Classifications

• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to edelfosin (INN; 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine, often also referred to as ET18OCH3) for the treatment of primary and secondary brain tumors based on solid and non-solid tumors.
• INN 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine, often also referred to as ET18OCH3
• the most common tumors originate from astrocytes, ependymocytes and oligodendrocytes.
• the forecast from Brain tumors are basically bad.
• Malignant gliomas are the most widespread brain tumors, of which in turn the glioblastoma multiforme and the anaplastic astrocytoma, which together approx. Make up 80% of all malignant gliomas that have the worst prognosis. Of all of these tumors, only partial resection is often possible.
• Malignant brain tumors are among the most malignant tumors; their prognosis is poor. Even with a combination of surgery, radiation and chemotherapy, the survival time from the time of diagnosis in patients with highly differentiated gliomas is usually. less than 1 year.
• chemotherapy is only used in the form of adjuvant therapy, i.e. immediately after surgical removal of the tumor.
• chemotherapy almost always fails in brain tumors because the blood-brain barrier - a natural barrier against toxins and pathogens - prevents most drugs from entering the brain.
• drugs mainly from the nitrosourea substance class
• the WHO classifies brain tumors as tumors that are not or only marginally sensitive to cytotoxic treatment.
• cytostatic carmustine a nitrosourea derivative
• the cytostatic carmustine a nitrosourea derivative
• this cytostatic agent if it is given systemically, like all known cytostatics as a non-selectively acting molecule, has a damaging effect on the normal cells of the body, i.e. its use is associated with corresponding undesirable side effects (such as genetic damage, pulmonary toxicity, myelosuppression, etc.).
• edelfosin as an active ingredient for a medicament for the treatment of brain tumors.
• Edelfosin can be used in dcer L form, the D form or as a racemate.
• Edelfosin has two advantages, which make its usefulness in the therapy of primary (ie originating from brain cells) and secondary (ie not originating from the body's own cells, but occurring in the brain) brain tumors appear to be best suited.
• the molecule acts strictly selectively (see Hickman 1 992, Fig. 7). After absorption into the cells, it only exerts its cytostatic effect on the degenerate cells, while it is broken down in healthy cells (cf. Magistrelli & al. 1 994, Table 2).
• this selectivity means that the molecule is neither mutagenic (see King & al. 1 981), nor carcinogenic (see Berdel & al. 1 983; Berger & al.
• edelfosin also means that the undesirable drug effects caused by the drug differ significantly in severity, degree and duration from that of the known cytotoxic chemotherapeutic agents. Because of this peculiarity, therapy with edelfosin can be carried out on an outpatient basis without any problems.
• a problem in the treatment of cancer not solved before the invention is the limited duration of the use of a therapy.
• the toxicity of the medicines available today allows them to be used only in cycles and also only for a limited time.
• Tumor cells that have "lost" information for genetically programmed cell death (apoptosis) are de facto immortal.
• the drug therapies used today require either a certain receptor status or a certain stage of the cell cycle. This means that not all cells, but only a part of them, can be effectively addressed during the already limited duration of therapy.
• the molecule does not exert its effect via receptors (cf. Snyder & al. 1 991); on the other hand, its effect is not dependent on the division stage of a cell, but works via enzymes that are active in every phase of a cell cycle and must be essentially present. Due to the proven selectivity of edelfosin, the drug can be given as a continuous therapy for a practically unlimited period of time, so that the brain tumor cells are permanently influenced in their division behavior. The longest known duration of therapy for a posterior tumor patient now extends over 6 years. With a total dose of approx. 640 g, the patient worked until his retirement and did not suffer from any significant undesirable drug effects (see Table 1, column "Pat.” - No.
• Edelfosin can easily be administered orally, conveniently dissolved in a drinkable carrier.
• Water-based carriers are preferably used, for example soups (in particular alloyed soups), beer, egg liqueur and other conventional beverages.
• Milk-based carriers such as milk, milk substitute, yogurt, kefir and the like are also suitable.
• edelfosin can also be used in chemotherapy-resistant tumors, since it has a completely different mechanism of action, which, in contrast to the DNA-interactive cytostatics, primarily attacks the tumor cell membrane and interferes with the signaling chain of the cells. Important enzymes, e.g. Phospholipase C, protein kinase C inhibited, whereby the cancer cell can no longer divide. Furthermore, edelfosin effects the re-induction of apoptosis (cf. Mollinedo & al. 1 993); cells affected in this way lose their "immortality status" as cancer cells.
• phase I studies the tolerability, pharmacokinetics and pharmacodynamics of a medication in humans are examined and examined after the end of the experimental animal part of drug development (testing of absorption, distribution in the body, breakdown products, excretion).
• results obtained from this do not allow any conclusion towards the therapeutic effectiveness of a drug. This statement can only be made after phase II studies have been carried out.
• Glioblastomas including gliosarcomas N 20 (48.8%)
• N 18 patients (around 44%) were younger than 40 years
• the Karnofsky index as a measure of the clinical condition or general condition, is an important prognostic factor that already decides on treatment or non-treatment with cytostatics. In general, it is recommended to use adjuvant (!) Chemotherapy only from a Karnofsky index of 70% (see Bogdahn & al. 1995). The general condition is usually measured according to the Karnofsky scale used internationally.
• edelfosin The patient population treated with edelfosin was approx. 85% pretreated several times; i.e. more than one type of treatment, including surgery, radiation, or chemotherapy, had been used prior to starting edelfosin therapy.
• Alternative therapy methods miistletoe, hyperthermia, etc. were not evaluated.
• the pharmacodynamic effect i.e. the effect of a drug directly on the tumor is usually measured 2 months after the start of therapy. This pharmacodynamic effect is determined differently depending on the substance class affiliation (i.e. cytostatic, hormone preparation, immunomodulator, etc.).
• Edelfosin is a phenotype modifier / biological response modifier and thus does not directly kill a cell directly, but rather inhibit its division, induce apoptosis and / or differentiate into a "normal" cell.
• the therapy goal is accordingly a tumor growth arrest (no change).
• NC Tumor growth arrest
• cNC clinical no change
• the “yes” rating means that a symptom is caused by the drug.
• the review "?” (questionable) means that the cause of the complaint is unclear; the rating “no” means that the symptom is clearly caused by the disease and not by the drug.
• the therapy according to the invention with edelfosin guarantees a maximum of quality of life.
• therapeutic efficacy is primarily measured in terms of quality of survival and survival time. It is undisputed today that the measurement of a pharmacodynamic effect alone (complete remission / partial remission / no change) is important within therapy studies, but does not have any value per se for the patient. This is particularly true for the palliative situation, in which healing is no longer possible. A possible therapeutic effect must then be placed particularly carefully in relation to the side effects of a treatment, because with palliative therapy the side effects of a drug have a much greater weight than with curative therapy. The aim of palliation is undoubtedly to strive to extend survival and / or improve quality of life, ideally the combination of the two.
• metastases located in the brain originate from solid tumors (e.g. lung carcinomas, breast carcinomas, colorectal carcinomas etc.) or from non-solid tumors (e.g. lymphomas, leukemias etc.). It should only be mentioned in passing that patients with brain metastases, e.g. starting from a non-small cell bronchial carcinoma, usually still have 6 months of survival and that brain metastases are usually considered an exclusion criterion for chemotherapy studies.
• solid tumors e.g. lung carcinomas, breast carcinomas, colorectal carcinomas etc.
• non-solid tumors e.g. lymphomas, leukemias etc.
• Neoplasms of the Central Nervous System 5th ed., Lippincott-Raven, Philadelphia,

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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 1998
  • 1998-05-19 DE DE19822509A patent/DE19822509A1/de not_active Withdrawn
• 1999
  • 1999-05-11 EP EP99952070A patent/EP1079838B1/de not_active Expired - Lifetime
  • 1999-05-11 US US09/700,903 patent/US6514519B1/en not_active Expired - Fee Related
  • 1999-05-11 DE DE59902666T patent/DE59902666D1/de not_active Expired - Lifetime
  • 1999-05-11 AT AT99952070T patent/ATE223721T1/de not_active IP Right Cessation
  • 1999-05-11 JP JP2000549264A patent/JP2002515439A/ja active Pending
  • 1999-05-11 WO PCT/EP1999/003241 patent/WO1999059599A1/de not_active Ceased

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