GB2189391A - Use of nucleoside analogue and uptake inhibitor therefor in anti-cancer compositions - Google Patents
Use of nucleoside analogue and uptake inhibitor therefor in anti-cancer compositions Download PDFInfo
- Publication number
- GB2189391A GB2189391A GB08630714A GB8630714A GB2189391A GB 2189391 A GB2189391 A GB 2189391A GB 08630714 A GB08630714 A GB 08630714A GB 8630714 A GB8630714 A GB 8630714A GB 2189391 A GB2189391 A GB 2189391A
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- United Kingdom
- Prior art keywords
- nucleoside analogue
- inhibitor
- administration
- nucleoside
- analogue
- 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.)
- Granted
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- 229940127073 nucleoside analogue Drugs 0.000 title claims abstract description 55
- 239000003112 inhibitor Substances 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 title description 3
- 230000001093 anti-cancer Effects 0.000 title 1
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 24
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims abstract description 22
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960002768 dipyridamole Drugs 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 230000008499 blood brain barrier function Effects 0.000 claims abstract description 11
- 210000001218 blood-brain barrier Anatomy 0.000 claims abstract description 11
- 201000011510 cancer Diseases 0.000 claims abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 5
- 241001465754 Metazoa Species 0.000 claims abstract description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 22
- 230000001954 sterilising effect Effects 0.000 description 10
- 238000004659 sterilization and disinfection Methods 0.000 description 10
- 238000001802 infusion Methods 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 206010000830 Acute leukaemia Diseases 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 4
- 230000000973 chemotherapeutic effect Effects 0.000 description 4
- 238000011221 initial treatment Methods 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 210000002798 bone marrow cell Anatomy 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000003439 radiotherapeutic effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940045688 antineoplastic antimetabolites pyrimidine analogues Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000003442 weekly effect Effects 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
There is disclosed a new use of a nucleoside analogue which is transferable across the blood brain barrier and/or of a nucleoside analogue cell uptake inhibitor which is substantially non-transferable across the blood brain barrier for the manufacture of a therapeutic agent for use in a method of treatment of the human or animal body to combat cancer cells within the central nervous system by the administration to said body of a said nucleoside analogue and a said inhibitor. Especially useful are cytosine arabinoside as nucleoside analogue, and dipyridamole as the uptake inhibitor.
Description
SPECIFICATION
Use of Chemical Compounds
The present invention relates to the treatment of cancerous cells in the central nervous system (CNS) and the use of nucleoside analogues and nucleoside analogue cell uptake inhibitors for the manufacture of therapeutic agents for use in such a treatment.
In cancer therapy, and in particular in the treatment of leukaemia, there is a severe danger of relapse following the initial treatment, e.g. by chemotherapy or surgery, of the affected tissues.
One of the factors likely to cause relapse is the migration of cancerous cells to apparently unaffected areas that may occur before or during the treatment of the tissue diagnosed as affected.
Migration of cancerous cells into the CNS is considered to be one particularly important cause of relapses occurring especially with acute leukaemia.
Therefore following the initial treatment of tissue diagnosed as cancerous, efforts may be made to sterilize the CNS, i.e. to destroy or inactivate cancerous cells therein.
This has been done particularly with acute leukaemia following initial chemotherapeutic treatment and to this end chemotherapeutic and/or radiotherapeutic methods have been used.
In the chemotherapeutic sterilization of the CNS, nucleoside analogues, such as cytosine arabinoside (Ara-C) have often been used. Such compounds are active against cancer tissue, especially leukaemia cells, lymphomas and brain tumours. In the case of
Ara-C, while its mode of action is not yet fully understood, it is effective against cells in the Sphase and thoughtto betaken up bythe cells and incorporated into nucleic acid metabolism thereby preventing cell replication. However, while the nucleoside analogues are particularly effective against certain cancer cells, bone marrow cells may also be inhibited and destroyed and it is bone marrow suppression that is the main dose-limiting toxicity of intravenously or subcutaneously administered Ara-C.
Ara-C is not taken up effectively on oral administration and so in CNS sterilization the administration route will be either systemic (i.v. or s.c.) or intrathecal (i.t.).
Intrathecal administration can lead to relatively
poor distribution of the nucleoside analogue in the
CNS and can be painful and distressing, especially to young patients. However, since Ara-C is relatively
poorly transported into the CNS, high systemic
doses have been required to ensure that cytotoxic
concentrations are achieved in the CNS and such
doses are limited of course by the bone marrow toxicity of systemic Ara-C.
Thus it is an object of the present invention to
provide a form of therapy by which effective CNS
sterilization can be achieved using systemic doses
of a nucleoside analogue without causing undue
damage to bone marrow tissue.
The present invention is based on the concept of a
combined therapy wherein as well as the cytotoxic
nucleoside analogue there is administered to the
patient an agent which inhibits cell uptake of nucleoside analogues.
According to one aspect of the present invention we therefore provide the use of a nucleoside analogue which is transferable across the blood brain barrier and/or of a nucleoside analogue cell uptake inhibitor which is substantially nontransferable across the blood brain barrier for the manufacture of a therapeutic agent for use in a method of treatment of the human or animal body to combat cancer cells within the central nervous system by the administration to said body of a said nucleoside analogue and a said inhibitor.
According to a further aspect of the present invention we provide a method of treatment of the human or animal body to combat cancer cells within the central nervous system by the administration to said body of a cytotoxic or cytostatic amount of a nucleoside analogue which is transferable across the blood brain barrier and of a cell uptake inhibiting amount of a nucleoside analogue cell uptake inhibitor which is substantially non-transferable across the blood brain barrier, said inhibitor, and preferably also said nuceloside analogue, not being administered directly into the central nervous system of said body.
In accordance with the invention, the nucleoside analogue is preferably administered intravenously or subcutaneously although the invention should be understood to encompass administration by oral and rectal or by other parenteral administration modes whereby an effective concentration of the nucleoside analogue in the CNS, and in the cerebrospinal fluid (CSF) in particular, may be achieved. Where the nucleoside analogue is Ara-C, however, administration will generally be subcutaneous or, preferably, intravenous.
For the inhibitor, the administration mode should be such as to provide a concentration in the blood or at the bone marrow which is effective to prevent undue damage of bone marrow cells by the nucleoside analogue. Depending on the nature of the inhibitor, oral, rectal, intravenous or subcutaneous administration may be contemplated, however oral and/or intravenous administration will generally be preferred.
The nucleoside analogue used according to the present invention is preferably a pyrimidine or
purine analogue, such as those listed in Goodman and Gilman "The Pharmacological Basis of
Therapeutics", 6th Edition, Chapter 55, pages 127S1287, however pyrimidine analogues and
particularly Ara-C, a pyrimidine analogue, are
especially preferred.
The inhibitor of cell uptake of the nucleoside
analogue may be any physiologically tolerable
substance having this effect. A particularly preferred
compound is dipyridamole (which is available from
Boehringer Ingelheim Ltd. of Bracknell under the
registered Trade Mark Persantin).
Dipyridamole acts to inhibit cell uptake of
nucleosides and nucleoside analogues, and of Ara-C
in particular, apparently by hindering the transfer of
the nucleoside or nucleoside analogue through the
cell walls, the hindering effect being greater for
ingress than egress.
In various in vitro studies (see for example King et a/. "Modulation of cytarabine uptake and toxicity by dipyridamole" Cancer Treatment Reports, Vol. 68
No. 2, February 1984, pages 361-366) it has been shown that co-administration of dipyridamole and
Ara-C serves to protect bone marrow cells from the cytotoxic effects of Ara-C. In such studies however it has also been shown that dipyridamole also protects cancerous, e.g. leukaemia, cells from Ara-C.
However dipyridamole, unlike Ara-C and the other suitable nucleoside analogues, does not cross the blood-brain barrier and thus co-administration of dipyridamole and Ara-C on one side of the bloodbrain barrier will suppress the cytotoxic effects of
Ara-C on that side of the barrier while allowing Ara Cto inhibit replication of cancerous cells on the other side of the barrier.
A further beneficial result flows from this coadministration ofthe nucleoside analogue and the nucleoside analogue cell uptake inhibitor in that, with its uptake on the blood side of the barrier suppressed, the rate of decrease of the nucleoside analogue's concentration in the blood is lowered and thus to transfer the same quantity through the blood-brain barrier into the CNS may require a smaller initial dose of the nucleoside analogue when administered with the inhibitor than when no inhibitor is administered.
In the combined CNS sterilization therapy of the present invention, the precise dosage of nucleoside analogue will of course depend i.a. upon the precise nucleoside analogue used, the administration route, the patient's size and the severity of the condition undertreatment. Nevertheless, where Ara-C is used the dosages will generally be about 4.3--12.9 mg/ m2/day (eg. as 10--30 mg/m2 (approximately 0.3--0.9 mg/kg bodyweight) given three times weekly) if administered intrathecally and 1-6 g/m2/ day (eg. as 0.5 to 3 g/m2 each 12 hours) if administered intravenously.The nucleoside analogue administration will generally be for period of up to 7, preferably 3 to 5 days; however, in many cases treatment may conveniently be terminated when sampling of the cerebro-spinal fluid (CSF) shows cancerous cells no longer two be present.
The CNS sterilization may form only one part of a cancer treatment, e.g. to prevent relapse in the treatment of acute leukaemia, and in that case the
CNS sterilization will generally be effected following the chemotherapeutic or radiotherapeutic treatment of the primary cancer site(s). In the case of the chemotherapy of acute leukaemia, CNS sterilization according to the invention will generally be effected about 12 weeks after chemotherapy of the primary site has started.
The dosage of the inhibitor of nucleoside analogue cell uptake will again be dependent on various factors such as the precise nature of the inhibitor and the nucleoside analogue, the administration route, the patient's weight, and the condition and sensitivity of the patient's bone marrow. Generally, the half life of the inhihitor in the blood and the uptake from oral administration of the inhibitor and of the nucleoside analogue will differ, often extremely as is the case with dipyridamole and Ara-C, and thus it may be convenient to select a different administration mode for the two active agents in the combined therapy of the invention.
Where the inhibitor is dipyridamole, the initial administration may conveniently be by oral administration followed if desired by an occasional oral or occasional or continuous intravenous "topping up" during the period during which the nucleoside analogue is continuously administered.
In general, for dipyridamole, the dosage should be chosen to maintain a blood level of about 2 llg/ml, preferably 3--4 IlM/i, especially about 3.5 pM/I during the period during which the nucleoside analogue is present in the blood at active or high levels. For this purpose it may be sufficient to administer 100 to 200 mg/kg dipyridamole p.o.
initially, followed by iv administrations of 10 mg/2 ml dipyridamole bolus each 6 hours for 6 doses.
Alternatively, dipyridamole may for example be administered intravenously with an initial bolus e.g.
of 20--100 mg followed by an infusion e.g. of 30 to 150 mg, the nucleoside analogue being administered during the infusion stage.
The nucleoside analogue and the inhibitor may each be formulated for administration according ho the present invention with a pharmaceutical carrier or excipient. In this respect substances and additives conventionally used in galenic formulations may be used. Injection solutions containing one or both of the active ingredient(s), conveniently dissolved in water for injections, are particularly preferred.
The following Examples are provided to illustrate the invention in a non-limiting fashion:
Example I
Patient Details:
Bodyweight: 70 kg
Condition: Acute lymphoblastic leukaemia.
Treatment Details: (A) Primary Treatment
300 mg/day of Ara-C administered intravenously, as 300 mg over 30 minutes, for 5 days.
(B) CNS Sterilization
Commence 12 weeks after start of the primary treatment.
Nucleoside analogue: Ara-C-administer intravenously 3--8 g over 24 hours each days for 5 days.
Inhibitor: dipyridamole-administer orally 100--200 mg 1-2 hours before initial nucleoside analogue dose. Thereafter administer 100 mg orally each 8 hours starting immediately after the initial nucleoside analogue dose and terminating after the final administration of the nucleoside analogue, or 10 mg/2 ml dipyridamole as an i.v. bolus each 6 hours for 6 days.
Formulation Details: Arn-C0 mg in 2 ml or 100 mg inS ml of water for injections (optionally containing 0.9% w/v
benzyl alcohol).
Dipyridamole-tablets containing 25 and 100 mg
dipyridamole for oral administration, and
solutions containing 10 mg in 2 ml water for
injections for intravenous administration.
Example II
Patient Details:
Female suffering relapse from acute lymphocytic leukaemia.
Treatment Details:
CNS Sterilization
(i) Nucleoside analogue: Ara-C-administer intravenously 0.5g/m2 over 1 hour.
(ii) Inhibitor: dipyridamol-initial i.v. bolus of 20
mg with a subsequent i.v. infusion of 30 mg over
one hour.
Intravenous administration of nucleoside analogue and inhibitor are effected over the same one hour period.
Example Ill
Patient Details:
Male suffering from leukaemia.
Treatment Details (in Addition to Routine Leukaemia
Therapy):
CNS Sterilization
(i) Inhibitor: dipyridamoleinitial i.v. bolus of 40
mg with a subsequent i.v. infusion of 30 mg
over 30 minutes.
(ii) Nucleoside analogue: Ara-C-initial i.v. bolus
of 330 mg/m2 with subsequent i.v. infusion of
666 mg/m2 over 30 minutes. The nucleoside
analogue is administered during the i.v.
infusion of inhibitor.
Claims (7)
1. Use of a nucleoside analogue which is transferable across the blood brain barrier and/or of a nucleoside analogue cell uptake inhibitor which is substantially non-transferable across the blood brain barrier for the manufacture of a therapeutic agent for use in a method of treatment of the human or animal body to combat cancer cells within the central nervous system by the administration to said body of a said nucleoside analogue and a said inhibitor.
2. Use as claimed in claim 1 for the manufacture of a therapeutic agent comprising said nucleoside analogue in an intrathecally, intravenously or subcutaneously administrable form.
3. Use as claimed in either one of claims 1 and 2 wherein said nucleoside analogue is a pyrimidine or purine analogue.
4. Use as claimed in any one of claims 1 to 4 wherein said nucleoside analogue is cytosine arabinoside.
5. Use as claimed in claim 1 for the manufacture of a therapeutic agent comprising said inhibitor in an orally, intravenously, rectally or subcutaneously administrable form.
6. Use as claimed in any one of claims 1 to 5 wherein said inhibitor is dipyridamole.
7. Use as claimed in claim 1 substantially as herein defined with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB868609290A GB8609290D0 (en) | 1986-04-16 | 1986-04-16 | Chemical compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8630714D0 GB8630714D0 (en) | 1987-02-04 |
| GB2189391A true GB2189391A (en) | 1987-10-28 |
| GB2189391B GB2189391B (en) | 1989-11-29 |
Family
ID=10596296
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB868609290A Pending GB8609290D0 (en) | 1986-04-16 | 1986-04-16 | Chemical compounds |
| GB8630714A Expired GB2189391B (en) | 1986-04-16 | 1986-12-23 | Use of chemical compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB868609290A Pending GB8609290D0 (en) | 1986-04-16 | 1986-04-16 | Chemical compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB8609290D0 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0457671A3 (en) * | 1990-05-14 | 1992-04-08 | Fidia S.P.A. | Dipyridamide for the treatment of diseases of the central or peripheral nervous system |
| WO2011085473A1 (en) * | 2010-01-13 | 2011-07-21 | Linda Penn | Treating cancer with statins and compounds having dipyridamole activity |
-
1986
- 1986-04-16 GB GB868609290A patent/GB8609290D0/en active Pending
- 1986-12-23 GB GB8630714A patent/GB2189391B/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0457671A3 (en) * | 1990-05-14 | 1992-04-08 | Fidia S.P.A. | Dipyridamide for the treatment of diseases of the central or peripheral nervous system |
| WO2011085473A1 (en) * | 2010-01-13 | 2011-07-21 | Linda Penn | Treating cancer with statins and compounds having dipyridamole activity |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8630714D0 (en) | 1987-02-04 |
| GB8609290D0 (en) | 1986-05-21 |
| GB2189391B (en) | 1989-11-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19991223 |