AU653619B2 - Medicament against cancer and AIDS - Google Patents
Medicament against cancer and AIDS Download PDFInfo
- Publication number
- AU653619B2 AU653619B2 AU21253/92A AU2125392A AU653619B2 AU 653619 B2 AU653619 B2 AU 653619B2 AU 21253/92 A AU21253/92 A AU 21253/92A AU 2125392 A AU2125392 A AU 2125392A AU 653619 B2 AU653619 B2 AU 653619B2
- Authority
- AU
- Australia
- Prior art keywords
- aids
- nadh
- treatment
- therapy
- nadph
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 14
- 201000011510 cancer Diseases 0.000 title claims abstract description 10
- 208000030507 AIDS Diseases 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title description 4
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims abstract description 30
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 claims abstract description 17
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 claims abstract description 4
- 229950006238 nadide Drugs 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 4
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
- 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
- 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
- 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
- 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
- 240000000171 Crataegus monogyna Species 0.000 claims 1
- 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 210000002837 heart atrium Anatomy 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 description 18
- 206010027457 Metastases to liver Diseases 0.000 description 7
- 206010027476 Metastases Diseases 0.000 description 6
- HWOLQKJPMRZMEX-PJKMHFRUSA-N diazonio-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)-2-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]azanide Chemical compound O=C1NC(=O)C(C)=CN1[C@]1(N=[N+]=[N-])O[C@H](CO)[C@@H](O)C1 HWOLQKJPMRZMEX-PJKMHFRUSA-N 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 5
- 206010027452 Metastases to bone Diseases 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 210000004366 CD4-positive T-lymphocyte Anatomy 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229940090009 myleran Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000004259 scirrhous adenocarcinoma Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- AIDS & HIV (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
Abstract
Use of nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADPH) or of a physiologically tolerated salt thereof for the treatment of cancer or AIDS.
Description
P100/011 2815101 Regulation 3.2(2)
AUSTRALIA
Patents Act 1990 653619
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: MEDICAMENT AGINST CANCER AND AIDS The following statement Is a full description of this lnven:n, Including the best method of performing It known to :-ME Medicament against cancer Ov AIDS.
The invention relates to the novel use of nicotinamide-adenine dinucleotide (NADH), nicotinamide-adenine dinucleotide phosphate (NADPH) or a physiologically compatible salt thereof.
Cancer has numerous different manifestations and the genesis thereof is in many cases not yet completely clarified and, apart from genetic predispositions, as a function of the tumour type certain risk factors would appear to play a part. The therapy of cancer is essentially based on operating, radiotherapy and chemotherapy, which are often used in combination and have different success rates as a function of the tumour type. Each of these therapy forms represents a severe course of action with all the associated risks and side effects.
S* Acquired immune deficiency syndrome or AIDS described as a separate disease for the first time in 1981 is characterized by persistent or recurrent diseases which only occur in the advanced stage thereof and Swhich indicate defects in the cellular immune system and which are caused by certain retroviruses. In Aids during the later phase almost always malignant carcinomas or sarcomas occur, such as e.g. Kaposi's disease.
At present no specific therapy for Aids is known. Treatment is still limited at combating to the maximum extent the life-threatening infections and neoplasms. Use is made of different antiviral substances, such as e.g. AZT (azidodeoxythymidine) or stimulators of the immune system, such as e.g. interferons or interleukins.
There is consequently a great need for a medicament making it possible to control, reduce or inhibit malignant tumours in humans and animals, or clinically manifest Aids.
The problem of the invention is consequently to make available such a therapeutic.
-2- According to the invention this is achieved by the use of nicotinamideadenine dinucleotide (NADH), nicotinamide-adenine dinucleotide phosphate (NADPH) or a physiologically compatible salt thereof, use being made of single doses between 1 and 50 mg and preferably 5 and 12.5mg.
The use of such endogenic substances leads to surprising therapeutic successes, without side effects being detected or expected. It is admittedly known that NADH can be successfully used in the treatment of Parkinson's disease (EP-A 89 730 051.3) or depressions (not previously published P 41 00 361.6). The completely surprising finding that these substances can be used in the above-indicated doses in an extremely successful manner in the treatment of malignant tumours or Aids, has resulted from the clinical findings described in detail hereinafter. It has been able to prove that NADH and NADPH or physiologically compatible salts thereof inhibit metastasis formation or bring about remissions thereof and that these substances improve the cellular immune reactions and therefore lead to a regression of clinical Aids symptoms.
Case Descriptions Case 1: Female, aged 63, August 1989 operation for invasive duct carcinoma. One year later multiple liver and bone metastases detected. Four therapy cycles, according to the CMF diagram, further increase of liver and bone metastases. Pain only reduceable with the strongest analgesics. Since January 1991 NADH, initially three times a week 12.5 mg, intravenously and then after four weeks parenteral therapy change to NADH orally, 5 mg every other day. April 1991 radiological detection of metastasis regression, some foci greatly reduced in size and some completely disappeared. Continuation of oral NADH therapy, check 1991, CT scanning reveals further marked regression of liver metastases and bone metastases virtually undetectable. Patient free from pain and no longer requires analgesics.
-3- Case 2: Male, aged 59, colon carcinoma three years earlier, 1990 sonographic and radiological detection of multiple liver metastases of cherry to plum size. Two chemotherapy cycles, Myleran or Endoxan unsuccessful, liver foci increase in size.
December 1990 start of therapy with NADH, initially 12.5mg intravenously three times a week and after four weeks change of therapy to NADH orally, 5 mg, every other day. March 1991 sonographic detection of reduced liver foci size. June 1991 check by CT scanning and sonography reveals an almost complete disappearance of the metastases in tht liver. Subjectively the Patient feels extremely well.
Case 3: Female, aged 52, three years earlier quadrantectomy due to invasive scirrhous carcinoma, January 1990 vertebral metastases detected, April 1990 liver metastases discovered by ultrasonics. Therapy with Novaldex leads to no regression of the metastases. Also no response to a therapy cycle according to the CMF diagram. November 1990 intravenous administration of NADH 12.5 mg every other day. After four weeks change to NADH orally, 5 mg, every other day. Two months after the start of NADH therapy clear regression of liver metastases, as well as disappearance/reduction of vertebral metastases. Check in June 1991 reveals complete regression of bone metastases. Liver metastases greatly reduced or Sfoci no longer detectable.
Case 4: Male, aged 66, February 1990 parvicellular bronchial carcinoma diagnosed, multiple foci in both pulmonary lobes, cytostatic therapy with methotrexate andEndoxan leads to no remission.
October 1990 administration of NADPH parenterally (10 mg intravenously) every other day. Radiographic check in 1991 reveals the remission of the new plastic foci both as regards number and size. Continuation of NADPH therapy, 10 mg intravenously every other day. Check in May 1991 by CT scanning confirms a further reduction of tumour foci in both pulmonary lobes.
-4- Case 5: Male, aged 42, HIV positive, Western Plot positive, since November 1989 clinically manifest Aids with development of Kaposi's disease. Therapy with AZT: stabilization of sarcoma growth for three months, but then despite continued AZT therapy occurrence o new additional sarcoma foci, which had to be operatively removed. Six weeks later reappearance of tumour tissue in the operation area, but also in alternate points-continuation of AZT therapy. Since December 1990 NADH administration; first phase 12.5 mg intravenously every other day, change after four weeks to NADH orally, 5 mg daily.
After eight weeks clear remission of the regenerated tumours.
Check after four months reveals no new growth in the treatment interval, almost complete regression of the sarcoma residue.
Case 6: Male, aged 28, since the end of 1989 clinical symptoms of Aids, recurrent infections, pneumonia, herpetic and fungal infections. HIV positive, Western Plot positive, since mid- 1990 under AZT therapy, no significant improvement in condition during six months administration. Since February 1991 therapy with NADPH, 10 mg intravenously, every other day, infections stopped, at present no pneumonia or fungal infections, laboratory examinations reveal decrease of T-suppressor cells, increase in the ratio of T4 and T8 cells, cellular immune status much better. HIV and Western Plot still positive.
The features of the invention disclosed in the above description and in the claims, both individually and in random combination, can be essential to the realization of the different embodiments of the invention.
Claims (2)
1. A method of treatment of cancer or AIDS comprising administering to a patient requiring such treatment an effective amount of nicotinamide-adenine dinucleotide (NADH), nicotinamide-adenine dinucleotide phosphate (NADPH) or a physiologically compatible salt thereof.
2. A method as claimed in claim 1 wherein single doses of 1 to 50 mg are administered to said patient. A method as claimed in claim 2 wherein singles doses of 5 to 12.5 mg are administered to said patient. DATED this 8th day of August, 1994 UNIV.-PROF. DDR. JORG BIRKMAYER o WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA DOC 034 AU2125392.WPC. DBM/KJS:KP I II -6- ABSTRACT Use of nicotillamideadenine dinucle0tide (NADH), nifotinamideaden~ine dinucleotide phosphate (NADPH) or a phgsiologically compatible salt thereof for the treatment of cancer or AIDS, r I r r r r s r to cc a rc i D
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4128625A DE4128625A1 (en) | 1991-08-26 | 1991-08-26 | MEDICINE AGAINST CANCER AND AIDS |
| DE4128625 | 1991-08-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2125392A AU2125392A (en) | 1993-03-04 |
| AU653619B2 true AU653619B2 (en) | 1994-10-06 |
Family
ID=6439356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU21253/92A Ceased AU653619B2 (en) | 1991-08-26 | 1992-08-25 | Medicament against cancer and AIDS |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0534097B1 (en) |
| JP (1) | JP3493202B2 (en) |
| AT (1) | ATE150313T1 (en) |
| AU (1) | AU653619B2 (en) |
| BR (1) | BR9203302A (en) |
| CA (1) | CA2072484C (en) |
| DE (2) | DE4128625A1 (en) |
| DK (1) | DK0534097T3 (en) |
| ES (1) | ES2099772T3 (en) |
| GR (1) | GR3023191T3 (en) |
| HU (1) | HUT61895A (en) |
| NO (1) | NO300915B1 (en) |
| ZA (1) | ZA924902B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999012951A1 (en) * | 1997-09-11 | 1999-03-18 | Oxigene, Inc. | Uses of nicotinamide adenine dinucleotide and its analogs for treatment of malignant and infectious diseases |
| US20040126751A1 (en) * | 2002-12-27 | 2004-07-01 | Birkmayer Jorg G.D. | Method of prolonging the life-span of living cells using NADH, NADPH and ADP-ribose |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1162938B (en) * | 1983-08-26 | 1987-04-01 | Dino Spisni | COMPOSITION FOR THE TREATMENT OF MALIGNANT CANCERS, IN PARTICULAR ON ANIMALS |
| EP0331620B1 (en) * | 1988-03-01 | 1993-08-11 | Birkmayer, Walther, Prof. Dr. | Agent for the treatment of parkinson's disease |
-
1991
- 1991-08-26 DE DE4128625A patent/DE4128625A1/en active Granted
-
1992
- 1992-06-26 CA CA002072484A patent/CA2072484C/en not_active Expired - Fee Related
- 1992-07-01 ZA ZA924902A patent/ZA924902B/en unknown
- 1992-08-04 ES ES92113288T patent/ES2099772T3/en not_active Expired - Lifetime
- 1992-08-04 AT AT92113288T patent/ATE150313T1/en not_active IP Right Cessation
- 1992-08-04 EP EP92113288A patent/EP0534097B1/en not_active Expired - Lifetime
- 1992-08-04 DE DE59208223T patent/DE59208223D1/en not_active Expired - Fee Related
- 1992-08-04 DK DK92113288.2T patent/DK0534097T3/en active
- 1992-08-24 BR BR929203302A patent/BR9203302A/en not_active Application Discontinuation
- 1992-08-24 JP JP22394492A patent/JP3493202B2/en not_active Expired - Fee Related
- 1992-08-25 NO NO923324A patent/NO300915B1/en unknown
- 1992-08-25 AU AU21253/92A patent/AU653619B2/en not_active Ceased
- 1992-08-25 HU HU9202739A patent/HUT61895A/en unknown
-
1997
- 1997-04-21 GR GR970400851T patent/GR3023191T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA924902B (en) | 1993-04-28 |
| NO923324L (en) | 1993-03-01 |
| HUT61895A (en) | 1993-03-29 |
| EP0534097A3 (en) | 1993-07-14 |
| ATE150313T1 (en) | 1997-04-15 |
| JPH072678A (en) | 1995-01-06 |
| AU2125392A (en) | 1993-03-04 |
| DE59208223D1 (en) | 1997-04-24 |
| NO300915B1 (en) | 1997-08-18 |
| EP0534097A2 (en) | 1993-03-31 |
| CA2072484C (en) | 2002-02-26 |
| BR9203302A (en) | 1993-03-30 |
| JP3493202B2 (en) | 2004-02-03 |
| NO923324D0 (en) | 1992-08-25 |
| DE4128625A1 (en) | 1993-04-08 |
| GR3023191T3 (en) | 1997-07-30 |
| DE4128625C2 (en) | 1993-08-12 |
| DK0534097T3 (en) | 1997-09-22 |
| EP0534097B1 (en) | 1997-03-19 |
| CA2072484A1 (en) | 1993-02-27 |
| ES2099772T3 (en) | 1997-06-01 |
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