USE OF CO-ENZYME ANTAGONISTS TO SLOW METABOLISM

Abstract

The invention relates to the use of at least one inhibitory structural analog or inhibitory functional analog of a coenzyme (such as thiamine for example) of an enzyme group, the enzyme members of which catalyze anabolic and/or catabolic and/or energy-releasing metabolic reactions that are of essential significance for the functionality of the overall metabolism of cells, in particular mammalian cells. The invention is used to treat patients in order to produce a general successive (in particular also continuous) slowing down of the metabolic processes of endogenous cells and exogenous cells in the body of the patient and thus achieve a slowing down of disease-causing processes in particular.

Claims

1. A method for successively slowing anabolic, catabolic and/or energy-releasing metabolic processes of cells in the body of a patient comprising: administering, in one or more doses of a dosage regimen, to a patient in need thereof an inhibitory structural analog or inhibitory functional analog of a co-enzyme of an enzyme group whose members catalyze anabolic and/or catabolic and/or energy-releasing metabolic reactions of essential importance for a functional capability of an overall metabolism of the cells in an amount effective to successively slow anabolic, and/or catabolic and/or energy-releasing metabolic processes of the cells in the body of the patient, wherein the administering results in a slowing of the patient's metabolism and wherein the cells whose metabolic processes are slowed comprise healthy and degenerated body cells of the patient and bacterial cells, fungal cells or cells of parasites present in the body of the patient.

2. The method of claim 1, wherein the inhibitory structural analog or functional analog of the co-enzyme is an inhibitory thiamine analog.

3. The method of claim 2, wherein the inhibitory thiamine analog of the co-enzyme is: oxythiamine, and/or benfo-oxythiamine, and/or an inhibitory thiamine derivative, and/or an inhibitory oxythiamine derivative, and/or an inhibitory benfo-oxythiamine analog, and/or an inhibitory benfo-oxythiamine derivative.

4. The method of claim 1, wherein patient suffers from (i) bacterial disease (infection), preferably as monotherapy or as co-therapy with at least one further medicament, in particular a medicament with antibacterial action, and in particular for suppressing the action of bacterial endotoxins on the patient's organism, in particular those endotoxins which are released as a result of the bactericidal effect of the further medicament, (ii) a disease originating from/caused by fungi, preferably as monotherapy or as co-therapy with at least one further drug, (iii) sepsis or impending sepsis, (iv) viral disease (infection), (v) an immunological disease, in particular an inflammatory disease and/or an autoimmune disease such as Systemic Lupus Erythemathodes (SLE), including such forms of disease which occur with an intermittent course, in particular rheumatoid arthritis and/or multiple sclerosis and/or inflammatory bowel diseases such as ulcerative colitis, Crohn's disease and/or inflammatory/degenerative diseases, in particular of the skeletal system such as Bekhterev's disease, (vi) cancer, or (vii) cardiac or cerebral infarction.

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. The method of claim 1, wherein the inhibitory structural analog or inhibitory functional analog of the co-enzyme is administered as part of a tumor cell treatment of the patient wherein the patient suffers from cancer.

10. The method of claim 1, wherein the inhibitory structural analog or inhibitory functional analog is administered to the patient as a pretreatment prior to surgical procedures and/or drug therapies.

11. The method of claim 1, wherein the patient suffers from (i) traumatic brain injury, (ii) nerve transection(s), in particular with spinal cord injury and risk of paraplegia or tetraplegia or with a recent onset of paraplegia, or (iii) painful blunt injuries, in particular strains, sprains or contusions.

12. (canceled)

13. (canceled)

14. (canceled)

15. The method of claim 9, wherein the inhibitory structural analog or inhibitory functional analog of the co-enzyme is administered orally according to a dosage regimen in which individual doses for the patient having 60 kg body weight range from about 0.1 mg to about 80 mg or, from about 1 mg to about 50 mg.

16. The method of claim 9, wherein the inhibitory structural analog or inhibitory functional analog of the co-enzyme is benfooxythiamine (B-OT).

17. The method of claim 9, wherein the inhibitory structural analog or inhibitory functional analog of the co-enzyme is used as a co-enzyme antagonist and active ingredient (co-enzyme antagonist/active ingredient) and is administered to the patient suffering from cancer in a pre- or co-therapy and/or in a continuous therapy lasting weeks or months, and is administered according to a dosage regimen determined by a method comprising: (1) on day 1: (1a) selection of the co-enzyme antagonist/active ingredient and measurement of the enzyme activity of a representative enzyme E from the group of enzymes dependent on the co-enzyme in a first body fluid sample I of the patient which is targeted by the co-enzyme antagonist/active ingredient, (1 b) subsequent administration of the co-enzyme antagonist/active ingredient to the patient in an amount T1 suitable of inducing in the co-enzyme-dependent enzymes an inhibition of their initial enzyme activity, wherein a target value of persistent enzyme activity inhibition is predetermined and aimed at; (2) on day 2: (2a) measurement of enzyme activity of enzyme E in a body fluid sample II of the patient obtained on that day; (2b) comparison of the enzyme activities measured in body fluid sample I and body fluid sample II and calculation of an extent of the inhibition of the enzyme activity of the representative enzyme E; (2c) subsequently administering the co-enzyme antagonist/active ingredient to the patient in an amount T2 calculated on the basis of amount T1 and the desired target value for enzyme activity inhibition and on the basis of the reduction in enzyme activity calculated in step (2b), such that the amount T2 is greater than or less than or equal to the amount T1; (3) on day 3 and subsequent days, (i), until a target value of enzyme activity inhibition is reached: repeating steps (2a) and (2b) and repeating step (2c) but wherein the co-enzyme antagonist/active ingredient is administered to the patient is in an amount T(i), which is calculated on basis of an amount previously administered on preceding day T(i-1) and the target value for the enzyme activity inhibition and on the basis of the reduction of the enzyme activity calculated in (2b), such that the amount T(i) is greater than or less than or equal to the previously administered amount T(i-1).

18. The method of claim 17, further comprising (4) monitoring medical parameters of the cancer and of medical parameters of basic functions of the body of the patient including number of heart beats per minute and/or occurring loss of appetite and/or a loss of weight, and adjusting the target value for the enzyme activity inhibition of the representative enzyme E in such a way that the medical parameters of the cancer reach desired values while sufficient enzyme activity of the representative enzyme E is still present, so that the basic functions of the patient's body are maintained continuously.

19. The method of claim 17, wherein the target value of enzyme inhibition of the representative enzyme E is at least 20%, at least 50%, or at least 70%, in each case based on the value of the original enzyme activity of the representative enzyme E measured in (1a).

20. The method of claim 17, wherein the co-enzyme antagonist/active ingredient is benfooxythiamine (B-OT), and the amount T1 of B-OT is about 1 mg to about 30 mg, or about 2 mg to about 15 mg, and that the administration of B-OT is oral.

21. The method of claim 9, wherein the patient the inhibitory structural analog or inhibitory functional analog is administered as a monotherapy or as pre- or co-therapy of chemotherapy, radiotherapy and/or as a targeted cancer therapy.

22. The method of claim 21, wherein the inhibitory structural analog or inhibitory functional analog is administered as pre- or co-therapy of chemotherapy and/or radiotherapy.

23. The method of claim 16, wherein B-OT is administered orally and, based on the patient having a body weight of 60 kg, in the following doses: (a) when used in combination with radiotherapy: on the day of radiotherapy before radiotherapy once at about 1-150 mg, about 10-75 mg, or about 30-50 mg, on the day after radiotherapy once at about 1-70 mg, about 3-40 mg, or about 4-20 mg, and on the second day after radiotherapy once at about 1-40 mg, about 3-25 mg, or about 4-18 mg; (b) when used in combination with chemotherapy, especially with the use of cytotoxic drugs: on the day before chemotherapy once at about 1-150 mg, about 10-75 mg, or about 30-50 mg, on the day of chemotherapy once at about 1-150 mg, about 10-75 mg, or about 5-50 mg, and on the day after chemotherapy once at about 1-100 mg, about 10-75 mg, or about 5-50 mg; (c) when used in combination with one, or more, targeted cancer therapies using imatinib and/or sorafenib and/or erbitux and/or avastin and/or gemcitabine and/or another anti-cancer drug: on the day before chemotherapy once at about 1-100 mg, about 10-75 mg, or about 5-50 mg, on the day of chemotherapy once at about 1-100 mg, about 10-75 mg, or about 5-50 mg, and on the day after chemotherapy once at about 1-100 mg, about 10-75 mg, or about 5-50 mg; or (d) when used as monotherapy or in combination with one or more other therapies, where the application lasts longer than one week, than two weeks, longer than three weeks or longer than four weeks: per day about 1-30 mg, about 2-15 mg, or about 3-10 mg, and in each case as a single dose or in the form of several partial doses.

24. The method of claim 1, comprising a treatment phase with the dosage regimen, wherein following the treatment phase, the metabolism of the healthy cells reactivates.

25. A method for successively slowing anabolic, catabolic and/or energy-releasing metabolic processes of cells comprising: administering, in one or more doses of a dosage regimen, to a patient in need thereof an inhibitory thiamine analog in an amount effective to successively slow anabolic, catabolic and/or energy-releasing metabolic processes of the cells in the patient, wherein: the patient is a cancer patient, the administering results in a slowing of the patient's metabolism, and the cells whose metabolic processes are slowed comprise healthy and tumor cells having a metabolism.

26. The method of claim 25, wherein the inhibitory thiamine analog is benfooxythiamine (B-OT) and/or derivates thereof.

27. The method of claim 26, wherein the inhibitory thiamine analog is benfooxythiamine (B-OT).

Description

[0207] The invention is explained in more detail below with reference to examples of embodiments with figures. In the figures show:

[0208] FIG. 1: Change in individual plasma concentrations of OT with time (over 24 hours) in male beagle dogs. The y-axis indicates—the plasma concentration in ng/ml. [0209] On the x-axis the time is indicated in hours (h=hours) [0210] (a) Change in individual plasma concentrations on day 1 after administration of a single dose of B-OT in an amount of 1 mg/kg/day. [0211] The symbols mean: [0212] —⋄—=dog no. 3001 [0213] —□—=dog no. 3002 [0214] (b) Change in individual plasma concentrations on day 1 after administration of a single dose of B-OT in an amount of 0.5 mg/kg/day. [0215] The symbols mean: [0216] —Δ—=dog no. 4001 [0217] —∘—=dog no. 4002 [0218] (c) Change in individual plasma concentrations at day 7 after seven days of administration of single doses of B-OT in an amount of 0.5 mg/kg/day. [0219] The symbols mean: [0220] —Δ—=dog no. 4001 [0221] —∘—=dog no. 3002 [0222] (d) Change in mean plasma concentrations on day 1 after administration of a single dose of B-OT at 1 mg/kg/day, and on day 1 and day 7 after daily administration of single doses of B-OT in an amount of 0.5 mg/kg/day. [0223] The symbols mean: [0224] —□—=group 3, 1.0 mg/kg/day, day 1 [0225] —Δ—=Group 4, 0.5 mg/kg/day, day 1. [0226] —∘—=group 4, 0.5 mg/kg/day, day 7.

[0227] FIG. 2: Graph showing the change in plus beat with time in dogs after administration of different amounts (doses) of B-OT. On the y-axis, the pulse beat (heart rate) is given in beats per minute (bpm). On the x-axis, the time is given in hours. [0228] The symbols mean: [0229] —.circle-solid.=0 mg/kg/day—Benfooxythiamine=0 mg/kg/day—B-OT [0230] —□—=0.05 mg/kg/day—Benfooxythiamine=0.05 mg/kg/day—B-OT [0231] —Δ—=0.15 mg/kg/day—Benfooxythiamine=0.15 mg/kg/day—B-OT [0232] −⋄—=0.5 mg/kg/day—Benfooxythiamine=0.5 mg/kg/day—B-OT

[0233] FIG. 3: Computed tomographic image of the lungs of patient 1 before and after B-OT treatment. A: before B-OT treatment, distinct areas of viral pneumonia infiltrates are visible. B: marked decrease in infiltrates after 7 days of B-OT therapy.

[0234] FIG. 4: Computed tomographic image of the lungs of patient 2 before and after B-OT treatment. A: distinct areas of viral pneumonia infiltrates are visible before B-OT treatment. B: marked decrease of infiltrates after 7 days of B-OT treatment.

[0235] FIG. 5: Computed tomographic image of the lungs of patient 3 before and after B-OT treatment. A: before B-OT treatment, distinct areas of viral pneumonia infiltrates are visible. B: marked decrease in infiltrates after 7 days of B-OT therapy.

[0236] FIG. 6: Computed tomographic image of the lungs of patient 4 before and after B-OT treatment. A and C: distinct areas of viral pneumonia infiltrates are visible before B-OT treatment. B and D: marked decrease in infiltrates after 7 days of B-OT therapy.

[0237] FIG. 7: Computed tomography of the lungs of patient 2 (see FIG. 4) one month after the end of therapy.

EXAMPLE 1: DETERMINING APPROPRIATE DOSAGES FOR THE DOSING REGIMEN AND MONITORING OF THERAPY

[0238] The determination of appropriate dosages for the dosing regimen and monitoring of therapy is described here using benfooxythiamine (B-OT) as an example. The effect of B-OT in the patient's body is influenced by various patient-specific factors such as gene variants, binding affinity of thiamine or B-OT to the respective thiamine-dependent enzymes, active uptake and transport of thiamine by transport systems in the body, and enzymatic degradation of thiamine. The desired or optimal amount of dosage of B-OT for a particular patient or group of patients and suitable for the individual situation of the patient(s) can be determined using various diagnostic procedures and parameters.

[0239] One possible method is to measure and monitor the pulse rate and pulse rate change in the patient(s) in question.

[0240] By slowing down (throttling) the metabolism, GSSV also causes a reduction in the energy released with it. The body attempts to compensate for the lower energy release by increasing the pulse rate in order to transport more oxygen into the body so that more energy can be released as a result. The increase in the patient's pulse beat is an indication and a suitable parameter that GSSV has inhibited energy release and to what extent. If there is a sharp increase in pulse rate, e.g., in a person a pulse rate above 90, countermeasures may be necessary to increase energy release again. This can be achieved by reducing the amounts of B-OT that continue to be administered (dose reduction) or by administering thiamine (especially the thiamine form benfotiamine) FIG. 2 shows the significant increase in pulse beat (heart rate) over 24 hours in dogs after administration of various amounts of B-OT.

[0241] Another possible method is the determination of transketolase enzyme activity in lysates of erythrocytes from the patient and use of the determined transketolase enzyme activity values as a diagnostic marker for monitoring B-OT therapy. Here, basal transketolase enzyme activity in erythrocytes is the preferred parameter.

[0242] The performance of assay procedures for the determination of transketolase enzyme activity in erythrocyte lysates is known in the prior art, for example from Smeets et al., 1971 and Takeuchi et al., 1984 and Michalak et al., 2013.

[0243] Here in the example and preferably prior to the start of administration of B-OT, transketolase enzyme activity is determined in lysates of erythrocytes from the patient(s). After administration of B-OT, transketolase enzyme activity is again determined on the following day in freshly obtained lysates of erythrocytes from the patient(s) in question. Also on (all) other days after further administrations of B-OT, the transketolase enzyme activity should be determined in freshly obtained lysates of erythrocytes of the respective patient(s). By comparing the determined transketolase enzyme activity values under B-OT therapy with the determined values before the start of B-OT administration, the extent of inhibition of transketolase enzyme activity in the erythrocytes is determined. This makes it possible to select the amount (dose) of B-OT to be administered so that the desired degree of inhibition of transketolase enzyme activity and that of other thiamine-dependent enzymes is achieved.

[0244] For example, 50% inhibition may be chosen to administer B-OT in the long term to permanently inhibit inflammation.

[0245] For example, 80% inhibition may be selected if B-OT is to be administered for approximately one month and daily to achieve inhibition of metastasis in cancer patients with very advanced disease.

[0246] For monitoring B-OT therapy, measurements of one or more of the following biochemical markers in the blood of patients can also be used:

[0247] Increase in bilirubin level, increase in ALAT (alanine aminotransferase) and ASAT (aspartate aminotransferase) enzymes, decrease in CK (creatine kinase) enzyme, decrease in protein concentration (not albumin level), decrease in white and red blood cells, increase in platelets (thrombocytes), decrease in reticulocytes.

EXAMPLE 2: USE ACCORDING TO THE INVENTION OF THE ACTIVE SUBSTANCE BENFO-OXYTHIAMINE “B-OT” FOR GSSV IN CANCER CELLS CIRCULATING IN THE BLOOD

[0248] Cancer cells circulating in the patient's blood are detected and separated and isolated from the blood. Detection, separation and isolation are preferably performed without the use of surface markers, i.e., for example, by means of cell sorting and multi-staining single-cell analysis “MSSCA”, so that the isolated cancer cells are a representative image of the malignancy (cancer tumor) in the patient.

[0249] These isolated cancer cells are treated in a test series “A” with the cancer therapeutic agent(s) under consideration, and in a parallel test series “B” first incubated with the agent benfo-oxythiamine (“B-OT”)—as a preferred example of an inhibitory thiamine analogue or an inhibitory co-enzyme antagonist—and subsequently treated with the cancer therapeutic agents from test series A (see also Example 3). The results from both test series A and B are compared, and in particular if it is determined that a preferred cancer therapeutic agent (or its active ingredient) from test series A appears to be ineffective or inadequately effective according to guidelines or for other reasons, but in contrast shows a satisfactory effect after pretreatment with B-OT according to the result in test series B, pretreatment with B-OT is indicated as a co-therapy of the actual established cancer therapy in the patient's upcoming cancer therapy. Regarding the duration and intensity of pretreatment or co-treatment with B-OT, experimental studies have shown that a two-day treatment immediately prior to application to concurrent co-therapy with the actual established cancer therapy is promising and thus appropriate.

EXAMPLE 3: DETERMINATION OF THE APPROPRIATE COMBINATION OF EFFECT OF GSSV ACCORDING TO THE INVENTION (GSSV THERAPY) AS PRE- OR CO-THERAPY AND SUBSEQUENT OR CONCURRENT DRUG THERAPY (E.G. CHEMOTHERAPY AND/OR TARGETED CANCER THERAPY) AND/OR RADIOTHERAPY IN A CANCER PATIENT

[0250] A suitable combination of (i) the application of a co-enzyme antagonist according to the invention and the GSSV thereby induced (GSSV therapy)—preferably using at least one inhibitory thiamine analogue (in particular oxythiamine, benfo-oxythiamine (“B-OT”) and/or a benfo-oxythiamine analogue)—as pre- or co-therapy (initiation of the administration of B-OT prior to or concurrently with or after the initiation of the established cancer therapy of the cancer patient in question) and (ii) the application of therapeutics (agents, drugs) that act in a non-directed manner (e.g., cisplatin) or targeted (e.g., sorafenib, imatinib, Erbitux, Avastin, Herceptin) and/or the application of radiotherapy (according to current evidence-based therapy rules) is ascertainable in different ways:

[0251] a) The cancer patient is initially treated with established chemotherapy (using classical cytostatics, i.e. cell type non-specific cell proliferation inhibitors) and/or targeted cancer therapy (using cell type specific agents such as sorafenib and others) and/or radiotherapy (according to current evidence-based therapy rules). If his tumor cells (a subset thereof or all of them) either already show resistance to the therapy or have developed resistance under the therapy, he will be further treated with a combined therapy comprising the administration of the co-enzyme antagonist according to the invention as active ingredient (drug) and the application of the established chemotherapy and/or targeted cancer therapy and/or radiotherapy. (b) Cancer cells are taken from a cancer patient who has not yet received established chemotherapy and/or targeted cancer therapy and/or radiation therapy and treated in vitro, preferably ex vivo (i.e., on a malignancy tissue sample freshly isolated from the organism), with the cancer therapeutic agents under consideration to determine which agent or combination of agents works best. In this way, a chemotherapeutic agent or targeted cancer therapeutic agent or radiation therapeutic agent or a combination of several of these therapeutic agents can be identified that is effective in the cancer patient's individual situation. This will also determine whether resistance to the therapeutics used is present in the malignancy cells in question. Parallel to this in vitro test series “A” of the cancer therapeutics under consideration per se, a test series “B” and/or a test series “C” is carried out. In test series B, the melanoma cells of the patient are first pretreated with a co-enzyme antagonist according to the invention as active substance (drug), —for example and preferably with an inhibitory thiamine analogue—, and then treated with the planned cancer therapeutic agent.

[0252] In test series C, the patient's malignant cells are treated simultaneously with both a co-enzyme antagonist according to the invention as active ingredient (drug), —for example and preferably with an inhibitory thiamine analogue —, and with the planned cancer therapeutic agent.

[0253] By comparing the results from test series A with the results from test series B and test series C, it can be determined whether a targeted cancer therapy will be effective or more effective by combining it with a drug according to the invention in the course of a pre-treatment (as in test series A) or in the course of a co-therapy (as in test series B, i.e. with parallel, approximately simultaneous administration of the drug according to the invention and the conventional cancer therapeutic) than alone (i.e. without this pre-treatment).

[0254] This procedure (b) has in particular the advantage that the time interval, within which any resistance of the cancer cells of the patient concerned to the chemotherapeutic and/or radiotherapeutic agent intended for use develops or existing resistance is detected, is considerably reduced. In other words, on the one hand, the interval between the formation of resistance and the time of detection of this resistance formation can be massively shortened, because the resistance of the cancer cells to the therapeutic agent in question can be determined directly ex vivo, and does not have to be determined indirectly and in vivo on the basis of surrogate markers such as cancer tumor markers or visualization of the size of the cancer tumor (malignancy), as has been the case to date. On the other hand, already existing resistances can be detected before therapy. Thus, statements can be made as to whether a specific chemotherapeutic agent (i.e., a cell-type non-specific cell proliferation inhibitor such as the classical cytostatics and/or a cell-type specific agent such as sorafenib) and/or radiotherapeutic agent can be used in a meaningful and promising manner. This enables a targeted therapy oriented to the individual situation of the cancer patient with the best possible success of the therapy. This opens up far-reaching perspectives, particularly with regard to individualized medicine.

EXAMPLE 4: STUDY IN DOGS ON THE CONVERSION OF BENFO-OXYTHIAMINE “B-OT” TO OXYTHIAMINE “OT” IN THE ORGANISM

[0255] Male and female dogs (Beagle breed) were administered B-OT (benfo-oxythiamine) orally once daily for periods of one to seven days in amounts of 1 mg/kg/day or 0.5 mg/kg/day.

[0256] The toxicokinetics of the active metabolite OT (oxythiamine) was determined in plasma samples obtained on the first day “Day 1” and on the seventh day “Day 7” after the start of administration. The measurement results obtained are shown graphically in FIGS. 1 (a) to (d).

[0257] FIG. 1a shows the changes in individual plasma concentrations of oxythiamine (OT) with time in male beagle dogs on day 1, i.e., the first day after administration of a single dose of B-OT in an amount of 1 mg/kg/day.

[0258] FIG. 1b and FIG. 1c show the changes in individual plasma concentrations of oxythiamine (OT) with time in male beagle dogs on day 1, i.e., on the first day (FIG. 1b) and day 7, i.e., on the seventh day (FIG. 1c) of daily administration of single doses of B-OT in an amount of 0.5 mg/kg/day.

[0259] FIG. 1d shows the changes in mean (averaged) plasma concentrations of oxythiamine (OT) with time in the male beagle dogs (of FIGS. 1a to 1c) on day 1 and day 7 during daily administration of single doses of B-OT at a concentration of 0.5 mg/kg/day and on day 1 after administration of a single dose of B-OT in an amount of 1.0 mg/kg/day.

[0260] Oxythiamine was not found in plasma samples obtained on day 1 before administration of B-OT. Systemic exposure with respect to OT was achieved in all animals treated with B-OT. For all applied doses of B-OT, the time of maximum OT plasma concentration (Tmax) after administration of B-OT was investigated, with the highest value obtained between one and two hours. With a stepwise increase in the applied B-OT dose from 0.2 mg/kg to 1.0 mg/kg, an increase in plasma concentrations of oxythiamine (OT) was observed that was approximately linearly proportional to the increase in dose.

[0261] After oral administration of B-OT single doses and based on a dose-normalized C max and partial AUC (area under the curve) values, a less than dose-proportional increase in plasma OT was observed in male beagle dogs over the range of applied doses of B-OT.

[0262] Treatment of the dogs with B-OT was well tolerated. No relevant abnormalities in the behavior or relevant changes in the physical condition of the dogs were observed throughout the study period, in particular no significant variations in body weight. The animals were exposed to the active metabolite OT but not to the preform (prodrug) B-OT.

EXAMPLE 5: ADMINISTRATION OF B-OT TO PATIENTS WITH SARS-COV-2 INFECTION

[0263] In the context of curative trials, four patients who had been diagnosed with covid-19 pneumonia requiring inpatient treatment were selected from a total collective of over 700 patients with covid-19 disease requiring inpatient treatment. Based on laboratory data and previous disease course, these patients were expected to have a severe course of COVID-19 disease and were therefore treated at the same treatment center with the current standard therapy, namely dexamethasone, anticoagulation, and oxygen therapy. In addition to the standard therapy, these four patients were treated with B-OT administration, i.e. they received 6 mg B-OT per day perorally for seven days.

[0264] Under this additional therapy with B-OT, none of the four patients required intensive care. None of the patients showed side effects that could be attributed to the administration of B-OT.

[0265] At the start of B-OT treatment, all patients had SARS-CoV-2-related pneumonia. The severe damage to the lungs was documented by computed tomography (CT). These CT images of the lungs show marked infiltrates due to viral pneumonia (see FIG. 3A-FIG. 6A).

[0266] A repeat imaging examination of the lungs by computed tomography at the end of the seven-day B-OT therapy documents the rapid healing process and shows a significant decrease in the previously pronounced infiltrates (see FIG. 3B—FIG. 6B).

[0267] For one patient (patient 2), a computed tomographic image of the lungs obtained during follow-up is available one month after the end of therapy, and it shows stable findings (FIG. 7).

[0268] In contrast to the overall collective of more than 700 patients, none of the four patients receiving additional therapy with B-OT, despite the initial severity of respiratory distress, required intensive care or respiratory support therapy beyond nasal cannula or mask oxygen insufflation, such as non-invasive or invasive ventilation, during the course of the disease.

[0269] In all patients with additional B-OT therapy, a significant reduction of the inflammatory parameters C-reactive Protein (CRP) and Interleukin-6 (IL-6) was also observed (see Table 1). The clinical levels of these immunoinflammatory markers represent important parameters for assessing the severity of the disease. High levels of the proinflammatory cytokine IL-6 and/or of C-reactive protein (CRP) indicate severe disease and a high-risk disease course.

[0270] The proinflammatory cytokine IL-6 with pleiotropic properties also appears to play a key role in the “cytokine storm” also described for patients with SARS-CoV-2 infections. Its constitutive expression causes organ damage and severe pain.

[0271] In all patients with additional B-OT therapy, the required inpatient stay was significantly shorter compared with the overall collective of more than 700 patients, on average one week less.

CITED NON-PATENT LITERATURE

[0272] Smeets E H, Muller H, de Wael J (July 1971): ‘A NADH-dependent transketolase assay in erythrocyte hemolysates’. Clin. Chim. Acta. 33 (2): 379-86. doi:10.1016/0009-8981(71)90496-7. hdl:1.874/24761. PMID 4330339. [0273] Takeuchi T, Nishino K, Itokawa Y: Improved determination of transketolase activity in erythrocytes, Clinical Chemistry, Vol. 30, Issue 5, 1 May 1984, Pages 658-661. https://doi.org/10.1093/clinchem/30.5.658 [0274] Michalak S, Michalowska-Wender G, Adamcewicz G, Wender M B: Erythrocyte transketolase activity in patients with diabetic and alcoholic neuropathies. Folia Neuropathol 2013; 51(3):222-226. https://doi: 10.5114/fn.2013.37706.