WO1996035435A1 - Compositions containing bismuth, for the treatment and prevention of gastrointestinal disorders - Google Patents
Compositions containing bismuth, for the treatment and prevention of gastrointestinal disorders Download PDFInfo
- Publication number
- WO1996035435A1 WO1996035435A1 PCT/US1996/006488 US9606488W WO9635435A1 WO 1996035435 A1 WO1996035435 A1 WO 1996035435A1 US 9606488 W US9606488 W US 9606488W WO 9635435 A1 WO9635435 A1 WO 9635435A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bismuth
- milligrams
- per day
- subject
- parasitic protozoa
- Prior art date
Links
- 229910052797 bismuth Inorganic materials 0.000 title claims abstract description 40
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 230000002265 prevention Effects 0.000 title claims abstract description 9
- 208000018522 Gastrointestinal disease Diseases 0.000 title claims description 21
- 239000000203 mixture Substances 0.000 title claims description 15
- 238000000034 method Methods 0.000 claims abstract description 25
- 230000003071 parasitic effect Effects 0.000 claims abstract description 25
- 230000001404 mediated effect Effects 0.000 claims abstract description 13
- 241001465754 Metazoa Species 0.000 claims abstract description 6
- ZQUAVILLCXTKTF-UHFFFAOYSA-H bismuth;tripotassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[K+].[K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O ZQUAVILLCXTKTF-UHFFFAOYSA-H 0.000 claims description 13
- 208000010643 digestive system disease Diseases 0.000 claims description 12
- 208000018685 gastrointestinal system disease Diseases 0.000 claims description 12
- ZREIPSZUJIFJNP-UHFFFAOYSA-K bismuth subsalicylate Chemical compound C1=CC=C2O[Bi](O)OC(=O)C2=C1 ZREIPSZUJIFJNP-UHFFFAOYSA-K 0.000 claims description 9
- 229960000782 bismuth subsalicylate Drugs 0.000 claims description 9
- 241000224431 Entamoeba Species 0.000 claims description 7
- 241000224466 Giardia Species 0.000 claims description 7
- KKMOSYLWYLMHAL-UHFFFAOYSA-N 2-bromo-6-nitroaniline Chemical compound NC1=C(Br)C=CC=C1[N+]([O-])=O KKMOSYLWYLMHAL-UHFFFAOYSA-N 0.000 claims description 6
- 229960004645 bismuth subcitrate Drugs 0.000 claims description 6
- SULICOHAQXOMED-YDXPQRMKSA-H dibismuth;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Bi+3].[Bi+3].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O.[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O.[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O SULICOHAQXOMED-YDXPQRMKSA-H 0.000 claims description 6
- 241000567229 Isospora Species 0.000 claims description 5
- 229940104825 bismuth aluminate Drugs 0.000 claims description 5
- PDSAKIXGSONUIX-UHFFFAOYSA-N hexaaluminum;dibismuth;oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Bi+3].[Bi+3] PDSAKIXGSONUIX-UHFFFAOYSA-N 0.000 claims description 5
- 229910000014 Bismuth subcarbonate Inorganic materials 0.000 claims description 4
- MGLUJXPJRXTKJM-UHFFFAOYSA-L bismuth subcarbonate Chemical compound O=[Bi]OC(=O)O[Bi]=O MGLUJXPJRXTKJM-UHFFFAOYSA-L 0.000 claims description 4
- 229940036358 bismuth subcarbonate Drugs 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 1
- 206010012735 Diarrhoea Diseases 0.000 description 7
- 230000002550 fecal effect Effects 0.000 description 7
- 150000001621 bismuth Chemical class 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 244000045947 parasite Species 0.000 description 4
- HWSISDHAHRVNMT-UHFFFAOYSA-N Bismuth subnitrate Chemical compound O[NH+]([O-])O[Bi](O[N+]([O-])=O)O[N+]([O-])=O HWSISDHAHRVNMT-UHFFFAOYSA-N 0.000 description 3
- 208000030852 Parasitic disease Diseases 0.000 description 3
- 229960001482 bismuth subnitrate Drugs 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229940101070 pepto-bismol Drugs 0.000 description 3
- 241000224467 Giardia intestinalis Species 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 206010037075 Protozoal infections Diseases 0.000 description 2
- 208000019790 abdominal distention Diseases 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229940085435 giardia lamblia Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 241000224482 Apicomplexa Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241001235574 Balantidium Species 0.000 description 1
- 241000726108 Blastocystis Species 0.000 description 1
- 241000223782 Ciliophora Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- 241000157305 Dientamoeba Species 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- 241000224432 Entamoeba histolytica Species 0.000 description 1
- 241001126836 Enterocytozoon Species 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 241000243190 Microsporidia Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 201000009840 acute diarrhea Diseases 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JAONZGLTYYUPCT-UHFFFAOYSA-K bismuth subgallate Chemical compound OC(=O)C1=CC(O)=C2O[Bi](O)OC2=C1 JAONZGLTYYUPCT-UHFFFAOYSA-K 0.000 description 1
- 229960000199 bismuth subgallate Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 208000019902 chronic diarrheal disease Diseases 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 229940007078 entamoeba histolytica Drugs 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 244000000053 intestinal parasite Species 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000003750 lower gastrointestinal tract Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 208000026775 severe diarrhea Diseases 0.000 description 1
- 210000003046 sporozoite Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
Classifications
-
- 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
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/29—Antimony or bismuth compounds
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- 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
- an object of the present invention is to provide a safe and effective method of preventing and/or treating gastrointestinal disorders caused or mediated by parasitic protozoa.
- a further object of the invention is to provide such a method comprising the administration of bismuth.
- the present invention relates to a method for treatment of a human or lower animal subject having a gastrointestinal disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 56 days.
- the present invention also relates to a method for prevention in a human or lower animal of a gastrointestinal disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 28 days.
- the methods of the present invention comprise the prevention and/or treatment of gastrointestinal disorder caused or mediated by one or more parasitic protozoa. Such gastrointestinal disorders are prevented and/or treated by the administration of bismuth.
- the components of the present invention are more fully defined below.
- gastrointestinal disorder encompasses any infection, disease or other disorder of body, typically of the upper and/or lower gastrointestinal tract, caused or mediated by one or more parasitic protozoa.
- disorders include one or more of the following conditions: diarrhea, abdominal pain and/or cramping, flatulence, nausea, abdominal distention, fever, constipation, blood, mucus and/or pus present in feces, vomiting, gastroenteritis, weight loss, anorexia, malaise, and any other condition commonly associated with infection by parasitic protozoa.
- gastrointestinal disorder also includes any condition commonly associated with protozoa infection in immunocompromised subjects and children, including but not limited to, acute diarrhea, dehydration, electrolyte imbalance, colitis, and fatal necrosis of the intestine.
- Parasitic Protozoa any condition commonly associated with protozoa infection in immunocompromised subjects and children, including but not limited to, acute diarrhea, dehydration, electrolyte imbalance, colitis, and fatal necrosis of the intestine.
- Protozoa are unicellular, eucaryotic organisms which contain a nucleus, or nuclei, and cytoplasm. Four groups of Protozoa contain parasites which are contemplated in the present invention. These organisms are fully described in Zinsser Microbiology. 20th Edition, 1163- 1173, (1992) and T. L. Kuhls, M.D., "Protozoal Infections of the Intestinal Tract in Children", Advances In Pediatric Infectious Diseases, vol. 8, 177- 202, (1993), both of which are incorporated herein by reference.
- parasitic protozoa refers to Protozoa of the phlya Sarcomastigophora such as Entamoeba, Giardia, Dientamoeba, and Blastocystis; Ciliophora such as Balantidium; Apicomplexa such as Isospora and Cryptospo dium; and Microspora such as Enterocytozoon.
- Preferred parasitic protozoa are Entamoeba, Cryptospo ⁇ dium, Giardia, Isospora, and combinations thereof. Most preferred parasitic protozoa are Entamoeba, Cryptospo ⁇ dium, Giardia, and combinations thereof.
- Diagnosis of gastrointestinal disorders caused or mediated by parasitic protozoa may be accomplished by any method commonly used in the medical community. Such methods are fully described in Zinsser Microbiology, and T.L. Kuhls, M.D. "Protozoal Infections of the Intestinal Tract in Children", as referenced above. Bismuth
- the methods of treatment and/or prevention in the present invention involve administration of bismuth.
- the quantity of bismuth is by weight of elemental bismuth.
- bismuth may be administered in an amount of from about 50 milligrams to about 5000 milligrams, and preferably from about 50 milligrams to about 2500 milligrams, per day, for from about 1 to about 56 days, preferably for from about 2 to about 28 days, and most preferably for from about 7 to about 21 days.
- bismuth may be administered in an amount of from about 50 milligrams to about 5000 milligrams, and preferably from about 50 milligrams to about 2500 milligrams, per day, for from about 1 to about 21 days, and preferably for from about 1 to about 14 days.
- bismuth may be administered prior to potential exposure to parasitic protozoa.
- Such administration of bismuth may vary depending on the likelihood of parasitic protozoa exposure and condition of the subject and may be commenced at any time deemed beneficial by the medical community including from about 1 to about 7 days, from about 2 to about 5 days, and from about 3 to about 4 days, prior to potential exposure.
- bismuth may be in the form of a pharmaceutically-acceptable salt or may be in the form of an organic complex which contains bismuth as an active ingredient.
- organic complexes include 2,2'-spirobi[1,3,2-benzodoxabismole].
- bismuth is administered in the present methods as a pharmaceutically- acceptable salt.
- Such bismuth salts include bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof.
- Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof are preferred bismuth salts for use in this invention.
- the bismuth useful herein may be administered alone, or in combination with other pharmaceutically-acceptable components in a bismuth-containing composition.
- a variety of such compositions containing bismuth salts are commercially available.
- compositions include DeNol, containing tripotassium dicitrato bismuthate (by Brocades); Bislumina, containing bismuth aluminate (by Mazuelos); Roter, containing bismuth subnitrate (by Roterpharma); Devrom®, containing bismuth subgallate (by The Parthenon Co., Inc.); and Pepto-Bismol®, containing bismuth subsalicylate (by The Procter & Gamble Company).
- administering refers to any method which, in sound medical practice delivers the compounds or compositions used in this invention to the subject to be treated in such a manner so as to be effective in the treatment of the gastrointestinal disorder.
- the bismuth is administered orally.
- a human subject, suffering from severe diarrhea, is treated by a method of the present invention.
- Fecal samples are taken from the subject and analyzed for the presence of intestinal parasites, including organism eggs, cysts, sporozoites, etc.
- Clinical parasitology specimens reveal the presence of Cryptospo ⁇ dium parvum.
- the subject is then treated by administering a composition containing bismuth subsalicylate, sold by The Procter & Gamble Company under the name "Pepto-Bismol®".
- the composition in liquid form, is administered four times daily in equal doses delivering approximately 2500 milligrams of bismuth per day, for 21 days. Thereafter, fecal samples from the subject are analyzed again, finding no trace of parasitic infection.
- a three-year-old child with diabetes and in a day care center is suffering from chronic diarrhea, and abdominal distention.
- Analysis of fecal specimens shows the presence of Giardia lamblia.
- the infection is diagnosed and treated by orally administering approximately 400 milligrams of bismuth in the form of bismuth subcitrate ("DeNol", sold by Brocades), in four equal doses daily, for about 28 days. Thereafter, fecal samples from the subject are analyzed again, finding no trace of parasitic infection.
- a Peace Corps volunteer preparing to travel to a developing country with sub-standard sanitation and water purification systems has a fecal sample clinically analyzed for the presence of Giardia lamblia, Cryptospo ⁇ dium parvum, and Entamoeba histolytica. Clinical results show no evidence of the parasites.
- the subject is given approximately 1200 milligrams of bismuth, (administered as bismuth subsalicylate in the composition Pepto-Bismol®, sold by The Procter & Gamble Company), in four equal doses daily, for about 21 days.
- the subject Upon return to the U.S., approximately 30 days after the initial clinical analysis, the subject remains asymptomatic. Fecal samples from the subject are analyzed and no evidence of parasitic infection is found.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96915593A EP0830134A1 (en) | 1995-05-09 | 1996-05-08 | Compositions containing bismuth, for the treatment and prevention of gastrointestinal disorders |
JP8534217A JPH11504939A (en) | 1995-05-09 | 1996-05-08 | Bismuth-containing composition for treatment and prevention of gastrointestinal disorders |
AU57335/96A AU5733596A (en) | 1995-05-09 | 1996-05-08 | Compositions containing bismuth, for the treatment and preve ntion of gastrointestinal disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US43785595A | 1995-05-09 | 1995-05-09 | |
US08/437,855 | 1995-05-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996035435A1 true WO1996035435A1 (en) | 1996-11-14 |
Family
ID=23738205
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/006488 WO1996035435A1 (en) | 1995-05-09 | 1996-05-08 | Compositions containing bismuth, for the treatment and prevention of gastrointestinal disorders |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0830134A1 (en) |
JP (1) | JPH11504939A (en) |
AU (1) | AU5733596A (en) |
CA (1) | CA2219771A1 (en) |
WO (1) | WO1996035435A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7300667B1 (en) | 1999-05-27 | 2007-11-27 | Euro-Celtique, S.A. | Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract |
US7364749B1 (en) | 1999-05-27 | 2008-04-29 | Euro-Celtique, S.A. | Preparations for the application of anti-infective and/or anti-inflammatory agents |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE654814A (en) * | 1963-10-26 | 1965-02-15 | ||
EP0103836A2 (en) * | 1982-09-14 | 1984-03-28 | Robert J. Herschler | Dietary and pharmaceutical compositions comprising methylsulfonylmethane |
US4940695A (en) * | 1987-12-10 | 1990-07-10 | The Procter & Gamble Company | Bismuth-containing pharmaceutical compositions |
-
1996
- 1996-05-08 AU AU57335/96A patent/AU5733596A/en not_active Abandoned
- 1996-05-08 JP JP8534217A patent/JPH11504939A/en active Pending
- 1996-05-08 EP EP96915593A patent/EP0830134A1/en not_active Withdrawn
- 1996-05-08 WO PCT/US1996/006488 patent/WO1996035435A1/en not_active Application Discontinuation
- 1996-05-08 CA CA002219771A patent/CA2219771A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE654814A (en) * | 1963-10-26 | 1965-02-15 | ||
EP0103836A2 (en) * | 1982-09-14 | 1984-03-28 | Robert J. Herschler | Dietary and pharmaceutical compositions comprising methylsulfonylmethane |
US4940695A (en) * | 1987-12-10 | 1990-07-10 | The Procter & Gamble Company | Bismuth-containing pharmaceutical compositions |
Non-Patent Citations (3)
Title |
---|
PITLIK S.D. ET AL: "Cryptosporidial cholecystitis", N. ENGL. J. MED., 1983, 308/16 (967), USA, XP000602894 * |
STEFFEN R.: "Worldwide efficacy of bismuth subsalicylate in the treatment of travelers' diarrhea", REV. INFECT. DIS., 1990, 12/SUPPL. 1 (S80-S86), USA, XP000602908 * |
WITTNER M. ET AL: "Parasitic infections in AIDS patients: Cryptosporidiosis, isosporiasis, microsporidiosis, cyclosporiasis", INFECT. DIS. CLIN. NORTH AM., 1993, 7/3 (569-586), USA, XP000603005 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7300667B1 (en) | 1999-05-27 | 2007-11-27 | Euro-Celtique, S.A. | Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract |
US7364749B1 (en) | 1999-05-27 | 2008-04-29 | Euro-Celtique, S.A. | Preparations for the application of anti-infective and/or anti-inflammatory agents |
Also Published As
Publication number | Publication date |
---|---|
JPH11504939A (en) | 1999-05-11 |
EP0830134A1 (en) | 1998-03-25 |
CA2219771A1 (en) | 1996-11-14 |
AU5733596A (en) | 1996-11-29 |
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