Benfo-oxythiamine and / or oxythiamine for use in the treatment of malaria

Abstract

The invention relates to the substances benfo-oxythiamine (B-OT) and / or oxythiamine (OT) as an active ingredient of a medicament, in particular a human medicament, for the therapeutic treatment of infections with sporozoa of the genus Plasmodium and malaria disease caused thereby in a patient or potential patient.

Description

[0001]Drug active ingredients for the treatment and prevention of malaria. Description: The invention relates to substances for use as an active ingredient of a drug for the therapeutic treatment of infections with sporozoans of the genus Plasmodium and the resulting malaria disease in a patient or potential patient. Malaria is one of the deadliest infectious diseases in the world. According to WHO estimates, in 2021, almost half of the world's population was at risk from malaria, and more than 0.6 million deaths were attributed to malaria. Malaria is caused by parasites of the genus Plasmodium. The two species Plasmodium falciparum and Plasmodium vivax cause most malaria infections in humans. Children under 5 years of age and pregnant women in sub-Saharan Africa are most affected. Every two minutes, a child dies from the consequences of malaria. Rapid diagnostic tests and improved prevention throughDrug prophylaxis had led to a decline in the number of malaria cases starting in 2010. A number of factors have now brought this positive trend of declining case numbers to a halt. A key reason for this is the increasing resistance of the plasmodia to drugs that were previously very effective. Combination therapy with the active ingredient artemisinin represents an essential therapeutic pillar, particularly for severe cases. However, resistance to artemisinin combination therapies is also increasingly being detected, and in these cases, no effective treatment options are available for affected malaria patients. The increasing global spread of resistance to malaria drugs hampers rapid and effective treatment of malaria. In addition, climate change could lead to the expansion of malaria-infested areas. The invasion of the mosquito Anopheles stephensi, whichThe introduction of a drug that can easily adapt to urban environmental conditions into regions that have previously been barely or unaffected is a major risk. A new drug against malaria would be extremely important, but would also be like searching for a needle in a haystack. There is therefore an urgent need to establish new antimalarial drugs. Of particular importance are drugs that have novel mechanisms of action. Unfortunately, many active substances currently in preclinical development or clinical trials are derived from already known drugs and their mode of action, so there is a great risk that resistance to these new malaria drugs will develop within a short period of time. It is therefore of utmost importance to use new chemical structures with new mechanisms of action to minimize the risk of emerging resistance (see also Wells, 2011). A key property of a malaria drug is its ability toTo inhibit the proliferation of Plasmodium in the host organism. The development of human malaria drugs has been and continues to be significantly shaped by the therapeutic approach of finding active substances that target points of attack that are selectively found in Plasmodium, but not in the human body. The strategy of establishing vaccines against Plasmodium also uses epitopes that are specific to Plasmodium. This is intended to prevent the vaccination from triggering an autoimmune reaction in the patient's body. The current status of the fight against malaria is sobering and extremely dangerous because resistance has now developed against all malaria drugs and there is still no vaccine that provides comprehensive protection against malaria. Plasmodium falciparum transketolase (PfTk) plays a crucial role in the proliferation and survival of the parasite. For this reason, and because the amino acid sequence of Plasmodium falciparum transketolase differs significantly fromBecause of the amino acid sequence of human transketolase, PfTk was considered a suitable target in the early 2000s for the development and establishment of inhibitors that specifically inhibit PfTk but not human transketolase. The latter was a mandatory feature of the sought-after inhibitors because human transketolase plays a crucial role in the proliferation and survival of human cells and of humans as a whole, and is particularly crucial for the formation of new immune cells, which are important for the immunological fight against plasmodia. A suitable inhibitor must exclusively inhibit plasmodia transketolase, but not human transketolase, so that humans do not suffer any general disadvantages from the inhibition of their transketolase and, in particular, from the inhibition of their immune system. To solve this problem, Joshi et al. expressed PfTk as a protein.and biochemically investigated. Based on this, a structural model of PfTk was created and differences in its kinetic properties compared to human (i.e., the host) transketolase were demonstrated. This enabled the authors to significantly facilitate the design of new inhibitors with the potential of an antimalarial drug that only inhibits Plasmodium falciparum transketolase. Recent publications (see Hasan et al. 2015, Boateng et al. 2020) also show that this approach is still relevant in the search for effective antimalarial drugs. In a study by a Nigerian research group (Fadare et al. 2021), PfTk was also used to identify specific inhibitors against this transketolase that do not inhibit human transketolase. In this study, the active ingredient LAN, a dinitrophenylhydrazine derivative of lanosterol, was identified. LAN showed better binding to the PfTk thanits natural cofactor thiamine pyrophosphate (TPP). The active ingredient LAN was tested in vivo for its efficacy against malaria, using a mouse model with the established anti-malarial drug chloroquine (trade name Resochin®) as a standard. It was found that LAN, at a concentration of 25 mg / kg, exhibits an activity comparable to that of chloroquine (of 10 mg / kg). Even 24 days after administration of the drug, no mortality was observed in the test animals, demonstrating that the active ingredient LAN, as an inhibitor of PfTk, indeed has the potential for a future antimalarial drug. The 2023 study by Kaushik et al. also focused on PfTk. This research group succeeded in producing PfTk as a recombinant protein. In their study, they investigated the antimalarial effect of extracts from the leaves of the plant Anacardium occidentale L., which is traditionally used to treatMalaria. Various extracts were prepared and tested in vitro for their inhibitory effect against the recombinant PfTk enzyme. In addition, the growth-inhibiting activity against cultured P. falciparum parasites in the blood stage was investigated. An aqueous-alcoholic extract of the leaves of A. occidentale (HELA) was used, and different concentrations were initially tested for side effects (toxic effects) in mouse and fish embryos. The HELA extract showed very pronounced inhibition of Plasmodium transketolase (75%) and an outstanding inhibition of the growth of intra-erythrocytic Plasmodium stages of over 99%. This result is strong evidence that the inhibition of Plasmodium transketolase is a very promising approach to establishing a new anti-malaria drug. In contrast to the aforementioned studies, the study by Chan et al. (2013) uses an active ingredient that does notSelective for Plasmodium transketolase, namely oxythiamine (OT). Data on the in vivo effect of OT on Plasmodium proliferation were generated using a mouse model in which mice were infected with Plasmodium vinckei vinckei. OT was administered at a concentration of 400 mg per kilogram of body weight per day. On day 5 after infection, Plasmodium proliferation (parasitemia) was approximately 6-fold lower than in mice from the control group that received water (i.e., no OT). However, OT treatment also led to significant weight loss in the mice. The survival time of the mice treated with OT was only extended from 6 to 8 days. After 8 days, all mice (with or without OT treatment) were dead. In discussing these results, the authors conclude that it is unlikely that oxythiamine will be developed as a standalone antimalarial drug. They suggest that it isThis could serve as a starting point for the development of new anti-malarial drugs that target the relevant metabolic pathway. They emphasize that new anti-malarial drugs or their active ingredients must be specific for Plasmodium, because otherwise, as in the case of OT, the immune system of the host (i.e., humans) would be inhibited. The publication of this study by Chan et al. and, in particular, the death of all mice infected with Plasmodium and treated with oxythiamine led to the discontinuation of the approach of using oxythiamine as an anti-malarial drug since 2013. Instead, the research groups attempted to establish active ingredients that selectively inhibit the transketolase of Plasmodium. The study by Fadare et al. (loc. cit.), published in 2021 and also conducted on a mouse model, shows that this approach works: In contrast to oxythiamine, in which all mice infected with Plasmodium died or had to be sacrificed,The active ingredient LAN, which selectively inhibits the transketolase of the Plasmodium, saves all mice. The present invention is based on the object of providing a new active ingredient for use in a medicament for the therapeutic treatment of malaria, preferably an active ingredient that has novel mechanisms of action against the pathogens. One solution to this object consists in the use of benfo-oxythiamine (B-OT) and / or oxythiamine (OT) as the active ingredient of a medicament, in particular a human medicament, for the therapeutic treatment of infections with sporozoa of the genus Plasmodium and the resulting malaria in a patient or potential patient. The use of B-OT and / or OT is particularly suitable and intended for a symptom-relieving and / or curative treatment, wherein B-OT and / or OT inhibits the development of the Plasmodium in the host cells of the patient, namely theErythrocytes. As a result, the plasmodia remain in the affected erythrocytes (host cells), which on the one hand significantly reduces or prevents their spread (via mosquitoes) to other potential patients (host organisms), and on the other hand reduces or prevents the suppression of the patient's immune system caused by the plasmodia and / or the erythrocytes infected by them. This reduction or elimination of suppression results in the immune system being activated to (i) develop an effective immunological defense reaction by means of which the plasmodia and / or the erythrocytes infected by them can be eliminated, and also (ii) develop an immune response that counteracts the proliferation of plasmodia in the patient during subsequent reinfections with plasmodia. This means that an immunological defense reaction or immune response will be triggered that will eliminate the plasmodia and / or the erythrocytes infected by them.Erythrocytes are eliminated or which is suitable and intended for the elimination of the plasmodia and / or the erythrocytes infected by them, and which also counteracts the proliferation of the plasmodia in subsequent reinfections of the patient. With the use according to the invention for the purpose of alleviating or curing a diagnosed plasmodia infection and / or malaria disease, one or more of the following effects are induced in the potential patient, preferably a human: - Inhibition or prevention of the formation of extracellular forms of plasmodia; - Cellular immune response against plasmodia; - Activation of the innate immune system, in particular of macrophages (phagocytic cells) with regard to the elimination of plasmodia by phagocytosis; - Humoral immune response (B-cell response) against plasmodia antigens; - Protective cellular immunity against infection by plasmodia or against plasmodia-induced pathology; - Reduction ofDevelopment of symptoms of a plasmodia infection and / or malaria disease; - Increased survival time of affected patients. The use of B-OT and / or OT is particularly suitable and intended for the preventive (prophylactic, preventative) treatment of potential patients, especially mammals, and especially humans. The preventive (preventive) administration of benfo-oxythiamine and / or oxythiamine ensures that, in the event of a plasmodia infection, the development of plasmodia in their host cells in the patient, particularly in the erythrocytes, is prevented or greatly reduced, thereby inhibiting their proliferation and causing them to remain in their host cells. This significantly reduces or prevents their spread to other potential patients. With the persistence of the plasmodia (essentially their "fixation") in the erythrocytes / host cells and the reduction in immunosuppression triggered by the active ingredient, the plasmodiaand / or the erythrocytes infected by them are effectively presented to the patient's immune system and thus become recognizable, so that the immune system is activated to generate an immune response by means of which the plasmodia and / or the erythrocytes infected by them can be eliminated. This reduces or prevents the manifestation of symptoms of a plasmodia infection and / or malaria disease. The use of B-OT and / or OT as a preventative (prophylactic, preventive) treatment of potential plasmodia infection and / or malaria disease is also intended according to the invention to provide the patient with lasting immunity against plasmodia. For this purpose, the plasmodia that have penetrated the patient during a plasmodia infection are effectively used as a quasi-live vaccine. With the preventative (prophylactic, preventive) use of B-OT and / or OT according to the invention for the purpose of avoiding plasmodia infection and / or malaria-In particular, one or more of the following effects are induced in the potential patient, preferably a human: - Protection against infections with Plasmodium; - Inhibition of extracellular forms of Plasmodium; - Cellular immune response against Plasmodium; - Activation of the innate immune system, in particular of macrophages (phagocytic cells) with regard to the elimination of Plasmodium by phagocytosis; - Humoral immune response (B-cell response) against Plasmodium antigens; - Protective cellular immunity against infection by Plasmodium or against Plasmodium-induced pathology; - Reduction or prevention of the manifestation of symptoms of a Plasmodium infection and / or malaria disease. The present invention is based on the novel and surprising discovery and finding of the inventor that Plasmodium have developed a strategy similar to cancer cells to grow and multiply in the human body. Plasmodium andCancer cells both survive at the expense of the organism by multiplying, and in many cases, damage it so severely that the organism / host dies. Both use the blood and the nutrients it contains to grow at the expense of the human host organism. Plasmodia and cancer cells have developed a metabolic dualism over the course of evolution. This metabolic dualism of Plasmodium displays striking similarities to the metabolic dualism in tumor cells. In Plasmodium, metabolism changes depending on the plasmodial stage. In tumor cells, the metabolic change leads to a change from benign tumor cells to malignant tumor cells (cancer cells). Traits that lead to evolutionary advantages for survival provide a selective advantage. In evolution, these changes, which provide positive advantages, are often achieved through different pathways. An example of an evolutionary advantage that relates toThe locomotion of living beings by flight has evolved independently via three different routes. Flight was first discovered by insects, then by birds, and finally even by mammals (bats). If a trait is advantageous, then, as with the development of flight, convergent developments can occur that lead to the same goal, namely a selective advantage, in different ways. In their evolution, Plasmodia have developed a metabolic pathway independently of mammals that gives them enormous advantages when reproducing in the host. This evolution was also characterized by coevolution with the host, which has led to the metabolism of Plasmodium in humans being significantly different from that of Plasmodium in rodents. The difference was and is largely due to the different diets of humans (omnivores) and rodents (high fiber content).Plasmodia can multiply very rapidly in humans. This is especially true in the intraerythrocytic stage. Rapid multiplication requires an anabolic metabolism, which is capable of rapidly generating large quantities of building blocks for the formation of new cells. Cancer cells also utilize large amounts of glucose from the blood for their proliferation. They thus carry out a fermentative metabolism that generates, in addition to lactic acid, ribose and acetyl-CoA. Intraerythrocytic plasmodia also carry out a metabolism that leads to the uptake of large amounts of glucose from the blood and is used for a fermentative metabolism that generates lactic acid, ribose, and acetyl-CoA. The uptake of glucose by erythrocytes that harbor intracellular plasmodia is 100 times higher than in non-infected erythrocytes. In relation to the starting product and also to the end products of the metabolism,Cancer cells and plasmodia-containing erythrocytes are thus very similar. This is an expression of anabolic metabolism, as this metabolism enables very rapid growth because glucose, as the basis for this metabolism, is present in large quantities in the blood, and the consumption of glucose is made possible by the continued provision of glucose by the body. In mammals, this anabolic metabolism based on glucose was made possible by the transketolase gene (TKT) being first duplicated during the evolution of vertebrates and then modified through several mutations into the so-called transketolase-like 1 (TKTL1) gene. The protein encoded by this gene, TKTL1, which occurs only in mammals, is largely responsible for the fact that in this extremely effective anabolic metabolism, not only a transketolase enzyme reaction takes place, which massively increases the formation of ribose, but also acetyl-CoA is directly formed. Furthermore, it helps toThe TKTL1 protein controls the cell cycle and forms a heterodimer with TKT transketolase. This TKTL1 / TKT heterodimer is responsible for the formation of large amounts of ribose via this anabolic pathway even before cell division (100% increase in ribose in the cells), so that ribose is available in sufficient quantities as a building block for DNA replication. Until the study by Li et al., published in 2019, experts thought that TKT transketolase was responsible for ribose formation. However, for a "housekeeping" gene / protein such as TKT transketolase, it is neither necessary nor sensible to produce large amounts of ribose if DNA replication is not required. A massive increase in ribose production only makes sense if DNA replication is to be achieved. The control of ribose production by TKTL1 allows for a very efficient adaptation of theRibose production is adapted to the current needs of the cells. At the same time, TKTL1 controls overall metabolism in such a way that the glucose flux is redirected from the Embden-Meyerhof pathway to pentose phosphate metabolism and thus to TKTL1 / TKT. In addition to ribose, acetyl-CoA is also required as another crucial building block for cell division and cell duplication. The TKTL1 protein also plays a key role in the formation of acetyl-CoA as a building block for new cells: When acetyl-CoA is needed for anabolic purposes such as cell division or cell duplication, TKTL1 is activated and the acetyl-CoA-forming enzyme pyruvate dehydrogenase is simultaneously inhibited. The redirection of glucose flow, triggered by TKTL1, away from the Embden-Meyerhof pathway and the associated pyruvate dehydrogenase to the pentose phosphate pathway with TKTL1 as the key enzyme, makes it possible for ribose and acetyl-CoA, as well as other important metabolites, to be produced in the same metabolic pathway.New cells are formed. TKTL1 represents the result of convergent evolution, because the so-called phosphoketolase protein also evolved during heterofermentative lactic acid fermentation in lactic acid bacteria. This protein directly forms acetyl-CoA and pyruvate from a C5 sugar, converting pyruvate into lactic acid. With the help of thiamine as a cofactor, both phosphoketolase and TKTL1 transketolase are able to form acetyl-CoA from a pentasaccharide without decarboxylation and the associated loss of carbon atoms. In contrast, pyruvate dehydrogenase, with the help of the cofactor thiamine, forms acetyl-CoA through decarboxylation, so that every third carbon atom is lost. For anabolic purposes, acetyl-CoA formation by phosphoketolase enzyme and acetyl-CoA formation by TKTL1 transketolase are therefore superior to acetyl-CoA formation by pyruvate dehydrogenase.Acetyl-CoA formation, lactic acid formation via TKTL1 is a key development in the course of mammalian evolution, as this TKTL1-mediated lactic acid formation also occurs when sufficient oxygen is available. Macrophages, for example, utilize this for lactic acid-mediated tissue remodeling / matrix degradation and the resulting suppression of the immune system. TKTL1-mediated lactic acid formation is independent of the lactic acid formation known to date in mammals via the Embden-Meyerhof pathway, and in contrast, it is not suppressed by oxygen. TKTL1 thus represents the enzymatic basis of the Warburg effect and significantly alters its significance, as not only lactic acid but also acetyl-CoA is an essential product of this metabolic pathway. In cancer cells, TKTL1 plays a crucial role in the suppression of the patient's immune system due to lactic acid formation, as the lactic acid formed prevents the attack.of the immune system and also triggers immunosuppression. This is achieved by, on the one hand, certain immune cells (e.g., killer cells) being arrested by the acid, and, on the other hand, by the lactic acid leading to the activation of PD-L1 ("programmed death-ligand 1") in the cancer cell membrane, which triggers immunosuppression. Very similarly, the metabolism of intracellularly growing plasmodia has changed during evolution in such a way that large amounts of glucose are taken up and large amounts of lactic acid are excreted. This is achieved by the fact that here, too, the glucose flow does not proceed via the Embden-Meyerhof pathway and pyruvate dehydrogenase (which then generates acetyl-CoA, which is utilized in the citric acid cycle), but rather by a thiamine-dependent enzyme that normally carries out the degradation of branched-chain amino acids, the so-called branched-chain ketodehydrogenase (BCKDH), which converts the glucose and therebyForms acetyl-CoA. From an evolutionary perspective, the metabolic pathways in intraerythrocytic plasmodia and the TKTL1 metabolism in humans, and particularly in invasively growing cancer cells, represent the result of a convergent metabolic development based on different enzymes, but with one thing in common: the use of thiamine as a cofactor for these enzymes. Thiamine-dependent enzymes allow the cleavage of carbon-carbon bonds. In the course of the evolution of life on Earth, two subfamilies have evolved: thiamine-dependent enzymes, which perform a single-substrate mechanism, and thiamine-dependent enzymes, which perform a two-substrate mechanism. In the two-substrate mechanism, a C2 unit is cleaved from a first substrate (S1) during a nucleophilic attack with the help of thiamine, which initially remains bound to the thiamine. The first substrate then leaves the enzyme, and a second substrate (S2) isbound to which the C2 unit is transferred. Transketolases are thiamine-dependent enzymes that operate according to the two-substrate principle and can thus convert sugar into other sugars. The formation of the energy-rich compound acetyl-CoA does not occur. This is quite different for thiamine-dependent enzymes that operate with the single-substrate mechanism. Here, in interaction with other enzyme components, acetyl-CoA is formed and decarboxylation occurs. Or, as in the case of phosphoketolase, the single-substrate reaction leads to the formation of acetyl-CoA without decarboxylation. An example of a single-substrate reaction with decarboxylation is pyruvate dehydrogenase (PDH), which catalyzes the decarboxylation of pyruvate to acetyl-CoA and carbon dioxide. The carbon dioxide is lost in the form of gas, and if the cell is pursuing an anabolic program, this represents a loss of valuable carbon atoms.If a cell wants to grow on the basis of glucose, i.e. if it wants to convert the carbon atoms from the glucose into new fats or membrane building blocks or other metabolites such as amino acids as effectively as possible, glucose breakdown using PDH is an extremely unsuitable method because one in three C atoms of the glucose, i.e. one-third of the total glucose, is lost. The TKTL1 gene and the resulting TKTL1 protein enable mammalian cells to carry out a phosphoketolase-like enzyme reaction that first emerged early in evolution in heterofermentative lactic acid bacteria: the breakdown of a C5 sugar directly into acetyl-CoA and pyruvate. The pyruvate is then converted into lactic acid or converted back into a C5 sugar. The cell can therefore decide how much lactic acid and how much acetyl-CoA to produce. If no lactic acid is required, 100% of the sugar can be converted into acetyl-CoA without any loss of carbon atoms.The advantage of the TKTL1 / phosphoketolase enzyme reaction is of immense importance in an anabolic metabolic situation: 100% of the available glucose can be converted into acetyl-CoA, whereas in the PDH reaction, only two-thirds of the glucose is converted into acetyl-CoA. The 33% increase in cell mass possible with the TKTL1 enzyme reaction provided a decisive evolutionary selective advantage for mammals. Only recently, it was shown that TKTL1-mediated acetyl-CoA formation is the basis for the increased neuron formation in the neocortex and the stronger folding of the neocortex cortex in Homo sapiens compared to Neanderthals, and that the TKTL1 enzyme was very likely crucial for the changes in cognitive-intellectual abilities of modern humans. The TKTL1 protein is thus an enzyme that, as a heterodimer, together with TKT carries out both the classical two-substrate reaction and thus the ribose formationmassively increases and also forms acetyl-CoA via a single-substrate reaction. This enables the extremely effective conversion of glucose into the building blocks ribose and acetyl-CoA, thus creating ideal conditions for rapid and efficient growth. At the same time, the formation of lactic acid opens up the possibility of fending off attacks by immune cells and also triggering immunosuppression via PD-L1. In the evolution of plasmodia, a convergent metabolic development has occurred: In the metabolic situation in which a rapid and effective buildup of cell material and proliferation of the plasmodia is necessary, i.e. in their intraerythrocytic life phase, the PDH enzyme reaction is not carried out for glucose breakdown, but rather a fermentative glucose metabolism in which acetyl-CoA and lactic acid are formed. Just as in the TKTL1 metabolism in mammals, a mutation in a thiamine-dependent enzyme in plasmodia hasEnzymatic properties are altered in such a way that fermentative glucose metabolism, without the use of pyruvate dehydrogenase, produces acetyl-CoA and lactic acid. The lactic acid is secreted by the erythrocytes, and just as with TKTL1 metabolism in mammalian cancer cells, this leads to defense against attack by immune cells and systematic immunosuppression. Previous research has shown that Plasmodia are capable of synthesizing the vitamins required for their growth, with the exception of vitamin B5 (pantothenate). For all other vitamins, Plasmodium is not dependent on external absorption, i.e., from host cells or the host organism. With regard to vitamin B1, thiamine, all genes encoding enzymes of thiamine biosynthesis are present in the genome of Plasmodium, and the enzymes they encode are capable of producing thiamine (vitamin B1). Nevertheless, plasmodiaThiamine from the host blood. This saves them the effort of synthesizing their own thiamine and allows them to use the saved resources for other processes necessary for their growth and reproduction. Apparently, the evolution of plasmodia has led to the establishment of uptake systems to absorb vitamin B1 from the host in order to grow faster. Due to the selective advantage that the uptake of thiamine from the host's blood provides to plasmodia, plasmodia in human erythrocytes predominantly use thiamine from human blood for their reproductive metabolism. A similar strategy has been developed by pathogenic bacteria such as Pseudomonas aeruginosa, which can produce thiamine themselves but use the thiamine from the infected human to grow faster and more effectively. Thiamine uptake from the infected organism thus represents another example of convergent evolution, which is evident in bothThis has led to a selective survival advantage in both bacteria and plasmodia. While most bacteria, fungi, and plants can produce thiamine (vitamin B1) de novo, mammals, including humans, are exclusively dependent on the intake of thiamine / vitamin B1 through their diet. Since thiamine (vitamin B1) in its active form, thiamine diphosphate (ThDP), is an essential cofactor for the human organism, thiamine is an essential component of human blood and the rest of the body. Many patients with plasmodia infection exhibit thiamine deficiency, which can be explained by the removal of thiamine from the host's blood by the plasmodia. Plasmodia, which generally act as parasites, have also developed parasitic behavior with regard to thiamine: They take the thiamine from the host's blood and thus save themselves the effort of synthesizing thiamine themselves. This has the great advantage for the plasmodia thatThey thus save energy and effort for growth and can therefore grow faster. The parasitic behavior of the plasmodia in relation to the uptake of thiamine from the host's blood opens up a therapeutic option for the control of plasmodia in the blood of the human host organism. Humans are omnivores who generally absorb only little thiamine. A diet consisting primarily of rice and / or raw fish can lead to a serious thiamine deficiency because husked rice is one of the few foods that is thiamine-free and because raw fish contains the enzyme thiaminase, which breaks down thiamine. A pronounced thiamine deficiency in the body can manifest itself in the form of beri beri, neurodegenerative diseases such as Wernicke-Korsakoff syndrome, or other thiamine deficiency diseases. In the course of evolution, humans have developed into omnivores who consume high-calorie foods with a relatively highProtein content (meat and / or fish) and with relatively few indigestible components (fiber) are preferred. In contrast, rodents such as mice and rats consume food with a high fiber content. Fiber cannot be digested directly. Only with the help of bacteria and single-cell organisms in the cecum, part of the fiber is used to form fermentation and other metabolic products during their growth. This includes thiamine (vitamin B1) produced by bacteria and single-cell organisms. The cecum is very large in rodents compared to humans. Rodents such as mice and rats therefore have no problem absorbing sufficient thiamine through the digestive tract, as the thiamine concentration is high due to the thiamine produced by the bacteria and single-cell organisms. In mixed diet eaters with a relatively small cecum and a diet that contains little fermentable fiber, for example in humans or dogs, theThe situation with regard to thiamine is completely different. They are fundamentally dependent on a very effective absorption of the thiamine present in the primary diet in the intestine, since no significant new synthesis of thiamine by bacteria and single-celled organisms increases the amount of thiamine. Due to the low amounts of thiamine in the human diet, absorption systems have developed in the human intestine over the course of evolution that make it possible to absorb thiamine very effectively from food. In contrast, the amounts of thiamine in the intestine of rodents are so high that there was no evolutionary need to develop such effective absorption systems for thiamine. These large differences between humans and rodents with regard to the amount of thiamine in the intestine and the different efficiency of thiamine absorption have had serious and very negative consequences for the research and therapy of diseases associated with thiamine:Mice and rats are used as animal models to conduct in vivo trials and preclinical development of active substances. The NOAEL value plays a crucial role here. The NOAEL value (no-observed-adverse-effect level) describes the exposure level of an active substance in an organism, determined experimentally or by observation, at which no biologically or statistically significant increase in the frequency or severity of adverse effects of the tested protocol is observed. In drug development, the NOAEL value of a new drug is determined in laboratory animals, particularly mice and rats, before human trials begin in order to establish a safe starting clinical dose for humans. However, the NOAEL values ​​obtained from mice or rats have had a lasting, extremely negative impact on research into thiamine-associated diseases for decades or even over a century because theThe data obtained from mice and rats on thiamine or thiamine derivatives such as oxythiamine cannot be extrapolated to humans due to the differences in thiamine intake described above. This extrapolation, however, has led to false-negative results, which have led to incorrect conclusions. Ultimately, this has prevented the development and establishment of medications associated with thiamine or that can be addressed with thiamine derivatives. Studies conducted by various research groups have repeatedly shown that mice and rats tolerate oral administration of oxythiamine in high concentrations over a relatively long period of time. Rais et al. (1999) administered high doses of 500 mg per kg body weight per day for 4 days and lower doses of 300 mg per kg body weight per day for 14 days without observing any toxicity. In a subsequent study by another research group (Yang et al.In the study (al. 2010), similar oxythiamine doses were used as in the study by Rais et al., but the drug was administered orally for a period of up to 5 weeks. No toxicity was observed here either. The inventor's own experiments have confirmed this high tolerability in mice and rats with regard to the oral administration of oxythiamine or benfo-oxythiamine (B-OT). The active ingredient B-OT (developed by the inventor) is a prodrug for the release of oxythiamine in the body. A Phase 1 clinical study and the associated pharmacokinetics showed that B-OT does not appear in the blood, but only oxythiamine. The release of oxythiamine occurs immediately after oral ingestion, and the maximum levels of released oxythiamine can be detected in the blood after 1 to 2 hours. B-OT is the world's first and only inhibitory thiamine derivative that has been successfully evaluated in a Phase 1 clinical trial. Since B-OT is a prodrug,which releases oxythiamine (OT), a direct link between OT data and B-OT is also possible. The inventor's experiments have shown that rats tolerate an oral administration of 1,000 mg B-OT per kg body weight for 7 days without toxicity. This confirms the studies described above on the tolerability of high doses of oxythiamine in mice and rats. If these data were extrapolated to humans, this would mean that a human weighing 80 kg could consume 80 grams of B-OT or 77 grams of OT every day for a week without experiencing side effects. However, preclinical experiments by the inventor have shown that the high orally administered doses of B-OT, and thus also OT, obtained from the mouse and rat experiments are not tolerated by dogs. Due to the above-described large differences in the digestive system of mixed feeders (human / dog) and rodents and the associated extremely different amount of naturally occurringThiamine and the absorption systems designed for it, the sensitivity of dogs to B-OT / OT is 1,000 times higher. The data on the tolerability of OT in mice and rats therefore do not represent the situation that exists in dogs. The inventor was able to demonstrate in a clinical phase I study with healthy volunteers that no serious side effects occur when B-OT / OT is administered at a dosage based on the NOAEL values ​​determined in dogs and a calculated adaptation to humans. Increasing the daily B-OT dose to 5 mg (per approximately 80 kg body weight) administered orally over seven days did not cause any serious side effects: Both in the first part of the clinical phase I, in which 0.5 mg to 5 mg of B-OT was administered orally as a single dose on one day (at approximately 80 kg body weight), and in the second part of the clinical phase I, in which 1 mg of B-OT was administered orally on seven consecutive days.No serious side effects were observed in studies ranging from 1 mg of B-OT up to the maximum dose of 5 mg B-OT (for approximately 80 kg body weight each). This demonstrates for the first time that B-OT represents a dosage form of OT that can be used clinically. Self-experiments by the inventor as well as the use of B-OT in terminal cancer patients and hospitalized coronavirus patients have also provided promising indications of the efficacy of B-OT. The therapeutic approach of inhibiting the proliferation of plasmodia in erythrocytes using B-OT and the OT released from it represents a completely new approach in several respects: Oxythiamine is an inhibitory thiamine derivative that, in contrast to many other thiamine derivatives, differs only slightly from thiamine and is therefore indistinguishable by enzymes that bind thiamine or by transport systems that transport thiamine, meaning it is bound and transported with similar affinity.It is precisely this pronounced similarity between thiamine and oxythiamine that enables the transport systems in the plasmodia membranes to capture oxythiamine (instead of thiamine) from the erythrocytes and transport it into the plasmodium, resulting in thiamine transport from the blood into the erythrocytes and then into the plasmodia. However, even this is not enough to inhibit thiamine-dependent enzymes inside the plasmodia because, just like thiamine, oxythiamine must first be converted into the pyrophosphate form by an enzymatic step. The enzymatic step that converts thiamine to thiamine pyrophosphate (TPP) is carried out by the enzyme thiamine pyrophosphokinase. The high similarity between thiamine and oxythiamine enables thiamine pyrophosphokinase to accept oxythiamine as a substrate and produce oxythiamine pyrophosphate (OTPP) from it. The OTPP is now in direct competition with the TPP in the Plasmodiumfor access to the binding sites of the thiamine-dependent enzymes of Plasmodium, particularly oxoglutarate dehydrogenase, pyruvate dehydrogenase, branched-chain keto acid dehydrogenase (BCKDH), and transketolase. The simultaneous inhibition of various enzymes, which in turn are essential in various metabolic pathways, is of enormous importance for the effectiveness of an active ingredient in inhibiting Plasmodium. Enzymatic alternative pathways often exist in the metabolism when a specific enzyme is blocked. In the case of B-OT / OT, the four thiamine-dependent enzymes oxoglutarate dehydrogenase, pyruvate dehydrogenase, branched-chain keto acid dehydrogenase (BCKDH), and transketolase are simultaneously inhibited. By blocking pyruvate dehydrogenase (in the apicoblast) and oxoglutarate dehydrogenase in the citric acid cycle (in the mitochondria), two metabolic pathways (in two different organelles) are inhibited, which are important for the intraerythrocyticPlasmodium growth is of relatively minor importance, as both metabolic pathways are rarely utilized. The key factor is the inhibition of transketolase in the pentose phosphate cycle, which inhibits the formation of ribose, so that no more ribose is formed and thus no more building blocks are available for the formation of DNA and RNA. By inhibiting BCKDH in the mitochondria, this enzyme, which is crucial for acetyl-CoA production, is inhibited, thus significantly inhibiting lipid synthesis and amino acid metabolism. Comparing the convergent metabolic situation in mammalian cells and plasmodia, in mammalian cells TKTL1 or the heterodimer with TKT is the decisive enzyme to inhibit ribose and acetyl-CoA production via its blockade by B-OT / OT, while in intraerythrocytic plasmodia the B-OT / OT-mediated blockade of the two independently working enzymes BCKDH and transketolase causes the ribose andAcetyl-CoA production can be inhibited. In both cases, however, the synthesis of two essential building blocks for the formation of new cells is prevented. The growth of cancer cells in mammals and the growth of intraerythrocytic plasmodia are therefore two sides of the same coin: Both metabolic pathways are based on mutations in thiamine-dependent enzymes that have enabled acetyl-CoA formation without decarboxylation and the associated loss of carbon atoms. The simultaneous inhibition of the formation of ribose and acetyl-CoA by B-OT / OT thus very effectively blocks the proliferation of plasmodia in erythrocytes. Erythrocytes are cells that no longer contain a nucleus and, in this respect, differ greatly from other cells. Therefore, erythrocytes do not have the normal ability to transcribe genes and translate mRNA into protein as needed. In the case of human transketolase in erythrocytes,During the formation of erythrocytes (during erythropoiesis in the bone marrow), thiamine binds to the newly synthesized transketolase protein. This bond is tight and virtually irreversible. This creates the functional enzyme consisting of a protein moiety and a cofactor. The addition of OT to erythrocytes does not inhibit the transketolase enzyme reaction, as OT is unable to displace the tightly bound thiamine. Therefore, there is no competitive displacement; rather, the timing of transketolase protein synthesis and the presence of the cofactor determine the permanent binding. If the transketolase protein is formed and OT reaches the cofactor binding site of the transketolase protein at this time, the OT is bound. The transketolase proteins formed previously and in the presence of thiamine contain tightly bound thiamine, which can no longer be displaced by the now present OT.(See Example 4) Therapeutically, this means that the status quo of the host cells' thiamine-dependent enzymes remains protected, allowing the cells to continue functioning, while newly formed cells are subject to strong inhibition by OT. This is precisely a decisive advantage in the treatment of people with Plasmodium infection and Plasmodium proliferation in erythrocytes. Normal (healthy) erythrocytes without Plasmodium infection are protected from the inhibitory effect of OT by the tight / firm binding of thiamine to the transketolase protein. In erythrocytes infected with Plasmodium, the same is true for the thiamine-dependent erythrocyte enzymes. The thiamine-dependent enzymes of the Plasmodium, on the other hand, are inevitably newly formed as the Plasmodium proliferates, and this is where the inhibitory effect of the applied OT takes effect. Although OT does not selectively inhibit Plasmodium transketolase, the tight binding of thiamine to erythrocyte transketolasea de facto selectivity of OT toward the inhibition of Plasmodium transketolase. Because OT is not toxic, but merely inhibits proliferation, this de facto selectivity applies to almost all cells of the host organism, as most cells and cell types do not proliferate continuously. Many cell types that normally proliferate continuously, such as hair root cells, intestinal epithelial cells, etc., do not need to proliferate continuously. Although their proliferation is inhibited by OT, they can tolerate a temporary pause in proliferation very well. The faster and more efficiently a Plasmodium multiplies in erythrocytes, the greater the damaging effect when benfo-oxythiamine is applied and oxythiamine inhibits the Plasmodium enzymes. Benfo-oxythiamine is therefore also suitable for saving patients who have already reached advanced stages of the disease. With the inventive application of B-OT / and / orOT offers the following advantages: It enables a new malaria therapy based on a novel mode of action and with extremely high protection against the development of resistance. The tolerability, safety and pharmacokinetics of B-OT / OT administration have already been successfully evaluated in a clinical phase I with healthy volunteers. It opens up the possibility of influencing the individual stages of Plasmodium development in such a way that their spread via mosquitoes is significantly reduced. It opens up the possibility of altering the metabolism of Plasmodium in such a way that replication in the host is inhibited and the immunosuppressive effect of the Plasmodium is reduced, and the patient's own immune system can better recognize and eliminate the Plasmodium. This also promotes the development of immunity in the patient against subsequent infections with Plasmodium. For other pathogenic sporozoa, which, like Plasmodium, are obligate asIntracellular parasites multiply in certain cells in the blood of the host organism and have a similar development cycle to plasmodia, for example Leishmania (flagellated protozoa, with a host switch between insects and vertebrates and with macrophages as host cells in the human blood), the above-described treatment with B-OT / OT also appears to be a suitable therapeutic approach. Against the background of the information known in the prior art on B-OT / OT tolerability and B-OT / OT efficacy, it is a routine task for the person skilled in the art to conduct appropriate clinical studies to determine suitable dosage and administration regimes with which the aforementioned effects can be achieved. The exemplary embodiments with figures given below illustrate the invention. The figures show: Fig. 1: Change in plasma concentrations of OT over time (over 24 hours and 168 hours) in maleSubjects. B-OT was administered orally once daily for a period of seven days at a dosage of 3.0 mg per subject (mean body weight 80 kg). The values ​​shown represent mean values ​​(with standard deviation of the geometric mean) of a cohort of six individuals. The x-axis indicates time in hours (h = hours). The y-axis indicates the plasma concentration of OT in ng / ml. (A) = Change in OT plasma concentration over the course of day 1 after B-OT administration. (B) = Change in OT plasma concentration over the course of day 7 after B-OT administration. Compared to day 1 (Fig. 1 A), a doubling of the amount of OT in the serum can be observed after twelve hours (12 h). (C) = Change in OT plasma concentration over the course of day 7 and the subsequent period up to day 14 (168 h). After 24 hours, the OT value had decreased to 0.5 ng / ml, and after 96 hours, 0.1 ng / ml of OT was still detectable. Fig. 2: Change in plasma concentrations of OT over time(over 24 hours and 168 hours) in male volunteers. B-OT was administered orally once daily for a period of seven days at a dosage of 5.0 mg per volunteer (mean body weight 80 kg). The values ​​shown represent mean values ​​(with standard deviation of the geometric mean) of a cohort of six individuals. The x-axis indicates time in hours (h = hours). The y-axis indicates the plasma OT concentration in ng / ml. (A) = Change in OT plasma concentration over the course of day 1 after B-OT administration. (B) = Change in OT plasma concentration over the course of day 7 after B-OT administration. Compared to day 1 (Fig. 1 A), after twelve hours (12 h) the OT value increased from 1.1 ng / ml to 1.9 ng / ml. (C) = Change in OT plasma concentration during day 7 and the subsequent period up to day 14 (168 h). After 24 h, the OT value has decreased to 0.8 ng / ml and after 96 h, 0.2 ng / ml OT is still detectable, i.e., twiceas much as with the administration of 3 mg B-OT at the same time point (96 h). Fig. 3: Parasitized erythrocytes in patients infected with either (Group I) a chloroquine-sensitive Plasmodium falciparum (Pf) strain or (Group II) a chloroquine-resistant Pf strain, each after treatment with (a) B-OT or (b) chloroquine or (c) B-OT and chloroquine in combination. Fig. 4: TKT activity in (a) washed and (b) unwashed erythrocytes Fig. 5: Inhibition of TKT enzyme activity using (a) B-OT and (b) OT in washed erythrocytes Fig. 6: Inhibition of TKT enzyme activity using (a) B-OT and (b) OT in unwashed erythrocytes Example 1: Study on healthy male volunteers on the oral application of benfo-oxythiamine "B-OT" and the detection of released oxythiamine "OT" in the organism (serum) Male volunteers were given B-OT (benfo-oxythiamine) orally once daily for periods of one to seven days in doses of 1 mg / person / day, 2 mg / person / day1, 3The toxicokinetics of the active metabolite OT (oxythiamine) were determined in plasma samples collected on the first day (day 1), on the seventh day (day 7), and from day 7 to day 14 after the start of administration, each at various time points on the respective day. The measured results for the dose of 3 mg / person (subject) / day are graphically presented in Figure 1 (A) to (C), and the measured results for the dose of 5 mg / person / day are graphically presented in Figure 2 (A) to (C). The values ​​shown represent mean values ​​from a cohort of six people (subjects). Figure 1 (A) shows the change in oxythiamine (OT) plasma concentration on day 1 after the oral administration of a single dose of B-OT in the amount of 3 mg per person. Figure 1 (B) shows the change in OT plasma concentration on day 7 after oral administration of a single dose of B-OT in the amount of 3 mg perPerson. On day 7, a doubling of the OT amount in the serum can be observed after twelve hours compared to day 1. Figure 1 (C) shows the change in OT plasma concentration on day 7 and in the subsequent period up to day 14 (168 h) after the oral administration of a single dose of B-OT in the amount of 3 mg per person. After 24 hours, the OT value has decreased to 0.5 ng / ml and after 96 hours 0.1 ng / ml OT is still detectable in the serum. Figure 2 (A) shows the change in OT plasma concentration on day 1 after the oral administration of a single dose of B-OT in the amount of 5 mg per person. Figure 2 (B) shows the change in OT plasma concentration on day 7 after the oral administration of a single dose of B-OT in the amount of 5 mg per person. On day 7, the OT value increased from 1.1 ng / ml to 1.9 ng / ml after twelve hours compared to day 1. Figure 2 (C) shows the change in OT plasma concentration on day 7 and in the subsequent period up to day 14 (168 h) after oral administration.Administration of a single dose of 5 mg of B-OT per person. After 24 hours (h), the OT level had decreased to 0.8 ng / ml, and after 96 hours (h), 0.2 ng / ml of OT was still detectable, twice as much as when 3 mg of B-OT was administered at the same time point (96 h). Both single and repeated doses of B-OT were very well tolerated by the subjects. This was confirmed by physical examinations of the subjects, their vital signs, their laboratory values, and electrocardiographic studies. The analysis of side effects showed that B-OT could be used safely and was well tolerated. The pharmacokinetics of B-OT were measured and documented in detail. The observed pharmacokinetics demonstrate that B-OT is well-suited for use in humans. Certain side effects such as hematuria, tachycardia, chills, and fever occurred in a few cases, albeit moderately. The evaluation of B-OT with healthy volunteers (men) in thePhase I clinical trials conducted by [company name] confirm that B-OT is a prodrug for humans, releasing OT in the blood. B-OT could not be detected in humans, only OT. Consequently, the humans were exposed to the active metabolite OT, but not the precursor (prodrug) B-OT. In principle, the same results have already been described in the prior art for rats and dogs. In these species, too, B-OT acts as a prodrug, releasing OT in the blood, and even there, it is not detectable. Example 2: Dosage and Administration Regimens. Due to the tolerability and efficacy established for B-OT / OT to date, the following dosage and administration regimens are suitable and intended for treatment with B-OT / OT according to the invention. They can be clinically tested and optimized without any special effort. Such testing and optimization procedures are part of the routine work of the person skilled in the art. (I) Dosage and Administration Regimen forInfected persons with symptoms: On day 1: 0.125 mg B-OT per kilogram of body weight per day On day 2: 0.094 mg B-OT per kilogram of body weight per day On day 3: 0.0625 mg B-OT per kilogram of body weight per day On day 4: 0.0625 mg B-OT per kilogram of body weight per day On day 5: 0.0625 mg B-OT per kilogram of body weight per day On day 6: 0.0625 mg B-OT per kilogram of body weight per day On day 7: 0.0625 mg B-OT per kilogram of body weight per day (II) Dosage and administration regimen in case of suspected Plasmodium infection (patient still without symptoms) On day 1: 0.0625 mg B-OT per kilogram of body weight per day On day 2: 0.03 mg B-OT per kilogram of body weight per day On day 3: 0.03 mg B-OT per kilogram of body weight per day On day 4: 0.03 mg B-OT per kilogram of body weight per day On day 5: 0.03 mg B-OT per kilogram of body weight per day On day 6: 0.03 mg B-OT per kilogram of body weight per day On day 7: 0.03 mg B-OT per kilogram of body weight per day (III) Dosage andAdministration schedule for people without symptoms but at increased risk of Plasmodium infection: On day 1: 0.02 mg B-OT per kilogram of body weight per day On day 2: 0.02 mg B-OT per kilogram of body weight per day On day 3: 0.02 mg B-OT per kilogram of body weight per day On day 4: 0.02 mg B-OT per kilogram of body weight per day On day 5: 0.02 mg B-OT per kilogram of body weight per day On day 6: 0.02 mg B-OT per kilogram of body weight per day On day 7: 0.02 mg B-OT per kilogram of body weight per day (IV) Dosage and administration schedule for people without symptoms but at moderately increased risk of Plasmodium infection: On day 1: 0.01 mg B-OT per kilogram of body weight per day On day 2: No B-OT intake On day 3: 0.01 mg B-OT per kilogram of body weight per day On day 4: No intake of B-OT On day 5: 0.01 mg B-OT per kilogram of body weight per day On day 6: No intake of B-OT On day 7: 0.01 mg B-OT per kilogram of body weight per day (V) Dosage andAdministration schedule for people without symptoms with a relatively low risk of Plasmodium infection: On day 1: 0.01 mg B-OT per kilogram of body weight per day On day 2: No intake of B-OT On day 3: No intake of B-OT On day 4: 0.01 mg B-OT per kilogram of body weight per day On day 5: No intake of B-OT On day 6: No intake of B-OT On day 7: 0.01 mg B-OT per kilogram of body weight per day All dosage amounts stated above under (I) to (V) for B-OT can be increased by up to 50% or even up to 100% or up to 75% less for the specific application in or against Plasmodium infections and malaria. Example 3: Measuring the efficacy of B-OT in malaria patients The efficacy of B-OT against the human parasite Plasmodium falciparum (Pf) was investigated as follows: Patients infected with a chloroquine-sensitive Plasmodium falciparum (Pf) strain (Group I) were compared with patients whowere infected with a chloroquine-resistant Pf strain (Group II). Both patient groups were subjected to a test developed for the evaluation of developmental substances against malaria (see Raether et al., 1989). The test procedure comprised the following steps: (1) Measurement of the patient's body temperature. (2) Collection of a blood sample and use of a 30 µl aliquot to prepare a classic methanol-fixed and Giemsa-stained blood smear on a glass slide. (The smear is dried and then stained in Giemsa solution for 8 minutes.) (3) Microscopic examination and evaluation of the smear preparation: 10 optical fields were analyzed with a 40x microscope objective, and the number of parasitized erythrocytes was determined. (4) Grouping of patients into groups Ia, Ib, Ic Ik and IIa, IIb, IIc IIk, and oral administration of (a) B-OT to the patients of groups Ia and IIa in theDosage: Initially (time 0) 0.125 mg / kg body weight (BW), after 24 h (day 1) 0.094 mg / kg BW, after 48 h (day 2) and 72 h (day 3) 0.0625 mg / kg BW each. (b) Chloroquine to patients in groups Ib and IIb at the following dosage: Initially (time 0) 10 mg / kg body weight (BW), after 6 hours 5 mg / kg BW, after a further 12 h and after 24 h (day 1) 5 mg / kg BW each (total dose 25-30 mg chloroquine). (c) B-OT and chloroquine in combination to patients in groups Ic and IIc at the dosages specified above under (4)(a) and (4)(b). (k) No treatment (control group). (5) 24 hours after the start of treatment: (i) Repeat measurement of body temperature in each patient to monitor treatment-related changes. (ii) Collect a blood sample and use a 30 µl aliquot for the preparation of a classic methanol-fixed and Giemsa-stained blood smear as described in (2) above. (iii) Microscopic examination and evaluation of theSmear preparation as described above under (3). (iv) Comparison of the value determined here (time 24 hours) with the baseline value determined in step 3 (time 0 hours) for the respective patient. (6) Repetition of step (5) after 48 hours and 72 hours. Test results: The results are shown in Table 1 of Figure 3. Columns 3 to 7 of this table show the mean value (calculated from the individual values ​​determined for the individual patients) for the respective patient group. Column 3 shows the total number of parasitized erythrocytes determined in step (3) at time 0 as the mean value (calculated from the individual values ​​determined for the individual patients). This total number is set as 100%. Columns 4, 5 and 6 show the reduction in the total number of parasitized erythrocytes compared to the baseline value at time 0 for theThe values ​​for the respective group are given as a mean value (calculated from the individual values ​​determined for each patient) and as a percentage relative to the baseline value at time 0 (which was set as 100%). It was shown that after just 24 hours (day 1) of treatment with B-OT – alone or in combination with chloroquine – the number of parasitized erythrocytes had decreased by at least 20% compared to the baseline value. On day 3, the effective therapeutic effect of treatment with B-OT – alone or in combination with chloroquine – was clearly evident: Body temperature had normalized and the number of parasitized erythrocytes had decreased significantly, namely by more than 90% or to less than 10% of the baseline value. Example 4: Measurement of transketolase enzyme activity in erythrocytes To measure the transketolase enzyme activity in erythrocytes and its inhibition by B-OT, the following enzyme test was established, in which theTransketolase (TKT) activity was measured by monitoring the oxidative reaction of NADH to NAD+. The decrease in NADH was measured by absorption at 340 nm (indirect measurement as described in K. Jones et al. (2020). The calculated TKT activity in milliunits (mU) was expressed in relation to milligrams (mg) of hemoglobin. The TKT activities were thus standardized in relation to the hemoglobin value. The test consists of three consecutive enzyme reactions: (I) Ribose-5-phosphate and xylulose-5-phosphate are converted to sedoheptulose-7-phosphate and D-glyceraldehyde-3-phosphate with the help of transketolase. (II) D-glyceraldehyde-3-phosphate is converted to dihydroxyacetone phosphate with the help of triose phosphate isomerase. (III) Dihydroxyacetone phosphate and NADH are converted to Glycerol-3-phosphate dehydrogenase to glycerol-3-phosphate and NAD + At the end of step (III) the rate of oxidation of NADH to NAD +measured by the decrease in absorbance at 340 nm. Recombinant transketolase protein (TKT) was used to establish the transketolase enzyme assay (available, for example, from benfovir AG, Darmstadt, Germany). Transketolase enzyme activity was determined using blood hemolysates obtained from K3EDTA whole blood from 10 healthy individual donors using two independent methods (a) and (b): Method (a) – with washed erythrocytes: 1) 2 ml aliquots of individual blood were made up to 10 ml with 0.9% NaCl solution (saline) (mixed gently by inversion). 2) The tubes were centrifuged at 3800 rpm at room temperature for 10 minutes. 3) The supernatant was removed. 4) Steps 1, 2, and 3 were repeated for a total of 3 wash cycles. The washed red blood cells were stored at -20°C or -80°C. 5) On the day of analysis: 0.5 ml of washed red blood cells were mixed with 0.5 ml of distilled water.6) The solution was thoroughly mixed and incubated at room temperature for 10 minutes to ensure complete lysis. 7) The lysed red blood cells were centrifuged if necessary. For further storage, the blood hemolysate was kept at -20°C or -80°C. A stability test was performed as described below. Procedure (b) with unwashed red blood cells: 1) 2 ml aliquots of individual whole blood were prepared. 2) The tubes were centrifuged at 3800 rpm and room temperature for 10 minutes. 3) The supernatant was removed. The red blood cells were stored at -20°C or -80°C. 4) On the day of analysis: 0.5 ml of red blood cells were mixed with 0.5 ml of distilled water. 5) The solution was thoroughly mixed and incubated at room temperature for 10 minutes to ensure complete lysis. 6) The lysed red blood cells were centrifuged if necessary. For further storage, the blood hemolysate was kept at -20°C or -80°C.A stability study was conducted as described below. Freeze-thaw stability studies: Samples of washed red blood cells, unwashed red blood cells, hemolysate, and diluted hemolysate were tested after four freeze / thaw cycles. The study was performed in triplicate. The samples were stored in a freezer at approximately -20°C and -80°C for at least 12 hours and thawed unaided. Once completely thawed, they were refrozen and stored for at least another 12 hours. The stability of the TKT was assessed by measuring the samples immediately after preparation and after the four freeze / thaw cycles. The same stability study was performed using QC. TKTHigh samples were tested after 5 freezing / thawing cycles. The stability of the test item was assessed by measuring the samples immediately after preparation and after 5 freezing / thawing cycles. Long-term stability was investigated using samples that had been stored at -20 °C and -80 °C for at least 1 month. The test was performed in triplicate before and after storage. The stability of TKT was assessed by measuring the samples immediately after preparation and after the storage period. The same stability test was performed with QC TKTHigh samples were tested. The stability of the test item was assessed by measuring the samples immediately after preparation and after the storage period. The TKT enzyme activity in the erythrocytes was determined in samples of the blood hemolysates obtained from the 10 volunteers using the enzyme assay described above. The TKT assay procedure included the following steps: 1) 245 μl of each calibration standard and blank sample were transferred to a 96-well microplate. 2) 30 μl of the hemolysate samples were transferred to a 96-well microplate. 3) 15 μl of Tris buffer was added to the hemolysate samples. 4) The plate was shaken for 30 seconds at 600 rpm using a microplate shaker. 5) The plate was covered and incubated for 15 minutes at 37 °C. 6) 200 μl of working reagent containing ribose-5-phosphate, NADH and Α-glycerophosphate dehydrogenase-triosephosphate isomerase were pipetted into the hemolysate samples.(Xylulose-5-phosphate is not required as a substrate in the described method because it can be obtained from ribose-5-phosphate by conversion using the thiamine-independent enzymes ribose phosphate 1-isomerase and ribulose phosphate 3-epimerase (cf. Jones et al., 2020). 7) 200 μl of blank working reagent were pipetted into the control samples. 8) The plate was shaken for 30 seconds at 600 rpm using a microplate shaker. 9) Finally, the absorbance at 340 nm was monitored for 6 hours at 37 °C. The results are tabulated in Fig. 4 (Table 2). TKT enzyme activity is expressed in units (U) per gram (g) of hemoglobin (Hb). Subsequently, TKT enzyme activity inhibition experiments using B-OT and OT were performed on samples of all lysates. For each lysate, one set of samples without addition and one set of samples with addition of B-OT or OT were subjected to the previously described TKT enzyme activity test.The following concentrations of B-OT and OT (each concentration based on the test mixture) were used: 1 nm, 5 nm, 50 nm, 100 nm, 500 nm, 1 mM, 5 mM, 10 mM The B-OT or OT was added together with the working reagent in the test procedure described above. Test results: The results of the determined TKT enzyme activities in the samples with the addition of B-OT or OT on the one hand and the samples without addition (controls) on the other hand are shown in Tables 3 and 4 of Figures 5 and 6. The comparison of the determined TKT enzyme activities in the presence of B-OT or OT with the controls (i.e. the samples without addition) showed that NONE of the amounts of B-OT or OT used led to a significant reduction in transketolase enzyme activity. Apparently, the transketolase enzyme activity in the erythrocytes of the hemolysates could not be inhibited by B-OT or OT.This fact can be explained by the extremely tight binding of thiamine to the TKT enzyme, so that added B-OT or the resulting OT is unable to displace thiamine from the TKT enzyme. This means that B-OT or OT cannot inhibit functional TKT enzymes (with the coupled cofactor thiamine). Only newly formed transketolases, which arise in large numbers during plasmodia proliferation in erythrocytes, can be inhibited by B-OT or OT, in which B-OT or OT binds to the new TKT enzyme instead of thiamine. Cited non-patent literature: Boateng RA, Tastan Bishop Ö., Musyoka TM: Characterisation of plasmodial transketolases and identification of potential inhibitors: an in silico study. Malar J. 2020 Nov 30; 19(1):442. doi: 10.1186 / s12936-020-03512-1. PMID: 33256744; PMCID: PMC7756947. Chan XW, Wrenger C, Stahl K, Bergmann B, Winterberg M, Müller IB, Saliba KJ: Chemical and genetic validation of thiamine utilization as an antimalarial drug target. Nat Commun. 2013; 4:2060. doi: 10.1038 / ncomms3060. PMID: 23804074. 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PMID: 33354793; PMCID: PMC8451777. Joshi S., Singh A.R., Kumar A., Misra P.C., Siddigi M.I., Saxena J.K.: "Molecular cloning and characterization of Plasmodium falciparum transketolase"; Mol. Biochem. Parasitol. 2008; 160(1):32-41; DOI:10.1016 / j.molbiopara.2008.03.005 Kaushik M., Hoti S.L., Saxena J.K., Hingamire T., Shanmugam D., Joshi R.K., Metgud S.C., Ungar B., Singh I., Hegde H.V.: Antimalarial Activity of Anacardium occidentale Leaf Extracts Against Plasmodium falciparum Transketolase (PfTK). Acta Parasitol. 2023 Dec; 68(4):832- 841. doi: 10.1007 / s11686-023-00718-6. Epub 2023 Oct 13. PMID: 37831282. Li Y., Yao C.F, Xu F.J., Qu Y.Y., Li J.T., Lin Y., Cao Z.L., Lin P.C., Xu W., Zhao S.M., Zhao J.Y.: APC / C. CDH1synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression. Nat Commun.2019 Jun 7; 10(1):2502. doi: 10.1038 / s41467-019-10375-x. PMID: 31175280; PMCID: PMC6555833. Rais, B. et al. Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich’s tumor cells through inhibition of the pentose cycle. FEBS Lett.456, 113–118 (1999). Raether W., Enders B., Hofmann J., Schwannecke U., Seidenath H., Hänel H., Uphoff M.:Antimalarial activity of new floxacrine-related acridinedione derivatives: studies on blood schizontocidal action of potential candidates against P. berghei in mice and P. falciparum in vivo and in vitro. Parasitol Res. 1989;75(8):619-26. doi: 10.1007 / BF00930959. PMID: 2671988. Yang, C. M., Liu, Y. Z., Liao, J. W. & Hu, M. L. The in vitro and in vivo anti-metastatic efficacy of oxythiamine and the possible mechanisms of action. Clin. Exp. Metastasis 27, 341–349 (2010).

Claims

Claims 1. Benfo-oxythiamine and / or oxythiamine for use as the active ingredient of a medicament for the therapeutic treatment of infections with sporozoa of the genus Plasmodium and the resulting malaria disease in a patient or potential patient.

2. Use according to claim 1, wherein the medicament is a human medicament. 3.Use according to claim 1 or 2, characterized in that the therapeutic treatment is a symptom-relieving and / or curative treatment, wherein benfo-oxythiamine and / or oxythiamine inhibit the development of plasmodia in the patient's erythrocytes, so that the plasmodia remain in their erythrocytes, thereby significantly reducing or preventing their spread to other potential patients, and thereby reducing or preventing the suppression of the patient's immune system caused by the plasmodia and / or the erythrocytes infected by them, so that the immune system is activated to develop an effective immunological defense reaction by means of which the plasmodia and / or the erythrocytes infected by them can be eliminated, and also to develop an immune response that counteracts the proliferation of plasmodia in the patient during subsequent reinfections with plasmodia. 4.Use according to claim 3, wherein benfo-oxythiamine and / or oxythiamine causes one or more of the following effects in the potential patient, preferably a human: - inhibition or prevention of the formation of extracellular forms of plasmodia; - cellular immune response against plasmodia; - activation of the innate immune system, in particular of macrophages (phagocytic cells), with regard to elimination of plasmodia by phagocytosis; - humoral immune response (B cell response) against plasmodia antigens; - protective cellular immunity against infection by plasmodia or against plasmodia-induced pathology; - reduction in the severity of symptoms of plasmodia infection and / or malaria; - increase in survival time.

5. Use according to claim 1 or 2, characterized in that the therapeutic treatment is a preventive treatment of potential patients, in particular mammals, in particular humans, wherein the preventively administered benfo-oxythiamine and / or oxythiamine, in the case of a plasmodia infection, causes / causes an inhibition of the development of the plasmodia in the host cells, in particular the erythrocytes of the patient, so that the proliferation of the plasmodia is inhibited and the plasmodia remain in their host cells, thus significantly reducing or preventing their spread to other potential patients, and whereby the plasmodia and / or the erythrocytes infected by them are recognizable by the immune system, so that an immune response is elicited by means of which the plasmodia and / or the erythrocytes infected by them can be eliminated.and whereby the manifestation of symptoms of a plasmodia infection and / or malaria disease is reduced or prevented.

6. Use according to claim 5, characterized in that the immune response mediates lasting immunity against the plasmodia acting as a live vaccine.

7. Use according to claim 6, wherein benfo-oxythiamine and / or oxythiamine induces one or more of the following effects in the potential patient, preferably a human: - Protection against infections with plasmodia; - Inhibition of extracellular forms of plasmodia; - Cellular immune response against plasmodia; - Activation of the innate immune system,particularly of macrophages (phagocytic cells) with regard to the elimination of plasmodia by phagocytosis; - humoral immune response (B cell response) against plasmodia antigens; - protective cellular immunity against plasmodia infection or against plasmodia-induced pathology; - reduction or prevention of the manifestation of symptoms of plasmodia infection and / or malaria.

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