EP4135714A1 - Phospholipides et métabolites de phospholipides destinés au traitement de la pneumonie virale et bactérienne et de la septicémie - Google Patents

Phospholipides et métabolites de phospholipides destinés au traitement de la pneumonie virale et bactérienne et de la septicémie

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Publication number
EP4135714A1
EP4135714A1 EP21718135.3A EP21718135A EP4135714A1 EP 4135714 A1 EP4135714 A1 EP 4135714A1 EP 21718135 A EP21718135 A EP 21718135A EP 4135714 A1 EP4135714 A1 EP 4135714A1
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Prior art keywords
lysopc
treatment
cancer
alpha
gpc
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German (de)
English (en)
Inventor
Ulrich Massing
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Andreas Hettich GmbH and Co KG
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Andreas Hettich GmbH and Co KG
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Publication of EP4135714A1 publication Critical patent/EP4135714A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to lyso-phosphatidylcholine (LysoPC), or a suitable precursor or derivative thereof, or a composition containing LysoPC and / or one or more suitable precursors or derivatives thereof, for use in the treatment and post-treatment of inflammatory diseases in humans with a Decrease of the LysoPC level, including the treatment, prevention or support of the treatment as well as the follow-up treatment of viral and bacterial pneumonia and sepsis, including pneumonia and sepsis as a result of influenza, Covid-19, ARDS, cancer, in support of immunotherapy Cancer in terms of its effectiveness and to reduce side effects such as pneumonitis, colitis or hepatitis and to reduce vaccination reactions.
  • LysoPC lyso-phosphatidylcholine
  • suitable precursor or derivative thereof or a composition containing LysoPC and / or one or more suitable precursors or derivatives thereof
  • a composition containing LysoPC and / or one or more suitable precursors or derivatives thereof for use in
  • the invention further relates to alpha-glycerophosphocholine (alpha-GPC) or a variant thereof, or a composition containing alpha-GPC and / or one or more variants thereof, for use in the treatment and post-treatment of cancer and tumor cachexia.
  • alpha-GPC alpha-glycerophosphocholine
  • Pneumonia is a serious illness that can be fatal, especially in older people and with previous illnesses. Pneumonia can be idiopathic, but it is often caused by viruses as well as bacteria. Viral pneumonia is often followed by bacterial pneumonia. The inflammation in the lung tissue is caused, among other things, by the often very strong immune reaction against viral or bacterial pathogens in the lung tissue. Due to the inflammatory reaction in the lung tissue, water, among other things, can penetrate the aveoli, which makes gas exchange more difficult.
  • the amount of surfactant lipids in the aveoli is reduced and the surface tension increases accordingly (up to 35 mN / m in pneumonia and ARDS), which makes it more difficult to keep the alveoli open and consequently the work of breathing more difficult (Günther, A. et al., Am. J. Respir. Crit. Care Med., 153 (1): 176-184 (1996)).
  • the reaction of the immune system can be very strong in pneumonia, causing a so-called cytokine storm.
  • the very strong inflammatory reaction takes place then no longer controlled and the clinical course resembles that of sepsis, ie the immune response is no longer primarily to the inflamed organ and the cause of the inflammation, e.g. B. by viruses, which can damage various other organs and tissues, sometimes severely.
  • influenza viruses e.g. pneumocog or influenza viruses.
  • a strong response of the immune system through the vaccination can result in flu-like symptoms, symptoms such as shivering, tiredness, or muscle pain.
  • Sepsis or septic shock can also be the result of cancer, multiple trauma or severe inflammation (e.g. pneumonia after Covid-19 or influenza).
  • ARDS acute Respiratory Distress Syndrome
  • ARDS acute respiratory distress syndrome
  • Cancer diseases are treated more and more often with the help of immunotherapy. It is the immune system z. B. through the use of checkpoint inhibitors enables an immune response against cancer cells to be triggered.
  • this promising therapy e.g. with ipilimumab or nivolumab or combinations of the two inhibitors
  • this promising therapy has its limitations.
  • only some of the cancer patients experience an immune reaction, i.e. a response to the therapy. If the immunotherapy fails, there may be an immune deficiency, possibly caused by the cancer, ie the immune system cannot be activated as expected.
  • the immune reaction can also get out of control, an important example is the occurrence of pneumonitis, colitis or hepatitis, all of which are life-threatening can (Kahler, KC., Pharmakon, 6: 463-468 (2016)).
  • Pneumonitis is an inflammatory change in the lungs that, in contrast to pneumonia, is not triggered by microorganisms (bacteria, fungi) or viruses, but by influences harmful to the pneumonia, with ionizing radiation, drugs or z.
  • B. chemical or physical noxae are important. In order to avoid organ damage after the occurrence of the above-mentioned side effects, the triggered immune reaction must be stopped again, e.g. B.
  • Phospholipids are a main component of animal cell membranes. They usually consist of a hydrophilic head that is linked to hydrophobic, non-polar residues via a negatively charged phosphate group. The most common PLs in biological membranes are glycerophospholipids. Glycerophospholipids (hereinafter “GPL”) are structured as shown in formula (I):
  • acylglycerophospholipids consist of a hydrophilic head, which is attached via a negatively charged phosphate group in the sn-3 position having a glycerol backbone and also with one or two hydrophobic apolar residues R 1 and R 2 (IUPAC Compendium of Chemical Technology, 2 nd Ed. ( 1997)).
  • the latter are usually O-acyl radicals from fatty acids with a length of 14-24 carbon atoms, but can also be O-alkyl or ol-alkenyl radicals.
  • GPLs with one or two O-acyl residues are also referred to as 1-acyl, 2-acyl or 1,2-diacylglycerophospholipids, or collectively as acylglycerophospholipids (hereinafter referred to as "AGPL").
  • Typical AGPLs are phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine (hereinafter “PE”), phosphatidylinositol (hereinafter “PI”), phosphatidic acid (hereinafter “PA”) and phosphatidylcholine (hereinafter “PC”).
  • Acylglycerophospho lipids are contained in particular in lecithin, the main component here is usually PC.
  • Glycerophospholipids especially PC or PC-containing mixtures such.
  • B. Lecithin because of their emulsifying effect, are used as a component of food supplements and foods, in cosmetics, in parenteral nutrition and as auxiliaries for formulating drugs.
  • hydrogenated phospholipids are preferred only for the formulation of medicaments for intravenous administration.
  • Glycerophospholipids can also be found as active components of food supplements and medicines (e.g. marine phospholipids (from salmon roe or krill)), which contain a high proportion of long-chain w-3 fatty acids and z. B. to support the therapy of prostate cancer or for the treatment of cachexia are known (EP-A-1745788).
  • soy phospholipids e.g. B. contained in Essentiale ® for the therapy of liver diseases, in Buer-Lecithin plus Vitamins ® , for the therapy of states of exhaustion and to strengthen the nerves or in Lipostabil ® , for the therapy of increased fat values, whereby the recommended doses of 1 , 5 g to approx. 6.5 g PL / day are sufficient (data from the package inserts).
  • PC is first split by pancreatic phospholipase A2 into LysoPC and free fatty acids, both of which are taken up by the mucosal cell in the intestine (enterocyte). It is the current opinion in the literature that the larger part of the LysoPC is further hydrolyzed in the mucosal cells, approx. 1/3 is reacylated to PC according to the current state of knowledge and then part of chylomicrons, which are released into the lymphatic system (Parthasarathy, p. et al., Biochem. J., 140 (3): 503-508 (1974)). Furthermore, hydrogenated PC is known to reduce tumor metastasis (as a liposome for IV application). An effect on the immune system is not described.
  • phospholipids are used to formulate preparations for parenteral nutrition.
  • Such preparations are emulsions and typically consist of 10, 20 or 30% triglycerides (e.g. soybean oil, MCT (medium chain triglycerides), olive oil, fish oil or their mixtures (e.g. soy / olive 4: 1 )).
  • the emulsions also contain a small amount of phospholipids (lecithin), e.g. B. from hen's eggs as emulsifiers, aiming for the lowest possible phospholipid / triglyceride ratio (e.g.
  • Emulsions with a higher triglyceride content obviously need emulsification less phospholipid, which is considered beneficial.
  • a low phospholipid / triglyceride ratio shows better metabolic tolerance with significantly lower accumulation of phospholipids and cholesterol in the plasma (Hartig, W. et al.
  • lecithins used are highly enriched lecithins with a glycerophosphatidylcholine content of typically 75 or 80% (e.g. Lipoid E 75 / E 80).
  • Alpha-glycerophosphocholine (alpha-GPC) consists of a glycerine base to whose sn-3 position a phosphocholine group is bound as a phosphodiester.
  • alpha-GPC is derived from phosphatidylcholine, in which the two fatty acid residues were removed by hydrolysis.
  • Alpha-GPC is used as an active ingredient in dietary supplements, where it serves as a source of choline.
  • Alpha-GPC has a positive effect on the increase in physical strength through exercise (Bellar, D. et al., J. Int. Soc. Sports Nutr. 12:42 (2015); Marcus, L. et al., J. Int. Soc . Sports Nutr. 14:39 (2017)), and shows positive effects in patients with Alzheimer's disease and other dementia symptoms (Review: Parnetti, L. et al., Mech. Aging Dev. 122 (16) 2041-2055 (2001)) and improves cognitive
  • alpha-GPC also serves directly as a precursor in the biosynthesis of LysoPC.
  • a GPC acyltransferase (GPCAT or Gpcl) was described here which acylates acyl-CoA-dependent alpha-GPC (Stalberg, K. et al., J. Lipid Res. 49: 1794-1806 (2008); Anaokar, S. et al., J. Biol. Chem. 25; 294 (4): 1189-1201 (2016)).
  • the new enzyme from yeast has already been cloned and shows little relationship with other acyltransferases from the lipid area (Glab, B. et al., J. Biol. Chem. 291 (48): 25066-25076 (2016)). The activity of this enzyme has also been demonstrated in safflower. GPCAT activities in animal or human tissue have not yet been detected.
  • Lyso-phospholipids are single-chain phospholipids and arise from 1,2- Diacyl phospholipids by phospholipase A-catalyzed cleavage or by chemical hydrolysis of a fatty acid residue. LysoPL have surface-active properties that are able to lyse red blood cells (hence the name).
  • Lysophospholipids (1-acyl- or 2-acyl-glycerophospholipids) can arise from the various two-chain, membrane-forming phospholipids.
  • lyso-phospholipids are lyso-phosphatidylcholine, lyso-phosphatidylethanolamine (lyso-kephalin), lyso-phosphatidylglycerol, -serine and lyso-phosphatidic acid, the starting phospholipids of which are all 1,2-diacylglycerophospholipids.
  • Lyso-phospholipids are also known as carcinostatic compounds (US 4,372,949).
  • lyso-phospholipids are not currently used as therapeutic agents.
  • every formulation with a double-chain phospholipid also always contains small proportions of its corresponding natural degradation product, namely the corresponding lysophospholipid.
  • LysoPC is a key metabolic product in the human body.
  • the current state of knowledge about the formation of LysoPC in the human body is that LysoPC is formed when a fatty acid is split off from the frequently occurring phosphatidylcholine (lecithin).
  • PC in turn, is provided by reacylation of LysoPC or via the Kennedy pathway or the phosphatidylethanolamine pathway (Lands, WEM. Et al., J. Biol. Chem. 231 (2): 883-888 (1958); Kennedy, EP. Et al., J. Biol. Chem., 222 (1): 193-214 (1956); Jacobs, RL. et al., J. Biol. Chem. 285 (29): 22403-22413 (2010)).
  • Other biosynthetic pathways for LysoPC or PC in humans are not described.
  • LysoPC should be excluded from the formation of LysoPC Phospholipids are formed by splitting off a (predominantly unsaturated) fatty acid from the sn-2 position of a PC by phospholipase A2, predominantly saturated LysoPC.
  • phospholipase A2 predominantly saturated LysoPC.
  • only a very slight excess of saturated LysoPC species is found in the plasma (e.g. Zhao, Z. et al., J. Clin. Oncol. 25 (19) 2696 ff (2007: 162 mM saturated LysoPC (55 %) vs. 129 mM unsaturated LysoPC (45%)).
  • LysoPC has 3-4 binding sites for LysoPC and binds about 80% of the plasma LysoPC (Switzer, S et al., J. Lipid Res. 6: 506-511 (1965)).
  • LysoPC values in the collectives of healthy subjects examined in each case always fluctuated considerably, which suggests individually different “optimal LysoPC values” in different people in spite of the fact that it seems beneficial for a person if he tends to have rather high LysoPC levels, it has been found that high levels of LysoPC species, which are known as fatty acids, include stearic acid lead to a lower risk of breast cancer, prostate cancer and colorectal tumors (Kühn, T. et al., BMC Medicine 14:13 (2016). It has also been shown that the serum LysoPC values are significantly increased in long-lived people (Montoliu, I. et al., Aging 6 (1) 9-25 (2014) - supplementary tables).
  • the studies mentioned above give an approximate mean LysoPC plasma value in healthy individuals of approx. B. for a man with a plasma volume of approx. 3.5 l means that there are approx. 500 mg LysoPC in the plasma.
  • the LysoPC half-life in humans has never been determined, but is likely to be in the range of a few hours. In the dead monkey, the half-life was determined to be 1.3 hours (Portman, OW. Et al. J. Lipid Res. 11: 596-604 (1970)), in the mouse it was approx. 4 hours (dissertation Anna Raynor, Uni- Dortmund, 2015)). An estimated value for humans of 2.5 hours would result in a conversion of approx. 2-3 g LysoPC / d.
  • LysoPC is formed, among other things, by hydrolysis of phospholipids in lipoproteins, e.g. B. by the enzymes LCAT (lecithin cholesterol acyl transferase) or by the endothelial lipase. Assuming the complete PL shell of chylomicrons (containing max. 10% PL) is hydrolyzed to LysoPL, this corresponds to approx. 5 g of PL with a fat absorption of approx. 50 g of fat (triglycerin), which corresponds to approx. 3-4 g of LysoPL would.
  • LCAT lecithin cholesterol acyl transferase
  • LysoPC A maximum of 6-12 g of LysoPC could result from the hydrolysis of phosphatidylcholine from the bile if the 10-20 g of PC (Northfield, TC., Et al. Gut, 16: 1-17 (1975)), which is daily with the bile get into the GI tract, would be hydrolyzed to LysoPC and this would then also be completely absorbed, which is not the case (see below).
  • One egg contains approx. 1 g PC.
  • LysoPC As described above, however, a larger proportion of the LysoPC is further hydrolyzed in the mucosal cell, only about 1/3 PC is reacylated and then part of chylomicrons that are released into the lymphatic system (Parthasarathy, S. et al., Biochem. J ., 140 (3): 503-508 (1974)). The direct release of LysoPC into the blood or the lymphatic system is not described.
  • LysoPC The consumption of LysoPC in the body has not yet been comprehensively researched, but some processes are known or likely. It has already been shown that the supply of the CNS with long-chain and highly unsaturated fatty acids and (probably) with choline takes place through the specific uptake of long-chain and highly unsaturated LysoPC species (Bernoud, N. et al., J. Neurochem. 72: 338- 345 (1999)). Recently, a sodium-dependent LysoPC transporter of the CNS was found and characterized (MFSD2A), which appears to be the first member of a superfamily of LysoPC transporters (Nguyen, LN. Et al. Nature 509: 503-506 (2014)).
  • Lung surfactant is produced by type II alveolar macrophages and consists largely of saturated phosphatidylcholine and surfactant proteins A to D (Agassandian, M. et al., BBA 1831 (3): 612-625 (2013) moist surface of the very small alveoli and represents the boundary to the air.Surfactant drastically reduces the surface tension of the alveolar water and mainly contributes to that the alveoli do not collapse due to excessive surface tension and that the work of breathing (to inflate the alveoli) remains low.
  • Lung surfactant consists largely of phosphatidylcholine (PC) and is constantly renewed by the alveolar macrophages type II to maintain gas exchange in the aveoli (Goss, V. et al. BBA 1831: 448-458 (2013)).
  • the PC required for this is produced by simple reacylation from LysoPC, the central enzyme in the biosynthesis of the saturated PC species is LPCAT 1 (Lyso-Phosphatidylcholine-Acyltransferase 1), which LysoPC converts into a PC using AcylCoA (Agassandian, M. et al., BBA 1831 (3): 612-625 (2013)).
  • LysoPC LysoPC from the alveolar macrophages themselves and from the periphery play a role in the build-up of lung surfactant.
  • LysoPC when radioactively labeled LysoPC is administered, a large amount of the activity accumulates in the lungs (Portman, OW. Et al. J. Lipid Res. 11: 596-604 (1970)).
  • aleovar macrophages type II i.e. the same cells that produce the lung surfactant also process and present the pathogens and thus guide them Immune response in the alveoli (American Journal of Respiratory & Critical Care Medicine, 2008: 179 (5), pp 344-55)).
  • LysoPC After administration of radioactively labeled LysoPC, a very high uptake of radioactivity in the kidneys was found in the dead monkey (Portman, OW. Et al. J. Lipid Res. 11: 596-604 (1970)). It is unclear why LysoPC is needed in the kidney. LysoPC also seems to be required in larger quantities, especially in pathological processes, since decreased LysoPC levels have been observed in many diseases and in special living conditions. Examples are people with cancer, patients with strong immune reactions (sepsis), diabetics (type 2) and overweight people (Barber, MN. Et al. Plos one 7 (7): e41456 (2012)) or the elderly (Johnson, AA. Et al., Aging Cell, 18 (6): el3048 (2019)).
  • LysoPC values in cancer patients are almost consistently low, especially in advanced cancer diseases. So has z. B. Zhao et al. Values of 228 mM found in CRC patients (controls: 292 mM) (J Clin Oncol 2007, 25 (19): 2696), in Taylor et al. were seen in various tumor diets at 207 pM (Lipids Health Dis. 2007, 6: 7). The variances of the values are higher in cancer patients than in healthy ones Controls. LysoPC levels are further lowered when patients cannot eat enough, e.g. B. due to an appetite disorder, cachexia, etc. (Lipids Health Dis. 2007, 6: 7)
  • LysoPC an important reason for the lowered LysoPC level in cancer patients is an increased LysoPC turnover, since solid tumor cells in particular break down large amounts of LysoPC very quickly, e.g. for use as an energy carrier (Lipids Health Dis. 2015, 14: 69).
  • a calculation based on cell culture data results in a LysoPC degradation of approx. 1 g LysoPC / g active tumor cells per day, so with correspondingly aggressive and / or large tumors there can be a dramatic decrease in LysoPC with a simultaneous increase in total turnover.
  • Tumor cachexia is a common syndrome in cancer patients with severe weight loss and changes in body composition. Adipose tissue and skeletal muscles are broken down and immunological defense mechanisms are impaired (Tisdale, MJ, Nutrition 17 (5): 438-442 (2001); Tisdale, MJ, Curr. Opin. Clin. Nutr. Metab. Care 5 (4 ): 401-405 (2002)).
  • the doses to be used range from very low to very high amounts of phospholipids (2-300 mg / kg).
  • both the cancer itself and the cancer treatment e.g. through chemotherapy, radiation and targeted therapies, seem to be able to trigger fatigue, since all of these therapies also affect healthy cells.
  • chemotherapy, radiation and targeted therapies seem to be able to trigger fatigue, since all of these therapies also affect healthy cells.
  • up to 90 percent of patients suffer from fatigue, which becomes chronic in an estimated 20 to 50 percent of patients.
  • Typical symptoms of fatigue in humans are reduced performance, a high need for sleep, persistent feeling of tiredness, lack of motivation and drive and, similar to depression, declining interest, sadness, fears, concentration disorders, increased distractibility, word-finding disorders.
  • Fatigue is also a well-known syndrome after operations or after severe inflammatory diseases, especially after Covid-19.
  • a rat model has been shown to correlate the severity of fatigue with a reduction in the LysoPC level (Y. Lu et al, J. Clin. Biochem. Nutr. 58: 210-215 (2016)).
  • Exercise can prevent fatigue or reduce existing symptoms of exhaustion.
  • Movement training aims to maintain or build up stamina and muscle mass.
  • a significantly excessive load can in turn lead to a worsening of the fatigue symptoms.
  • LysoPC also plays an important role in immune responses. It was found that triggering a strong systemic immune response (sepsis) results in a dramatic decrease in the LysoPC level. In a study with 100 sepsis patients, for example, a mean LysoPC value of only 95 mM was measured (healthy controls in this study: 280 mM), with the risk of death being highest at the lowest LysoPC values (J. Lipid Res. 2003 , 44: 754-761). LysoPC in combination with other parameters has been suggested as a prognostic factor for survival in sepsis (Arshad, H., et al., J. Transl. Med. 2019, 17: 365 and Law, S.-H., et al., Int. J. Mol. Sci. 2019, 20: 1149).
  • LysoPC is described in a peritoneal sepsis and pneumonia model of the mouse (Younes, S., et al., Antimicrobial Agents and Chemotherapy 2015, 59 (7): 3920-24).
  • LysoPC was determined before and after surgery for colorectal cancer. The LysoPC values drop significantly as a result of the operation and the associated immune reaction. Patients with postoperative complications had significantly lower LysoPC values than the patients without complications (Surg Today 2018, 48 (10): 936-943).
  • LysoPC supports the activation of the immune system and also induces INFy and TNFa secretion. Macrophages are activated, as are B cells (Huang, YH. Et al., Clin. Exp. Immunol. 116: 326-331 (1999); Yamamoto, N. et al., J. Immunol.
  • LysoPC appears here in a Dual function as a signaling molecule and as a metabolite / building block for the rapid activation and proliferation of immune cells.
  • LysoPC A sufficient amount of LysoPC is therefore very important for a reasonable immune reaction and for survival from sepsis, which has been confirmed in various animal experiments.
  • LysoPC improves the survival of mice in an E.coli-based sepsis model in a dose-dependent manner (from approx. 20% to 90% survival at 20 mg / kg LysoPC).
  • LysoPC up to 10 mg / kg, iv
  • the protective effects of LysoPC were accompanied by a reduction in the ILl-ß level (Brit. J. Pharmacol 2006, 148: 769-777)
  • LysoPC shows an effect as an adjuvant when administered simultaneously with various antigens in mice.
  • the effect of LysoPC in the production of the antigen-specific antibodies was identical to that of Alum. LysoPC also induces cytotoxic T cells (Vaccine 2006, 24 (9): 1254-1263)
  • LysoPC plays a role in the activation of an immune response, after activation, obviously increased amounts of LysoPC levels are required for the immune response, which is manifested in the above-mentioned decreased LysoPC levels.
  • LysoPC levels are in a very strong immune reaction, such as. B. but not limited to sepsis, if critically low LysoPC levels are reached, a vicious circle is obviously triggered.
  • the (over) activated immune system "consumes" a lot of LysoPC, but does not manage to find the cause of the inflammation neutralize (e.g. pathogen), which leads to a further decrease in the LysoPC level.
  • the critically lowered LysoPC levels are then no longer sufficient to supply the normally healthy organs, which can contribute to organ failure.
  • LysoPC also plays a regulating role in immune reactions, which is why a greatly reduced level may accelerate the overshoot of an immune reaction. It is known that LysoPC induces the differentiation of regulatory T cells and stimulates TGF-ß production (Hasegawa, H. et al., Biochem. Biophys. Res. Commun. 415: 526-531 (2011)).
  • the correlations shown can also lead to the often poor response of cancer patients to immunotherapies, e.g. B. with checkpoint inhibitors, but also explain why immunotherapies often have to be stopped due to an overreaction of the immune system.
  • the lower LysoPC level in cancer patients during immunotherapy due to the increased consumption by tumor cells can on the one hand result in the immune reaction not being activated properly, or on the other hand in a strong, in principle desired immune reaction due to the additional lowering of the LysoPC level undesirable side effects, such as B. pneumonitis, colitis or hepatitis.
  • LysoPC plasma levels are also reduced in patients with overweight and / or type II diabetes (Barber, MN. Et al. Plos one 7 (7): e41456 (2012), which occurs in critical situations, e.g. with sepsis , the capacity of the immune system (see above) could be exhausted faster than in normal-weight, non-diabetic patients. There is also a trend towards lower LysoPC plasma levels in older people (Johnson, AA. et al., Aging Cell, 18 (6)) : el3048 (2019)).
  • the object on which the invention is based was thus to develop a medicament which is capable of eliminating or at least reducing the LysoPC deficiency caused by the respective disease, and thus for the treatment, for the prevention or for the support of the treatment and for the follow-up treatment of Pneumonia and sepsis, including pneumonia and sepsis as a result of influenza, Covid-19, ARDS, cancer and pneumonitis, hepatitis or colitis after immunotherapy for cancer is suitable.
  • the aim is to strengthen the immune system while avoiding organ damage, which in the case of Covid-19 could currently make herd immunity possible while avoiding deaths.
  • LysoPC turnover is more than an order of magnitude higher than previously assumed, roughly estimated at at least 50 g per day.
  • the LysoPC level can be effectively increased by the oral administration of 1,2-acyl-glycerophosphocholines (PC). Contrary to the textbook opinion, a practically complete transition of the orally administered PC as LysoPC into the plasma and the deeper compartments is possible - at least when larger amounts of PC are given, the LysoPC formed in the intestine from PC is predominantly not broken down in the enterocytes and enters the blood directly above. It was also found that the LysoPC level can be increased by oral or systemic administration of alpha-glycerophosphocholine. It appears possible that alpha-GPC is converted directly into LysoPC in the liver by an acylation reaction that has not yet been described.
  • PC 1,2-acyl-glycerophosphocholines
  • LysoPC level can be increased by the oral or systemic administration of glucose. Most likely the glucose gets in the liver Ultimately used for fatty acid biosynthesis, the fatty acids formed are then released into the system as LysoPC.
  • LysoPC despite its potential hemolytic effects, could be released directly into the blood as an infusion. Since LysoPC is mostly not in the plasma, i.e. H. The direct application of LysoPC appears to be possible if the LysoPC-plasma-tissue equilibrium is not found bound to albumin, but is located in deeper compartments (tissue). If LysoPC is slowly infused into the blood in large, therapeutically relevant amounts, it is spontaneously bound to albumin and thus loses its hemolytic properties. From there, due to the concentration gradient, it also goes over very quickly into deeper compartments, and the albumin is again ready to bind LysoPC and thus to prevent its hemolytic activity.
  • LysoPC levels and / or low alpha-GPC levels after cancer or an inflammatory reaction impede the restoration of physical performance, which is expressed in fatigue symptoms. It is therefore to be expected that a targeted increase in the LysoPC level, for example by administering alpha-GPC to fatigue patients, will lead to a reduction in the symptoms of fatigue.
  • a targeted increase in the LysoPC level for example by administering alpha-GPC to fatigue patients, will lead to a reduction in the symptoms of fatigue.
  • One facet could be improved muscle building during physical training.
  • alpha-GPC is suitable for viral and bacterial lung infections, ARDS, sepsis, including pneumonia and sepsis as a result of influenza, Covid-19, ARDS, cancer , pneumonitis, colitis or hepatitis after immunotherapy for cancer as well as fatigue after the mentioned diseases or treatments to reduce or prevent LysoPC deficiency.
  • alpha-GPC is a suitable, inexpensive and easy to apply LysoPC derivative for the treatment and post-treatment of cancer and tumor cachexia. The invention thus relates to
  • Lyso-phosphatidylcholine or a suitable precursor or derivative thereof, or a composition containing LysoPC and / or one or more suitable precursors or derivatives thereof, for use in the treatment and post-treatment of inflammatory diseases in humans with a Lowering of the LysoPC level go hand in hand, here in particular the viral and bacterial pneumonia and sepsis, including the
  • Inflammatory diseases in humans that are associated with a decrease in the LysoPC level particularly viral and bacterial lung infections and sepsis, including the administration of LysoPC, or of a suitable precursor or derivative thereof, or of a composition containing LysoPC and / or one or more suitable precursors or derivatives thereof to a patient in need of such treatment or follow-up treatment;
  • alpha-glycerophosphocholine (alpha-GPC) or a variant thereof (which of course is not or comprises LysoPC or PC), or a composition containing alpha-GPC and / or one or more variants thereof, for use in treatment and aftercare of cancer and tumor cachexia, as well as to support convalescence after cancer or cancer treatment; and (4) a method for the treatment and follow-up treatment of cancer diseases and tumor cachexia, as well as to support convalescence after cancer or cancer treatment, comprising the administration of alpha-GPC or a variant thereof, or a composition containing alpha-GPC and / or one or more variants the same to a patient in need of such treatment.
  • compositions orally or systemically (i.v.), Is preferred in order to quickly increase the LysoPC level and because a higher turnover is to be expected in the event of inflammation or cancer / cachexia.
  • the inventive phospholipid-containing compositions for oral administration can contain soy, egg PC or lecithin, marine phospholipids, e.g. B. contain phospholipids from krill or from salmon roe or from algae.
  • the phospholipids used can come from various sources or be synthetically produced, the PL should contain little or no o- 6 fatty acids, but preferably w-3 fatty acids, such as. B. marine phospholipids or krill oil, or w- 9 fatty acids or saturated fatty acids.
  • acylglycerophospholipids in particular acylglycerophosphatidylcholines and their metabolites such as lysophosphatidylcholines (LysoPC) and alpha-glycerophosphocholine (alpha-GPC) as defined in more detail below:
  • acylglycerophospholipid in the context of the present invention is z.
  • B a 1,2-diacylglycerophospholipid, 1-acylglycerophospholipid or 2-acylglycerophospholipid with saturated or unsaturated acyl radicals, including phosphatidylcholine, lysophosphatidylcholine and lecithin, or their pharmaceutically suitable salts.
  • AGPL preferably has the structure of formula (I)
  • R 1 and R 2 are independently selected from H, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl and cycloalkylcarbonyl radicals, in which the alkyl radicals can be straight-chain, branched or cyclic, saturated or unsaturated and substituted by 1 to 3 radicals R 3 and one or more of the carbon atoms in the alkyl radicals can be replaced by 0 or NR 4;
  • X is selected from H (the compound is then a PA), - (CH2) nN (R 4 ) 3 + (this class of compounds includes PE and PC), - (CH2) n-CH (N (R 4 ) 3 + ) -COO ⁇ (this class of compounds includes PS) and - (CH2) n-CH (OH) -CH20H (this class of compounds includes PG), where n is an integer from 1 to 5;
  • R 3 independently of the occurrence of further R 3 radicals, is selected from H, lower alkyl (in which the lower alkyl radicals can be straight-chain, branched or cyclic, saturated or unsaturated), F, CI, CN and OH; and
  • R 4 independently of the occurrence of further R 4 radicals, is selected from H, CH 3 and CH 2 CH 3, or a pharmacologically suitable salt thereof.
  • the acyl radicals are preferably alkylcarbonyl radicals. These can be saturated or unsaturated and have the same or different lengths, chain lengths from CIO to C24 are preferred, chain lengths from C14 to C22 are particularly preferred. Unsaturated alkylcarbonyl radicals are preferably selected from w-3 and w-9 fatty acids, in particular from oleic acid (18: 1), ⁇ -linolenic acid (18: 3), eicosapentaenoic acid (20: 5) and docosahexaenoic acid (22: 6).
  • AGPLs with naturally occurring head groups in particular phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines and phosphatidic acids, especially APGL selected from the group of phosphatidylcholines, are preferred for use according to the invention.
  • the alkylcarbonyl radicals have 10 to 24 carbon atoms, are saturated or contain one or more double bonds, the number of carbon atoms preferably being a multiple of 2 and the double bonds not being conjugated, and the alkyl radicals being particularly preferably fatty acid radicals ;
  • the lower alkyl radicals have 1-3 carbon atoms and are preferably saturated;
  • n is an integer from 1 to 3.
  • R 1 and R 2 independently of one another, are H or unbranched and unsubstituted alkylcarbonyl radicals which are either saturated and are then preferably selected from lauryl (n-dodecanyl), myristyl (n-tetradecanyl), palmitoyl (n -Hexadecanyl-), stearyl- (n-octadecanyl-), arachinyl- (n-eicosanyl-), behenyl- (n-docosanyl-) and lignoceryl- (n-tetracosanyl-) residues and very particularly preferably from myristyl, palmitoyl -, stearyl and arachnyl radicals, or are unsaturated and are then preferably selected from oleyl (18: 1), ⁇ -linolenyl (18: 3), eicosapentaenyl (20: 5)
  • R 3 is H
  • X is - (CH 2 -) 2-N (CH 3 ) 3 + , - (CH 2 -) 2-NH 3 + , or -CH 2 -CH (NH 3 + ) -COO.
  • AGPL The origin of the AGPL (synthetic or isolated from natural sources) is irrelevant for its use according to the invention. Hydrogenated AGPLs can also be used.
  • AGPLs according to the invention are also lyso-acylglycerophospholipids which differ from AGPLs with two acyl residues in that there is no acyl residue in the sn-1 or sn-2 position.
  • Commercially available mixtures of glycerophospholipids or fractions of such mixtures can also be used.
  • One example is the so-called lecithin, which must contain at least 20% phosphatidylcholine.
  • AGPL of the formula (II) are particularly preferred
  • R 1 and R 2 independently of one another, are H or unbranched and unsubstituted alkylcarbonyl radicals, which are either saturated and then preferably selected from lauryl, myristyl, palmitoyl, stearyl, arachinyl, behenyl and lignoceryl radicals and are very particularly preferred from myristyl, palmitoyl, stearyl and arachnyl radicals, or unsaturated and then preferably selected from oleyl, ⁇ -linolenyl, eicosapentaenyl and docosahexaenyl radicals;
  • R 4 is CH 3 or H
  • n 2 or 3.
  • PC dipalmitoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • a particularly suitable lecithin is egg or soy lecithin or hydrogenated egg or soy lecithin.
  • the fatty acid is preferred
  • a w-3 or w-9 fatty acid which is preferably at least C18 in length, particularly preferably C20 and in particular eicosapentaenoic acid (20: 5) or docosahexaenoic acid (22: 6).
  • AGPL is an alpha-glycerophosphocholine (alpha-GPC)
  • alpha-GPC alpha-glycerophosphocholine
  • it is one of the compounds of the above formula (II) in which both radicals R 1 and R 2 are hydrogen, n is 2 and R 4 is CH 3.
  • Alpha-GPC is derived from AGPC, but positions 1 and 2 are not substituted. Alpha-GPC is therefore water-soluble and no longer a lipid.
  • Active ingredients in the context of the present invention are compounds which can cause a physiological reaction in living beings, in particular in humans or animals. In particular, they are active ingredients used in therapy.
  • a “pharmacologically active agent” is understood to mean a compound which, as a component of a medicament, is the cause of its effectiveness.
  • a “triglyceride” is a triester of glycerol with identical or different, saturated or unsaturated acyl radicals with 10 to 30 carbon atoms.
  • Preferred triglycerides for use according to the invention in combination with the AGPL are saturated fatty acids and those unsaturated fatty acids which do not form eicosanoids in vivo, in particular not the biologically highly effective eicosanoids of the 2-series such.
  • B. PGE2 can be implemented.
  • saturated / hydrogenated triglycerides MCT, fish oils or oils from the microalgae Ulkenia ( ⁇ chtzeitung dated August 26, 2004), both of which contain a lot of EPA and DHA, olive oils, rapeseed oils, evening primrose oils or flaxseed oils.
  • a 1,2-diacyl-AGPL is the only active ingredient present in the composition, particularly preferably the only GPL present. In the latter case, it is again preferred that only 1,2-acylglycerophosphocholine is present.
  • LysoPC is the only active ingredient contained in the drug.
  • alpha-GPC is the only active ingredient contained in the drug.
  • AGPL, LysoPC and alpha-GPC can each be present as the only active ingredient in the drug, or as combinations, with 1,2-AGPL and alpha-GPC for oral application and LysoPC and alpha-GPC are preferred.
  • the individual active ingredients or the combinations can be present as the only active ingredients in the medicament, but they can also be combined with other active ingredients, it being possible for these additional active ingredients to be present in the same composition or as a separate dosage form.
  • Combinations of the phospholipid formulations or of alpha-GPC with triglycerides, fatty acid monoesters, waxes or free fatty acids are possible, whereby these lipids should preferably contain anti-inflammatory or at least non-inflammatory fatty acids, i. H. triglycerides, fatty acid monoesters, waxes or free fatty acids are preferred which contain little or no o- 6 fatty acids, but instead w-3- or o- 9-fatty acids or saturated fatty acids.
  • Alpha-GPC oral or IV
  • PL fish oils
  • suitable fatty acids can be used in combination with the PL (see above) or with fish oils, or other oils with suitable fatty acids.
  • albumin with system. Administration
  • glucose possibly with insulin
  • anti-inflammatory agents e.g., anti-fungal agents
  • Antibiotics e.g., Antibiotics
  • phospholipids introduced into the system are ultimately metabolized and that fatty acids bound to the phospholipids are also released in the process. Since o- 6 fatty acids like arachidonic acid can be converted into proinflammatory eicosanoids, these are avoided in a preferred embodiment of the AGPL. AA and its precursor fatty acid linoleic acid can be converted into the eicosanoid PGE2.
  • PGE2 not only has a pro-inflammatory effect, but also has an autocrine effect on tumor cells and stimulates their growth; an increased PGE2 level is also associated with an increased metastasis rate (Attiga, FA et al., Cancer Res. 60 (16): 4629-4637 (2000)) ).
  • LysoPC Since we have found that there is much more LysoPC in the body than previously thought and the body compartments are in a rapid equilibrium and LysoPC is also reduced by other important consumers, which include not only the lungs and the CNS, but also muscles and Herz, particularly efficient ways of doing this had to be found.
  • the effect according to the invention of the active ingredients mentioned is thus coupled to the administration of sufficient amounts of the active ingredients in order to ensure at least an amount of LysoPC in the body that is sufficient for the function of the tissues and organs.
  • acylglycerophosphocholines and their metabolites LysoPC and alpha-GPC as active ingredients in a drug have proven to be a surprisingly effective method for therapy and for supporting therapy and for after-treatment of pneumonia, sepsis, influenza, Covid-19, ARDS, or a Pneumonitis, colitis or hepatitis after immunotherapy and / or the side effects associated with these diseases highlighted, this includes prevention and support for convalescence, among other things by treating fatigue.
  • the present invention shows that the administration of AGPL and its metabolites can support the therapy and follow-up treatment of Covid-19.
  • determining the total amount of LysoPC in the body is essential. This could be determined by determining the LysoPC concentration in the plasma - which is in equilibrium with the deeper compartments. For this purpose, on the one hand, a large amount of phospholipid from egg was administered to a test person (Example 1 (determination of plasma LysoPC) and Example 2). The plasma volume was calculated, the increase in LysoPC concentration was determined, and the amount of plasma LysoPC associated with this change in concentration was calculated.
  • LysoPC in relation to the amount ingested gives the distribution of the ingested LysoPC equivalent between the plasma and the deeper compartments, from which the total amount of LysoPC in the body can then be calculated. A 100% absorption of the phospholipid as LysoPC was assumed.
  • Example 3 In another experiment, a test person was given a large amount (25 g) of pure triglyceride (Example 3). The plasma volume was calculated. The decrease in the LysoPC concentration was determined due to the consumption of LysoPC for the production of PC for the biosynthesis of chylomicrons (one chylomicron contains approx. 5-10% PC in relation to the amount of triglyceride). The amount of plasma LysoPC associated with this change in concentration was calculated. This amount of LysoPC in relation to the amount ingested gives the distribution of the ingested LysoPC equivalents between the plasma and the deeper compartments, from which the total amount of LysoPC in the body can then be calculated. A 100% conversion of plasma LysoPC to PC was assumed.
  • Examples 2 and 3 made it possible to estimate the amount of LysoPC in deeper compartments to be approx. 95% of the total body LysoPC, i.e. H. approx. 5% are in the blood plasma.
  • the amount of total body LysoPC can be estimated to be at least 10 g.
  • LysoPC Based on an estimated total body half-life for LysoPC of 2.5 h (see above), this results in a daily turnover of at least 50 g. This value alone makes LysoPC one of the most important energy carriers in the body; in comparison, the glucose turnover is approx. 200 g / day.
  • Example 4 the plasma LysoPC levels of a group of marathon runners were examined directly before and after the run. In all seven examined runners (male / female) the levels fell very clearly, at the top by 45%, on average by 28%, which indicates a high LysoPC consumption by the working muscle mass. If necessary, LysoPC acts here as a fatty acid transporter, which is split back into free fatty acids in the periphery of the muscle cells, resulting in a higher level of fatty acids Fatty acid gradient is built up, which is the prerequisite for rapid absorption of fatty acids via carnitine.
  • the absorption of glucose into the heart muscle may be impaired. If, in such a case, the energy supply is also impaired by fatty acids or a deficiency as LysoPC, this can possibly contribute to damage to the heart muscle.
  • a possible therapy option here would not only be to increase the LysoPC values, but also the administration of glucose and optionally also of insulin in order to improve glucose uptake.
  • alpha-GPC released during the splitting off of fatty acids from LysoPC can be reaylated again, possibly in the liver as the site of fatty acid biosynthesis and as a known source of LysoPC, at least when albumin is present, to remove the LysoPC from the hepatocytes outside of the cell (Baisted, DJ. et al. Biochem. J. 253: 693-701 (1988)).
  • Such a reacylation reaction of alpha-GPC is not described for humans and animals, but it is for yeasts (Saccharomyces cerevisiae) (Stalberg, K. et al., J. Lipid Res. 49: 1794-1806 (2008); Anaokar, S.
  • Example 5 shows that the oral ingestion of 600 mg alpha-GPC in a test person leads to an increase in the amount of LysoPC in the body which suggests the above reaction and shows a way how the necessary high amounts of LysoPC can be provided in the body.
  • Example 6 In a further experiment (Example 6) an attempt was made to increase the amount of LysoPC by increasing the fatty acid biosynthesis in the liver. For this purpose, a test person ingested 50 g of glucose, which also led to a rapid increase in the LysoPC plasma level.
  • the inventive effect of the AGPL and the alpha-GPC in the treatment, prevention, treatment support and post-treatment (convalescence) of pneumonia, sepsis, influenza, Covid-19, ARDS, cancer including one of the underlying disease fatigue or pneumonitis , Colitis or hepatitis after cancer immunotherapy presumably due to the fact that the substances can at least partially compensate for the severe loss of LysoPC associated with these diseases and thus strengthen the immune defense, on the other hand prevent an overshooting of the immune reaction, as well as the supply of important organs and Secure muscle tissue with LysoPC, especially the lungs and heart.
  • the effect of the AGPL and the alpha-GPC according to the invention is also presumably based on the fact that the LysoPCs supplied or formed in the body are ultimately broken down again in large proportions into fatty acids and alpha-GPC in vivo. These two components then develop, individually or together, an effect which could not be achieved without problems by administering one of the two components alone. In this way, alpha-GPC can in turn be reacylated to LysoPC and thus - beyond the initial substitution - ensures a long-term stabilization of the LysoPC household.
  • a very particularly preferred embodiment is based on what has been said above, the use of AGPL (PC or LysoPC), which preferably contain predominantly or exclusively hydrogenated, w-3 or w-9 fatty acids as fatty acids, and they contain no or only small amounts of w- 6 fatty acids. In other words: they contain predominantly or exclusively fatty acid residues which in vivo do not belong to the biologically highly active, proinflammatory eicosanoids, e.g. B. prostaglandia E2 can be implemented.
  • These AGPL can be, inter alia, w-3-containing phospholipids, as they are e.g. B. be obtained from salmon roe or krill.
  • phospholipids or LysoPCs which are produced by the hydrogenation of phospholipids from natural resources, e.g. B. obtained from egg or from soy. Synthetically produced phosphatidylcholines such as DPPC are also possible.
  • a particularly preferred embodiment is the use according to the invention of the AGPL and the alpha-GPC in combination with a triglyceride or the free fatty acids, mono- and diglycerides or free fatty acids, waxes or fatty acid monoesters that can be prepared from a triglyceride.
  • a triglyceride or the free fatty acids, mono- and diglycerides or free fatty acids, waxes or fatty acid monoesters that can be prepared from a triglyceride is preferred.
  • Said compounds are or preferably contain predominantly or exclusively hydrogenated, w-3 or w-9 fatty acids, and they contain little or no w-6 fatty acids. In other words: they contain or are predominantly or exclusively Fettsä u re residues, which in vivo do not belong to the biologically highly active, proinflammatory eicosanoids, e.g. B.
  • prostaglandia E2 can be implemented.
  • Such triglycerides or the resulting di- and monoglycerides and fatty acids are z.
  • the effect of the drug in particular the effect on the inflammation to be treated, can be intensified.
  • the cause of this effect is on the one hand the well-known effect of triglycerides as a high-energy food and energy supplier.
  • soy or egg is given in combination with a fish oil containing w-3, the resources of which are not so limited. Furthermore, the administration of appropriate oils can lead to an increased presence of saturated as well as w-3 and w-9 fatty acids in the liver, which means that alpha-GPC can easily become a LysoPC with these fatty acids.
  • the said saturated, w-3 or o-9 fatty acids are of course also distributed in the body via the normal lipid metabolism and can thus develop their potentially anti-inflammatory effectiveness in various organs or tissues and thus work synergistically with the drugs defined here. It is essential in the use according to the invention of the AGPL and alpha-GPC in combination with one or more triglycerides that the AGPL portion of the total lipid content of the medicament is high.
  • This AGPL proportion should thus be at least 10% by weight, but preferably at least 20% by weight, very particularly preferably at least 40% by weight of the total lipid weight.
  • This is equivalent to an AGPL: triglyceride ratio of 1: 9, preferably 2: 8, particularly preferably from 4: 6.
  • the action of the AGPL as active ingredients is only supported by the presence of the triglycerides.
  • This also distinguishes the medicaments of the present invention from lipid preparations for artificial nutrition, in which the PL content has to be kept as low as possible, and from oils with high contents of ⁇ -3 or ⁇ -6 fatty acids, especially when taken is about increasing the fatty acids mentioned in the body.
  • the AGPL in combination with triglycerides can contain a wide range of fatty acids (hydrogenated, unsaturated) and come from a wide variety of sources (egg, soy, fish, etc.), so they are not limited to egg lecithin like the preparations for artificial nutrition .
  • LysoPC is not used orally as a further embodiment, but systemically, in particular i. v. given, this is preferably done as a continuous infusion so that no high peak concentrations arise in the blood, which could lead to hemolysis.
  • LysoPC also in combination with albumin, at least in the first infusions, in order to ensure that the albumin level in the patient is not lowered, which in turn increases the risk of hemolysis. It is also known that the presence of albumin is necessary for the release of LysoPC from the liver.
  • a further embodiment of the invention is the combination of the administration of AGPL and / or alpha-GPC with carnitine, which could contribute to improving the fatty acid transport in the cells.
  • Another very particularly preferred embodiment is the use according to the invention of the AGPL in combination with substances which have an effect on the eicosanoid synthesis and thus can synergistically support the effect of the AGPL.
  • PLA2 inhibitors in particular inhibitors of sPLA2 (Type II-sPLA, as described, for example, in Uhl et al., Phospholipase A2 Basic and Clinical Aspects in Inflammatory Diseases Vol. 24, Karger, Basel, pp. 123-175 (1997) and in DE-A-4234130 are).
  • compositions according to the invention are suitable for systemic administration, especially for oral (p. O.) Or intravenous (i.v.) Administration.
  • composition according to the invention can be used as an emulsion or solution, as tablets, capsules or as a powder, e.g. B. for stirring into food.
  • concentration of the AGPL can be up to 100%.
  • solutions or aqueous solutions are preferred for administration.
  • composition according to the invention can also contain customary, pharmaceutically acceptable carriers, auxiliaries, stabilizers, diluents, binders, etc.
  • composition according to the invention for the treatment and post-treatment of cancer and tumor cachexia can, in addition to the alpha-GPC or the derivatives thereof, also the above-defined LysoPC or suitable precursors or derivatives thereof, as well as the further active ingredients mentioned and customary, pharmaceutically acceptable carriers, auxiliaries, stabilizers, diluents , Binders, etc. included.
  • the dosage of the composition is individually adapted to the respective patient by the attending physician. It depends, among other things, on the type of Disease, the severity of the symptoms to be treated, the constitution of the patient, etc., usually doses of 2-300 mg AGPL / kg body weight per day and at least 500 mg alpha-GPC, with a dose of at least 20 mg AGPL / kg body weight per day is preferred.
  • the LysoPC level in the patient concerned is determined in order to determine the optimal dosage.
  • the dose (a) preferably greater than approx. 2 g PC / d, particularly preferably greater than 6 g PC / d, (b) greater than 1, 3 g LysoPC / d, particularly preferably greater than 4 g LysoPC / d and (c) greater than 0.6 g alpha-GPC / d, particularly preferably greater than 2 g alpha-GPC / d.
  • a particular advantage of the composition according to the invention lies in its importance for the production of medicaments for the treatment, for the prevention or for the support of the treatment as well as for the post-treatment (convalescence) of pneumonia, sepsis, influenza, Covid-19, ARDS, or for the support of the immunotherapy in cancer in terms of effectiveness and to reduce side effects such as pneumonitis, colitis or hepatitis and to reduce vaccination reactions.
  • this also relates to the after-treatment of cancer diseases, here in particular cachexia and fatigue.
  • Example 1 Determination of LvsoPC in plasma. Serum or blood.
  • LysoPC from plasma, serum or blood was extracted in one step using a newly developed method and then determined using HPTLC (high performance thin layer chromatography).
  • Each 50 ⁇ l sample was extracted with the aid of salt-assisted extraction.
  • a ceramic ball (3.4 mm, ceramic) was placed in a 2 ml twist-top vial, and then 50 ⁇ l dist. Water, 50 ml sample, 192 ml conc. Ammonium acetate solution and 300 ml acetonitrile / l-pentanol (2.5: 1 v / v) were added.
  • the vial is shaken intensively centrifugally for 4 min at 2000 rpm and 20 ° C. with the aid of dual centrifugation (ZentriMix 380 R, Hettich, Tuttlingen). The vials are then centrifuged for 10 min at 16,000 rpm. Of the 200 ml of the upper phase are removed, transferred to a beaded rim glass with a micro insert, flanged and fed to the HPTLC.
  • LysoPC concentrations using HPTLC, five LysoPC standards (16, 40, 80, 120 and 160 mM LysoPC in acetonitrile / l-pentanol (2.5: 1 v / v.) And up to 12 samples - Extracts applied to a 20 x 10 cm silica gel plate using the automatic applicator ATS4 (CAMAG, Switzerland) The applied volume is 6 ml in each case.
  • the plate After the application, after a waiting time of five minutes, in order to ensure uniform evaporation of the solvent, the plate is placed in a preconditioned TLC chamber for 20 minutes, which is filled with 35 ml of chloroform / methanol / water (65: 35: 4 v / v) and 200 ml of 25 % Ammonia solution is filled. During this time, a running distance of approx. 9 cm is achieved. To evaporate the solvent, the plate is then dried on a thermal plate at 150 ° C and immersed three times for two seconds in a copper sulfate solution (83.3 g of copper sulfate pentahydrate and 66.6 ml of phosphoric acid (85%) to 1000 ml of water).
  • a copper sulfate solution 83.3 g of copper sulfate pentahydrate and 66.6 ml of phosphoric acid (85%) to 1000 ml of water.
  • the back of the plate is then dabbed dry and developed for 10 min in a preheated drying cabinet at 160 ° C.
  • the optical density of the LysoPC bands (Rf approx. 0.1) is determined using the evaluation unit (TLC Visualizer 2, CAMAG, Switzerland) and the LysoPC concentrations are determined by comparison with the calibration substances using the HPTLC software "VisionCATS" (Camag, Switzerland) is evaluated. If the LysoPC value is not determined directly from plasma but from whole blood, the value must be corrected by the respective hematocrit value and a factor of 1.3. The inter-assay precision of the determination can be described as good with a COV of 11.3%.
  • Example 2 Determination of the total amount of LvsoPC in the body A healthy test person (male, 57 years old, 84 kg) with a plasma volume of approx or 50 ml of blood taken from the fingertip for 30 minutes over 3 hours. The blood LysoPC concentration was determined as described in Example 1.
  • the fasting plasma LysoPC concentration was determined to be 190 mM. After eating 5 eggs with a total of 86.5 g egg yolk, which contains approx. 5.8 g phosphatidylcholine and 360 mg LysoPC (Blesso, CH., Nutrients 7: 2731-2747 (2015)), the LysoPC value in the plasma increases rapidly on and reached after 75 min the highest value with an increase in the LysoPC level by 70%, to then remain at a constant level of approx. 60-70% above the initial LysoPC level until the end of the measurement.
  • Example 3 Determination of the total amount of LvsoPC in the body A healthy test person (male, 57 years old, 84 kg) with a plasma volume of approx or 50 ⁇ l blood taken from the fingertip for 30 minutes over 3 hours. The blood LysoPC concentration was determined as described in Example 1.
  • Example 2 This experiment was carried out because the result in Example 2 could also be explained by the fact that only a very small proportion of the LysoPC formed from the PC in the GI tract is ultimately transferred to deeper compartments and only a small proportion reaches the blood, the majority would be broken down by the enterocytes. To show that this is not the case, pure triglyceride was added, which ultimately reaches the blood as a chylomicron via the lymphatic system. In addition to the apolipoproteins and the triglycerides, about 10% phospholipids, which have to be synthesized by the enterocytes, are required to build up chylomicrons. The reacylation of LysoPC from the plasma is a very fast synthetic route for this.
  • Examples 2 and 3 made it possible to estimate the amount of LysoPC in deeper compartments to be 95-96% of the total body LysoPC, i. H. 4-5% are in the blood plasma.
  • Example 4 Determination of the change in LvsoPC concentrations as a result of physical activity
  • Example 4a Determination of the LvsoPC concentration in endurance performance
  • the plasma LysoPC levels were examined directly before and after a marathon run.
  • the mean values before the run were 294.9 mM (222.3-367.9 mM).
  • the levels fell on average to 213.6 mM, ie by 27.6% (156.3-258.4 mM), the greatest decrease was - 150 mM (-45%).
  • the LysoPC waste measured here can be explained by a very high consumption due to the long-lasting physical performance and that the additional consumption of LysoPC necessary for athletic performance can no longer be compensated by the normal mechanisms of LysoPC biosynthesis.
  • Example 4b Determination of the LvsoPC concentration before and after a 3-month strength training session
  • the plasma LysoPC levels were examined before and after a 3-month strength training (3x per week).
  • the mean fat-free mass increased by 11.7% (10.5-34.6%), on average by 6.6 kg.
  • the LysoPC values after the end of the training correlate significantly with the relative increase in muscle mass (increase in muscle mass / body weight) with an R 2 of 0.77.
  • a healthy test person male, 57 years old, 84 kg
  • a plasma volume of approx. 3.5 l was administered 600 mg of alpha-GPC in the fasted state and then at intervals of 15 or 30 minutes over 2 hours each 50 ml of blood from the Fingertip removed.
  • the blood LysoPC concentration was determined as described in Example 1.
  • the determination of the plasma LysoPC concentration in the fasting state again resulted in approx. 190 mM.
  • the LysoPC level did not change in the first hour after the uptake of alpha-GPC, but then increased by approx. 20% in the next 30 minutes in order to remain constant at this value until the end of the measurement.
  • a healthy test person male, 57 years old, 84 kg
  • a plasma volume of approx. 3.5 l was administered 50 g of glucose in the fasted state and then 50 ⁇ l of blood were taken from the fingertip at intervals of 15 or 30 minutes.
  • the blood LysoPC concentration was determined as described in Example 1.
  • the LysoPC values determined in Examples 2, 3, 4 and 6 were recorded over a period of 1 week with always the same healthy test person (male, 57 years old, 84 kg) with a plasma volume of approx. 3.5 l.
  • the blood tests for the starting values were all taken in the morning at around 9:00 a.m. on an empty stomach (no food starting the evening before at around 7:00 p.m.).
  • the starting values found were surprisingly always 190 mM LysoPC, fluctuations were not observed. This shows that the individual LysoPC values can, at least with a steady lifestyle, vary from person to person, but fluctuate very little for a particular person.

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Abstract

L'invention concerne la lysophosphatidylcholine (LysoPC), ou un précurseur ou un dérivé approprié correspondant, ou une composition contenant de la LysoPC et/ou un ou plusieurs précurseurs ou dérivés appropriés correspondants, destiné à être utilisé dans le traitement et le post-traitement de maladies inflammatoires humaines associées à une diminution des taux de LysoPC, comprenant le traitement, la prévention ou le soutien thérapeutique et le soutien post-traitement de la pneumonie virale et bactérienne et de la septicémie, y compris la pneumonie et la septicémie suite à la grippe, au SDRA, au cancer, pour soutenir l'efficacité de l'immunothérapie anticancéreuse et pour réduire des effets secondaires tels que la pneumonite, la colite ou l'hépatite, et pour réduire des réactions aux vaccins. L'invention concerne également l'alpha-glycérophosphocholine (alpha-GPC) ou une variante de cette dernière, ou une composition comprenant de l'alpha-CPG et/ou une ou plusieurs variantes de cette dernière, destinée à être utilisée dans le traitement et le post-traitement du cancer et de la cachexie tumorale.
EP21718135.3A 2020-04-17 2021-04-16 Phospholipides et métabolites de phospholipides destinés au traitement de la pneumonie virale et bactérienne et de la septicémie Pending EP4135714A1 (fr)

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EP20170199.2A EP3895709A1 (fr) 2020-04-17 2020-04-17 Phospholipide et métabolites de phospholipide destinés au traitement des viraux et des pneumonies bactériennes et de la septicémie
PCT/EP2021/059881 WO2021209589A1 (fr) 2020-04-17 2021-04-16 Phospholipides et métabolites de phospholipides destinés au traitement de la pneumonie virale et bactérienne et de la septicémie

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EP21718135.3A Pending EP4135714A1 (fr) 2020-04-17 2021-04-16 Phospholipides et métabolites de phospholipides destinés au traitement de la pneumonie virale et bactérienne et de la septicémie

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Publication number Priority date Publication date Assignee Title
GB2046092B (en) 1979-03-05 1983-11-02 Toyama Chemical Co Ltd Pharmaceutical composition containing a lysophospholid and a phospholipid
US4347599A (en) 1980-10-20 1982-08-31 Discovision Associates Spindle clamp assembly for a video recorder-playback machine
DE3127503A1 (de) 1981-07-11 1983-02-17 Boehringer Mannheim Gmbh, 6800 Mannheim Neue phospholipide, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel
DE3204735A1 (de) 1982-02-11 1983-08-18 Boehringer Mannheim Gmbh, 6800 Mannheim Neue phospholipide, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel
DE3367219D1 (en) 1982-10-25 1986-12-04 Nattermann A & Cie Substituted aminoalcanol phospholipids and process for their preparation
DE3304870A1 (de) 1983-02-12 1984-08-16 Boehringer Mannheim Gmbh, 6800 Mannheim Neue phospholipide, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel
JPS59184195A (ja) 1983-04-04 1984-10-19 Takeda Chem Ind Ltd グリセロ−ル誘導体
JPS6081193A (ja) 1983-10-11 1985-05-09 Takeda Chem Ind Ltd リン脂質
JPS6140218A (ja) 1984-08-02 1986-02-26 Takeda Chem Ind Ltd 抗腫瘍剤
US6172050B1 (en) 1992-07-11 2001-01-09 Asta Medica Aktiengesellschaft Phospholipid derivatives
DE4234130A1 (de) 1992-10-09 1994-04-14 Max Planck Gesellschaft Phospholipase A¶2¶ inhibierende Phosphatidylcholinverbindungen
US5489580A (en) 1992-11-05 1996-02-06 University Of Connecticut Phospholipid compounds and use therefor
DE4408011C1 (de) 1994-03-10 1995-11-02 Max Delbrueck Centrum Pharmazeutisches Mittel zur Tumortherapie
DE10015814A1 (de) 2000-03-30 2001-10-11 Max Planck Gesellschaft Arzneimittel zur Stimulierung der Leukopoese, zur Behandlung von Tumor- und Protozoenerkrankungen und Verfahren zu seiner Herstellung
EP1745788A1 (fr) 2005-07-22 2007-01-24 KTB Tumorforschungsgesellschaft mbH Acylglycerophospholipides pour le traitement du cancer et de la cachexie

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EP3895709A1 (fr) 2021-10-20
US20230226087A1 (en) 2023-07-20

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