NZ520283A - Use of enoxaparin, a low molecular weight heparin, for the preparation of medicaments containing between 5 and 280 mg for the treatment of cerebral ischaemia - Google Patents
Use of enoxaparin, a low molecular weight heparin, for the preparation of medicaments containing between 5 and 280 mg for the treatment of cerebral ischaemiaInfo
- Publication number
- NZ520283A NZ520283A NZ520283A NZ52028301A NZ520283A NZ 520283 A NZ520283 A NZ 520283A NZ 520283 A NZ520283 A NZ 520283A NZ 52028301 A NZ52028301 A NZ 52028301A NZ 520283 A NZ520283 A NZ 520283A
- Authority
- NZ
- New Zealand
- Prior art keywords
- enoxaparin
- treatment
- preparation
- molecular weight
- medicaments containing
- Prior art date
Links
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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The use of enoxaparin (Lovenox(r), Clexane(r)), a low-molecular weight heparin, for treating cerebral ischemia is described, wherein the enoxaparin makes it possible to reduce cerebral ischemic sequelae.
Description
<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 520283 <br><br>
5202 83 <br><br>
WO 01/49298 <br><br>
PCT/FR01/00014 <br><br>
1 <br><br>
NOVEL THERAPEUTIC APPLICATION OF ENOXAPARIN <br><br>
The present invention relates to a novel therapeutic application of enoxaparin. <br><br>
Enoxaparin (Lovenox®, Clexane®) is a low- <br><br>
5 molecular-weight heparin which is marketed for the prophylactic treatment of venous thromboembolic disease in moderate- or high-risk surgery, the prevention of coagulation in the extracorporeal circulation system during hemodialysis, the treatment of constituted deep 10 venous thromboses and in combination with aspirin for the treatment of unstable angina and of acute non-Q wave myocardial infarction. Enoxaparin is also useful in the prevention and/or the treatment of trauma of the central nervous system (WO 98/53833) and of cerebral 15 edemas (WO 98/53834). <br><br>
tested in the prevention and/or treatment of deep venous thromboses in patients with cerebral ischemia but no effect on the ischemia has been shown (A. ELIAS 20 et al. , La Revue de Medecine Interne, 1, vol. XI, 95-98 (1990); MH. PRINS et al., Haemostasis, 19, 245-250 (1989); AGG. TURPIE et al., The Lancet, 523-526 (1987) ) . <br><br>
25 it possible to reduce cerebral ischemic sequelae and can thus be used for the treatment of cer0^"1 <br><br>
* <br><br>
Low molecular weight heparins have been <br><br>
It has now been found that enoxaparin makes ischemias. <br><br>
1 9 JUL 2002 <br><br>
2 <br><br>
This novel therapeutic use was determined in rats according to the following protocol: <br><br>
Male Sprague Dawley rats (230-250 g Iffa Credo) are fed and watered ad libitum and kept in a 5 light-dark cycle of 12 hours. Surgery was carried out under halothane (1.4% in a mixture of 70% N20/30% 02). During anesthesia, normothermia is maintained by placing the rat under a thermostated cover. The left common carotid artery is isolated and a loose ligature 10 is put in place. The left middle cerebral artery is exposed via a subtemporal craniotomy and a microclamp is placed in the proximal region of the artery, immediately followed by the ligation of the carotid artery. Two hours later, the animals are reanesthetized 15 and the cerebral circulation is reestablished by removing the clamp from the middle cerebral artery and the ligature from the carotid artery. The rats are then placed in their cage in a thermostated room at 26-28°C. <br><br>
48 hours after the surgery, a neurological 20 examination is carried out for each rat by an examiner unaware of the treatment. The neurological scale used is described in Table 1. <br><br>
3 <br><br>
TABLE 1 <br><br>
Item <br><br>
Normal <br><br>
Deficit <br><br>
Gripping reflex right foreleg <br><br>
1 <br><br>
0 <br><br>
Placing reaction <br><br>
Loss of right foreleg <br><br>
1 <br><br>
0 <br><br>
support right hindleg <br><br>
1 <br><br>
0 <br><br>
Righting reflex <br><br>
Rotation right side <br><br>
1 <br><br>
0 <br><br>
left side <br><br>
1 <br><br>
0 <br><br>
Abnormal postures <br><br>
Absent <br><br>
Present <br><br>
Flexing of right foreleg <br><br>
1 <br><br>
0 <br><br>
Twisting of the body <br><br>
1 <br><br>
0 <br><br>
Overall neurological score <br><br>
7 <br><br>
0 <br><br>
After the neurological examination, the rats are humanely killed and their brains removed. 1.5 mm thick serial sections are prepared and stained with 5 2, 3, 5-triphenyltetrazolium chloride (TTC) at 2%. After 24 hours of post-fixing in a 10% formaldehyde solution, the lesion areas (cerebral infarct) are measured at the cortical and striatal levels; the volumes are calculated by integrating the lesioned surface areas . 10 The values are expressed in mm3 (mean ± S.E.M) . <br><br>
Statistical analysis was carried out by a Mann-Whitney test or by a Kruskal-Wallis test for non-parametric variance analysis followed by a Dunn test for comparison between groups (*:p<0.05, **:p<0.01, 15 ***:p<0.001 vs control group). <br><br>
In Study 1, enoxaparin is administered to 12 rats at 1.5 mg/kg iv, 2 hours and 24 hours after the <br><br>
4 <br><br>
onset of the ischemia. A control group of 10 rats receives only the vehicle (physiological solution of sodium chloride at 0.9%) following the same protocol. <br><br>
In Study 2, the therapeutic window of 5 opportunity for enoxaparin is explored. The treatment starts 5 hours after the ischemia followed by a second administration at 24 hours. This study consists in an enoxaparin dose-effect on the cerebral lesions. The doses studied are 0.5:1 and 1.5 mg/kg iv (9-10 rats per 10 group). A control group of 11 rats receives only the vehicle (physiological solution of sodium chloride at 0.9%). <br><br>
In Study 3, enoxaparin is administered to 10 rats at 1.5 mg/kg iv, 5 and 24 hours after the onset of 15 the ischemia. The control group of 13 rats receives only the vehicle (physiological solution of sodium chloride at 0.9%). <br><br>
In Study 4, the protocol is the same as in the other studies but the left middle cerebral artery 20 is permanently cauterized and no occlusion of the left carotid artery is performed. Enoxaparin is administered to 13 rats at 1.5 mg/kg iv, 5 and 24 hours after the onset of the ischemia. A control group of 13 rats receives only the vehicle (physiological solution of 25 sodium chloride at 0.9%) . <br><br>
The results obtained are stated in Table 2. <br><br>
5 <br><br>
TABLE 2 <br><br>
STUDIES <br><br>
CORTICAL LESION (mm3) <br><br>
NEUROLOGICAL <br><br>
SCORE 7-point scale <br><br>
Study 1 <br><br>
control group enoxaparin group 2 x 1.5 mg/kg iv <br><br>
186 ± 18 131 ± 13* <br><br>
1.7 ± 0.3 3.1 ± 0.2** <br><br>
Study 2 <br><br>
control group enoxaparin group 2x0.5 mg/kg iv 2x1 mg/kg iv 2x1.5 mg/kg iv <br><br>
203 ± 12 <br><br>
164 ± 15 142 ± 2 4* 129 + 17* <br><br>
Study 3 <br><br>
control group enoxaparin group 2 x 1.5 mg/kg iv <br><br>
195 ± 12 129 + 16** <br><br>
1.8 ± 0.3 3.4 ± 0.3*** <br><br>
Study 4 <br><br>
control group enoxaparin group 2 x 1.5 mg/kg iv <br><br>
137 + 23 71 ± 13* <br><br>
1.7 ± 0.2 2.9 ± 0.3** <br><br>
These results demonstrate that in Study 1, enoxaparin significantly improves the neurological score 48 hours after the cerebral ischemia 5 and, furthermore, significantly reduces the cortical lesion by 30%, <br><br>
- in Study 2, enoxaparin reduces the cortical lesion by 30% (2x1 mg/kg) and 36% (2 x 1.5 mg/kg), <br><br>
- in Study 3, enoxaparin significantly improves the 10 neurological score and reduces the cortical lesion by 34%, <br><br>
in Study 4, enoxaparin significantly improves the neurological score and reduces the cortical lesion by 49%. <br><br>
6 <br><br>
No problem of bleeding was encountered during these studies. <br><br>
The medicaments consist of enoxaparin in the form of a composition in which it is combined with any 5 other pharmaceutically compatible product which may be inert or physiologically active. The medicaments according to the invention may be preferably used by the intravenous or subcutaneous route. <br><br>
Sterile compositions for intravenous or 10 subcutaneous administration are generally aqueous solutions. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. The sterilization can be carried out in several ways, for 15 example by aseptisizing filtration, by incorporating sterilizing agents into the composition, by irradiation. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other 20 injectable sterile medium. <br><br>
As an example of a composition, 20 mg of enoxaparin are dissolved in distilled water in a sufficient quantity to prepare 0.2 ml of solution. <br><br>
The doses depend on the desired effect, the 25 duration of the treatment and the route of administration used; they are generally between 0.2 mg and 4 mg/kg per day by the subcutaneous route, that is <br><br></p>
</div>
Claims (3)
1. Use of enoxaparin for the preparation, of a medicament for the treatment of cerebral ischemia.<br><br>
2. ' Use according to claim 1, for the preparation of medicaments containing 5 to 280 mg of enoxaparin.<br><br>
3. Use according to claim 1 or claim. 2 and substantially as hereinbefore described or exemplified.<br><br> END OF CLAIMS<br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z.<br><br> 21 JUL 2004<br><br> received<br><br> </p> </div>
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0000137A FR2803522B1 (en) | 2000-01-06 | 2000-01-06 | NEW THERAPEUTIC APPLICATION OF ENOXAPARIN |
PCT/FR2001/000014 WO2001049298A2 (en) | 2000-01-06 | 2001-01-03 | Novel therapeutic use of enoxaparin |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ520283A true NZ520283A (en) | 2004-09-24 |
Family
ID=8845669
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ520283A NZ520283A (en) | 2000-01-06 | 2001-01-03 | Use of enoxaparin, a low molecular weight heparin, for the preparation of medicaments containing between 5 and 280 mg for the treatment of cerebral ischaemia |
Country Status (30)
Country | Link |
---|---|
EP (1) | EP1248638B1 (en) |
JP (1) | JP2003519185A (en) |
KR (1) | KR20020069240A (en) |
CN (1) | CN1400905A (en) |
AR (1) | AR026804A1 (en) |
AT (1) | ATE344671T1 (en) |
AU (1) | AU784656B2 (en) |
BR (1) | BR0107442A (en) |
CA (1) | CA2396178A1 (en) |
CZ (1) | CZ20022303A3 (en) |
DE (1) | DE60124373T2 (en) |
DK (1) | DK1248638T3 (en) |
EA (1) | EA006035B1 (en) |
EE (1) | EE200200374A (en) |
ES (1) | ES2275648T3 (en) |
FR (1) | FR2803522B1 (en) |
HK (1) | HK1052649A1 (en) |
HR (1) | HRP20020573A2 (en) |
HU (1) | HUP0204040A3 (en) |
IL (1) | IL150477A0 (en) |
MX (1) | MXPA02006672A (en) |
NO (1) | NO20023243D0 (en) |
NZ (1) | NZ520283A (en) |
PL (1) | PL357192A1 (en) |
PT (1) | PT1248638E (en) |
SK (1) | SK9612002A3 (en) |
UA (1) | UA75587C2 (en) |
WO (1) | WO2001049298A2 (en) |
YU (1) | YU51802A (en) |
ZA (1) | ZA200205415B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR063530A1 (en) * | 2006-10-30 | 2009-01-28 | Aventis Pharma Sa | PROCEDURE FOR THE USE OF SODIUM ENOXAPARINE FOR THE PREPARATION OF A MEDICINAL PRODUCT |
ITMI20091445A1 (en) * | 2009-08-07 | 2011-02-08 | Inalco S P A A Socio Unico | SEMI-SYNTHETIC DERIVATIVES OF K5 POLISACCARIDE FOR THE PREVENTION AND TREATMENT OF TISSUE DAMAGE ASSOCIATED WITH ISCHEMIA AND / OR REPERFUSION |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994008595A1 (en) * | 1992-10-13 | 1994-04-28 | Virginia Commonwealth University | Use of non-anticoagulant heparin for treating ischemia/reperfusion injury |
US5767269A (en) * | 1996-10-01 | 1998-06-16 | Hamilton Civic Hospitals Research Development Inc. | Processes for the preparation of low-affinity, low molecular weight heparins useful as antithrombotics |
-
2000
- 2000-01-06 FR FR0000137A patent/FR2803522B1/en not_active Expired - Fee Related
-
2001
- 2001-01-03 EE EEP200200374A patent/EE200200374A/en unknown
- 2001-01-03 DK DK01903859T patent/DK1248638T3/en active
- 2001-01-03 IL IL15047701A patent/IL150477A0/en unknown
- 2001-01-03 EA EA200200750A patent/EA006035B1/en not_active IP Right Cessation
- 2001-01-03 SK SK961-2002A patent/SK9612002A3/en not_active Application Discontinuation
- 2001-01-03 KR KR1020027008754A patent/KR20020069240A/en not_active Application Discontinuation
- 2001-01-03 CZ CZ20022303A patent/CZ20022303A3/en unknown
- 2001-01-03 YU YU51802A patent/YU51802A/en unknown
- 2001-01-03 HU HU0204040A patent/HUP0204040A3/en unknown
- 2001-01-03 NZ NZ520283A patent/NZ520283A/en unknown
- 2001-01-03 AT AT01903859T patent/ATE344671T1/en not_active IP Right Cessation
- 2001-01-03 DE DE60124373T patent/DE60124373T2/en not_active Expired - Fee Related
- 2001-01-03 PL PL01357192A patent/PL357192A1/en unknown
- 2001-01-03 WO PCT/FR2001/000014 patent/WO2001049298A2/en not_active Application Discontinuation
- 2001-01-03 MX MXPA02006672A patent/MXPA02006672A/en active IP Right Grant
- 2001-01-03 CN CN01803471A patent/CN1400905A/en active Pending
- 2001-01-03 BR BR0107442-3A patent/BR0107442A/en not_active IP Right Cessation
- 2001-01-03 JP JP2001549666A patent/JP2003519185A/en active Pending
- 2001-01-03 PT PT01903859T patent/PT1248638E/en unknown
- 2001-01-03 ES ES01903859T patent/ES2275648T3/en not_active Expired - Lifetime
- 2001-01-03 AU AU31830/01A patent/AU784656B2/en not_active Ceased
- 2001-01-03 CA CA002396178A patent/CA2396178A1/en not_active Abandoned
- 2001-01-03 EP EP01903859A patent/EP1248638B1/en not_active Expired - Lifetime
- 2001-01-05 AR ARP010100054A patent/AR026804A1/en unknown
- 2001-03-01 UA UA2002076399A patent/UA75587C2/en unknown
-
2002
- 2002-07-04 HR HR20020573A patent/HRP20020573A2/en not_active Application Discontinuation
- 2002-07-04 NO NO20023243A patent/NO20023243D0/en not_active Application Discontinuation
- 2002-07-05 ZA ZA200205415A patent/ZA200205415B/en unknown
-
2003
- 2003-07-09 HK HK03104944.6A patent/HK1052649A1/en unknown
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