Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
  • A61K31/51—Thiamines, e.g. vitamin B1
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention relates to the use of at least one inhibitory structural analog or inhibitory functional analog of a coenzyme (such as thiamine) of an enzyme group, the enzyme members of which are anabolic and / or catabolic and / or energy-releasing metabolic reactions with essential importance for the functionality of the overall metabolism of cells, especially mammalian cells , catalyze, for the treatment of patients for the purpose of generally successive (in particular also stepless) slowing down of the metabolic processes of endogenous and exogenous cells in the patient's body.
• a coenzyme such as thiamine
• the negative consequences of the release of toxins should be controlled and inhibited in such a way that there are no septic complications or sepsis and the patient is thus protected from serious and / and fatal consequences. If the amount of toxin exceeds a threshold value, the consequences of the toxin effect on the body can no longer be compensated and the patient dies. Since the amount of toxin correlates with the amount of bacteria in a bacterial infection, the bacterial proliferation is largely responsible for the amount of toxin released and contributes to the risk of the patient dying due to the toxin effect. A general slowdown in bacterial growth in the body is therefore a starting point for influencing the amount of toxin and thus also the probability of dying from the amount of toxin in such a way that the patient has a higher probability of surviving.
• antibiotic therapy that successfully kills the bacteria is also the reason for the failure of the therapy, since the amounts of toxin released by killing the bacteria can lead to septic complications and sepsis. Since toxins such as endotoxin exert their dangerous effects via toll-like receptors and / or inflammatory signal pathways, the dangerous toxin effect can be inhibited by inhibiting these toll-like receptors or inflammatory signal pathways. This enables the actual antibiotic therapy to be made safer and more successful by inhibiting the effect of the toxins by inhibiting the signaling pathways linked to them.
• the present invention is based on the object of satisfying this need.
• One solution to this problem is to provide at least one inhibitory structural analogue or inhibitory functional analogue of a coenzyme (such as thiamine) of an enzyme group, the enzyme members of which have anabolic and / or catabolic and / or energy-releasing metabolic reactions that are essential for the functionality of the overall metabolism of Catalyze mammalian cells (preferably also from bacterial cells or other living beings located in the organism of a mammal) for use in the treatment of a patient for the purpose of a general successive (in particular also stepless) throttling / slowing down / decelerating the anabolic, catabolic and energy-producing metabolic processes of the (ie in principle all or almost all) cells in the patient's body (ie the body's own and also non-body cells in the patient's body).
• a coenzyme such as thiamine
• processes that maintain health and cause illness are slowed down at the same time so that time is saved.
• the patient's organism can react to pathogenic processes itself, and / or the pathogenic processes in the patient's body are slowed down so that the amount of damage per time interval is reduced in such a way that the damage to the patient's organism is less overall and / or more time for finding therapies with a good chance of success is available.
• the time saved can also be used to reduce the effect of therapies and / or their side effects so that the side effects are fewer. The latter is particularly advantageous when it is a fundamentally successful therapy. If, for example, the negative effect of the toxins (e.g.
• the slowing down of the cell metabolism can lead to a complete blockage of the metabolism.
• the duration and / or amount of the applied amount of active ingredient should be chosen so that most of the healthy cells can reactivate their metabolism after the metabolic slowdown has been eliminated and do not suffer any permanent damage, or that the permanent damage is tolerable in view of the success of the therapy.
• coenzyme of an enzyme group means here in the context: All enzymes of this group (the so-called “enzyme members”) absolutely need this coenzyme to exercise their catalytic activity or in other words: with all enzymes of this group this co- Enzyme essential for the exercise of its catalytic activity.
• inhibitory structural analogue of the coenzyme - or “coenzyme antagonist” for short - stands for a structural analogue of the coenzyme which, instead of the coenzyme, binds to the enzyme in question and its catalytic activity (the enzyme activity ) inhibits (inhibits).
• inhibitory functional analogue of the coenzyme stands for a substance that does not have a structure analogous to the coenzyme, but is able to take its place in / on the enzyme and / or due to an interaction with the coenzyme Functional inhibition of the enzyme's action and thus the action of the enzyme in question.
• inhibitory coenzyme analogue stands for an inhibitory structural analogue according to the invention and / or an inhibitory functional analogue of a coenzyme according to the two definitions given above.
• GSSV stands for the formulation "general, successive (especially if necessary also stepless) metabolic slowing down", whereby under metabolic slowing down the slowing down (or throttling or deceleration) of anabolic, and / or catabolic and / or energy-producing and metabolic processes that are essential for the existence of mammalian cells are to be understood.
• dosage scheme used in the following (synonyms: dosage regime, administration scheme) means here in the context the planned sequence of the individual doses (synonyms: administration quantities, single doses) of a drug with information on the time intervals between the doses, the amount (amount) of the individual dose to be taken , the duration of the treatment phase (s), and information on how and in which formulation (dosage form) the active ingredient or drug is to be taken.
• targeted cancer therapy or “targeted therapies” for short stands here in the context of a drug-based cancer therapy in which one or more active substances are administered that are aimed at defined tumor-specific target structures of the tumor cells.
• These defined target structures include, for example, receptors or enzymes of the tumor cells.
• the active ingredients which are also referred to as "cell-type-specific active ingredients" in this context, include, for example, antibodies (e.g. anti-EGFR) or differently designed protein structures (e.g.
• hormone antagonists or soluble receptors for signal molecules include hormones, derivatives of hormones, substances, the signals pass on or inhibit (eg substances with an immunomodulating effect), and so-called “small molecules” (eg tyrosine kinase inhibitors such as sorafenib, imatinib, etc.).
• small molecules eg tyrosine kinase inhibitors such as sorafenib, imatinib, etc.
• the essence of the invention consists in the specification of a completely new way of treating diseases, which is characterized in that the metabolism of the sick person is specifically inhibited and thus overall slowed down in order to slow down processes taking place in the body that are directly or indirectly damaging .
• This new form of therapy is referred to below as GSSV therapy.
• the use according to the invention and the GS SV brought about (brought about) do not differentiate between healthy and degenerate cells and also not between autologous and exogenous cells in the patient's body.
• the nonself cells include, in particular, prokaryotes such as bacteria, single-cell or multicellular eukaryotes such as fungi, parasitic flagellates or worms, and also infectious organic structures that mammalian cells use for their reproduction, such as RNA viruses or DNA viruses.
• the strength and duration of the metabolic inhibition can be practically arbitrary and in particular also via the dosage regime (time intervals and amount of the administered drug) continuously varied and precisely controlled.
• This period is selected or dimensioned in such a way that no (or only minor) irreversible damaging effects are caused in the body's own healthy cells, and that after the end of the metabolic inhibition (by discontinuing the drug according to the invention or the administration of the functionally active co-factor) Above all, the healthy body cells of the patient strengthen their metabolism again (start up), all enzymatic processes can be fully carried out again and the great majority of the healthy body cells do not suffer any permanent damage.
• the present invention represents a new aid for protecting against and combating both existing and future diseases that are currently not yet foreseeable.
• the body of a mammal / human is ultimately a system in which mammalian cells or human cells are in contact with other living beings, and all of them are in competition for resources such as energy for survival.
• the mammalian organism itself is a resource that is the target of many of the living beings around it.
• Bacteria, viruses, protozoa and parasites represent living beings or reproductive units that multiply in living beings, which either live in peaceful coexistence with the mammal / human organism or cause it health damage up to and including death. Evolution has led to constant competition between attacker and defender, and thereby triggered a constant improvement in attackers and defenders.
• the effects that such a new pathogen exerts on the organism in question can be slowed down in such a way that the extent of the disease is targeted , can be slowed down and reduced gradually and, if necessary, continuously.
• the time course of the disease is thus stretched so that the organism (or body) has more time to react to it, and at the same time the extent of the damage per unit of time is reduced. This makes it possible to reduce the extent of the damage per unit of time so that the body can withstand it.
• the gain in time that is generated by slowing down the metabolism also provides the decisive advantage that the body and its defense mechanisms, such as the immune system, are given more time to find the right defense against external intruders.
• the formation of antibodies by the human immune system is a stochastic process in which new antibody variants are formed through the random recombination of the corresponding genes. By testing the antibodies, it is then determined which of the antibodies the body produces in order to ward off the intruder from outside or to eliminate the unwanted endogenous cell, e.g. tumor cell.
• a GSSV is a way of slowing down viruses or bacterial infections that run very quickly so that the body's immune system has enough time for an effective response to fight the pathogens.
• the GSSV brought about according to the invention is a measure with which an effective antibiotic therapy, but which may have severe / fatal side effects, can be made tolerable in such a way that it can be used for the benefit of the patient.
• a GSSV is able to slow down the growth of metastasizing cancer cells in such a way that exponential growth is prevented, or an already existing exponential growth of these cells is inhibited in such a way that they only multiply slowly or not at all.
• the application of the GSSV according to the invention represents a significant difference to previous therapeutic approaches in oncology, because it does not consist in a therapy specifically aimed at the undesired cells (cancer cells), but aims and effects a non-specific inhibition of the metabolism of all endogenous cells.
• the GSSV and its application in the field of oncology therefore represent a primarily not curative, but rather a palliative approach which, above all, gives cancer patients more life and does so without reducing the quality of their life, since, in contrast to conventional cancer therapies, there are no or only minor side effects from the GSSV go out.
• the inhibitory structural analog or inhibitory functional analog is an inhibitory thiamine analog - also called thiamine antagonist below -, in particular oxythiamine and / or benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo-oxythiamine derivative .
• inhibitory thiamine analogs in the singular “inhibitory thiamine analogs” and thiamine antagonist (s) stand for any substance that (i) preferably belongs to the small molecules (small compounds), ie to the organic compounds a molecular weight below 900 Dalton, which influences a biological process, and which is also preferably (ii) either (a) a structural analogue of thiamine, in particular a thiamine derivative that inhibits the enzyme activity of thiamine-dependent enzymes, or (b) is a functional analog of thiamine, in particular an active ingredient that has no analogy to the thiamine structure, but functionally inhibits the action of thiamine by either competing with thiamine for binding to the thiamine-dependent enzyme, or the effect of thiamine, which bound to the thiamine-dependent enzyme.
• Thiamine-dependent enzymes catalyze an extremely wide range of catabolic, anabolic and energy-releasing metabolic reactions and thus enable the associated metabolic pathways.
• this group of enzymes namely all enzymes that use thiamine as a coenzyme, are blocked in their activity and thus intervene in the biochemical processes of the cell on a broad basis and in many places at the same time.
• the inhibited catabolic reactions include, in particular, the breakdown of carbohydrates and proteins with the release of energy in the form of high-energy bonds such as acetyl-CoA and ATP.
• Acetyl-CoA plays a crucial role in the formation of new cell structures, especially in the formation of fatty acids, lipids and cholesterol.
• These components play an essential role in the formation of cell membranes and membranes of organelles such as the mitochondria, which in turn play an important role in releasing energy from hydrogen and fixing it in the form of the energy-rich compound ATP.
• the inventive use of the thiamine antagonists causes, for example, an inhibition of all alpha-keto acid dehydrogenases, ie the inhibition of an enzyme family that is crucial for the breakdown of carbohydrates and proteins and for the release of energy therefrom.
• alpha-keto acid dehydrogenases ie the inhibition of an enzyme family that is crucial for the breakdown of carbohydrates and proteins and for the release of energy therefrom.
• these include, in particular, the three enzymes pyruvate dehydrogenase, a-ketoglutarate dehydrogenase and branched-chain alpha-keto acid dehydrogenase, each of which decarboxylates and forms a high-energy bond in the form of acetyl-CoA, and which each split off hydrogen and NADH + H + form.
• thiamine antagonists An inhibition of alpha-keto acid dehydrogenases by thiamine antagonists leads to an inhibition of the catabolic metabolic pathways and the possible release of energy from carbohydrates and proteins. Both the reactions that directly form high-energy bonds such as acetyl-CoA and the reactions that lead to the formation of ATP through the oxidation of the released hydrogen are inhibited. Thiamine antagonists are therefore very good starting points for inhibiting the release of energy and the formation of high-energy compounds such as acetyl-CoA and ATP.
• thiamine-dependent enzymes that are inhibited with the use of the thiamine antagonists according to the invention are, for example, the transketolases, which do not carry out decarboxylation or hydrogen splitting and enable the conversion of sugars such as the formation of riboses from glucose.
• the technical effect of the use according to the invention of the thiamine antagonists for the purpose of effecting (bringing about) the GSSV according to the invention thus consists primarily in the fact that both the catabolic metabolism (in particular of carbohydrates and proteins) and the anabolic metabolism and also the release of energy and its fixation in high-energy compounds are massively inhibited.
• the inhibition of the metabolism is based on an extremely large number of different levers in the form of different thiamine-dependent enzymes.
• the inhibitory thiamine analog is the substance benfo-oxythiamine (hereinafter "B-OT" for short).
• B-OT is a precursor ("prodrug") of oxythiamine.
• B-OT can be administered orally and releases oxythiamine shortly after ingestion into the mammalian organism.
• Oxythiamine inhibits thiamine-dependent enzymes.
• the conversion (metabolism) of B -OT in oxythiamine takes place in the blood of mammals.
• B-OT can travel through the bloodstream to all cells in all parts of the body.
• In vivo pharmacokinetic data has shown that oxythiamine is present in the brain in significant amounts after B-OT is administered, meaning that oxythiamine crosses the blood-brain barrier.
• B-OT In vivo pharmacokinetic data from rat experiments on the bioavailability of B-OT after oral administration have shown that 0% B-OT can be measured in the blood, i.e. the prodrug form cannot be measured in the blood, but 44 % of the total amount of B-OT administered in the form of oxythiamine (OT) can be measured in the blood. This means that there is a very efficient cleavage of B-OT into OT, and a high percentage of OT is present in the blood. B-OT is thus a pharmacokinetically good and orally applicable substance that enables good and efficient provision of OT. Since OT usually has to / should be administered intraperitoneally, oral administration of B-OT represents an important advantage. The bioavailability and absorption of B-OT is also better for therapy due to the more lipophilic basic structure of B-OT compared to OT suitable for humans. Compared to OT, B-OT is better, easier and safer to use as a drug.
• B-OT benfo-oxythiamine
• Sepsis is a systemic reaction of the organism to an uncontrolled infection and is mostly caused by bacteria, but increasingly also by fungi. Sepsis is a life-threatening condition that occurs when the body's response to an 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 quickly. Sepsis is the leading cause of infection-related death worldwide.
• Sepsis is one of the most common causes of death. Infections caused by injuries or contamination during an operation can develop into explosive bacterial growth. This releases toxins that lead to multiple organ failure and ultimately to the death of the patient.
• the GSSV brought about according to the invention not only influences the patient's own cells and the signaling pathways via which toxins can trigger septic complications or sepsis, but also the bacterial metabolism is addressed and can thus be inhibited. This means that the cell division ability of the bacteria is disturbed and their explosive multiplication is prevented. This saves time that can be used to select the appropriate drug through laboratory tests and then select it in a targeted manner to use.
• the human metabolism and associated reactions or excessive reactions of the body in response to the infection are also inhibited by the GSSV.
• excessive reactions e.g. excessive immune reactions, are also inhibited.
• GSSV in the form of the simultaneous effect on the bacterial metabolism and the patient's metabolism is particularly beneficial for the therapy and survival of the patient in the case of bacterial infections and the associated risk of developing sepsis.
• bacterial growth can be slowed down so much that hardly any or no damage is triggered by the bacterium and the patient's own immune system has significantly more time to develop antibodies against the bacteria.
• a simultaneous (simultaneous and parallel) blockade of the attacker's metabolism (e.g. bacteria, fungi) and the defender's metabolism (humans) can prevent the relationship between bacterial multiplication and / or fungal growth with accompanying damage of the body deteriorates the defense performance of the patient's organism, because an increase in bacterial multiplication and / or fungal growth in relation to the defense performance of the body is prevented.
• Simultaneous inhibition of attackers and defenders does not heal per se, but it stabilizes the patient's situation and frees up time to identify therapies that are effective. In addition, it opens up the possibility of suppressing negative reactions of the body to bacteria and released toxins.
• the present invention therefore also relates to an inhibitory structural analog or functional analog according to the invention, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo-oxythiamine Derivative for use in the treatment of a patient with bacterial disease (infection). It is preferably used as a monotherapy or as a co-therapy with at least one further medicament, in particular a medicament with an antibacterial effect.
• the purpose of the application is, in particular, to suppress the effect of the bacterial endotoxins on the patient's organism, in particular those endotoxins which are released as a result of the bactericidal effect of the further medicament.
• the inhibitory active ingredient according to the invention is preferably administered orally and according to a dosage scheme which includes, for example, the following information:
• the recommended dosage is (based on 60 kg body weight): about 40 mg twice on the first day; about 20 mg twice on the second day; about 10 mg twice on the third day.
• the present invention also relates to an inhibitory structural analog and / or inhibitory functional analog according to the invention, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo Oxythiamine derivative, for use in the treatment of a patient with a disease originating from / caused by fungi, preferably as monotherapy or as co-therapy with at least one further medicament.
• an inhibitory thiamine analog thiamine antagonist
• oxythiamine oxythiamine
• benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo Oxythiamine derivative for use in the treatment of a patient with a disease originating from / caused by fungi, preferably as monotherapy or as co-therapy with at least one further medicament.
• the inhibitory active ingredient according to the invention is preferably administered orally and according to a dosage scheme which includes, for example, the following information:
• the recommended dosage is (based on 60 kg body weight): about 30 mg twice on the first day; about 15 mg twice on the second day; about 5 mg twice on the third day.
• the present invention also relates to an inhibitory structural analog according to the invention and / or inhibitory functional analog, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo Oxythiamine derivative, used in the treatment of a patient with sepsis or threatened sepsis.
• an inhibitory structural analog according to the invention and / or inhibitory functional analog preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo Oxythiamine derivative, used in the treatment of a patient with sepsis or threatened sepsis.
• thiamine analog thiamine antagonist
• This inhibitory active ingredient according to the invention is administered according to the invention preferably orally and according to a dosage scheme which includes, for example, the following information: a) The recommended dosage for sepsis is already present (for 60 kg body weight): about 40 mg twice on the first day; the next day about 20 mg twice; on the third day about 10 mg twice.
• the recommended dose for the prophylaxis of sepsis is (for a body weight of 60 kg): about 20 mg twice on the first day; about 10 mg twice on the second day; about 5 mg twice on the third day.
• the present invention also relates to an inhibitory structural analogue according to the invention and / or an inhibitory functional analogue, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo- Oxythiamine derivative, used in the treatment of a patient with a viral disease (or infection).
• This inhibitory active ingredient according to the invention is administered, according to the invention, preferably orally and according to a dosage scheme which includes, for example, the following information:
• the recommended dosage is (based on 60 kg body weight):
• Acute viral diseases such as the flu can be fatal in patients, especially those with impaired immune systems. What is also special about viral diseases is the explosive growth with which the viruses can multiply and subsequently attack more and more body cells. The latest studies show that drugs that limit the ability of viruses to replicate can usually only achieve therapeutic success if they are used at an early stage. If the viral load is too high, they are usually ineffective.
• the GSSV brought about according to the invention all cells in the patient's body are influenced.
• the cell's metabolism is activated to provide the building blocks for virus replication.
• the metabolic blockage counteracts this and inhibits the virus' ability to replicate. This reduces the viral load and the anti-viral effects of drugs can be used to fight the viruses effectively.
• the replication of the viruses can be slowed down so that little or no damage is caused by the viruses and the human immune system has significantly more time to develop antibodies against the viruses.
• the GSSV according to the invention can also be used in patients with viral diseases, although viruses do not have their own metabolism. Since viruses reprogram the host cell in such a way that the host cell's metabolism enables the virus to multiply, inhibiting the metabolism of the immune system infected by viruses is a new, previously unused method of treating viral diseases. Viruses that are new to humans and very dangerous for them, such as the coronavirus SARS-COV-2 and the associated disease COVID-19, lead to immunological and cellular reactions that can be fatal. Excessive reactions such as excessive cytokine formation are often the main reason for the severity of the viral disease or the death of the patient.
• any reaction is slowed down and thus excessive reactions of the patient's body a virus attack.
• By slowing down the metabolism all reactions associated with the viral infection are slowed down. This not only ensures that the peak viral load is reduced, but also that all reactions triggered by the viral infection, including the body's reaction to the viral infection, can be slowed down in a targeted manner.
• the slowing down of the metabolism can be achieved steplessly by increasing the concentration of the active substance, whereby the slowing down of the metabolism can be easily adapted to the necessary slowing down. As a result, the entire infection process and the response of the human body to it can be slowed down in a targeted and stepless manner.
• the present invention also relates to an inhibitory structural analog according to the invention and / or an inhibitory functional analog, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo- Oxythiamine derivative for use in the treatment of a patient with an immunological disease, in particular an inflammatory disease and / or an autoimmune disease.
• an inhibitory structural analog according to the invention and / or an inhibitory functional analog preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog and / or a benfo- Oxythiamine derivative for use in the treatment of a patient with an immunological disease, in particular an inflammatory disease and / or an autoimmune disease.
• an immunological disease in particular an inflammatory disease and / or an autoimmune disease
• the autoimmune diseases include in particular systemic lupus erythematosus (SLE) and those forms of disease that occur in relapses, in particular rheumatoid arthritis and / or multiple sclerosis and / or inflammatory bowel diseases such as ulcerative colitis, Crohn's disease and / or inflammatory / degenerative diseases, in particular the Skeletal system such as ankylosing spondylitis.
• SLE systemic lupus erythematosus
• inflammatory bowel diseases such as ulcerative colitis, Crohn's disease and / or inflammatory / degenerative diseases
• the Skeletal system such as ankylosing spondylitis.
• This inhibitory active ingredient according to the invention is administered, according to the invention, preferably orally and according to a dosage scheme which includes, for example, the following information:
• the recommended dosage is (based on 60 kg body weight):
• autoimmune diseases come on in flare-ups.
• the immune system is particularly active and causes inflammation, as a result of which healthy cells can be excessively damaged.
• the general condition of the patient worsens after the episode compared to the previous condition.
• the GS SV brought about according to the invention also affects (influences) the immune cells, the activation and reproduction of which is restricted under the GS SV.
• Chronic autoimmune diseases such as rheumatism, Crohn's disease, ulcerative colitis and others are characterized by increased inflammation. Since these are chronic processes, one can use the application and effect according to the invention to GS SV according to the invention permanently control the diseases by slowing down the metabolism. For this purpose, lower doses are chosen so that healthy cells are not permanently damaged, but the overall inflammation is reduced by the slowdown.
• the drug-based slowing of the metabolism according to the invention allows the improvement of disease courses which are characterized by disease relapses.
• An example of a relapsing disease is multiple sclerosis. In 90% of the cases, the patients suffer from relapsing multiple sclerosis.
• the slowing down of the metabolism makes it possible to treat such relapsing illnesses by slowing down the metabolism when relapses occur and thus counteracting the development of the relapse.
• This application according to the invention can also be used to reduce the risk of organ rejection after transplants.
• the present invention also relates to an inhibitory structural analog and / or inhibitory functional analog according to the invention, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog, for use in tumor treatment of a patient, in particular in the treatment of cancer (malignancies) of a patient (human or mammal) as monotherapy or as pre- or co-therapy of chemotherapy and / or radiation therapy and / or targeted cancer therapy.
• an inhibitory thiamine analog thiamine antagonist
• oxythiamine oxythiamine
• benfo-oxythiamine and / or a benfo-oxythiamine analog for use in tumor treatment of a patient, in particular in the treatment of cancer (malignancies) of a patient (human or mammal) as monotherapy or as pre- or co-therapy of chemotherapy and / or radiation therapy and / or targeted cancer therapy.
• the primary purpose of this application in cancer patients is a multiple simultaneous inhibition of the enzymes of the enzyme group and thus throttling / slowing down the anabolic, catabolic and energy-producing metabolic processes in all cells of the body, i.e. in all healthy and also in uncontrolled growing cells (tumor cells).
• the application of the GSSV therefore does not specifically target the tumor cells, but in principle slows down the metabolism of all body cells.
• healthy cells and also cells that are growing in an uncontrolled manner, such as tumor cells are less able to carry out catabolic, anabolic and energy-releasing metabolic processes.
• the formation of radicals in the cell is increased both through endogenous processes and through exogenous measures such as radiation, and the neutralization of radicals is slowed down, thereby reducing the Radical stress and also the DNA damage increase.
• the cancer cells can react much more poorly to stress (eg radical stress) or damage (eg as a result of chemotherapy and / or radiation therapy), and the threshold at which stress and damage lead to their death (apoptosis) is lowered.
• stress eg radical stress
• damage eg as a result of chemotherapy and / or radiation therapy
• apoptosis apoptosis
• the cell lacks sufficient substrates and energy as a result of the GSSV brought about according to the invention, enzymatic reactions, which are required for the most diverse areas of cell repair, cannot take place. This leads cells to cell death that could normally repair existing damage.
• the RedOx homeostasis is also influenced, so that the ratio of oxidizing to reducing processes is increased in favor of the oxidizing processes. Both effects, the reduction of substrates and available energy in the cell as well as the shift of the RedOx homeostasis in favor of oxidative processes lower the threshold value for the death of the cells including the tumor cells.
• the GSSV therapy thus leads to a weakening of the cancer cells and thus to a lowering of the threshold value of the cells for their death.
• the cancer cell can withstand the damaging effects of the therapies used more poorly and also not evade (because alternative metabolic processes, which are called " Evasion and bypass route "could serve for those injured by the therapeutic agent, are also inhibited or almost completely blocked).
• a tumor consists of several million or more tumor cells.
• the degree of damage to a cell is dose-dependent. It cannot be guaranteed that the dose will be the same for all tumor cells.
• the damage is not sufficient to kill the cell or the cell can activate its repair mechanisms to repair damage and thus prevent cell death. It is therefore hardly possible to kill all cells at the same time with cancer therapy.
• active ingredients are used in high concentrations in the prior art and it is accepted that patients have to struggle with severe side effects.
• coenzyme antagonist according to the invention and the GSS V brought about by it represent a useful addition to practically all known therapeutic principles -Therapy (anti-tumor therapy) multiple catabolic, anabolic and energy-releasing / energy-fixing metabolic processes at the same time and as required gradually or as soon as possible and moderately, more or more strongly or strongly inhibited or completely blocked, specifically geared to the type of co-therapy (anti Tumor therapy).
• anti Tumor therapy anti Tumor therapy
• the GSSV lowers the threshold value for tumor cell death on the one hand and counteracts the malignant properties of the tumor cells on the other hand so that they are less malignant, e.g. form less lactic acid and thus grow less invasively, form fewer metastases, suppress the immune system less strongly, e.g.
• the GSSV brought about according to the invention can also be used as a monotherapy.
• the dosage regimen for the inhibitory coenzyme analog according to the invention in the treatment of tumors depends on whether it is monotherapy or pre- or co-therapy. If the application according to the invention takes place as pre- or co-therapy in combination with established cancer therapies, the dosage regimen for the inhibitory coenzyme analog according to the invention varies depending on the additionally applied cancer chemotherapy and / or radiation therapy and / or targeted cancer therapy. In the case of the combination of radiation therapy with the use according to the invention of the inhibitory coenzyme analogue, for example and preferably in the form of the thiamine antagonist B-OT, B-OT is administered after the radiation treatment.
• B-OT is administered before the start of chemotherapy, so that some of the thiamine-dependent enzymes are already inhibited by the time chemotherapy is started.
• the administration of B- OT should preferably be started about two days before the start of the targeted cancer therapy in order to optimally promote the effect of the targeted therapies.
• the B-OT administration takes place as part of a type of pretreatment before the surgical intervention.
• You start preferably about three days before the surgical procedure so that at the time of the procedure the number of disseminating tumor cells (i.e. the tumor cells released into the blood or other body fluids) is reduced and their invasiveness and metastatic potential are inhibited. This lowers the likelihood of locally growing relapses and femoral metastases.
• the administration of the inhibitory active ingredient according to the invention in the course of a co-therapy takes place according to the invention preferably orally and preferably according to a dosage scheme which includes the following information:
• Cancer therapy in particular using imatinib and / or sorafenib and / or Erbitux and / or Avastin and / or gemcitabine: the day before chemotherapy once about 1 - 100 mg, preferably about 10-75 mg, particularly preferably about 5 - 50 mg; on the day of chemotherapy once about 1-100 mg, preferably about 10-75 mg, particularly preferably about 5-50 mg; on the day after chemotherapy once about 1-100 mg, preferably about 10-75 mg, particularly preferably about 5-50 mg.
• a dose of 30 mg or 15 mg per day can be administered, for example, as a single dose of 30 mg or 15 mg, or in correspondingly smaller doses of e.g. 2 x 15 mg or 1 x 5 mg and 1 x 10 mg per day.
• a dosage regimen that has worked well in practice is: (a) Recommended dosage when used in combination with radiation therapy:
• Cancer therapy (e.g. using sorafenib or imatinib): 10 mg once two days before therapy; the day before therapy once 8 mg; 6 mg once on the day of therapy; 4 mg on the day after therapy.
• the dose amounts apply in particular when the active substance applied is the thiamine antagonist B-OT.
• the GSSV offers a new way of therapy that is not curative, but can significantly extend the survival of cancer patients by inhibiting the spread of the tumor, including its invasive growth behavior, and the formation of new metastases. Since the spread and metastasis of tumors are the most common and in many cases also the decisive reason for the death of the patient, it is clinically and for the survival of cancer patients a milestone that with the coenzyme antagonist according to the invention, especially in the form from B-OT, an agent that can inhibit invasiveness and metastasis.
• the use of the active ingredient according to the invention ie the coenzyme antagonist according to the invention, in particular in the form of B-OT
• the use of the active ingredient according to the invention is preferably not carried out in combination with chemotherapy and / or radiation therapies, but as monotherapy.
• the inhibitory coenzyme analogue is used according to the invention, for example and preferably in the form of the thiamine antagonist B-OT, preferably as monotherapy.
• the administration of the active ingredient according to the invention in the course of a monotherapy is preferably carried out orally according to the invention and according to a dosage scheme which includes, for example, the following information:
• the present invention thus offers several further options for cancer therapy.
• it can be treated with lower doses without endangering the success of the therapy.
• This new option is particularly advantageous for therapies with strong side effects, which often have to be stopped because the side effects are too strong.
• malignant properties such as invasiveness and metastasis can be inhibited, whereby the patient may not be cured, but the patient's situation can be stabilized (stable dieease).
• the effect of the immune system in particular that of the killer cells, which kill tumor cells, can be increased by inhibiting the lactic acid production of tumor cells, which counteracts the acid-related blockade / defense against the attack of the killer cells by the tumor cells.
• the coenzyme antagonist according to the invention for example and in particular B-OT, lowers the lactic acid production of tumor cells and thus reduces the acid residue of the killer cells, so that the tumor cells can then be better attacked and killed by killer cells.
• the advantageous increase in efficiency of the established tumor therapies also consists in the fact that (a) less active ingredient is required to achieve the same effect (because the threshold value for death has been lowered, a lower dose of the drug therapy and / or radiation therapy needed to kill the cells), and that (b) additional cells die (because: tumors usually consist of a heterogeneous mixture of different tumor cells, and the lowering of the threshold value of death by the application of Coenzyme antagonists according to the invention lead to cancer cells that would not have died under conventional therapy, now die.)
• a tumor consists of millions of cells and no therapy can guarantee that the dose of the active ingredient / radiation is the same in all cells. There will often be a proportion of cells in which the active ingredient leads to damage without this triggering cell death. Every cell has repair mechanisms to repair the damage it has caused. The repair takes place via enzymatic reactions, which require substrate and energy for this. If these are not present in the cell, or only to a limited extent, because the cell metabolism has been slowed down or inhibited beforehand, the ability to repair is limited. This means that cells with less severe damage from chemotherapy and / or radiation therapy and / or targeted cancer therapy also suffer cell death.
• the application according to the invention does not differentiate between healthy and degenerate cells.
• the strength and duration of the GSSV caused can vary via your dosage regimen (in particular the time at which the GSSV starts in relation to the start of established cancer therapies that are additionally used, time intervals and amounts of the coenzyme antagonist administered) as pre- or co-therapy or as monotherapy and controlled precisely. This means: the provision of essential substrates that are necessary for downstream specific enzyme reactions is blocked in the tumor cells (and also in all other body cells) for a predetermined limited period of time.
• This period of time (of co-therapy or mono-therapy) is selected or dimensioned so that the extent of the damage it causes in the cells is chosen so that, after the end of the blockade (by discontinuing the drug according to the invention), the healthy body cells in particular start up their metabolism again, restart all enzymatic processes and not suffer permanent damage.
• cancer patients An almost explosive growth of cancer cells is often observed in cancer patients, especially when tumors no longer grow locally but invasively metastasize.
• Cancer patients with a very rapid progression of the disease, such as metastatic forms of cancer often only have a few months or even weeks to live.
• these cancer patients only have the choice of therapies, such as chemotherapy, which have massive side effects, massively reduce the quality of life and only allow a slight extension of the life span.
• a cancer patient basically buys a life extension of, for example, a month and pays for the fact that he suffers from pain and nausea in that month, feels bad overall and is so weakened that he cannot lead a good life.
• the GSSV therapy according to the invention can also be used in the case of glioblastomas and other cancer tumors (malignancies) in the brain with good prospects of success, in particular as co-therapy with an established chemotherapy and / or radiation therapy and / or targeted cancer therapy.
• the present invention also relates to an inhibitory structural analog and / or inhibitory functional analog according to the invention, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog, for use in the treatment of a patient as pretreatment before surgical interventions and / or drug therapies.
• This inhibitory active ingredient according to the invention is administered, according to the invention, preferably orally and according to a dosage scheme which includes, for example, the following information:
• the recommended dosage is: two days before the operation, 4 mg once a day (morning, or noon, or evening); on the day of the operation before the operation 5 mg.
• the preventive use of the application according to the invention and thus caused GSSV Surgical interventions have the advantage that adverse side effects as a result of the intervention and any complications are slowed down. Such complications can be excessive reactions of the body, for example excessive immune reactions or triggering of programmed cell death.
• the GSSV brought about according to the invention can also be used before drug therapies in order to reduce or avoid side effects, precisely because the metabolism is slowed down.
• the present invention also provides an inhibitory structural analog and / or inhibitory functional analog according to the invention, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog, for use in the treatment of a patient with traumatic brain injury.
• This inhibitory active ingredient according to the invention is administered, according to the invention, preferably orally and according to a dosage scheme which includes, for example, the following information:
• the stress / injury to the brain can lead to swelling of the brain, so that the internal pressure in the skull becomes too strong and consequential damage occurs. So far, in such cases, the skull has been surgically opened to give the brain more space.
• the inventive use of the GSSV therapy according to the invention allows the physiological reactions of the brain tissue to the effects of the accident to be suppressed in a targeted manner, so that the brain does not swell and the internal pressure in the skull does not become too high. By avoiding the excessive internal pressure in the skull, consequential damage is prevented.
• the present invention also relates to an inhibitory structural analogue according to the invention and / or an inhibitory functional analogue, preferably one inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog, for use in the treatment of a patient with nerve transection (s), in particular with spinal cord injuries and the risk of paraplegia with paraplegia or quadriplegia or with a recently developed paraplegia.
• thiamine antagonist inhibitory thiamine analog
• oxythiamine oxythiamine
• benfo-oxythiamine and / or a benfo-oxythiamine analog for use in the treatment of a patient with nerve transection (s), in particular with spinal cord injuries and the risk of paraplegia with paraplegia or quadriplegia or with a recently developed paraplegia.
• the inhibitory active ingredient according to the invention is preferably administered orally and according to a dosage scheme which includes, for example, the following information: Recommended dose on the day on which the spinal cord injury occurred 38 mg, recommended dose on the following day 7 mg, recommended dose on the 3 mg for five subsequent days.
• Injuries that lead to partial or complete severing or bruising of the spinal cord usually also injure blood vessels and leak blood.
• the contact of the blood with the injured nerves can lead to further damage to the nerves, this damage being triggered or intensified by the blood pigment hemoglobin, among other things.
• the blood pigment hemoglobin contains iron bound to it, which plays a role in oxidation processes and can trigger radicals or other cell damage.
• the aim of the GS SV brought about according to the invention is, among other things, to counteract the damaging effects of the blood released by the blood vessel injuries or to reduce the damaging effect by reducing the effect of radical formation and / or the effect of changing the RedOx homeostasis with regard to triggering cell death is inhibited because the GSSV prevents or reduces cell death.
• the present invention also provides an inhibitory structural analog and / or inhibitory functional analog according to the invention, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog, for use in the treatment of a patient with a heart or heartfact.
• This inhibitory active ingredient according to the invention is administered, according to the invention, preferably orally and according to a dosage scheme which includes, for example, the following information:
• the recommended dosage is:
• the programmed cell death is a process stored in the DNA and thus in the (human) organism in order to eliminate unwanted cells. This makes it possible, for example, to eliminate immune cells that are no longer wanted in a planned manner. Another example is apoptosis, which leads to the elimination of tumor cells. Apoptosis is thus a program that helps and protects the human organism. However, apoptosis can also have negative effects if it is triggered, for example, by an oxygen deficiency or a heart attack. An insufficient supply of oxygen (ischemia) triggers apoptosis and thus leads to a loss of important cells.
• ischemia insufficient supply of oxygen
• a heart attack which is triggered by a thrombosis of a blood vessel, can then lead to an insufficient supply of oxygen and the resulting apoptosis in heart cells. Even if the heart muscle is quickly supplied with oxygen again through intensive medical treatment, the apoptosis that has been triggered can lead to further consequential damage.
• the use of the application according to the invention and the GSSV brought about by it make it possible to inhibit apoptosis in order to counteract the death of cells.
• the GSSV inhibits the metabolism and thus also the apoptosis-triggering and apoptosis-performing processes and also reduces the oxygen consumption of the body cells, so that damage caused by an oxygen deficiency is reduced or prevented.
• the GSSV thus works on three levels: With the inhibition of the metabolism, the oxygen consumption and thus also the oxygen demand is reduced, so that the triggering of apoptosis by ischemia is counteracted. With the inhibition of the metabolism, the extent of apoptosis (triggering and execution of apoptosis) and its consequences are also reduced, since all metabolic processes are slowed down. The slowing down of the damaging processes also saves time to use drugs and therapies that counteract the damage.
• the application according to the invention and the GSSV brought about thereby also represents a therapeutic option in emergency medicine, namely a measure that can be carried out immediately at the scene of the accident.
• the GSSV can be triggered at the site of the accident, for example with oral administration of B-OT, whereby all damaging processes in the body can be slowed down or stopped entirely.
• the specific therapy can then be started relatively sooner started because damaging processes such as the triggering of apoptosis, which can take place in the hospital between the accident and the start of therapy, have been considerably reduced as a result of the GSSV.
• the present invention also provides an inhibitory structural analog and / or inhibitory functional analog according to the invention, preferably an inhibitory thiamine analog (thiamine antagonist), in particular oxythiamine, and particularly preferably benfo-oxythiamine and / or a benfo-oxythiamine analog, for use in the treatment of painful blunt injuries (traumas / trauma) to a patient, especially strains, sprains or bruises.
• an inhibitory thiamine analog thiamine antagonist
• oxythiamine oxythiamine
• benfo-oxythiamine and / or a benfo-oxythiamine analog for use in the treatment of painful blunt injuries (traumas / trauma) to a patient, especially strains, sprains or bruises.
• the inhibitory active ingredient according to the invention is preferably administered orally and according to a dosage scheme which includes, for example, the following information:
• the recommended dosage is: on the day on which the strain, sprain, contusion occurred 15 mg; the following day 5 mg; 3 mg the following day.
• lowering the temperature by 10 degrees Celsius results in a halving to a third of the enzyme speed.
• By cooling the injured area it is achieved that the enzymatic reactions that are set in motion by the body as a result of the injury are clearly inhibited.
• Lowering the tissue temperature is only possible to a certain extent, however, because excessive cooling leads to tissue damage.
• the GSSV according to the invention allows it on the other hand, lowering the metabolism even more than is possible with cooling, without causing irreversible cell and tissue damage.
• the cooling of the tissue with externally applied refrigerants such as ice is also only gradual, because it is strongest near the refrigerant and significantly less pronounced further inside the tissue. Especially with deeper lying injuries such as joint injuries, the cooling system is only able to cool deeply lying tissue areas to a very limited extent.
• an inhibition of the metabolism caused by cooling can only be used to a very limited extent, since the available temperature range extends maximally to freezing point.
• this factor is unlimited, since by inhibiting the metabolism with drugs, this can be carried out independently of the temperature up to complete inhibition.
• a suitable dosage regimen for the administration of the inhibitory active ingredient according to the invention can according to the invention for any desired application, in particular for use in a pre- or co-therapy in the treatment of cancer and / or for Use in a week-long or month-long long-term therapy, according to the following procedure, i.e. determined using a method that includes the following steps:
• step (2c) Repetition of steps (2a) and (2b) and repetition of step (2c) with the modification that the administration of the coenzyme antagonist / active ingredient (for example and preferably B-OT) to the patient in an amount / dose T ( i) takes place, which is determined (calculated) on the basis of the amount / dose of the previous day T (il) and the desired target value for the enzyme activity inhibition and on the basis of the reduction in enzyme activity calculated in step (2b).
• the amount / dose T (i) can be larger or smaller in comparison to the previously administered amount / dose T (il), that is, the dose T (il) is adjusted to the dose T (i) in a reduction or increase the previously administered amount of B-OT.
• medical parameters of the disease are monitored in a step (4), for example the inhibition of the formation of new metastases or the growth of bacteria or fungi in the body, and of medical parameters of the basic functions of the patient's body, for example and preferably the number of heartbeats per minute (pulse rate) and / or loss of appetite and / or weight loss in the patient. Adjustment of the target value for the inhibition of enzyme activity in such a way that on the one hand the medical parameters of the disease reach the desired values and on the other hand there is still sufficient residual enzyme activity so that the basic functions of the patient's body are maintained over the long term.
• the target value for the inhibition of the enzyme activity should be set in such a way that, on the one hand, the desired values for these medical parameters are achieved , on the other hand, there is still sufficient residual enzyme activity to enable the patient's basic functions in the long term.
• the number of heartbeats per minute can be used to measure the basic function of the body. If the pulse rate becomes too high, the amount or dose of the coenzyme antagonist / active ingredient to be administered (for example the amount of B-OT) must be reduced. Loss of appetite or a loss of weight in the patient can also be evaluated and used as an indication of a necessary reduction in the amount or dose of the coenzyme antagonist / active ingredient to be administered (for example the B-OT amount)
• the target value of the enzyme inhibition is for example and preferably at least 20%, particularly preferably at least 50%, very particularly preferably at least 70%, in each case based on the value of the original enzyme activity measured in step (la) (as the starting value).
• the administration is preferably carried out orally and the amount / dose TI of B-OT is preferably about 1 mg to about 30 mg, preferably about 2 mg to about 15 mg.
• the target value of the inhibition of the enzyme activity can be achieved of, for example, 50% or 70% in the patient in question can be achieved and maintained in a relatively short time.
• the (high) amount of the individual doses for patients is preferably and usually a value from the range from about 0.1 mg to about 80 mg, particularly preferably a value from the range from about 1 mg to about 50 mg, in each case based on a body weight of 60 kg.
• Figure 1 Change in the individual plasma concentrations of OT with time (over 24 hours) in male beagle dogs.
• the plasma concentration in ng / ml is given on the y-axis.
• Figure 2 Graphical representation of the change in the plus beat over time in dogs after administration of various amounts (doses) of B-OT.
• the x-axis shows the time in hours.
• FIG. 3 Computed tomographic image of the lungs of patient 1 before and after B-OT treatment.
• A Prior to B-OT treatment, pronounced areas with viral pneumonia infiltrates are visible.
• B clear decrease in infiltrates after 7 days of B-OT therapy.
• FIG. 4 Computed tomographic image of the lungs of patient 2 before and after B-OT treatment.
• A Prior to B-OT treatment, pronounced areas with viral pneumonia infiltrates are visible.
• B clear decrease in infiltrates after 7 days of B-OT therapy.
• FIG. 5 Computed tomographic image of the lungs of patient 3 before and after B-OT treatment.
• A Prior to B-OT treatment, pronounced areas with viral pneumonia infiltrates are visible.
• B clear decrease in infiltrates after 7 days of B-OT therapy.
• FIG. 6 Computed tomographic image of the lungs of patient 4 before and after B-OT treatment.
• a and C before B-OT treatment, pronounced areas with infiltrates of viral pneumonia are visible.
• B and D clear decrease in infiltrates after 7 days of B-OT therapy.
• Figure 7 Computed tomography of the lungs of patient 2 (see Fig. 4) one month after the end of therapy.
• Example 1 Determination of suitable dosages for the dosage regimen and the monitoring of the therapy
• the effect of B-OT in the patient's body is determined by various patient-specific factors such as gene variants, binding affinity of thiamine or B-OT to the respective thiamine-dependent enzymes, the active uptake and transport of thiamine through transport systems in the body and the enzymatic breakdown of Thiamine affects.
• the desired or optimal amount of the dosage of B-OT for a specific patient or group of patients and suitable for the individual situation of the patient (s) can be determined using various diagnostic methods and parameters.
• One possible method is the measurement and monitoring (monitoring) of the pulse rate and pulse rate change in the patient (s) concerned.
• the GSSV slows down (throttles) the metabolism and also reduces the energy released.
• the body tries to compensate for the lower energy release by increasing the pulse rate in order to transport more oxygen into the body so that more energy can be released.
• the increase in the patient's pulse rate is an indication and a suitable parameter for the fact that and to what extent the GSSV has inhibited the release of energy. If the pulse rate rises sharply, e.g. a human pulse rate over 90, countermeasures may be necessary to increase the energy release again. This can be achieved by reducing the amount of B-OT (dose reduction) that continues to be administered or by administering thiamine (especially the thiamine form benfotiamine).
• FIG. 2 shows the significant increase in the heart rate over 24 hours in dogs after administration of various amounts of B-OT.
• transketolase enzyme activity in lysates of erythrocytes of the patient is the determination of the transketolase enzyme activity in lysates of erythrocytes of the patient and use of the determined transketolase Enzyme activity values as diagnostic markers for monitoring B-OT therapy.
• the basal transketolase enzyme activity in erythrocytes should preferably be selected as a parameter.
• test methods to determine the transketolase enzyme activity in erythrocyte lysates is known in the prior art, for example from Smeets et ab, 1971 and Takeuchi et al., 1984 and Michalak et al, 2013,
• the transketolase enzyme activity in lysates of erythrocytes of the patient is determined before the administration of B-OT is started. After the administration of B-OT, the transketolase enzyme activity is determined again on the following day in freshly obtained lysates from erythrocytes of the patient (s) concerned. On (all) other days after further administrations of B-OT, the transketolase enzyme activity should be determined in freshly obtained lysates of erythrocytes of the patient concerned. The extent of the inhibition of the transketolase enzyme activity in the erythrocytes is determined by comparing the determined transketolase enzyme activity values during B-OT therapy with the values determined before the start of administration of B-OT. This makes it possible to choose the amount (dose) of B-OT to be administered so that the desired degree of inhibition of the transketolase enzyme activity and that of other thiamine-dependent enzymes is achieved.
• a 50% inhibition can be chosen, for example, in order to administer B-OT over the long term so that inflammation is permanently inhibited.
• An 80% inhibition can be chosen, for example, if the administration of B-OT is to be carried out daily for about a month in order to inhibit metastasis in cancer patients with very advanced disease.
• measurements of one or more of the following biochemical markers in the patient's blood can also be used: increase in bilirubin level, increase in the enzymes ALAT (alanine aminotransferase) and ASAT (aspartate aminotransferase) , Decrease in the enzyme CK (creatine kinase), decrease in protein concentration (not albumin level), decrease in white and red blood cells, increase in platelets (thrombocytes), decrease in reticulocytes.
• ALAT alanine aminotransferase
• ASAT aspartate aminotransferase
• Example 2 Use according to the invention of the active ingredient benfo-oxythiamine "B-OT” for GSSV in cancer cells circulating in the blood Cancer cells circulating in the patient's blood are detected and separated and isolated from the blood. Detection, separation and isolation are preferably carried out without the use of surface markers, ie for example by means of cell sorting and multi-staining single-cell analysis "MSSCA", so that the isolated cancer cells represent a representative image of the malignancy (cancer tumor) in the patient.
• MSSCA multi-staining single-cell analysis
• test series A with the cancer therapeutic agent (s) in question, and in a parallel test series “B” initially with the active ingredient benfo-oxythiamine (“B-OT”) - as a preferred example of an inhibitory thiamine analog or an inhibitory coenzyme antagonist - incubated and then treated with the cancer therapeutics from test series A (see also Example 3).
• B-OT benfo-oxythiamine
• test series A and B are compared, and especially if it is found that a preferred cancer therapeutic agent (or its active ingredient) from test series A does not appear to be effective or only inadequately effective according to guidelines or for other reasons, after pretreatment with B-OT according to the result in test series B, on the other hand, shows a satisfactory effect, pretreatment with B-OT as a co-therapy of the actual established cancer therapy is indicated for the patient's upcoming cancer therapy.
• Example 3 Determination of the appropriate combination of effecting the GSSV (GSSV therapy) according to the invention as pre- or co-therapy and subsequent or simultaneous drug therapy (e.g. chemotherapy and / or targeted cancer therapy) and / or radiation therapy in a cancer patient
• Sorafenib, Imatinib, Erbitux, Avastin, Herceptin) and / or the application of radiation therapy can be determined in various ways: a) The cancer patient is first treated with established chemotherapy (using classic cytostatics, ie cell type-unspecific cell proliferation inhibitors) and / or targeted cancer therapy (using cell-type-specific agents such as sorafenib, etc.) and / or radiation therapy (according to valid evidence-based therapy rules).
• cancer cells are removed from a cancer patient who has not yet received any established chemotherapy and / or targeted cancer therapy and / or radiation therapy and treated in vitro, preferably ex vivo (ie on a malignant tissue sample freshly isolated from the organism) with the cancer therapeutics that can be considered to determine which agent or combination of agents works best.
• a chemotherapeutic agent or a targeted cancer therapeutic agent or a radiation therapeutic agent or a combination of several of these therapeutic agents can be identified which is effective in the individual situation of the cancer patient. This also determines whether the malignancy cells in question are resistant to the therapeutic agents used.
• test series B and / or a test series “C” is carried out in parallel to this in vitro test series “A” of the cancer therapeutics in question.
• test series B the patient's malignant cells are first pretreated with a coenzyme antagonist according to the invention as the active ingredient (medicament) - for example and preferably with an inhibitory thiamine analog - and then treated with the planned cancer therapeutic.
• test series C the patient's malignancy cells are treated simultaneously both with a coenzyme antagonist according to the invention as an active ingredient (medicament) - for example and preferably with an inhibitory thiamine analog - and with the planned cancer therapeutic.
• a targeted cancer therapy through the combination with a medicament according to the invention in the course of a pretreatment (as in test series A) or in the course of a co-therapy (such as in test series B, ie with parallel, approximately simultaneous administration of the medicament according to the invention and the conventional cancer therapeutic) will be effective or more effective than alone (ie without this pretreatment).
• This procedure (b) has the particular advantage that the time span within which any resistances of the cancer cells of the patient in question to the chemotherapy and / or radiation therapeutic agent intended for use arise or existing resistances are recognized is considerably reduced.
• the interval between the formation of resistance and the point in time at which this formation of resistance is detected can be massively shortened because the resistance of the cancer cells to the therapeutic agent in question can be determined directly ex vivo, and not, as has been the case up to now, using surrogate markers such as cancer tumor markers or the visualization of the size of the cancerous tumor (malignancy) must be determined indirectly and in vivo.
• existing resistances can be recognized before therapy.
• a certain chemotherapeutic agent i.e. a cell-type-unspecific cell proliferation inhibitor such as classic cytostatics and / or a cell-type-specific agent such as sorafenib
• a radiation therapeutic agent can be used sensibly and successfully. This enables a targeted therapy tailored to the individual situation of the cancer patient with the best possible success of the therapy. This results in far-reaching perspectives, particularly with regard to individualized medicine.
• the toxicokinetics of the active metabolite OT was determined in plasma samples taken on the first day “day 1" and on the seventh day “day 7" after the start of administration were won. The measurement results determined are shown graphically in FIGS. 1 (a) to (d).
• FIG. 1 a shows the changes in the individual plasma concentrations of oxythiamine (OT) over time in male beagle dogs on day 1, ie on the first day after administration of a single dose of B-OT in an amount of 1 mg / kg / day .
• OT oxythiamine
• FIG. 1 b and FIG. 1 c show the changes in the individual plasma concentrations of oxythiamine (OT) with time in male beagle dogs on day 1, ie on day 1 (FIG. 1 b) and on day 7, ie on day seven ( Fig. 1 c) the daily administration of single doses of B-OT in an amount of 0.5 mg / kg / day.
• OT oxythiamine
• FIG. 1 d shows the changes in the mean (mean) plasma concentrations of oxythiamine (OT) over time in the male beagle dogs (from FIGS. 1 a to 1 c) on day 1 and on day 7 during the daily administration of single doses of B. -OT at a concentration of 0.5 mg / kg / day and on day 1 after administration of a single dose of B-OT at an amount of 1.0 mg / kg / day.
• OT oxythiamine
• Oxythiamine was not found in plasma samples obtained on day 1 prior to administration of B-OT. Systemic exposure to OT was achieved in all animals treated with the active ingredient B-OT. For all administered doses of B-OT, the point in time of the maximum OT plasma concentration (Tmax) after administration of B-OT was investigated and the highest value was determined in the period between one and two hours. When the applied B-OT dose was gradually increased from 0.2 mg / kg to 1.0 mg / kg, an increase in the plasma concentrations of oxythiamine (OT) was observed, which was approximately linearly proportional to the increase in dose.
• Example 5 Administration of B-OT to patients with SARS-CoV-2 infection
• CT computed tomography
• a computed tomography image of the lungs taken as part of the follow-up is available one month after the end of therapy, and this shows a stable result (Fig. 7).
• C-reactive protein C-reactive protein
• IL-6 interleukin-6
• cytokine IL-6 The proinflammatory cytokine IL-6 with pleiotropic properties also seems to play a key role in the "cytokine storm", which is also described for patients with SARS-CoV-2 infections. Its constitutive expression causes organ damage and severe pain.
• the required inpatient stay was significantly shorter than the total collective of more than 700 patients, on average by one week.

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