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WO1996003996A1 - Compositions pharmaceutiques contenant du deuterium pour detruire des tumeurs - Google Patents

Compositions pharmaceutiques contenant du deuterium pour detruire des tumeurs Download PDF

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Publication number
WO1996003996A1
WO1996003996A1 PCT/EP1995/003100 EP9503100W WO9603996A1 WO 1996003996 A1 WO1996003996 A1 WO 1996003996A1 EP 9503100 W EP9503100 W EP 9503100W WO 9603996 A1 WO9603996 A1 WO 9603996A1
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Prior art keywords
deuterium
cells
tumor
pharmaceutical composition
use according
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PCT/EP1995/003100
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German (de)
English (en)
Inventor
Ulrich Bogdahn
Albrecht Bauer
Axel Haase
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Ulrich Bogdahn
Albrecht Bauer
Axel Haase
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Publication date
Application filed by Ulrich Bogdahn, Albrecht Bauer, Axel Haase filed Critical Ulrich Bogdahn
Priority to AU32570/95A priority Critical patent/AU3257095A/en
Priority to EP95929079A priority patent/EP0773784A1/fr
Publication of WO1996003996A1 publication Critical patent/WO1996003996A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients

Definitions

  • the invention relates to the use of a pharmaceutical composition containing deuterium and / or deuterated substances and / or substances which enrich or release deuterium for the selective killing of tumor cells and / or tumor metastases or for the prevention of metastasis and / or local recurrence of tumors and their regrowth.
  • Previous tumor therapeutic agents also suffer from the disadvantage of causing high side effects even in the lowest concentrations, in particular immune suppression and changes in the blood count and bone marrow depression as well as induction of new tumors.
  • the present invention is therefore based on the object of exerting a selective and cytotoxic effect on tumor cells and / or metastases and of largely leaving the growth of normal cells unaffected and of preventing the metastasis and / or recurrence of tumors and / or their regrowth. This would also avoid some of the side effects known for tumor therapeutics.
  • the direct cytotoxic effect can be demonstrated in vitro on cell culture material.
  • Cells are killed in vitro by adding a deuterium-containing substance or compound to the culture medium.
  • the following% by volume are to be understood as follows.
  • Substance containing 100% by volume of deuterium means that all H atoms at one (or more) specific positions are replaced by D atoms.
  • D atoms For example, contains pure D 2 O, molecular weight 20.03 g / mol, 2 atoms of deuterium (4 g / mol) and one atom of oxygen (1 6 g / mol). If the concentration of a "deuterium-containing substance" is therefore determined, its pure deuterium content in this example is only a maximum of 20% by weight, corresponding to 100% by volume.
  • a suitable concentration for killing over 95% of cells for example the tumor HTZ-1 9 (malignant melanoma), under suitable culture conditions as a monolayer is over 50% by volume of D 2 0 or 99.86 g of deuterium per kg of active substance or another deuterium-containing substance with H atoms replaced by D at a certain point in 50% by volume, preferably over 70% by volume (1 39.81 g deuterium / kg), very preferably over 90% by volume (1 79.75 g deuterium / kg).
  • higher or lower concentrations are also suitable for killing tumor cells to a greater or lesser extent.
  • deuterium has a cytotoxic effect on tumor cells by inhibiting DNA synthesis [ 3 H-thymidine incorporation, Coligan, JE, Kruisbeek, AM, Margulies, DH Shevach, EM, Strober, W., Current Protocols Immunology , NIH Monographie, J. Wiley & Sons, New York, 1 992], and also demonstrated by cell membrane defect [trypan blue staining, GK Smith, Duch, DS, Dev, IK Kaufmann, SH, Metabolie Effects and Kill of Human T-Cell Leukemia by 5-Deaza acyclotetrahydrofolate, a Specific Inhibitor of Glycineamide Ribonucleotide Transformylase, Cancer Res.
  • deuterium-containing substances are suitable for producing a therapeutic agent for killing tumor cells and / or metastases and for preventing metastases and / or the local recurrence of tumors and their regrowth.
  • a therapeutic agent is particularly suitable for the therapy of malignant melanomas, gliomas and astrocytomas, bronchial carcinomas (in particular small-cell bronchial carcinomas), neuroblastomas and carcinomas of the gastrointestinal tract.
  • deuterium or deuterium-containing or deuterium-releasing or deuterium-enriching substances are usually combined with auxiliaries, fillers and / or additives (for example flavorings, electrolytes, nutrients, vitamins, substances which influence absorption) in one, preferably sterile , isotonic and / or pyrogen-free, pharmaceutical preparation or formulation used, preferably in the form of suppositories, ointments, solutions, dispersions and emulsions, aerosols, foams, particulate agents (for example granules, agglomerates, powder, microbeads and adsorbates), pills , Lozenges, tablets, dragees, capsules or microcapsules, types of chewing gum, tissue, leaf or thread bases, with bandages or bandages, for smoking or inhaling and in carriers, such as liposomes.
  • auxiliaries for example flavorings, electrolytes, nutrients, vitamins, substances which influence absorption
  • the administration is preferably local, intracutaneous or transcutaneous;
  • For systemic use preferably intravenously, by partially exchanging the body water or blood water content (e.g. by dialysis), intraarterially, orally, rectally; for use in cavities, preferably intrapleural, intrathecal, intraventricular, intraperitoneal, intracavitary, in operating theaters.
  • Use in operating theaters is preferably used to prevent relapse of the removed tumor, i.e. to prevent local recurrence and regrowth of the tumor.
  • Extracorporeal killing of tumor cells is also possible (e.g. "purging" in bone marrow neoplasia).
  • deuterium or deuterium-containing or deuterium-releasing or deuterium-enriching substances are also combined with other active substances, preferably other cytostatics or tumor therapeutics.
  • the newly discovered effect of cell killing and the tumor specificity mean that additive or superadditive (synergistic) effects can be achieved in combination with other cytostatics and tumor therapeutics. This is preferably done by attacking the cytoskeleton, especially by attacking the tubulin.
  • a reduction in the dose of the combined cytostatic / tumor therapeutic can be expected from a combination with deuterium-containing therapeutic agents according to the invention consequently also a reduction in the side effects, which often restrict therapy.
  • cytostatics / tumor therapeutics are promising, based on the same or similar principles of action as deuterium, namely cell killing (also apoptosis).
  • TGF-ß tumor growth factor ß
  • TNF tumor necrosis factor
  • Substances that attack the tubulin cytoskeleton e.g. Vinca alkaloids, taxol, taxol derivatives and colchicine and colchicine derivatives
  • Alkylating agents such as Cyclophosphamide, busulfan, ACNU and other nitrous urea derivatives
  • Purine and pyrimidine antagonists such as e.g. Azathioprine, 6-mercaptopurine, cytarabine
  • the hemotoxic / immunosuppressive (side) effect is restrictive of therapy.
  • Such an effect is not to be expected from deuterium or deuterium-containing or enriching substances for normal cells, as shown for normal brain cells and in particular lymphocytes (example 6), ie tumor cells are selectively killed.
  • the treatment of tumor-infiltrated bone marrow or bone marrow stem cells before bone marrow transplantation ("purging") is used for the selective elimination of tumor cells possible, which can be done intracorporeally as well as extracorporeally.
  • the same effect can therefore be achieved by combining such tumor therapeutic agents with deuterium or deuterium-containing and releasing substances at a lower dose.
  • a greater anti-tumor effect than previously possible can be achieved by combining it with deuterium.
  • Deuterated tumor therapeutic agents are therefore particularly suitable for combination with
  • Antimetabolites such as Methotrexate, thioguanine
  • Alkaloids such as Vinblastine, vincristine, taxol
  • Antibiotics with tumor therapeutic potency such as Daunorubicin, Bleomycin, Epirubicin
  • bone marrow depressive tumor therapeutics such as Hydroxyurea, procarbazine and alkylating agents, and purine / pyrimidine derivatives.
  • a synergistic or potentiating effect also results when the pharmaceutical composition is used in combination with irradiation methods such as gamma radiation, electron radiation ( ⁇ -radiation), neutrons and corpuscular radiation.
  • irradiation methods such as gamma radiation, electron radiation ( ⁇ -radiation), neutrons and corpuscular radiation.
  • the cell proliferation was determined by means of 3 H-thymidine incorporation, as described for example in "Bogdahn, U., R. Apfel, M. Hahn, M. Gorlach, C. Bohl, J. Hoppe and R. Martin: Autocrine tumor cell growth inhibiting activities from Human Malignant Melanoma, Cancer Res. 49, 5358-5363 (1,989) ". Growth and survival curves are based on cell counting with trypan blue dye.
  • Solid tumors such as glioblastoma multiforme, astrocytoma, malignant melanoma, small cell bronchial carcinoma, colon carcinoma, are preferred.
  • cells from normal brain after skull trauma, normal brain or IL-2 stimulated (freshly isolated) lymphocytes, PHA stimulated (freshly isolated) lymphocytes can be used.
  • the effect of deuterium on cells is preferably achieved with D 2 0.
  • the suitably concentrated D 2 0 was preferably produced in the experiment by diluting high-purity D 2 0 (> 99%) with H 2 0.
  • D 2 0 intended for therapy is preferably produced directly in the desired concentration.
  • the effect of deuterium according to the invention can also be achieved by other substances which contain deuterium or which release or enrich deuterium in a suitable manner. This includes all conceivable inorganic or organic compounds that contain deuterium, z. B.
  • deuterated amino acids such as deuterated glutamine, deuterated alanine and deuterated glutamate
  • deuterated sugars such as deuterated glucose, deuterated fructose
  • deuterated fats deuterated DNA or RNA building blocks
  • deuterated metabolic products eg deuterated pyruvate, deuterated lactate
  • Fig. 5, 6, 1 1, 1 7, 21, 25 survival rate of tumor cells in relation to the length of stay in media containing deuterium
  • Fig. 7, 8, 1 2, 1 8, 22, 26 survival fraction of tumor cells in relation to the length of stay in deuterium-containing media
  • Fig. 27a + b Cell cycle of untreated HTZ-1 9 melanoma cells
  • Fig.28a + b Cell cycle of HTZ-1 9 melanoma cells after 3 days in 50 vol% D 2 O
  • Fig.29a + b Cell cycle of HTZ-1 9 melanoma cells after 3
  • Fig. 31 Migration area of a tumor
  • Fig. 32 Comparison of the number of liver metastases in untreated test animals and with D 2 0-treated test animals after implantation of a sarcoma M 5076
  • Fig. 33 Comparison of the number of surviving test animals after intraperitoneal implantation of a sarcoma M 5076
  • HTZ-209B, HTZ 243, HTZ 1 9, HTB 69, HTZ 25, CaCo-2 or HT 29 cells are each used for at least 24 hours in microculture plates with 96 wells (Costar, Zurich) sown in 200 ⁇ ⁇ culture medium with a density of 3000 cells per well [according to Chambard et al. J. Cell. Physiol. 1 35 (1 988), 1 01 -1 07].
  • the culture medium consists of Dulbecco's MEM with 1 0% FCS addition, 1% vitamins, 1% non-essential amino acids and 0.3% L-glutamine.
  • Deuterated media are produced using MEM powder medium and heat-sterilized D 2 O as well as Ultra Pure Water for dilution with identical additives as conventional culture medium.
  • the cells are in deuterated medium in the desired concentration / 03996 PC17EP95 / 03100
  • HTB 69 malignant melanoma 71
  • HTZ-1 9, HTZ 209, HTZ are used analogously to Example 1 243, HTB 69, HTZ 25, CaCo-2 or HT 29 cells sown for at least 24 hours in microculture plates with 96 wells or in microculture plates with 24 wells with a density of 1 0,000 cells per well.
  • the culture medium consists of Dulbeccos MEM with 10% FCS addition, 1% vitamins, 1% non-essential amino acids and 0.3% L-glutamine.
  • a medium change is then carried out and deuterated medium is added in the desired concentration.
  • the cells are incubated in a concentrated medium in the desired concentration for a defined period of time at 37 ° C., 5% CO 2 .
  • the cells are then detached with trypsin and trypan blue (Trypan Blue Stain 0.4%, Sigma Chemicals St. Louis) is added in a defined volume.
  • trypsin Trypan Blue Stain 0.4%, Sigma Chemicals St. Louis
  • the cell number of vital and damaged cells is counted in the Fuchs-Rosenthal chamber and plotted as a growth curve or survival curve.
  • the surviving fraction ie the proportion of surviving cells of the treated group compared to untreated controls, can be given after 3 or 6 days of incubation with 90% by volume of D 2 O medium.
  • HTZ 209 glioblastoma multiforme 0.55 0.07
  • HTZ 1 9 malignant melanoma 0.25 0.05
  • CFE Coldy Forming Efficiency
  • Fig. 30 From Fig. 30 it can be seen that the two tested tumors HT-29 (colon carcinoma) and HTZ1 9 (malignant melanoma) show a high effectiveness of D 2 0 and below 90 vol% D 2 0 there is a decrease by 4 or 5 powers of ten of vital colony-forming tumor cells.
  • HTZ-1 9 and HTB-69 Two different tumors, HTZ-1 9 and HTB-69, were tested.
  • the tumors were expanded in MEM with 10 vol .-% FCS addition.
  • 3 H thyrridine assays were carried out in 96-well plates, growth curves in some cases also in 24-well plates.
  • the growth curves (Fig. 3,4) for HTZ-1 9 showed a significant slowdown in growth at 50% by volume D 2 0 (99.86 g deuterium / kg), at 90% by volume D 2 0 ( 1 79.75 g D 2 O / kg) the growth stagnated over the full observation period of 1 3 days.
  • HTB-69 showed a clear absolute decrease in cell count, while the untreated controls showed exponential growth.
  • the resulting overall effect from deuterium was measured as a surviving fraction (Fig. 7,8); after 6 days in 90% by volume of deuterium medium, the survival fraction for HTZ-19 was 0.04, for HTB 0.07, after 12 days for both tumors it was less than 0.01. This means a decrease in vital tumor cells under deuterium treatment of more than two powers of ten (2 log-cell kill).
  • the survival fraction of HTB-69 was already less than 0.5 after 1 day.
  • Figures 27a, 28a, 29a show the frequency distributions ("distribution") of HTZ-19 melanoma cells in the cell cycle.
  • a compensation curve (diagram: dashed line) is calculated from the primary data of the frequency of the occurrence of a certain amount of DNA (shown in the diagram as individual measuring points).
  • the distribution functions of the individual cell cycle compartments (diagram: solid lines for G, S and G 2 phase) are adapted to this compensation curve and the relative frequencies are determined from these distribution functions. This results in the percentage distribution of the cells over the cell cycle compartments, which can be read on the edge of the figures.
  • Figures 27a-29a always show the number of cells (ordinate) depending on their DNA content (abscissa). The ordinate unit is therefore the cell number, the abscissa unit is the relative DNA content in arbitrary units of the fluorescence intensity.
  • Figures 27b, 28b, 29b show the intensity of the ethidium bromide fluorescence as ordinate ("Y axis") and the intensity of the maximum fluorescence as abscissa ("X axis").
  • the number of cells is indicated by the blackening and the point density.
  • the intensity for both axes results from the content of fluorescence-stained DNA. In the case of ethidium bromide fluorescence, the intensity is therefore proportional to the DNA content of non-vital cells.
  • the 3 H-thymidine incorporation (Fig. 9) shows an almost linear dose-response relationship which is largely independent of time. A saturation behavior has already occurred on the time scale 1 to 6 days, the effects are evident very quickly in the range of hours. In the case of HTZ-25, a very high effect was achieved with 94% inhibition after exposure to 90% by volume of D 2 0 (1 79.75 g of deuterium / kg) in the medium for 6 days.
  • the growth curves show a clear decrease in the treated cells with good growth of the untreated tumor cells.
  • the survival rate (Fig. 1 1) drops to 80%, with flow cytometry being able to show a cell kill percentage of 56% after 2 days.
  • the survival fraction (Fig. 1 2) reaches 0, 1 7, and 1 3 after 6 days Days even 0.09, so that the overall effect on the tumor cells at least 90 vol .-% D 2 0 concentration represents a full order of magnitude reduction of vital tumor cells.
  • Colon carcinomas of the ATCC cell lines CaCo-2 and HT-29 were tested.
  • the tumors were expanded in MEM with 10 vol% FCS.
  • 3 H thymidine assays and growth curves were carried out in 96-well plates.
  • the 3 H-thymidine incorporation (Fig. 13, 14) shows an almost linear dose-effect relationship which also tends to be largely independent of time.
  • the effects are evidently also expressed in the range of hours, but the full expression is achieved, in particular in the case of CaCo-2 cells, only after 3 days of incubation.
  • HT-29 an extremely high effect could be achieved with 98% inhibition after 6 days exposure of 90 vol.% D 2 0 (1 79.75 g deuterium / kg) in the medium, CaCo-2 achieved with 94% inhibition similar values after 6 days of incubation.
  • the growth curves (Fig. 1 5, 1 6) indicate a fulminant absolute decline in the cells in both colon carcinomas, while the untreated controls are in exponential growth.
  • the survival rate (Fig. 1 7) shows a clear decrease, in particular with CaCo-2, with 39% survival rate, a significant cell kill was achieved after 9 days of treatment.
  • the survival fraction (Fig. 1 8) shows values of less than 0.1 in both colon carcinomas after 3 days (CaCo-2: 0.08, HT-29: 0.04), after 9 days it was in both tumors even below 0.01, ie two powers of ten, reduction of vital tumor cells at 90 vol.% D 2 0 concentration.
  • Example e Lymphocytes (control; normal cells)
  • Freshly isolated blood lymphocytes were tested, expanded according to the Ficoll gradient in RPMI medium with 10% by volume of human AB serum addition.
  • the lymphocytes were stimulated with interleukin 2 (IL-2) or phythaemagglutinin (PHA).
  • IL-2 interleukin 2
  • PHA phythaemagglutinin
  • IL-2 stimulated lymphocytes showed time-dependent behavior; at 3 and 6 days there was inhibition, a maximum of 65% inhibition was determined at 90% by volume of deuterium.
  • the growth curves show a decrease compared to the controls both with 50 vol.% (99.86 g deuterium / kg) and with 90 vol.% Deuterated medium, but this is significantly less pronounced than with the tested tumors.
  • the survival rate (Fig. 21) as a measure of the cell death caused by deuterium is significantly reduced only in the IL-2-stimulated cells in 90% by volume of deuterium; there were values up to 60% "survival rate" corresponding to 40 % killed cells measured with 6d IL-2 stimulation.
  • the survival fraction (Fig. 22) was also reduced only in IL-2 stimulated lymphocytes (up to 0.36 at 6d in 90 vol.% Deuterium medium with II-2 stimulation).
  • the PHA-stimulated cells remain largely unaffected (0 , 8 with 6d PHA stumulation in 90 vol.% Deuterium).
  • the system of stimulated lymphocytes lags significantly behind the effects on tumor cells with regard to the inhibition of proliferation and cytotoxicity caused by deuterium.
  • the deuterium-mediated effects are not dependent on proliferation, or at least not all differential effects are only caused by the greater proliferation in tumor cells: the IL-2-stimulated cells with the lower division rate are more strongly inhibited and show higher cell-kill Sensitivity "as the rapidly dividing PHA-stimulated lymphocytes, which are stimulated even in growth by low doses of deuterium and have hardly any" cell kill ".
  • glioblastoma glioblastoma multiforme
  • astrocytoma HTZ-243 astrocytoma WHO grade III
  • the 3 H-thymidine incorporation (Fig. 23) shows a clear shoulder formation in the dose range between 1 and 50 vol.% D 2 O, which is largely independent of time.
  • a very clear tumor selectivity can be seen, in particular when using D 2 0 over 6 days, with HTZ-243 having already achieved 10% D 2 0 over 60% inhibition.
  • the growth curves (Fig. 24) indicate an absolute decline in the cells in both gliomas, especially HTZ-209, while the untreated controls are in exponential growth.
  • the survival rate (Fig. 25) shows a clear decrease in both tumors, especially in HTZ-209, with 33% survival rate, a high degree of tumor cell kill was achieved after 6 days of treatment.
  • the survival fraction (Fig. 26) shows an almost linear decline in both brain tumors, and after 6 days for HTZ-209 values below 0, 10, i.e. a full power of ten decrease in vital tumor cells.
  • lymphocytes in which both "growth arrest” and “cell kill” are significantly less pronounced in the more rapidly proliferating PHA-stimulated cells, indicate that the extent of the effects is not only dependent on the proliferation rate. / 03996 PC17EP95 / 03100
  • a suitable method for checking the effect of a cytostatic on the ability to migrate and thus the metastasis of a tumor is to assess the migration of tumor spheroids.
  • Tumor cells are converted back into uncoated plates after the formation of spheroids on agricultured 48-well plates. The tumor cells return to adherent growth within 72 hours; the area covered is a measure of the migration and invasion behavior of a tumor and thus of its ability to metastasize and its inhibition.
  • Fig. 31 it can be seen that D 2 0 leads to a reduction in the migration area to 20% of the otherwise occupied area after 72 hours, which corresponds to a significant reduction in the ability to metastasize or to form metastases.
  • the cells migrated to this area, which was reduced to 20%, are also devitalized (demonstrated by trypan blue staining), since D 2 0, in particular, completely kills off the migrating cells.
  • the use of D 2 O therefore prevents potential metastasis.
  • sarcoma M 5076 was implanted subcutaneously in mice. Half of these mice were treated with 50% by volume D 2 O.
  • mice were given 10 5 cells of sarcoma M 5076 intraperitoneally. Half of the mice (8 animals) became 50% by volume D 2 0, the other / 03996 PC17EP95 / 031 0

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Abstract

L'invention concerne l'utilisation d'une composition pharmaceutique contenant du deutérium et/ou des substances deutérisées et/ou des substances qui enrichissent ou libèrent le deutérium, pour détruire de manière sélective des cellules tumorales et/ou des métastases tumorales ou pour prévenir la formation de métastases et/ou la résurgence locale de tumeurs ainsi que leur régénérescence.
PCT/EP1995/003100 1994-08-04 1995-08-03 Compositions pharmaceutiques contenant du deuterium pour detruire des tumeurs WO1996003996A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU32570/95A AU3257095A (en) 1994-08-04 1995-08-03 Deuterium-containing pharmaceutical compositions for destroying tumors
EP95929079A EP0773784A1 (fr) 1994-08-04 1995-08-03 Compositions pharmaceutiques contenant du deuterium pour detruire des tumeurs

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DEP4427690.7 1994-08-04
DE19944427690 DE4427690A1 (de) 1994-08-04 1994-08-04 Deuterium enthaltende pharmazeutische Zusammensetzung als Zytostatikum oder Tumor-Therapeutikum

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WO1996003996A1 true WO1996003996A1 (fr) 1996-02-15

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AU (1) AU3257095A (fr)
CA (1) CA2196671A1 (fr)
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WO (1) WO1996003996A1 (fr)

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EP0893123A1 (fr) * 1995-09-13 1999-01-27 Eduard Maximovich Peganov Moyen de traitement preventif et curatif de pathologies liees a differentes formes de vieillissement de l'organisme
WO2006019327A3 (fr) * 2004-08-18 2006-04-13 Regia Autonoma Pentru Activita Utilisation de l'eau appauvrie en deuterium comme adjuvant dans la therapie du cancer pour reduire la toxicite des cytostatiques
WO2008046407A3 (fr) * 2006-10-18 2008-10-16 Thomas Bayerl Utilisation de dioxyde de deutérium pour traiter des maladies hyperprolifératives de la peau
US8609147B2 (en) 2007-07-05 2013-12-17 D2 Bioscience Group Ltd. Use of deuterium oxide for treatment of herpes virus-based diseases of the skin
US8709496B2 (en) 2009-01-07 2014-04-29 D2 Bioscience Group Ltd. Use of deuterium oxide for the treatment of virus-based diseases of the respiratory tract
CN106659735A (zh) * 2014-05-26 2017-05-10 陈松源 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物

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US7601737B2 (en) 2005-07-26 2009-10-13 Nycomed Gmbh Isotopically substituted proton pump inhibitors
DK2110132T3 (da) 2008-04-20 2014-04-28 D2 Bioscience Group Ltd Anvendelse af deuteriumoxid som elastasehæmmer

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EP0893123A4 (fr) * 1995-09-13 2001-05-02 Eduard Maximovich Peganov Moyen de traitement preventif et curatif de pathologies liees a differentes formes de vieillissement de l'organisme
WO2006019327A3 (fr) * 2004-08-18 2006-04-13 Regia Autonoma Pentru Activita Utilisation de l'eau appauvrie en deuterium comme adjuvant dans la therapie du cancer pour reduire la toxicite des cytostatiques
WO2008046407A3 (fr) * 2006-10-18 2008-10-16 Thomas Bayerl Utilisation de dioxyde de deutérium pour traiter des maladies hyperprolifératives de la peau
US8609147B2 (en) 2007-07-05 2013-12-17 D2 Bioscience Group Ltd. Use of deuterium oxide for treatment of herpes virus-based diseases of the skin
US8709496B2 (en) 2009-01-07 2014-04-29 D2 Bioscience Group Ltd. Use of deuterium oxide for the treatment of virus-based diseases of the respiratory tract
CN106659735A (zh) * 2014-05-26 2017-05-10 陈松源 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物
JP2017516854A (ja) * 2014-05-26 2017-06-22 ソンヤン チン、 抗腫瘍相乗減毒効果を有する薬用溶液及びそれを含む薬用組成物
EP3150212A4 (fr) * 2014-05-26 2017-11-22 Songyuan Chen Solution pharmaceutique promotrice de l'effet anti-tumeur et ayant un effet réducteur de toxicité, et composition pharmaceutique la comprenant
US11090330B2 (en) 2014-05-26 2021-08-17 Songyuan Chen Pharmaceutical solution having a toxicity-reducing effect for antitumor drugs, and pharmaceutical composition comprising same
CN114831931A (zh) * 2014-05-26 2022-08-02 大江生物医药科技(广州)有限公司 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物
CN114848589A (zh) * 2014-05-26 2022-08-05 大江生物医药科技(广州)有限公司 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物
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