of the central nervous system against cell damage.

[0015] Paresthesia and peripheral polyneuropathy are common symptoms in chronic dialysis patients, which can be alleviated by intradialytic creatine administration. Intradialytic creatine administration also provides some protection of the peripheral nervous system against cell damage.

[0016] Intradialytic creatine administration alleviates muscle weakness such as loss of muscle mass, strength, and power, muscle hypotonia, and muscle fatigue, as well as problems associated with reduced muscle relaxation (muscle cramps). Replenishment of the creatine pool through intradialytic creatine administration counteracts muscle mass loss (sarcopenia), muscle atrophy, and catabolic muscle breakdown. Muscle fatigue, the physiological parameter for performance decline during endurance exercise, is slowed by intradialytic creatine administration. Impaired muscle relaxation, which manifests as the muscle cramps frequently experienced by dialysis patients, is improved by intradialytic creatine administration, thus reducing muscle cramps. Myalgic muscle pain is also reduced by intradialytic creatine administration.

[0017] Creatine improves muscle strength, increases muscle mass, and promotes the regeneration of muscle tissue, thus enhancing recovery after strenuous exercise. Therefore, creatine acts as a performance enhancer, endurance enhancer, and recovery enhancer.

[0018] Cardiomyocytes, with their high and highly fluctuating energy turnover, are strengthened by creatine administration; intradialytic creatine administration counteracts cardiac muscle disorders, myocardial insufficiency and cardiomyopathies, as well as generally left ventricular hypertrophy and other myocardial bioenergetic abnormalities.

[0019] Bone mineralization and the deposition of organic extracellular bone matrix are energy-intensive processes; furthermore, osteoblasts are limited in their diffusion by their environment and shape. Intradialytic creatine administration counteracts osteopenia, osteoporosis, and uremic osteodystrophy, and also has a generally positive effect on bone and cartilage as well as mineral density.

[0020] Blood cell production in general, and erythropoiesis in particular, are energy-intensive processes that are improved by intradialytic creatine administration. Renal anemia due to insufficient blood cell production can be alleviated by creatine.

[0021] Although erythrocytes themselves do not have an aerobic metabolism, a creatine transporter is found in the erythrocyte membrane. Intradialytic creatine administration protects the membranes of erythrocytes, which are particularly stressed by dialysis, against both mechanical and oxidative stress, which can lead to hemolysis, and thus extends the lifespan of the erythrocytes. Intradialytic creatine administration therefore reduces anemia in dialysis patients and has the added benefit of lowering the amount of erythropoietin required to stimulate erythropoiesis in these patients, resulting in significant cost savings in their treatment.

[0022] Movement coordination disorders can be reduced by intradialytic creatine administration through improved muscle and central nervous system function, as well as a strengthened peripheral nervous system and improved muscle relaxation. Thus, intradialytic creatine administration improves overall movement coordination.

[0023] The increased susceptibility to infection and the elevated risk of adverse outcomes from infectious diseases in dialysis patients can be reduced by intradialytic creatine administration, which also protects immune cells from mechanical, oxidative, and metabolic stress. Furthermore, the immune system is significantly strengthened by creatine through metabolic support of macrophages, neutrophils, B lymphocytes, and T cells.

[0024] Dialysis patients suffer from a significantly increased frequency of falls and a correspondingly increased frequency of bone fractures, which can be reduced by intradialytic creatine administration.

[0025] Intradialytic creatine administration reduces immobilization-induced muscle atrophy (muscle wasting due to lying down, plaster casts, etc.), promotes bone fracture healing, and also improves wound and skin healing. Furthermore, creatine can also alleviate fall-related brain injuries.

[0026] Intradialytic creatine administration reduces the effects of ischemia and anoxia on body cells by increasing the creatine pool and the associated longer energy buffer time; thus, it mitigates the consequences of thrombosis, such as stroke, heart attack, pulmonary embolism, but also of ischemia due to internal bleeding.

[0027] Creatine supplementation improves the barrier function of the intestinal epithelium and reduces inflammation in the intestinal mucosa of patients with chronic intestinal inflammation.

[0028] Creatine supplementation, especially in older adults, improves musculoskeletal health and slows the progressive, age-related muscle loss (sarcopenia), thereby delaying frailty in seniors. At the same time, creatine counteracts age-related vision and hearing loss. It also helps alleviate dizziness, contributing to safer mobility in daily life. All these factors contribute to an improved quality of life in old age and can postpone the need for long-term care. Overall, regular creatine supplementation contributes to healthier aging. The same applies to dialysis patients.

[0029] In addition to medications for treating various comorbidities that are very common and occur in combination, dialysis patients undergoing renal replacement therapy require a larger number of medications in significant quantities (polypharmacy). All orally administered medications must be taken with the smallest possible amount of fluid that this volume-controlled patient group is permitted to consume.

[0030] That creatine supplementation can have various positive effects for dialysis patients is undisputed, but the question here is how the relatively large amount of creatine can be ingested daily without excessive additional fluid intake. The fact that dialysis patients feel they have to take their very large doses of medication with far too little fluid means that adherence and compliance to medication regimens are generally a major issue for this patient group. Therefore, prescribing additional large amounts of dry creatine or creatine suspended in only a small amount of water would overwhelm many patients and result in even poorer adherence.In addition, this fragile patient group faces an increased risk of swallowing and choking, as well as frequent gastrointestinal problems, which are not conducive to regular and regulated creatine absorption under these circumstances.

[0031] Another significant and clinically relevant advantage of intradialytic versus oral creatine administration is that with intradialytic creatine, administered directly into the patient's bloodstream, the amount of creatine to which the patient is effectively exposed can be precisely controlled and is therefore accurately defined. This is not the case with oral creatine administration, where creatine must be absorbed into the bloodstream via the intestines, because the absorption of creatine and other substances through the intestines varies depending on the condition and health of the intestines in different patients.

[0032] In other words, the effective amount of orally administered creatine that actually appears in the patients' blood is not known in advance.

[0033] The additional significant advantage of intradialytic creatine administration is that individual body organs can independently absorb precisely the amount of creatine they need from the precisely defined intradialytically administered amount in the blood. Any excess creatine is removed directly via the dialysate during the intradialytic process, so that, unlike oral creatine administration, which circulates in the dialysis patient's blood until the next dialysis session, an overdose of creatine is impossible with intradialytic administration.

[0034] Intradialytic administration allows for precise definition and control of creatine dosage and exposure in dialysis patients, which is a significant advantage, or even essential, for the clinical use of creatine in patients. This is not possible with oral creatine administration. After a single oral bolus dose of creatine in dialysis patients, the concentration of creatine entering the bloodstream follows a bell-shaped curve over time. However, both the maximum concentration (peak of the curve), as well as the curve's duration and width, can vary from individual to individual, and especially in dialysis patients with various comorbidities, depending on the amount of creatine effectively absorbed into the bloodstream via the intestines. Therefore, with oral creatine administration, neither the total amount of creatine nor the patient's exposure to creatine over time is a controllable, defined parameter.In contrast, with intradialytic creatine administration, the creatine concentration in the blood, which follows a well-approximated rectangular function over the course of dialysis, can be precisely controlled and remains nearly constant throughout the entire dialysis treatment. Therefore, only the intradialytic method of creatine administration meets the requirements for controlled creatine administration to patients in a clinical setting.

[0035] The invention aims to remedy this problem. With the present invention, the intradialytic administration of creatine is integrated into the dialysis process itself. The latter represents the only consistently repetitive process in the course of dialysis patients, and this process essentially consists of a defined, dosed, and diffusive administration of creatine into the blood via the addition of creatine through the dialysis fluid, which is in direct dialytic-bidirectional exchange with the blood.

[0036] The invention describes this process using a creatine compound which has the features according to claim 1.

[0037] The present invention makes it possible to easily determine and administer intradialytic creatine to dialysis patients based on a desired creatine concentration in the blood, which is returned to the patient from a dialysis device simultaneously connected to the patient.

[0038] The dosage method according to the invention refers to the amount of a creatine compound per blood plasma as a measure that is easy and reliable to determine, since blood cells, especially erythrocytes, have a creatine transporter in their cell membrane that pumps the non-membrane-permeable creatine into their cytosol, so that the creatine concentration in the cytosol of erythrocytes is many times higher than outside of it. Since the hematocrit (percentage of blood cells per total blood volume) is not insignificant, dosage methods that refer to the amount of creatine per blood volume (or total blood volume) – which include the amount of creatine located within the erythrocytes that is not freely accessible to the body – have proven to be imprecise and less reliable.

[0039] The molar concentration (M) used in the present invention is the concentration of a chemically active substance in a solution, measured in moles per liter of solution. Common units and symbols for molar concentration are mM (millimolar) and pM (micromolar). The advantages achieved by the invention lie essentially in the fact that, thanks to the dosing procedure according to the invention for the creatine compound to be added to the dialysis solution, creatine deficiency in dialysis patients is prevented or reversed. The amount of creatine supplied to the body by the dialysis process in the blood returned to the body by the dialysis machine is clearly defined. The amount of a creatine compound disclosed herein provides a simple and sufficient indication for carrying out dialysis treatment on the patient.The unavoidable, difficult-to-quantify, and always simultaneous losses of creatine from the blood supplied to the dialysis machine by the patient in the used dialysis solution are not relevant to treatment success and do not need to be considered further with the present dosing regimen. It is important, however, that with the dosing regimen in this invention, the creatine dose is supplied essentially until the end of the dialysis session and is not reduced or stopped before the end of the session. In other words, the last blood returned to the patient from the dialysis machine also contains creatine according to the dosing regimen. The difference in flow rate resulting from reverse osmotic hemofiltration for volume adjustment of the patient can be disregarded.

[0040] Administering creatine directly via the dialysis fluid is equivalent to parenteral administration, bypassing the gastrointestinal tract. This is because the patient's blood comes into direct contact with the dialysis fluid, and creatine, as a low-molecular-weight compound (molecular weight = 131.13 grams), diffuses directly into the bloodstream practically freely, with its molecular or particle size being below that of the dialysis membrane. Low-molecular-weight byproducts and breakdown products of creatine also pass freely into the blood. This contrasts with oral administration, where the gastrointestinal tract acts as a physical barrier to the blood, and creatine can only be absorbed into the blood via a specific creatine transporter.

[0041] The functioning of the creatine system depends directly on the cytosolic creatine concentration to fulfill its role as an energy buffer and endocellular energy transport system. In fact, dialysis patients without intradialytic creatine administration are severely creatine-depleted, and all the symptoms described above affect organs containing cells with high energy turnover, highly fluctuating energy consumption, or long cytosolic diffusion pathways from the mitochondria to the site of energy consumption. Optimal creatine system function is particularly important for all these cells. Synergistic interactions of various symptoms, such as fatigue and muscle weakness, which can lead to increased falls, are plausible and relevant in clinical practice and for the well-being of dialysis patients.The dosage regimen according to the invention is particularly suitable for treating the symptoms / diseases / diseases listed below, as it supplies the body with the amount of creatine which a) in chronic dialysis patients with creatine deficiency, compensates for this deficiency to such an extent that a healthy creatine pool is achieved in the patient's body over a period of several weeks of dialysis treatment with creatine-containing dialysis solution. The exact period depends on patient-specific parameters such as lean body mass, weight, degree of deficiency, metabolic parameters, etc.However, it has been shown that the dosage according to the invention provides the body with exactly the amount that leads to a stabilization of the creatine pool, independent of the above patient-specific parameters in the body; and b) keeps the creatine pool in the body of the chronic dialysis patient stable at a healthy level in such a way that the creatine administration thus compensates well for the inevitable loss resulting from the non-enzymatic, uncontrollable conversion of creatine to creatinine in a way that is well tolerated by the patient.

[0042] This replenishment and maintenance of the creatine pool is essential for the healthy functioning of the creatine system within the cells. It is precisely those cell types with high and / or highly fluctuating energy turnover and those with diffusion-restricted creatine that benefit most: myofibrils, neurons, cardiomyocytes, osteoblasts, chondroblasts, cells with many ion pumps, such as the epithelial cells of the renal tubules, as well as auditory and balance cells, but also immune cells and all cells that actively take up creatine via the creatine transporter. These are a multitude of cell types in a wide variety of tissues, which is why the indications according to claim 23 appear diverse at first glance, but share a common (co-)cause: a dysfunctional creatine system that causes a general cellular energy deficit.However, creatine deficiency can be treated with this invention.

[0043] The indications listed below therefore relate to tissues or organs, or the interaction of such organ systems, which are (co-)built from cells in which the creatine system is important for healthy functioning:

[0044] Especially for nerve cells and the brain and brain function, specifically in cases of: a) fatigue (Chronic Fatigue Syndrome, ME / CFS Myalgic Encephalomyelitis, general tiredness and exhaustion) b) cognitive impairment and reduced performance (memory, mental performance, concentration disorders, mental and post-traumatic stress) c) coordination disorders d) depression, anxiety disorders, sleep disorders, as well as e) protection against cell damage from trauma f) protection against neurodegeneration g) protection against the consequences of ischemia, asphyxia and anoxia h) and, via cell and ischemia protection, to reduce the consequences of fall- and accident-related brain trauma.

[0045] As well as for the protection and regeneration of nerve cells in the spinal cord and peripheral nervous system.

[0046] And especially for myofibrils and muscles (musculoskeletal system) specifically in cases of a) muscle weakness (weak muscle tone and fatigue of muscles and the musculoskeletal system), b) sarcopenia and age-related muscle loss, c) muscle atrophy, muscle wasting and rehabilitation, d) to reduce frailty and fragility, e) in cases of movement coordination disorders, reduced (muscle) endurance and rapid fatigue, and for fall prevention (through improved muscle performance), f) muscle relaxation (muscle cramps) and ischemia prevention in cases of g) myalgia (muscle pain), and for strengthening to promote h) an increase in muscle mass and strength, and i) improved musculoskeletal healing after injuries, especially to reduce immobilization-related muscle atrophy.

[0047] And especially in cardiomyocytes with their periodic, highly fluctuating energy consumption, therefore in the following heart and cardiovascular diseases: a) heart muscle diseases and myocardial insufficiency; b) left ventricular hypertrophy to strengthen c) cardiovascular health; and d) to protect cells, i.e., to reduce the consequences of myocardial ischemia (heart attack) and the associated ischemia-reperfusion damage.

[0048] As well as in hepatocytes (liver) to prevent fatty liver, and in kidneys: renal ischemia and to improve residual kidney function.

[0049] As well as, in particular, osteoblasts, osteoclasts, and chondrocytes, and bone and cartilage, especially in a) osteopenia and osteoporosis, and also b) for bone and cartilage calcification and bone healing in fractures.

[0050] As well as in the intestines in cases of: intestinal inflammation, colitis, Crohn's disease

[0051] As well as for improved skin and wound healing.

[0052] As well as the hair cells in the ear and inner ear: a) hearing loss, tinnitus; b) dizziness, orthostatic intolerance

[0053] As well as in the retina: degeneration and vision loss. And especially in erythrocytes, their formation (blood formation) and their lifespan against anemia and anemia, as well as for the mechanical and osmotic protection of the erythrocyte cell membranes.

[0054] As well as strengthening and activating immune cells such as macrophages, neutrophils, and T cells. Effective against inflammation and generally as cell protection against ischemia and asphyxia, against reactive oxygen species (ROS), and against radiation damage.

[0055] Further advantageous embodiments of the invention can be commented on as follows:

[0056] In a particular embodiment of the invention, the creatine compound is added to the hemodialysis solution continuously, essentially until the end of the dialysis session, by adding a predetermined or in-situ prepared solution of the creatine compound, preferably in the form of a stock solution. The advantage of this dosing method is that the fresh dialysis solution supplied to the dialysis filter contains the creatine compound for the entire duration of the dialysis session. In cases where the hemodialysis solution is mixed online by the dialysis machine (or by a central preparation system) from liquid and / or solid concentrates and water, it is preferable that the creatine compound be added continuously for at least the duration of the treatment, such that the fresh dialysis solution supplied to the dialysis filter contains the creatine compound continuously, i.e., throughout the entire duration of the dialysis session.By continuously adding the creatine compound to the hemodialysis solution, the patient's blood is supplied with the creatine compound according to the invention throughout the entire duration of the dialysis session, i.e., until its conclusion. It has proven advantageous that this is carried out until the end of the dialysis session and that the concentration of the creatine compound in the dialysis solution is not reduced before the blood flow back to the patient has ceased.

[0057] Another embodiment is a creatine compound which exists in solution in the form of creatine molecules.

[0058] Preferably, the creatine compound is: creatine, creatine monohydrate or a physiologically acceptable creatine salt.

[0059] Advantageously, the hemodialysis solution is administered to the patient for at least 60 minutes, preferably at least 180 minutes. In a preferred embodiment, the hemodialysis solution is administered during

[0060] (i) 3 to 6 h, 1 to 4 times per week; or (ii) 1 to 3 h, 6 to 7 times per week.

[0061] The blood returned to the patient can have a concentration of creatine compound in the blood plasma in the range of 500-1000 ppm, preferably 600-950 ppm and specifically 650-900 ppm.

[0062] The blood flow from the dialysis device is preferably 300 - 350 ml / min.

[0063] In a particular embodiment, the phospho)creatine compounds comprise the group consisting of (phospho)creatine, (phospho)creatine monohydrate, (phospho)cyclocreatine, and homocyclocreatine. The (phospho)creatine derivatives may include the group consisting of (phospho)creatine salts, and preferably creatine pyruvate, lactate, ascorbate, acetate, citrate, hydroxycitrate, laureate, phytate, mandelate, malate, glycolate, cinnamate, salicilate, hyaluronate, and β-hydroxygutyrate. -gluconate, -choline, -carnitine, -propionylcarnitine, -coenzyme Q10, -adenosine, -fructose, -fructose-1,6-bisphosphate, -adenosine ester, -acid anhydrous, and -glutamine.

[0064] Creatine precursors can include guanidinoacetic acid, 3-guanidinopropionic acid, guanidinobenzoic acids, and the combination of glycine, arginine, and methionine, as well as their physiologically acceptable salts and derivatives. Creatine analogs can include guanidinoacetic acid and guanidinoacetate.

[0065] The amount of creatine compound to be added to the hemodialysis solution is expediently adjusted according to the molar mass ratio to creatine.

[0066] The creatine compound is preferably in solid form or in the form of a dialysis concentrate or a dialysis solution.

[0067] In a particular embodiment of the invention, the creatine compound contains at most 10 mol% creatinine (based on creatine + creatinine or on the total concentration of all creatine compounds plus creatinine), preferably at most 5 mol% creatinine. Creatinine (Crn), a cyclized, non-enzymatic breakdown product of creatine that is excreted in the urine in healthy individuals, is removed from the body of dialysis patients by the dialysis solution. Simultaneously, it is inevitably produced as a breakdown product of creatine before and during each intradialytic administration process in varying amounts, also at the formulation stage, e.g., during creatine synthesis, preparation, as well as in creatine-containing stock solutions and also in the dialysis solution itself, so that creatine is never truly completely free of creatinine.A technically feasible implementation of intradialytic creatine administration therefore required experimental investigations to determine the permissible creatinine levels or concentrations in the dialysis solution without endangering patients. The common perception among physicians that creatinine is supposedly nephrotoxic (presumably based on the fact that plasma creatinine concentration is the most frequently used clinical proxy marker for the glomerular filtration rate of the kidneys) stems from the misconception that the marker itself is a harmful substance, which has proven to be false. This has led to considerable technical effort being made to keep the creatinine concentration in the creatine as low as possible for certain applications, which can be complex and expensive.

[0068] The preferred creatinine concentrations dramatically simplify processing, logistics, and storage requirements (e.g., refrigerated storage), thus saving costs, extending shelf life, and, above all, also improving technical aspects.

[0069] Implementation options have gained many cost-relevant and complexity-reducing degrees of freedom, such as increasing the pH range (strongly pH-dependent).

[0070] Rate constant for creatine to creatinine conversion and the position of the creatine-creatinine equilibrium), possible processing times and temperatures (strong temperature dependence of creatine solubility and the rate constant for creatine to creatinine conversion, as well as the position of the creatine-creatinine equilibrium), volume reduction (logistics and production), etc. of precursors or components, stock solutions, solid stock preparations, and other dialysis solution precursors that are prepared to form a finished dialysis solution.

[0071] The maximum creatinine limits listed here for intradialytic creatine administration have surprisingly proven optimal for safe treatment. Given that intradialytic creatine administration is a parenteral method bypassing the natural gastrointestinal barrier, this is essential for practical application in patients, as creatinine, along with other low-molecular-weight substances, passes directly into the bloodstream unfiltered. The surprisingly high creatinine concentration limits we determined eliminate the need for technically complex and therefore expensive methods to minimize creatinine levels. Furthermore, there is no known process that actively pumps creatinine from the dialysis solution into the body, and since creatinine is present in the body (in blood plasma) at a higher concentration than the defined 10⁻⁵ mol⁻¹, this limit is not a significant factor.Even with a creatinine concentration of -% in the dialysis solution, the creatinine is still removed from the body (albeit marginally more slowly) using the dosage regimen for creatine according to the present invention. It is important that setting a maximum creatinine concentration does not negatively affect the dialysis process with creatine.

[0072] Preferably, the dialysis solution contains at most 200 pM creatinine, preferably at most 100 pM creatinine.

[0073] In a particular embodiment of the invention, the creatine compound contains at most 50 mg / kg, preferably at most 25 mg / kg, of dicyandiamide. The dialysis solution expediently contains at most 13.1 pg / l, preferably at most 6.55 pg / l, of dicyandiamide.

[0074] In a further embodiment of the invention, the creatine compound contains at most 3 mg / kg, preferably at most 2 mg / kg, of dihydrotriazine. The dialysis solution expediently contains at most 786 ng / l, preferably at most 542 ng / l, of dihydrotriazine.

[0075] The maximum concentration of impurities with synthesis by-products that can arise during the production of creatine serves to avoid endangering the health of dialysis patients.

[0076] In a particular embodiment of the invention, the dialysis solution contains a maximum of 100 pM of phosphates bound to (or dissociated with) creatine substances according to substance groups (i), (ii) and (iii) of claim 1, claim 9 or claim 10. Advantageously, the dialysis solution contains a maximum of 100 pM, preferably 50 pM, of phosphates bound to (or dissociated with) creatine substances according to substance groups (i), (ii) and (iii) of claim 1, claim 9 or 10.

[0077] The creatine compound according to the invention serves for the prophylaxis and treatment of the following symptoms in hemodialysis patients:

[0078] I. Brain & Brain Function: a) Symptoms of Fatigue:

[0079] 1. Chronic Fatigue Syndrome

[0080] 2. ME / CFS Myalgic Encephalomyelitis

[0081] 3. General fatigue, exhaustion b) Cognitive impairment, cognitive performance of the / the / of

[0082] 1. Working memory

[0083] 2. Long-term memory

[0084] 3. Mental performance

[0085] 4. Brain fog 5. Concentration problems

[0086] 6. Reduced stress resistance c) Coordination disorders d) Depression, anxiety disorders e) Sleep disorders:

[0087] 1. Difficulty falling asleep

[0088] 2. Sleep disturbance

[0089] 3. Daytime sleepiness

[0090] 4. Reduced sleep quality f) to protect against cell damage from trauma g) to protect against neurodegeneration

[0091] II. Spinal Cord & Peripheral Nervous System: a) Paresthesias b) Peripheral Polyneuropathies c) for the protection and regeneration of the spinal cord and peripheral nervous system

[0092] III. Muscles: a) Muscle weakness

[0093] 1. Muscle tone weakness

[0094] 2. Muscle fatigue b) Sarcopenia, age-related loss of muscle mass c) Muscle atrophy, muscle wasting & rehabilitation d) Frailty & fragility e) Movement coordination disorders & fall prevention Muscle endurance & fatigue f) Muscle relaxation, muscle cramps & ischemia g) Myalgia, muscle pain h) For increasing muscle mass and strength i) For improved musculoskeletal healing,

[0095] IV. Heart & Cardiovascular System: a) Cardiac muscle diseases, myocardial insufficiency, cardiac ischemia, heart failure, myocardial infarction b) Left ventricular hypertrophy c) Cardiovascular health d) Myocardial ischemia, ischemia and reperfusion injury

[0096] V. Liver: a) to prevent fatty liver VI. Kidneys: a) to follow renal ischemia, b) to improve residual renal function

[0097] VII. Bones and cartilage: a) Osteopenia b) Osteoporosis c) Uremic osteodystrophy d) for improved bone and cartilage mineralization

[0098] VIII. Blood and blood cells: a) Anemia b) Renal anemia

[0099] 1. reduced blood cell production

[0100] 2. the reduced lifespan of erythrocytes

[0101] 3. and to protect erythrocytes from osmotic and mechanical stress

[0102] IX. Immune system: a) Increased susceptibility to infection b) Increased risk of an unfavorable course of infectious diseases c) and to protect immune cells from mechanical, oxidative and osmotic stress d) to strengthen the immune system by supporting macrophages, B lymphocytes and T cells

[0103] X. Movement coordination disorders

[0104] XI. Fall prevention: a) increased frequency of falls b) increased frequency of bone fractures

[0105] XII. Fall prevention: a) Reduction of immobilization-induced muscle atrophy b) Impaired bone healing c) Impaired wound healing d) Impaired skin healing e) Fall-related brain trauma

[0106] XIII. Prevention of the consequences of ischemia to reduce the effects of ischemia and

[0107] Anoxia on body cells: a) Thrombosis

[0108] 1. Stroke

[0109] 2. Heart attack

[0110] 3. Pulmonary embolism b) and in cases of ischemia due to bleeding

[0111] XIV. Intestine: a) Intestinal inflammation, colitis, Crohn's disease b) Reduced intestinal health c) Colitis

[0112] XV. Frailty (Fragility)

[0113] XVI. Orthostatic problems and dizziness a) In the ear, energy for ion transport against ear cell loss b) Against dizziness

[0114] XVII. General cell protection: a) against ischemia & asphyxia b) against oxygen radicals (ROS) c) against radiation damage

[0115] The invention and further developments of the invention are explained in more detail below with reference to a partially schematic representation of an exemplary embodiment.

[0116] It shows:

[0117] Fig. 1 shows a schematic representation of a dialysis device connected to a patient for the dosing procedure according to the invention.

[0118] Figure 1 shows a dialysis patient 1 with the blood flow 3, which is drawn from him by a dialysis device 2, dialyzed in a dialysis filter 5 with a dialysis membrane 6, and returned to him. The blood flow 4, which is returned to the patient 1 by the dialysis device 2, contains the creatine compound according to the invention during (and especially until the end of) the dialysis session. The dialysis device 2 supplies the dialysis filter 5 with fresh dialysis solution via line 7 during the dialysis session and removes the used solution via line 8. The fresh dialysis solution supplied to the dialysis filter 5 enters into osmotic exchange with the blood flow pumped through the dialysis filter on the other side of the dialysis membrane 6.The fresh dialysis solution contains the creatine compound according to the invention in such a way that the creatine compound according to the invention is dosed into the bloodstream 4, which is returned to the patient. Furthermore, the fresh dialysis solution, which is supplied to the dialysis filter 5, may contain a certain amount of creatinine as well as phosphate bound to the creatine compound and other additives. The invention and further developments of the invention are explained in more detail below with reference to several non-limiting embodiments.

[0119] Example 1

[0120] A patient undergoing hemodialysis three times a week (skipping one day plus one two-day skip) for four hours is connected to a dialysis machine that draws, dialyzes, and returns 350 ml of blood per minute. The difference in flow rate resulting from reverse osmotic hemofiltration for volume adjustment can be disregarded. The returned blood has been enriched with creatine from the dialysis solution through the dialysis membrane (intradialytically), so that it contains 9 mg of creatine per dl of blood plasma during and until the end of dialysis. The fresh dialysis solution contains 50 pM creatinine without any adverse effects on the patient.

[0121] Example 2

[0122] A patient who connects to a home dialysis machine for hemodialysis six times a week (skipping one day a week) for approximately two hours each session, with the machine drawing 300 ml of blood per minute, dialyzing it, and returning it to the patient (the difference in flow rate due to reverse osmotic hemofiltration for volume adjustment can be disregarded). The returned blood has been enriched with creatine from the dialysis solution through the dialysis membrane (intradialytically), so that it contains 8.5 mg of creatine per dl of blood plasma during and until the end of dialysis. The fresh dialysis solution contains 100 pM creatinine without any adverse effects on the patient.

[0123] Example 3

[0124] A female patient weighing 55 kg with a lean body mass of approximately 38 kg, who had been on dialysis for an extended period (three times a week for four hours each session at a blood flow rate of 175 ml / min), is now being treated with a dialysis solution such that the blood returned to the patient contains 850 pM creatine in the plasma. Creatine uptake is initially high, between 6.5 and 7 g per session, and stabilizes after a few weeks at approximately 3 to 3.6 g per session, which, given this treatment interval and body mass, corresponds to a healthy creatine pool. The fresh dialysis solution contains 50 pM creatinine without any adverse effects on the patient.

[0125] Example 4

[0126] A 75 kg female patient with a lean body mass of approximately 60 kg, who is not producing urine and has been on dialysis for some time (3 times a week for 4 hours each session), is now being treated with a dialysis solution such that the blood returned to the patient at flow rates between 300-350 ml / min contains 550 pM creatinine in the plasma. He absorbs 2.4 g of creatinine in the first session and 2.3 g per session after 6 weeks; this value is slightly below what is needed for a healthy, balanced creatinine level. The patient remains slightly deficient. The fresh dialysis solution contains 50 pM creatinine without any adverse effects on the patient.

[0127] Example 5

[0128] A 67 kg male patient with a lean body mass of approximately 50 kg, who had been on dialysis for an extended period (3 times per week for 3 hours each session), is now being treated with a dialysis solution such that the blood returned to the patient at 300 ml / min contains 1030 pM creatinine in the plasma. Initially, creatine uptake is very high at approximately 9.5 g per dialysis session, but after 3 weeks it drops to 5.5-6 g per session and stabilizes early on at approximately 4 g per session. The excess creatine has led to a rapid replenishment of the creatine pools, but is not needed for chronic treatment, which maintains a healthy balance between creatine intake and breakdown, and is therefore wasted. The fresh dialysis solution contains 100 pM creatinine without any adverse effects on the patient.

[0129] Example 6

[0130] A 75 kg male patient with a lean body mass of approximately 43 kg, who has been on dialysis for an extended period (twice a week for 4 hours each session at a blood flow rate of 300 ml / min), is now being treated with a dialysis solution such that the blood returned to the patient contains 450 pM creatinine in the plasma. He absorbs 6 g of creatinine in the first session and, after 6 weeks, still 3.6 g per session. This value is below what is needed for a healthy, balanced creatinine level. The patient remains deficient. The fresh dialysis solution contains 50 pM creatinine without any adverse effects on the patient.

[0131] Example 7

[0132] A 100 kg male patient with a lean body mass of approximately 65 kg, who has been on dialysis for an extended period (3 times per week for 3.5 hours each session at a blood flow rate of 300 ml / min), is newly treated with a dialysis solution such that the blood returned to the patient contains 280 pM creatinine in the plasma. In the first session, the patient absorbs 2.9 g of creatinine, and after 6 weeks, still 2.5 g per session. This value is clearly below what is needed for a healthy, balanced creatinine level. The patient remains deficient. The fresh dialysis solution contains 50 pM creatinine without any adverse effects on the patient. Example 8

[0133] A patient population of 9 individuals (male and female) weighing between 50-120 kg and with a lean body mass between 35-75 kg, all of whom had been on dialysis for an extended period (2-3 times per week for 2.5-4 hours at blood flow rates of 200-300 ml / min), is now being treated with a dialysis solution such that the blood returned to each patient contains 800 pM creatine in the plasma but no phosphate bound to creatine compounds. The fresh dialysis solution contains 20-50 pM creatinine without any adverse effects on the patients. Phosphate excretion and the calcium-phosphate product remain unchanged, the patients' creatine pool is normalized, and hand-grip strength, a measure of muscle performance, increases significantly.

[0134] Although, as described above, there are various embodiments of the present invention, these are to be understood as meaning that the various features can be used both individually and in any combination.

[0135] This invention is therefore not simply limited to the particularly preferred embodiments mentioned above.

Claims

Patent claims 1. Creatine compound selected from the following groups: (i) Creatine and its pharmaceutically acceptable salts (ii) (Phospho)creatine compounds; (iii) (Phospho)Creatine derivatives; (iv) creatine precursors, (v) Creatine analogues, and Mixtures thereof, for the prophylaxis and treatment of creatine deficiency and the associated symptoms in hemodialysis patients, characterized in that the creatine compound is added to a hemodialysis solution intended for the patient in such an amount that the blood which is returned to the patient from a dialysis device simultaneously connected to the patient has a concentration of 400-1100 M creatine compound in the blood plasma, at a blood flow from the dialysis device to the patient of 100 ml / min to 500 ml / min.

2. Creatine compound according to claim 1, characterized in that its addition to the hemodialysis solution is carried out continuously, essentially until the end of the dialysis session, by adding a predetermined or in situ prepared solution of the creatine compound, preferably in the form of a stock solution.

3. Creatine compound according to claim 1 or 2, characterized in that it is a creatine compound which is present in solution in the form of creatine molecules.

4. Creatine compound according to claim 3, characterized in that the creatine compound is: creatine, creatine monohydrate or a physiologically acceptable creatine salt.

5. Creatine compound, according to one of claims 1 to 4, characterized in that the hemodialysis solution is administered to the patient for at least 60 minutes, preferably at least 180 minutes.

6. Creatine compound, according to one of claims 1 to 5, characterized in that the hemodialysis solution during (i) 3 to 6 hours, 1 to 4 times per week; or (ii) 1 to 3 hours, 6 to 7 times per week is administered to the patient.

7. Creatine compound, according to one of claims 1 to 6, characterized in that the blood which is returned to the patient has a concentration of creatine compound in the blood plasma in the range of 500-1000 pM, preferably of 600-950 pM and in particular of 650-900 pM.

8. Creatine compound, according to one of claims 1 to 7, characterized in that the blood flow from the dialysis device is 300 - 350 ml / min.

9. Creatine compound according to any one of claims 1 to 8, characterized in that the (phospho)creatine compounds comprise the group consisting of (phospho)creatine, (phospho)creatine monohydrate, (phospho)cyclocreatine, and homo-cyclocreatine.

10. Creatine compound according to any one of claims 1 to 9, characterized in that the (phospho)creatine derivatives comprise the group of (phospho)creatine salts, and preferably creatine pyruvate, lactate, ascorbate, acetate, citrate, hydroxycitrate, laureate, phytate, mandelate, malate, glycolate, cinnamate, salicilate, hyaluronate, β-hydroxygutyrate, gluconate, choline, carnitine, propionylcarnitine, coenzyme Q10, adenosine, fructose, fructose-1,6-bisphosphate, adenosine ester, acid anhydrous dihydrogenase, and glutamine.

11. Creatine compound according to one of claims 1 to 10, characterized in that the creatine precursors comprise the group consisting of guanidinoacetic acid, 3-guanidinopropionic acid, guanidinobenzoic acids and the combination of glycine, arginine, and methionine as well as their physiologically acceptable salts and derivatives.

12. Creatine compound according to one of claims 1 to 11, characterized in that the creatine analogues comprise guanidinoacetic acid and guanidinoacetate.

13. Creatine compound according to one of claims 1 to 12, characterized in that the amount of creatine compound to be added to the hemodialysis solution is adapted according to the molar mass ratio to creatine.

14. Creatine compound according to one of claims 1 to 13, characterized in that it is in solid form or in the form of a dialysis concentrate or a dialysis solution.

15. Creatine compound according to one of claims 1 to 14, characterized in that it contains at most 10 mol% creatinine (based on creatine + creatinine), preferably at most 5% mol% creatinine.

16. Creatine compound according to one of claims 1 to 15, characterized in that the dialysis solution has a concentration of at most 200 pM creatinine, preferably at most 100 pM creatinine.

17. Creatine compound according to any one of claims 1 to 16, characterized in that it contains at most 50 mg / kg, preferably at most 25 mg / kg dicyandiamide.

18. Creatine compound according to one of claims 1 to 17, characterized in that the dialysis solution has a concentration of at most 13.1 pg / l, preferably at most 6.55 pg / l dicyandiamide.

19. Creatine compound according to any one of claims 1 to 18, characterized in that it contains at most 3 mg / kg, preferably at most 2 mg / kg dihydrotriazine.

20. Creatine compound according to one of claims 1 to 19, characterized in that the dialysis solution has a concentration of at most 786 ng / l, preferably at most 542 ng / l dihydrotriazine.

21. Creatine compound according to any one of claims 1 to 20, characterized in that the dialysis solution contains a maximum of 100 pM of phosphates bound (or dissociated) to creatine substances according to the substance groups (i), (ii) and (iii) of claim 1, claim 9 or claim 10.

22. Creatine compound according to any one of claims 1 to 21, characterized in that the dialysis solution contains a maximum of 100 pM, preferably 50 pM, of phosphates bound (or dissociated) to creatine substances according to substance groups (i), (ii) and (iii) of claim 1, claim 9 or 10.

23. Creatine compound according to one of claims 1 to 22 for the prophylaxis and treatment of the following symptoms in hemodialysis patients: I. Brain & Brain Function: a) Symptoms of Fatigue:

1. Chronic Fatigue Syndrome 2. ME / CFS Myalgic Encephalomyelitis 3. General fatigue, exhaustion b) Cognitive impairment, cognitive performance of the / the / of 1. Working memory 2. Long-term memory 3. Mental performance 4. Brain fog 5. Concentration difficulties 6. Reduced stress resistance c) Coordination disorders d) Depression, anxiety disorders e) Sleep disorders:

1. Difficulty falling asleep 2. Sleep disturbance 3. Daytime sleepiness 4. Reduced sleep quality f) to protect against cell damage from trauma g) to protect against neurodegeneration II. Spinal Cord & Peripheral Nervous System: a) Paresthesias b) Peripheral Polyneuropathies c) for the protection and regeneration of the spinal cord and peripheral nervous system III. Muscles: a) Muscle weakness 1. Muscle tone weakness 2. Muscle fatigue b) Sarcopenia, age-related loss of muscle mass c) Muscle atrophy, muscle wasting & rehabilitation d) Frailty & fragility e) Movement coordination disorders & fall prevention Muscle endurance & fatigue f) Muscle relaxation, muscle cramps & ischemia g) Myalgia, muscle pain h) For increasing muscle mass and strength i) For improved musculoskeletal healing, IV. Heart & Cardiovascular System: a) Cardiac muscle diseases, myocardial insufficiency, cardiac ischemia, heart failure, myocardial infarction b) Left ventricular hypertrophy c) Cardiovascular health d) Myocardial ischemia, ischemia and reperfusion injury V. Liver: a) to prevent fatty liver VI. Kidneys: a) Follow renal ischemia, b) to improve residual renal function VII. Bones and cartilage: a) Osteopenia b) Osteoporosis c) Uremic osteodystrophy d) for improved bone and cartilage mineralization VIII. Blood and blood cells: a) Anemia b) Renal anemia 1. reduced blood cell production 2. the reduced lifespan of erythrocytes 3. and to protect erythrocytes from osmotic and mechanical stress IX. Immune system: a) Increased susceptibility to infection b) Increased risk of an unfavorable course of infectious diseases c) and to protect immune cells from mechanical, oxidative and osmotic stress d) to strengthen the immune system by supporting macrophages, B lymphocytes and T cells X. Movement coordination disorders XI. Fall prevention: a) increased frequency of falls b) increased frequency of bone fractures XII. Fall prevention: a) Reduction of immobilization-induced muscle atrophy b) Impaired bone healing c) Impaired wound healing d) impaired skin healing e) fall-related brain trauma XIII. Prevention of the consequences of ischemia to reduce the effects of ischemia and anoxia on body cells: a) Thrombosis 1. Stroke 2. Heart attack 3. Pulmonary embolism b) and in cases of ischemia due to bleeding XIV. Intestine: a) Intestinal inflammation, colitis, Crohn's disease b) Reduced intestinal health c) Colitis XV. Frailty (Fragility) XVI. Orthostatic problems and dizziness a) In the ear, energy for ion transport against ear cell loss b) Against dizziness XVII. General cell protection: a) against ischemia & asphyxia b) against oxygen radicals (ROS) c) against radiation damage

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