WO2007013841A1 - Use of 4-((tert-butylimine)methyl) benzene-1,3-disulfonate n-oxide against cerebral oedema - Google Patents
Use of 4-((tert-butylimine)methyl) benzene-1,3-disulfonate n-oxide against cerebral oedema Download PDFInfo
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- WO2007013841A1 WO2007013841A1 PCT/SE2006/000896 SE2006000896W WO2007013841A1 WO 2007013841 A1 WO2007013841 A1 WO 2007013841A1 SE 2006000896 W SE2006000896 W SE 2006000896W WO 2007013841 A1 WO2007013841 A1 WO 2007013841A1
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- oedema
- benzene
- cerebral oedema
- methyl
- compound
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- WAYUHDOQZFBKNV-YWEYNIOJSA-N O/N=C\c(ccc(S(O)(=O)=O)c1)c1S(O)(=O)=O Chemical compound O/N=C\c(ccc(S(O)(=O)=O)c1)c1S(O)(=O)=O WAYUHDOQZFBKNV-YWEYNIOJSA-N 0.000 description 1
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Definitions
- the present invention relates to a novel method for the treatment or prophylaxis of cerebral oedema.
- the invention relates to the use of disodium A- ⁇ (tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide [ ⁇ -(2,4-disulfophenyl)-N- tert- butylnitrone disodium salt] for the treatment or prophylaxis of cerebral oedema.
- U.S. patent 5,488,145 discloses the compound ⁇ -(2,4-disulfophenyl)-N-tert-butyhiitrone and pharmaceutically acceptable salts thereof.
- U.S. patent 5,475,032 discloses the use of such compounds in the treatment of stroke and of progressive central nervous system function loss conditions.
- U.S. patent 5,508,305 discloses the use of such compounds for ameliorating the side effects caused by oxidative damage resulting from antineoplastic disease treatment. Similar disclosures are also made in WO 95/17876.
- U.S. patent 5,780,510 discloses the use of these same compounds in the treatment of concussion.
- Cerebral oedema is also known as brain oedema.
- a method of treating cerebral oedema which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
- Salts of compounds of formula (I) may be formed by reacting the free acid or another salt thereof, with two or more equivalents of an appropriate base, using methods that are well known in the art.
- the salts of compounds of formulae (I) will normally be those formed with pharmaceutically acceptable cations.
- the cation may be a monovalent material such as sodium, potassium, lithium, ammonium, alkylammonium or diethanolammonium.
- it may be a polyvalent cation such as calcium, magnesium, aluminium or zinc. It may also be a mixed salt formed with a polyvalent cation such as calcium or magnesium in combination with a pharmaceutically acceptable anion such as halide (for example chloride), phosphate, sulphate, acetate, citrate or tartrate.
- a pharmaceutically acceptable anion such as halide (for example chloride), phosphate, sulphate, acetate, citrate or tartrate.
- the compound of formula (I) is the disodium salt of formula (II).
- the invention provides a method of treating cerebral oedema which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- the invention provides a method of treating cerebral oedema associated with stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of cerebral oedema.
- the invention provides a compound of formula (II) for use in the treatment or prophylaxis of cerebral oedema.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema.
- the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema.
- the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema associated with stroke.
- therapy also includes prophylaxis unless there are specific indications to the contrary.
- Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
- Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
- Processes for the manufacture of compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed in WO 01/51460 and WO 01/51461.
- oedema Swelling of the brain (oedema) occurs as a consequence of a variety of insults including trauma, anoxia, ischemia, space (mass) occupying lesions, for example, tumours, intracerebral haemorrhage and radiation damage.
- the brain is especially vulnerable to the effects of swelling because of its rigid encasement by the skull. Excessive oedema can therefore result in secondary compression of small blood vessels resulting in new or further ischemia. In severe cases, oedema can progress to produce massive swelling and eventually death.
- Stroke is caused by an interruption of blood flow to a portion of the brain. This is most often due to a blockage within an artery causing an ischemic stroke. Such strokes account for about 88% of all strokes.
- the most common cause of an ischemic stroke is intrinsic narrowing of an artery to the brain due to a combination of atherosclerosis (accumulation of fatty materials plus secondary inflammation) culminating in the formation of a blood clot in the narrowed area.
- the obstruction is due to a blood clot (embolus) originating elsewhere, especially the heart or a major blood vessel supplying the brain, that dislodges and travels to the brain to block a smaller artery within the brain itself.
- About 12% of all strokes are caused by rupture of a blood vessel within the brain, called an intracerebral haemorrhage, or over the surface of the brain, called a subarachnoid haemorrhage.
- Disodium 4-[(tert-butylimino)methyl]benzene-l,3-disulfonic acid N-oxide (II) has beneficial effects on the development of cerebral oedema following acute ischaemic stroke or haemorrhagic stroke.
- the invention provides a method of treating cerebral oedema associated with acute ischaemic stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- the invention provides a method of treating cerebral oedema associated with haemorrhagic stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema associated with acute ischaemic stroke.
- the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema associated with haemorrhagic stroke.
- the compounds of formula (I) and pharmaceutically acceptable salts thereof will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound or salt thereof (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
- a pharmaceutically acceptable adjuvant diluent or carrier.
- Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
- compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat. Suitable methods will be readily apparent to the man skilled in the art.
- Parenteral administration particularly intravenous administration, is preferred.
- the administration may involve the use of a bolus dose or doses and /or infusion.
- the dosage administered will, of course, vary with the mode of administration, the treatment desired and the severity of the condition or disorder to be treated. Such parameters will normally be decided by the attending physician.
- the pharmaceutical composition may also contain, or be co-administered (simultaneously or sequentially) with, one or more other pharmacological agents of value in conjunction with cerebral oedema.
- a total of 1705 patients treated within 6 h of suffering an acute ischaemic stroke were randomised to receive either an intravenous bolus dose of disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acidN-oxide over 1 h and then a continued infusion over the next 71 h, or matching placebo, in addition to standard care.
- Patients who were also receiving thrombolysis with rt-PA (Alteplase) were eligible for inclusion in the study.
- Disodium 4-[(tert-butylimino)methyl]benzene-l,3-disulfonate acidN-oxide concentrate solution for infusion 400 mg/ml; 20 ml vial (WO 01/89507) was diluted in 500 ml of physiologic (9 mg/ml) saline to a final concentration of approximately 15 mg/ml.
- a loading dose of 151 ml (2270 mg) of the diluted solution was administered over the first hour and was followed by a maintenance dose adjusted for the patient's creatinine clearance (Clcrea - a measure of kidney function). The maintenance infusion was continued for another 71 hours.
- the maintenance doses adjusted for creatinine clearance were as follows:
- Cerebral oedema developed as a serious adverse event in 9 (1%) of the 858 patients who received disodium 4-[(?ert-butylimino)methyl]benzene-l,3-disulfonate acid N-oxide. In comparison, cerebral oedema developed as a serious adverse event in 25 (3%) of 847 patients who received placebo.
- disodium 4-[(fer?-butylimino)metl ⁇ yl]benzene-l,3- disulfonate acid N-oxide 240 also received rt-PA.
- CT/MR scans were at the discretion of the attending physician.
- Patients treated within 6 h of suffering an acute intracerebral haemorrhage were randomised to receive either an intravenous bolus dose of disodium 4-[ ⁇ tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide (II) over 1 h and then a continued infusion over the next 71 h, or matching placebo, in addition to standard care.
- the protocol for the administration of compound (II) was essentially as described in Example 1.
- the diagnosis of intracerebral haemorrhage was established by an initial neuroimaging scan (CT or MRI) and a follow-up scan was performed at 72 hours.
- Haematoma and oedema volumes were derived from the scans using standard procedures and the volume changes between baseline and 72 hours were monitored. Typically, haematoma volume and the volume of the oedema surrounding the primary intracerebral haemorrhage increase during this time period.
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Abstract
The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment or prophylaxis of cerebral oedema is disclosed.
Description
USE OF 4-((TERT-BUTYLIMINO) METHYL)
BENZENE-1,3-DISULFONATE N-OXIDE AGAINST
CEREBRAL OEDEMA
Field of the Invention
The present invention relates to a novel method for the treatment or prophylaxis of cerebral oedema. In particular, the invention relates to the use of disodium A-{(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide [α-(2,4-disulfophenyl)-N- tert- butylnitrone disodium salt] for the treatment or prophylaxis of cerebral oedema.
Background of the Invention U.S. patent 5,488,145 discloses the compound α-(2,4-disulfophenyl)-N-tert-butyhiitrone and pharmaceutically acceptable salts thereof. U.S. patent 5,475,032 discloses the use of such compounds in the treatment of stroke and of progressive central nervous system function loss conditions. U.S. patent 5,508,305 discloses the use of such compounds for ameliorating the side effects caused by oxidative damage resulting from antineoplastic disease treatment. Similar disclosures are also made in WO 95/17876. U.S. patent 5,780,510 discloses the use of these same compounds in the treatment of concussion.
We have now surprisingly discovered that 4-[(ter^-butylimino)methyl]benzene-l,3- disulfonic acid Ν-oxide and pharmaceutically acceptable salts thereof are useful as a novel method for the treatment or prophylaxis of cerebral oedema. Cerebral oedema is also known as brain oedema.
Disclosure of the Invention
In accordance with the present invention, there is provided a method of treating cerebral oedema which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
Salts of compounds of formula (I) may be formed by reacting the free acid or another salt thereof, with two or more equivalents of an appropriate base, using methods that are well known in the art.
The salts of compounds of formulae (I) will normally be those formed with pharmaceutically acceptable cations. The cation may be a monovalent material such as sodium, potassium, lithium, ammonium, alkylammonium or diethanolammonium.
Alternatively, it may be a polyvalent cation such as calcium, magnesium, aluminium or zinc. It may also be a mixed salt formed with a polyvalent cation such as calcium or magnesium in combination with a pharmaceutically acceptable anion such as halide (for example chloride), phosphate, sulphate, acetate, citrate or tartrate.
In one embodiment, the compound of formula (I) is the disodium salt of formula (II).
In another aspect, the invention provides a method of treating cerebral oedema which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
In another aspect, the invention provides a method of treating cerebral oedema associated with stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of cerebral oedema.
In another aspect, the invention provides a compound of formula (II) for use in the treatment or prophylaxis of cerebral oedema.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema.
In another aspect, the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema.
In another aspect, the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema associated with stroke.
In the context of the present specification, the term therapy also includes prophylaxis unless there are specific indications to the contrary.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
Processes for the manufacture of compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed in WO 01/51460 and WO 01/51461.
Swelling of the brain (oedema) occurs as a consequence of a variety of insults including trauma, anoxia, ischemia, space (mass) occupying lesions, for example, tumours, intracerebral haemorrhage and radiation damage. The brain is especially vulnerable to the effects of swelling because of its rigid encasement by the skull. Excessive oedema can therefore result in secondary compression of small blood vessels resulting in new or further ischemia. In severe cases, oedema can progress to produce massive swelling and eventually death.
The development of cerebral oedema is a potential serious adverse event following stroke.
Stroke is caused by an interruption of blood flow to a portion of the brain. This is most often due to a blockage within an artery causing an ischemic stroke. Such strokes account for about 88% of all strokes. The most common cause of an ischemic stroke is intrinsic narrowing of an artery to the brain due to a combination of atherosclerosis (accumulation of fatty materials plus secondary inflammation) culminating in the formation of a blood clot in the narrowed area. In about 30% of strokes the obstruction is due to a blood clot (embolus) originating elsewhere, especially the heart or a major blood vessel supplying the brain, that dislodges and travels to the brain to block a smaller artery within the brain itself. About 12% of all strokes are caused by rupture of a blood vessel within the brain, called an intracerebral haemorrhage, or over the surface of the brain, called a subarachnoid haemorrhage.
In both ischemic and hemorrhagic strokes oedema may begin within hours, and in severe cases can progress to major swelling and death. There is no currently available agent that has been shown to have a beneficial effect on cerebral oedema.
We have now surprisingly established that 4-[(terf-butylimino)methyl]benzene-l,3- disulfonic acid N-oxide (I) and pharmaceutically acceptable salts thereof, particularly the disodium salt (II), are useful as a novel method for the treatment or prophylaxis of cerebral oedema.
Disodium 4-[(tert-butylimino)methyl]benzene-l,3-disulfonic acid N-oxide (II) has beneficial effects on the development of cerebral oedema following acute ischaemic stroke or haemorrhagic stroke.
Thus, in one aspect, the invention provides a method of treating cerebral oedema associated with acute ischaemic stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
In another aspect, the invention provides a method of treating cerebral oedema associated with haemorrhagic stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
In another aspect, the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema associated with acute ischaemic stroke.
In another aspect, the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema associated with haemorrhagic stroke.
The compounds of formula (I) and pharmaceutically acceptable salts thereof will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound or salt thereof (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example,
"Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
Specific formulations of pharmaceutically acceptable salts of a compound of formula (I), particularly formulations of a compound of formula (II), suitable for parenteral administration are disclosed in WO 01/89507.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat. Suitable methods will be readily apparent to the man skilled in the art.
Parenteral administration, particularly intravenous administration, is preferred. The administration may involve the use of a bolus dose or doses and /or infusion.
For the treatment of cerebral oedema the dosage administered will, of course, vary with the mode of administration, the treatment desired and the severity of the condition or disorder to be treated. Such parameters will normally be decided by the attending physician.
In addition to the compound of the present invention, the pharmaceutical composition may also contain, or be co-administered (simultaneously or sequentially) with, one or more other pharmacological agents of value in conjunction with cerebral oedema.
Example 1
A total of 1705 patients treated within 6 h of suffering an acute ischaemic stroke were randomised to receive either an intravenous bolus dose of disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acidN-oxide over 1 h and then a continued infusion over the next 71 h, or matching placebo, in addition to standard care. Patients who were also receiving thrombolysis with rt-PA (Alteplase) were eligible for inclusion in the study.
Disodium 4-[(tert-butylimino)methyl]benzene-l,3-disulfonate acidN-oxide concentrate solution for infusion (400 mg/ml; 20 ml vial) (WO 01/89507) was diluted in 500 ml of physiologic (9 mg/ml) saline to a final concentration of approximately 15 mg/ml. A loading dose of 151 ml (2270 mg) of the diluted solution was administered over the first hour and was followed by a maintenance dose adjusted for the patient's creatinine clearance (Clcrea - a measure of kidney function). The maintenance infusion was continued for another 71 hours. The maintenance doses adjusted for creatinine clearance were as follows:
Patients were formally assessed at enrolment, at 24 and 72 hours after enrolment, and at 7, 30 and 90 days.
Cerebral oedema developed as a serious adverse event in 9 (1%) of the 858 patients who received disodium 4-[(?ert-butylimino)methyl]benzene-l,3-disulfonate acid N-oxide. In comparison, cerebral oedema developed as a serious adverse event in 25 (3%) of 847 patients who received placebo.
Cerebral oedema leading to death occurred in 0.6% of patients who received disodium 4- [(ter^bu1ylirnino)methyl]benzene- 1 ,3 -disulfonate acid N-oxide compared to 1.2% of the placebo patients.
Of the 858 patients who received disodium 4-[(fer?-butylimino)metlαyl]benzene-l,3- disulfonate acid N-oxide, 240 also received rt-PA. Of 847 patients who received placebo, 249 also received rt-PA. For patients also receiving rt-PA, an initial CTYMR scan and a follow-up CT/MR scan at 72 hours were mandatory. For patients who did not also receive rt-PA, CT/MR scans were at the discretion of the attending physician.
For patients who did not also receive rt-PA, the follow-up CT/MR scan indicated the presence of cerebral oedema in 79.7% (n = 69) of the patients who received disodium 4- [(ter^butylimmo)methyl]benzene-l,3-disulfonate acid N-oxide. The corresponding figure for patients who received placebo was 86.2% (n = 65).
For patients who also received rt-PA, the follow-up CT/MR scan indicated the presence of cerebral oedema in 71.6% (n = 229) of the patients who received disodium 4-[{tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide. The corresponding figure for patients who received placebo was 75.6% (n = 238).
These data clearly demonstrate the efficacy of disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide (II) in significantly reducing cerebral oedema due to acute ischemic stroke. The effect is equally apparent whether or not the patients were also being treated with rt-PA.
Example 2
Patients treated within 6 h of suffering an acute intracerebral haemorrhage were randomised to receive either an intravenous bolus dose of disodium 4-[{tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide (II) over 1 h and then a continued infusion over the next 71 h, or matching placebo, in addition to standard care. The protocol for the administration of compound (II) was essentially as described in Example 1. The diagnosis of intracerebral haemorrhage was established by an initial neuroimaging scan (CT or MRI) and a follow-up scan was performed at 72 hours. Haematoma and oedema volumes were derived from the scans using standard procedures and the volume changes
between baseline and 72 hours were monitored. Typically, haematoma volume and the volume of the oedema surrounding the primary intracerebral haemorrhage increase during this time period.
For those patients who received disodium 4-[(tert-butylimino)methyl]benzene- 1,3- disulfonate acid N-oxide (II) (n = 287), the mean increase in oedema volume was 16.8 mL, whereas for those patients who received placebo (n = 288), the mean increase in oedema volume was 17.9 mL.
These data demonstrate the efficacy of disodium 4-[(fer/-butylimino)methyl]benzene-l,3- disulfonate acid N-oxide (II) in reducing the growth of cerebral oedema following an intracerebral haemorrhage.
Claims
1. A method of treating cerebral oedema which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a 5 patient in need thereof.
0
2. A method according to Claim 1 wherein the compound is disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide.
3. A method according to either Claim 1 or Claim 2 wherein the oedema is a 5 consequence of trauma.
4. A method according to either Claim 1 or Claim 2 wherein the oedema is a consequence of anoxia.
o 5. A method according to either Claim 1 or Claim 2 wherein the oedema is a consequence of stroke.
6. A method according to Claim 5 wherein the stroke is ischaemic stroke.
5 7. A method according to Claim 5 wherein the stroke is hemorrhagic stroke.
8. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of cerebral oedema.
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Citations (1)
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US5780510A (en) * | 1993-12-23 | 1998-07-14 | Oklahoma Medical Research Foundation | 2,4-disulfo phenyl butyl nitrone, its salts and their use as pharmaceuticals |
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US5780510A (en) * | 1993-12-23 | 1998-07-14 | Oklahoma Medical Research Foundation | 2,4-disulfo phenyl butyl nitrone, its salts and their use as pharmaceuticals |
Non-Patent Citations (1)
Title |
---|
CAO X. ET AL.: "alpha-Phenyl-tert-butyl nitrone reduces cortical infarct and edema in rats subjected to focal ischemia", BRAIN RESEARCH, vol. 644, no. 2, 1994, pages 267 - 272, XP003004217 * |
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