Use of coenzyme antagonists in order to slow down metabolic process

Abstract

To provide an inhibitory structural analog or inhibitory functional analog for a general successive (in particular also continuous) slowing down of metabolic processes of endogenous and exogenous cells in the body of a patient.SOLUTION: Provided is a use of at least one inhibitory structural analog or inhibitory functional analog of a coenzyme (for example thiamine) of an enzyme group, the enzyme members of which catalyze anabolic and / or catabolic and / or energy-releasing metabolic reactions that are of essential significance for the functional capability of the overall metabolism of cells, in particular mammalian cells, the use being for treating a patient in order to produce a general successive (in particular also continuous) slowing down of the metabolic processes of endogenous cells and exogenous cells in the body of the patient and thus achieve in particular a slowing down of disease-causing processes.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the use of at least one inhibitory structural or functional analog of a coenzyme (such as thiamine) of a group of enzymes that catalyze anabolic and / or catabolic and / or energy-releasing metabolic reactions of great importance for the overall metabolic function of cells, in particular mammalian cells, for treating a patient with the aim of slowing down the endogenous and exogenous cellular metabolic processes in the patient's body in a general, continuous (particularly also stepless) manner.

[0002] Any patient's illness is a process. The faster this process progresses / evolves, the less time there is for treatment (therapeutic measures / therapeutic interventions) to alleviate or cure. The process of damaging the body can be characterized by the damage that occurs per unit of time. As a general rule, the more damage per unit of time, the more severe the overall damage.

[0003] In addition to the degree of the damaging process, the speed of the damaging process also determines the severity of the disease and the patient's death, and in many cases, the speed is even the determining factor in whether the damaging process will be fatal.

[0004] In bacterial and viral diseases, the exponential growth / multiplication of bacteria or viruses per unit time determines the severity of the disease course. Examples of viral diseases that cause influenza, influenza-like illness, or, more recently, Covid-19, as well as bacterial infections that cause sepsis, are common examples. When bacteria or fungi enter the bloodstream, they or the substances or toxins they release can trigger serious diseases, such as potentially fatal blood poisoning. In the most severe cases, successful antibiotic therapy, which is designed to kill bacteria in the body, can become fatal because toxins released during the killing process (e.g., endotoxins) trigger potentially fatal reactions in patients. Therefore, it is important to consider not only the bacterial killing activity but also the consequences of bacterial killing. For example, endotoxins released by killed and subsequently disintegrated bacteria can induce fever attacks. The released toxins can ultimately lead to acute sepsis, which can quickly lead to organ failure and death. A slow, protracted process lasting weeks can also lead to sepsis complications and death. Therefore, in addition to primary antibiotic therapy, it is reasonable to implement therapeutic measures to address the consequences of antibiotic therapy and the resulting toxin release. The negative consequences of toxin release should be controlled and suppressed so that sepsis complications and sepsis do not occur, sparing the patient from serious or even fatal consequences. When the amount of toxin exceeds a threshold, the body can no longer compensate for the effects of the toxin, and the patient dies. Because the amount of toxin in a bacterial infection correlates with the amount of bacteria, bacterial proliferation is closely related to the level of toxin release, which determines the patient's risk of death from toxin effects. Therefore, slowing bacterial proliferation in the body generally is the starting point for influencing the amount of toxin and, therefore, the probability of death at that level, thereby increasing the patient's chances of survival.

[0005] Furthermore, antibiotic therapies that successfully kill bacteria can also cause treatment failure because the amount of toxins released during bacterial killing can lead to sepsis complications and sepsis. Because toxins such as endotoxin exert their dangerous effects through Toll-like receptors and / or inflammatory signaling pathways, inhibiting these Toll-like receptors or inflammatory signaling pathways can suppress the dangerous effects of the toxin. This could make the original antibiotic therapy safer and more successful by inhibiting the toxin's action through the inhibition of the relevant signaling pathways.

[0006] In diseases involving immunological and / or excessive inflammatory responses and symptoms, as well as autoimmune diseases, the proliferation of inflammatory cells and / or cells of the immune system per unit time also determines the severity of the disease process, such as rheumatoid attacks in patients with rheumatoid arthritis or relapsing MS attacks in patients with relapsing-remitting multiple sclerosis.

[0007] In all these cases, patients and their treating physicians would benefit if they could temporarily slow the cell proliferation of rapidly proliferating immune cells, or (almost) all immune cells, to buy time for targeted therapeutic intervention or to mobilize the patient's own body's defenses.

[0008] The present invention is based on the task of meeting this need.

[0009] The solution to this problem is to provide at least one inhibitory structural or functional analog of a coenzyme (such as thiamine) of a group of enzymes which catalyze anabolic and / or catabolic and / or energy-releasing metabolic reactions that are crucial for the overall metabolic function of mammalian cells (preferably also bacterial cells or other organisms present in the mammalian body) for use in treating a patient for the purpose of generally and continuously (in particular also steplessly) inhibiting / slowing / abrogating anabolic, catabolic and energy-releasing metabolic processes of cells (i.e. essentially all or almost all) in the patient's body (i.e. endogenous and even exogenous cells in the patient's body).

[0010] On the one hand, this provides a time gain by simultaneously slowing down healthy processes and pathogenic processes. During this time, the patient's body can respond to the pathogenic process itself, and / or the pathogenic process in the patient's body slows down, reducing the level of damage per time interval and causing less damage to the patient's body overall, and / or more time is available to find a more successful treatment. This time gain can also be used to reduce the effectiveness of the treatment and / or its side effects, resulting in fewer side effects. The latter is particularly advantageous when the treatment is essentially successful. For example, if the adverse effects of toxins (e.g., endotoxins) released upon successful killing of bacteria are suppressed by slowing down metabolism, the treatment will be more successful overall, since the signaling pathways involved in the action of the toxins are generally and nonspecifically inhibited. Suppressing / slowing / inhibiting metabolic processes also leads to a lowering of the threshold for cell death.

[0011] The slowing of cellular metabolism can occur up to a complete blockage of metabolism, and the duration and / or amount of agent applied must be selected so that most healthy cells are able to reactivate their metabolism after the metabolic slowing is lifted without suffering any permanent damage, or such permanent damage is tolerable in terms of successful treatment.

[0012] The term "coenzyme of an enzyme group" as used herein in its context means that all the enzymes of the group (the so-called "constituent enzymes") absolutely require this coenzyme for the exertion of their catalytic activity, or in other words, that this coenzyme is essential for the exertion of the catalytic activity of all the enzymes of the group.

[0013] The term "inhibitory structural analog" of a coenzyme, or simply "coenzyme antagonist," as used herein, refers to a structural analog of a coenzyme that binds to an enzyme in place of the coenzyme and inhibits (suppresses) its catalytic (enzymatic) activity.

[0014] The term "inhibitory functional analog" of a coenzyme, as used herein, refers to a substance that does not have a similar structure to a coenzyme, but that can occupy a location in / on an enzyme and / or interact with the coenzyme to functionally inhibit its action, thereby functionally inhibiting the action of the enzyme.

[0015] In the following, the term "inhibitory coenzyme analogue" means an inhibitory structural analogue and / or an inhibitory functional analogue according to the invention of a coenzyme according to the two definitions given above.

[0016] In the following, the abbreviation "GSSV" means "general and continuous (particularly, if necessary, even stepless) metabolic slowing", where metabolic slowing is to be understood as a slowing down (or suppression or arrest) of metabolic processes that are anabolic and / or catabolic and / or energy-supplying and essential for the existence of a mammalian cell.

[0017] The term "administration scheme" (synonyms: administration regimen, dosing scheme) as used hereinafter means, in the present context, a series of plans for individual doses (synonyms: dosage, unit dose) of a drug, together with the time intervals between doses, the level (amount) of individual intake to be carried out in each case, an indication of the duration of the treatment phase, and an indication of how and in what formulation (dosage form) the active substance or drug is to be taken.

[0018] The term "targeted cancer therapy" or "targeted therapy" for short, as used herein in context, refers to a drug-based cancer treatment in which one or more agents are administered that are directed to predetermined tumor-specific target structures in tumor cells. These predetermined target structures include, for example, receptors or enzymes on tumor cells. The agents, also referred to herein in context as "cell-type specific agents," include, for example, antibodies (e.g., anti-EGFR) or protein structures of different configurations (e.g., hormone antagonists or soluble receptors for signaling molecules), hormones, hormone derivatives, substances that transmit or inhibit signals (e.g., immunomodulators), and so-called "small molecules" (e.g., tyrosine kinase inhibitors such as sorafenib, imatinib, etc.).

[0019] The essence of this invention is to present a completely new method of treating disease, characterized by a targeted inhibition of the patient's metabolism, thus slowing down processes that directly or indirectly cause damage in the body, and thus slowing down the metabolism overall. This new form of treatment is hereinafter referred to as GSSV therapy.

[0020] The use according to the invention and the GSSVs it causes (evokes) do not distinguish between healthy and degenerated cells, nor between endogenous cells in the patient's body and exogenous cells, including, inter alia, prokaryotes such as bacteria, unicellular or multicellular eukaryotes such as fungi, parasitic flagellates or worms, and infectious organisms that use mammalian cells for their propagation, such as RNA and DNA viruses.

[0021] By means of the administration regimen (time interval and amount of administration), the strength and duration of metabolic inhibition can be varied virtually at will, in particular even steplessly, and controlled to suit the purpose. This means that the supply of essential substrates required for subsequent specific enzymatic reactions is suppressed in principle in all cells of the patient's body (i.e., in both the healthy and, if present, degenerated somatic cells of the patient's organism, as well as the bacterial, fungal, or parasitic or commensal cells present in the body) for a predetermined, limited period of time. This period is selected or set so that no (or only slight) irreversible damaging effects occur in endogenous healthy cells, and after the metabolic inhibition is terminated (by discontinuing the drug according to the invention or by discontinuing the administration of functionally effective cofactors), in particular the patient's healthy somatic cells can strengthen (increase) their metabolism again, all enzymatic processes can again carry out their full range, and the majority of healthy somatic cells do not (are) subjected to any permanent damage.

[0022] During the course of the experiments underlying the present invention, it was surprisingly discovered that the inhibitory thiamine analogue B-OT exerts the desired effect in dogs and humans at significantly lower concentrations than in rats and mice.When the same amount of B-OT (amount per kg of body weight) applied to rats and mice (i.e., rodents) was used in dogs and humans, the latter caused much more severe, and in some circumstances undesirably strong, reactions, often leading to death.This surprising discovery underlying the present invention is particularly remarkable in that, compared with the published amount used in rats and mice (rodents), about 200 times lower amounts are used in humans and dogs (non-rodents) to avoid serious, sometimes fatal, progression.

[0023] The present invention provides novel tools to protect against and combat both existing diseases and future, currently unforeseen, diseases that may arise.

[0024] The mammalian / human body is ultimately a system in which mammalian or human cells interact with other organisms, all competing for resources such as energy for survival. Within this system, the mammalian organism itself is a target resource for many of the organisms surrounding it. In particular, bacteria, viruses, protozoa, and parasites are living organisms or reproductive units that grow within living organisms, either peacefully coexisting with the mammalian / human organism or causing fatal health problems. Evolution has led to a constant competition between attackers and defenders, resulting in the constant improvement of both attackers and defenders. Losers in this constant improvement race die out over the course of evolution, leaving both today's attackers and today's surviving defenders in a relatively stable state in relation to each other. However, from an evolutionary perspective, this current stability is extremely fragile, since no one can predict whether attackers will develop entirely new strategies in the future that will render defenders unable to defend against them. The current spread of the coronavirus SARS-COV-2 and the disease it causes, COVID-19, demonstrates that attackers can evolve to inflict damage on new hosts where they can spread on a large scale and cause new disease patterns, with many people unable to adequately defend themselves against these mutated attackers, resulting in severe illness and even death.

[0025] Regardless of the principles of how a new attacker inflicts damage on a mammalian / human organism, the present invention makes it possible to slow the effects of such new pathogens on the organism so that the extent of the disease can be slowed and reduced in a targeted, continuous, and, if necessary, stepless manner. By prolonging the time course of the disease, the organism (or body) has more time to react, while simultaneously reducing the degree of damage per unit of time. This reduction in the degree of damage per unit of time allows the organism to tolerate it. In other words, by lengthening the timeline over which the damage acts, while simultaneously reducing the intensity of the damage, the damage can be reduced so that the overall damage to the body is reduced. The level or intensity of the damage is reduced so that the body can better tolerate or cope with it.

[0026] This effect of reducing damage and prolonging the disease provides valuable time to test which treatments will benefit the patient. In the past, when a disease progressed very quickly, doctors often had to make quick decisions about which drugs to administer and which treatments to use. Because bacteria, parasites, or viruses grow exponentially within an infected patient, the time available for such decisions is extremely short. In such cases, if the first drug or treatment choice proves ineffective, it is not possible to test another drug or treatment in the patient. By slowing the growth of the attacker (e.g., bacteria, parasite, or virus) within the patient's body, doctors have the time they need to test which drugs or treatments are effective.

[0027] This time advantage, which allows identifying an effective drug or effective treatment for the patient, is a very crucial advantage of the present invention.The use according to the present invention can be adapted to the individual needs of the patient's organism, so that it works essentially equally well in all patients with the same disease.Thus, the slowing down of the patient's metabolism provides the possibility to determine at an individual level which drug or which treatment is effective in the patient, that is, in this very individual individual case.

[0028] The time gains offered by metabolic slowing also offer a crucial advantage: they allow the body and its defense mechanisms, such as the immune system, more time to develop appropriate defenses against foreign invaders. For example, the formation of antibodies by the human immune system is a stochastic process, with new antibody variations formed through random recombination of corresponding genes. Antibody testing then determines which antibodies the body will produce to fend off foreign invaders or eliminate unwanted endogenous cells, such as tumor cells. Because the random de novo formation and selection of antibodies is a time-dependent process, very fast-acting diseases, such as viral infections that multiply exponentially within the body or bacterial infections that enter the bloodstream and cause sepsis, are particularly difficult for the endogenous immune system to combat. In many cases, the endogenous immune system ultimately lacks sufficient time to mount an appropriate immune response. GSSV offers a way to slow very fast viral and bacterial infections, allowing the endogenous immune system sufficient time to mount an effective response to combat the pathogen.

[0029] However, for example, treatments that kill bacteria in the body may be initially successful but ultimately fail because the toxins (endotoxins) released by the killed bacteria can have adverse effects in the patient's body, even leading to death. GSSV creates a means to suppress the adverse effects of toxin release so that the body does not experience adverse outcomes, such as sepsis complications or septicemia. In other words, GSSV produced by the present invention is a measure to make antibiotic therapy, which is effective but potentially has severe or fatal side effects, tolerable so that it can be used to the benefit of patients.

[0030] Furthermore, endogenous but uncontrollable cells that proliferate in the body, such as tumor cells, can grow invasively and metastasize, eventually leading to the exponential growth of these aggressive tumor cells (cancer cells), which then often leads to the metabolic death of cancer patients. In such cases, GSSV can slow the growth of metastatic cancer cells, preventing their exponential growth or suppressing the existing exponential growth of these cells, causing them to proliferate slowly or not at all. The use of GSSV according to the present invention represents a significant departure from conventional therapeutic approaches in oncology, as it is not a treatment specifically directed at unwanted cells (cancer cells), but rather aims and exerts its effect by nonspecifically inhibiting the metabolism of all endogenous cells. Therefore, GSSV and its application in the field of oncology are primarily palliative rather than curative approaches, and unlike conventional cancer treatments, GSSV has no or minimal side effects, thereby providing cancer patients with a particularly longer survival period without compromising their quality of life.

[0031] In a preferred embodiment, the inhibitory structural or functional analogue is an inhibitory thiamine analogue, hereinafter also referred to as a thiamine antagonist, in particular oxythiamine and / or benphooxythiamine and / or benphooxythiamine analogues and / or benphooxythiamine derivatives.

[0032] The terms "inhibitory thiamine analogue" and thiamine antagonist, as used herein, refer to a substance (respectively) that (i) preferably belongs to the class of small molecules (small molecule compounds), i.e., organic compounds having a molecular weight of less than 900 daltons that affect biological processes, and preferably further (ii) is either (a) a structural analogue of thiamine, in particular a thiamine derivative that inhibits the enzymatic activity of a thiamine-dependent enzyme, or (b) a functional analogue of thiamine, in particular an agent that does not resemble the thiamine structure but functionally inhibits the action of thiamine by competing with thiamine for binding to a thiamine-dependent enzyme or by inhibiting the action of thiamine binding to a thiamine-dependent enzyme.

[0033] Thiamin-dependent enzymes catalyze a wide range of catabolic, anabolic, and energy-releasing metabolic reactions and enable related metabolic pathways.

[0034] The thiamine antagonists of the present invention inhibit the activity of this group of enzymes, i.e., all enzymes that use thiamine as a coenzyme, thereby simultaneously interfering with cellular biochemical processes at multiple sites across a wide range of areas. In particular, numerous essential catabolic, anabolic, and energy-releasing metabolic pathways are targetedly slowed, inhibited, or completely blocked. The inhibited catabolic reactions include the breakdown of carbohydrates and proteins, which release energy in the form of energy-rich compounds such as acetyl-CoA and ATP. Acetyl-CoA plays an important role in the de novo formation of cells, particularly the formation of fatty acids, lipids, and cholesterol. These components play an essential role in the formation of cell membranes and organelle membranes such as mitochondria, and they also play an important role in the release of energy from hydrogen and its fixation in the form of the energy-rich compound ATP.

[0035] The use of thiamine antagonists according to the invention, for example, leads in particular to the inhibition of all α-keto acid dehydrogenases, i.e., a family of enzymes important in the breakdown of carbohydrates and proteins and the release of energy therefrom, including in particular the three enzymes pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and branched-chain α-keto acid dehydrogenase, each of which decarboxylates to form an energy-rich compound in the form of acetyl-CoA, each of which releases hydrogen to form NADH+H. + Form.

[0036] Inhibition of α-ketoacid dehydrogenase by thiamine antagonists leads to inhibition of catabolic metabolic pathways, resulting in the inhibition of all energy release from carbohydrates and proteins. This inhibits both the reactions that directly form energy-rich compounds such as acetyl-CoA and the reactions that lead to the formation of ATP by oxidation of the released hydrogen. Therefore, thiamine antagonists are a very good starting point for inhibiting the release of energy and the formation of energy-rich compounds such as acetyl-CoA and ATP.

[0037] Other important thiamine-dependent enzymes that are inhibited by the use of thiamine antagonists according to the invention are, for example, transketolase, which does not carry out decarboxylation and hydrogen elimination, allowing the conversion of sugars, for example the formation of ribose from glucose.

[0038] Because essential anabolic metabolic processes within cells require a supply of energy, thiamine antagonists can also be used to inhibit essential energy-dependent anabolic metabolic reactions, through inhibition of catabolic and energy-releasing metabolic reactions, necessary for the production of building blocks for the maintenance, repair, and de novo formation of cellular structures. For example, the synthesis of nuclear DNA during mitosis and the repair of DNA damage depend on the presence of both the four base building blocks and sufficient energy in the form of ATP to energetically activate the base building blocks. In principle, the same is true for RNA synthesis and repair.

[0039] The technical effect of the use of the thiamine antagonists according to the invention for the purpose of inducing (producing) GSSV according to the invention is therefore in particular that in cells, due to the inhibition of thiamine-dependent enzymes, catabolic metabolism (in particular catabolism of carbohydrates and proteins) and anabolic metabolism, as well as the release of energy and its fixation in energy-rich compounds, are significantly inhibited. Thus, the inhibition of metabolism involves a large number of different regulators in the form of different thiamine-dependent enzymes.

[0040] In a preferred embodiment of the use according to the present invention, the inhibitory thiamine analogue is a substance called benphooxythiamine (hereinafter abbreviated as "B-OT"). B-OT is a precursor ("propharmacon", "prodrug") of oxythiamine. B-OT can be administered orally and releases oxythiamine immediately after absorption in the mammalian body. Oxythiamine inhibits thiamine-dependent enzymes. In mammals, the conversion (metabolism) of B-OT to oxythiamine occurs in the blood. Through the blood circulation, B-OT can reach cells in all parts of the body.

[0041] In vivo pharmacokinetic data show that significant amounts of oxythiamin are present in the brain after B-OT administration, indicating that oxythiamin crosses the blood-brain barrier.

[0042] In vivo pharmacokinetic data from rat studies on the bioavailability of B-OT after oral administration showed that 0% of B-OT was measurable in the blood, meaning that the prodrug form was virtually undetectable, but 44% of the total administered B-OT was measurable in the blood in the form of oxythiamine (OT). This indicates that B-OT is cleaved very efficiently to OT, resulting in a high percentage of OT present in the blood. Thus, B-OT is an orally available substance with favorable pharmacokinetics and capable of providing OT effectively and efficiently. Oral administration of B-OT offers a significant advantage over intraperitoneal administration, which is typically required / desired. Furthermore, because the basic structure of B-OT is more lipophilic than that of OT, its bioavailability and absorption are more suitable for human therapy. Thus, B-OT can be used as a drug better, more easily, and more safely than OT.

[0043] The chemical structure (structural formula) of benphoxythiamine can be shown as follows: [ka]

[0044] The production of benphoxythiamine (B-OT) in accordance with EU GMP guidelines for human and veterinary medicines is well established in the prior art, and benphoxythiamine can be used in mammals (e.g., dogs, cats) and in particular in humans.

[0045] Drug development has traditionally been driven by the idea that in mammalian / human systems colonized with symbionts, commensals, and parasites, agents must be found that kill or at least inhibit the attackers. To achieve this, selectively acting drugs must be found that inhibit the attackers but not the defenders (e.g., humans). From this perspective, it makes no sense to find an agent that inhibits both the attacker and the defender. However, there are situations in which it makes perfect sense to inhibit both the attacker and the defender simultaneously. One such situation is, for example, when the attacker proliferates so strongly in the defender's body that sepsis develops.

[0046] Sepsis is the body's systemic response to an uncontrolled infection, usually caused by bacteria, but increasingly by fungi. Sepsis is a life-threatening condition that occurs when the body's response to infection damages its own tissues and organs. Sepsis can lead to shock, multiple organ failure, and ultimately death, especially if not recognized early and treated promptly. Sepsis is the leading cause of infection-related death worldwide.

[0047] Sepsis is one of the most common causes of death: infections triggered by injury or contamination during surgery can lead to explosive bacterial growth, releasing toxins that can cause multiple organ failure and ultimately lead to the patient's death.

[0048] To date, the only hope of saving patients is to kill bacteria as quickly as possible with effective antibiotics. However, even then, patients may still die because toxins (endotoxins) released by killed bacteria can induce sepsis or sepsis through signaling pathways (e.g., Toll-like receptors and inflammatory signaling pathways). Currently, there is often no time required to select appropriate, effective antibiotics through laboratory testing, and there is a risk of selecting ineffective drugs due to resistance. Furthermore, even if an effective antibiotic is selected, there is a risk that the toxins released by the antibiotic as it kills the bacteria can lead to sepsis or sepsis.

[0049] The GSSV induced by the present invention not only affects the signaling pathways through which endogenous cells and toxins in a patient can induce sepsis complications or sepsis, but also addresses and inhibits bacterial metabolism. This inhibits the bacterial cell division ability and prevents its explosive proliferation. This allows time for the selection and targeted use of appropriate drugs through laboratory testing. Furthermore, GSSV inhibits human metabolism and related reactions, as well as excessive body responses in response to infection. In addition to harmful processes emanating from toxins (e.g., endotoxins) released by bacteria, excessive responses, such as excessive immune responses, are also inhibited. In many cases, it is the body's responses through signaling pathways and immune responses that can cause serious injury or even death to the patient. The dual effect of GSSV, which simultaneously affects bacterial metabolism and the patient's metabolism, is particularly advantageous for the treatment and survival of patients at risk of bacterial infection and the associated sepsis.

[0050] By generating stronger GSSV in accordance with the present invention, bacterial growth can be slowed to the point where little or no damage is done by the bacteria, and the patient's endogenous immune system has much more time to produce antibodies against the bacteria.

[0051] That is, by simultaneously (at the same time and in parallel) inhibiting the metabolism of attackers (e.g., bacteria, fungi) and defenders (humans), the increased proliferation of bacteria and / or fungi relative to the body's defenses is prevented, thereby preventing a worsening of the ratio of bacterial and / or fungal proliferation, which would otherwise be damaging to the body, to the patient's defenses. While simultaneously inhibiting both attackers and defenders does not necessarily result in a cure, it can stabilize the patient's condition and buy time to identify an effective treatment. This also opens up the possibility of suppressing the body's negative response to bacteria and their released toxins. In the case of a patient suffering from a bacterial attack that cannot be contained or eliminated by the human immune system, the use of the present invention can prevent the uncontrolled proliferation of these bacteria within the body. By simultaneously inhibiting the metabolism of the bacteria and the patient's own body, both metabolisms are put into a state of stasis, creating a stable situation, allowing time to test bacteria for antibiotic resistance, for example, to determine which antibiotics are likely to be effective. Furthermore, negative consequences of successful bacterial elimination, such as the adverse effects of toxins released during the process, can be suppressed by using GSSV to inhibit signaling pathways activated by toxins and other factors released by the bacteria.

[0052] The present invention therefore also provides an inhibitory structural or functional analogue according to the present invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogues and / or benphooxythiamine derivatives, for use in treating patients with bacterial diseases (infectious diseases). This use is preferably carried out as a monotherapy or in combination with at least one further agent, in particular an agent with antibacterial activity. This use is particularly aimed at inhibiting the effects of bacterial endotoxins on the patient's organism, in particular the effects of endotoxins released as a result of the bactericidal action of the further agent.

[0053] Here, the administration of the inhibitory agents according to the invention is preferably carried out orally according to the invention and according to an administration scheme which includes, for example, the following data: The recommended dose is (based on a body weight of 60 kg): Approximately 40 mg twice on day 1; about 20 mg twice on the second day; On the third day, approximately 10 mg twice a day is.

[0054] The subject of the present invention is also an inhibitory structural and / or functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogues and / or benphooxythiamine derivatives, for use in the treatment of patients with a disease caused / derived from a fungus, preferably as a monotherapy or in combination with at least one further drug.

[0055] Here, the administration of the inhibitory agents according to the invention is preferably carried out orally according to the invention and according to an administration scheme which includes, for example, the following data: The recommended dose is (based on a body weight of 60 kg): Approximately 30 mg twice on day 1; about 15 mg twice on the second day; On the third day, approximately 5 mg twice a day is.

[0056] The subject of the present invention is also an inhibitory structural and / or functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogues and / or benphooxythiamine derivatives, for use in treating patients with sepsis or impending sepsis, wherein the administration of this inhibitory agent according to the invention is preferably carried out orally and, for example, according to an administration scheme comprising the following data: a) If sepsis has already developed, the recommended dose is (for a patient weighing 60 kg): Approximately 40 mg twice on day 1; about 20 mg twice on the second day; On the third day, approximately 10 mg twice a day and (b) The recommended dose for preventing sepsis is (for a person weighing 60 kg): Approximately 20 mg twice on day 1; about 10 mg twice on the second day; On the third day, approximately 5 mg twice a day is.

[0057] The subject of the present invention is also an inhibitory structural and / or functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogues and / or benphooxythiamine derivatives, for use in treating patients with a viral disease (or infectious disease), wherein the administration of this inhibitory agent according to the invention is preferably carried out orally and, for example, according to an administration scheme comprising the following data: The recommended dose is (based on a body weight of 60 kg): (a) If you already have a strong viral infection or a strong (excessive) immune response, Approximately 40 mg twice on day 1; about 20 mg twice on the second day; On the third day, approximately 10 mg twice a day and (b) If symptoms are moderate, to prevent serious viral damage, Approximately 20 mg twice on day 1; about 10 mg twice on the second day; about 10 mg twice on the third day; From the 4th to 7th day, it is about 5 mg once a day. (c) If you have mild or no symptoms, to prevent the virus from strengthening, Approximately 4 mg twice daily during the first week; About 3 mg twice daily in the second week; In the third week, approximately 3 mg once daily is.

[0058] Acute viral diseases such as influenza can be life-threatening, especially in patients with suppressed immune systems. Viral diseases are also characterized by explosive proliferation, allowing the virus to multiply and subsequently attack more and more body cells. Recent studies have shown that drugs that limit the virus's ability to replicate are usually only effective in the early stages of disease. These drugs are often ineffective when the viral load is too high.

[0059] The GSSV induced by the present invention affects all cells in the patient's body. When endogenous cells are attacked by a virus, the cell's metabolism is activated to provide building blocks for viral replication. Metabolic blockade counters this and inhibits the virus's ability to replicate. This reduces the amount of virus and allows the antiviral effects of drugs to effectively combat the virus.

[0060] By generating stronger GSSV in the patient's body through the present invention, the virus can be slowed down so that it causes little or no further damage and the human immune system has much more time to produce antibodies against the virus.

[0061] In other words, the GSSV of the present invention can be used in patients with viral diseases, even though the virus does not have its own metabolism. Because viruses reprogram host cells so that they can replicate using their own metabolism, inhibiting the metabolism of virus-infected defenders is a novel and previously unapplied treatment method for viral diseases. New and highly dangerous viruses for humans, such as the coronavirus SARS-COV-2 and its associated disease, COVID-19, trigger potentially fatal immune and cellular responses. In many cases, excessive responses, such as excessive cytokine formation, are the main cause of the severity of viral diseases and patient death. By inhibiting the metabolism of cells in a virus-infected patient, all responses, including the patient's body's excessive response to viral infection, are slowed. Slowing metabolism slows all responses associated with viral infection. This not only achieves a reduction in peak viral load, but also allows for targeted slowing of all responses triggered by viral infection, including the body's response to viral infection. The metabolic slowing can be achieved continuously by increasing the concentration of the active substance, allowing the metabolic slowing to be very well adapted to the required slowing. This allows for targeted and continuous slowing of the entire infection phenomenon and the human body's response to it. This prevents the immune system from overreacting too strongly, thereby avoiding the damage caused by an overactive immune system. The inhibition of metabolism in the human body (and mammalian body), and the associated inhibition of viral proliferation in the patient's body, can be quantitatively implemented, so that viral proliferation continues, but the process proceeds so slowly that no damage or serious injury is caused by the virus or an overactive immune system. By prolonging the viral infection and slowing viral amplification in the body (i.e., within the patient's body), the patient's immune response has more time to develop an immune response.Ultimately, many patients die because some immune responses, such as excessive immune responses, proceed too strongly, but also because the immune response proceeds too slowly per unit time in terms of antibody formation. Even if an infected person's immune system is able to form neutralizing antibodies, they must be available quickly enough to contain or eliminate the virus. Therefore, the immune system must successfully respond and form antibodies within a few days to protect the patient from severe illness or death. By slowing the infection process in the body with metabolically slowed GSSV according to the present invention, the immune system is given much more time to allow a successful immune response in terms of antibody formation.

[0062] The subject of the present invention is also an inhibitory structural and / or inhibitory functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogues and / or benphooxythiamine derivatives, for use in treating patients with immune diseases, in particular inflammatory and / or autoimmune diseases. In this context, autoimmune diseases include in particular systemic lupus erythematosus (SLE) and episodic disease forms, in particular rheumatoid arthritis and / or multiple sclerosis and / or inflammatory bowel disease, such as ulcerative colitis, Crohn's disease and / or inflammatory / degenerative diseases, in particular inflammatory / degenerative diseases of the skeletal system, such as ankylosing spondylitis.

[0063] The administration of this inhibitory agent according to the invention is now preferably carried out orally and according to an administration scheme which includes, for example, the following data: The recommended dose is (based on a body weight of 60 kg): (a) If a seizure occurs: Approximately 15 mg once a day for 1 week (b) For seizure prevention: Approximately 3 mg once a day for one month is.

[0064] Autoimmune processes are often characterized by excessive or inaccurate immune responses. Many autoimmune diseases progress in a paroxysmal fashion. During the paroxysmal phase, the immune system is particularly active, causing inflammatory phenomena that can result in excessive damage to healthy cells. In many cases, the patient's overall condition worsens after a paroxysmal attack compared to the condition before the attack.

[0065] Activation of the immune system promotes the formation of new cells, differentiation of cells to perform specific roles, and activation of cells increases metabolic activity. GSSV induced by the present invention also targets (affects) immune cells whose activation and proliferation are restricted under GSSV.

[0066] Chronic autoimmune diseases such as rheumatoid arthritis, Crohn's disease, and ulcerative colitis are characterized by increased inflammation. Because this is a chronic process, the use and action of GSSV according to the present invention can slow down metabolism and thus permanently control the disease. For this reason, lower doses are selected, so that healthy cells are not permanently damaged, but inflammation is generally reduced by slowing down.

[0067] The slowing of metabolism by the drug of the present invention can improve the course of diseases characterized by attacks of the disease. An example of a disease that progresses in paroxysmal episodes is multiple sclerosis. In 90% of cases, patients suffer from multiple sclerosis in paroxysmal episodes. By slowing metabolism, it is possible to treat such paroxysmal diseases by slowing metabolism when attacks occur, thereby counteracting the progression of the attacks.

[0068] This use according to the invention can also be used to reduce the risk of organ rejection after transplantation.

[0069] The subject of the present invention is also inhibitory structural and / or inhibitory functional analogs, preferably inhibitory thiamine analogs (thiamine antagonists), in particular oxythiamine, particularly preferably benphoxythiamine and / or benphoxythiamine analogs, according to the invention, for use in the treatment of tumors in patients, in particular in the treatment of cancer (malignant tumors) in patients (human or mammalian), as monotherapy or as pre- or combined therapy with chemotherapy and / or radiotherapy and / or targeted cancer therapy.

[0070] The primary goal of its use in cancer patients is the simultaneous inhibition of multiple enzymes, thereby suppressing / slowing anabolic, catabolic, and energy-releasing metabolic processes in all cells of the body, i.e., all healthy cells as well as uncontrollably proliferating cells (tumor cells). Therefore, the use of GSSV does not specifically target tumor cells, but rather slows the metabolism of all somatic cells in principle. As a result, healthy cells as well as uncontrollably proliferating cells such as tumor cells are reduced in their ability to carry out catabolic, anabolic, and energy-releasing metabolic processes. Consequently, intracellular radical formation increases due to both endogenous processes and exogenous measures such as radiation exposure, slowing the neutralization of radicals, thereby increasing radical stress and even DNA damage. Cancer cells have a much lower ability to respond to stress (e.g., radical stress) and damage (e.g., as a result of chemotherapy and / or radiation therapy), and their threshold for stress and damage to lead to their death (apoptosis) is lower. In other words, if treatment of established tumors or cancers is initiated before or after metabolic blockade, the cells' repair capacity is limited. Cellular repair requires substrates, which are converted by enzymes into end products, consuming energy. As a result of the GSSV induced by the present invention, cells lack sufficient substrates and energy, preventing the enzymatic reactions necessary for various areas of cellular repair. This results in cell death, even in cells that would otherwise be able to repair existing damage. At the same time, redox homeostasis is affected, shifting the ratio of oxidative to reductive processes in favor of oxidative processes. The dual effects of reducing intracellular substrates and available energy and shifting redox homeostasis in favor of oxidative processes lower the death threshold of cells, including tumor cells. Thus, GSSV therapy weakens cancer cells, thereby lowering the cell death threshold.Due to this lowering of the cell death threshold, cancer cells are unable to withstand or avoid the damaging effects of the applied therapies following or concomitant chemotherapy and / or radiotherapy and / or targeted cancer treatment with established agents (because alternative metabolic processes that could serve as "avoidance and bypass pathways" for those damaged by the therapeutic agents are likewise inhibited or almost completely blocked).

[0071] Many tumor treatments aim to directly damage tumor cells and induce cell death. Tumors consist of millions of tumor cells. The degree of cell damage depends on the dose. It is not possible to guarantee the same dose for all tumor cells. At low doses, the damage is insufficient to kill the cells, or the cells activate repair mechanisms to repair the damage and prevent cell death. Therefore, it is almost impossible to kill all cells simultaneously with cancer treatment.

[0072] Yet, to achieve the greatest possible effect, the current practice is to use high concentrations of active substances, at the expense of patients' acceptance of severe side effects.

[0073] The use of coenzyme antagonists according to the present invention and the GSSV they induce is a useful complement to virtually all known therapeutic principles.

[0074] In particular, in the course of a combined therapy with an established antitumor therapy, by selecting the timing of the initiation of GSSV in relation to the combined therapy (antineotherapy), several catabolic, anabolic, and energy-releasing / energy-fixing metabolic processes can be inhibited or completely blocked simultaneously, gradually if necessary or as quickly as possible, and moderately, more strongly, or strongly, particularly adapted to the type of combined therapy (antineotherapy). GSSV lowers the threshold for tumor cell death, on the one hand, and counteracts the malignant properties of tumor cells, so that the tumor cells become less malignant, for example, form less lactic acid, and therefore grow less invasively, form less metastases, and are less inhibited by the immune system, for example, by suppressing acid inhibition of killer cells, which allows the killer cells to attack and kill tumor cells again or better, thereby creating the prerequisites for the more efficient effectiveness of established antitumor therapies, particularly established cancer chemotherapy and / or cancer radiotherapy and / or targeted cancer therapies, which may be applied subsequently. This is because the cell damage thus produced induces the death of the tumor cells (and especially cancer cells) more quickly, more reliably (i.e., with a higher probability) and in greater numbers / more abundantly.

[0075] Especially because of this dual effect, the GSSV produced by the present invention can also be used as a monotherapy.

[0076] The administration scheme of the inhibitory coenzyme analogue according to the present invention in tumor treatment depends on whether it is a monotherapy, a pre-therapy, or a combination therapy. When the use according to the present invention is carried out as a pre-therapy or a combination therapy in combination with an established cancer treatment, the administration scheme of the inhibitory coenzyme analogue according to the present invention varies depending on the additionally applied cancer chemotherapy and / or cancer radiotherapy and / or targeted cancer treatment.

[0077] When radiotherapy is combined with the use of an inhibitory coenzyme analogue according to the present invention, for example, advantageously in the form of B-OT, a thiamine antagonist, B-OT is administered after radiotherapy. This avoids the inhibition of cell proliferation and DNA replication by B-OT, which would reduce the effectiveness of radiotherapy, since non-proliferating cells are less sensitive to radiation. At the time of irradiation, tumor cells are in full swing in cell proliferation, and radiotherapy causes maximum damage. The subsequent administration of B-OT inhibits repair of radiation damage, thereby promoting tumor cell death.

[0078] When chemotherapy with classical cytostatics (i.e. cell-type non-specific cytostatics) is combined with the use of an inhibitory coenzyme analogue according to the invention, for example in the form of B-OT, which is advantageously a thiamine antagonist, B-OT is administered before the start of chemotherapy so that some of the thiamine-dependent enzymes are already inhibited at the start of chemotherapy.

[0079] When combining targeted cancer therapy (e.g., with agents such as sorafenib or imatinib) with the use of an inhibitory coenzyme analogue according to the invention, e.g., in the form of B-OT, which is advantageously a thiamine antagonist, it is preferred that the administration of B-OT begins already about 2 days before the start of the targeted cancer therapy, in order to optimally promote the effect of the targeted therapy.

[0080] When surgical tumor resection is combined with the use of an inhibitory coenzyme analogue according to the present invention, for example, advantageously in the form of B-OT, a thiamine antagonist, administration of B-OT is carried out as a kind of preparatory treatment before the surgical intervention. Administration of B-OT, preferably beginning about 3 days before the surgical intervention, reduces the number of disseminated tumor cells (i.e., tumor cells released into the blood or other body fluids) at the time of the intervention and suppresses their invasiveness and metastatic potential. This reduces the probability of local recurrence and the formation of distant metastases.

[0081] The administration of the inhibitory agents according to the invention in the course of combination therapy is preferably carried out orally according to the invention and preferably according to an administration scheme comprising the following data: (a) When used in combination with radiation therapy: On the day of radiotherapy, before radiotherapy, about 1 to 150 mg, preferably about 10 to 75 mg, particularly preferably about 30 to 50 mg, once; One dose of about 1 to 70 mg, preferably about 3 to 40 mg, particularly preferably about 4 to 20 mg, on the day after radiotherapy; Two days after radiotherapy, about 1 to 40 mg, preferably about 3 to 25 mg, particularly preferably about 4 to 18 mg, is administered once. and (b) Especially when used in combination with cytotoxic chemotherapy: One dose of about 1 to 150 mg, preferably about 10 to 75 mg, particularly preferably about 30 to 50 mg, on the day before chemotherapy; On the day of chemotherapy, about 1 to 150 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, once; The day after chemotherapy, about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, is administered once. and (c) When used in combination with one or more targeted cancer treatments, particularly with imatinib and / or sorafenib and / or erbituximab and / or avastin and / or gemcitabine: One dose of about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, on the day before chemotherapy; On the day of chemotherapy, about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, once; The day after chemotherapy, about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, is administered once. and (d) When used as monotherapy or in combination with one or more other therapies for a duration of more than 1 week, especially more than 2 weeks, more than 3 weeks, or more than 4 weeks: The daily dose is about 1 to 30 mg, preferably about 2 to 15 mg, and very preferably about 3 to 10 mg, in each case administered as a single dose or in the form of several partial doses. For example, a dose of 30 mg or 15 mg per day may be administered as a single dose of 30 mg or 15 mg, or in appropriately smaller doses such as 2 x 15 mg or 1 x 5 mg and 1 x 10 mg per day.

[0082] A dosing scheme that has been well documented in practice is as follows: (a) Recommended dose when used in combination with radiation therapy: Approximately 34 mg once before radiation therapy on the day of radiation therapy; 12 mg once the day after radiation therapy; 5 mg 2 days after radiation therapy and (b) Recommended dose when used in combination with classical cytostatic chemotherapy: 25 mg once the day before chemotherapy; 13 mg once on the day of chemotherapy; 6 mg the day after chemotherapy and (c) Recommended dose when used in combination with targeted cancer therapy (e.g., with sorafenib or imatinib): 10 mg once 2 days before treatment; 8 mg once the day before treatment; 6 mg once on the day of treatment; 4 mg the day after treatment is.

[0083] In addition to the dosages mentioned above, all dosages given below also apply to a person weighing 60 kg and should be adjusted in each individual case according to the patient's actual weight.

[0084] These dosages apply in particular in the case of B-OT, where the agent applied is a thiamine antagonist.

[0085] The mechanisms of action of established tumor treatments can be broadly divided into direct therapy, which aims to damage tumor cells, and indirect therapy, which activates the immune system and ultimately damages / destroys tumor cells. In addition to these two established therapeutic strategies, GSSV offers a new, non-curative treatment that can significantly extend the survival of cancer patients by suppressing tumor invasive growth behavior and tumor spread, including the formation of new metastases. Because tumor spread and metastasis are the most common, and often fatal, reasons for patient death, the availability of agents capable of suppressing invasiveness and metastasis, particularly with the coenzyme antagonist B-OT of the present invention, represents a breakthrough both clinically and for the survival of cancer patients.

[0086] The use of the active substances according to the invention (i.e. the coenzyme antagonists according to the invention, particularly in the form of B-OT) for the purpose of inhibiting invasiveness and metastasis in patients is preferably carried out as a monotherapy and not in combination with chemotherapy and / or radiotherapy.

[0087] In the case of advanced tumor diseases, the use according to the invention of an inhibitory coenzyme analogue, for example in the form of B-OT, which is advantageously a thiamine antagonist, is preferably carried out as monotherapy.

[0088] The administration of the active substances according to the invention in the course of monotherapy is preferably carried out according to the invention orally and according to an administration scheme which includes, for example, the following data: (a) Recommended Dosage—Variant A: 5 mg daily for 1 week, then off for 1 week, then again 5 mg daily for 1 week, then off for 1 week. (b) Recommended Dosage—Variant B 2.5mg per day for one month.

[0089] Thus, the present invention provides several additional options for cancer treatment. On the one hand, treatment can be performed at lower doses without compromising therapeutic success. This new option is particularly advantageous for treatments with severe side effects that often have to be discontinued due to excessive side effects. On the other hand, it can suppress malignant tumor characteristics such as invasion and metastasis, thereby stabilizing the patient's condition (stable disease) rather than curing the patient. Furthermore, by suppressing lactic acid production by tumor cells, it is possible to counteract the acid-induced blockage / defense of killer cell attack by tumor cells and enhance the effectiveness of the immune system, particularly killer cells, in killing tumor cells. The coenzyme antagonists of the present invention, such as B-OT in particular, reduce lactic acid production by tumor cells, thereby minimizing acid-induced blockage of killer cells, thereby allowing tumor cells to be more effectively attacked and killed by killer cells.

[0090] The beneficial efficiency increase of established tumor treatments is particularly due to (a) less agent being needed to achieve the same effect (lower doses of therapeutic agent and / or radiation therapy are needed to kill the cells because the death threshold is lowered), and (b) more cells are killed (because tumors generally consist of a heterogeneous mixture of different tumor cells, and the lowering of the death threshold by the use of the coenzyme antagonists according to the invention results in the death of cancer cells that would not have been killed by conventional treatments).

[0091] The effect of cancer treatment on tumor cells is always dose-dependent. A tumor consists of millions of cells, and no treatment can guarantee that the dose of agent / radiation is the same in all cells. Agents often cause damage to a certain percentage of cells, but this damage does not lead to cell death. Each cell has repair mechanisms to repair the damage that occurs. Repair is carried out by enzymatic reactions, which require substrates and energy. If these are absent within the cell or are present only to a limited extent due to a corresponding inhibition or suppression of the cell's metabolism, the repair capacity is limited. In this case, even cells that are less damaged by chemotherapy and / or radiotherapy and / or targeted cancer treatments will suffer cell death.

[0092] The use according to the present invention does not distinguish between healthy cells and degenerated cells. As a pre-treatment or combination therapy, or as a monotherapy, the strength and duration of the induced GSSV can be varied and purposefully controlled through its administration regimen (particularly the timing of the initiation of GSSV relative to the initiation of an additionally applied established cancer treatment, the time interval and amount of the administered coenzyme antagonist). In other words, the supply of essential substrates required for subsequent specific enzymatic reactions is blocked in tumor cells (and also in all other somatic cells) for a predetermined, limited period of time. This period (in combination therapy or monotherapy) is selected or set so that the degree of damage induced in cells accordingly is such that, after the end of the blockade (by discontinuing the drug according to the present invention), particularly healthy somatic cells can resume their metabolism and start all enzymatic processes anew, without (being) subjected to any permanent damage.

[0093] Cancer patients often experience an almost explosive proliferation of cancer cells, especially when tumors no longer grow locally but invasively and metastasize. Patients with rapidly progressing cancers, such as metastatic forms of cancer, often have only a few months or even weeks to live. Currently, these patients are limited to treatments such as chemotherapy, which have significant side effects and a significant reduction in quality of life, resulting in only a small extension of life. In this case, the cancer patient effectively gains, for example, a month of life extension, but in exchange for this month, they suffer from pain, nausea, and general deterioration, resulting in debilitation that prevents them from living a good life. By using the GSSV induced by the present invention, it is now possible to slow the metabolism of cancer patients and the cancer growing within their bodies, thereby extending the patient's life without causing pain or debilitation that significantly reduces the patient's quality of life. By using GSSV to slow a patient's metabolism by 50% in both healthy and cancerous cells, it is possible to extend a patient's lifespan by 100% without side effects such as pain and nausea.

[0094] The GSSV therapy according to the invention can also be used with good prospects of success in the case of glioblastoma and other cancer tumors (malignant tumors) in the brain, especially as a combined therapy with established chemotherapy and / or radiotherapy and / or targeted cancer treatments.

[0095] The subject of the present invention is also an inhibitory structural and / or functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogue, for use in the treatment of patients as a preparatory treatment before surgical intervention and / or drug therapy, wherein the administration of this inhibitory agent according to the invention is preferably carried out orally and, for example, according to an administration scheme comprising the following data: The recommended dose is 4 mg once daily (morning, midday, or evening) for 2 days before surgery; 5mg before surgery on the day of surgery.

[0096] The prophylactic use of the GSSV produced by the present invention before surgical intervention has the advantage of slowing down harmful side effects and possible complications that may occur as a result of the intervention. Such complications may be excessive reactions by the body, such as an excessive immune response or the induction of programmed cell death. Precisely because of the slowed metabolism, the GSSV produced by the present invention can also be used before drug therapy to reduce or avoid side effects.

[0097] The subject of the present invention is also an inhibitory structural and / or inhibitory functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogue, for use in treating patients with craniocerebral injuries, wherein the administration of this inhibitory agent according to the invention is preferably carried out orally and, for example, according to an administration scheme comprising the following data: The recommended dose on the day of craniocerebral injury is approximately 45 mg; Recommended next day dose: approximately 5 mg; The recommended dose the day after next is approximately 3 mg.

[0098] In particular, in cases of severe head injury, stress / injury to the brain can cause the brain to expand, increasing intracranial pressure and leading to secondary injuries. Until now, such cases have involved surgically opening the skull to create more space for the brain. The use of GSSV therapy according to the present invention can targetably suppress the physiological response of brain tissue to the effects of the accident, preventing brain expansion and excessive intracranial pressure. Preventing excessive intracranial pressure prevents the resulting secondary injuries.

[0099] Recommended dose on the day of severe head injury: 52 mg; Recommended next day dose 7mg; Recommended dose for the next 5 days is 3mg.

[0100] The subject of the present invention is also an inhibitory structural and / or functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogue, for use in the treatment of patients who have suffered a nerve cut, in particular a spinal cord injury, and who are at risk of developing paraplegia or quadriplegia or who have newly developed paraplegia, wherein the administration of the inhibitory active substance according to the invention is preferably carried out orally and, for example, according to an administration scheme comprising the following data: The recommended dose on the day of spinal cord injury is 38 mg; The recommended dose the next day is 7 mg; Recommended dose for the next 5 days is 3mg.

[0101] Injuries in which part or all of the spinal cord is severed or crushed also usually cause blood vessel damage and blood outflow. Contact of this blood with damaged nerves can further damage the nerves, and this damage is particularly induced or enhanced by the blood pigment, hemoglobin. Hemoglobin contains iron, which can participate in oxidation processes and trigger radicals and other cell damage. The purpose of the GSSV produced by the present invention is to counteract the damaging effects of blood released by vascular injury or reduce the damaging effects by inhibiting the effects of radical formation and / or altered redox homeostasis on inducing cell death, so that the GSSV prevents or minimizes the execution of cell death.

[0102] The subject of the present invention is also an inhibitory structural and / or inhibitory functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogue, for use in treating patients with myocardial or cerebral infarction, wherein the administration of this inhibitory agent according to the invention is preferably carried out orally and, for example, according to an administration scheme comprising the following data: The recommended dosage is as follows: 35 mg on the day of the onset of infarction; 5 mg the next day, 3mg the day after.

[0103] Programmed cell death (apoptosis) is a process for eliminating unnecessary cells, which are stored in DNA and thus in the human body. This allows, for example, the planned elimination of unnecessary immune cells. Another example is apoptosis, which leads to the elimination of tumor cells. Thus, apoptosis is a program that helps and protects the human body. However, apoptosis can also have adverse effects, for example, when caused by oxygen deficiency or infarction. For example, oxygen deficiency (ischemia) triggers apoptosis, resulting in the loss of important cells. Furthermore, myocardial infarction caused by vascular thrombosis can lead to oxygen deficiency and the resulting apoptosis of cardiac cells. Even if intensive care quickly restores oxygen supply to the myocardium, once apoptosis is induced, it can cause further secondary damage. The use of the present invention and the resulting GSSV makes it possible to suppress apoptosis to counteract cell death. GSSV inhibits metabolism, thereby inducing apoptosis and inhibiting the processes that carry out apoptosis, and also reduces oxygen consumption by somatic cells, thereby minimizing or preventing damage caused by oxygen deficiency. Thus, GSSV acts at three levels: metabolic inhibition reduces oxygen consumption and thus oxygen demand, thereby suppressing the induction of apoptosis by ischemia. Metabolic inhibition slows down all metabolic processes, thereby reducing the extent (induction and execution) and consequences of apoptosis. Furthermore, slowing the damaging processes allows time for the application of drugs and therapies to counter the damage.

[0104] Therefore, the use according to the present invention and the GSSV induced thereby also represent a treatment option in emergency medicine, i.e., a measure that can be implemented immediately at the scene of an accident. In severely injured patients, GSSV can be induced already at the scene of the accident, for example, by oral administration of B-OT, thereby slowing down or completely stopping all damaging processes in the body. Since damaging processes, such as the induction of apoptosis, that may occur between the accident and the start of treatment in the hospital are significantly reduced as a result of the induced GSSV, specific treatment can be started relatively quickly after arrival at the hospital.

[0105] The subject of the present invention is also an inhibitory structural and / or functional analogue according to the invention, preferably an inhibitory thiamine analogue (thiamine antagonist), in particular oxythiamine, particularly preferably benphooxythiamine and / or benphooxythiamine analogues, for use in treating painful but non-bleeding injuries (trauma), in particular overstretching, sprains or bruises, in patients, wherein the administration of the inhibitory active substance according to the invention is preferably carried out orally and, for example, according to an administration scheme comprising the following data: The recommended dosage is as follows: 15 mg on the day of the onset of hyperextension, sprain, or bruise; 5mg the next day; 3mg the day after.

[0106] Less dramatic injuries to patients, such as painful but non-bleeding trauma, particularly hyperextension, sprains, or contusions, can also be better treated by the use of the present invention and the resulting GSSV. In the past, attempts have been made to slow the body's response to injury through cooling. Cold compresses or ice are often used to cool the injured body part. The principle of this treatment is based on the temperature-dependent progression of enzymatic reactions. This dependence between the rate of enzymatic reactions and temperature is mathematically explained by the so-called reaction rate-temperature law (also known as van't Hoff's law). A 10°C increase in temperature doubles or triples the enzyme rate. Conversely, a 10°C decrease in temperature halves or thirds the enzyme rate. Therefore, cooling the injury site significantly inhibits the progression of enzymatic reactions occurring in the body as a result of the injury. However, excessive cooling can lead to tissue damage, so tissue temperature can only be lowered to a certain extent. On the other hand, the GSSV of the present invention can reduce metabolism more severely than cooling can without causing irreversible damage to cells and tissues. Furthermore, cooling of tissue with an externally applied coolant, such as ice, is most intense near the coolant and significantly less pronounced further inside the tissue, and therefore only progresses slowly. In particular, in the case of deep injuries, such as joint injuries, cooling can only cool deep tissue regions to a very limited extent.

[0107] In general, metabolic inhibition caused by cooling is only applicable to a very limited range, since the available temperature range is limited to freezing. A drop from 37°C to 1°C (i.e., to 36°C) would result in a slowing of approximately 50 times at most, assuming a 10°C drop of 3 times. In the case of GSSV, this factor is unlimited, since drug-induced metabolic inhibition can be achieved independently of temperature, up to complete inhibition.

[0108] The selection of a suitable administration scheme for the administration of the inhibitory agents, i.e., coenzyme antagonists, of the present invention for any desired use, in particular for use in pre- or combination therapy in the treatment of cancer, and / or for use in continuous therapy lasting for several weeks or months, can be determined according to the following procedure, i.e., by a method comprising the steps of: (1) Day 1: (1a) A coenzyme antagonist / agent (e.g., advantageously, benphosphatidylcholine phosphate oxalate) is selected, and the enzymatic activity of a representative enzyme E of the group of enzymes, i.e., the group of coenzyme-dependent enzymes (e.g., advantageously, the enzymatic activity of transketolase in erythrocytes of the group of thiamine-dependent enzymes) is measured in a first prepared body fluid sample I (e.g., advantageously, blood sample I) obtained in advance from the patient. (1b) thereafter (i.e., on the same day) administering to the patient a coenzyme antagonist / agent (e.g., advantageously, B-OT) in an amount or dose T1 suitable for causing inhibition of the coenzyme-dependent (e.g., advantageously, thiamine-dependent) enzyme's intrinsic enzymatic activity, aiming at a predetermined (defined) target value of sustained enzymatic activity inhibition (inhibited enzymatic activity) (for weeks or months, if necessary); (2) Day 2: (2a) measuring the enzymatic activity of enzyme E in a prepared body fluid sample II (e.g., advantageously, blood sample II) of the patient obtained on this day; (2b) comparing the enzyme activity measured in body fluid sample I and body fluid sample II (e.g., advantageously, blood sample I and blood sample II) and calculating the extent (range, degree) of reduction (inhibition) of enzyme activity that has occurred; (2c) Subsequently (i.e., on the same day), a coenzyme antagonist / agent (e.g., advantageously, B-OT) is administered to the patient in an amount T2 (dose T2) determined (calculated) based on the amount T1 (dose T1) and the target level of enzyme activity inhibition and the decrease in enzyme activity calculated in step (2b) (as a result of administering dose T1). Amount T2 (dose T2) can be greater or less than amount T1 (dose T1), i.e., an adjustment from dose T1 to dose T2 is made, which is a decrease or increase in the amount of coenzyme antagonist / agent (e.g., B-OT) administered on day 1.

[0109] (3) From day 3 onwards, until the target enzyme activity inhibition is reached (i.e., until the desired enzyme activity inhibition target is reached): Steps (2a) and (2b) are repeated, and step (2c) is repeated, except that the patient is administered a coenzyme antagonist / agent (e.g., advantageously, B-OT) at an amount / dose T(i) determined (calculated) based on the previous day's amount / dose T(i-1) and the target enzyme activity inhibition target, and based on the decrease in enzyme activity calculated in step (2b). The amount / dose T(i) can be more or less than the previous dose / dose T(i-1), i.e., an adjustment is made from dose T(i-1) to dose T(i), which is a decrease or increase in the amount of B-OT previously administered.

[0110] Optionally but preferably, in step (4), monitoring is carried out of medical parameters of the disease, such as the inhibition of new metastasis formation or bacterial or fungal growth in the body, as well as medical parameters of the basic functions of the patient's body, such as, advantageously, the heart rate (pulse) and / or the occurrence of appetite loss and / or the patient's weight loss. The target value of the enzyme activity inhibition is adjusted so that, on the one hand, the medical parameters of the disease reach the desired value, and, on the other hand, sufficient residual enzyme activity is still present so that the basic functions of the patient's body are maintained in the long term.

[0111] In individual cases, it may be found necessary to modify the initially targeted inhibition target. Based on the medical parameters of each disease to be treated, such as the inhibition of de novo metastasis formation or the proliferation of bacteria or fungi in the body, it is desirable to set the target inhibition of enzyme activity so that, on the one hand, the desired values ​​of these medical parameters are achieved, and, on the other hand, sufficient residual enzyme activity remains to enable the patient's basic bodily functions in the long term. For example, the number of heartbeats per minute (pulse) can be used to measure the basic bodily functions. If the pulse rate becomes too high, the dosage or dose of the coenzyme antagonist / agonist (e.g., B-OT dose) should be reduced. Loss of appetite and weight loss in the patient can also be evaluated and used as an indication that the dosage or dose of the coenzyme antagonist / agonist (e.g., B-OT dose) should be reduced.

[0112] The target value of the enzyme inhibition is, for example, advantageously at least 20%, particularly preferably at least 50%, very particularly preferably at least 70%, based on the original enzyme activity value measured in step (1a) (as the initial value), respectively.

[0113] When benphoxythiamine is used as the coenzyme antagonist / agent, administration is preferably carried out orally and the amount / dose T1 of B-OT is advantageously between about 1 mg and about 30 mg, preferably between about 2 mg and about 15 mg.

[0114] By preferably daily monitoring and adjusting the dosage / dosage of B-OT as needed, a target level of inhibition of enzyme activity, e.g., 50% or 70%, can be achieved and maintained in the patient in a relatively short period of time.

[0115] In general, the individual doses (levels) for a patient are advantageously usually values ​​in the range of about 0.1 mg to about 80 mg, particularly preferably values ​​in the range of about 1 mg to about 50 mg, based on a body weight of 60 kg.

[0116] The present invention will be described in more detail below with reference to the accompanying drawings based on examples. [Brief explanation of the drawings]

[0117] [Figure 1] Figure 1 shows the time course (24 hours) of individual plasma concentrations of OT in male beagle dogs. On the y-axis, plasma concentrations are shown in ng / ml. On the x-axis, time is shown in hours (h = hours). (a) The time course (24 hours) of individual plasma concentrations on day 1 after a single dose of B-OT at 1 mg / kg / day. The symbols have the following meanings: [ka] (b) Changes in individual plasma concentrations on day 1 after a single dose of B-OT at 0.5 mg / kg / day. The symbols have the following meanings: [ka] (c) Changes in individual plasma concentrations on day 7 after a single dose of B-OT at 0.5 mg / kg / day for 7 days. The symbols have the following meanings: [ka] (d) Changes in mean plasma concentrations on day 1 after a single dose of B-OT at 1 mg / kg / day, and on days 1 and 7 after single daily doses of B-OT at 0.5 mg / kg / day. The symbols have the following meanings: [ka] [Figure 2] Figure 1 shows a graph of the change in pulse rate over time in dogs administered different amounts (doses) of B-OT. On the y-axis, pulse rate (heart rate) is shown in beats per minute (bpm = beats per minute). On the x-axis, time is shown in hours (h = hours). The symbols have the following meaning: [ka] [Figure 3]Computed tomography images of the lungs of patient 1 before and after B-OT treatment. A: Before B-OT treatment, areas of viral pneumonia infiltration are clearly visible. B: After 7 days of B-OT therapy, the infiltration is clearly reduced. [Figure 4] Computed tomography images of the lungs of patient 2 before and after B-OT treatment. A: Before B-OT treatment, areas of viral pneumonia infiltration are clearly visible. B: After 7 days of B-OT therapy, the infiltration is clearly reduced. [Figure 5] Computed tomography images of the lungs of patient 3 before and after B-OT treatment. A: Before B-OT treatment, areas of viral pneumonia infiltration are clearly visible. B: After 7 days of B-OT therapy, the infiltration is clearly reduced. [Figure 6] Computed tomography images of the lungs of patient 4 before and after B-OT treatment. A and C: Before B-OT treatment, areas of viral pneumonia infiltration are clearly visible. B and D: After 7 days of B-OT therapy, the infiltration is clearly reduced. [Figure 7] Figure showing computed tomography of the lungs of patient 2 (see Figure 4) one month after the end of treatment.

[0118] Example 1. Determining the appropriate dose for the administration scheme and monitoring the treatment Herein, determination of dosage appropriate for the administration scheme and monitoring of treatment will be explained using benphoxethiamine (B-OT) as an example.

[0119] The effects of B-OT in a patient's body depend on a variety of patient-specific factors, such as genetic mutations, the binding affinity of thiamin or B-OT to the respective thiamin-dependent enzymes, the active uptake and transport of thiamin by the body's transport systems, and the enzymatic degradation of thiamin. The desired or optimal dose of B-OT for a particular patient or group of patients, appropriate for the patient's individual situation, can be determined based on a variety of diagnostic procedures and parameters.

[0120] One possible method is to measure and monitor the patient's pulse rate and pulse rate variability.

[0121] GSSV slows (inhibits) metabolism, thereby reducing energy release. The body compensates for this by increasing pulse rate, allowing for more oxygen to be delivered to the body and therefore more energy to be released. An increase in the patient's pulse rate is a relevant parameter indicating whether and to what extent GSSV has inhibited energy release. A rapid increase in pulse rate, e.g., a pulse rate above 90 beats per minute in humans, may indicate the need for measures to increase energy release again. This can be achieved by further reducing the amount of B-OT administered or by reducing the administration of thiamin (particularly the thiamin form, benfotiamine). Figure 2 shows a significant increase in pulse rate (heart rate) over 24 hours in dogs after administration of various doses of B-OT.

[0122] Another possible method is to measure transketolase enzyme activity in a patient's erythrocyte lysate and use the measured transketolase enzyme activity value as a diagnostic marker for monitoring B-OT therapy. Here, the basal transketolase enzyme activity in erythrocytes can be preferably selected as a parameter.

[0123] The process of the test procedure for measuring transketolase enzyme activity in erythrocyte lysates is known in the prior art, for example from Smeets et al. (1971) and Takeuchi et al. (1984) and Michalak et al. (2013).

[0124] In the examples, transketolase enzyme activity is measured in a patient's erythrocyte lysate, preferably before the start of B-OT administration. After B-OT administration, transketolase enzyme activity is measured again in a freshly obtained erythrocyte lysate from the patient on the following day. It is also desirable to measure transketolase enzyme activity in a freshly obtained erythrocyte lysate from the patient on each subsequent day after further B-OT administration. The degree of inhibition of transketolase enzyme activity in erythrocytes is determined by comparing the measured transketolase enzyme activity during B-OT therapy with the measured value before the start of B-OT administration. This allows the dosage of B-OT to be selected so that transketolase enzyme activity and other thiamine-dependent enzymes are suppressed to the desired degree.

[0125] For example, for long-term administration of B-OT to permanently suppress inflammation, 50% inhibition can be selected.

[0126] For example, when B-OT is administered daily for about one month to achieve inhibition of metastasis in patients with very advanced cancer, an 80% inhibition can be selected.

[0127] Measurement of one or more of the following biochemical markers in the patient's blood can also be used to monitor B-OT therapy: Increased bilirubin levels, increased ALAT (alanine aminotransferase) and ASAT (aspartate aminotransferase) enzymes, decreased CK (creatine kinase) enzymes, decreased protein levels (but not albumin levels), decreased white and red blood cells, increased platelets, and decreased reticulocytes.

[0128] Example 2: Use according to the invention of the agent benphoxethiamine "B-OT" for GSSV in cancer cells circulating in the blood Cancer cells circulating in the patient's blood are detected, separated, and isolated from the blood, preferably without the use of surface markers, i.e., by cell sorting and multi-staining single cell analysis (MSSCA), so that the isolated cancer cells are representative of the patient's malignant tumor (carcinoma).

[0129] These isolated cancer cells are treated with the cancer therapeutic agent in test series "A," and in parallel with test series "B," they are first incubated with the agent benphoxthiamine ("B-OT"), a preferred example of an inhibitory thiamine analog or inhibitory coenzyme antagonist, followed by treatment with the cancer therapeutic agent in test series A (see also Example 3). The results of test series A and B are compared, and if the results of test series B indicate a satisfactory effect after pretreatment with B-OT, particularly if the preferred cancer therapeutic agent (or agent thereof) in test series A is deemed ineffective or insufficient by guidelines or for other reasons, then pretreatment with B-OT is indicated as a combination therapy with the original, established cancer therapy in the patient's future cancer treatment.

[0130] Regarding the duration and intensity of pretreatment or combined treatment with B-OT, experimental studies have shown that a 2-day treatment period immediately prior to application in combination with concurrent established cancer therapy is promising and therefore reasonable.

[0131] Example 3: Determining the Effect of GSSV According to the Invention (GSSV Therapy) as Pre- or Adjunctive Therapy in Cancer Patients and the Appropriate Combination with Subsequent or Concomitant Drug Therapy (e.g., Chemotherapy and / or Targeted Cancer Therapy) and / or Radiation Therapy The appropriate combination of (i) the use of a coenzyme antagonist according to the present invention and the resulting GSSV (GSSV therapy), preferably with at least one inhibitory thiamine analogue (in particular oxythiamine, benphooxythiamine ("B-OT") and / or benphooxythiamine analogues) as a preparatory or combined therapy (starting the administration of B-OT before, simultaneously with or after the start of the established cancer treatment of the cancer patient) and (ii) the application of a therapeutic agent (agent, drug) with a non-directed action (e.g., cisplatin) or a targeted action (e.g., sorafenib, imatinib, erbitux, avastin, herceptin) and / or radiation therapy (in accordance with current evidence-based treatment rules) can be confirmed in various ways:

[0132] a) A cancer patient is first treated with established chemotherapy (using classical cytostatics, i.e., cell-type non-specific cytostatics) and / or targeted cancer therapy (using cell-type specific agents, e.g., sorafenib) and / or radiation therapy (according to current evidence-based treatment rules). If the patient's tumor cells (a subgroup or all of them) are already resistant to the treatment or develop resistance under treatment, the patient is further treated with a combination therapy comprising the administration of a coenzyme antagonist according to the present invention as an agent (drug) and the application of established chemotherapy and / or targeted cancer therapy and / or radiation therapy.

[0133] b) Cancer cells are collected from a cancer patient who has not yet received established chemotherapy and / or targeted cancer therapy and / or radiation therapy, and treated with the cancer therapeutic agent in vitro, preferably ex vivo (i.e., on a freshly isolated malignant tumor tissue sample from a living body), to determine which agent or combination of agents is most effective. In this way, it is possible to determine which chemotherapy agent, targeted cancer therapy agent, radiation therapy agent, or some combination of these therapeutic agents is effective in the individual cancer patient's situation. Here, it is also determined whether resistance to the therapeutic agent exists in the malignant tumor cells.

[0134] In parallel with this in vitro test series "A" of the cancer therapeutic agent itself, a test series "B" and / or a test series "C" are carried out. In test series B, the patient's malignant tumor cells are first pretreated with a coenzyme antagonist according to the present invention as an active ingredient (drug), such as an inhibitory thiamine analogue, and then treated with the proposed cancer therapeutic agent.

[0135] In test series C, the patient's malignant cells are treated simultaneously with both a coenzyme antagonist according to the invention as an agent (drug), such as, advantageously, an inhibitory thiamine analogue, and a proposed cancer therapeutic agent.

[0136] By comparing the results of Test Series A, Test Series B and Test Series C, it can be determined whether the cancer treatment of interest is more effective when administered in combination with an agent of the present invention in the course of pretreatment (as in Test Series A) or in the course of combination therapy (as in Test Series B, i.e., by administering an agent of the present invention and a conventional cancer therapeutic agent in parallel and at approximately the same time) than when administered alone (i.e., without this pretreatment).

[0137] This procedure (b) has the particular advantage of significantly shortening the time period during which potential resistance in the patient's cancer cells to the proposed chemotherapeutic and / or radiotherapeutic agents develops or existing resistance is detected. On the one hand, the interval between resistance development and its detection can be significantly shortened, since resistance in cancer cells to the proposed therapeutic agents can be determined directly ex vivo, rather than indirectly and in vivo based on surrogate markers, such as cancer tumor markers, or on visualization of the size (grade) of the cancer tumor, as has been the case until now. On the other hand, existing resistance can be detected prior to treatment. It is therefore possible to determine whether specific chemotherapeutic agents (i.e., cell-type non-specific cytostatics, such as classical cytostatics, and / or cell-type specific agents, such as sorafenib) and / or radiotherapeutic agents can be used meaningfully and promisingly. This allows for targeted therapy tailored to the individual situation of each cancer patient, maximizing the success rate of treatment. This opens up far-reaching prospects, especially for personalized medicine.

[0138] Example 4: Study on the in vivo conversion of benphosphatidylcholine (B-OT) to oxythiamine (OT) in dogs Male and female beagle dogs were orally administered B-OT (benphoxythiamine) once daily at a dose of 1 mg / kg / day or 0.5 mg / kg / day for 1 to 7 days.

[0139] The toxicokinetics of the active metabolite OT (oxythiamin) was measured in plasma samples obtained on the first day (day 1) and the seventh day (day 7) after the start of administration. The measurement results obtained at that time are shown in graphs in Figure 1(a) to (d).

[0140] Figure 1 a shows the time course of individual plasma concentrations of oxythiamine (OT) in male beagle dogs on day 1, i.e., after a single dose of B-OT at 1 mg / kg / day.

[0141] Figures 1b and 1c show the time course of individual plasma concentrations of oxythiamine (OT) in male beagle dogs on day 1, i.e., the first day (Fig. 1b) and day 7, i.e., the seventh day (Fig. 1c), after a single daily dose of B-OT at a dose of 0.5 mg / kg / day.

[0142] Figure 1d shows the time course of mean plasma concentrations of oxythiamine (OT) in male beagle dogs (Figures 1a-c) on days 1 and 7 after a single daily dose of B-OT at a concentration of 0.5 mg / kg / day, and on day 1 after a single dose of B-OT at 1.0 mg / kg / day.

[0143] No oxythiamin was detected in plasma samples obtained on day 1 before B-OT administration. Systemic exposure to OT was achieved in all animals treated with the agonist B-OT. The time point of maximum OT plasma concentration (Tmax) after B-OT administration was investigated for all applied doses of B-OT, and the highest value was obtained between 1 and 2 hours. When the applied B-OT dose was gradually increased from 0.2 mg / kg to 1.0 mg / kg, the plasma concentration of oxythiamin (OT) increased approximately linearly with increasing dose.

[0144] After oral administration of a single dose of B-OT, dose-normalized Cmax and partial AUC (area under the curve) values ​​confirmed that plasma OT increased less than dose-proportionally in male beagle dogs over the applied dose range of B-OT.

[0145] Treatment of dogs with B-OT was well tolerated. No significant behavioral abnormalities or significant changes in body condition, especially weight, were observed throughout the study. Animals were exposed to the active metabolite OT, but not to the prodrug form of B-OT.

[0146] Example 5: Administration of B-OT to patients with SARS-CoV-2 infection In the cure trial, four patients diagnosed with COVID-19 pneumonia requiring hospitalization were selected from a total population of over 700 COVID-19 patients requiring hospitalization. These patients were predicted to develop severe COVID-19 based on their laboratory data and previous history, so they were treated at the same treatment center with the currently effective standard of care: dexamethasone, anticoagulation, and oxygen therapy. These four patients received B-OT in addition to standard therapy: 6 mg of B-OT orally administered daily for 7 days.

[0147] None of the four patients required intensive care as a result of this additional B-OT treatment, and no side effects attributed to the administration of B-OT were observed in any of the patients.

[0148] At the start of B-OT treatment, all patients had pneumonia caused by SARS-CoV-2. Severe lung damage was documented by computed tomography (CT). CT images of these lungs show significant infiltration due to viral pneumonia (see Figures 3A–6A).

[0149] At the end of the 7-day B-OT treatment, lung reimaging by computed tomography documented rapid progression of healing and revealed a marked reduction in the previously prominent infiltrates (Figures 3B-6B).

[0150] For one patient (patient 2), a computed tomography image of the lungs was obtained during follow-up 1 month after the end of treatment, showing stable findings (Fig. 7).

[0151] In contrast to the total population of over 700 patients, none of the four patients who received additional treatment with B-OT required intensive care or respiratory support other than oxygen inhalation by nasal cannula or mask, such as non-invasive or invasive ventilation, during the course of their disease, despite the severity of their initial respiratory distress.

[0152] Furthermore, a significant decrease in the inflammatory parameters C-reactive protein (CRP) and interleukin-6 (IL-6) was observed in all patients who received additional treatment with B-OT (see Table 1). The clinical values ​​of these immunoinflammatory markers are important parameters for assessing the severity of the disease. High values ​​of the inflammatory cytokines IL-6 and / or C-reactive protein (CRP) indicate severe disease and a high-risk disease course.

[0153] The pleiotropic pro-inflammatory cytokine IL-6 also appears to play a key role in the "cytokine storm" observed in patients infected with SARS-CoV-2, where its constitutive expression leads to organ damage and severe pain.

[0154] In all patients who received additional treatment with B-OT, the length of hospital stay required was significantly shorter compared to the total population of over 700 patients, on average by one week.

[0155] Non-patent literature cited: [ka]

Claims

1. An inhibitory structural or functional analogue of a coenzyme of an enzyme group, the constituent enzymes of which catalyse anabolic and / or catabolic and / or energy-releasing metabolic reactions of great importance for the overall metabolic functional capacity of cells, in particular mammalian cells, for treating a patient with the aim of slowing down the anabolic and / or catabolic and / or energy-releasing metabolic processes of cells in the patient's body in a general, continuous (particularly also stepless) manner.

2. The inhibitory structural analogue or inhibitory functional analogue according to claim 1, wherein the inhibitory structural analogue or inhibitory functional analogue is an inhibitory thiamine analogue, in particular oxythiamine, benphooxythiamine and / or an inhibitory thiamine derivative and / or an inhibitory oxythiamine derivative and / or an inhibitory benphooxythiamine derivative.

3. The inhibitory thiamine analogue of claim 2, wherein the inhibitory thiamine analogue is benphoxythiamine and / or an inhibitory benphoxythiamine analogue and / or an inhibitory benphoxythiamine derivative.

4. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in the treatment of patients with bacterial diseases (infectious diseases), preferably as a monotherapy or in combination with at least one further agent, in particular an agent with antibacterial activity, in particular for inhibiting the effect of bacterial endotoxins on the patient's organism, in particular the effect of endotoxins released as a result of the bactericidal action of the further agent.

5. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in the treatment of patients with a disease caused / derived from a fungus, preferably as a monotherapy or in combination therapy with at least one further drug.

6. 10. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in treating a patient with sepsis or impending sepsis.

7. 10. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in treating a patient with a viral disease (infectious disease).

8. 4. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in treating patients with immune diseases, in particular inflammatory and / or autoimmune diseases, including episodic forms of the disease, in particular rheumatoid arthritis and / or multiple sclerosis and / or inflammatory bowel disease, e.g. ulcerative colitis, Crohn's disease and / or inflammatory / degenerative diseases, in particular inflammatory / degenerative diseases of the skeletal system, e.g. ankylosing spondylitis, e.g. systemic lupus erythematosus (SLE).

9. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in the treatment of tumor cells in a patient, in particular in the treatment of cancer, as a monotherapy or as a pre- or combination therapy with chemotherapy and / or radiotherapy and / or targeted cancer therapy.

10. 4. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in the treatment of a patient as a preparatory treatment prior to surgical intervention and / or drug therapy.

11. 10. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in the treatment of patients with craniocerebral injury.

12. 4. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in the treatment of patients who have suffered a nerve transection, in particular a spinal cord injury, and who are at risk of paraplegia or quadriplegia, or who have newly developed paraplegia.

13. 10. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in treating patients with myocardial infarction or cerebral infarction.

14. 4. An inhibitory structural or functional analogue according to any one of claims 1 to 3 for use in treating painful but non-bleeding injuries in a patient, in particular hyperextension, sprain or contusion.

15. The inhibitory structural or functional analogue according to any one of claims 1 to 13, wherein the administration of the inhibitory structural or functional analogue is preferably carried out orally and according to an administration scheme in which the amount (level) of an individual administration for a patient weighing 60 kg has a value in the range of about 0.1 mg to about 80 mg, particularly preferably a value in the range of about 1 mg to about 50 mg.

16. The active substance is benphoxethiamine (B-OT), the administration of B-OT is preferably oral and according to a dosing scheme comprising the following dosing data for a patient weighing 60 kg: (a) When used in combination with radiation therapy: On the day of the radiotherapy, before the radiotherapy, about 1 to 150 mg, preferably about 10 to 75 mg, particularly preferably about 30 to 50 mg, once; The day after the radiotherapy, about 1 to 70 mg, preferably about 3 to 40 mg, particularly preferably about 4 to 20 mg, is administered once. Two days after the radiotherapy, about 1 to 40 mg, preferably about 3 to 25 mg, particularly preferably about 4 to 18 mg, is administered once. and (b) particularly when used in combination with cytotoxic chemotherapy: On the day before the chemotherapy, about 1 to 150 mg, preferably about 10 to 75 mg, particularly preferably about 30 to 50 mg, is administered once; On the day of the chemotherapy, about 1 to 150 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, is administered once. The day after the chemotherapy, about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, is administered once. and (c) When used in combination with one or more targeted cancer treatments, particularly with imatinib and / or sorafenib and / or erbitux and / or avastin and / or gemcitabine: On the day before the chemotherapy, about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, is administered once; On the day of the chemotherapy, about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, is administered once. The day after the chemotherapy, about 1 to 100 mg, preferably about 10 to 75 mg, particularly preferably about 5 to 50 mg, is administered once. and (d) When used as monotherapy or in combination with one or more other therapies for a duration of more than 1 week, particularly more than 2 weeks, more than 3 weeks, or more than 4 weeks: Approximately 1 to 30 mg, preferably approximately 2 to 15 mg, and very preferably approximately 3 to 10 mg per day, in each case administered as a single dose or in the form of multiple partial doses. The inhibitory structural or functional analogue of claim 9, which is produced according to the formula:

17. 19. An inhibitory structural or functional analogue of a coenzyme of the enzyme group according to any one of claims 1 to 16, in particular as a coenzyme antagonist and agonist according to claim 9, for use in preparatory or combination therapy in the treatment of cancer and / or in sequential therapy lasting for several weeks or months, wherein the administration of said inhibitory structural or functional analogue comprises the following steps: (1) Day 1: (1a) selecting said coenzyme antagonist / agonist and measuring the enzymatic activity of an enzyme E representative of the group of coenzyme-dependent enzymes in an initially prepared body fluid sample I of the patient; (1b) then administering the coenzyme antagonist / agent to the patient in an amount / dose T1 suitable for causing inhibition of the coenzyme-dependent enzyme's intrinsic enzymatic activity, with a predetermined target value for sustained enzymatic activity inhibition being targeted; (2) Day 2: (2a) measuring the enzymatic activity of Enzyme E in a prepared body fluid sample II of the patient obtained on this day; (2b) comparing the enzyme activity measured in the body fluid sample I and the body fluid sample II, and calculating the extent (range, degree) of reduction (inhibition) of the enzyme activity that has occurred; (2c) subsequently administering the coenzyme antagonist / agent to the patient in an amount T2 (dose T2) determined (calculated) based on the amount T1 (dose T1) and the target value of the target enzyme activity inhibition and the decrease in enzyme activity calculated in step (2b), whereby the amount T2 (dose T2) is greater than, less than, or equal to the amount T1 (dose T1); (3) From the third day onwards, until the target enzyme activity inhibition value is reached: Repeat steps (2a) and (2b) and repeat step (2c), except that the patient is administered the coenzyme antagonist / agent at an amount / dose T(i) determined (calculated) based on the previous day's amount / dose T(i-1) and the target enzyme activity inhibition target and the decrease in enzyme activity calculated in step (2b), such that the amount / dose T(i) is greater than, less than, or the same as the previous dose / dose T(i-1). an inhibitory structural analog or an inhibitory functional analog administered according to an administration scheme determined by a method comprising:

18. The method for determining the administration scheme includes step (4), wherein step (4) comprises: The medical parameters of the disease and the medical parameters of the basic functions, such as, preferably, the heart rate (pulse) per minute and / or the occurrence of appetite loss and / or weight loss in the patient's body, are monitored, and the target value of the inhibition of the enzyme activity is adjusted so that, on the one hand, the medical parameters of the disease reach the desired value, and, on the other hand, sufficient enzyme activity is still present so that the basic functions of the patient's body are maintained in the long term.

18. The inhibitory structural or functional analogue of claim 17, comprising the steps of:

19. The target value of the enzyme inhibition is preferably at least 20%, particularly preferably at least 50%, and very particularly preferably at least 70%, respectively, based on the original enzyme activity value measured in step (1a) (as the initial value), an inhibitory structural analogue or an inhibitory functional analogue according to claim 17 or 18.

20. 20. The inhibitory structural or functional analogue according to any one of claims 17 to 19, wherein the coenzyme antagonist / agonist is benphoxythiamine, the amount / dose T1 of B-OT is from about 1 mg to about 30 mg, preferably from about 2 mg to about 15 mg, and the administration of B-OT is preferably performed orally.

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