Benfo-oxythiamine (b-ot) and / or oxythiamine (OT) as an active ingredient of a medicament for the topical treatment of viral diseases of the skin

Abstract

The invention relates to the substances benfo-oxythiamine and / or oxythiamine for use as an active ingredient of a medicament to be administered topically for the therapeutic treatment of patients with a disease of the body surface skin (cutis and subcutis) and / or one or more mucous membranes (mucosa), said disease having been triggered (caused) by viruses. The medicament is administered at a point in time at which viral replication has already taken place and viral shedding from the host cell(s) is imminent. Benfo-oxythiamine and / or oxythiamine has / have the following effects: (I) a throttling or prevention of the propagation mechanisms of the viruses so that the viruses remain in the host cells thereof after replication has taken place and cell damage to the patient organism (host organism) is reduced or does not occur and (II) an immunological reaction to the viruses remaining in the cells so that the patient's immune system is activated or reactivated in order to generate an effective immune response to the viruses.

Description

[0001] Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) as the active ingredient in a medicinal product for the topical treatment of viral skin diseases

[0002] Description

[0003] The invention relates to the substances benfo-oxythiamine and / or oxythiamine for use as an active ingredient in a topically administered medicinal product for the therapeutic treatment of patients with a disease of the body surface skin (cutis and subcutis) and / or one or more mucous membranes (mucosa) caused by viruses.

[0004] Viruses are organic structures that spread outside of cells (extracellularly) as so-called virions through transmission, but as viruses they can naturally only multiply within a suitable host cell (intracellularly) because they do not have their own metabolism.

[0005] All viruses contain nucleic acids that encode the information necessary for their reproduction and spread. They naturally depend on the metabolism of a host cell for replication. However, viruses possess the ability to control their replication and the capacity for biological evolution.

[0006] In viruses that infect eukaryotic cells, and especially mammalian cells, the viral nucleic acid is replicated in the host cell. Coating proteins and, if necessary, other components of the virions are also synthesized by the host cell based on the viral genome (protein biosynthesis). New viruses are formed (morphogenesis) and released from the host cell as so-called virions, either by dissolving the host cell (cell lysis, lytic viral replication) or by expelling (secreting) the virions (viral budding).

[0007] Viruses can affect infected tissue, organs, or even the entire organism in such a way that significant damage occurs, which in the worst case leads to the death of the entire organism. Furthermore, viruses can trigger reactions within the entire organism that lead to severe damage, for example, by damaging infected cells or triggering reactions in other cells that harm or even kill the organism.

[0008] Viral infections still play a significant role, particularly in dermatology. Some types of viruses can inhibit programmed cell death (apoptosis) to such an extent that uncontrolled cell growth results. The human papillomavirus (HPV) is one example. Infected cells have an increased likelihood of developing into carcinoma cells, i.e., cancer cells.

[0009] Despite more than a century of intensive research, viral diseases still pose a major medical problem, responsible for much suffering and death. There are currently relatively few antiviral medications, and for a large proportion of different virus types, there are no medications at all.

[0010] Throughout medical history, various strategies have been developed to treat viral infections and their consequences, or to stop them at an early stage of infection.

[0011] Firstly, active substances have been developed that attack specific components of the virus's auxiliary structures in order to inhibit its replication within the infected organism. Such specific anti-virus strategies target, for example, virus-specific enzymes or the replication of viral DNA or viral RNA.

[0012] Another strategy is vaccination with virus-specific structures. This involves, for example, injecting killed or weakened viruses (live attenuated virus vaccine) into the body or administering them orally (oral vaccine). This vaccination with killed or weakened viruses aims to trigger an immune response in the vaccinated individual, which can then also be used to defend against more aggressive viruses. Past experience has shown that the immune response to such vaccination is often so strong that it provides lifelong protection against infections. Examples of successful vaccinations include those against polioviruses and the viruses that cause yellow fever.

[0013] Instead of killed or weakened viruses, sequences of viral nucleic acid (DNA or RNA) or derivatives thereof, which lead to the formation of viral epitopes in host cells, can also be injected into the body of the vaccinated individual (e.g., into a skeletal muscle). The aim is to cause these sequences to be expressed in the cells of the vaccinated individual, resulting in the formation of viral epitopes that are recognized by the immune system and trigger an immune response against these epitopes.

[0014] Despite these successful strategies, there are still numerous viral diseases for which no effective prophylactic therapy using a vaccine to mitigate future viral infections and their associated symptoms has yet been developed. This is particularly true for viral infections of the skin, specifically both the surface skin (cutis and subcutis) and the mucous membranes inside the body (mucosa).

[0015] For the vast majority of viral skin infections, i.e., those affecting the skin surface and / or mucous membranes, there is currently no effective medication. In most cases, only symptomatic therapies are available as treatment options; the healing process is left to the immune system of the affected patient.

[0016] Currently, only a few viral infections or viral skin diseases have reliably effective antiviral drugs available to inhibit viral replication. These known antiviral drugs for treating viral skin diseases are almost exclusively based on active ingredients that target specific points in the viral replication cycle; this makes them effective and specific to a particular virus type, but ineffective against (most) other virus types.

[0017] The antiviral creams known in the prior art for the treatment of herpes simplex and varicella-zoster infections of the skin usually contain one of the two active ingredients: aciclovir or penciclovir.

[0018] Aciclovir (ATC J05AB01) is a nucleoside analogue, specifically an acyclic analogue of the nucleoside deoxyguanosine, a building block of DNA. After aciclovir is taken up by the virus-infected cell (eukaryotic cell), it is metabolized by a viral thymidine kinase, characteristic of herpes simplex and varicella-zoster viruses, and subsequently by cellular kinases to the active compound aciclovir triphosphate. This is incorporated into the new viral DNA in place of guanosine triphosphate (dGTP), leading to chain termination during nucleic acid synthesis and thus inhibiting viral replication.

[0019] However, aciclovir is ineffective against other viruses from the herpes family, such as the Epstein-Barr virus, which do not possess this thymidine kinase characteristic of herpes simplex viruses and the varicella-zoster virus.

[0020] One disadvantage of acyclovir is its relatively low bioavailability and relatively short half-life, which means that medications containing this active ingredient must be administered relatively frequently—in the case of creams, several times a day at intervals of just a few hours. To address this disadvantage, the active ingredient penciclovir has already been introduced to the market. Penciclovir has the same mechanism of action as acyclovir, but a significantly longer half-life (10 to 20 hours versus 0.7 to 1 hour) and higher bioavailability.

[0021] Another, considerably more serious disadvantage of acyclovir (hereinafter referred to as "ACV") results from the fact that ACV has been widely used for more than 40 years, and that ACV-resistant strains of herpes simplex virus have since developed.

[0022] Since herpes simplex virus infection is incurable and recurs frequently, there is a strong need for an alternative antiviral drug, especially one for topical treatment, based on a different mechanism of action than that of acyclovir and penciclovir, particularly for patients infected with ACV-resistant strains of herpes simplex virus.

[0023] Aciclovir and penciclovir belong to the class of topical antiviral drugs that are prodrugs. They are only phosphorylated into the active agent, which inhibits the replication of viral DNA, by viral thymidine kinase.

[0024] According to the Gelbe Liste Pharmindex (a German drug directory containing information on medications, including relevant information on uses, contraindications, drug interactions, side effects, dosage, etc.), the active ingredient penciclovir relieves pain and itching and accelerates crusting and healing in cold sores (https: / / www.gelbe-liste.de / wirkstoffe / Penciclovir_25944). According to the Gelbe Liste Pharmindex, acyclovir relieves itching, reduces pain, and supports and shortens the natural healing process by inhibiting viral replication and accelerating crusting of the cold sores.

[0025] In many cases, the formation of blisters is not prevented by applying acyclovir or penciclovir, for example because either the timing of the first application is too late, or because there is resistance to these preparations, or because the effect of the preparations is not strong enough to prevent blister formation, but merely shortens the healing process.

[0026] Aciclovir and penciclovir are ineffective against other herpesviruses, such as the Epstein-Barr virus, because these viruses do not use the same viral thymidine kinase as the herpes simplex viruses and the varicella-zoster virus, and cannot convert acyclovir or penciclovir into the pharmacologically active triphosphate form.

[0027] A recently published study by Ming Yan et al. (2022) using an in vitro model of human primary gingival cells to simulate the oral rinsing process yielded results indicating that oral cells exhibit good tolerance to the previously known active ingredient benfo-oxythiamine (B-OT). The authors conclude that B-OT could be suitable as an antiviral reagent in mouthwashes and nasal sprays for antiviral treatment.

[0028] Benfo-oxythiamine (hereinafter referred to as "B-OT") is an inhibitory thiamine (vitamin B1) analogue and a prodrug that is rapidly released in the human body into oxythiamine (hereinafter referred to as "OT"). OT is a thiamine derivative and, as a thiamine antagonist, a known inhibitor of thiamine-dependent enzymes such as transketolases. The pharmacology of B-OT has been investigated in vitro and in animal studies, as well as in a Phase I clinical trial with healthy volunteers.

[0029] The conversion (metabolism) of B-OT to OT occurs very rapidly in animal models and in humans after ingestion. B-OT can be administered orally and releases OT shortly after ingestion in the mammalian organism. Even with topical application, the metabolism of B-OT to OT occurs very rapidly in the skin or mucous membranes.

[0030] A phase 1 clinical study and its associated pharmacokinetics showed that B-OT does not appear in the blood, but only the oxythiamine released from Benfo-Oxythiamine.

[0031] B-OT is the world's first and, to date, only inhibitory thiamine derivative to have been successfully evaluated in a Phase I clinical trial. Since B-OT is a prodrug that releases oxythiamine (OT), a direct correlation between OT data and B-OT is also possible.

[0032] The production of Benfo-Oxythiamine (B-OT) according to the EU-GMP guidelines for human and veterinary medicinal products is established in the state of the art, which allows the use of Benfo-Oxythiamine in mammals (e.g. dogs, cats) and especially also in humans.

[0033] The present invention is based on the objective of providing a medicament for topical application in viral infections of the skin and mucous membranes, the active ingredient of which does not depend on virus-specific activation processes of a prodrug and cannot be rendered ineffective by mutations of virus-specific components, and which is effective in principle against all virus types and regardless of their DNA or RNA sequence and has both a soothing-healing effect and a preventive effect against viral reinfections.

[0034] One solution to this problem is the provision of benfo-oxythiamine and / or oxythiamine for use (as the active ingredient in a topically administered drug for the therapeutic treatment of patients with a disease of the body surface skin (cutis and subcutis) and / or one or more mucous membranes (mucosa) caused by viruses, in particular viruses with a lytic replication cycle, wherein the drug is administered at a time when viral replication has already taken place in the patient's cells (host cells) and viral release from the cell(s) is imminent, as evidenced by the presence of the first symptoms of viral replication.for example, and in particular, a skin change (e.g., swelling, redness) and / or itching and / or pain and / or changes in skin growth and / or a positive result of a test to detect the viruses in a tissue sample (e.g., in a medical swab) is present, and wherein Benfo-Oxythiamine and / or Oxythiamine (I) slow down (inhibit) or prevent the spread mechanisms of the viruses, so that the viruses remain in their host cells after replication and cell damage (in particular cell lysis and / or tissue destruction) in the host organism is reduced or prevented, while also inhibiting neurological (e.g., sneezing and coughing) and immunological or inflammatory processes (e.g., fluid formation containing viruses, such as a runny or sore nose) that lead to the spread of the viruses, and (II) cause an immune response against the viruses remaining in the cells.triggers / triggers), so that the patient's immune system is enabled (i.e. activated or reactivated) to generate an effective immune response against the viruses, which weakens or prevents future infection with these viruses.

[0035] This use of Benfo-Oxythiamine and / or Oxythiamine is intended and suitable to produce (provoke) one or more of the following effects in the potential patient (host organism):

[0036] (a) Inhibition or prevention of virus-induced cell and / or tissue damage and / or cell and / or tissue changes (e.g., cell lysis, wounds, blister formation, secretion); (b) Inhibition or prevention of the virus's mechanisms of spread by inhibiting neurological (e.g., sneezing and coughing reflex) and / or immunological or inflammatory processes (e.g., inflammation of the nasal mucosa with the formation of virus-containing secretions such as a runny or dripping nose);

[0037] (c) Relief and / or cure of symptoms caused by viral infection, such as coughing or sneezing, or breathing difficulties or problems due to reduced oxygen uptake in the lungs or reduced air supply through the nose, or reduction of pain caused by swelling or tissue damage caused by viruses, or reduction of itching.

[0038] (d) Reduction or prevention of the symptoms of viral infection such as body aches, headaches, fatigue;

[0039] (e) Reduction of the duration of illness;

[0040] (f) Reduction of the severity of the disease course;

[0041] (g) Reduction or reversal of the immunosuppression caused by the viruses;

[0042] (h) Activation of the patient's own immune system, in particular macrophages (phagocytic cells), with regard to the elimination of viruses or virus-infected cells, in particular by phagocytosis;

[0043] (i) cellular immune response against the viruses, which is suitable to eliminate the viruses and / or prevent reinfection;

[0044] (j) humoral immune response (B-cell response) against viral antigens;

[0045] (k) protective cellular immunity against reinfection with the viruses concerned or against virus-induced pathology;

[0046] (l) Protection against viral reinfections.

[0047] Since the present invention enables a therapy that is independent of the virus sequence, it also allows for the treatment of viruses that have not yet infected humans or that may only emerge in the future. The present invention thus represents an important contribution to the protection of humanity, as therapy is immediately possible even before the type of virus has been identified and long before a drug or vaccine can be developed that specifically makes the new virus treatable or protects people from infection.

[0048] Suitable and intended drug formulations for topical application include ointments, creams, gels, tinctures, sprays, and inhalation sprays or solutions. In other words, topical treatment is preferably administered by means of an ointment or cream containing Benfo oxythiamine and / or oxythiamine.

[0049] Gels, sprays, inhalation sprays or inhalation solutions.

[0050] The present invention is based on the surprising discoveries and insights gained by the inventor, as set out below:

[0051] The inventor discovered the gene transketolase-like 1 (TKTL1) as early as 1995 and postulated that the protein it encodes is capable of forming a heterodimer with the long-known TKT transketolase protein. This postulate was confirmed in 2019 by a study by Li et al. Expression of TKTL1 leads to the formation of a TKTL1-TKT heterodimer, which triggers a massive increase in the ribose-5 concentration in the cell, thus making this building block for DNA and RNA available in large quantities, enabling cells to divide and replicate.

[0052] The inventor discovered during research with the SARS-CoV-2 virus that the TKTLl gene is activated by it, thereby massively increasing the production of ribose-5-phosphate, which in turn greatly increases the production of the SARS-CoV-2 virus by the host cell it infects.

[0053] The inventor also developed benfo-oxythiamine (B-OT), the first transketolase inhibitor to be successfully evaluated in a Phase I clinical trial. Based on the role of the TKTL1-TKT heterodimer in the formation and replication of SARS-CoV viruses, the inventor aimed to use B-OT to inhibit the replication of the SARS-CoV-2 virus within the host cell. To this end, tests were also conducted to determine the tolerance of fibroblasts to incubation with B-OT, in order to ascertain the maximum amount of B-OT that could be tolerated to prevent viral replication.

[0054] The invention is based on a self-experiment conducted by the inventor, which led to the unexpected result that, when applied topically, benfo-oxythiamine (B-OT) prevented the lip from splitting in cases of lip swelling caused by herpes viruses. Furthermore, the inventor observed that the sensory perception of the B-OT-treated area of ​​the lip changed dramatically within seconds, resulting in a moderate numbness that disappeared with the disappearance of pain. Even pressing on the lip did not elicit the previously noticeable pain. The inventor added the active ingredient B-OT to a commercially available skin cream and mixed it in. He then applied the B-OT-containing cream to the swollen area of ​​the lip. When he pressed his lips together, the cream he had applied to the herpes-affected area was rubbed onto the unaffected upper lip.The same numbness then occurred, leading the inventor to realize that B-OT triggered this sensation in both the swollen and the normal lip. Because this sensation occurred immediately, it became clear to the inventor that the observed sensorimotor-neurological effect could not be explained by the inhibition of the transketolase enzyme reaction and the associated ribose production. Through a literature review, the inventor identified publications demonstrating that inhibitory thiamine derivatives such as oxythiamine and pyrithiamine influence the release of neurotransmitters and affect nerve signal transmission.

[0055] For many decades, it has been suspected that thiamine, in addition to its enzymatic role as a cofactor, also plays a non-enzymatic (non-cofactor) role. For a long time, these non-enzymatic functions remained hypothetical, but data have repeatedly been generated that have supported this hypothesis. Within the cell, thiamine is phosphorylated to thiamine pyrophosphate (thiamine diphosphate; ThPP). As thiamine pyrophosphate, it then binds to thiamine-dependent enzymes and performs its cofactor role in the enzymatic reaction, which involves a nucleophilic attack on a carbon-carbon bond. In the case of transketolases, a C2 unit of a sugar is cleaved. After the rest of the sugar leaves the enzyme, the C2 unit is transferred to a second sugar that is bound.A C5 sugar can be converted to a C7 sugar by transferring a C2 unit from the first sugar to a second sugar. Transketolases thus carry out a two-substrate reaction. Besides thiamine pyrophosphate, other phosphorylated thiamine derivatives have also been identified, in which thiamine triphosphate (ThTP) plays an important role. In the bacterium E. coli, significant amounts of thiamine triphosphate are produced under amino acid deficiency or energy stress. While this compound is much less well known in animals, the fact that mammalian cells possess a highly specific soluble thiamine triphosphatase that controls cytosolic ThTP concentrations suggests that ThTP also plays a role in mammalian cells. Furthermore, there is increasing evidence for the existence of thiamine-binding proteins, which play a specific role in the nervous system, among other things.These also play a role in regulating neurotransmitter release. Pharmacological experiments with the inhibitory thiamine antagonists pyrithiamine and oxythiamine, both in vivo and in vitro, have shown that pyrithiamine acts on the central nervous system in vivo, while oxythiamine does not. This demonstrates that different inhibitory thiamine derivatives have different effects on the nervous system. In addition to their antagonistic effect on thiamine's role as a cofactor in carbohydrate metabolism, these compounds act directly on neuronal excitation and neurotransmitter release. Pyrithiamine prolongs the duration of the action potential at individual nodes of Ranvier. Oxythiamine, on the other hand, does not have this effect. In unmyelinated mammalian nerve fibers, pyrithiamine increases the amplitude in the millimolar range. Oxythiamine does not exhibit this effect.Oxythiamine, on the other hand, increases the release of the neurotransmitter acetylcholine from electroplaques of marbled electric rays (Torpedo marmorata), but pyrithiamine does not show this effect. An inhibitory effect on the release of the neurotransmitter acetylcholine has been demonstrated by the thiamine derivatives pyrithiamine and oxythiamine in the rat brain. Here, too, significant differences were observed between pyrithiamine and oxythiamine. Further research has shown that oxythiamine plays a neuromodulatory role in calcium-mediated synaptic transmission. Another study demonstrated that, in addition to acetylcholine, the release of norepinephrine, another neurotransmitter, is also influenced by inhibitory thiamine derivatives. Based on the data available so far, it is clear that inhibitory thiamine derivatives have an effect on the release of the neurotransmitters acetylcholine and norepinephrine.B-OT appears to interfere with the release of neurotransmitters in such a way as to inhibit viral spread strategies. B-OT allows, in a previously unknown manner, the inhibition of enzymatic and non-enzymatic processes that play a crucial role in viral transmission.

[0056] A particularly surprising discovery by the inventor is that B-OT can also be used after viral replication has already occurred. This new discovery clearly distinguishes it from the original application of B-OT, which aimed to inhibit the production of ribose-5-phosphate in host cells infected with SARS-CoV-2 viruses. Although the inventor had no scientific rationale for testing B-OT after viral replication had already taken place, his inquisitive nature led him to apply B-OT at a time when viral replication had already occurred in a case of cold sores he had experienced.

[0057] The inventor was greatly surprised to discover firsthand that such a late application of B-OT had a soothing effect, preventing his swollen lip from cracking. He subsequently tested B-OT on various viral infections, including influenza and rhinoviruses, and found that it inhibited a wide range of viral transmission mechanisms. He was also surprised by its ability to suppress or prevent coughing in cases of influenza and to clear a runny nose. These surprising findings led to further discoveries, which are detailed in this patent application.An unexpected and surprising finding that emerged from the inventor's experiments and considerations is that medical and pharmacological research and therapy have so far focused very strongly on inhibiting viral replication through active substances that selectively inhibit viral replication, or have pursued the strategy of vaccination, in which virus-specific epitopes are administered into the body to trigger an immune response, thus eliciting an antibody response that should protect the vaccinated person from viral replication in their body so that they do not become ill or only experience moderate illness.

[0058] The new doctrine revealed here by the inventor represents a new form of combating viruses, since the multiplication of the viruses is allowed, but then the various spread strategies of the different viruses are inhibited so that they can no longer spread effectively, and at the same time immunological reactions against the viruses located in the host cells are triggered, which weaken future infections with these viruses or combat them in such a way that symptoms are prevented.

[0059] In the course of studies that led to the present teaching according to the invention, it was found that, in the case of a viral infection, the administration of the transketolase inhibitor B-OT (and thus OT) at a time when viral replication (multiplication) in the host cells has already taken place and viral release from the infected cells is imminent but has not yet occurred, results in the viruses not being released but remaining in their host cells. Furthermore, it was found that this attenuated or reduced the frequency of subsequent viral infections or outbreaks (e.g., with herpesviruses).

[0060] Once viral replication is complete, the viral proteins normally trigger processes that destroy and / or alter the virus-containing cells (host cells) and their surrounding cells, allowing the viruses to exit their host cells and spread within and outside the host organism. Treating infected cells with B-OT (and thus OT) during this phase of viral development inhibits the virus-induced fermentative metabolism of the host cells, thereby reducing or even halting the production of ribose, acetyl-CoA, and lactic acid. This has the effect (I) of inhibiting or completely blocking (preventing / disrupting) the viral spread mechanisms. Consequently, cell damage and / or tissue destruction in the host organism are avoided or at least significantly reduced.A second essential effect (II) of this inhibition of fermentative metabolism and thus reduced or stopped provision of ribose, acetyl-CoA and lactic acid is the reduction or reversal of the tissue destruction and suppression of the immune system caused by the viruses in the patient's body, so that it becomes effective again and can attack and eliminate viruses and virus-infected cells.

[0061] This immune response of the body can lead to the viruses being effectively combatted early in the event of future reinfections, thus mitigating or preventing symptoms and discomfort (i.e., reducing the severity of outbreaks), and / or suppressing the replication and release of viruses already persisting in the cell, such as herpesviruses, to such an extent that no symptoms or discomfort are detectable. In effect, this is a way of using a viral infection to create a live vaccine, because the viruses remain in the cell after multiplying and serve as the vaccine.

[0062] In other words:

[0063] Topical application of the active ingredient B-OT and / or OT (hereinafter referred to as "B-OT / OT"), administered after viral replication in the body, prevents the viruses from leaving infected cells and tissue. Simultaneously, the immunosuppressive effect of the viral infection is reduced to such an extent that the body mounts an immunological response against the virus present in the infected cells. Preventing viral release often avoids the destruction of cells or tissues, thus preventing wounds such as chapped lips. This prevents the associated pain and also prevents others from seeing these virus-related injuries, which is a significant psychological benefit.

[0064] The inventive measure of administering B-OT / OT at a time when viral replication has already occurred and initial symptoms are detectable is based on the following principles: Viral replication is only a first step in enabling viruses to multiply and spread. If viruses remain in the host cell after replication, they can persist, but this significantly hinders or even prevents transmission to other people. With the death of the infected person, the virus would also die and thus disappear. Therefore, in addition to replication, the virus must trigger further mechanisms in the infected person that lead to viral spread. As soon as the viruses have replicated in their host cells and are present in high quantities within the cell, they activate their propagation mechanisms, such as blister formation, coughing, sneezing, and increased nasal discharge, etc.In this process, the host cell, which has been infected by the virus and carried out viral replication, and is now no longer needed, is altered by the virus in such a way that, for example, blisters are formed containing fluid with extremely high viral concentrations. The rupture of these blisters releases the fluid containing the viruses, allowing the viruses to infect other people. This can occur through direct skin contact, such as kissing or sexual intercourse, or the virus-containing fluid can be transferred to other people via objects such as drinking cups or glasses.

[0065] The optimal time to inhibit viral spread and simultaneously trigger an immune response against the viruses is precisely when viral replication is complete and large quantities of viral proteins are present in the cells. Since the viruses are present in increased numbers within the cells after replication, but their spread is prevented, they are presented to the patient's immune system in such a way that it is able to generate an effective immunological defense or immune response that eliminates the viruses and, moreover, counteracts viral replication as early as possible in the event of subsequent reinfections. The presence of a high number of viral proteins in the cells and the reversal of the immunosuppression induced by the viruses thus lead to immunization against the viruses.The use of B-OT and / or OT as the active ingredient in a topically applied drug allows for the inhibition of various viral spread mechanisms and strategies by applying the drug to virus-infected cells and tissues such as the nasal mucosa, oral and pharyngeal cavities, genital mucosa, eyes and adjacent tissues, rectal mucosa, and lung epithelium in the form of an ointment, cream, tincture, gel, spray, or via inhalation. In contrast, previously known topical antiviral agents aim to inhibit viral replication in host cells as early as possible. The success of these drugs depends crucially on minimizing the time between the onset of viral replication and the start of drug treatment, as these medications are designed to inhibit viral replication.

[0066] The effect (I) of B-OT / OT treatment, namely the inhibition or complete blockage (suppression / prevention) of the viral spread mechanisms, generally results in a significantly shortened course of the illness and fewer or no symptoms, or a substantial reduction in the severity of any symptoms that do occur. The inflammatory processes triggered by the viruses in the infected cells and surrounding tissue (such as secretion, mucus production, blister formation, and painful skin changes) are inhibited by B-OT / OT, and the associated bodily reactions (such as runny nose, sneezing, and coughing) are correspondingly less pronounced or do not occur at all. In addition to enzymatic inhibition, B-OT / OT also exhibits a significant neurological effect capable of influencing neurological processes.This effect is also based on influencing the release of neurotransmitters such as acetylcholine and norepinephrine and binding to thiamine-binding proteins without enzyme activity. By binding to thiamine-dependent enzymes and thereby inhibiting their activity, B-OT allows for the suppression of enzymatic processes necessary to trigger cell and tissue changes that are essential for efficient viral spread. Furthermore, it also inhibits immunological and inflammatory processes, such as inflammation of the nasal and pulmonary mucosa, which are necessary for viral spread. In addition, neuronal processes such as neurotransmitter release are altered, and stimuli like coughing and sneezing are inhibited to prevent them from spreading the virus throughout the body.The consequence of inhibiting these various processes is that the spread of the viruses to the environment of the affected patient is significantly hindered and occurs only to a limited extent or not at all, thereby significantly minimizing the risk of infecting others. This reduces the relevant virus pool in the population, and fewer people become ill from these viruses. This means that B-OT / OT is a medication that secondarily protects other people from viral diseases and has the potential, through the systematic inhibition of viral transmission, to enable the eradication of viruses that are highly dependent on their transmission strategies.The effect (II) of B-OT / OT treatment, namely the reduction or reversal of viral-induced immunosuppression and the activation or reactivation of the patient's own immune system to generate an effective immune response against the viruses, generally results in a further reduction and, ideally, the disappearance of any remaining symptoms and complaints of the viral disease, and in a milder severity of future viral infections and a longer interval between viral outbreaks or infections. Furthermore, the generated immune response in the patient promotes the development of long-term, or at least long-term, immunity against the viral disease in question.The consequences of this are that fewer new or reinfections occur, people become immune to such viruses, the relevant virus pool in the population is reduced, and overall fewer people become ill from viruses.

[0067] It is known that viruses manipulate the glucose metabolism of their host cells to increase available energy and the production of building blocks such as ribose, thereby promoting their own replication within the host cell. Most viruses achieve this by inducing the Warburg effect, also known as aerobic glycolysis, i.e., the fermentation of glucose to lactate, even in the presence of oxygen. This results in the accumulation of lactic acid, fewer glycolytic intermediates contributing to the TCA cycle (tricarboxylic acid cycle = Krebs cycle), and high glucose consumption (see Girdhar et al. 2021 and the literature cited therein).

[0068] It is also known that cancer cells of various cancer entities produce lactate (lactic acid) to more easily penetrate the surrounding tissue and spread throughout the organism, and to suppress immune responses of this organism (see Sharma et al. 2022).

[0069] Knopf et al. (2023) further demonstrate that, using various tumors as examples, in vitro and in vivo studies have shown that lactic acid is able to increase the concentration of IFN-gamma-induced PD-Ll expression, thus enabling tumor cells to escape the immune system. If the (lactic) acid is neutralized in the extracellular space, e.g., by sodium bicarbonate, the expression of IFN-gamma-induced PD-Ll is suppressed, thereby promoting the infiltration of immune cells into the tumor and reducing tumor growth. This shows that inhibiting (lactic) acid production overcomes immunosuppression, allowing the immune system to become active again. Furthermore, it is known that there are cancer entities whose development is associated with viral infections; for example, human papillomaviruses (HPV) are considered the main cause of cervical cancer. (See: https: / / www.krebsinformationsdienst.de / ...de / cervical cancer / risk factors).

[0070] It is also known that TKTL1 is a key enzyme in lactate formation via aerobic glycolysis / Warburg effect (see Diaz-Moralli 2016; Xu et al., 2009, Sun et al., 2010; Jayachandran et al., 2016), and that B-OT is an inhibitor of TKTL1 (see DE 102021109341 Al).

[0071] This prior art supports the finding underlying the teaching according to the invention that inhibiting virus-induced lactate production leads to (1.) preventing the release and spread of replicated virus particles from the host cell, and (2.) (re)activating the host organism's immune system with regard to combating / eliminating the viruses.

[0072] If B-OT is administered at a time when the viruses have already replicated, B-OT can inhibit the enzyme TKTL1 and the associated production of lactic acid. As a result, the immune system is no longer suppressed and can attack and eliminate virus-infected cells. Viral epitopes are used as immunogenic structures to generate an immune response, including the production of antibodies that protect against future viral infections. Thus, in the application according to the invention, B-OT also causes the viruses in question to be transformed into a quasi-live vaccine.

[0073] The following publications, which were published after the relevant priority date, describe study results that support the above statements and the teaching according to the invention:

[0074] The studies by Lu et al. (2024), using sepsis-induced acute lung injury as an example, show that lactic acid (lactate) causes the degradation of the pulmonary glycocalyx of the lung endothelium and exacerbates lung damage. Lactic acid thus represents a signaling molecule that triggers the expression of enzymes that dissolve cell clusters. In other words, lactic acid directly and indirectly, via lactylation, triggers the degradation of cell-cell contacts and cell structures. Inhibition of lactic acid production inhibits this degradation. The publication by Gumer et al. (2025) begins by noting that it is now known to those skilled in the art that lactic acid (lactate) serves as a signaling molecule and, for example, in the case of carcinoma, facilitates the spread of cancer cells into surrounding tissue and promotes the formation of blood vessels during wound healing.In their publication, the authors show, using the example of blastocysts, that a blastocyst produces lactic acid, thereby triggering tissue remodeling so that it can implant.

[0075] The studies by Tyl et al. 2025 show, using the human cytomegalovirus (HCMV) and herpes simplex virus-1 as examples, that herpes viruses trigger lactic acid production, thereby protecting themselves from attack by the immune system and promoting their spread.

[0076] The application of B-OT / OT according to the invention is particularly suitable and intended for the treatment of viral diseases (viral infectious diseases) of the skin and / or mucous membrane caused by herpes viruses.

[0077] The human herpesvirus family is an important group of viruses that cause a variety of human diseases. This family comprises eight members, which are classified into one of three subgroups—alpha herpesviruses, beta herpesviruses, and gamma herpesviruses—depending on the cells they primarily infect and the site of latency. Alpha herpesviruses include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus (VZV). Beta herpesviruses include human cytomegalovirus (HCMV), human herpesvirus type 6 (HHV-6), and human herpesvirus type 7 (HHV-7). Gamma herpesviruses include Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). Herpesviruses can switch between the latent stage and the lytic stage.

[0078] Use in the treatment of cold sores (Herpes Labialis):

[0079] Cold sores are primarily caused by the herpes simplex virus type 1. In Germany, an estimated 60 to 90% of people carry the herpes simplex virus type 1. Symptoms typically begin with pain, tingling, burning, and a feeling of tightness on the lip. Later, the affected area of ​​skin reddens. Painful bumps (papules) then develop, and these bumps eventually fill with fluid and become blisters (vesicles). These can also spread to the surrounding skin, into the mouth, or towards the nose. The blisters rupture easily when speaking, laughing, or chewing and then weep. Acidic foods or liquids such as juice or vinegar can irritate the resulting wound. As the sores heal, scabs or crusts form. The swelling of the lip, typical of cold sore infections, indicates the replication of the herpes virus in the infected skin cells. The virus must now, i.e.,After replication, viruses trigger further mechanisms in infected individuals that lead to viral spread. One such mechanism in herpesviruses is the lytic phase, in which the host cell, infected by the virus and responsible for its replication, is no longer needed. This leads to the formation of the characteristic blisters containing fluid and extremely high concentrations of the virus. The rupture of these blisters releases the fluid containing the virus, thus enabling the virus to infect other people.

[0080] If B-OT / OT is applied to the affected skin areas at the time of swelling, but before blisters form on the swollen lip, it inhibits the transketolase enzyme reaction. This prevents subsequent blister formation and the destruction of the cell and the surrounding tissue matrix, even after viral replication has ceased within an infected cell. This prevents virus release and spread to other people. Simultaneously, the virus-induced suppression of the immune system is reversed, triggering an immune response in the patient's body. This prevents the symptoms of subsequent infections or suppresses the internal release of viruses already persisting in cells, thus preventing further symptoms.

[0081] Application studies have shown that treatment with B-OT and / or OT should preferably follow an administration pattern or dosage guideline that stipulates topical application of Benfo-Oxythiamine and / or oxythiamine to the affected skin areas as soon as the first symptoms of increased and uncontrolled cell proliferation are observed. This has the advantage that the patient can always keep the B-OT and / or OT-containing medication, such as a B-OT cream, B-OT ointment, or B-OT solution (e.g., spray or tincture), readily available and apply it almost immediately upon noticing the first symptoms. This prevents the process of host cell lysis in many cases.

[0082] Since cell lysis on the skin (cutis) or mucous membranes is associated with open wounds, related pain and cosmetic impairments (e.g., crusting and scarring) (e.g., in the case of cold sores or genital herpes), inhibiting lysis means, on the one hand, significant relief for the affected patient and the avoidance of skin changes that can lead to scarring, and on the other hand, a prevention of the spread of the viruses to other potential host organisms, i.e., protection against infection of third parties.

[0083] Use in the treatment of genital herpes:

[0084] Genital herpes also presents a significant medical problem, causing considerable suffering. Genital herpes is a highly contagious viral infection caused by herpes simplex virus type 2 or herpes simplex virus type 1. It is one of the most common sexually transmitted infections. Infection occurs through skin-to-skin contact and often goes unnoticed, as approximately 90% of infected individuals develop no or only mild symptoms. When symptoms do occur, they can be severe and very painful: painful rashes or ulcers may develop, the entire body may feel unwell, and fever may occur. Symptoms often subside after a few weeks. After infection, the herpes viruses remain in the body for life. They lie dormant and therefore inactive until the next outbreak. During this time, the viruses persist in nerve cells / nerve ganglia near the spinal cord.Nerve fibers connecting these ganglia to previously infected areas are used by the viruses again to travel from the ganglia back into the tissue, triggering another rash or ulcer. This can lead to recurring outbreaks throughout an infected person's life. People with genital herpes typically experience repeated outbreaks. To complicate matters, the virus can also spread to other areas of the body in some cases, including the eyes, mouth, esophagus, or even the brain. Infected individuals without symptoms contribute significantly to the spread of this viral disease. Newborns are also frequently infected by herpes simplex virus type 1 and herpes simplex virus type 2.

[0085] The use of B-OT / OT for genital herpes has proven exceptionally effective in initial clinical trials. Blister formation was prevented, thus avoiding both the painful skin lesions and the effective spread of the virus via the blister fluid. After complete resolution of symptoms, the interval until a possible recurrence (in the affected patient) is significantly longer than before, and the severity of symptoms is lower from the outset. This is particularly surprising because, in dermatological circles, it is generally accepted that topical treatment with known antiviral creams or ointments provides no relief for genital herpes and can promote the development of resistance. Therefore, experts advise against topical treatment with these known antiviral agents. Use in herpes zoster (shingles) and chickenpox:

[0086] The varicella-zoster virus (VZV), like herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2), is an alpha herpesvirus that also causes blisters. VZV infection often occurs in childhood and triggers chickenpox. In the case of chickenpox, itchy blisters usually develop, which are frequently scratched by the affected person. This promotes the spread of the virus and can also lead to secondary infections caused by bacteria or fungi. Following this initial infection, the VZV virus resides in neurons and glial cells of the spinal ganglia and can remain there for life. Reactivation of the VZV virus in these cells then leads to the clinical picture of herpes zoster, also known as shingles. This reactivation of the virus often occurs in older or immunocompromised individuals, or as a result of stress.When the viruses transition from their dormant, persistent state, the so-called lysogenic cycle, to the lytic cycle, the disease manifests. During the first 3 to 6 days, nonspecific symptoms such as fatigue and muscle aches occur. This is followed by a phase of pulling, dull pain located along the nerves supplied by the ganglion. The affected skin areas are usually supplied by ganglia in the thorax and lumbar region (T3 to L3). Subsequently, pinhead- to rice-comb-sized blisters develop on the skin, containing a high concentration of the virus in their fluid. However, other ganglia, such as the geniculate ganglion, can also be involved, leading to herpes zoster opticus, which is accompanied by ear pain and facial paralysis. In this case, the blisters develop in the external auditory canal. The Gasserian ganglion, with associated eye pain, can also be affected.Blisters can also form on the tip of the nose, indicating an increased risk of eye disease. In the case of varicella-zoster virus (VZV), blister formation is also a crucial factor in the virus's spread. Lifelong persistence in nerve and glial cells would lead to the elimination of VZV upon the death of the infected individual. From an evolutionary perspective, the viral infiltration of body cells and the periodic formation of blisters to spread and thus maintain or increase the viral load in the population is an extremely effective reproductive strategy.

[0087] The application of B-OT / OT according to the invention prevents or reduces the formation of blisters, thereby alleviating the patient's suffering and significantly reducing viral spread. The application of B-OT / OT according to the invention is also suitable and intended for the treatment of skin and / or mucous membrane diseases caused by herpesviruses from the group comprising Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus: Herpesviruses can trigger skin changes in various parts of the body, which subsequently lead to Kaposi's sarcoma. Such skin changes, which initially manifest as numerous red, pink, or purple spots or nodules, are mainly caused by human herpesvirus type 8 (HSV-8).

[0088] Initially, often only one or a few spots are visible on the skin, which can be located on the outer skin, such as on the legs or toes, as well as in the genital area and on the mucous membranes of the mouth. Further development can lead to the involvement of internal organs. Currently, individuals with multiple affected areas are treated with radiation and chemotherapy. Unlike HSV-1 and HSV-2 viruses, HSV-8 does not use nerve cells for its latent phase, but rather cells derived from endothelial cells.

[0089] The application of the medicament according to the invention, e.g., in cream or gel form, to the affected skin areas inhibits the further development of HSV-8-infected skin areas into malignant tumors and (completely or partially) reverses the immunosuppression triggered by HSV-8 in the host organism, so that the immune system can attack and eliminate the viruses and altered host cells. Furthermore, apoptosis is triggered in cells in which HSV-8 is in the latent stage, causing these infected cells to die. The elimination of latent infections with viruses from the gamma family of herpesviruses, such as HSV-8, by means of the application of B-OT / OT according to the invention represents a completely new form of therapy for these virus-induced skin lesions and offers effective protection against their development into malignant tumors.

[0090] For all the aforementioned diseases resulting from herpesvirus infection, the very limited gene expression of herpesviruses during latent infection makes them extremely difficult to combat. Currently, no drugs are available for treating latently infected cells. The available approved drugs target only the lytic replication of the viruses and are unable to specifically combat latently infected cells. The application of B-OT and / or OT according to the invention thus represents, for the first time, a therapy for the treatment of latent infection with HSV-8 and other viruses of the gammaherpesvirus family.

[0091] The application of B-OT / OT according to the invention is also well suited and intended for treatment in cases of infections with rhinitis viruses.

[0092] Another form of viral transmission occurs with viruses that cause the common cold and infect the nasal mucosa (e.g., rhinoviruses, adenoviruses, influenza viruses, and coronaviruses) – hereinafter referred to simply as "common cold viruses." Like the lungs, the nasal mucosa does not come into direct contact with other people. During the evolution of common cold viruses, those viruses that were able to alter the nasal mucosa in such a way as to cause inflammation (rhinitis) became dominant. As a result of the inflammation, a secretion that is initially watery and becomes increasingly mucousy is produced. This secretion or mucus flows out of the nose or is actively blown out by nose-blowing, thus spreading the viruses contained within it and allowing them to infect other people.Furthermore, "cold viruses" also trigger stimuli such as sneezing or coughing, which lead to an airflow in the nose that actively expels virus particles. Consequently, viruses that infect the nasal mucosa are also an example of how viral replication alone is insufficient for evolutionary success. Successful viral replication in the nasal mucosa does not yet enable the virus to leave the host. Only the triggering of nasal mucosal inflammation with mucus production and excretion of virus-containing secretions makes viral spread effective. The application of B-OT and / or OT as the active ingredient of a topically applied drug according to the invention inhibits the inflammatory processes triggered by the viruses in the nasal mucosa, thus preventing nasal discharge, the associated need for nose blowing, and the urge to sneeze.

[0093] In the case of cold viruses, the application of B-OT / OT according to the invention prevents the nasal mucosa from producing excessive mucus, thus preventing a runny nose and triggering the urge to sneeze. This significantly reduces viral spread by inhibiting the processes that lead to a runny nose and sneezing, and substantially lowers the risk of infection for others.

[0094] The application of B-OT / OT according to the invention is also well suited and intended for the treatment of diseases resulting from viral infection of the lung epithelia.

[0095] In the case of an illness resulting from infection with viruses that attack lung epithelia, such as influenza, the inflammatory processes in the lungs and bronchi that lead to coughing and mucus production are significantly inhibited, so that a cough is only minimal or nonexistent and expectoration of mucus is minimal. When coughing, the infected person actively generates a strong airflow through a powerful contraction of the lungs, which expels the viruses through the mouth and nose. The transmission mechanism of these viruses consists of triggering a cough reflex so that, after replication, they are expelled from the infected person's body by the cough and the associated strong airflow, where they can be inhaled by other people. This example also shows that viral replication alone is not sufficient for viruses to survive and spread through evolution.

[0096] The application of B-OT / OT according to the invention in diseases caused by infections with rhinoviruses and / or viruses that infect the lungs represents a new form of combating viral diseases in individuals and in the general population: Because the coughing and / or sneezing triggered by the viruses is systematically prevented and consequently avoided, the spread of the viruses in the population that normally occurs through this mechanism is significantly reduced. This allows infection chains to be inhibited and viral diseases to be reduced preventively. Influenza outbreaks can thus be countered. B-OT / OT therefore represents a new class of drugs that does not target viral replication / multiplication in cells, but rather addresses the transmission strategies in order to inhibit infection chains, so that fewer people become ill from viruses and the viral pool is thereby reduced.

[0097] The application of B-OT / OT according to the invention is also suitable and intended for the treatment of infections with the human papillomavirus (HPV).

[0098] Other types of viruses, such as human papillomaviruses (HPV), also cause a variety of human diseases. Almost everyone becomes infected with HPV at some point in their lives. HPV primarily infects the skin and mucous membranes. Intimate skin-to-skin contact between people leads to transmission of the virus. HPV infections can cause skin changes in the mouth and throat, vagina, vulva, anus, and penis. More than 200 HPV types are now known.

[0099] An HPV infection often initially progresses without symptoms, so it goes unnoticed. In many cases, the immune system recognizes the HPV and eliminates it within about 6 to 12 months. In other cases, however, the immune system is unable to eliminate the virus, so that a few weeks after infection, genital warts develop in the genital area, which are known as genital or condylomata acuminata. In the genital area, genital warts represent a major group of HPV-related diseases. Because genital warts can develop into precancerous lesions and malignant tumors over time, it is of particular importance to develop therapeutics to treat the affected skin and mucous membrane areas locally, i.e., topically, for example with a cream or gel.

[0100] Despite the diagnostic option of detecting HPV in swabs using PCR, a large number of people in Germany develop illnesses each year as a result of HPV infection. This is because there are currently no approved, effective medications for treating the affected skin and mucous membranes. More than 110,000 people in Germany develop genital warts annually. Furthermore, there are more than 60,000 cases of HPV-related precancerous lesions of the cervix in Germany each year. The number of more than 7,500 cancers in women and men each year caused by HPV is also alarming. This underscores the need to establish therapies for HPV-infected skin and mucous membranes, as well as other HPV-related skin lesions in the head and neck area (e.g., throat and tonsils) or in the genital area (e.g., anus, vagina, labia, penis).Genital warts can be treated to inhibit the immunosuppression caused by HPV, allowing the body's immune system to recognize and eliminate the virus-infected cells.

[0101] Human papillomaviruses (HPV) can also infect skin areas if there are injuries. Even diabetes or excessive sweating can facilitate HPV infection of the skin, leading to skin changes and wart formation. Typically, warts are treated with salicylic acid solutions several times a day for several weeks. Alternatively, the warts can be frozen with liquid nitrogen, which destroys them but often results in scarring.

[0102] An application of the medicinal product according to the invention, containing the active ingredient B-OT and / or OT, initially results in no visible external change to the wart during a treatment period of 7-14 days. However, tissue remodeling takes place within the wart, causing it to fall off or become removable. The exposed skin is new, undamaged, and shows neither scars nor other damage.

[0103] For all the aforementioned applications, the active ingredient should preferably be applied to virus-induced swelling at least three times daily to best support the immune response. A preferred pharmaceutical preparation containing the active ingredient B-OT for topical application consists of a semi-solid dosage form, such as a paste, cream, ointment, gel, or lotion, containing B-OT and / or OT of approximately 0.1% to 10%, preferably approximately 0.3% to 10%, and particularly preferably approximately 0.3% to 5%. The percentage (here and in the following) refers to weight percent, i.e., % wt / wt, for example, mg / mg.

[0104] A B-OT-containing cream based on a commercially available skin ointment or skin cream with a B-OT content of 1% to 10% wt. / wt., preferably 5% wt. / wt., has already been tested in practice and found to be well suited.

[0105] A B-OT-containing gel based on a gel formulation comprising the components propylene glycol, glycerin, citrate buffer pH 4.5, hydroxyethylcellulose, potassium sorbate and / or benzoic acid, and with a B-OT and / or OT content of about 0.1% to 10%, preferably about 0.3% to 10%, particularly preferably about 0.3% to 5%, has also been tested in practice and found to be well suited.

[0106] According to the invention, treatment with B-OT and / or OT or with the B-OT and / or OT-containing drug (or medication) should be carried out according to a dosage regimen that includes the following measures:

[0107] (a) first application upon noticing (detecting) the first symptoms

[0108] (b) Repeat application, preferably after about 2-4 hours

[0109] (c) Repeat step (b) as needed (for symptom relief) until symptoms have completely subsided.

[0110] The invention is explained in more detail below with reference to exemplary embodiments and figures. The figures show:

[0111] Fig. 1: Topical B-OT treatment of acute cold sores.

[0112] 1 A, 1B = typical swelling on the left side of the lower lip due to herpes infection on the morning of day (1).

[0113] IC = Lip region according to 1A and 1B four hours after topical application of a custom preparation from a commercially available skin ointment containing 5% by weight (% w / w) mg / mg of B-OT. The swelling has noticeably decreased. ID = Lip region according to IC after a second topical application of the B-OT-containing cream at time IC and approximately 10 hours later (in the evening). The swelling has remained unchanged and the lip has not cracked.

[0114] IE = Lip region according to ID after a third topical application of the B-OT-containing cream at time ID (as an overnight treatment) on the morning of day (2). The lip is not cracked and the swelling is barely noticeable.

[0115] 1F = Lip region according to IE on the following day (3). The lip looks healthy.

[0116] Fig. 2: Comparative trial with B-OT treatment for acute cold sore disease. Topical B-OT application not on the affected area of ​​the lip itself, but only on the adjacent skin area above the lip:

[0117] 2A, 2B = typical swelling on the left side of the upper lip due to herpes infection on the morning of day (1).

[0118] 2C = Lip region according to 2A, 2B four hours after topical application of an individual preparation from a commercially available skin ointment with 5 wt% (% wt. / wt.) mg / mg exclusively to the adjacent skin area above the lip.

[0119] D = Lip region according to 2C after a second topical application of the B-OT-containing cream at time point 2C and approximately 10 hours later. Small openings have formed in the skin of the lip proper, from which fluid is leaking. The skin above the lip proper appears normal.

[0120] 2E = Lip region according to 2D on day (2).

[0121] 2F = Lip region according to 2E per day (3).

[0122] Fig. 3: Results of B-OT treatment for cold sores; tabular presentation of individual patient reports on self-treatment with the active ingredient B-OT in the form of a topical application.

[0123] Fig. 3 - Part 2 is the continuation of the table Fig. 3 - Part 1 in a vertical direction, Fig. 3 - Part 3 is the continuation of the table Fig. 3 - Part 2 in a vertical direction, and Fig. 3 - Part 4 is the continuation of the table Fig. 3 - Part 3 in a vertical direction.

[0124] Fig. 4: Results of B-OT treatment for rhinovirus infection (common cold); tabular presentation of individual patient reports on self-treatment with the active ingredient B-OT in the form of topical application. Fig. 5: Results of B-OT treatment for genital herpes; tabular presentation of the

[0125] Individual patient reports on self-treatment with the active ingredient B-OT in the form of a topical application.

[0126] Fig 6: Results of B-OT treatment in the case of an HPV-positive finding of a cervical smear; tabular presentation of the individual reports of the patients on self-treatment with the active ingredient B-OT in the form of a topical application.

[0127] Example 1: Topical B-OT treatment of cold sores - a patient report:

[0128] (I) On day (1), the patient experienced the characteristic lip swelling from several previous cold sore infections, which is typical of such infections. This swelling indicates viral replication. In this case, the swelling was located on the left side of the lower lip (see Fig. 1, Fig. A, Fig. B). A custom-made preparation of a commercially available skin ointment containing 5% by weight (% w / w) mg / mg of B-OT was applied to the affected area of ​​the lip and the adjacent skin below the lip. Within the following four hours, the swelling noticeably subsided (see Fig. 1, Fig. C). After four hours, the B-OT cream was reapplied to the lip. For the next approximately 10 hours, the swelling remained unchanged, and the lip did not rupture (see Fig. 1, Fig. D). The B-OT cream was then applied once more for overnight treatment.On the morning of day (2), the lip was still not cracked and the swelling was barely noticeable (see Fig. 1, Fig. E). The patient only noticed that the lip felt abnormal. By day (3), this sensation was gone; the lip felt completely normal and looked healthy (see Fig. 1, Fig. F).

[0129] (II) Comparative experiment:

[0130] Several months later, the same patient again experienced the characteristic lip swelling from previous cold sore infections, a swelling he recognized from several previous outbreaks. This time, the swelling was located on the left side of the upper lip (see Fig. 2, Fig. AF). A custom preparation, analogous to the one described above in (I), was applied to the area of ​​skin above the lip adjacent to the affected area, but not to the affected area itself. After four hours (Fig. 2, Fig. C), the B-OT-containing cream was applied again, solely to the area of ​​skin above the lip adjacent to the affected area, again avoiding the lip itself. After approximately 10 hours, the patient noticed small openings in the skin of the lip itself, from which fluid was leaking (Fig. 2, Fig. D). The skin above the lip appeared completely normal.The swelling itself was limited to the actual skin of the lip. The splitting of the lip was limited to small areas in the lip region (see Fig. 2, Fig. D). Over the course of the following two days (2) and (3), the lip damage healed (see Fig. 2, Figs. E and F).

[0131] In this comparative study, a deliberately chosen approach was taken in which B-OT was applied not to the actual lip, but only to the skin above it, in order to determine whether partial rupture of the lip occurred in the actual lip area. It was found that the destruction of lip tissue was limited to the actual lip tissue that had not been treated with B-OT. The formation and rupture of the cold sores were allowed to verify that the swelling of the lip was caused by a virus, which then led to the rupture of the lip.

[0132] In some people, the mechanical stress on the lips during dental treatment triggers an outbreak of cold sores. In this particular case, after noticing the swelling of the lip typical of a cold sore infection, the patient applied a custom-made preparation of a commercially available skin ointment containing 3% by weight (mg / w) of B-OT to the affected area of ​​the lip and the surrounding skin. This prevented the formation of blisters and the cracking of the lip. This result was repeatedly confirmed.

[0133] Example 2: Topical B-OT treatment of cold sores—individual reports from various patients

[0134] Several individuals suffering from recurrent cold sores were provided with a specific quantity of B-OT by the applicant or a pharmacy, upon request, for the purpose of self-treatment and reporting on the course of the disease and treatment success.

[0135] The application instructions read: "Mix B-OT with a commercially available skin cream in a ratio of 3-5% B-OT by weight plus 97-95% skin cream and apply this mixture to the infected skin areas morning, noon, and evening. Only begin treatment when the first symptoms of increased and uncontrolled cell proliferation are noticeable (e.g., a feeling of tightness and / or tingling and / or swelling in the skin area), because by then viral replication has already taken place in the affected cells and viral release from the cell(s) is imminent."

[0136] The reports of patients No. 1 to No. 53 regarding the course of their cold sore disease under topical treatment with the active ingredient B-OT are summarized in the table in Figure 3 (Parts 1 to 4). The table shows the condition of the affected skin areas on the day of detection of the first symptoms and initial application of B-OT, approximately 24 hours later (the first day after detection), and approximately 48 hours later (the second day after detection).

[0137] The disease progression (columns 1, 2, 3) of the individual patients shows that all experienced a reduction in symptoms under B-OT treatment, and in particular, the typical herpes blisters did not appear at all. In all cases, lip cracking was prevented, and the lip swelling subsided within the respective time intervals shown.

[0138] Example 3: Cold:

[0139] (A) a patient report

[0140] On day (1), the patient experienced the first signs of a cold upon waking, particularly increasing nasal congestion. His nose began to run, and breathing through it became increasingly difficult. The patient used a custom-prepared solution of 6 mg B-OT dissolved in 150 ml of water, drawing the solution up his nose until it was filled. He held the solution in his nose for three seconds and then let it drain out. This process was repeated seven times (7x), ensuring that almost the entire 150 ml of B-OT solution was drawn into the nose. Just 10 minutes later, the nasal mucosa had decongested sufficiently for the patient to breathe much more easily through his nose. After a total of 20 minutes, his nose felt clear and normal. The nasal mucosa was not dry.No nasal discharge was observed, and it was no longer necessary to blow the nose. This "clear nose" effect lasted for approximately four hours. After these four hours, another nasal irrigation with B-OT was performed. This also resulted in a reduction of the nasal mucosal swelling, so that the patient no longer experienced any cold symptoms and could breathe normally through his nose. To verify whether the effect was due to B-OT and not to spontaneous reduction of the nasal mucosal swelling, the patient did not perform any further nasal irrigation with an aqueous B-OT solution. Subsequently, a normal cold developed with significant swelling of the nasal mucosa. The nose began to run again (i.e., fluid was once more discharged), and it was again necessary to frequently blow the nose to clear the discharge.Furthermore, a tingling sensation accompanied by the urge to sneeze occurred repeatedly, resulting in sneezing. This indicates that the cold viruses in the nasal mucosa had not disappeared, but rather that their developmental stages and their effects leading to nasal mucosa swelling were inhibited by B-OT. Additionally, the neurological effects of the viruses, which cause nasal tingling and the urge to sneeze, were prevented. This demonstrates that, in addition to its inhibitory effect on inflammation of the nasal mucosa, B-OT is also capable of preventing sensory-neurological processes such as nasal tingling and the urge to sneeze.

[0141] (B) Individual reports from various patients

[0142] A study on self-treatment of rhinoviruses (common cold) using B-OT in topical application included a group of 24 patients.

[0143] The active ingredient B-OT was provided to the patients for this purpose by the applicant or by a pharmacy.

[0144] The application was in the form of a nasal spray using a solution of B-OT in water, which was prepared by the patients themselves with approximately 0.05-0.4% (weight / weight) B-OT with water and sprayed into the nose.

[0145] The results of these B-OT self-treatments were documented by the patients in individual reports on the course and success of the therapy. They are summarized in the table in Fig. 4.

[0146] The course of the disease (columns 1, 2 and 3, 4) of the individual patients shows how quickly the nose cleared and how long this lasted.

[0147] Example 4: Treatment of the lungs with B-OT-containing aerosol to prevent

[0148] Cough

[0149] A B-OT-containing aerosol, produced using commercially available aerosol generators, is inhaled by the affected patient. For this purpose, a 1% B-OT solution in water was prepared. B-OT inhibits the processes that lead to the formation of a cough reflex, thus preventing the spread of viruses from the lungs via coughing. Furthermore, this treatment inhibited the inflammatory processes in the lung mucosa to such an extent that the formation of mucus, which would otherwise need to be coughed up, was prevented. The urge to cough was thus significantly reduced and limited to the first two days of the illness. The expectoration of mucus, which is often necessary for many days after a viral lung infection, was completely prevented.

[0150] Example 5: Genital herpes:

[0151] (A) a patient report

[0152] A patient with recurrent genital herpes prepared a commercially available skin cream containing 4% (w / w) B-OT (i.e., he mixed the commercially available skin cream with the appropriate amount of B-OT) and applied it to the affected skin areas. This prevented the formation of blisters. Applying the B-OT cream extended the time between outbreaks. The severity of the outbreaks also decreased with each application of B-OT.

[0153] (B) Individual reports from various patients

[0154] A study on self-treatment of genital herpes using B-OT in topical application included a group of 15 patients with recurrent genital herpes disease.

[0155] The active ingredient B-OT was provided to the patients for this purpose by the applicant or by a pharmacy.

[0156] The application was performed in the morning, at midday and in the evening, each time using a commercially available skin cream which was mixed by the patients themselves with approximately 3-5% (weight / weight) B-OT.

[0157] The results of these B-OT self-treatments were documented by the patients in individual reports on the course and success of the therapy. They are summarized in the table in Fig. 5.

[0158] The course of the disease (columns 1, 2, 3, ff.) of the individual patients shows that the recurrence of genital herpes was delayed further and further.

[0159] Example 6: Presence of human papillomaviruses (HPV) in the cervix:

[0160] A group of patients with confirmed HPV infection of the cervix via PCR analysis received topical treatment of the cervix once daily for one week with a 2% (w / w) B-OT cream. Subsequently (on day 7), another PCR test for HPV was performed. Quantitative PCR revealed a significant reduction (>30%) in HPV infection. Treatment of the cervix was continued for four weeks with daily application of the B-OT cream. After four weeks, HPV was no longer detectable in 40% of the women. Treatment of the cervix in the remaining HPV-positive women was continued for another four weeks with daily application of the B-OT cream. HPV was then detected again using quantitative PCR. HPV was no longer detectable in 45% of these women.The women in whom HPV remained detectable were treated for another four weeks with a daily application of a B-OT-containing cream. Afterwards, another HPV test was performed using quantitative PCR. HPV was no longer detectable in 80% of these women.

[0161] In a subsequent study, a group of 26 patients who had been found to have HPV infection in their cervix by PCR analysis received the active ingredient B-OT for self-treatment of HPV by means of a topical application.

[0162] The active ingredient B-OT was provided to the patients for this purpose by the applicant or by a pharmacy.

[0163] The application was performed once daily for seven days, using a commercially available skin cream that the patients themselves mixed with approximately 1-3% (wt / wt) B-OT. After a one-week break, the application was continued for another week. The days with B-OT treatment were therefore days 1 to 7 and days 15 to 21.

[0164] The individual reports of patients No. 1 to No. 26 on the course of HPV disease under topical treatment with the active ingredient B-OT are summarized in the table in Fig. 6.

[0165] The detection of HPV (columns 3 and 4) in the individual patients shows that a significant proportion of the patients experienced a loss of HPV infection on day 8 and day 22.

[0166] All these results show that treating the cervix with B-OT significantly reduces HPV infection and leads to its disappearance in most cases. Example 7: Treatment of a skin wart on the back of the hand:

[0167] A 3% (w / w) B-OT cream was applied to the wart twice daily. During the first few days, there was no visible change in the wart. After seven days, the wart fell off, revealing normal, undamaged skin in its place. This demonstrates the significant advantage over surgical removal of the wart or cryo-removal by freezing the wart, both of which can lead to skin damage or even scarring.

[0168] Example 8: Treatment of genital warts:

[0169] A 3% (w / w) B-OT cream was applied to the warts twice daily. This treatment was continued for six days. By the seventh day, some of the warts had reduced in size or had visibly disappeared completely. After 14 days, more than 50% of the original warts showed a visible reduction or disappearance. After a total of four weeks, more than 80% of the warts had significantly reduced in size or disappeared completely.

[0170] Example 9: Reducing the transmission of sexually transmitted viruses:

[0171] Unprotected sexual intercourse (without a condom) between men and women or men and men often leads to the transmission of viruses such as the herpes simplex virus or the human papillomavirus. To reduce the transmission of such viruses, the penis should be treated with a 1% (wt. / wt.) B-OT cream to reduce the number of viruses that can infect the penis and also to reduce the number of viruses transmitted from the penis to the sexual partner(s).

[0172] In a study on this topic, women underwent a quantitative PCR test for HPV in the cervix to determine if they were infected with HPV. Men who had sexual intercourse with one of the HPV-positive women subsequently had an HPV test performed on penile swabs.

[0173] In a group of men who had sexual intercourse with HPV-positive women, the HPV count was determined and compared to that of a similarly sized group of men who had applied a 1% (w / w) BOT cream to their penises before intercourse. In the BOT treatment group, a significant reduction in HPV infection was observed compared to the untreated group—both quantitatively, i.e., in terms of the number of viruses detected, and qualitatively, i.e., in terms of the number of men without HPV infection. In corresponding experiments with the reverse HPV infection scenario, the transmission of HPV from the penis to the woman (vagina and cervix) was investigated.Topical pretreatment of the vagina and cervix of women who had sexual intercourse with men who had HPV infection on the penis led to a significant reduction in the transmission of HPV and herpes viruses during sexual intercourse.

[0174] Similar results were obtained in analogous studies on the transmission of genital herpes.

[0175] Example 10: B-OT-containing gel - composition and tolerability

[0176] Based on a gel formulation comprising the components propylene glycol, glycerin, citrate buffer pH 4.5, hydroxyethylcellulose, potassium sorbate and / or benzoic acid, three differently dosed Benfo-oxythiamine (B-OT) gels were produced, namely in dosages of 0.3%, 1.0% and 5.0% B-OT.

[0177] The local tolerability of these Benfo-Oxythiamine (B-OT) gel formulations was investigated in female and male 6-week-old hairless Skh-l mice.

[0178] The test animals (3 female and 3 male mice each) in the groups "0.3% B-OT", "1.0% B-OT", and "5.0% B-OT" received daily topical application of the B-OT gel with the respective B-OT concentration for 14 consecutive days. In parallel, a control group of animals received daily topical application of the gel formulation without B-OT (gel placebo) for the same 14 consecutive days.

[0179] Throughout the entire study, no mortality, no abnormal behavior (except for some signs of aggression in certain males after treatment), similar weight changes and similar food intake, and no signs of erythema or edema were observed in the female and male Skh-l mice of the three test groups and the control group.

[0180] The local tolerability of the Benfo oxythiamine (B-OT) gel formulation was very good at the three dosages of 0.3%, 1.0%, and 5.0%. Non-patent literature cited:

[0181] Diaz-Moralli S, Aguilar E, Marin S, Coy JF, Dewerchin M, Antoniewicz MR, Meca-Cortes O, Notebaert L, Ghesquiere B, Eelen G, Thomson TM, Carmeliet P, Cascante M. A key role for transketolase-like 1 in tumor metabolic reprogramming. Oncotarget. 2016 Aug 9;7(32):51875- 51897. doi: 10.18632 / oncotarget.10429. PMID: 27391434; PMCID: PMC5239521.

[0182] Yellow List Pharmindex: https: / / www.gelbe-liste.de / wirkstoffe /

[0183] Girdhar K., Powis A., Raisingani A., Chrudinovä M., Huang R., Tran T., Sevgi K., Dogus Dogru Y., Altindis E., Viruses and metabolism: The effects of viral infections and viral insulins on host metabolism. Annu. Rev. Virol. 8, 373-391 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]

[0184] Gumer, K.H.; Gardner, D.K.: Blastocyst-Derived Lactate as a Key Facilitator of Implantation. Biomolecules 2025, 15, 100. https: / / doi.org / 10.3390 / bioml5010100.

[0185] Jayachandran A, Lo PH, Chueh AC, Prithviraj P, Molania R, Davalos-Salas M, Anaka M, Walkiewicz M, Cebon J, Behren A. Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells. BMC Cancer. 2016 Feb 22;16: 134. doi: 10.1186 / sl2885-016-2185-5. PMID: 26907172; PMCID: PMC4763451.

[0186] Knopf P, Stowbur D, Hoffmann SHL, Hermann N, Maurer A, Bucher V, Poxleitner M, Tako B, Sonanini D, Krishnamachary B, Sinharay S, Fehrenbacher B, Gonzalez-Menendez I, Reckmann F, Bomze D, Flatz L, Kramer D, Schaller M, Forchhammer S, Bhujwalla ZM, Quintanilla-Martinez L, Schulze-Osthoff K, Pagel MD, Fransen MF, Röcken M, Martins AF, Pichler BJ, Ghoreschi K, Kneilling M. Acidosis-mediated increase in IFN-y-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors. Mol Cancer. 2023 Dec 15;22(l):207. doi: 10.1186 / sl2943-023-01900-0. PMID: 38102680; PMCID: PMC 10722725.

[0187] 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 CDH1 synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression. Nat Commun. 2019 Jun 7; 10(l):2502. doi: 10.1038 / s41467-019-10375-x. PMID: 31175280; PMCID: PMC6555833.

[0188] Lu, Z.; Fang, P.; Li, S.; Xia, D.; Zhang, J.; Wu, X.; Pan, J.; Cai, H.; Fu, L.; Sun, G.; et al. Lactylation of Histone H3kl 8 and Egrl Promotes Endothelial Glycocalyx Degradation in Sepsis-Induced Acute Lung Injury. Adv. Sei. 2024; epub ahead of print. Sharma D, Singh M, Gupta R, Kumar V, Kumar V, Rani R. Intervention on lactate in cancer: a promising approach for the development of cancer therapeutics. Adv Cancer Biol Metastasis.

[0189] 2022;5: 100058. https: / / doi.Org / 10.1016 / j.adcanc.2022.100058

[0190] Sun W, Liu Y, Glazer CA, Shao C, Bhan S, Demokan S, Zhao M, Rudek MA, Ha PK, Califano JA. TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis through increased aerobic glycolysis and HIFI alpha stabilization. Clin Cancer Res. 2010 Feb 1; 16(3):857-66. doi: 10.1158 / 1078-0432.CCR-09- 2604. Epub 2010 Jan 26. PMID: 20103683; PMCID: PMC2824550.

[0191] Tyl MD, Merengwa VU, Cristea IM. Infection-induced lysine lactylation enables herpesvirus immune evasion. Sei Adv. 2025 Jan 10;l l(2):eads6215. doi: 10.1126 / sciadv.ads6215. Epub 2025 Jan 8. PMID: 39772686; PMCID: PMC11708889.

[0192] Xu X., zur Hausen A., Coy FC, Löchelt M: Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells. Cancer Cell Biology Volumel24, Issue 6,15 March 2009, Pages 1330-133, https: / / doi.org / 10.1002 / ijc.24078 Yan, M.; Smeets, R.; Gosau, M.; Vollkommer, T.; Fuest, S.; Stetzer, E.; Kluwe, L.; Coy, J.F.; Burg, S. Tolerance of Human Fibroblasts to Benfo-Oxythiamine In Vitro. Int. J. Environ. Res. Public Health 2022, 19, 4112. https: / / doi.org / 10.3390 / ijerphl9074112.

Claims

A n s p r ü c h e 1. Benfo-oxythiamine and / or oxythiamine for use as the active ingredient of a topically administered medicinal product for the therapeutic treatment of patients with a disease of the body surface skin (cutis and subcutis) and / or one or more mucous membranes (mucosa) caused by viruses, wherein the medicinal product is administered at a time when viral replication has already taken place in the patient's cells (host cells) and viral release from the orthe cell(s) is about to undergo replication, recognizable by the first symptoms of viral replication being detectable, in particular a skin change (e.g., swelling, redness) and / or itching and / or pain and / or skin growth changes and / or a positive result of a test to detect the viruses in a tissue sample (e.g., in a medical swab), and wherein Benfo-Oxythiamine and / or Oxythiamine (I) slow down or prevent the spread mechanisms of the viruses, so that after replication, the viruses remain in their host cells and cell damage in the patient organism (host organism) is reduced or prevented, and (II) induce an immune response against the viruses remaining in the cells, so that the patient's immune system is activated or reactivated to generate an effective immune response against the viruses.

2. Use according to claim 1, wherein Benfo-oxythiamine and / or oxythiamine produces (provokes) one or more of the following effects in the patient (host organism): (a) Inhibition or prevention of virus-induced cell and / or tissue damage and / or changes in cells and / or tissues; (b) Inhibition or prevention of the spread mechanisms of viruses by inhibiting neurological and / or immunological processes; (c) Relief and / or cure of the symptoms caused by the viral infection; (d) Reduction or prevention of the symptoms of the viral infection; (e) Reduction of the duration of illness; (f) Reduction of the severity of the disease course; (g) Reduction or reversal of the immunosuppression caused by the viruses; (h) Activation of the patient's own immune system with regard to the elimination of the viruses; (i) cellular immune response against the viruses, which is suitable to eliminate the viruses and / or prevent reinfection; (j) humoral immune response (B-cell response) against viral antigens; (k) protective cellular immunity against reinfection with the viruses concerned or against virus-induced pathology; (l) Protection against viral reinfections; 3. Application according to claim 1 or 2, characterized in that the therapeutic treatment is a preventive treatment in case of viral re-infection.

4. Application according to one of claims 1 to 3, characterized in that the viruses have a lytic replication cycle.

5. Use according to any one of claims 1 to 4 in the treatment of patients with disease of the skin and / or mucous membrane caused by herpes viruses from the group comprising herpes simplex virus type 1, herpes simplex virus type 2 and varicella-zoster virus.

6. Use according to any one of claims 1 to 4 in the treatment of patients with disease of the skin and / or mucous membrane caused by herpesviruses from the group comprising human cytomegalovirus, human herpesvirus type 6 and human herpesvirus type 7.

7. Use according to any one of claims 1 to 4 in the treatment of patients with disease of the skin and / or mucous membrane caused by herpesviruses from the group comprising Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus.

8. Use according to any one of claims 1 to 4 in the treatment of patients with skin and / or mucous membrane disease caused by human papillomaviruses.

9. Use according to any one of claims 1 to 4 in the treatment of patients with disease of the skin and / or mucous membrane caused by viruses that infect the nasal mucosa and / or the epithelia of the lungs and / or bronchi.

10. Application according to any one of claims 1 to 9, characterized in that the medicinal product is a human medicinal product.

11. Application according to any one of claims 1 to 10, characterized in that the topical treatment is carried out in the form of the administration of a Benfo-oxythiamine and / or oxythiamine-containing ointment, cream, gel, tincture, spray, inhalation spray or inhalation solution.

12. Application of Benfo-Oxythiamine according to any one of claims 1 to 11, characterized in that the topical treatment is carried out by administering a paste or cream or ointment or gel preparation or lotion containing Benfo-Oxythiamine of about 0.1 to 10% wt / w, preferably about 0.3 to 10% wt / w, particularly preferably about 0.3 to 5% wt / w.

13. Application of Benfo-Oxythiamine according to any one of claims 1 to 12, characterized in that the topical treatment is carried out by administering a gel based on a gel formulation comprising the components propylene glycol, glycerin, citrate buffer, hydroxyethylcellulose, potassium sorbate and / or benzoic acid, and with a Benfo-Oxythiamine content of about 0.1 to 10% wt / w, preferably about 0.3 to 10% wt / w, particularly preferably about 0.3 to 5% wt / w.

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